Author Of 9 Presentations
BD01.01 - Presentation 01 (ID 172)
P0238 - Sustained reduction of disability and cognitive decline with long-term siponimod treatment in patients with active SPMS: EXPAND data up to 5 years (ID 1471)
Abstract
Background
In the EXPAND Core part, in the subgroup of patients with active secondary progressive multiple sclerosis (aSPMS: presence of relapses in the 2 years prior to screening and/or ≥1 T1 gadolinium-enhancing (Gd+) lesion at baseline), siponimod reduced the risk of 3-/6-month confirmed disability progression on Expanded Disability Status Scale (3m/6mCDP) by 31% and 37%, respectively, and the risk of decline in cognitive processing speed (CPS, 6-month confirmed cognition worsening of ≥4-point on Symbol Digit Modalities Test [6mCCW]) by 27% versus placebo.
Objectives
To assess the long-term efficacy and safety of siponimod in patients with aSPMS in the Core and Extension parts of the EXPAND study.
Methods
In patients with aSPMS who had received ≥1 dose of randomized treatment during Core part, and who entered the Extension (36 month extension data cut-off [6 April 2019]; total study duration ≤5 years), time to 3m/6mCDP, 6mCCW, and annualized relapse rate (ARR) were assessed for the Continuous (siponimod in the Core and Extension) and Switch (placebo in the Core and switched to open-label siponimod in the Core/Extension) groups.
Results
Of the 1651 patients randomized in the EXPAND Core part, 779 were with aSPMS (Continuous group: N=516; Switch group: N=263), of which 582 entered the Extension. The risk of 6mCDP was reduced by 29% (0.71 [0.57‒0.90]; p=0.0044) for the Continuous versus Switch group, corresponding to an about 70% delay in time to 6mCDP across the 25th–40th percentile). Median time to 6mCDP was 48 months for the Switch group and was not reached for the Continuous group. The risk of 6mCCW for the Continuous versus Switch group was reduced by 33% (0.67 [0.53‒0.86]); p=0.0018), corresponding to an about 70% delay in time to 6mCCW across the 25th–30th percentile, median time to 6mCCW (55.5 months) was reached only for the Switch group. In patients without active disease, a nonsignificant trend for reduced risk of disability progression and cognitive worsening was observed for the Continuous vs Switch groups. A significant reduction in ARR for the Continuous versus Switch groups was observed in patients with (0.08 vs 0.12; p=0.0023) or without active disease (0.03 vs 0.08; p<0.0001).
Conclusions
In EXPAND, long-term data analyses in the Continuous versus Switch groups showed that siponimod treatment effects on disability, cognitive processing speed, and relapse outcomes in patients with active SPMS are sustained for up to 5 years, and highlight the value of early treatment initiation.
P0566 - Diffusion tensor imaging of the nucleus basalis of Meynert reveals associations with cognitive state in patients with multiple sclerosis (ID 1427)
Abstract
Background
Previous studies have shown that the nucleus basalis of Meynert (NBM), a group of neurons in the basal forebrain representing the major source of cholinergic innervations for the cerebral and subcortical cortex, is particularly vulnerable to neurodegeneration in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Microstructural NBM damage, as reflected by increased diffusion tensor imaging (DTI)-derived measures of diffusivity, has been shown to be related to cognitive impairment in these diseases. As of now, the NBM has been scarcely investigated in multiple sclerosis (MS).
Objectives
To determine associations between microstructural properties of the NBM and cognitive outcomes in patients with MS (PwMS).
Methods
84 PwMS (54 relapsing-remitting MS, 30 secondary progressive MS) underwent 3T MRI with a protocol that included a diffusion-weighted imaging acquisition. All PwMS underwent cognitive assessment with the Brief International Cognitive Assessment for MS (BICAMS), which includes the Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R) and California Verbal Learning Test-2nd edition (CVLT-2). Standard DTI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were calculated. A probabilistic map of the NBM was utilized to calculate DTI-derived measures. Partial correlations were used to assess the relationship between BICAMS cognitive outcomes and DTI assessments of the NBM, controlling for age and education.
Results
Neuropsychological outcomes correlated with altered diffusivity within the NBM in PwMS. SDMT scores were associated with NBM measures of MD (r=-0.38, p<0.001), AD (r=-0.26, p=0.017), and RD (r=-0.40, p<0.001). BVMT-R was associated with MD (r=-0.33, p=0.002) and RD (r=-0.37, p=0.001), while CVLT-2 was associated with MD (r=-0.27, p=0.015), AD (r=-0.22, p=0.050) and RD (r=-0.27, p=0.016). After accounting for normalized NBM volume, NBM RD explained additional variance for SDMT (R2=0.24, p<0.001) and BVMT-R (R2=0.18, p=0.001), while NBM MD was retained for CVLT-2 (R2=0.17, p=0.015).
Conclusions
Our results show an association between cognitive impairment and microstructural NBM damage in PwMS, highlighting the potential role of NBM damage in determining the cognitive state in PwMS.
P0617 - Predicting Disease Progression in Multiple Sclerosis from Clinical Routine T2-FLAIR MRI (ID 1670)
Abstract
Background
Although quantitative measures from research-quality MRI relate well to clinical outcomes in persons with multiple sclerosis (PwMS), these metrics are largely unavailable in clinical settings.
Objectives
To determine how well a quantitative snapshot of brain pathology, measured on routine clinical T2-FLAIR MRI, relates to standard research-quality MRI, clinical disability, and clinical progression over mid-term.
Methods
This retrospective study of prospectively collected data was approved by the local Institutional Review Board. 3T MRI was acquired for 172 PwMS at baseline and neurologic disability was assessed at baseline and five-years later. Five measures (thalamus volume, lateral ventricle volume, medulla oblongata volume, lesion volume, and network efficiency) for quantifying disparate aspects of brain pathology from low-resolution T2-FLAIR were applied to predict similar measures obtained from research-quality MRI and associated with neurologic disability and disease progression over five years.
Results
The combination of the five T2-FLAIR measures explained most of the variance in standard research-quality MRI, including T2-lesion volume (R2=0.97, p<0.001) and thalamus volume (R2=0.90, p<0.001). T2-FLAIR measures (R2=0.279, p<0.001; R2=0.382, p<0.001) were associated with neurologic disability and cognitive function five-years later, similar to standard research-quality MRI (R2=0.279, p<0.001; R2=0.366, p<0.001). They also similarly predicted disability progression over five years (%-correctly-classified=69.8, R2=0.145, p=0.034), compared to standard research-quality MRI (%-correctly-classified=72.4%, R2=0.196, p=0.022) in relapsing-remitting MS.
Conclusions
T2-FLAIR measures explained considerable variance of standard research-quality MRI, correlated with neurologic disability, and predicted progression of disability over five years. Quantifying brain pathology at a single time-point with clinical-quality T2-FLAIR can be useful in clinical settings.
P0789 - Benchmarks of meaningful improvement on neurocognitive tests (ID 1372)
Abstract
Background
Background: The Brief International Cognitive Assessment for MS (BICAMS) and Multiple Sclerosis Outcomes Assessment Consortium (MSOAC) battery are frequently used to monitor cognitive and motor function in people with MS (PwMS). While previous studies established benchmarks of clinically meaningful change on these tests, the real-world anchors were based on deterioration in function. Little is known about meaningful testing benchmarks based on gains in function, an increasingly relevant anchor considering improvements that may arise with higher efficacy disease modifying medication.
Objectives
Objective: We aimed to investigate ‘work status gains’ in PwMS, and compare BICAMS and MSOAC test scores of those with said gains to patients reporting work stability or decline.
Methods
Methods: A retrospective analysis was performed on a longitudinal database of 783 PwMS. All subjects were monitored with an online tool called the Buffalo Vocational Monitoring Survey. This analysis included 208 patients with a follow-up timepoint coincident with BICAMS and MSOAC tests.
Results
Results: At follow-up, 36.1% of PwMS reported at least one type of work status gain, such as a reduction in negative work events (25.5%) or an actual improvement in work status, such as from part-time to full-time (6.7%), among others. 8.2% reported a decrease in work status (e.g., full-time to unemployed) and 43.3% reported being work stable without any positive work gains. ANCOVA models comparing those with and without work status gains showed significant differences between the groups in longitudinal change on the Symbol Digit Modalities Test (SDMT), F(1)=3.92, p=0.049. Among the work status improved group, subjects showed an average increase (or clinically meaningful improvement) of 4.87 points on the SDMT.
Conclusions
Conclusions: Benchmarks for clinically meaningful improvement on the SDMT mirror those previously established for clinically meaningful decline. The importance of such benchmarks is reaffirmed, particularly that of score increases, and is especially relevant in considering the efficacy of certain interventions for maintaining and/or improving employment outcomes.
P0806 - Effect of siponimod on cognitive processing speed in SPMS patients with active and non-active disease (ID 1251)
Abstract
Background
Siponimod significantly reduced the relative risk of 3-month (m) confirmed disability progression (CDP) by 21% and 6mCDP by 26% versus placebo in the EXPAND core study. Siponimod also showed a significant benefit on cognitive processing speed (CPS) as measured by change in the Symbol Digit Modalities Test (SDMT).
Objectives
To evaluate the effect of siponimod on CPS in subgroups of patients with active (aSPMS) and non-active (naSPMS) disease from the EXPAND core study.
Methods
EXPAND (N=1651) was a double-blind Phase 3 study that randomized a broad range of SPMS patients to siponimod or placebo (2:1). This subgroup post-hoc analysis included patients with aSPMS (siponimod, n=516; placebo, n=263; defined as presence of relapses in the 2 years before screening and/or ≥1 T1 gadolinium-enhancing lesions at baseline) and naSPMS (siponimod, n=557; placebo, n=270; counterpart of aSPMS). The outcomes analyzed were change in SDMT score from baseline to M24 derived from the mixed model for repeated measures; time to 6m confirmed ≥4-points cognitive worsening/improvement (6mCW/6mCI) on SDMT and a categorical analysis showing the proportion of patients with worsened, stable and improved SDMT scores (worsened/improved by ≥4 points since baseline and until the end of the trial, or otherwise stable) at M24.
Results
Change in SDMT (95% CI) versus placebo from baseline to M24 in the aSPMS and naSPMS groups was 2.34 (0.66; 4.02) and 2.44 (0.67; 4.22; p<0.01 for both), respectively, consistent with the overall EXPAND core population (2.28 [1.09; 3.48]; p<0.001). In patients with aSPMS, siponimod reduced the risk of 6mCW by 27% (hazard ratio [95% CI]: 0.73 [0.53; 1.01]; p=0.06) and improved the chance of 6mCI by 62% (1.62 [1.14; 2.29]; p=0.007) versus placebo. Corresponding values in the naSPMS group were: 6mCW, 24% (0.76 [0.53; 1.09]; p=ns) and 6mCI, 19% (1.19 [0.86; 1.65]; p=ns). In the aSPMS group, a lower proportion of patients worsened (27.3% vs 38.2%, p=0.002) and a higher proportion of patients improved (34.1% vs 22.9%, p=0.001) on SDMT versus placebo. Corresponding proportions for the naSPMS group were: worsened, 21.2% vs 23.7%, p=ns; improved, 35.6 vs 31.2%, p=ns.
Conclusions
Siponimod was associated with relevant benefits in CPS as measured by change in SDMT in patients with active and non-active SPMS. In patients with active disease, both a reduced risk for clinically relevant worsening and an increased chance for clinically relevant improvement were observed.
P0874 - Fingolimod therapy in real world relapsing MS patients: Cognition, quantitative MRI and deep gray matter quantitative susceptibility mapping (ID 1238)
Abstract
Background
Limited data is available regarding the effect of disease modifying therapies on cognitive decline and brain volume change in real world multiple sclerosis (MS) patients. Novel deep gray matter (DGM) quantitative susceptibility mapping (QSM) techniques have not been extensively studied in MS.
Objectives
To assess cognitive performance, magnetic resonance imaging (MRI) brain volumetrics and deep gray matter QSM at baseline, 6 months, 12 months and 24 months in a real world relapsing MS patient cohort treated with fingolimod, referenced to age- and sex-matched healthy controls (HCs).
Methods
Relapsing MS patients from 2 centers (Sydney, Australia and Buffalo, United States of America) were recruited to this observational, prospective study following the decision by their treating neurologist to commence fingolimod therapy. Neurological assessment (Expanded Disability Status Scale (EDSS)), cognitive testing (Minimal Assessment of Cognitive Function (MACFIMS)), and 3 tesla (3T) MRI brain acquisition occurred at baseline, 6 months, 12 months and 24 months. Matched HCs were recruited prospectively from both centers and were followed longitudinally at the same time points.
Results
The relapsing MS (n = 50) and HC (n = 41) cohorts were well matched for age and sex. With fingolimod treatment, clinical relapse rates and MRI lesion activity were significantly reduced, and the EDSS remained stable, in the relapsing MS patient group. Baseline DGM volumes, but not whole brain volumes, were significantly lower in the patient cohort compared to the HC cohort (p < 0.05). Longitudinal DGM volume changes were not significantly different between the groups. Between the baseline and 24 month time points the percentage whole brain atrophy, as measured using Structural Image Evaluation using Normalisation of Atrophy (SIENA), was higher in the patient group (mean: -1.25%) compared with the HC group (mean: -0.44%) (p = 0.006). Baseline thalamus QSM was significantly lower, and the baseline caudate and pallidus QSM were significantly higher, in the MS patient group (p < 0.05). Longitudinal DGM QSM changes were not significantly different between groups. Baseline cognitive performance was worse in the MS group (p < 0.05), but longitudinal cognitive stability/improvement was not significantly different between the two groups.
Conclusions
This real world prospective observational study suggests that fingolimod reduced clinical relapses and MRI lesion activity, and stabilized cognitive performance in the relapsing MS patient cohort. DGM volume and DGM QSM change rates were comparable between the fingolimod treated relapsing MS patients and the age- and sex-matched healthy controls. Whole brain atrophy between baseline and 24 months was greater in the fingolimod treated MS patients compared with HCs, but the differences were not significant for other epochs; further subgroup analysis is underway to explore this finding.
P1026 - Employment outcomes in multiple sclerosis (ID 852)
Abstract
Background
Multiple sclerosis (MS) causes physical and cognitive deficits that are known to impact employment.1 Approximately 50% of people with MS (PwMS) will lose their job 5 years after diagnosis.2 This quick vocational deterioration emphasizes a need to study MS specific work problems prior to job loss.
Objectives
Report descriptive statistics and analyze differences of baseline time points comparing an employed sample of 607 PwMS and 140 healthy controls (HC).
Methods
Using the Buffalo Vocational Monitoring Survey, respondents were asked questions about demographics, work status, job-type, work duties, income, hours worked, disclosure, negative work events (NWEs), and work accommodations.
Results
MS and HC groups were matched on age, sex, and education. Of the PwMS, 89.9% had relapsing remitting MS with an average disease duration of 10.1±8.8 years and of this group 58.9% self-reported having physical disability.3 Additionally, 76.1% and 85.4% of PwMS disclosed their MS diagnosis to an employer or co-workers respectively. The five most common job descriptions among both PwMS and HCs were healthcare support/technician, office/administrative support, education/training or library work, sales, and business or financial operations. PwMS worked significantly more years for their employer (10.4±9.6 vs. 7.8±8.8, p=0.003), worked more hours unpaid (3.0±5.9 vs. 1.9 ± 4.2, p=0.014), and experienced significantly more NWEs (0.5±1.0 vs. 0.2±0.5, p<0.001) than HCs. Specifically, verbal criticism (p=0.012), removal of job responsibility (p=0.005), harassment (p=0.013), and “other” (p=0.019), coded as attendance complaints, poor performance reviews, deteriorated employer/co-worker relationships, dissatisfied clients, and unspecified. Groups were equivalent in annual income/hourly wage, hours worked, years working their current position (p>0.05), but trended toward significant difference when comparing missed work days (p=0.108). PwMS used significantly more work accommodations than HCs (2.4±3.5 vs. 1.1±2.5, p<0.001), most frequently flexible work hours (28.9%), air-conditioning (18.4%), and working from home (14.8%).
Conclusions
PwMS and HCs share similar jobs and incomes but the impact from MS is clear. PwMS use more accommodations to maintain job performance, work more hours unpaid, report a higher number of NWEs, and experience more harassment. Further study into factors and interventions that prevent negative work outcomes is warranted.
TC07.01 - Assessment and Monitoring of Cognitive Function in MS (ID 607)
Abstract
Abstract
The hallmarks of cognitive impairment (CI) in MS are slowed cognitive processing and deficient learning, as originally described by Charcot nearly 150 years ago. This session undertakes the question of what specific tools should be applied in clinical routine care of MS patients, and how often they should be applied? Cognitive assessment is becoming a mainstay of routine care in MS clinics, as a result of initiatives such as the Brief International Cognitive Assessment for MS (BICAMS) and the MS Outcomes Assessment Consortium (MSOAC). Computerized Assessment Neuropsychological Devices (CNADs) are more common and were recently reviewed by a Cognition Work Group from the National MS Society (NMSS). In this lecture, we will cover recent research on CI that presents as progressive decline, and, acute disease activity. Using the Symbol Digit Modalities Test (SDMT), slowed cognitive processing has been documented in clinical relapses, and in isolation, presumably an isolated transient decline in cognition. The authors will review recommendations of a recent National MS Society (NMSS) consensus opinion paper, and discuss ways to apply conventional and computer-assisted methods to address various triggers for neuropsychological evaluation, including cognitive relapse, treatment monitoring, negative work events, and psychiatric exacerbation.
Presenter Of 2 Presentations
BD01.01 - Presentation 01 (ID 172)
TC07.01 - Assessment and Monitoring of Cognitive Function in MS (ID 607)
Abstract
Abstract
The hallmarks of cognitive impairment (CI) in MS are slowed cognitive processing and deficient learning, as originally described by Charcot nearly 150 years ago. This session undertakes the question of what specific tools should be applied in clinical routine care of MS patients, and how often they should be applied? Cognitive assessment is becoming a mainstay of routine care in MS clinics, as a result of initiatives such as the Brief International Cognitive Assessment for MS (BICAMS) and the MS Outcomes Assessment Consortium (MSOAC). Computerized Assessment Neuropsychological Devices (CNADs) are more common and were recently reviewed by a Cognition Work Group from the National MS Society (NMSS). In this lecture, we will cover recent research on CI that presents as progressive decline, and, acute disease activity. Using the Symbol Digit Modalities Test (SDMT), slowed cognitive processing has been documented in clinical relapses, and in isolation, presumably an isolated transient decline in cognition. The authors will review recommendations of a recent National MS Society (NMSS) consensus opinion paper, and discuss ways to apply conventional and computer-assisted methods to address various triggers for neuropsychological evaluation, including cognitive relapse, treatment monitoring, negative work events, and psychiatric exacerbation.
Moderator Of 1 Session
Invited Speaker Of 2 Presentations
BD01.01 - Presentation 01 (ID 172)
TC07.01 - Assessment and Monitoring of Cognitive Function in MS (ID 607)
Abstract
Abstract
The hallmarks of cognitive impairment (CI) in MS are slowed cognitive processing and deficient learning, as originally described by Charcot nearly 150 years ago. This session undertakes the question of what specific tools should be applied in clinical routine care of MS patients, and how often they should be applied? Cognitive assessment is becoming a mainstay of routine care in MS clinics, as a result of initiatives such as the Brief International Cognitive Assessment for MS (BICAMS) and the MS Outcomes Assessment Consortium (MSOAC). Computerized Assessment Neuropsychological Devices (CNADs) are more common and were recently reviewed by a Cognition Work Group from the National MS Society (NMSS). In this lecture, we will cover recent research on CI that presents as progressive decline, and, acute disease activity. Using the Symbol Digit Modalities Test (SDMT), slowed cognitive processing has been documented in clinical relapses, and in isolation, presumably an isolated transient decline in cognition. The authors will review recommendations of a recent National MS Society (NMSS) consensus opinion paper, and discuss ways to apply conventional and computer-assisted methods to address various triggers for neuropsychological evaluation, including cognitive relapse, treatment monitoring, negative work events, and psychiatric exacerbation.