Multiple Sclerosis: Cutter GR

Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. · Department of Neurology, Free University Medical Center in Amsterdam, PO Box 4075, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #18362273 No free full text.

Abstract: 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.

Cutter GR, Lublin FD. · No affiliation provided · Neurology. · Pubmed #18362265 No free full text.

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Schwid SR, Cutter GR. · No affiliation provided · Neurology. · Pubmed #16534098 No free full text.

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Giovannoni G, Cutter GR, Lunemann J, Martin R, Münz C, Sriram S, Steiner I, Hammerschlag MR, Gaydos CA. · Department of Neuroinflammation, Institute of Neurology, University College London, UK. · Lancet Neurol. · Pubmed #16987736 No free full text.

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Fischer JS, Rudick RA, Cutter GR, Reingold SC. · Mellen Center (U-10), Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio OH 44195-5244 USA. · Mult Scler. · Pubmed #10467383 No free full text.

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

Mark VW, Taub E, Bashir K, Uswatte G, Delgado A, Bowman MH, Bryson CC, McKay S, Cutter GR. · Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, Alabama 35249-7330, USA. · Mult Scler. · Pubmed #18573826 No free full text.

Abstract: OBJECTIVE: To evaluate whether Constraint-Induced Movement therapy (CI therapy) may benefit chronic upper extremity hemiparesis in progressive multiple sclerosis (MS). METHODS: Five patients with progressive MS, who had chronic upper extremity hemiparesis and evidence for learned non-use of the paretic limb in the life situation, underwent 30 hours of repetitive task training and shaping for the paretic limb over 2-10 consecutive weeks, along with physical restraint of the less-affected arm and a "transfer package" of behavioral techniques to reinforce treatment adherence. RESULTS: The patients showed significantly improved spontaneous, real-world limb use at post-treatment and 4 weeks post-treatment, along with improved fatigue ratings and maximal movement ability displayed in a laboratory motor test.Conclusions The findings suggest for the first time that slowly progressive MS may benefit from CI therapy. Further studies are needed to determine the retention of treatment responses.

Rudick RA, Cutter GR, Baier M, Weinstock-Guttman B, Mass MK, Fisher E, Miller DM, Sandrock AW. · Department of Neurology, Mellen Center for Multiple Sclerosis Treatment and Research, The Cleveland Clinic Foundation, OH 44195, USA. · Mult Scler. · Pubmed #16323317 No free full text.

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

Baier ML, Cutter GR, Rudick RA, Miller D, Cohen JA, Weinstock-Guttman B, Mass M, Balcer LJ. · Center for Research Methodology and Biometrics, Cooper Institute, 14023 Denver West Parkway, 100, Golden, CO 80401, USA. · Neurology. · Pubmed #15781814 No free full text.

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

Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, Sandrock AW, Rudick RA, Simon JH, Simonian NA, Tsao EC, Whitaker JN, Anonymous00071. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, OH 44195, USA. · Neurology. · Pubmed #12221157 No free full text.

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

Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Jak AJ, Kniker JE, Kooijmans MF, Lull JM, Sandrock AW, Simon JH, Simonian NA, Whitaker JN. · The Mellen Center-U10, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA. · Arch Neurol. · Pubmed #11405811 links to  free full text

Abstract: BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS. OBJECTIVE: To assess the practice effects, reliability, and validity of the MSFC clinical outcome measure. DESIGN: Examining technicians underwent formal training using standardized materials. The MSFC was performed according to a standardized protocol. The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before randomization. RESULTS: Practice effects were evident initially for the MSFC but stabilized by the fourth administration. The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects. The reliability of the MSFC was excellent, with an intraclass correlation coefficient for session 3 (final prebaseline session) vs session 4 (baseline) of 0.90. The MSFC at baseline correlated moderately strongly with the Kurtzke Expanded Disability Status Scale. Among the MSFC components, the Timed 25-Foot Walk correlated most closely. Correlations among the 3 MSFC components were weak, suggesting they assess distinct aspects of neurologic function in patients with MS. CONCLUSIONS: The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial. Three prebaseline testing sessions were sufficient to compensate for practice effects. The pattern of correlations among the MSFC, its components, and the Kurtzke Expanded Disability Status Scale supported the validity of the MSFC.

Balcer LJ, Baier ML, Pelak VS, Fox RJ, Shuwairi S, Galetta SL, Cutter GR, Maguire MG. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. · Mult Scler. · Pubmed #10871827 No free full text.

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

Mehta LR, Schwid SR, Arnold DL, Cutter GR, Aradhye S, Balcer LJ, Calabresi PA, Cohen JA, Cole PE, Glanzman R, Goelz S, Inglese M, Kapoor R, Kappos L, Kreitman R, Lublin FD, Mann A, Marrie RA, O'Looney P, Polman CH, Ravina BM, Reingold SC, Richert JR, Sandrock AW, Waubant E. · University of Rochester Department of Neurology, Rochester, NY, USA. · Mult Scler. · Pubmed #19389749 No free full text.

Abstract: BACKGROUND: There is considerable interest in tissue-protective treatments for multiple sclerosis (MS). METHODS AND OBJECTIVES: We convened a group of MS clinical trialists and related researchers to discuss designs for proof of concept studies utilizing currently available data and assessment methods. RESULTS: Our favored design was a randomized, double-blind, parallel-group study of active treatment versus placebo focusing on changes in brain volume from a post-baseline scan (3-6 months after starting treatment) to the final visit 1 year later. Study designs aimed at reducing residual deficits following acute exacerbations are less straightforward, depending greatly on the anticipated rapidity of treatment effect onset. CONCLUSIONS: The next step would be to perform one or more studies of potential tissue-protective agents with these designs in mind, creating the longitudinal data necessary to refine endpoint selection, eligibility criteria, and sample size estimates for future trials.

Sormani MP, Bonzano L, Roccatagliata L, Cutter GR, Mancardi GL, Bruzzi P. · Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy. · Ann Neurol. · Pubmed #19334061 No free full text.

Abstract: OBJECTIVE: The aim of this work was to evaluate whether the treatment effects on magnetic resonance imaging (MRI) markers at the trial level were able to predict the treatment effects on relapse rate in relapsing-remitting multiple sclerosis. METHODS: We used a pooled analysis of all the published randomized, placebo-controlled clinical trials in relapsing-remitting multiple sclerosis reporting data both on MRI variables and relapses. We extracted data on relapses and on MRI "active" lesions. A regression analysis weighted on trial size and duration was performed to study the relation between the treatment effect on relapses and the treatment effect on MRI lesions. We validated the estimated relation on an independent set of clinical trials satisfying the same inclusion criteria but with a control arm other than placebo. RESULTS: A set of 23 randomized, double-blind, placebo-controlled trials in relapsing-remitting multiple sclerosis was identified, for a total of 63 arms, 40 contrasts, and 6,591 patients. A strong correlation was found between the effect on the relapses and the effect on MRI activity. The adjusted R(2) value of the weighted regression line was 0.81. The regression equation estimated using the placebo-controlled trials gave a satisfactory prediction of the treatment effect on relapses when applied to the validation set. INTERPRETATION: More than 80% of the variance in the effect on relapses between trials is explained by the variance in MRI effects. Smaller and shorter phase II studies based on MRI lesion end points may give indications also on the effect of the treatment on relapse end points.

Mowry EM, Loguidice MJ, Daniels AB, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Cutter GR, Maguire MG, Balcer LJ. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. · J Neurol Neurosurg Psychiatry. · Pubmed #19240050 No free full text.

Abstract: OBJECTIVE: To examine the relation between low contrast letter acuity, a new visual function test for multiple sclerosis (MS) trials, and vision targeted health related quality of life (HRQOL). METHODS: Patients in this cross sectional study were part of an ongoing investigation of visual function in MS. Patients were tested binocularly using low contrast letter acuity and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) charts. The 25 Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), 10 Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, Impact of Visual Impairment Scale and Short Form 36 Health Survey (SF-36) were administered. RESULTS: Among 167 patients, mean age was 48 (10) years, with median Expanded Disability Status Scale (EDSS) 2.0 (range 1.0-7.5), and median binocular Snellen acuity equivalent (ETDRS charts) 20/16 (range 20/12.5 to 20/100). Reductions in vision specific HRQOL were associated with lower (worse) scores for low contrast letter acuity and VA (p<0.001, linear regression, accounting for age). Two line differences in visual function were associated, on average, with >4 point (6.7-10.9 point) worsening in the NEI-VFQ-25 composite score, reductions that are considered clinically meaningful. Scores for the 10 Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25 also correlated well with visual function. Associations between reduced low contrast acuity and worse vision targeted HRQOL remained significant in models accounting for high contrast VA, EDSS and history of acute optic neuritis. CONCLUSIONS: Low contrast letter acuity scores correlate well with HRQOL in MS. Two line differences in scores for low contrast acuity and VA reflect clinically meaningful differences in vision targeted HRQOL. Low contrast acuity testing provides information on patient reported aspects of vision, supporting use of these measures in MS clinical trials.

Zaveri MS, Conger A, Salter A, Frohman TC, Galetta SL, Markowitz CE, Jacobs DA, Cutter GR, Ying GS, Maguire MG, Calabresi PA, Balcer LJ, Frohman EM. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Arch Neurol. · Pubmed #18625859 links to  free full text

Abstract: BACKGROUND: Optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx) are similar yet provide information on different aspects of retinal nerve fiber layer (RNFL) structure (thickness values similar to histology for OCT vs birefringence of microtubules for GDx). OBJECTIVES: To compare the ability of OCT and GDx to distinguish eyes of patients with multiple sclerosis (MS) from eyes of disease-free controls and thus identify RNFL abnormalities. We also sought to examine the capacity of these techniques to distinguish MS eyes from those without a history of optic neuritis and to correlate with visual function. DESIGN: Cross-sectional study. SETTING: Academic tertiary care MS center. PARTICIPANTS: Eighty patients with MS (155 eyes) and 43 disease-free controls (85 eyes) underwent both OCT and GDx imaging using protocols that measure RNFL thickness. MAIN OUTCOME MEASURES: Areas under the curve (AUC), adjusted for within-patient, intereye correlations, were used to compare the abilities of OCT and GDx temporal-superior-nasal-inferior-temporal average RNFL thicknesses to discriminate between MS and control eyes and to distinguish MS eyes with a history of optic neuritis. Visual function was evaluated using low-contrast letter acuity and high-contrast visual acuity. RESULTS: Average peripapillary RNFL thickness (360 degrees around the optic disc) was reduced in patients with MS compared with controls for both methods. Age-adjusted AUC did not differ between OCT (0.80; 95% confidence interval [CI], 0.72-0.88) and GDx (0.78; 95% CI, 0.68-0.86; P = .38). Optical coherence tomography-measured RNFL thickness was somewhat better at distinguishing MS eyes with a history of optic neuritis from those without (OCT: AUC, 0.73; 95% CI, 0.64-0.82; GDx: AUC, 0.66; 95% CI, 0.57-0.66; P = .17). Linear correlations of RNFL thickness for OCT vs GDx were significant yet moderate (r = 0.67, P < .001); RNFL thickness measures correlated moderately and significantly with low-contrast acuity (OCT: r = 0.54, P < .001; GDx: r = 0.55, P < .001) and correlated less with high-contrast visual acuity (OCT: r = 0.44, P < .001; GDx: r = 0.32, P < .001). CONCLUSIONS: Scanning laser polarimetry with variable corneal compensation measurements of RNFL thickness corroborates OCT evidence of visual pathway axonal loss in MS and provides new insight into structural aspects of axonal loss that relate to RNFL birefringence (microtubule integrity). These results support validity for RNFL thickness as a marker for axonal degeneration and support use of these techniques in clinical trials that examine neuroprotective and other disease-modifying therapies.

Petkau J, Reingold SC, Held U, Cutter GR, Fleming TR, Hughes MD, Miller DH, McFarland HF, Wolinsky JS. · Department of Statistics, University of British Columbia, Vancouver, BC, Canada. · Mult Scler. · Pubmed #18535021 links to  free full text

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

Reich DS, Zackowski KM, Gordon-Lipkin EM, Smith SA, Chodkowski BA, Cutter GR, Calabresi PA. · Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA. · AJNR Am J Neuroradiol. · Pubmed #17974617 links to  free full text

Abstract: BACKGROUND AND PURPOSE: The association of MR imaging abnormalities with clinical disability in multiple sclerosis (MS) has been disappointing. This association might be improved by imaging specific functional systems in the central nervous system-for example, the motor system in a patient with weakness. Our aim was to assess the relationship between muscle strength in MS and corticospinal tract (CST) abnormalities detected with multimodality MR imaging of the brain. MATERIALS AND METHODS: In 47 individuals with MS, diffusion tensor imaging (DTI) at 3T was used to reconstruct the intracranial CSTs. Tract profiles depicted the variation in T2 relaxation time, magnetization transfer ratio (MTR), and DTI-derived indices (fractional anisotropy and diffusivity) as a function of normalized position along the tract. Brain parenchymal fraction was calculated as a normalized measure of brain volume. Stepwise linear regression modeling was used to determine the MR imaging indices most closely related to ankle dorsiflexion and hip flexion strength assessed with quantitative dynamometry. RESULTS: Individuals with MS were significantly weak: Average ankle strength fell 1.7 SDs below the age-, handedness-, and sex-corrected healthy mean. Brain parenchymal fraction was not associated with weakness. A parsimonious model that includes MTR in the brain stem and MS clinical subtype explained 30%-45% of the variance in ankle and hip strength. The model was successfully applied to scans and strength data from the same individuals at an earlier time point. CONCLUSION: MR imaging abnormalities specific to the motor tract are associated with clinical dysfunction related to that tract. The relevant abnormalities are found in the brain stem, distant from the periventricular inflammatory lesions that are common in MS. This suggests that neurodegeneration, rather than primary inflammation, at least partially explains the findings.

Wu GF, Schwartz ED, Lei T, Souza A, Mishra S, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Desiderio LM, Cutter GR, Calabresi PA, Udupa JK, Balcer LJ. · Departments of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Neurology. · Pubmed #17881718 No free full text.

Abstract: OBJECTIVE: To examine the relation between low-contrast letter acuity, an emerging visual outcome for multiple sclerosis (MS) clinical trials, and brain MRI abnormalities in an MS cohort. METHODS: T2 lesion volume and brain parenchymal fraction were determined for whole brain and within visual pathway regions of interest. Magnetization transfer ratio histograms were examined. Vision testing was performed binocularly using low-contrast letter acuity (2.5%, 1.25% contrast) and high-contrast visual acuity (VA). Linear regression, accounting for age and disease duration, was used to assess the relation between vision and MRI measures. RESULTS: Patients (n = 45) were aged 44 +/- 11 years, with disease duration of 5 years (range <1 to 21), Expanded Disability Status Scale score of 2.0 (0 to 6.0), and binocular Snellen acuity of 20/16 (20/12.5 to 20/25). The average T2 lesion volume was 18.5 mm(3). Patients with lower (worse) low-contrast letter acuity and high-contrast VA scores had greater T2 lesion volumes in whole brain (2.5% contrast: p = 0.004; 1.25%: p = 0.002; VA: p = 0.04), Area 17 white matter (2.5%: p < 0.001; 1.25%: p = 0.02; VA: p = 0.01), and optic radiations (2.5%: p = 0.001; 1.25%: p = 0.02; VA: p = 0.007). Within whole brain, a 3-mm(3) increase in lesion volume corresponded, on average, to a 1-line worsening of low-contrast acuity, whereas 1-line worsening of high-contrast acuity corresponded to a 5.5-mm(3) increase. CONCLUSIONS: Low-contrast letter acuity scores correlate well with brain MRI lesion burden in multiple sclerosis (MS), supporting validity for this vision test as a candidate for clinical trials. Disease in the postgeniculate white matter is a likely contributor to visual dysfunction in MS that may be independent of acute optic neuritis history.

Fisher JB, Jacobs DA, Markowitz CE, Galetta SL, Volpe NJ, Nano-Schiavi ML, Baier ML, Frohman EM, Winslow H, Frohman TC, Calabresi PA, Maguire MG, Cutter GR, Balcer LJ. · Division of Neuro-ophthalmology, Departments of Neurology, Ophthalmology, and Biostatistics, University of Pennsylvania School of Medicine, Scheie Eye Institute, Philadelphia, Pennsylvania, USA. · Ophthalmology. · Pubmed #16406539 No free full text.

Abstract: PURPOSE: To examine the relation of visual function to retinal nerve fiber layer (RNFL) thickness as a structural biomarker for axonal loss in multiple sclerosis (MS), and to compare RNFL thickness among MS eyes with a history of acute optic neuritis (MS ON eyes), MS eyes without an optic neuritis history (MS non-ON eyes), and disease-free control eyes. DESIGN: Cross-sectional study. PARTICIPANTS: Patients with MS (n = 90; 180 eyes) and disease-free controls (n = 36; 72 eyes). METHODS: Retinal never fiber layer thickness was measured using optical coherence tomography (OCT; fast RNFL thickness software protocol). Vision testing was performed for each eye and binocularly before OCT scanning using measures previously shown to capture dysfunction in MS patients: (1) low-contrast letter acuity (Sloan charts, 2.5% and 1.25% contrast levels at 2 m) and (2) contrast sensitivity (Pelli-Robson chart at 1 m). Visual acuity (retroilluminated Early Treatment Diabetic Retinopathy charts at 3.2 m) was also measured, and protocol refractions were performed. MAIN OUTCOME MEASURES: Retinal nerve fiber layer thickness measured by OCT, and visual function test results. RESULTS: Although median Snellen acuity equivalents were better than 20/20 in both groups, RNFL thickness was reduced significantly among eyes of MS patients (92 mum) versus controls (105 mum) (P<0.001) and particularly was reduced in MS ON eyes (85 mum; P<0.001; accounting for age and adjusting for within-patient intereye correlations). Lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every 1-line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 mum. CONCLUSIONS: Scores for low-contrast letter acuity and contrast sensitivity correlate well with RNFL thickness as a structural biomarker, supporting validity for these visual function tests as secondary clinical outcome measures for MS trials. These results also suggest a role for ocular imaging techniques such as OCT in trials that examine neuroprotective and other disease-modifying therapies. Although eyes with a history of acute optic neuritis demonstrate the greatest reductions in RNFL thickness, MS non-ON eyes have less RNFL thickness than controls, suggesting the occurrence of chronic axonal loss separate from acute attacks in MS patients.

Tullman MJ, Oshinsky RJ, Lublin FD, Cutter GR. · Department of Neurology, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, The Mount Sinai Hospital, New York, NY 10029, USA. · Mult Scler. · Pubmed #15327045 No free full text.

Abstract: OBJECTIVE: Patients with progressive relapsing (PR) multiple sclerosis (MS) may accrue disability by incomplete recovery from acute exacerbations and by ongoing deterioration. In primary progressive (PP) MS, disability accumulates solely by continuous decline. Because it is the least common form of MS, there is scant information regarding the clinical characteristics of PRMS, but relapses are reportedly uncommon. The purpose of this study is to describe the clinical features of a cohort of patients with PRMS. METHODS: A retrospective chart review of 16 patients diagnosed with PRMS at two academic MS centres over a four-year period. RESULTS: Nine men and seven women had PRMS. The mean age at onset was 35.1+/-11.2 years. The most common presenting symptom was a progressive myelopathy. The mean disease duration was 10.1+/-8.5 years and the average time to first exacerbation was 4.1+/-3.7years. Patients had an average of 2.8+/-2.3 relapses with an annualized relapse rate of 0.6+/-0.8. Time to Expanded Disability Status Scale (EDSS) 6.0 was strongly associated with time to first exacerbation. Although there was no correlation between the number of relapses and time to EDSS 6.0, there was a modest inverse relation between time to EDSS 6.0 and annualized relapse rate. CONCLUSIONS: Relapses in PRMS may occur more often than previously described and disability may accumulate more rapidly in PRMS than in PPMS. We suggest differentiating between these two forms of MS.

Hoogervorst EL, Kalkers NF, Cutter GR, Uitdehaag BM, Polman CH. · Department of Neurology, VU Medical Center, Amsterdam, The Netherlands. · Mult Scler. · Pubmed #14760953 No free full text.

Abstract: OBJECTIVE: To prospectively characterize the relation between two-year changes in functional impairment as measured by the Multiple Sclerosis Functional Composite (MSFC) and changes in patient perceived disability as measured by the Guy's Neurological Disability Scale (GNDS). METHODS: One hundred and eighty-eight patients with multiple sclerosis (MS) were recruited at our outpatient clinic. Impairment and disability were assessed using the MSFC and GNDS at baseline and follow-up. Longitudinal correlations were studied between changes in MSFC and GNDS and their corresponding components. We also studied changes in GNDS in relation to what can be classified as a reliable change in MSFC; for example, 20% change in each MSFC component or a change of 0.5 in total MSFC score. In addition, we studied the change in total number of GNDS subcategories with a score of 3 or higher in relation to the predefined MSFC changes, these subcategories being indicative of the requirement for help by another person. RESULTS: Despite good cross-sectional correlations between MSFC and GNDS, no significant correlation was found between longitudinal changes in MSFC and GNDS. Analysing the change in GNDS in relation to the predefined MSFC changes shows that GNDS changes are nicely rank ordered when more stringent definitions of reliable change were applied. In addition, analysing the number of GNDS subcategories scored 3 or higher indicate that there is a profile of worsening on the MSFC being associated with increase in the amount of help required from others. CONCLUSION: Our longitudinal data suggest that a reliable change is associated with a likewise change in patient perceived disability, the smallest reliable change being identified by at least 20% change in each MSFC component.

Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, Pfohl DC, Mills M, Bowen J, Ford C, Heidenreich FR, Jacobs DA, Markowitz CE, Stuart WH, Ying GS, Galetta SL, Maguire MG, Cutter GR. · Division of Neuro-Ophthalmology, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. · Neurology. · Pubmed #14638957 No free full text.

Abstract: BACKGROUND: Visual dysfunction is one of the most common causes of disability in multiple sclerosis (MS). The Multiple Sclerosis Functional Composite (MSFC), a new clinical trial outcome measure, does not currently include a test of visual function. OBJECTIVE: To examine contrast letter acuity as a candidate visual function test for the MSFC. METHODS: Binocular contrast letter acuity testing (Sloan charts) was performed in a subgroup of participants from the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial (IMPACT Substudy) and in MS patients and disease-free control subjects from a cross-sectional study of visual outcome measures (Multiple Sclerosis Vision Prospective cohort [MVP cohort]). High-contrast visual acuity was measured in both studies; MVP cohort participants underwent additional binocular testing for contrast sensitivity (Pelli-Robson chart), color vision (D-15 desaturated test), and visual field (Esterman test, Humphrey Field Analyzer II). RESULTS: Contrast letter acuity (Sloan charts, p < 0.0001, receiver operating characteristic curve analysis) and contrast sensitivity (Pelli-Robson chart, p = 0.003) best distinguished MS patients from disease-free control subjects in the MVP cohort. Correlations of Sloan chart scores with MSFC and Expanded Disability Statue Scale (EDSS) scores in both studies were significant and moderate in magnitude, demonstrating that Sloan chart scores reflect visual and neurologic dysfunction not entirely captured by the EDSS or MSFC. CONCLUSIONS: Among clinical measures, contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli-Robson chart) demonstrate the greatest capacity to identify binocular visual dysfunction in MS. Sloan chart testing also captures unique aspects of neurologic dysfunction not captured by current EDSS or MSFC components, making it a strong candidate visual function test for the MSFC.

Sorman MP, Bruzzi P, Rovaris M, Barkhof F, Comi G, Miller DH, Cutter GR, Filipp M. · Unit of Clinical Epidemiology and Trials, National Institute for Cancer Research, Genoa, Italy. · Mult Scler. · Pubmed #11724445 No free full text.

Abstract: Magnetic resonance imaging (MRI) has been established as the most relevant paraclinical tool for diagnosing and monitoring multiple sclerosis (MS). In this context, counting the number of new enhancing lesions on monthly MRI scans is widely used as a surrogate marker of MS activity when evaluating the effect of treatments. In this study, we investigated whether parametric models based on mixed Poisson distributions (the Negative Binomial (NB) and the Poisson-Inverse Gaussian (P-IG) distributions) were able to provide adequate fitting of new enhancing lesion counts in MS. We found that the NB model gave good approximations in relapsing-remitting and secondary progressive MS patients not selected for baseline MRI activity, whereas the P-IG distribution modelled better new enhancing lesion counts in relapsing-remitting MS patients selected for baseline activity. This study shows that parametric modelling for MS new enhancing lesion counts is feasible. This approach should provide more targeted tools for the design and the analysis of MRI monitored clinical trials in MS.

Balcer LJ, Baier ML, Kunkle AM, Rudick RA, Weinstock-Guttman B, Simonian N, Galetta SL, Cutter GR, Maguire MG. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, USA. · Mult Scler. · Pubmed #11212133 No free full text.

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

Cohen JA, Fischer JS, Bolibrush DM, Jak AJ, Kniker JE, Mertz LA, Skaramagas TT, Cutter GR. · Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology, Cleveland Clinic Foundation, OH 44195, USA. · Neurology. · Pubmed #10690966 No free full text.

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