Jill S. Fischer

The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcome assessment

Clinical outcome assessment in Multiple Sclerosis (MS) is challenging due to the diversity and fluctuating nature of MS symptoms. Traditional clinical scales such as the EDSS are inadequate in their assessment of key clinical dimensions of MS (e.g., cognitive function), and they have psychometric limitations as well. Based on analyses of pooled data from natural history studies and from placebo groups in clinical trials, the National MS Societys Clinical Outcomes Assessment Task Force recently proposed a new multidimensional clinical outcome measure, the MS Functional Composite (MSFC). The MSFC comprises quantitative functional measures of three key clinical dimensions of MS: leg function/ambulation, arm/hand function, and cognitive function. Scores on component measures are converted to standard scores (z-scores), which are averaged to form a single MSFC score. Preliminary analyses confirm that: (1) the three clinical dimensions of the MSFC are relatively independent; (2) the MSFC is sensitive to clinical changes over 1- and 2-year intervals; and (3) the MSFC has acceptable criterion validity (i.e., predicts both concurrent and subsequent EDSS change). The advantages and potential limitations of incorporating quantitative functional outcome measures such as the MSFC into collaborative databases are discussed.

Minimal Neuropsychological Assessment of MS Patients: A Consensus Approach

Cognitive impairment is common in multiple sclerosis (MS), yet patients seen in MS clinics and neurologic practices are not routinely assessed neuropsychologically. In part, poor utilization of NP services may be attributed to a lack of consensus among neuropsychologists regarding the optimal approach for evaluating MS patients. An expert panel composed of neuropsychologists and psychologists from the United States, Canada, United Kingdom, and Australia was convened by the Consortium of MS Centers (CMSC) in April, 2001. Our objectives were to: (a) propose a minimal neuropsychological (NP) examination for clinical monitoring of MS patients and research, and (b) identify strategies for improving NP assessment of MS patients in the future. The panel reviewed pertinent literature on MS-related cognitive dysfunction, considered psychometric factors relevant to NP assessment, defined the purpose and optimal characteristics of a minimal NP examination in MS, and rated the psychometric and practical properties of 36 candidate NP measures based on available literature. A 90-minute NP battery, the Minimal Assessment of Cognitive Function in MS (MACFIMS), emerged from this discussion. The MACFIMS is composed of seven neuropsychological tests, covering five cognitive domains commonly impaired in MS (processing speed/working memory, learning and memory, executive function, visual-spatial processing, and word retrieval). It is supplemented by a measure of estimated premorbid cognitive ability. Recommendations for assessing other factors that may potentially confound interpretation of NP data (e.g., visual/sensory/motor impairment, fatigue, and depression) are offered, as well as strategies for improving NP assessment of MS patients in the future.

Benefit of interferon β-1a on MSFC progression in secondary progressive MS

BackgroundInterferon &bgr;-1a (IFN&bgr;-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFN&bgr; preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFN&bgr;-1a slowed disease progression in SP-MS. MethodsA total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFN&bgr;-1a (60 &mgr;g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT]). ResultsMedian MSFC Z-score change was reduced 40.4% in IFN&bgr;-1a subjects (−0.096 vs −0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFN&bgr;-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFN&bgr;-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFN&bgr;-1a–treated subjects. ConclusionsIFN&bgr;-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.

A longitudinal study of brain atrophy in relapsing multiple sclerosis

Objective: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon β-1a (Avonex). Methods: All subjects had mild to moderate disability, with baseline expanded disability status scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry. Atrophy measures included third and lateral ventricle width, brain width, and corpus callosum area. Results: Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement. Conclusion: In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.

Neuropsychological effects of interferon β-1a in relapsing multiple sclerosis

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon β‐1a (IFNβ‐1a, 30 μg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6‐month intervals. The primary NP outcome measure was 2‐year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNβ‐1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between‐group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNβ‐1a group. These results support and extend previous observations of significant beneficial effects of IFNβ‐1a for relapsing MS. Ann Neurol 2000;48:885–892

Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis

Background and Objective: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-la (IFNβ-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as≥1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. Methods: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. Results: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFNβ-1a was observed when ≥2.0 point worsening from baseline EDSS was required or when worsening was required to persist for ≥1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFNβ-1a recipients who reached the primary study outcome. (3) Significantly fewer IFNβ-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0(unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFNβ-1a treatment. Conclusions: The primary clinical outcome for the IFNβ-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFNβ-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

Recent developments in the assessment of quality of life in Multiple Sclerosis (MS)

Multiple sclerosis (MS) and its treatment have broad-ranging effects on quality of life. This article reviews recent efforts to assess the impact of MS on activities of daily living (ADLs) and health-related quality of life (HRQL), and describes the development of the Multiple Sclerosis Quality of Life Inventory (MSQLI). The MSQLI is a modular MS-specific HRQL instrument consisting of a widely-used generic measure, the Health Status Questionnaire (SF-36), supplemented by nine symptom-specific measures (covering fatigue, pain, bladder function, bowel function, emotional status, perceived cognitive function, visual function, sexual satisfaction, and social relationships). Content validation consisted of evaluating its adherence to a conceptual model of the impact of MS, and review by MS specialists (neurologists and allied health professionals), HRQL experts, patients, and caregivers. The reliability and construct validity of the MSQLI were rigorously evaluated in a field test with 300 North American patients (198 female, 102 male) with definite MS (Poser criteria) and a broad range of physical impairment (EDSS=0.0-8.5). This article concludes by comparing the MSQLI with two other MS-specific HRQL measures (MS Quality of Life-54 (QOL-54) and Functional Assessment of Multiple Sclerosis (FAMS)) and discussing key issues to consider in selecting an HRQL instrument for a collaborative database.

The Goldman Consensus statement on depression in multiple sclerosis

Background. In January 2002 the New York City Chapter of the National Multiple Sclerosis Society convened a panel of experts to review the issue of depressive affective disorders associated with multiple sclerosis (MS). This Consensus Conference was supported by a grant from the Goldman family of New York City. Results. The panel reviewed summaries of current epidemiologic, neurobiologic, and therapeutic studies having to do with depressive disorders among MS patient populations. Depressive disorders occur at high rates among patients with MS, and there is reason to believe that the immunopathology of the disease is involved in the clinical expression of affective disorders. The depressive syndromes of MS have a major, negative impact on quality of life for MS sufferers, but are treatable. At the present time, most MS patients with depression do not receive adequate recognition and treatment. Conclusions. The Goldman Consensus Conference Study Group provides recommendations for improved screening, diagnosis, and clinical management for depressive affective disorders among patients suffering from MS.

A longitudinal study of T1 hypointense lesions in relapsing MS MSCRG trial of interferon β-1a

Background: T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS. Objective: To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials. Methods: MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon β-1a (IFNβ-1a)–treated patients with mild to moderate disability relapsing-remitting MS. Results: There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNβ-1a–treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline. Conclusion: The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNβ-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.

Intrarater and interrater reliability of the MS functional composite outcome measure

Objective: To assess practice effects, and intrarater and interrater reliability of the MS functional composite (MSFC) outcome measure. Background: To address the poor reliability and insensitivity to change of available MS clinical rating scales, the National MS Society’s Clinical Outcomes Assessment Task Force developed the MSFC, a multidimensional quantitative clinical outcome measure that includes tests of leg function/ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). Methods: Ten patients with secondary progressive MS underwent six testing sessions over a 2-week period. The MSFC was administered by the same examining technician in the first five sessions and by the other technician in the sixth. Patients were reassessed by both technicians after 6 months (sessions 7 and 8). The MSFC score was calculated as the mean of the Z scores of the three components. A pooled dataset derived from secondary progressive MS patients in the placebo arms of previous clinical trials and natural history studies served as the reference population to standardize scores. Results: Practice effects were evident initially but stabilized by the fourth administration. The intraclass correlation coefficient (ICC) was 0.97 for the MSFC for session 4 versus session 5 (intrarater reliability). The ICC was 0.95 for session 5 versus session 6 (interrater reliability), and was 0.96 for session 7 versus session 8 when patients were reassessed 6 months later. Conclusions: The MS functional composite (MSFC) outcome measure had excellent intrarater and interrater reliability when standardized procedures were used to train examining technicians and to assess patients. Prebaseline testing sessions should be included in clinical trials employing the MSFC to compensate for practice effects.