Multiple Sclerosis Treatment Trials Research Articles

Effect of disease-modifying treatment on spinal cord lesion formation in multiple sclerosis: A retrospective observational study

BackgroundSpinal cord lesions in multiple sclerosis (MS) are an important contributor to disability. Knowledge on the effect of disease-modifying treatment (DMT) on spinal lesion formation in MS is sparse, as cord outcome measures are seldom included in MS treatment trials. We aim to investigate whether intermediate- or high-efficacy DMTs (i/hDMT) can reduce spinal lesion formation, compared with low-efficacy DMTs (lDMT) and/or no treatment. MethodsRelapse-onset MS patients with ≥2 spinal MRIs (interval >3 months and <10 years) were retrospectively identified. The i/hDMT-group was defined as patients who were treated with i/hDMTs during ≥90% of spinal MRI follow-up time. Controls received lDMTs and/or no treatment ≥90% of follow-up duration. In a secondary analysis, only patients using lDMT for ≥90% of follow-up were considered controls. Patients were matched using propensity-scores. Cox proportional hazards models were used to estimate the risk of new spinal lesions. Results323 patients had ≥2 spinal cord MRIs. 49 satisfied i/hDMT and 168 control group criteria. 34 i/hDMT patients were matched to 83 controls. Patients in the i/hDMT-group were significantly less likely to develop new cord lesions at follow-up (HR 0.29 [0.12–0.75], p = 0.01). When the i/hDMT-group was matched to only controls using lDMT ≥90% of follow-up time (n = 17 and n = 25, respectively), there was no statistically significant difference (HR 1.01 [0.19–5.24], p = 0.99). ConclusionTreatment with intermediate- or high-efficacy DMTs reduces the risk of new spinal cord lesions compared with matched patients receiving no treatment and/or lDMTs. No conclusions could be drawn on whether i/hDMTs provide a larger risk reduction compared to only lDMTs (control group receiving lDMTs ≥90% of follow-up time).

Harnessing Real-World Data to Inform Decision-Making: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS)

Background: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is the first example of a learning health system in multiple sclerosis (MS). This paper describes the initial implementation of MS PATHS and initial patient characteristics.Methods: MS PATHS is an ongoing initiative conducted in 10 healthcare institutions in three countries, each contributing standardized information acquired during routine care. Institutional participation required the following: active MS patient census of ≥500, at least one Siemens 3T magnetic resonance imaging scanner, and willingness to standardize patient assessments, share standardized data for research, and offer universal enrolment to capture a representative sample. The eligible participants have diagnosis of MS, including clinically isolated syndrome, and consent for sharing pseudonymized data for research. MS PATHS incorporates a self-administered patient assessment tool, the Multiple Sclerosis Performance Test, to collect a structured history, patient-reported outcomes, and quantitative testing of cognition, vision, dexterity, and walking speed. Brain magnetic resonance imaging is acquired using standardized acquisition sequences on Siemens 3T scanners. Quantitative measures of brain volume and lesion load are obtained. Using a separate consent, the patients contribute DNA, RNA, and serum for future research. The clinicians retain complete autonomy in using MS PATHS data in patient care. A shared governance model ensures transparent data and sample access for research.Results: As of August 5, 2019, MS PATHS enrolment included participants (n = 16,568) with broad ranges of disease subtypes, duration, and severity. Overall, 14,643 (88.4%) participants contributed data at one or more time points. The average patient contributed 15.6 person-months of follow-up (95% CI: 15.5–15.8); overall, 166,158 person-months of follow-up have been accumulated. Those with relapsing–remitting MS demonstrated more demographic heterogeneity than the participants in six randomized phase 3 MS treatment trials. Across sites, a significant variation was observed in the follow-up frequency and the patterns of disease-modifying therapy use.Conclusions: Through digital health technology, it is feasible to collect standardized, quantitative, and interpretable data from each patient in busy MS practices, facilitating the merger of research and patient care. This approach holds promise for data-driven clinical decisions and accelerated systematic learning.

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study.

BackgroundThe association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood.ObjectiveThe objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS.Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre.ResultsThere was a significant increase in INL volume in eyes with new MSON during the study (N = 61/1562, β = 0.01 mm3, p < .001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (β = 0.005, p = .025). INL volume was independent of disease progression (β = 0.002 mm3, p = .474).ConclusionOur data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials.

Treatment trials in progressive MS—current challenges and future directions

The introduction of immunomodulatory treatments has transformed the management of patients with relapsing-remitting multiple sclerosis (MS), but has had no consistent benefit in progressive MS. Patients with primary or secondary progressive MS, therefore, are faced with relentless functional decline that remains without treatment. Clinical trials in progressive MS are clearly needed, but their design and conduct is challenging, and different from that of trials in relapsing-remitting MS. Challenges to reliable measurement of clinical progression, uncertainties about the natural history of progressive MS, and the unclear role of imaging outcomes all impede optimal trial design. Clinical trials in progressive MS have used time to a predefined change on the Expanded Disability Status Scale as their main outcome measure, which has had important consequences for trial duration and has led to inclusion of only a highly selected minority of patients. Here, we review the current approach to clinical trial design in progressive MS, outline key ongoing challenges, and suggest strategies to overcome such hurdles.

Neurofilament light and heavy subunits compared as therapeutic biomarkers in multiple sclerosis

Neurofilaments are promising biomarkers in multiple sclerosis (MS) and increased levels in cerebrospinal fluid (CSF) indicate axonal damage or degeneration. In a previous study, neurofilament light chain (NfL) levels in CSF of relapsing remitting (RR) patients with MS were normalized by natalizumab treatment. We compared the coherence between NfL and neurofilament heavy chain (NfH(SMI) (35) ) levels in longitudinal CSF samples in a subset of these patients. In 30 patients with RRMS, CSF was obtained prior to and following 12months of natalizumab treatment. NfH(SMI) (35) was measured by an electrochemiluminescence-based immunoassay. NfL levels were determined previously by the UmanDiagnostics NF-light(®) assay. NfH(SMI) (35) decreased in 73.3% and NfL in 90% of the patients following natalizumab treatment (32.4 vs 27.4pg/ml, P=0.002 and 820 vs 375pg/ml, P<0.0001). Patients experiencing a relapse showed higher NfH(SMI) (35) levels compared with patients in remission (47.7 vs 27.6pg/ml, n=8, P=0.001). This difference was less obvious for NfL (1055 vs 725pg/ml, P=0.256). In patients in remission, NfL levels were lower following natalizumab treatment (830 vs 365pg/ml, n=20, P=0.0002), whereas the same comparison failed significance for NfH(SMI) (35) (28.3 vs 26.9pg/ml, P=0.086). We confirm previous findings, indicating reduced axonal damage under natalizumab treatment by measuring NfH(SMI) (35) , using an assay with independent methodology. In comparison with NfH(SMI) (35) , NfL changes were more pronounced and the treatment effect also included patients in remission. Our results suggest that NfL is superior over NfH(SMI) (35) as therapeutic biomarker and is a promising candidate to measure neuroaxonal damage in MS treatment trials.

The Combined Effect of Nursing Support and Adverse Event Mitigation on Adherence to Interferon Beta-1b Therapy in Early Multiple Sclerosis

There is limited clinical evidence on the impact of nurse support and adverse event (AE) mitigation techniques on adherence to interferon beta-1b (IFNβ-1b) therapy in multiple sclerosis (MS) in a real-world setting. The aim of the Success of Titration, analgesics, and BETA nurse support on Acceptance Rates in MS Treatment (START) trial was to assess the combined effect of titration, analgesics, and BETA (Betaseron Education, Training, Assistance) nurse support on adherence to IFNβ-1b therapy in patients with early-onset MS and to evaluate safety. Participants were instructed to titrate IFNβ-1b and use analgesics to minimize flu-like symptoms. All received BETA nurse follow-up at frequent intervals: live training, two telephone calls during the first month of therapy, and monthly calls thereafter. Participants were considered adherent if they took at least 75% of the total prescribed doses over 12 months (≥75% compliance). Safety was monitored via reported AEs and laboratory test results. Participants who took at least one IFNβ-1b dose over 12 months were analyzed (N = 104); 73.8% of participants completed the study. The mean age of participants was 37.2 years; 72.1% were women and 78.8% were white. Ninety participants had relapsing-remitting MS and 14 had clinically isolated syndrome. The mean compliance rate, reported for 96 participants with complete dose interruption records, was 84.4%. At 12 months, 78.1% of participants were considered adherent. The serious adverse event rate was 9.6%; most events were unrelated to therapy. Thus in the START study, in which participants received nursing support combined with dose titration and use of analgesics, the majority of participants were adherent to therapy.

Advances in Imaging to Support the Development of Novel Therapies for Multiple Sclerosis

Multiple sclerosis (MS) is a common neurological disease in North America and Europe. Although most patients develop major locomotor disability over the course of 15-20 years, in approximately one-third of patients the long-term course is favorable, with minimal disability. Although current disease-modifying treatments reduce the relapse rate, their long-term effects are uncertain. MS treatment trials are challenging because of the variable clinical course and typically slow evolution of the disease. Magnetic resonance imaging (MRI) is sensitive in monitoring MS pathology and facilitates evaluation of potential new treatments. MRI measurements of lesion activity have identified new immunomodulatory treatments for preventing relapse. Quantitative measurements of tissue volume and structural integrity, capable of detecting neuroprotection and repair, should facilitate new treatments designed to prevent irreversible disability. Higher-field MR scanners and new positron emission tomography (PET) radioligands are providing new insights into cellular and pathophysiological abnormalities, and should be valuable in future therapeutic trials. Retinal axonal loss measured using optical coherence tomography (OCT) can assess acute neuroprotection in optic neuritis.

Functional system scores provide a window into disease activity occurring during a multiple sclerosis treatment trial

<title/>Background: Average expanded disability status scale (EDSS) score on entry into pivotal trials of multiple sclerosis (MS) therapies lies between 2 and 3. These lower EDSS levels are determined by functional system score (FSS).Objective: We examined contributions of each FSS to characterization of MS patients at entry to and exit from the pivotal trial of intramuscular interferon beta-1a (IM IFN-beta-1a), as well as contribution of changes in FSS to changes in EDSS.Methods: We reviewed FSS and EDSS data collected at 6-month examinations during the IM IFN-beta-1a pivotal trial (n = 286). To describe which functional systems were most affected by disease, we used an FSS cutoff of 2 (mild to moderate impairment) and defined sustained progression as a 1 point change in EDSS score or FSS being maintained for 6 months.Results: The most frequently involved functional systems at baseline (FSS level of 2) were cerebellar (38%), pyramidal (37%), and sensory (34%). While all functional systems were affected to some extent by progressing MS, these FSSs were also most often affected at study end, with pyramidal and cerebellar FSSs being the greatest contributors to sustained EDSS progression. Treatment effect with IM IFN-beta-1a was most strongly seen in the pyramidal system.Conclusion: In this trial, some FSSs contributed more to detection of progression than others. While changes in lower EDSS were heavily weighted by the pyramidal FSS, all of the FSSs appeared to be important in understanding the overall impact of MS progression, demonstrating the responsive nature of the widely utilized EDSS.

Optic neuritis

The aim of this study is to provide a clinical update on optic neuritis (ON), its association with multiple sclerosis (MS), and neuromyelitis optica (NMO). This study included a PubMed review of the literature written in the English language. ON in adults is typically idiopathic or demyelinating, and is characterised by unilateral, subacute, painful loss of vision that is not associated with any systemic or other neurological symptoms. Demyelinating ON is associated with MS, and we review the key studies of ON including the ON treatment trial and several other MS treatment trials and NMO. Acute demyelinating ON can occur in isolation or be associated with MS. Typical ON does not require additional evaluation other than cranial magnetic resonance imaging. NMO is likely a separate disorder from MS and the ON in NMO has a different treatment and prognosis. The authors conducted an English language search using Pubmed from the years 1964 to 2010 using the search terms 'ON', 'MS' and 'NMO'. The authors included original articles, review articles, and case reports, which revealed new aspects as far as epidemiology, histopathology, clinical manifestations, imaging, genetics, and treatment of ON. Titles were reviewed for topicality and full references were obtained. Letters to the editor, unpublished work, and abstracts were not included in this review.

Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis

Progressive brain atrophy in multiple sclerosis (MS) may reflect neuroaxonal and myelin loss and MRI measures of brain tissue loss are used as outcome measures in MS treatment trials. This study investigated sample sizes required to demonstrate reduction of brain atrophy using three outcome measures in a parallel group, placebo-controlled trial for secondary progressive MS (SPMS). Data were taken from a cohort of 43 patients with SPMS who had been followed up with 6-monthly T1-weighted MRI for up to 3 years within the placebo arm of a therapeutic trial. Central cerebral volumes (CCVs) were measured using a semiautomated segmentation approach, and brain volume normalized for skull size (NBV) was measured using automated segmentation (SIENAX). Change in CCV and NBV was measured by subtraction of baseline from serial CCV and SIENAX images; in addition, percentage brain volume change relative to baseline was measured directly using a registration-based method (SIENA). Sample sizes for given treatment effects and power were calculated for standard analyses using parameters estimated from the sample. For a 2-year trial duration, minimum sample sizes per arm required to detect a 50% treatment effect at 80% power were 32 for SIENA, 69 for CCV, and 273 for SIENAX. Two-year minimum sample sizes were smaller than 1-year by 71% for SIENAX, 55% for CCV, and 44% for SIENA. SIENA and central cerebral volume are feasible outcome measures for inclusion in placebo-controlled trials in secondary progressive multiple sclerosis.

Treatment and treatment trials in multiple sclerosis

This review focuses on advances in current and novel treatment approaches in multiple sclerosis. New therapeutic approaches in multiple sclerosis are emerging. Orally available treatment strategies are more acceptable for patients and may improve adherence to therapy. An oral formulation of glatiramer acetate failed to demonstrate efficacy in a clinical trial, but other promising compounds are on the horizon, such as FTY720. Advances are currently being made in use of therapeutic monoclonal antibodies that specifically target key molecules involved in the immunopathogenesis of multiple sclerosis. Natalizumab directed against the adhesion molecule very late antigen-4 represents the first specific antibody to be added to our therapeutic armamentarium for multiple sclerosis. Further evidence that immunomodulation should be initiated as early as possible has been reported. Treatment of multiple sclerosis has changed dramatically over the past decade. Enhanced understanding of the immunopathological processes that underlie the disease, advances in biotechnology and development of powerful magnetic resonance imaging technologies, together with improvements in clinical trial design have led to a variety of valuable therapeutic approaches, which are currently being studied in detail.

Increasing benefit of magnetic resonance imaging in multiple sclerosis

Magnetic resonance imaging (MRI) has emerged as an essential tool of multiple sclerosis (MS) diagnosis and has opened up completely new prospects in MS research and treatment trials. It is a sensitive method that gives direct evidence of tissue pathology and has greatly increased our knowledge of MS. In clinical work, MRI is used to confirm and exclude the diagnosis of MS. The international recommendation is that every suspected MS patient should undergo at least one brain MRI. T2-weighted images are the standard tool in clinical work, and functional imaging methods are mainly used in MS research. The subtypes and the course of the disease cause variation in MRI findings. Here, we present a general overview of MR findings in MS.

Short-term effects of methylprednisolone on cerebral volume in multiple sclerosis relapses

We prospectively investigated the short-term effects of intravenous methyl-prednisolone (IVMP) on cerebral volume in patients suffering a multiple sclerosis (MS) relapse. Ten patients underwent MRI brain studies immediately before and after IVMP treatment, and 4 and 8 weeks later. Whole brain volumes decreased significantly over the 8-week period. The greatest change occurred during IVMP administration. This has implications for MS treatment trials using cerebral atrophy as an endpoint.

A standardised method for measuring magnetisation transfer ratio on MR imagers from different manufacturers—the EuroMT sequence

Magnetisation transfer ratio (MTR) is increasingly used to evaluate neurological disorders, especially those involving demyelination. It shows promise as a surrogate marker of disease progression in treatment trials in multiple sclerosis (MS) but the value measured is highly dependent on pulse sequence parameters, making it hard to include the technique in large multi-centre clinical trials. The variations can be reduced by a normalisation procedure based on the flip angle and timing of the presaturation pulse, but correction for parameters such as saturation pulse shape, amplitude, duration and offset frequency remains problematic. We have defined a standard pulse sequence, to include a standard presaturation pulse and set of parameters, which can be implemented on scanners from both General Electric and Siemens, and has also been used on Phillips scanners. To validate the sequence and parameters, six European centres measured MTR in the frontal white matter of normal volunteers. It was possible to measure MTR values in controls which were consistent to within approximately +/-2.5 percentage units across sites. This degree of precision may be adequate in many situations. The remaining differences between sites and manufacturers are probably caused by B1 errors.

Brain atrophy, interferon beta, and treatment trials in multiple sclerosis

Definitive evaluation of potential new disease-modifying treatments in multiple sclerosis is difficult. To show an effect on the traditional clinical endpoints—relapse rate and disability accumulation—large randomised controlled studies are required. These studies should typically investigate several hundred patients for 2–3 years.

Towards a european network for multiple sclerosis trials (ENMST).

Quality standards for clinical studies in the field of multiple sclerosis (MS) have improved significantly, to the great benefit of patients. This development has been accompanied by soaring costs and ever increasing complexity, with industry-independent trials having become virtually impossible. We propose establishing a European network that would include expertise in all the relevant aspects of MS treatment trials. In a stepwise approach, all interested active centres across Europe should be recruited into the network, based on agreement upon common scientific standards and quality requirements. Three main goals are discussed: to facilitate identification of potentially useful agents for MS treatment; to establish protocols for the interaction between investigators and industry; and to identify common standards and a core set of data to allow for comparisons of MS trials. Collaboration with existing international organizations and institutions, especially the Sylvia Lawry Centre for MS Research, as well as with similar initiatives in North America and other parts of the world is envisaged.

Estimating cerebral atrophy in multiple sclerosis patients from various MR pulse sequences.

The purpose of this study was to determine how measures reflecting cerebral atrophy (CA) are influenced by pulse sequence (PS) and segmentation algorithm (SA) used in multiple sclerosis (MS) patients and healthy control (HC)s. Magnetic resonance imaging (MRI) scans from 10 relapsing-remitting MS (RRMS) patients and five HCs were used to determine the change in brain fractional volume (BFV) over a two-year period. T1-weighted, fluid-attenuated inversion recovery (FLAIR), and proton density (PD)/T2-weighted sequences were analysed Image segmentation to determine brain volume was performed using the following a histogram SA, an adaptive fuzzy c-means algorithm (AFCM), and an adaptive Bayesian segmentation with a K-means clustering. Combinations of the SA and PS in MS patents demonstrated significant differences in the per cent change in BFV from baseline. For the combination of PS and SA the per cent change in BFV for year one and year two varied from +2.05% to - 1.6% and +0.79% to -3.11%, respectively. Analysis of the HCs data revealed fluctuations in BFV varying from +0.26% to -0.29%. MRI estimates of CA are dependent on both the type of PS and SA; therefore, the choice of SA technique and PS should be consistent during an MS treatment trial. The progression of CA in MS should only be used as a secondary or tertiary outcome measure in treatment trials until a better understanding of how this measurement is affected by the disease, the image acquisition and analysis techniques.

MRI monitoring of MS in clinical trials

While it is logical that definitiv ee valuation of new therapies is based on clinical outcomes, there are major difficulties in conducting treatment trials in multiple sclerosis (MS) with clinical endpoints such as relapse rate or disability progression. The slow clinical evolution requires large studies (several hundred patients) of long duration (2 � /3 years), with an active treatment group being compared to a control group. It is thus not surprising that there has been much effort to identify alternative measures of disease activity to monitor treatment efficacy. To be an effective replacement, or surrogate, of clinical outcomes, the measure of disease activity should be objective, sensitive, accurate, and reproducible. Most importantly, it should reflect and predict a clinically meaningful outcome. This review considers the role of magnetic resonance (MR) techniques in monitoring MS clinical trials. Because serial MRI has become a mandatory part of therapeutic monitoring, and because the effects of new therapies on MR outcomes have been very influential in conditioning the use of treatments in practice, an appraisal of its role in this setting is appropriate. 2. Potential of MRI as a tool to monitor treatment

The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure.

Changes in health policy have underlined the importance of evidence-based clinical practice and rigorous evaluation of patient-based outcomes. As patient-based outcome measurement is particularly important in treatment trials of multiple sclerosis, a number of disease-specific instruments have been developed recently. One limitation of these instruments is that none was developed using the standard psychometric approach of reducing a large item pool generated from people with multiple sclerosis. Consequently, an outcome measure for clinical trials of multiple sclerosis that is disease specific and combines patient perspective with rigorous psychometric methods will complement existing instruments. The aim of this study was to develop such a measure. Standard psychometric methods were used. A pool of 129 questionnaire items was generated from interviews with 30 people with multiple sclerosis, expert opinion and literature review. The questionnaire was administered by postal survey to 1530 people selected randomly from the Multiple Sclerosis Society membership database. Redundant items and those with limited measurement properties were removed. The remaining items (n = 41) were grouped into scales using factor analysis, and then refined to form the Multiple Sclerosis Impact Scale (MSIS-29), an instrument measuring the physical (20 items) and psychological (nine items) impact of multiple sclerosis. Five psychometric properties of the MSIS-29 (data quality, scaling assumptions, acceptability, reliability and validity) were examined in a separate postal survey of 1250 Multiple Sclerosis Society members. A preliminary responsiveness study of the MSIS-29 was undertaken in 55 people admitted for rehabilitation and intravenous steroid treatment of relapses. The MSIS-29 satisfied all psychometric criteria. Data quality was excellent, missing data were low (maximum 3.9%), item test-re-test reliability was high (r = 0.65-0.90) and scale scores could be generated for >98% of respondents. Item descriptive statistics, item convergent and discriminant validity, and factor analysis indicated that it was legitimate to generate scores for MSIS-29 scales by summing items. MSIS-29 scales showed good variability, small floor and ceiling effects, high internal consistency (Cronbach's alpha <or=0.91) and high test-re-test reliability (intraclass correlation <or=0.87). Correlations with other measures and the analysis of group differences provided evidence that the MSIS-29 measures the physical and psychological impact of multiple sclerosis. Effect sizes (physical scale = 0.82, psychological scale = 0.66) demonstrated preliminary evidence of good responsiveness. These results indicate the MSIS-29 is a clinically useful and scientifically sound patient-based outcome measure of the impact of multiple sclerosis suitable for clinical trials and epidemiological studies.

The precision of T1 hypointense lesion volume quantification in multiple sclerosis treatment trials: a multicenter study.

The volume of hypointense lesions on T1 weighted brain MRI represents an increasingly used MR endpoint in phase III MS treatment trials. In this study we evaluated the reproducibility of hypointense T1 lesion volume quantification in a cohort of Multiple Sclerosis (MS) patients. The gadolinium enhanced T1 weighted brain MR images of 33 MS patients from three European centers were used in this study. These images were acquired as part of a phase III trial of interferon beta-1b in secondary progressive MS. The MRI machine manufacturers and imaging parameters varied according to the MRI acquisition center. Three experienced observers used a semi-automated local thresholding technique to quantify the hypointense T1 lesion volume on two occasions, separated by a delay. The intra and inter observer coefficients of variation were 3.7% and 4.9% respectively, with similar values derived for images obtained at all three sites. There was a generally high level of agreement between the lesion volumes obtained by the three raters. However, a modest but significant measurement drift was identified between the first and second sessions for one of the three raters, highlighting the very real possibility of measurement drift even for experienced observers. Our results support the increasing role for T1 hypointense lesion volume as an outcome measure in multicenter phase III MS treatment trials. Multiple Sclerosis (2000) 6 237 - 240