Enlarged perivascular spaces are not associated with vascular co-morbidities, clinical outcomes, and brain volumes in people with secondary progressive multiple sclerosis

Background In secondary progressive multiple sclerosis (SPMS) significance of enlarged perivascular spaces (ePVS) is unknown. Objectives, Methods: Analysis of associations between vascular co-morbidities, clinical outcomes, and volumetrics with categorical ePVS scores in midbrain, basal ganglia (BG), and centrum semiovale (CSO) in SPMS(n-46). Results, Conclusion: In BG, advancing age (Z = 2.68) and lower Expanded Disability Status Scale (Z = −2.04) were associated with increasing ePVS score. In CSO, advancing age (Z = 2.66) and male gender (Z = 2.45) were associated with increasing ePVS score. No associations between ePVS score and vascular co-morbidities or volumetrics existed; ePVS may not be an informative marker for SPMS.

Download Full-text

TP1-11 MS-STAT2: a phase 3 trial of high dose simvastatin in secondary progressive multiple sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-abn.40 ◽

2019 ◽

Vol 90 (3) ◽

pp. e13.1-e13 ◽

Cited By ~ 1

Author(s):

E Williams ◽

NA John ◽

J Blackstone ◽

W Brownlee ◽

C Frost ◽

...

Keyword(s):

Multiple Sclerosis ◽

Unmet Need ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

High Dose ◽

List Type ◽

Expanded Disability Status Scale ◽

Phase 3 ◽

Secondary Progressive ◽

Disability Status

ObjectivesDisease modifying treatment for secondary progressive multiple sclerosis (SPMS) represents a major unmet need. We outline here the rationale for the MS-STAT2 trial – a phase 3 study of simvastatin in decreasing clinical progression in SPMS. MS-STAT2 will be a landmark study not only for patients with SPMS, but also for the area of drug repurposing and academically led clinical trials as a whole.DesignMulticentre, double blind, parallel group randomised placebo-controlled trial. It follows the positive outcome from the phase 2 MS-STAT1 trial, which demonstrated a 43% reduction in the annualised rate of brain atrophy compared to placebo.1Subjects1180 patients with SPMS with an expanded disability status scale (EDSS) score of 4.0–6.5. Patients need to show evidence of disease progression over the preceding 2 years.MethodsSubject will be recruited at 28 sites across the UK, and randomised to simvastatin 80 mg or matched placebo and assessed every 6 months over the 3 year trial.ResultsThe primary outcome measure is time to 6 month confirmed disability progression, based on change in Expanded Disability Status Scale (EDSS) scores compared to baseline. Secondary outcomes include assessments of cognition, walking, upper limb function and vision. Sub-studies will include advanced imaging outcomes, ocular coherence tomography and fluid biomarkers.ConclusionsMS-STAT2 is set to be a pivotal trial for SPMS. Recruitment has now commenced and further sites are welcome.ReferenceChataway J, et al. MS-STAT. Lancet2014;383:2213–21.

Download Full-text

Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis

Brain ◽

10.1093/brain/awz156 ◽

2019 ◽

Vol 142 (8) ◽

pp. 2276-2287 ◽

Cited By ~ 29

Author(s):

Wallace J Brownlee ◽

Dan R Altmann ◽

Ferran Prados ◽

Katherine A Miszkiel ◽

Arman Eshaghi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Expanded Disability Status Scale ◽

Spinal Cord Lesions ◽

Secondary Progressive ◽

Disability Status ◽

Serial Addition

Abstract The clinical course of relapse-onset multiple sclerosis is highly variable. Demographic factors, clinical features and global brain T2 lesion load have limited value in counselling individual patients. We investigated early MRI predictors of key long-term outcomes including secondary progressive multiple sclerosis, physical disability and cognitive performance, 15 years after a clinically isolated syndrome. A cohort of patients with clinically isolated syndrome (n = 178) was prospectively recruited within 3 months of clinical disease onset and studied with MRI scans of the brain and spinal cord at study entry (baseline) and after 1 and 3 years. MRI measures at each time point included: supratentorial, infratentorial, spinal cord and gadolinium-enhancing lesion number, brain and spinal cord volumetric measures. The patients were followed-up clinically after ∼15 years to determine disease course, and disability was assessed using the Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test. Multivariable logistic regression and multivariable linear regression models identified independent MRI predictors of secondary progressive multiple sclerosis and Expanded Disability Status Scale, Paced Auditory Serial Addition Test and Symbol Digit Modalities Test, respectively. After 15 years, 166 (93%) patients were assessed clinically: 119 (72%) had multiple sclerosis [94 (57%) relapsing-remitting, 25 (15%) secondary progressive], 45 (27%) remained clinically isolated syndrome and two (1%) developed other disorders. Physical disability was overall low in the multiple sclerosis patients (median Expanded Disability Status Scale 2, range 0–10); 71% were untreated. Baseline gadolinium-enhancing (odds ratio 3.16, P < 0.01) and spinal cord lesions (odds ratio 4.71, P < 0.01) were independently associated with secondary progressive multiple sclerosis at 15 years. When considering 1- and 3-year MRI variables, baseline gadolinium-enhancing lesions remained significant and new spinal cord lesions over time were associated with secondary progressive multiple sclerosis. Baseline gadolinium-enhancing (β = 1.32, P < 0.01) and spinal cord lesions (β = 1.53, P < 0.01) showed a consistent association with Expanded Disability Status Scale at 15 years. Baseline gadolinium-enhancing lesions was also associated with performance on the Paced Auditory Serial Addition Test (β = − 0.79, P < 0.01) and Symbol Digit Modalities Test (β = −0.70, P = 0.02) at 15 years. Our findings suggest that early focal inflammatory disease activity and spinal cord lesions are predictors of very long-term disease outcomes in relapse-onset multiple sclerosis. Established MRI measures, available in routine clinical practice, may be useful in counselling patients with early multiple sclerosis about long-term prognosis, and personalizing treatment plans.

Download Full-text

Reliability of Outcome Measures in Clinical Trials in Secondary Progressive Multiple Sclerosis

Neurology ◽

10.1212/wnl.0000000000011123 ◽

2020 ◽

Vol 96 (1) ◽

pp. e111-e120 ◽

Cited By ~ 1

Author(s):

Marcus W. Koch ◽

Jop Mostert ◽

Pavle Repovic ◽

James D. Bowen ◽

Bernard Uitdehaag ◽

...

Keyword(s):

Multiple Sclerosis ◽

Outcome Measures ◽

Controlled Trial ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Disability Progression ◽

Secondary Progressive ◽

Randomized Controlled ◽

Disability Status ◽

Over Time

ObjectiveTo investigate the reliability of clinical outcomes in secondary progressive multiple sclerosis (SPMS) trials, we compared the frequency of progression and improvement events on different clinical outcome measures in the placebo arms of 2 large randomized controlled trial (RCT) datasets.MethodsUsing original trial data from the placebo arms of IMPACT (International MS Secondary Progressive Avonex Controlled Trial) and ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis), 2 large RCTs in SPMS, we compared disability progression and similarly defined improvement with and without 3- or 6-month confirmation on the outcome measures Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and their combinations.ResultsIn both datasets, the EDSS showed the highest rates of improvement over time, and the smallest difference between progression and improvement rates, followed by the T25FW and the 9HPT. For the T25FW and 9HPT, improvement rates were fairly stable over time and remained at below or around the 10% level. For the EDSS, improvement rates increased in parallel with disability progression rates.ConclusionsAll investigated outcome measures in SPMS showed some evidence of random variation and measurement error, the T25FW and 9HPT less so than the more established outcome EDSS. Our findings are relevant for the design and critical appraisal of trials in SPMS.

Download Full-text

The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458516638941 ◽

2016 ◽

Vol 23 (1) ◽

pp. 94-105 ◽

Cited By ~ 31

Author(s):

Diego Cadavid ◽

Jeffrey A Cohen ◽

Mark S Freedman ◽

Myla D Goldman ◽

Hans-Peter Hartung ◽

...

Keyword(s):

Multiple Sclerosis ◽

Composite Endpoint ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Dominant Hand ◽

Expanded Disability Status Scale ◽

Disability Progression ◽

Minimum Threshold ◽

Secondary Progressive ◽

Disability Status

Background: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. Objective: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. Methods: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm ( n = 215) data, we analyzed disability progression using a novel progression endpoint, “EDSS-Plus,” defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. Results: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors’ times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. Conclusion: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.

Download Full-text

Decreasing impact of late relapses on disability worsening in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458519848090 ◽

2019 ◽

Vol 26 (8) ◽

pp. 924-935

Author(s):

Kevin Ahrweiller ◽

Chloé Rousseau ◽

Emmanuelle Le Page ◽

Emma Bajeux ◽

Emmanuelle Leray ◽

...

Keyword(s):

Multiple Sclerosis ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Short Term ◽

Secondary Progressive ◽

Increased Risk ◽

Disability Status ◽

Long Term Follow Up

Background: Changes in relapse activity during secondary progressive multiple sclerosis (SPMS) need to be accurately characterized in order to identify patients who might benefit from continuing disease-modifying therapies. Objective: To describe relapse occurrence in patients with SPMS during long-term follow-up and assess its impact on disability worsening. Methods: This retrospective cohort study included 506 patients. We assessed the influence of relapses on time from SPMS onset to an Expanded Disability Status Scale score of 6 (EDSS 6), and on irreversible worsening of EDSS scores across different periods. Results: The annualized relapse rate (ARR) decreased with patient’s age (mean reduction of 43% per decade) and SPMS duration (mean reduction of 46% every 5 years). Post-progression relapses were associated with shorter time from secondary progressive (SP) phase onset to EDSS 6 (hazard ratio (HR) = 1.29, 95% confidence interval (CI) = (1.01, 1.64)). Relapse occurrence during the first 3 years and 3–5 years after SP onset was associated with an increased risk of irreversible EDSS worsening (OR = 3.12 (1.54, 6.31) and 2.04 (1.16, 3.58)). This association was no longer significant after 5 years. Conclusion: The occurrence of relapses was a marker of short-term disability progression during early SPMS, but did not have decisive impact in later SPMS.

Download Full-text