Multiple Sclerosis Performance Test: validation of self-administered neuroperformance modules.

BACKGROUND AND PURPOSE: The purpose was to determine the test-retest reliability, practice effects, convergent validity and sensitivity to multiple sclerosis (MS) disability of neuroperformance subtests from the patient self-administered Multiple Sclerosis Performance Test (MSPT) designed to assess low contrast vision (Contrast Sensitivity Test, CST), upper extremity motor function (Manual Dexterity Test, MDT) and lower extremity motor function (Walking Speed Test, WST) and to introduce the concept of regression-based norms to aid clinical interpretation of performance scores using the MSPT cognition test (Processing Speed Test, PST) as an example. METHODS: Substudy 1 assessed test-retest reliability, practice effects and convergent validity of the CST, MDT and WST in 30 MS patients and 30 healthy controls. Substudy 2 examined sensitivity to MS disability in over 600 MS patients as part of their routine clinic assessment. Substudy 3 compared performance on the PST in research volunteers and clinical samples. RESULTS: The CST, MDT and WST were shown to be reliable, valid and sensitive to MS outcomes. Performance was comparable to technician-administered testing. PST performance was poorer in the clinical sample compared with the research volunteer sample. CONCLUSIONS: The self-administered MSPT neuroperformance modules produce reliable, objective metrics that can be used in clinical practice and support outcomes research. Published studies which require patient voluntary consent may underestimate the rate of cognitive dysfunction observed in a clinical setting.

Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing-remitting multiple sclerosis: A retrospective analysis.

BACKGROUND: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). OBJECTIVES: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. METHODS: Patients (n=140) with relapsing-remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. RESULTS: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. CONCLUSIONS: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials.

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis.

BACKGROUND: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies. OBJECTIVES: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS. METHODS: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005. RESULTS: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted. CONCLUSIONS: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.

Change in quality of life in patients with relapsing-remitting multiple sclerosis over 2 years in relation to other clinical parameters: results from a trial of intramuscular interferon {beta}-1a.

BACKGROUND: A randomized, placebo-controlled, multicenter study of weekly intramuscular injections of interferon beta-1a (IFNß-1a) in relapsing-remitting multiple sclerosis included the Sickness Impact Profile (SIP), a validated measure of patient-reported quality of life (QoL). OBJECTIVE: To demonstrate the impact of moderate to severe SIP disability at baseline and change in QoL as measured by SIP over 2 years in relation to other study parameters. METHODS: In 158 patients, SIP scores were determined at baseline and 2 years. Scores were correlated with disease progression and treatment. RESULTS: Patients who experienced disability progression, as defined by Expanded Disability Status Scale (EDSS) and annualized relapse rate, during the study demonstrated significant worsening in Physical SIP scores compared with patients who did not progress (p=0.031). In patients with low SIP scores, indicating moderate or severe disability at baseline, treatment with IFNß-1a significantly improved Physical SIP subscores. CONCLUSIONS: Patients with disability progression defined using EDSS, the physician-derived primary outcome measure, had Physical SIP scores indicating worsening disability, validating the physician-derived primary outcome measure using patient self-report. Treatment with IFNß-1a had beneficial effects on QoL in patients with worse SIP scores at baseline.

Gender effects on intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: analysis of 1406 patients.

BACKGROUND: We aimed to evaluate effects of gender on efficacy and safety of intramuscular (IM) interferon beta (IFNß)-1a in patients with relapsing-remitting MS (RRMS) or clinically isolated syndromes (CIS) characteristic of early MS. METHODS: Pooled data from 1406 (1027 women; 379 men) patients enrolled in five clinical studies of IM IFNß-1a were analyzed. One analysis examined data for all patients treated with IM IFNß-1a from all studies. Separate analyses were conducted of pooled IM IFNß-1a-treated groups from all studies and pooled IFNß-1a-treated and placebo-treated patients from the placebo-controlled studies. Outcome measures included time to first relapse, annualized relapse rate, time to disability progression, number of gadolinium-enhanced lesions, adverse events, laboratory evaluations, and neutralizing antibodies. RESULTS: All efficacy assessments indicated similar treatment effects of IM IFNß-1a in men and women with no significant treatment-by-gender interactions. Women reported more headaches, urinary tract infections, and depression in the analysis; however, these were also common in women who received placebo. Men reported more frequent flu-like symptoms in the placebo-controlled studies only. There were no other differences in the safety profile of IM IFNß-1a between men and women. CONCLUSIONS: We conclude that no significant gender-related differences were found in the efficacy and safety of IM IFNß-1a in patients with RRMS or CIS.

Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks.

BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study.

Disease-modifying drugs are initiated early and continued for years in patients with multiple sclerosis. Long-term tolerability and impact are not known. The objective of this study was to evaluate long-term tolerability of intramuscular interferon beta-1a and effects on disability and quality of life. Patients were evaluated an average of 15 years after randomization into a placebo-controlled, double-blind trial of intramuscular interferon beta-1a for relapsing multiple sclerosis. Patient-reported Expanded Disability Status Scale, the Short Form-36, a visual analog scale of self-care independence, and a living situation questionnaire were administered. Status was ascertained in 79% (136/172) of eligible patients. Analysis focused on 122 living patients. Despite open-label, non-standardized treatment after the 2-year clinical trial, 46% (n= 56) of the patients remained on intramuscular interferon beta-1a. Expanded Disability Status Scale scores were correlated highly with Short Form-36 subcategories and visual analog scale scores. Patients currently using intramuscular interferon beta-1a had a significantly lower mean Expanded Disability Status Scale score (p= 0.011), less progression to Expanded Disability Status Scale milestones, significantly better scores on the physical component of the Short Form-36 (p< 0.0001), and reported better general health and greater independence. We conclude that patients continuing to use intramuscular interferon beta-1a had less disability and better quality of life compared with patients not currently using intramuscular interferon beta-1a 15 years after randomization into a clinical trial.

Using an automated recruitment process to generate an unbiased study sample of multiple sclerosis patients.

The objective of this study was to test the efficiency of an automated recruitment methodology developed as a component of a practical controlled trial to assess the benefits of a Web-based personal health site to guide self-management of multiple sclerosis symptoms called Mellen Center Care On-line. We describe the study's automated recruitment methodology using clinical and administrative databases and assess the comparability between subjects who completed informed consent (IC) forms, and individuals who were invited to participate but did not reply, designated as patient nonresponders (PNR). The IC and PNR groups were compared on demographics, number of physician or advanced practice nurse/physician assistant visits during the 12 months prior to the initial invitation, and level of disability as measured by the Charlson Comorbidity Index (CCI). Out of a total dynamic potential pool of 2,421 patients, 2,041 had been invited to participate, 309 had become ineligible to participate during the study, and 71 individuals remained in the pool at the end of recruitment. The IC group had a slightly greater proportion of females. Both groups were predominantly white with comparable marital status. The groups had comparable mean household income, education level, and commercial insurance. The computed mean CCI was similar between the groups. The only significant difference was that the PNR group had fewer clinic visits in the preceding 12 months. The subjects were highly representative of the target population, indicating that there was little bias in our selection process despite a constantly changing pool of eligible individuals.

Assessing disability progression with the Multiple Sclerosis Functional Composite.

BACKGROUND: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. OBJECTIVE: Evaluate a new method for analyzing disability progression using the MSFC. METHODS: MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for >or=3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. RESULTS: Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. CONCLUSION: MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.

Effect of statins on clinical and molecular responses to intramuscular interferon beta-1a.

BACKGROUND: Findings from a small clinical study suggested that statins may counteract the therapeutic effects of interferon beta (IFNbeta) in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We conducted a post hoc analysis of data from the Safety and Efficacy of Natalizumab in Combination With IFNbeta-1a in Patients With Relapsing-Remitting Multiple Sclerosis (SENTINEL) study to determine the effects of statins on efficacy of IFNbeta. SENTINEL was a prospective trial of patients with RRMS treated with natalizumab (Tysabri, Biogen Idec, Inc., Cambridge, MA) plus IM IFNbeta-1a (Avonex, Biogen Idec, Inc.) 30 microg compared with placebo plus IM IFNbeta-1a 30 microg. Clinical and MRI outcomes in patients treated with IM IFNbeta-1a only (no-statins group, n = 542) were compared with those of patients taking IM IFNbeta-1a and statins at doses used to treat hyperlipidemia (statins group, n = 40). RESULTS: No significant differences were observed between treatment groups in adjusted annualized relapse rate (p = 0.937), disability progression (p = 0.438), number of gadolinium-enhancing lesions (p = 0.604), or number of new or enlarging T2-hyperintense lesions (p = 0.802) at 2 years. More patients in the statins group reported fatigue, extremity pain, muscle aches, and increases in hepatic transaminases compared with patients in the no-statins group. Statin treatment had no ex vivo or in vitro effect on induction of IFN-stimulated genes. CONCLUSIONS: Statin therapy does not appear to affect clinical effects of IM interferon beta-1a in patients with relapsing-remitting multiple sclerosis or the primary molecular response to interferon beta treatment.

Multiple sclerosis: chemokine receptor expression on circulating lymphocytes in correlation with radiographic measures of tissue injury.

BACKGROUND: Leukocytes expressing inflammatory chemokine receptors (CKRs), most consistently CCR2, CCR5, and CXCR3, have been identified in multiple sclerosis (MS) tissue lesions and provide attractive therapeutic targets. Our previous studies found large inter-individual differences in expression of these CKRs but stable levels over time within subjects. This observation suggests a CKR "set-point" within individuals, which might relate to inflammatory injury in MS. We evaluated the correlation between CKR levels and magnetic resonance imaging (MRI) measures of disease activity. METHODS: Fifty-five relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients were prospectively followed with annual CKR and MRI studies. Multiparameter flow cytometry was used to determine CCR2, CCR5, and CXCR3 expression on CD4 and CD8 cells. Simultaneous cranial MRIs were performed, and quantitative measures of T2, T1, and gadolinium lesions, brain parenchymal fraction (BPF), and whole brain and fractionated magnetization transfer ratio (MTR) were performed using automated software. Spearman's rank correlations evaluated the relationship between CKR levels and MRI measures. RESULTS: Significant correlations were observed between CXCR3 expression on CD8 cells and measures of new (T1) and total (T1, T2) lesion volumes, lesion MTR, and BPF; higher levels of CXCR3 expression were correlated with greater injury on MRI (|r| = 0.27-0.42). In contrast, CD4 cell CKR expression was only minimally correlated with MRI measures. CONCLUSIONS: Over 2 years, we observed significant correlations between the percent of CD8 cells expressing CXCR3 and MRI measures of MS inflammatory activity and tissue destruction. These observations are consistent with a pathogenic role for cytotoxic T cells in MS brain and have significant implications regarding T-cell targeted therapeutic strategies.

Repeated assessment of neuropsychological deficits in multiple sclerosis using the Symbol Digit Modalities Test and the MS Neuropsychological Screening Questionnaire.

BACKGROUND: Brief cognitive performance tests and self-report measures of neuropsychological symptoms have been proposed for screening purposes in multiple sclerosis (MS) clinics. To better understand the reliability of screening methods, two tests, the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Screening Questionnaire (MSNQ), were administered to 76 patients with MS and 25 healthy controls, matched on demographic characteristics. METHODS: Tests were administered at monthly intervals, over 6 months. In addition, the Beck Depression Inventory Fast Screen for medical patients (BDIFS) was administered to monitor for changes in depression. Our objectives were to determine the reliability of these measures and the relative contribution of cognitive impairment and depression in predicting self-report MSNQ scores. RESULTS: Results showed that both the SDMT and MSNQ have good to excellent reproducibility over repeated testing. In MS, there are minimal practice effects over successive tests, in the order of 0.2 SD for SDMT and minimal change in the MSNQ. Regression analyses modeled to predict MSNQ based on SDMT and BDIFS showed significant contribution for both, but with the majority of variance being accounted for depression. CONCLUSIONS: We conclude that these brief screening tests provide some independent information about the mental status of patients with MS and are reliable, even when used in monthly, successive examinations.

The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL.

OBJECTIVE: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. METHODS: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon beta-1a [INF beta]1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as "transiently positive" if they had detectable antibodies (>or=0.5 microg/mL) at a single time point or "persistently positive" if they had antibodies at two or more time points >or=6 weeks apart. RESULTS: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p

Optimal reference population for the multiple sclerosis functional composite.

A reference population is used when integrating the individual components of the Multiple Sclerosis Functional Composite (MSFC) into a single composite score. The choice of reference populations may have a significant impact on the resulting MSFC score, yet the impact of different reference populations has not been evaluated. We evaluated the impact of different reference populations when deriving the Multiple Sclerosis Functional Composite (MSFC) in a group of MS patients followed longitudinally for two years. Reference populations included the study population at baseline (n = 60), a group of healthy controls (n = 18) and the National MS Society Task Force reference population (n = variable). We found that the choice of reference population had a significant impact on the resulting MSFC Z-score, sometimes compromising the statistical sensitivity to change over time. Our results suggest that longitudinal studies employing a multisystem composite Z-score should use a reference population with similar patients, which can most easily be achieved by using the baseline measures of the population under study. These results have significant implications to sample size estimates for longitudinal clinical studies and therapeutic trials.

Natalizumab reduces visual loss in patients with relapsing multiple sclerosis.

OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

Estimating long-term effects of disease-modifying drug therapy in multiple sclerosis patients.

Two methods were used to estimate the long-term impact of disease-modifying drug therapy (DMDT) in patients with relapsing multiple sclerosis (MS) who completed a placebo-controlled, randomized clinical trial of interferon beta-1a (IFNbeta-1a). The study cohort consisted of patients with ambulatory relapsing MS who had previously participated in a placebo-controlled clinical trial for two years. At its end, patients were managed in an unstructured fashion by their neurologists and re-evaluated at an average of 6.1 years after the end of the trial. Follow-up evaluation was obtained for 93% of the 172 eligible patients. Because study inclusion criteria required that all patients have an Expanded Disability Status Scale (EDSS) score of < or = 3.5 at entry, disability progression at follow-up was defined as EDSS > or = 6.0. Two methods were used to estimate the expected proportions that reached EDSS > or = 6.0 at follow-up. Estimates were compared with observed proportions. Method 1 used progression rates observed during the two-year phase III clinical trial and the percentage of time that patients were on DMDT during the follow-up period. Method 2 used progression rates from a natural history comparison group of relapsing-remitting MS patients. At the eight-year follow-up, 42.0% of the original placebo patients and 29.1% of the original IFNbeta-1a patients reached an EDSS > or = 6.0, an observed treatment effect of approximately 30%. Using method 1, it was estimated that 36.3% of the original placebo patients and 27.6% of the original IFNbeta-1a patients should have reached an EDSS > or = 6.0. Use of the natural history control group (method 2) predicted less plausible outcomes. Estimated proportions of patients reaching the endpoint were 63.3% for the original placebo group and 55.8% for the original IFNbeta-1a group. Treatment effect sizes of 75-90% would be required to match estimates from method 2 with the observed outcome. The paucity of data on the long-term treatment of patients with MS may be aided by applying these or similar methods to vigorously followed cohorts of patients.

Longitudinal single-cell cytokine responses reveal recurrent autoimmune myelin reactivity in relapsing--remitting multiple sclerosis patients.

The relationship between multiple sclerosis (MS) disease activity and myelin protein-induced cytokine responses over time is not elucidated. We addressed this relationship by examining longitudinal cytokine responses to myelin proteins every three months for one year, in the context of gadolinium (gad)-enhancing brain lesions and of clinical relapses. The ELISPOT assay was used to determine the ex vivo cytokine production in response to nine amino acid long peptides spanning the entire proteolipid protein (PLP) and myelin basic protein (MBP) molecules in relapsing-remitting (RR) MS patients and matched healthy controls. We identified three longitudinal levels of myelin-induced cytokine secretion by adding up the positive responses for all PLP or MBP peptides obtained for five timepoints, at three-month intervals: low reactivity (< 200 cumulative cytokine-secreting cells), isolated peptide reactivity (201-450 cumulative cytokine-secreting cells) and recurrent protein-wide bursts of cytokine reactivity (> 451 cumulative cytokine-secreting cells). The majority of MS patients showed recurrent bursts to PLP and MBP. In contrast, controls showed a more even distribution between all levels of cytokine reactivity. The majority of patients with gad-enhancing lesions showed PLP/IFN gamma and MBP/IFN gamma recurrent burst responses. This is the first longitudinal study on MS patients in which nine amino acid long myelin peptides are used to reveal the broad range of PLP- and MBP-peptide cytokine reactivity across the whole molecule of these two major myelin proteins. This study also reveals the extremely dynamic nature of the immune reactivity to numerous regions of myelin, which can fluctuate dramatically over time. Such fluctuation could hamper the efficacy of antigen-based therapies for MS.

Long-term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis.

To determine the effects of high dose methylprednisolone (HDMP) pulses on bone mineral density (BMD) in patients with multiple sclerosis (MS), we studied 25 MS patients who received regular pulses of HDMP as well as pulses of HDMP for relapses, 18 MS patients who received HDMP at the same dose schedule only for relapses, and 61 healthy controls. We measured BMDs at lumbar spine and femoral neck and we assessed biochemical markers of bone metabolism and turnover. The average lifetime dosage of MP was 75.4 (SD 11.9) g in the pulsed HDMP group and 28.6 (SD 18.3) g in the HDMP for relapses group (P < 0.0001). Two MS patients (4.7%) and four controls (6.6%) had osteoporosis (P = NS), whereas 25 patients with MS (58.1%) and 21 controls (34.4%) had osteopenia (P = 0.016). BMDs measured at lumbar spine and femoral neck and biochemical indices of bone metabolism did not differ in MS patients and controls. BMD measures were not associated with lifetime methylprednisolone dosage. In partial correlation analysis, controlling for age, gender and menopausal status there was a significant inverse correlation between BMD at femoral neck and Expanded Disability Status Scale (EDSS) score (r = -0.31, P = 0.05). In conclusion, treatment with repeated HDMP pulses was not associated with osteoporosis in patients with MS who participated in a trial of methylprednisolone. However, osteopenia was observed more frequently in MS patients than healthy controls. Our data are reassuring, as them suggest that repeated pulses of methylprednisolone do not result in substantially increased risk of osteoporosis in MS patients. Moreover, osteopenia was found only in patients treated for relapses, who had a significantly higher EDSS score than patients in the HDMP group, suggesting that decreased mobility may contribute to bone loss more than corticosteroid use. BMD should be monitored in patients with MS, regardless of the use of methylprednisolone.

Low-contrast letter acuity testing captures visual dysfunction in patients with multiple sclerosis.

OBJECTIVE: To evaluate concurrent and predictive validity for low-contrast letter acuity (L-CLA) testing as a candidate visual component for the Multiple Sclerosis Functional Composite (MSFC). METHODS: L-CLA testing was conducted in two MS patient cohorts. In the MSFC Validation Study, 137 participants from a Phase III trial of inteferon beta-1a (Avonex) for relapsing-remitting MS were followed. A second cohort included 65 patients with secondary progressive MS who participated in a substudy of the International MS Secondary Progressive Avonex Controlled Trial (IMPACT). The total number of letters read correctly at four contrast levels (100, 5, 1.25, and 0.6%) was correlated with Expanded Disability Status Scale (EDSS), MSFC, Sickness Impact Profile, Multiple Sclerosis Quality of Life Inventory, and brain parenchymal fraction (BPF), as determined by MRI. RESULTS: Low- and high-contrast letter acuity scores correlated with BPF at follow-up in the MSFC Validation Study (5%: r = 0.40, p < 0.0001; 100%: r = 0.31, p = 0.0002). L-CLA also correlated with EDSS (5%: r = -0.35, p < 0.0001; 1.25%: r = -0.26, p = 0.0003) and MSFC (5%: r = 0.47, p < 0.0001; 1.25%: r = 0.45, p < 0.0001). In the IMPACT Substudy, change in L-CLA scores from baseline to year 1 predicted subsequent change in the EDSS from year 1 to 2 at the 5% (p = 0.0142) and the 1.25% (p = 0.0038) contrast levels, after adjusting for change in MSFC scores from baseline to year 1. CONCLUSIONS: Low-contrast letter acuity (L-CLA) scores demonstrate concurrent and predictive validity in patients with relapsing-remitting and secondary progressive multiple sclerosis (MS). L-CLA testing provides additional information relevant to the MS disease process that is not entirely captured by the Multiple Sclerosis Functional Composite.