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1.
Eur J Neurol ; 26(8): 1068-1074, 2019 08.
Article in English | MEDLINE | ID: mdl-30761708

ABSTRACT

BACKGROUND AND PURPOSE: Diffuse white matter (WM) injury is prominent in primary-progressive multiple sclerosis (PP-MS) pathology and is a potential biomarker of disease progression. Diffusion kurtosis imaging allows the quantification of non-Gaussian water diffusion, providing metrics with high WM pathological specificity. The aim of this study was to characterize the pathological changes occurring in the normal-appearing WM of patients with PP-MS at baseline and at 1-year follow-up and to assess their impact on disability and short-term disease progression. METHODS: A total of 26 patients with PP-MS and 20 healthy controls were prospectively enrolled. Diffusion kurtosis imaging single-shot echo-planar imaging (EPI) was acquired on a 3-T scanner (Philips Achieva, Best, The Netherlands) (voxel size, 2 × 2 × 2 mm3 , 30 directions for each b-value = 1000, 2000 s/mm2 and one b = 0 s/mm2 ). A two-compartment biophysical model of WM tract integrity was used to derive spatial maps of axonal water fraction (AWF), intra-axonal diffusivity, extra-axonal axial and radial diffusivities (De,axial , De,radial ) and tortuosity from the following WM tracts: corpus callosum (CC), corticospinal tract (CST) and posterior thalamic radiation (PTR). RESULTS: At baseline, patients with PP-MS showed a widespread decrease of AWF, tortuosity and De,axial and an increase of De,radial in CC, CST and PTR (P ranging from 0.001 to 0.036). At 1-year follow-up, a significant AWF decrease was detected in the body of CC (P = 0.048), PTR (P = 0.008) and CST (P = 0.044). Baseline AWF values in CST significantly discriminated progressed from non-progressed patients (P = 0.021; area under the curve, 0.854). CONCLUSION: Based on its change over time and its relationship with disease progression, among the analyzed metrics, AWF seems the most sensitive metric of WM tissue damage in PP-MS and therefore it could be considered as a marker for monitoring disease progression.


Subject(s)
Axons/pathology , Brain/diagnostic imaging , Multiple Sclerosis, Chronic Progressive/diagnostic imaging , White Matter/diagnostic imaging , Adult , Biomarkers , Brain/pathology , Diffusion Magnetic Resonance Imaging , Diffusion Tensor Imaging/methods , Disease Progression , Female , Humans , Longitudinal Studies , Male , Middle Aged , Multiple Sclerosis, Chronic Progressive/pathology , Netherlands , Water , White Matter/pathology
2.
Mult Scler Relat Disord ; 3(1): 67-71, 2014 Jan.
Article in English | MEDLINE | ID: mdl-25877975

ABSTRACT

OBJECTIVES: Determine the likelihood of worsening clinical status in the near-term course of progressive MS and evaluate the predictive validity of our diagnostic impression of progressive forms of MS. METHODS: Retrospective review of charts from 175 patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis. Data extracted included demographic factors, neurological examination findings to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation. Significant change in T25FW was defined as a ±20% difference from baseline. RESULTS: Of the 175 charts reviewed, 35 patients met criteria and had sufficient documentation to allow for EDSS abstraction. Twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened and none improved. For those patients that had T25FW data available, 6 out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved. CONCLUSION: In this observational study at a tertiary care MS center, patients classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested. Greater than two-thirds of patients in this cohort, did not increase 1 step on the EDSS.

3.
Mult Scler Relat Disord ; 1(2): 81-6, 2012 Apr.
Article in English | MEDLINE | ID: mdl-25876935

ABSTRACT

BACKGROUND: Interferon-ß1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions. CONCLUSION: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.

4.
Neurology ; 76(22): 1858-65, 2011 May 31.
Article in English | MEDLINE | ID: mdl-21543733

ABSTRACT

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


Subject(s)
Antibodies, Monoclonal/adverse effects , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/pathology , Adult , Antibodies, Monoclonal, Humanized , Clinical Trials as Topic , Female , Humans , Male , Natalizumab , Recurrence
5.
Mult Scler ; 16(11): 1385-92, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20739335

ABSTRACT

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


Subject(s)
Antibodies, Monoclonal/therapeutic use , Cognition Disorders/diagnosis , Immunologic Factors/therapeutic use , Multiple Sclerosis/complications , Neuropsychological Tests , Adult , Antibodies, Monoclonal, Humanized , Cognition Disorders/etiology , Female , Humans , Male , Multiple Sclerosis/drug therapy , Natalizumab , Surveys and Questionnaires
7.
Mult Scler ; 15(8): 984-97, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19667023

ABSTRACT

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


Subject(s)
Disability Evaluation , Health Status Indicators , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Adult , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Cognition , Disease Progression , Drug Therapy, Combination , Female , Humans , Immunologic Factors/therapeutic use , Interferon beta-1a , Interferon-beta/therapeutic use , Kaplan-Meier Estimate , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Multiple Sclerosis, Relapsing-Remitting/psychology , Natalizumab , Predictive Value of Tests , Proportional Hazards Models , Randomized Controlled Trials as Topic , Recurrence , Sensitivity and Specificity , Time Factors , Treatment Outcome , Upper Extremity/physiopathology , Walking
8.
Neurology ; 72(23): 1989-93, 2009 Jun 09.
Article in English | MEDLINE | ID: mdl-19506220

ABSTRACT

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


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hyperlipidemias/drug therapy , Interferon-beta/antagonists & inhibitors , Multiple Sclerosis/drug therapy , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/antagonists & inhibitors , Adult , Cell Line, Tumor , Central Nervous System/drug effects , Central Nervous System/immunology , Central Nervous System/pathology , Disease Progression , Drug Interactions/physiology , Drug-Related Side Effects and Adverse Reactions/physiopathology , Female , Humans , Injections, Intramuscular/adverse effects , Injections, Intramuscular/statistics & numerical data , Interferon beta-1a , Interferon-beta/administration & dosage , Jurkat Cells , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/physiopathology , Prospective Studies , Secondary Prevention , Treatment Outcome
9.
Mult Scler ; 15(5): 542-6, 2009 May.
Article in English | MEDLINE | ID: mdl-19389749

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.


Subject(s)
Multiple Sclerosis/drug therapy , Multiple Sclerosis/pathology , Neuroprotective Agents/therapeutic use , Humans , Randomized Controlled Trials as Topic
10.
Mult Scler ; 14(9): 1157-74, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18805839

ABSTRACT

BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.


Subject(s)
Multiple Sclerosis/diagnosis , Practice Guidelines as Topic , Algorithms , Diagnosis, Differential , Humans
11.
Neurology ; 71(4): 265-71, 2008 Jul 22.
Article in English | MEDLINE | ID: mdl-18645164

ABSTRACT

OBJECTIVE: Several studies have reported a reduction of relapses after the long-term administration of IV immunoglobulin (IVIG) to patients with relapsing-remitting multiple sclerosis (RRMS), but they were mostly small and differed in terms of predefined outcome variables and treatment regimen. We therefore set out to test two different doses of a new formulation of immunoglobulin termed IGIV-C 10% for suppression of both clinical and MRI disease activity as well as safety. METHODS: One hundred twenty-seven patients with RRMS participated in this multicenter, randomized, double-blind, placebo-controlled trial. Forty-four and 42 patients received treatment with 0.2 and 0.4 g/kg of IGIV-C 10%, and 41 patients received an equal volume of placebo (0.1% albumin) every 4 weeks for 48 weeks. The primary endpoint was the proportion of relapse-free patients. The main secondary endpoint was lesion activity assessed by 6-weekly MRI. RESULTS: Baseline variables were similar in IVIG- and placebo-treated groups. After 1 year, the proportion of relapse-free patients did not differ statistically according to treatment (IVIG 0.2 g/kg: 57%; IVIG 0.4 g/kg: 60%; placebo: 68%), and there was no difference regarding the cumulative number of unique newly active MRI lesions (median numbers: IVIG 0.2 g/kg: 8.0; IVIG 0.4 g/kg: 5.0; placebo: 7.2) after 48 weeks. There were no significant between-group differences in the rates of adverse events. CONCLUSION: Although IV immunoglobulin (IVIG) treatment was well tolerated, this study did not substantiate a beneficial effect of IVIG in doses ranging from 0.2 to 0.4 g/kg. This result seriously questions the utility of IVIG for the treatment of relapsing-remitting multiple sclerosis.


Subject(s)
Immunoglobulins, Intravenous/administration & dosage , Immunotherapy/methods , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/immunology , Adolescent , Adult , Central Nervous System/drug effects , Central Nervous System/immunology , Central Nervous System/pathology , Disability Evaluation , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Humans , Immunoglobulins, Intravenous/adverse effects , Infusions, Intravenous/adverse effects , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Placebos , Secondary Prevention , Treatment Outcome
12.
Neurology ; 70(13 Pt 2): 1134-40, 2008 Mar 25.
Article in English | MEDLINE | ID: mdl-18362273

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.


Subject(s)
Clinical Trials as Topic/ethics , Informed Consent/ethics , Mental Competency/standards , Multiple Sclerosis/drug therapy , Placebos/standards , Drug Resistance , Health Services Accessibility/ethics , Health Services Accessibility/standards , Humans , Informed Consent/standards , Placebo Effect , Risk Assessment/ethics , Treatment Outcome
13.
Neurology ; 69(14): 1391-403, 2007 Oct 02.
Article in English | MEDLINE | ID: mdl-17761550

ABSTRACT

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

Subject(s)
Antibodies, Blocking/blood , Antibodies, Blocking/immunology , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/immunology , Antibodies, Blocking/analysis , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Antibody Specificity/immunology , Brain/drug effects , Brain/immunology , Brain/pathology , Disability Evaluation , Double-Blind Method , Enzyme-Linked Immunosorbent Assay/methods , Flow Cytometry/methods , Humans , Interferon beta-1a , Interferon-beta/administration & dosage , Magnetic Resonance Imaging , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Natalizumab , Placebo Effect , Secondary Prevention , Treatment Outcome
14.
Neurology ; 68(17): 1390-401, 2007 Apr 24.
Article in English | MEDLINE | ID: mdl-17452584

ABSTRACT

BACKGROUND: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study. METHODS: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. RESULTS: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients. CONCLUSION: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Brain/pathology , Magnetic Resonance Imaging , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Adolescent , Adult , Antibodies, Monoclonal, Humanized , Contrast Media , Double-Blind Method , Female , Follow-Up Studies , Gadolinium , Humans , Image Processing, Computer-Assisted , Male , Middle Aged , Multiple Sclerosis, Relapsing-Remitting/pathology , Natalizumab , Organ Size , Treatment Outcome
15.
Neurology ; 68(16): 1299-304, 2007 Apr 17.
Article in English | MEDLINE | ID: mdl-17438220

ABSTRACT

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


Subject(s)
Antibodies, Monoclonal/administration & dosage , Multiple Sclerosis, Relapsing-Remitting/complications , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Vision, Low/drug therapy , Vision, Low/etiology , Adolescent , Adult , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Brain/drug effects , Brain/immunology , Brain/physiopathology , Contrast Sensitivity/drug effects , Contrast Sensitivity/physiology , Double-Blind Method , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Kaplan-Meier Estimate , Male , Middle Aged , Natalizumab , Neurologic Examination/methods , Placebos , Predictive Value of Tests , Treatment Outcome , Vision Tests/methods , Visual Acuity/drug effects , Visual Pathways/drug effects , Visual Pathways/immunology , Visual Pathways/physiopathology
17.
Mult Scler ; 10(4): 451-4, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15327045

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.


Subject(s)
Multiple Sclerosis, Chronic Progressive/physiopathology , Adult , Cohort Studies , Disability Evaluation , Disease Progression , Female , Humans , Male , Medical Records , Middle Aged , Multiple Sclerosis, Chronic Progressive/complications , Retrospective Studies , Spinal Cord Diseases/etiology , Spinal Cord Diseases/physiopathology
20.
Ann Neurol ; 50(1): 121-7, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11456302

ABSTRACT

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."


Subject(s)
Multiple Sclerosis/diagnosis , Humans , Magnetic Resonance Imaging
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