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While the majority of individuals with multiple sclerosis (MS) develop significant clinical disability, a subset experiences a disease course with minimal impairment even in the presence of significant apparent tissue damage on magnetic resonance imaging (MRI). Functional magnetic resonance imaging (fMRI) in MS patients with low disability suggests that increased use of the cognitive control system may limit the clinical manifestation of the disease. The current fMRI studies tested the hypothesis that nondisabled MS patients show increased recruitment of cognitive control regions while performing sensory, motor and cognitive tasks. Twenty two patients with relapsing–remitting MS and an Expanded Disability Status Scale (EDSS) score of ≤ 1.5 and 23 matched healthy controls were recruited. Subjects underwent fMRI while observing flashing checkerboards, performing right or left hand movements, or executing the 2-back working memory task. Compared to control subjects, patients demonstrated increased activation of the right dorsolateral prefrontal cortex and anterior cingulate cortex during the performance of the working memory task. This pattern of functional recruitment also was observed during the performance of non-dominant hand movements. These results support the mounting evidence of increased functional recruitment of cognitive control regions in the working memory system of MS patients with low disability and provide new evidence for the role of increased cognitive control recruitment in the motor system.

The human brain thalami play essential roles in integrating cognitive, sensory, and motor functions. In multiple sclerosis (MS), quantitative magnetic resonance imaging (qMRI) measurements of the thalami provide important biomarkers of disease progression, but late development and aging confound the interpretation of data collected from patients over a wide age range. Thalamic tissue volume loss due to natural aging and its interplay with lesion-driven pathology has not been investigated previously. In this work, we used standardized thalamic volumetry combined with diffusion tensor imaging, T2 relaxometry, and lesion mapping on large cohorts of controls (N= 255, age range = 6.2–69.1 years) and MS patients (N= 109, age range = 20.8–68.5 years) to demonstrate early age- and lesion-independent thalamic neurodegeneration.

Background: Accurate classification of multiple sclerosis (MS) lesions in the brain cortex may be important in understanding their impact on cognitive impairment (CI). Improved accuracy in identification/classification of cortical lesions was demonstrated in a study combining two magnetic resonance imaging (MRI) sequences: double inversion recovery (DIR) and T1-weighted phase-sensitive inversion recovery (PSIR). Objective: To evaluate the role of intracortical lesions (IC) in MS-related CI and compare it with the role of mixed (MX), juxtacortical (JX), the sum of IC + MX and with total lesions as detected on DIR/PSIR images. Correlations between CI and brain atrophy, disease severity and disease duration were also sought. Methods: A total of 39 patients underwent extensive neuropsychological testing and were classified into normal and impaired groups. Images were obtained on a 3T scanner and cortical lesions were assessed blind to the cognitive status of the subjects. Results: Some 238 cortical lesions were identified (130 IC, 108 MX) in 82% of the patients; 39 JX lesions were also identified. Correlations between CI and MX lesions alone ( p = 0.010) and with the sum of IC + MX lesions ( p = 0.030) were found. A correlation between severity of CI and Expanded Disability Status Scale was also seen ( p = 0.009). Conclusion: Cortical lesions play an important role in CI. However, our results suggest that lesions that remain contained within the cortical ribbon do not play a more important role than ones extending into the adjacent white matter; furthermore, the size of the cortical lesion, and not the tissue-specific location, may better explain their correlation with CI.

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011

Significant progress in multiple sclerosis (MS) treatment has been made over the last two decades, including the emergence of disease-modifying therapy (DMT). However, substantial unmet medical need persists and has stimulated the search for new therapeutics. Teriflunomide, one of the several oral DMTs under investigation, is a selective inhibitor of de novo pyrimidine synthesis which exerts a cytostatic effect on proliferating T- and B lymphocytes in the periphery and thus has both antiproliferative and anti-inflammatory properties. Anti-inflammatory effects have been demonstrated in rodent MS models, with reductions in macrophage and B- and T-cell infiltration in the central nervous system and preservation of myelin and oligodendrocytes. Delays in disease onset, reductions in disease relapses and improvements in clinical symptoms were also observed. A proof-of-concept clinical trial in patients with relapsing MS demonstrated that teriflunomide significantly reduced magnetic resonance imaging (MRI) activity and improved clinical endpoints, with both effects maintained with longer-term treatment. Additional studies have shown that teriflunomide can be safely added to beta interferon or glatiramer acetate therapy, with some evidence of additional improvements in MRI disease burden and clinical signs. Teriflunomide has an acceptable and manageable safety and tolerability profile. A large clinical programme is underway to further elucidate the role of teriflunomide in the treatment of MS.

Background: Quantitative measures derived from magnetic resonance imaging (MRI) have been widely investigated as non-invasive biomarkers in multiple sclerosis (MS). However, the correlation of single measures with Expanded Disability Status Scale (EDSS) is poor, especially for studies with large population samples. Objective: To explore the correlation of MRI-derived measures with EDSS through composite MRI scores. Methods: Magnetic resonance images of 126 patients with relapsing—remitting MS were segmented into white and gray matter, cerebrospinal fluid, T2-hyperintense lesions, gadolinium contrast-enhancing lesions, T1-hypointense lesions (‘black holes’: BH). The volumes and average T2 values for each of these tissues and lesions were calculated and converted to a z-score (in units of standard deviation from the mean). These z-scores were combined to construct composite z-scores, and evaluated against individual z-scores for correlation with EDSS. Results: Composite scores including relaxation times of different tissues and/or volumetric measures generally correlated more strongly with EDSS than individual measures. The maximum observed correlation of a composite with EDSS was r = 0.344 ( p < 0.0001), which is an improvement over the highest-performing single MRI measure (BH; r = 0.298, p < 0.001). Conclusion: Z-transformation permits construction of composite scores including volumetric and T2-relaxation measures. Inclusion of multiple MRI measures in the composite can provide a broader characterization of the disease process, resulting in more robust correlations with EDSS.

IntroductionOcrelizumab-(OCR) showed superior efficacy vs interferon beta-1a-(IFNβ1a) in OPERA I/II trials in RMS. Confirmed disability progression-(CDP) based on composite of Expanded Disability Status Scale-(EDSS), timed 25-foot walk-(T25FW) and 9-hole peg test-(9HPT) may better characterise aspects of disability progression than EDSS alone and has improved sensitivity for assessing progression in secondary progressive MS-(SPMS).MethodsRMS patients, including relapsing SPMS patients, in OPERA I/II-(NCT01247324/NCT01412333) received IV-OCR 600 mg (q24w) or SC-IFNβ1a 44 µg (tiw) over 96 weeks. CCDP was defined as disability progression measured by EDSS (increase ≥1.0 or 0.5 if baseline >5.5) or ≥20% T25FW increase or ≥20% 9 HPT increase, confirmed after ≥12/≥24 weeks. Definition-1 of CCDP-IRA=reference EDSS/T25FW/9HPT was re-baselined at first available assessment ≥30 days, after each relapse and no relapse should occur between baseline and initial disability progression [IDP], and within 30 days post-IDP and 30 days prior to IDP confirmation. Definition-2=period of no relapse for 30 days post-IDP confirmation. Subgroup analysis included patients at potentially higher SPMS risk based on baseline-EDSS ≥4.0 and pyramidal Kurtzke Functional Systems Score ≥2.ResultsIn the pooled intention-to-treat (ITT) cohort (n=1,656), risk reduction (RR; OCR vs IFNβ1a) for 12-/24 week CCDP was 34% (30.7% vs 21.5%; pConclusionResults show that considerable disability progression in RMS occurs independently of protocol-defined relapses. Ocrelizumab significantly reduced progression vs IFNβ1a in the OPERA ITT population of RMS patients and more so in the subgroup at higher SPMS risk.

IntroductionIn a blinded SIENA (Structural Image Evaluation using Normalisation of Atrophy) analysis of TEMSO (NCT00134563), teriflunomide significantly reduced brain volume loss (BVL) over 2 years vs placebo. Further analysis indicated a strong correlation between 2 year BVL and disability worsening, showing better disability outcomes for patients with lower rates of BVL. Here, we explore the relationship between BVL and long-term changes in cognitive function in TEMSO and its extension (NCT00803049).MethodsThe effect of teriflunomide on cognitive function was assessed by change from baseline in Paced Auditory Serial Addition Test (PASAT)−3 scores in the TEMSO core (n=1086) and extension (n=740) studies. To evaluate change in PASAT-3 scores over 5 years, the TEMSO population was categorised into groups defined by percentage brain volume change from baseline to Year 2 (assessed by SIENA).ResultsAdjusted mean changes from baseline to Week 96 in PASAT-3 raw/Z-scores were –0.265/–0.022 and 0.870/0.073 for placebo and teriflunomide 14 mg, respectively (difference vs placebo, p=0.0435 in both instances). Long-term improvements in PASAT-3 Z-scores were observed with teriflunomide 14 mg treatment: mean (SD) changes from baseline at Weeks 156 and 276 were 0.194 (0.634) and 0.200 (0.677), respectively. Mean (SD) units of change from baseline in raw PASAT-3 scores for teriflunomide 14 mg–treated patients at Weeks 156 and 276 were 2.36 (7.73) and 2.43 (8.24), respectively. In an association analysis, the group with least BVL from baseline to Year 2 demonstrated a significant improvement in PASAT-3 score with teriflunomide treatment over 5 years vs the group with most BVL.ConclusionTeriflunomide significantly improved PASAT-3 performance vs placebo over 5 years in the TEMSO core and extension studies. Slower rates of BVL over 2 years correlated with better long-term PASAT-3 improvement. This study suggests that BVL earlier in the disease course predicts longer-term cognitive function.Study supportSanofi.

IntroductionUpper limb (UL) functional impairment is prevalent among PPMS patients and alters quality of life. The nine-hole peg test (9HPT) is a validated quantitative assessment of UL function in MS.Methods9HPT was administered at baseline and every 12 weeks until study end. The average 9HPT-times from two trials of dominant- and non-dominant-hands were compared; the hand with the lower baseline time was termed ‘better-hand’, and the hand with the higher baseline time was termed ‘worse-hand’. Average dominant- and non-dominant-hand times were combined and termed ‘both-hands’. Analyses included time-to-confirmed progression (CP) in hand function, defined as ≥15%, ≥20% or ≥25% increase in 9HPT-time from baseline, confirmed at 12- and 24 weeks, and change in 9HPT-time from baseline to Week-120.ResultsCompared with placebo, ocrelizumab reduced the time-to 12- and 24-week-CP of ≥15% increase on 9HPT by 37% (hazard ratio [HR]=0.627; p=0.001) and 39% (HR=0.607; p=0.002) for both-hands, 30% (HR=0.699; p=0.011) and 40% (HR=0.599; pConclusionOcrelizumab treatment lowered the risk of progression of upper extremity disability, measured by 9HPT, compared with placebo in PPMS patients.

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing—remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 ± 5.2, 4.81 ± 3.69, and 13.6 ± 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 ± 0.82 at baseline to 0.25 ± 0.34 per year; 57% had stable/improved EDSS scores (change ≤ 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43 ± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

Background Ocrelizumab significantly reduced the risk of confirmed disability progression (CDP) versus placebo in the Phase III ORATORIO study (NCT01194570) in primary progressive multiple sclerosis (PPMS). A composite measure of CDP (cCDP) that also includes upper extremity function and ambulation speed may address limitations in using the Expanded Disability Status Scale to define CDP. Objective To assess the effect of ocrelizumab on 12- and 24 week cCDP in patients with PPMS. Methods Patients received ocrelizumab (n=488) 600 mg (administered as two 300 mg infusions 14 days apart) or matching placebo (n=244) every 24 weeks for ≥120 weeks, and were assessed for cCDP (ie, time to first onset of either CDP,≥20% worsening on the timed 25-foot walk [T25FW] test or ≥20% worsening on the 9-hole peg test [9HPT]), sustained for ≥12 or≥24 weeks. Results Ocrelizumab reduced the risk of 12- and 24 week cCDP versus placebo by 26% (HR: 074; p=0.0014) and 29% (HR: 0.71; p=0.0008), respectively. Ocrelizumab also significantly reduced the risk of individual cCDP components versus placebo, including 12- and 24 week CDP and confirmed ≥20% worsening on T25FW and 9HPT. Conclusions Ocrelizumab showed consistent benefit on disability progression, ambulation and upper limb function assessed using cCDP in patients with PPMS.

Background Infusion-related reactions (IRRs) have been observed with ocrelizumab treatment. Objective To evaluate the pattern of IRRs in studies of ocrelizumab in relapsing (OPERA I/II [NCT01247324/NCT01412333]) and primary progressive (ORATORIO [NCT01194570]) multiple sclerosis. Methods During the 96 week OPERA studies, patients received ocrelizumab 600 mg via intravenous (IV) infusion every 24 weeks or subcutaneous interferon beta-1a (IFNβ−1a) 44 µg three-times weekly. In ORATORIO, patients received ocrelizumab 600 mg IV given as two 300 mg infusions 14 days apart or matching placebo every 24 weeks for ≥120 weeks. Patients were pretreated with IV methylprednisolone 100 mg or blinded equivalent; analgesics/antipyretics and antihistamines were recommended. Results Safety analyses included patients from OPERA I/II (ocrelizumab, n=825; IFNβ−1a, n=826) and ORATORIO (ocrelizumab, n=486; placebo, n=239). Infusion-related reactions were more common with ocrelizumab versus comparator in OPERA I/II (34.3% vs 9.7% with IFNβ−1a) and ORATORIO (39.9% vs 25.5% with placebo), and were most frequent with the first infusion, decreasing thereafter. The majority of IRRs were mild to moderate in severity and most commonly included pruritus, rash, throat irritation and flushing. Conclusions The most common adverse event in these studies was IRRs, which were mostly mild to moderate in severity and decreased in incidence after the first infusion.

In a large multicenter randomized, and double blind placebo controlled trial of glatiramer acetate (GA) in primary progressive multiple sclerosis (PPMS), an originally unplanned post hoc analysis suggested that males assigned to GA therapy experienced less progression of disability than their counterparts assigned to placebo; no similar potential treatment differences were seen among the females in this study. In this report we further explore the data from that trial in an attempt to determine if this outcome could have been the expression of a gender dependant treatment effect. The analyses conducted do not support a treatment by gender interaction for GA in either PPMS or relapsing forms of MS. Nor could we find consistent precedence in the literature for important effects of gender on outcome, recognizing that such effects have not always been carefully sought. It remains reasonable to consider that there exist differences in the rates of clinical disease progression between men and women with MS that should be better studied.

Tensor based morphometry (TBM) was applied to determine the atrophy of deep gray matter (DGM) structures in 88 relapsing multiple sclerosis (MS) patients. For group analysis of atrophy, an unbiased atlas was constructed from 20 normal brains. The MS brain images were co-registered with the unbiased atlas using a symmetric inverse consistent nonlinear registration. These studies demonstrate significant atrophy of thalamus, caudate nucleus, and putamen even at a modest clinical disability, as assessed by the expanded disability status score (EDSS). A significant correlation between atrophy and EDSS was observed for different DGM structures: (thalamus: r = −0.51, p = 3.85×10−7; caudate nucleus: r = −0.43, p = 2.35×10−5; putamen: r = −0.36, p = 6.12×10−6). Atrophy of these structures also correlated with 1) T2 hyperintense lesion volumes (thalamus: r = −0.56, p = 9.96×10−9; caudate nucleus: r = −0.31, p = 3.10×10−3; putamen: r = −0.50, p = 6.06×10−7), 2) T1 hypointense lesion volumes (thalamus: r = −0.61, p = 2.29×10−10; caudate nucleus: r = −0.35, p = 9.51×10−4; putamen: r = −0.43, p = 3.51×10−5), and 3) normalized CSF volume (thalamus: r = −0.66, p = 3.55×10−12; caudate nucleus: r = −0.52, p = 2.31×10−7, and putamen: r = −0.66, p = 2.13×10−12). More severe atrophy was observed mainly in thalamus at higher EDSS. These studies appear to suggest a link between the white matter damage and DGM atrophy in MS.

Intellectual property protections for biologic medicinals for multiple sclerosis (MS) are beginning to expire, opening the possibility of development, regulatory approval, and marketing of so-called follow-on biologics, biosimilars, or subsequent entry biologics that might be offered at lower price to consumers and third-party payers, as has been the case for generic drugs. Determining the comparability of a follow-on biologic to its innovator product is more difficult than for small-molecule drugs because of the greater complexity of biologics and the possibility that manufacturing differences can introduce differences in biologic activity and immunogenicity that could result in unpredictable differences in safety or efficacy. We provide a perspective on issues surrounding development, regulatory approval, and potential use of follow-on biologics, with an emphasis on disease-modifying agents for MS.

Background Gray matter lesions are known to be common in multiple sclerosis (MS) and are suspected to play an important role in disease progression and clinical disability. A combination of magnetic resonance imaging (MRI) techniques, double-inversion recovery (DIR), and phase-sensitive inversion recovery (PSIR), has been used for detection and classification of cortical lesions. This study shows that high-resolution three-dimensional (3D) magnetization-prepared rapid acquisition with gradient echo (MPRAGE) improves the classification of cortical lesions by allowing more accurate anatomic localization of lesion morphology. Methods 11 patients with MS with previously identified cortical lesions were scanned using DIR, PSIR, and 3D MPRAGE. Lesions were identified on DIR and PSIR and classified as purely intracortical or mixed. MPRAGE images were then examined, and lesions were re-classified based on the new information. Results The high signal-to-noise ratio, fine anatomic detail, and clear gray-white matter tissue contrast seen in the MPRAGE images provided superior delineation of lesion borders and surrounding gray-white matter junction, improving classification accuracy. 119 lesions were identified as either intracortical or mixed on DIR/PSIR. In 89 cases, MPRAGE confirmed the classification by DIR/PSIR. In 30 cases, MPRAGE overturned the original classification. Conclusion Improved classification of cortical lesions was realized by inclusion of high-spatial resolution 3D MPRAGE. This sequence provides unique detail on lesion morphology that is necessary for accurate classification.

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

To prospectively perform a direct measurement of fractional anisotropy (FA) and mean diffusivity (MD) in cortical lesions of patients with multiple sclerosis (MS).The study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained. Magnetic resonance (MR) images, including double inversion-recovery (DIR), phase-sensitive inversion-recovery (PSIR), and diffusion-tensor images, were acquired from nine MS patients with cortical lesions (five women, four men; median age, 47 years) and nine age- and sex-matched volunteer control subjects. Following nonlinear elastically constrained image registration for aligning diffusion-weighted images to DIR images, maps of FA and MD were computed for each subject. Cortical lesions were identified on DIR images and validated by using PSIR images. The diffusion-tensor imaging maps were then overlaid on the coregistered DIR images, and mean FA and MD values were measured in regions of interest drawn on the cortical lesions. Differences between normal gray matter (GM) and cortical lesions were evaluated by using the generalized estimating equation. FA and MD histograms of whole brain and GM (global analysis) in healthy control subjects and MS patients were also computed for comparison with those in previously published studies.FA and MD values were significantly higher in cortical lesions compared with similar regions in healthy control subjects. Histogram peak FA was significantly decreased and peak MD was significantly increased in patients relative to control subjects.DIR and PSIR combined with nonlinear image registration allowed direct focal measurement of FA and MD in cortical lesions.

BACKGROUND AND PURPOSE: Accurate detection and classification of purely intracortical lesions in multiple sclerosis (MS) are important in understanding their role in disease progression and impact on the clinical manifestations of the disease. However, detection of these lesions with conventional MR imaging remains a challenge. Although double inversion recovery (DIR) has been shown to improve the sensitivity of the detection of cortical lesions, this sequence has low signal-to-noise ratio (SNR), poor delineation of lesion borders, and is prone to image artifacts. We demonstrate that intracortical lesions can be identified and classified with greater confidence by the combination of DIR with phase-sensitive inversion recovery (PSIR) images. MATERIALS AND METHODS: A total of 16 subjects with MS were included in this study. DIR, PSIR, and fluid-attenuated inversion recovery (FLAIR) images were acquired and inspected by 3 experts, with identification of lesions by consensus. PSIR and DIR images were jointly used to classify lesions as purely intracortical, mixed gray-white matter, and juxtacortical. The difference in the number of lesions detected in each category was compared between combined PSIR and DIR and conventional FLAIR. RESULTS: PSIR consistently allowed a clearer classification and delineation of lesions. Combined PSIR and DIR images showed a 337% improvement in the total number of lesions detected compared with FLAIR alone. Detection of intracortical lesions was improved by 417% compared with FLAIR. Detection of mixed gray-white matter and juxtacortical lesions was improved by 396% and 130%, respectively, compared with FLAIR. CONCLUSION: Reliable detection and classification of intracortical lesions in MS are greatly improved by combined use of PSIR and DIR.

Purpose To develop and implement a method for identification and quantification of gadolinium (Gd) enhancements with minimal human intervention. Materials and Methods Dual fast spin echo (FSE), fluid attenuation inversion recovery (FLAIR), and pre- and postcontrast T1-weighted spin echo were acquired on 22 subjects. The enhancements were identified on the postcontrast T1-weighted images based on morphological operations. A single threshold based on the ratio of the difference of postcontrast and precontrast T1 images with that of precontrast T1 images is applied to the reconstructed images to reduce the false classifications. False classification of enhancements arising from enhancing vasculature and structures such as the choroid plexus that lack a blood-brain barrier were reduced by assuming that the true enhancements are always associated with hyperintense lesions on T2-weighted images (T2 lesions). The enhanced lesions were further delineated based on fuzzy connectivity. Results The segmented Gd enhancements were evaluated quantitatively with manually identified enhancements based on similarity measures. The average similarity index (SI) of 0.76 suggests excellent performance of the proposed methodology. The Bland-Altman plot shows a close agreement between the results obtained manually and those based on the proposed methodology. Conclusion The proposed algorithm identifies and quantifies Gd enhancements accurately with minimal human intervention. J. Magn. Reson. Imaging 2007;25:932–937. © 2007 Wiley-Liss, Inc.

To quantify the change in cerebral spinal fluid (CSF) production rate and maximum systolic velocity in astronauts before and after exposure to microgravity and identify any physiologic trend and/or risk factor related to intracranial hypertension.Following Institutional Review Board (IRB) approval, with waiver of informed consent, a retrospective review of 27 astronauts imaged at 3T was done. Qualitative analysis was performed on T2 -weighted axial images through the orbits for degree of flattening of the posterior globe according to the following grades: 0 = none, 1 = mild, 2 = moderate, and 3 = severe. One grade level change postflight was considered significant for exposure to intracranial hypertension. CSF production rate and maximum systolic velocity was calculated from cine phase-contrast magnetic resonance imaging and compared to seven healthy controls.Fourteen astronauts were studied. The preflight CSF production rate in astronauts was similar to controls (P = 0.83). Six astronauts with significant posterior globe flattening demonstrated a 70% increase in CSF production rate postflight compared to baseline (P = 0.01). There was a significant increase in CSF maximum systolic velocity in the subgroup without posterior globe flattening (P = 0.01).The increased postflight CSF production rate in astronauts with positive flattening is compatible with the hypothesis of microgravity-induced intracranial hypertension inferring downregulation in CSF production in microgravity that is upregulated upon return to normal gravity. Increased postflight CSF maximum systolic velocity in astronauts with negative flattening suggests increased craniospinal compliance and a potential negative risk factor to microgravity-induced intracranial hypertension.

Background: Previous studies have shown only modest correlation between multiple sclerosis (MS) lesions on MRI and clinical disability. Objective: To investigate the relationship between proton density/T2-weighted (T2) burden of disease (BOD) quantitatively measured on MRI scans and clinical determinants including disability. Methods: Using the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database, the authors studied baseline T2 BOD data from a pooled subsample of 1,312 placebo MS patients from 11 randomized controlled trials. Univariate comparisons guided development of multiple regression models incorporating the most important clinical predictors. Results: Significant, although weak to moderate, correlations were found between T2 BOD and age at disease onset, disease duration, disease course, disability (as measured by the Expanded Disability Status Scale [EDSS]), relapse rate, certain presenting symptoms, and gadolinium enhancement. An unexpected but key finding that persisted in the multiple regression analyses was a plateauing relationship between T2 BOD and disability for EDSS values above 4.5. Conclusions: This study confirmed the limited correlation between clinical manifestations and T2 burden of disease (BOD) but revealed an important plateauing relationship between T2 BOD and disability.

Despite prolonged survival, patients with multiple sclerosis (MS) experience considerable morbidity, which adversely impacts quality of life. To assess the risk-benefit of a clinical trial of high dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation for MS, we sought to determine the natural history of the disease in a comparison group of untreated patients. We identified 285 individuals with 2132 combined observation years (median: 5.6 years; 5th to 95th percentile: 1-21 years), with Expanded Disability Status Scale (EDSS) scores of 3.0-5.5 at baseline observation. Disease-related mortality was zero at five years, 5.4% at 10 years, and 22% at 15 years (40 patients contributing to the data point; 95% confidence interval: 4-32%). Risk for progression to advanced disability, defined as an EDSS score of 8, was very low for the subgroup with a baseline EDSS score of 3-3.5; however, for those with a baseline EDSS score of 4-5.5, 3% had advanced disability after two years, 5% after three years, 6% after four years, 12% after five years, and 40% after 10 years. The estimated probability of disease progression, defined as an increase in EDSS score by ≥ 1.0 sustained for at least 180 days, was 5% after one year, 14% after two years, 22% after three years, 38% after five years, 57% after 10 years, and-80% after 20 years of observation. The relevance of these features to the design of the clinical trial is discussed.

Magnetic resonance (MR)-based techniques are widely used for the assessment of patients with suspected and definite multiple sclerosis (MS). However, despite the publication of several position papers, which attempted to define the utility of MR techniques in the management of MS, their application in everyday clinical practice is still suboptimal. This is probably related, not only, to the fact that the majority of published guidelines focused on the optimization of MR technology in clinical trials, but also to the continuing development of modern, quantitative MR-based techniques, that have not as yet entered the clinical arena. The present report summarizes the conclusions of the 'EFNS Expert Panel of Neuroimaging of MS' on the application of conventional and non-conventional MR techniques to the clinical management of patients with MS. These guidelines are intended to assist in the use of conventional MRI for the diagnosis and longitudinal monitoring of patients with MS. In addition, they should provide a foundation for the development of more widespread but rational clinical applications of non-conventional MR-based techniques in studies of MS patients.

On October 9-11, 2003, the third meeting of the White Matter Study Group of the International Society for Magnetic Resonance in Medicine was held in Venice, Italy. This article is the report of the meeting on how to use MRI in the diagnostic workup of multiple sclerosis (MS) and allied white matter disorders, and to define the nature and the extent of MS pathology in vivo. Both of these steps are central to the design of future treatment strategies aimed at limiting the functional consequences of the most disabling aspects of this disease.

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Magnetic resonance imaging (MRI) has greatly enhanced our appreciation for the highly dynamic pathologic activity that silently advances in multiple sclerosis (MS). New lesions appear on MRI at a frequency that greatly exceeds clinically announced relapses. Moreover, evidence of more widespr

Multicentre baseline proton magnetic resonance spectro scopic data on primary progressive multiple sclerosis (PPMS) patients are acquired and analysed, using automatic analysis software. The metabolite ratios did not differ from centre to centre. The average N-acetylaspar tate/creatine (NA A/C r) ratio in PPMS was significantly lower compared to normal controls. No significant differences were observed in this ratio between lesion-containing regions (LC R) and normal-appearing tissues (NAT). Strong lipid resonances, even in the absence of lesions, are observed in the both grey and white matter in these patients. These observations suggest extensive diffuse and/or microscopic pathology in PPMS. No significant correlation between any of the metabolite ratios and the Extended Disability Scale Score (EDSS) or with other MR measures such as lesion burden and enhancement volumes is observed.

The PRO MiSe trial is a multinational, multicentre, double-blind, placebo -controlled trial evaluating the effects of glatiramer acetate treatment over 3 years in patients with primary progressive multiple sclerosis (PPMS). A total of 943 patients were enrolled, and all those remaining on-study had completed at least 24 months as of O ctober 2002. Baseline clinical and MRI character istics and select correlations are reported here. A total of 3.9% of patients exhibited confirmed relapse over 1904 patient-years of exposure, indicating success of efforts to exclude relapsing MS types. O f the 26.3% of patients who have prematurely withdrawn from the study, only 36% discontinued after meeting the study primary endpoint of disease progression. The progression rate in patients in the low Expanded Disability Status Scale (EDSS) stratum (3.0-5.0) observed thus far is markedly lower than the 50% annual progression rate estimate used for determining size and statistical power of the trial; progression was observed in 16.1% of patients with 12 months of study exposure. These early findings raise some concern about the ability of the trial to demonstrate a significant treatment effect, and suggest that the short-term natural history of PPMS may not be as aggressive as previously assumed.

Glatiramer acetate (Copaxone, Teva Pharmaceuticals Ltd) is a collection of immunomodulatory, synthetic polypeptides indicated for the treatment of relapsing-remitting multiple sclerosis (RR MS). Preclinical and clinical studies provide an evolving understanding of the mechanisms by which glatiramer acetate exerts both immunological and potential neuroprotective effects that account for its clinical efficacy. The results of pivotal controlled clinical trials and long-term data, derived from organised extension studies, are evaluated in detail and supportive data from open-label comparison, combination treatment and therapeutic switch studies are considered in order to determine the place of glatiramer acetate among other approved therapies for RR MS. The efficacy of glatiramer acetate is stable or may increase over time and the drug has a favourable side effect profile. Glatiramer acetate is an appropriate first-line immunomodulatory therapy for RR MS.

In measuring the association between magnetic resonance spectroscopic imaging (MRSI)-observed neurochemicals from multiple sclerosis (MS) patients, the classic correlation coefficients such as the Pearson's r, Spearman's A and Kendall's F do not take into account the spatial dependence of the observations. This paper reports a comparative study on these classic correlation coefficients (Pearson's r, Spearman's A and Kendall's F ) and some more recent correlation coefficients (Tjostheim's a, the modified t) that take into account the spatial dependence of the intensities of the concentrations of several neurochemicals in MS patients. Our study indicates that the use of the classic correlation coefficients that ignores the spatial dependence of the observations may overestimate the statistical significance of the results.

Three randomized, double-blind, placebo-controlled trials have shown that glatiramer acetate (GA) is effective in reducing relapse rate in patients with relapsing-remitting (RR) multiple sclerosis (MS). Using raw data pooled from 540 patients, we performed a meta-analysis of these three trials, to investigate whether the extent of G A efficacy varies according to disease-related variables at study entry. Three regression models were developed to assess the efficacy of G A on the annualized relapse rate (primary outcome measure), on the total number of on-trial relapses and on the time to first relapse. We also explored the efficacy of G A on accumulated disability and the potential role of baseline clinical variables as predicto rs of relapse-rate variables and treatment efficacy. The mean adjusted annualized relapse rate on study was 1.14 in the pooled placebo -treated subjects and 0.82 in the pooled GA group (P =0.004), indicating an average reductio n in annualized relapse rate of 28%. A bout a one third reductio n of the total number of on-trial relapses was also observed in patients receiving GA (P B-0.0001), who had a median time to the first relapse of 322 days versus a median time to the first relapse of 219 days seen in those receiving placebo (P =0.01). A beneficial effect on accumulated disability was also found (risk ratio of 0.6; 95%; C I =0.4-0.9; P =0.02). The drug assignment (P =0.004), baseline EDSS score (P =0.02) and number of relapses during the two years prior to study entry (P =0.002) were significant predicto rs of on-trial annualized relapse rate. No other demographic or clinical variable at baseline significantly influenced the treatment effect. This meta-analysis reaffirms the effectiveness of G A in reducing relapse rate and disability accumulatio n in RRMS, at a magnitude comparable to that of other available immunomodulating treatments. It also suggests that G A efficacy is not significantly influenced by the patients’ clinical characteristics at the time of treatment initiation.

The new international panel guidelines for diagnosis of multiple sclerosis (MS) raised a number of concerns regarding their use and application, particularly in relation to their impact on treatment issues and options. As a result, a consensus panel composed primarily of North American neurologists with inclusion of several members from the International Panel was convened in Fort Worth, Texas, November 30 to December 2, 2001, to discuss these concerns, resulting in the following consensus statement regarding the guidelines and their appropriate use. (Int J MS Care. 2002; 4: 170–173)

Magnetic resonance spectroscopy provides noninvasive insight into the regional and global biochemical alterations that are concomitants of the dynamic processes that underlie the evolution of fundamental pathologic changes in multiple sclerosis. These include now well-recognized alterations of neuronal biochemical markers that accompany tissue destruction readily visualized by magnetic resonance imaging, but also dynamic changes in several metabolites that indicate pathological processes that precede the magnetic resonance imaging-defined lesion, or completely escape current high-resolution imaging.

Background Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+B cells. The pathogenesis of multiple sclerosis (MS), including neurodegeneration, is thought to be influenced by B cells. Volumetric magnetic resonance imaging (MRI) measurements can be used to assess neurodegeneration. Objective To evaluate the effect of OCR vs interferon beta-1a (IFN β -1a) on brain MRI markers of neurodegeneration in patients with relapsing MS enrolled in two identical Phase III, randomised, double-blind, double-dummy trials (OPERA I and OPERA II). Methods In OPERA I and OPERA II, patients were randomised (1:1) to receive OCR 600 mg via intravenous infusion every 24 weeks or subcutaneous IFN β -1a 44 μ g three-times weekly over 96 weeks. MRI endpoints thought to be related to neurodegeneration included the change in whole brain volume, change in cortical grey matter volume and change in cerebral white matter volume. Results Compared with IFN β -1a, OCR reduced the rate of whole brain volume loss from baseline to Week 96 by 23.5% ( p p = 0.0001), and from Week 24 to Week 96 by 22.8% ( p = 0.0042) and 14.9% ( p = 0.0900) in OPERA I and OPERA II, respectively. OCR-treated patients showed a smaller mean percentage of cortical grey matter volume loss compared with IFN β -1a from baseline to Week 96, with a mean difference of 0.273% ( p = 0.0005) in OPERA I and 0.516% ( p β -1a from baseline to Week 96, with a mean difference of 0.261% ( p = 0.0024); in OPERA II, there was no difference ( p = 0.2748) in cerebral white matter volume loss in patients treated with OCR compared with IFN β -1a from baseline to Week 96. Conclusion The rate of neurodegeneration as measured by whole brain, cortical grey and cerebral white matter volume loss on MRI was reduced by OCR compared with IFN β -1a in patients with relapsing MS over 96 weeks. This study is sponsored by F. Hoffmann-La Roche Ltd.

Objectives To preliminarily assess annualised relapse rate (ARR) at 144 weeks among patients with relapsing multiple sclerosis (RMS) who received ocrelizumab or interferon beta-1a (IFNβ−1a) in the Phase III 96 week OPERA I and II trials, followed by ocrelizumab in an open-label extension (OLE). The efficacy and safety of ocrelizumab in RMS have been demonstrated in the OPERA trials. Oon completion of the controlled treatment period, all patients were eligible to enter an ocrelizumab OLE phase. Methods During the controlled treatment period, patients received intravenous ocrelizumab 600 mg every 24 weeks or subcutaneous IFNβ−1a 44 mg three times weekly for 96 weeks. During the OLE, patients from the IFNβ−1a group were switched to ocrelizumab. Results Patients from OPERA I (ocrelizumab, 352/410; IFNβ−1a, 326/411) and OPERA II (ocrelizumab, 350/417; IFNβ−1a, 297/418) enrolled in the OLE. At the time of analysis, 317 (90.1%) and 322 (92.0%) continuous ocrelizumab patients and 307 (94.2%) and 268 (90.2%) patients switching from IFNβ−1a in OPERA I and II, respectively, had ≥48 weeks of follow-up in the OLE (144 weeks total). Across groups, patients received a median of two doses of ocrelizumab in the OLE. Among patients switching from IFNβ−1a to ocrelizumab, the unadjusted ARR improved from 0.245 and 0.254 over 96 weeks in OPERA I and II, respectively, to 0.092 and 0.115 in the OLE. Among continuous ocrelizumab patients, the unadjusted ARR was 0.136 and 0.138 in OPERA I and II, respectively; during the OLE, the ARR in this group was 0.118 and 0.100, respectively. Imaging metrics will be presented. Conclusions Patients who originally received ocrelizumab in the OPERA studies continued to have favourable ARR outcomes in the OLE. Patients who switched from IFNβ−1a to ocrelizumab in the OLE rapidly experienced ARR outcomes consistent with those of patients who received continuous ocrelizumab.

Introduction Ocrelizumab (OCR) est un anticorps monoclonal humanise ciblant selectivement les lymphocytes B CD20+. Des reactions liees a la perfusion (RLP) ont ete observees apres administration d’OCR. Objectifs Evaluer le profil des IRR dans les etudes randomisees, en double aveugle, de phase III, dans la recurrente (SEP-R ; OPERA I/II) et progressive primaire (SEP-PP ; ORATORIO). Patients et methodes Dans OPERA I/II, les patients SEP-R ont recu, OCR 600 mg IV tous les 6 mois ou IFNβ-1a44 μgSC 3x/semaine pendant 96 semaines (randomisation 1:1). Dans ORATORIO, les patients SEP-PP ont recu OCR 600 mg IV (2 × 300 mg a 14 jours d’intervalle) tous les 6 mois ou placebo pendant 120 semaines (randomisation 2:1). Les patients etaient premediques avec 100 mg de methylprednisolone IV ou equivalent. Un pretraitement par analgesiques/antipyretiques et antihistaminiques etait recommande. Resultats Cette analyse de tolerance a ete realisee sur 1311 patients OCR, 826 IFNβ-1a et 239 placebo. Dans les etudes OPERA I/II, 34,3 % vs 9,7 % des patients presentaient une RLP (respectivement OCR vs IFNβ-1a) et 39,9 % vs 25,5 % dans l’etude OPERA (respectivement OCR vs placebo). La majorite des RLP (≥92 %) etaient de severite legere a moderee. Dans le groupe OCR les RLP etaient plus frequentes lors de la premiere perfusions et diminuaient avec les perfusions suivantes. Discussion Dans les etudes de phase III (OPERA I/II et ORATORIO), OCR a demontre un profil de tolerance favorable chez les patients SEP-R et PP. Les RLP sont les effets indesirables les plus frequents sous OCR. Dans la plupart des cas, les RLP ont ete gere grâce a la premedication, des traitements symptomatiques et l’ajustement de la perfusion. Conclusion Les RLP sont de severite legere a moderee, diminuent au cours des perfusions et du temps. Elles sont gerables grâce a la premedication et l’utilisation de traitements symptomatiques. Informations complementaires Etude F. Hoffmann-La Roche Ltd Promoteur.

Introduction Dans l’etude TEMSO, des patients atteints de SEP evoluant par poussees ont recu un placebo ou du teriflunomide 7 ou 14 mg pendant 108 semaines. Les patients ayant fini l’etude pouvaient entrer dans l’extension ( NCT00803049 ). Objectifs Presenter les resultats de securite d’emploi et d’efficacite des patients participant a la phase d’extension de l’etude TEMSO jusqu’a son terme (10,5 ans de traitement). Patients et methodes Pendant l’extension, les patients traites par le teriflunomide ont recu la meme dose que dans l’etude pivot ; les patients sous placebo ont ete a nouveau randomises selon un rapport 1/1 pour recevoir le teriflunomide 7 ou 14 mg (dose en insu). Les resultats de securite d’emploi sont presentes pour l’extension ; les resultats d’efficacite (taux annualise de poussees [TAP], progression du handicap et parametres IRM) sont presentes pour toute la duree du traitement (etude pivot et extension). Resultats Au total, 742 patients sont entres dans l’extension. La duree mediane de traitement etait de 7 ans. Les evenements indesirables (EI) etaient majoritairement d’intensite legere ; conduisant a l’arret chez moins de 13 % des patients. Le TAP est reste bas pendant toute l’extension (288 patients sans poussee). Quatre cents patients n’ont pas presente de progression du handicap confirmee a 12 semaines. Le volume et le nombre des lesions en T1 rehaussees par le gadolinium sont restes faibles entre l’inclusion et la cinquieme annee. Discussion La nature et l’incidence des EI etaient concordantes avec les autres etudes avec le teriflunomide, confirmant les observations precedentes indiquant que le teriflunomide presente un profil de securite d’emploi a long terme gerable. Le TAP, le taux de progression du handicap et l’activite IRM sont restes bas, et les scores EDSS (Expanded Disability Status Scale) sont restes stables sur toute la periode. Conclusion Les resultats de l’extension de TEMSO confirment les observations precedentes. Le teriflunomide a un profil de securite d’emploi a long terme bien caracterise, et son efficacite est maintenue a long terme. Informations complementaires Etude soutenue par Sanofi Genzyme.

Introduction Un risque accru d’infection avec les traitements de fond de la (SEP) est rapporte. Le taux d’infections est un composant important du profil de tolerance d’ocrelizumab (OCR). Objectifs Evaluer les infections et infections graves chez les patients traites par OCR atteints de SEP recurrente (SEP-R) ou primaire-progressive (SEP-PP) dans les etudes OPERA I, OPERA II et ORATORIO. Patients et methodes Dans OPERA I/II, les patients SEP-R ont recu, OCR 600 mg IV tous les 6 mois ou IFNβ-1a44 μg SC trois fois par semaine pendant 96 semaines (randomisation 1 :1). Dans ORATORIO, les patients SEP-PP ont recu OCR 600 mg IV (2 × 300 mg a 14 jours d’intervalle) tous les 6 mois ou un placebo pendant 120 semaines (randomisation 2:1). Les infections ont ete classifiees selon la terminologie du dictionnaire medical des affaires reglementaires MedDRA (Medical Dictionary for Regulatory Activities). Resultats Dans l’analyse poolee d’OPERAI/II, 58,4 % et 52,4 % des patients ont declare une infection et 1,3 % et 2,9 % ont declare des infections graves dans les groupes OCR et IFNβ-1a respectivement. Dans ORATORIO, 69,8 % et 67,8 % des patients ont declare une infection et 6,2 % et 5,9 % ont declare une infection grave dans les groupes OCR et PBO respectivement. Deux deces lies a des infections ont ete rapportes dans ORATORIO dans le groupe OCR. Discussion Aucune infection opportuniste n’a ete rapportee. Les infections les plus frequentes dans le groupe OCR etaient les infections des voies respiratoires superieures (IVRS) et les rhinopharyngites dans OPERA et les IVRS et la grippe dans ORATORIO. La majorite des infections etaient legeres a moderees et le taux d’arret du traitement du a des infections etait faible dans les deux etudes. Conclusion La proportion d’infections graves est plus faible chez les patients traites par OCR comparativement a l’IFNβ-1a chez les patients SEP-R et semblable au PBO chez les patients SEP-PP. Informations complementaires Etude F. Hoffmann-La Roche Ltd Promoteur.

Background and purpose Participant recruitment is central to all clinical trials. Any delay in recruitment affects the completion and ultimate success of the trial. We report our experience with patient screening and randomization in CombiRx, which may inform the design of other trials. CombiRx was a multicenter, phase III, double-blind, randomized clinical trial comparing the combined use of interferon beta-1a and glatiramer acetate to either agent alone in patients with relapsing–remitting multiple sclerosis (RRMS). This trial was launched in January 2005 in 69 centers in the United States and Canada under a co-operative agreement with the National Institute of Neurological Disorders and Stroke (NINDS). The goal was to recruit 1000 patients over 1.5 years after a 6-month start-up period. Instead, the investigators required 4.25 years to enroll 1008 patients. Methods During this trial, we assessed the effectiveness of various recruitment strategies, utility of rescreening prior screen failures, and potential factors and strategies used in study conduct, research, and infrastructure, all of which affected recruitment of participants and ultimately time to completion of CombiRx. We particularly were interested in the variability in time to site initiation between academic centers and private practice sites. Results Physicians who were directly involved in the medical care of patients with RRMS were the primary source of patients recruited to CombiRx. A flexible study design that allowed for rescreening of the initial screen failures after a period of time was useful due to the relapsing/remitting course of the disease. Academic centers took longer to implement the trial than the private practice centers, but once sites were approved for enrollment, there was no important difference in the number of participants enrolled. Limitations The CombiRx trial was conducted during a period when multiple new medications were being tested, thus affecting the pace of recruitment and limiting ability to generalize our experiences. However, the lessons we learned about process are relevant. Conclusion Participants can be enrolled successfully in a clinical trial for RRMS, but factors affecting the time to achieve the requirements needed to start screening can be unpredictable and problematic. Prospective planning by the sponsors and investigators, use of central institutional review boards (IRBs), master trial agreements and secure remote desktop access to the trial database may expedite trial implementation and participant recruitment. A good scientific research question with flexible study design and active involvement of the clinicians are important factors driving recruitment. Clinical trials can be implemented successfully both in private practices and at academic centers, a consideration when selecting sites.

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.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Background: MRI-derived metrics such as atrophy, burden of disease (BOD), and cortical lesions (CL) have independently been reported to be associated with Multiple Sclerosis (MS) related cognitive impairment (CI). Composite scores combining some of these individual metrics have also been shown to improve correlations with MS-related physical disability; however the value of a composite score for MS-related CI has not yet been evaluated. In this study we assessed the relationship between CI and a quantitative composite score constructed from MRIderived metrics to include total white matter lesion volume, CL number, and normalized cerebrospinal fluid (nCSF), a measure of brain atrophy. Methods: Thirty three (n=33) patients underwent neuropsychological testing and were classified into CI groups using a 4-point severity scale (0, 1, 2, 3) where zero indicates non-impaired, “1” represents borderline, “2” represents mild, and “3” represents moderate CI. Images obtained at 3T were segmented into tissue and lesion compartments from which BOD and nCSF were quantitatively measured. CL number was identified visually by consensus. BOD, nCSF, and CL number were then transformed to z-scores: zBOD, znCSF and zCL, and a composite score “Z3”was constructed from these measures. The associations between Z3 and CI and the individual transformed measures (z-scores) and CI were evaluated via ordinal logistic regression. Results: Z3 was significantly associated with CI (OR=1.443, 95% Confidence Interval: 1.048-1.987, p=0.024) with a slightly larger OR than any individual measure. Of the individual measures, only BOD had a significant association with CI (OR=1.064, 95% Confidence Interval: 1.008-1.123, p=0.025). No significant association was found between atrophy or CL and CI. Conclusion: The Z3 score is associated with increased CI severity. This association was mainly driven by BOD. Larger studies are needed to assess the potential advantage of a composite score over measures of white matter lesion burden alone.

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2,447 +/- 61 days (mean +/- standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3 +/- 51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1,476 +/- 63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2,433 +/- 59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86 +/- 1.78, oGA=1.03 +/- 1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.2 7, +/- 0.45 oGA=0.28 +/- 0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66 +/- 0.71, oGA reduced by 0.23 +/- 0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16 +/- 2.52, total enhanced tissue volume=97 +/- 26 microl). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol. Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2447+61 days (mean+standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3+51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1476+63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2433+59 ...

Introduction B cells are implicated in MS pathophysiology, including primary progressive MS (PPMS). Ocrelizumab (OCR) is a humanised monoclonal antibody that selectively targets CD20+ B cells. OCR was evaluated in PPMS in a Phase III, randomised, double-blind, placebo-controlled study (ORATORIO; NCT01194570). Methods Eligible PPMS patients were randomised 2:1 to receive OCR 600 mg or placebo every 24 weeks for ≥120 weeks, until a pre-specified number of 12-week confirmed disability progression (CDP) events occurred. The primary endpoint was time-to-onset of 12-week CDP. Secondary endpoints included: time-to-onset of ≥24-week CDP; changes in timed 25-foot walk (T25-FW), total T2 lesion volume at 120 weeks and total brain volume between 24 and 120 weeks; and safety. Results Compared with placebo, OCR significantly reduced: risk of 12- (24%; p=0.0321) and 24-week CDP (25%; p=0.0365); T25FW progression rate (29% [OCR: +39%; placebo: +55%; p=0.0404]); T2 lesion volume (OCR: –3.4%; placebo: +7.4%; p Conclusions OCR is the first investigational therapy to meet key efficacy outcomes with a favourable safety profile in a Phase III PPMS study. Sponsored by F. Hoffmann-La Roche Ltd.

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266