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Background: Magnetic resonance imaging (MRI) of brain volume measures are widely used outcomes in secondary progressive multiple sclerosis (SPMS), but it is unclear whether they are associated with physical and cognitive disability. Objective: To investigate the association between MRI outcomes and physical and cognitive disability worsening in people with SPMS. Methods: We used data from ASCEND, a large randomized controlled trial ( n = 889). We investigated the association of change in whole brain and gray matter volume, contrast enhancing lesions, and T2 lesions with significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT) with logistic regression models. Results: We found no association between MRI measures and EDSS or SDMT worsening. T25FW worsening at 48 and 96 weeks, and NHPT worsening at 96 weeks were associated with cumulative new or newly enlarging T2 lesions at 96 weeks. NHPT worsening at 48 and 96 weeks was associated with normalized brain volume loss at 48 weeks, but not with other MRI outcomes. Conclusion: The association of standard MRI outcomes and disability was noticeably weak and inconsistent over 2 years of follow-up. These MRI outcomes may not be useful surrogates of disability measures in SPMS.

Background: The timed 25-foot walk (T25FW) is a key clinical outcome measure in multiple sclerosis patient management and clinical research. Objectives: To evaluate T25FW performance and factors associated with its change in the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) Placebo Database ( n = 2465). Methods: We created confirmed disability progression (CDP) variables for T25FW and Expanded Disability Status Scale (EDSS) outcomes. We used intraclass correlation coefficients (ICCs) and Bland Altman plots to evaluate reliability. We evaluated T25FW changes and predictive validity using a mixed-effects model, survival analysis, and nested case–control analysis. Results: The mean baseline score for the T25FW in this study population was 9.2 seconds, median = 6.1 (standard deviation = 11.0, interquartile range (IQR) = 4.8, 9.0). The T25FW measure demonstrated excellent test–retest reliability (ICC = 0.98). Walk times increased with age, disability, disease type, and disease duration; relapses were not associated with an increase. Patients with T25FW progression had a faster time to EDSS-CDP compared to those without (hazards ratio (HR): 2.6; confidence interval (CI): 2.2, 3.1). Changes in the T25FW were more likely to precede changes in EDSS. Conclusion: This research confirms the association of the T25FW with disability and provides some evidence of predictive validity. Our findings support the continued use of the T25FW in clinical practice and clinical trials.

Background: The expanded disability status scale (EDSS) is the standard clinical outcome measure in primary progressive multiple sclerosis (PPMS), even though the timed 25-foot walk (T25FW), nine-hole peg test (NHPT) or combinations of these measures may be more useful. The paced auditory serial addition test (PASAT) is a widely used cognitive measure in MS, but little is known about change in PASAT scores over time in PPMS. Objective: The objective of this study is to compare clinical outcome measures in a large PPMS trial data set. Methods: We determined significant worsening events on the EDSS, T25FW and NHPT, and PASAT scores over the course of this 3-year trial. We compared unconfirmed, confirmed and sustained disability worsening and contrasted disability worsening with similarly defined improvement. We examined the association of baseline characteristics with the risk of disability worsening at 12, 24 and 36 months with logistic regression models. Results: The EDSS and T25FW showed most worsening events, while only few patients worsened on the NHPT. Adding the NHPT to a combined outcome added only few further worsening events. PASAT scores slightly increased over time, possibly due to a practice effect. Conclusion: Both the EDSS and T25FW, but not NHPT or PASAT, appear to be useful outcome measures in PPMS.

Background: Health-related quality of life (HRQOL) outcomes are often included as secondary outcomes in clinical trials in secondary progressive MS (SPMS), but little is known about the longitudinal association of HRQOL and clinical and imaging outcome measures in SPMS. Objective: To assess the association of change in clinical and imaging outcomes with HRQOL in people with SPMS. Methods: We used data from ASCEND, a large randomized controlled trial ( n = 889), to investigate the association of significant worsening on the Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk (T25FW), Nine Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and change in lesional and volumetric imaging outcomes with significant worsening on the 36-Item Short Form Health Survey (SF-36) and the Multiple Sclerosis Impact Scale (MSIS-29) during 2 years of follow-up using logistic regression models. Results: HRQOL measures were most associated with EDSS and T25FW, less so with NHPT and SDMT, and not associated with lesional and volumetric imaging outcomes. Discussion: Worsening of the EDSS and T25FW was associated with two commonly used HRQOL measures. These outcomes therefore appear to be more patient relevant than either the NHPT or SDMT in the context of a 2-year clinical trial.

Background: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). Objective: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. Methods: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions. Results: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population ( n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials. Conclusion: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed.

Background: Researchers studying health-related quality of life (HRQOL) in multiple sclerosis (MS) can choose from many instruments, but findings from studies which use different instruments cannot be easily combined. We aimed to develop a crosswalk that associates scores from the RAND-12 to scores on the Health Utilities Index—Mark III (HUI3) in persons with MS. Methods: In 2018, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry completed the RAND-12 and the HUI3 to assess HRQOL. We used item-response theory (IRT) and equipercentile linking approaches to develop a crosswalk between instruments. We compared predicted scores for the HUI3 from each crosswalk to observed scores using Pearson correlations, intraclass correlation coefficients (ICCs), and Bland–Altman plots. Results: Of 11,389 invited participants, 7129 (62.6%) responded. Predicted and observed values of the HUI3 from the IRT-linking method were moderately correlated (Pearson r = 0.76) with good concordance (ICC = 0.72). However, the Bland–Altman plots suggested biased prediction. Predicted and observed values from the equipercentile linking method were also moderately correlated (Pearson r = 0.78, ICC = 0.78). The Bland–Altman plots suggested no bias. Conclusion: We developed a crosswalk between the RAND-12 and the HUI3 in the MS population which will facilitate data harmonization efforts.

Background: We recently compared clinical outcomes in secondary progressive MS (SPMS) clinical trials and found an association of timed 25 foot walk (T25FW) worsening events and baseline disability scores. It is unclear whether disability worsening in clinical trials is comparable to that seen in clinical practice. Objective: The objective of this study is to compare disability worsening between the IMPACT and ASCEND data sets and data from the Calgary MS clinic and to characterize the association of baseline T25FW and expanded disability status scale (EDSS) scores with disability worsening. Methods: We combined the three data sets and investigated the impact of baseline characteristics on disability worsening with a logistic regression model. We calculated T25FW, EDSS, and ‘EDSS or T25FW’ worsening events as a function of ascending cut-off baseline disability scores. Results: Data source was not associated with T25FW worsening at 12 months. There was a strong association of baseline T25FW and EDSS cut-off scores with T25FW worsening. No such association was present for the EDSS and ‘EDSS or T25FW’. Conclusion: Our results suggest that it is possible to ‘enrich’ a trial cohort for expected T25FW worsening events using specific baseline T25FW and EDSS cut-off scores. These analyses inform the selection of inclusion criteria for clinical trials in SPMS.

Background: Outcome measures need to be valid and have good test–retest reliability and responsiveness. We compared the responsiveness of the RAND-12 and the Health Utilities Index—mark III (HUI3) in persons with multiple sclerosis (MS). Methods: In Spring 2018 and 2019, North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants completed the HUI3, the RAND-12, and reported disability (Patient Determined Disease Steps (PDDS)) and employment status (full-time, part-time, and no). We used changes in PDDS and employment status as anchors. We assessed responsiveness using effect size, standardized response mean, and the responsiveness index. We used relative efficiency (RE) to compare the responsiveness of the health-related quality of life (HRQOL) scores, adjusting for sociodemographic factors. Results: We included 4769 participants in the analysis. They had a mean (standard deviation (SD)) age of 60.9 (10.1) years, and 3826 participants (80.2%) were women. RE was highest for the HUI3 for changes in in disability status (HUI3: 1.0, Physical Component Score-12 (PCS-12): 0.80, and Mental Component Score-12 (MCS-12): 0.41) and for changes in employment status (HUI3: 1.0, PCS-12: 0.70, and MCS-12: 0.17). Conclusion: The HUI3 was more responsive to changes in disability and employment status than the PCS-12 or MCS-12. Given the HUI3’s other strong psychometric properties, it may be the preferred generic measure of HRQOL in MS.

Background: Metabolic comorbidity is overrepresented in people with multiple sclerosis (MS) and is associated with adverse MS outcomes. Excess visceral adiposity, approximated using waist circumference (WC), is a risk factor for metabolic comorbidity and predicts poorer outcomes in other neurologic diseases. Objective: To evaluate the association between WC and clinical and disease characteristics in people with MS. Methods: North American Research Committee on MS (NARCOMS) registry participants reported height and weight (used to calculate body mass index (BMI)) and were mailed a tape measure with instructions to measure WC. We considered WC continuously and used cut-points derived from the abdominal obesity criteria for the metabolic syndrome (men: WC ⩾ 40 in; women: WC ⩾ 35 in). We assessed the association between WC and disability (Patient-Determined Disease Steps) and symptom severity (validated scales) using multivariable-adjusted multinomial models. Results: Of 6367 responders with MS, we included 5832 (92%). Of these, 3181 (55%) reported WC meeting criteria for the abdominal obesity component of metabolic syndrome. In multivariable models adjusting for overall obesity status, WC was associated with 47% increased odds of severe versus mild disability (odds ratio (OR): 1.47; 95% confidence interval (CI): 1.22–1.78). Conclusions: Increased WC is associated with more severe disability, even after adjusting for overall obesity in this large cross-sectional survey.

Background: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. Objective: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical–scientific integrity. Methods: We assessed the “standard of care” for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. Results: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. Conclusion: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.

Background: Studies of cancer incidence and prevalence in multiple sclerosis (MS) have produced conflicting results. Objective: To estimate the incidence and prevalence of cancer in persons with MS and review the quality of included studies. Methods: We searched the PUBMED, SCOPUS, Web of Knowledge, and EMBASE databases, conference proceedings, and reference lists of all articles retrieved. Abstracts were screened for relevance by two reviewers. Data from included articles were captured using a standardized form, and the abstraction was verified by a second reviewer. We assessed quality of the included studies. We quantitatively assessed studies using the I2 statistic, and conducted meta-analyses for population-based studies. Results: We identified 38 studies. Estimates for incidence and prevalence varied substantially for most cancers. In population-based studies, cervical, breast, and digestive cancers had the highest incidence. The risk of meningiomas and urinary system cancers appeared higher than expected, while the risks of pancreatic, ovarian, prostate and testicular cancer were lower than expected.Conclusion: The complexity of understanding cancer risk in MS is augmented by inconsistencies in study design, and the relative paucity of age, sex and ethnicity-specific risk estimates from which the strong impact of age on the incidence of cancers can be assessed.

Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.

Background: As new therapies emerge which increase the risk of autoimmune disease it is increasingly important to understand the incidence of autoimmune disease in multiple sclerosis (MS). Objective: The purpose of this review is to estimate the incidence and prevalence of comorbid autoimmune disease in MS. Methods: The PUBMED, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched, and abstracts were independently screened by two reviewers. The data were abstracted by one reviewer using a standardized data collection form, and the findings were verified by a second reviewer. We assessed quality of the included studies using a standardized approach and conducted meta-analyses of population-based studies. Results: Sixty-one articles met the inclusion criteria. We observed substantial heterogeneity with respect to the populations studied, methods of ascertaining comorbidity, and reporting of findings. Based solely on population-based studies, the most prevalent autoimmune comorbidities were psoriasis (7.74%) and thyroid disease (6.44%). Our findings also suggest an increased risk of inflammatory bowel disease, likely uveitis and possibly pemphigoid. Conclusion: Fewer than half of the studies identified were of high quality. Population-based studies that report age, sex and ethnicity-specific estimates of incidence and prevalence are needed in jurisdictions worldwide.

Background: The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials. Objective: This study evaluated composite disability end points as alternatives to EDSS alone. Methods: SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D). Results: Overall agreements between EDSS and other disability measures in defining SDP were 66%−73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials. Conclusion: Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials.

Relapse rates and thus the impact of therapies have been decreasing. Why they decline and the impact on our ability to understand which treatments are better require more than simple math. The objective of this review is to discuss the impact of regression to the mean, changes in outcome effects and how we compare outcomes over time and among studies. This paper provides discourse on the topics of regression to the mean, some examples of the pitfalls of changes and some difficulties in the interpretation of the common percentage change in outcomes. The results show that we can often be deceived by what we think we see and they also demonstrate how such confusion evolves in the literature. This article aims to caution against the over-interpretation of changes from baseline, which are helped along by regression towards the mean and other factors. Furthermore, how we interpret changes from baseline requires care and not wishful thinking, coupled with careful digestion of seemingly reasonable explications of results.

Background: Visual comorbidities are common in multiple sclerosis (MS) but the impact of visual comorbidities on visual disability is unknown. Objective: We assessed the impact of visual and vascular comorbidities on severity of visual disability in MS. Methods: In 2006, we queried participants of the North American Research Committee on Multiple Sclerosis (NARCOMS) about cataracts, glaucoma, uveitis, hypertension, hypercholesterolemia, heart disease, diabetes and peripheral vascular disease. We assessed visual disability using the Vision subscale of Performance Scales. Using Cox regression, we investigated whether visual or vascular comorbidities affected the time between MS symptom onset and the development of mild, moderate and severe visual disability. Results: Of 8983 respondents, 1415 (15.9%) reported a visual comorbidity while 4745 (52.8%) reported a vascular comorbidity. The median (interquartile range) visual score was 1 (0–2). In a multivariable Cox model the risk of mild visual disability was higher among participants with vascular (hazard ratio [HR] 1.45; 95% confidence interval [CI]: 1.39–1.51) and visual comorbidities (HR 1.47; 95% CI: 1.37–1.59). Vascular and visual comorbidities were similarly associated with increased risks of moderate and severe visual disability. Conclusions: Visual and vascular comorbidities are associated with progression of visual disability in MS. Clinicians hearing reports of worsening visual symptoms in MS patients should consider visual comorbidities as contributing factors. Further study of these issues using objective, systematic neuro-ophthalmologic evaluations is warranted.

Objective Multiple sclerosis (MS) is associated with substantial morbidity. The impact of comorbidity on MS is unknown, but comorbidity may explain some of the unpredictable progression. Comorbidity is common in the general population, and is associated with adverse health outcomes. To begin understanding the impact of comorbidity on MS, we need to know the breadth, type, and frequencies of comorbidities among MS patients. Using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry, we aimed to describe comorbidities and their demographic predictors in MS. Methods In October 2006, we queried NARCOMS participants regarding physical comorbidities. Of 16,141 participants meeting the inclusion criteria, 8983 (55.7%) responded. Results Comorbidity was relatively common; if we considered conditions which are very likely to be accurately self-reported, then 3280 (36.7%) reported at least one physical comorbidity. The most frequently reported comorbidities were hypercholesterolemia (37%), hypertension (30%), and arthritis (16%). Associated with the risk of comorbidity were being male [females vs. males, odds ratio (OR) 0.77; 0.69–0.87]; age (age >60 years vs. age ≤44 years, OR 5.91; 4.95–7.06); race (African Americans vs. Whites, OR 1.46; 1.06–2.03); and socioeconomic status (Income $100,000, OR 1.37; 1.10–1.70). Conclusions Comorbidity is common in MS and similarly associated with socioeconomic status.

Background Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. Objective The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. Methods We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. Results Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. Conclusions Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy.

Background The IMPACT study demonstrated the benefit of interferon beta-1a (IFNβ-1a, Avonex®) two-year change in disability measured by the Multiple Sclerosis Functional Composite (MSFC) in secondary progressive multiple sclerosis (SP-MS) and health-related quality of life (HRQoL) measured by the Multiple Sclerosis Quality of Life Inventory (MSQLI). The IMPACT data permit a detailed assessment of the relation between clinical and self-reported measures. Methods IMPACT was an international randomized, double-blind, placebo-controlled trial of SP-MS patients. As the MSQLI is only in English, this report includes US and Canadian subjects. Subjects were randomized to weekly intramuscular (im) injections of INb-1a (60 mg) or placebo for 24 months. Results At baseline and follow-up, MSQLI correlations were generally stronger with the EDSS than with the MSQLI, MSFC but comparable with MSFC components. Combining the two groups, MSQLI changes for those in the best and worst MSFC change quartiles demonstrated a statistical difference for six of the 11 MSQLI scales. Linear regression demonstrated that EDSS change from baseline to month-24 scores was correlated with change in two MSQLI components. Conclusion These data support the appropriateness of using the MSQLI with individuals who have SP-MS.

The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry is a multiple sclerosis (MS) self-report registry with more than 24 000 participants. Participants report disability status upon enrolment, and semi-annually using Performance Scales (PS), Patient Determined Disease Steps (PDDS) and a pain question. In November 2000 and 2001, we also collected the Pain Effects Scale (PES). Our aim was to validate the NARCOMS pain question using the PES as our criterion measure. We measured correlations between the pain question and age, disease duration, various PS subscales and PDDS to assess construct validity. We correlated pain question responses in participants who reported no change in PDSS or the PS subscales between questionnaires to determine test—retest reliability. We measured responsiveness in participants who reported a substantial change in the sensory, spasticity PS subscales. The correlation between the pain question and PES was r=0.61 in November 2000, and r=0.64 in November 20...

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.

Objective: Patients with progressive relapsing (PR) multiple sclerosis (MS) may accrue disability by incomplete recovery from acute exacerbations and by ongoing deterioration. In primary progressive (PP) MS, disability accumulates solely by continuous decline. Because it is the least common form of MS, there is scant information regarding the clinical characteristics of PRMS, but relapses are reportedly uncommon. The purpose of this study is to describe the clinical features of a cohort of patients with PRMS. Methods: A retrospective chart review of 16 patients diagnosed with PRMS at two academic MS centres over a four-year period. Results: Nine men and seven women had PRMS. The mean age at onset was 35.19/11.2 years. The most common presenting symptom was a progressive myelopathy. The mean disease duration was 10.19/8.5 years and the average time to first exacerbation was 4.19/3.7 years. Patients had an average of 2.89/2.3 relapses with an annualized relapse rate of 0.69/0.8. Time to Expanded Disability Status Scale (EDSS) 6.0 was strongly associated with time to first exacerbation. Although there was no correlation between the number of relapses and time to EDSS 6.0, there was a modest inverse relation between time to EDSS 6.0 and annualized relapse rate. Conclusions: Relapses in PRMS may occur more often than previously described and disability may accumulate more rapidly in PRMS than in PPMS. We suggest differentiating between these two forms of MS.

Background: Risk factors for short-term progression in early relapsing-remitting MS have been identified recently. Previously we determined potential risk factors for rapid progression of early relapsing-remitting MS and identified three groups of high-risk patients. These non-mutually exclusive groups of patients were drawn from a consecutively studied sample of 98 patients with newly diagnosed MS. High-risk patients had a history of either poor recovery from initial attacks, more than two attacks in the first two years of disease, or a combination of at least four other risk factors. Objective: To determine differences in sample sizes required to show a meaningful treatment effect when using a high-risk sample versus a random sample of patients. Methods: Power analyses were used to calculate the different sample sizes needed for hypothetical treatment trials. Results: We found that substantially smaller numbers of patients should be needed to show a significant treatment effect by employing these high-risk groups of patients as compared to a random population of MS patients (e.g., 58% reduction in sample size in one model). Conclusion: The use of patients at higher risk of progression to perform drug treatment trials can be considered as a means to reduce the number of patients needed to show a significant treatment effect for patients with very early MS.

Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNb-1a (Avonex) in relapsing-remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing-remitting MS.

Visual impairment is one of the most common clinical manifestations of Multiple Sclerosis (MS), and is strongly related to overall health-related quality of life (HRQOL) in MS and other disorders. However, the assessment of vision-specific HRQOL in patients with MS has been limited. The purpose of this study was to examine self-reported visual dysfunction in a clinically heterogeneous MS cohort using the 25-Item National Eye Institute Visual Function Questionnaire (VFQ-25). The VFQ-25 was administered by telephone interview to a subset of participants in a follow-up study to a phase III trial of interferon β-1a for relapsing-remitting MS. Mean VFQ-25 composite scores and selected sub-scale scores were significantly lower (worse) among patients in our MS cohort (n=35) compared with a published reference group of patients with no history of chronic eye disease (n=118). These differences were observed despite a relatively younger age and tighter distribution of binocular visual acuities in the MS cohort. Patients with MS in this study thus demonstrated a greater degree of self-reported visual dysfunction, as measured by the VFQ-25, compared with an eye disease-free reference group. The VFQ-25 is a potentially useful measure of vision-specific HRQOL in patients with MS.

The quantitative assessment of visual function in multiple sclerosis (MS) clinical trials has been limited to Snellen visual acuity. The purpose of this study was to examine the inter-rater reliability and test characteristics of a new visual outcome measure, the Low-Contrast Sloan Letter Charts, in patients with MS and visually-asymptomatic volunteers. Contrast letter acuity scores (letter scores) were measured at each of four contrast levels (100, 5, 1.25 and 0.6%) by two independent raters. Inter-rater agreement was described with the intraclass correlation coefficient (ICC) and comparison of mean scores. Excellent inter-rater agreement (ICC=0.86-0.95) was demonstrated at each contrast level among MS patients (n=100) and visually-asymptomatic volunteers (n=33). Average letter scores at the lowest contrast level (0.6%) were highly variable in the MS group, even among patients with visual acuities of 20/20 or better, and among those who required no assistance for ambulation. Low-Contrast Sloan Letter Chart testing is a highly reliable method of visual assessment, and provides information on an aspect of neurologic impairment in MS which is not captured by Snellen visual acuity or ambulation status. This new method demonstrates excellent potential as a visual function outcome measure for future MS clinical trials.