State University of New York at Buffalo
Department of Neurology

Author Of 3 Presentations

Microbiome Late Breaking Abstracts

LB01.05 - Network analysis identifies gut bacteria associated with multiple sclerosis relapse among pediatric-onset patients

Abstract

Background

Commensal gut microbes are known to affect host immune function and may be modifiable. Recent work suggests gut microbiota composition contributes to onset of MS; however, little is known about its contribution to MS disease activity.

Objectives

Estimate the association between gut microbiota and subsequent disease activity among individuals with pediatric-onset MS (pedMS) from the U.S. Network of Pediatric MS Centers.

Methods

Stool samples were collected from cases (MS symptom onset <18 years) and profiled using 16S rRNA sequencing of the V4 region. Amplicon sequence variants (ASVs) were identified using the Divisive Amplicon Denoising Algorithm-2 (DADA2). ASVs present in <20% of samples were removed. ASV clusters (modules) were identified using weighted genetic correlation network analysis (WGCNA) and sparCC transformation of ASV abundance. Cox proportional hazard recurrent event models were used to examine the relationship between individual ASVs and then ASV clusters, adjusted for age, sex, and disease modifying therapy (DMT) use.

Results

Of 53 pedMS cases, 72% were girls. At stool sample collection, the mean age was 15.5 years (SD: 2.7) and disease duration was 1.1 years (SD: 1.0). Less than half (45%) had one relapse and 30% had >1 relapse over the subsequent mean follow-up of 2.5 years (SD:1.3). Over this time, 91% used a DMT. Among 270 individual ASVs included in the analyses, 20 were nominally significant (p<0.05), e.g. the presence of Blautia stercoris was associated with higher relapse risk (hazard ratio [HR]=2.50; 95% confidence interval [CI]=1.43, 4.37). WGCNA identified 6 ASV modules. Higher values of one module’s eigengene was significantly (false discovery rate q<0.2) associated with higher relapse risk (HR=1.23, 95% CI=1.02, 1.50). Four ASVs nominally associated with higher relapse risk were in this module. These included Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.

Conclusions

We found that a high relative abundance of a gut microbiota species within the Blautia genus, and its interconnected variants, was associated with a higher relapse risk in pedMS cases. While our study represents the largest of its kind in MS, findings need to be replicated. However, Blautia stercoris has been linked to disease activity in other immune-mediated diseases such as systemic lupus erythematosus.

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Pediatric MS Oral Presentation

PS04.04 - Evidence for an interaction between ozone pollution and HLA-DRB1*15 alleles in pediatric multiple sclerosis

Abstract

Background

We previously reported a relationship between air pollutants and increased risk of pediatric MS (ped-MS). Environmental risk factor research in ped-MS offers the advantage of shorter duration between exposure and disease onset. Ozone, an air pollutant, is a major global health hazard thought to have a role in MS pathoetiology. Identifying gene-environment interactions advances the understanding of biological processes at play in MS susceptibility.

Objectives

We sought to examine the interaction between ozone pollution and DRB1*15 status as the main genetic variant associated with MS susceptibility.

Methods

Cases and controls enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers were analysed. County-level modeled ozone data were acquired from the CDC’s Environmental Tracking Network air pollution database. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS were assessed by logistic regression. Interaction between tertiles of ozone level and presence of DRB1*15 alleles on odds of ped-MS was evaluated. Models were adjusted for sex, race, ethnicity, age, second-hand smoke exposure, and mother’s education. Additive interaction was estimated using relative risk due to interaction (RERI) and attributable proportion of disease were calculated.

Results

355 ped-MS cases and 565 controls contributed to the analyses. Ozone levels were associated with MS with an odds ratio (OR) of 2.35 (95%CI 1.57–3.51) and 2.21 (95%CI 1.48–3.32) in the upper two tertiles, respectively, compared with the lowest tertile. DRB1 status was also independently associated with MS (OR 1.99; 95%CI 1.43–2.78). There was a significant additive interaction between ozone and DRB1, with a RERI of 2.74 (95%CI 0.50–4.98) and 2.43 (95%CI 0.36–4.5) in the upper two tertiles, respectively. Approximately 60% of the ped-MS risk in those with HLA-DRB1*15 haplotype and high ozone exposure was attributable to the interaction between these risk factors.

Conclusions

Our data revealed additive interaction between higher exposure to ozone and DRB1 alleles on ped-MS susceptibility. Further evaluation of additional genetic variants that might play a role in ozone-induced ped-MS is underway to provide mechanistic insight.

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Imaging Oral Presentation

PS07.05 - Leptomeningeal, dura mater and meningeal vessel wall enhancements in multiple sclerosis

Speakers
Presentation Number
PS07.05
Presentation Topic
Imaging
Lecture Time
13:39 - 13:51

Abstract

Background

Leptomeningeal inflammation (LMI) in multiple sclerosis (MS) can be putatively identified by leptomeningeal contrast enhancement (LMCE) on gadolinium-enhanced 3D T2-fluid attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. Dura mater (DME), inclusive falx cerebri (FCE) enhancement and meningeal vessel wall enhancement (VWE) represent two other meningeal enhancement patterns in MS that have not been extensively studied.

Objectives

To investigate the frequency of LMCE, DME/FCE and VWE in patients with MS and their associations with demographic, clinical and MRI characteristics in a longitudinal retrospective study.

Methods

217 MS patients (193 relapsing-remitting MS, 24 progressive MS) were assessed at baseline and over 18 months follow-up using 3T 3D FLAIR pre- and post-contrast and subtraction images. Lesion and brain volume outcomes were additionally calculated. Analysis of covariance (ANCOVA) and regression models were used to assess the relationship between MRI variables and clinical variables, controlling for age.

Results

24% of MS patients revealed LMCE, and 47% and 24% revealed DME/FCE and VWE, respectively. LMCE presence correlated with age and higher ventricular cerebrospinal fluid (vCSF) volume. More LMCE positive subjects (38%) showed additional VWE, compared to LMCE negative subjects (20%, p=0.055). DME/FCE presence was associated with higher T1/T2 lesion load, higher vCSF volume and decreased total deep gray matter (GM) and hippocampus volumes. All three meningeal enhancement patterns showed a high persistence in shape and size at follow-up.

Conclusions

Different patterns of meningeal enhancement, i.e. LMCE, DME/FCE and VWE can be identified by gadolinium-enhanced 3D FLAIR MR imaging. LMCE positive patients show a trend for higher frequency of VWE than LMCE negative patients. DME/FCE is the most frequent meningeal enhancement pattern in MS, which correlates with imaging markers of lesion burden and brain atrophy and may indicate abnormal lymphatic drainage in these patients.

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Moderator Of 1 Session

Parallel Session Fri, Sep 11, 2020
Session Type
Parallel Session
Date
Fri, Sep 11, 2020
Time (ET)
12:45 - 14:15

Author Of 14 Presentations

COVID-19 Late Breaking Abstracts

LB1244 - Manifestations and Impact of the COVID-19 Pandemic in Neuroinflammatory Diseases (ID 2130)

Abstract

Background

We have limited understanding of the risks and impact of COVID-19 in neuroinflammatory diseases (NID) of the central nervous system, particularly among patients receiving disease modifying therapies (DMTs).

Objectives

To report initial results of a planned multi-center year-long prospective study examining the risk and impact of COVID-19 among persons with NID.

Methods

In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of COVID-19 symptoms in persons with and without NID.

Results

Our cohort included 1,115 participants (630 NID, 98% MS; 485 reference) as of April 30, 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. Persons with NID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of persons with NID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (ORadj=1.45, 1.17-1.84).

Conclusions

Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries that capture an excess of severe cases. Overall, persons with NID seem to have a risk of suspected COVID-19 similar to the reference population.

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Clinical Trials Poster Presentation

P0221 - Ocrelizumab treatment in patients with RRMS who had a suboptimal response with one or more prior disease-modifying therapies: CHORDS 2-year results (ID 1216)

Presentation Number
P0221
Presentation Topic
Clinical Trials

Abstract

Background

In the pivotal trials of ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis (RRMS; OPERA I, OPERA II), ≈75% of participants had no previous disease-modifying therapy (DMT).

Objectives

To report 2-year findings from the Phase IIIb CHORDS study (NCT02637856) investigating OCR in patients with RRMS who had a suboptimal response with previous DMT.

Methods

CHORDS enrolled patients who had a suboptimal response (≥1 relapse, ≥1 T1 gadolinium [Gd]-enhancing lesion or ≥2 new/enlarging T2 lesions) after ≥6 months of treatment with 1 to 3 previous DMTs. All participants received OCR 600 mg every 24 weeks for 96 weeks and were included in the intention-to-treat (ITT) population. Annualized relapse rate (ARR), changes in Expanded Disability Status Scale (EDSS) and safety were assessed in the ITT population. The primary endpoint was the proportion of patients free of any protocol-defined event (i.e. relapse, T1 Gd-enhancing lesion, new/enlarging T2 lesion, 24-week confirmed disability progression [CDP] on the EDSS) and was evaluated using a modified ITT (mITT) population, which imputed as having an event those patients who terminated early for lack of efficacy or death and excluded patients who discontinued for reasons other than an event.

Results

The ITT population included 608 patients with a mean (SD) time since diagnosis of 4.2 (3.03) years. The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%). In the mITT population (576 [94.7%]), 48.1% of patients were free of all protocol-defined events, and most experienced freedom from individual events (relapse, 89.6%; T1 Gd-enhancing lesions, 95.5%; new/enlarging T2 lesions, 59.5%; 24-week CDP, 89.6%) over 96 weeks. Similar results were observed for the primary endpoint in those who received 1 vs >1 prior DMT (50.9% vs 44.5%) as well as for individual events (relapse, 90.0% vs 89.2%; T1 Gd-enhancing lesion, 95.8% vs 95.1%; new/enlarging T2 lesion, 61.4% vs 57.1%; 24-week CDP, 90.9% vs 87.9%). The adjusted ARR over 96 weeks was 0.046. Most patients had stable (<1-point change; 61.5%) or improved (≥1-point decrease; 22.7%) EDSS scores. There were no deaths or new safety signals.

Conclusions

This analysis demonstrates the potential benefits of ocrelizumab treatment over 2 years in patients with RRMS who are relatively early in the disease course and have experienced suboptimal response on prior DMTs.

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Clinical Trials Poster Presentation

P0233 - Safety and tolerability of conversion to siponimod in patients with relapsing multiple sclerosis: interim results of the EXCHANGE study (ID 1134)

Speakers
Presentation Number
P0233
Presentation Topic
Clinical Trials

Abstract

Background

In the USA, siponimod is approved in adults for the treatment of relapsing multiple sclerosis (RMS), including active secondary progressive MS (SPMS). Understanding washout requirements when converting from other disease-modifying treatments (DMTs) to siponimod is important in clinical practice and should be assessed prospectively.

Objectives

To report results from an interim analysis of EXCHANGE (NCT03623243), a prospective, 6 month, multicenter, open-label, single-arm study evaluating safety and tolerability of overlapping effects when converting to siponimod from other DMTs.

Methods

Patients aged 18-65 years with advancing RMS, Expanded Disability Status Scale (EDSS) score of >2.0 to 6.5, and on continuous oral/injectable DMTs for ≥3 months at time of consent were included in the analysis. Patients were immediately converted to siponimod, except those previously on teriflunomide who required 11-14 days’ washout (with cholestyramine or activated charcoal). During days 1-6, siponimod was titrated from 0.25 mg to 2 mg. Primary endpoint was incidence of drug-related adverse events (AEs). About 100 patients are being enrolled in a parallel, novel virtual cohort, with telemedicine tools.

Results

112 patients (1 in the virtual arm; 70.5% female) from 42 centers in the USA were enrolled, completed screening and were eligible for safety analysis (33.9% ongoing; 20.5% discontinued; 45.5% completed). At screening, 74.1% (n=83) of patients had relapsing-remitting MS, 21.4% (n=24) had SPMS, 3.6% (n=4) had primary progressive MS and 0.9% (n=1) had a single demyelinating event; 42.0% (n=47) had ≥1 relapse in the prior 12 months. At baseline, median age was 45.5 years, median time since MS diagnosis was 11.2 years and median EDSS score was 3.5. In the safety analysis set, ≥1 drug-related AE was reported in 34.8% of patients (n=39) (95% confidence interval [CI]: 26.2-44.5); 4.5% (n=5) had ≥1 serious AE and 5.4% (n=6) had ≥1 AE leading to drug discontinuation. In the subgroup of patients who had completed or discontinued from the study (n=74), 40.5% (n=30) (95% CI: 29.5-52.6) had ≥1 drug-related AE. Change from baseline in heart rate to 6 hours post first dose and AEs by prior DMT will be presented.

Conclusions

Conversion from oral/injectable DMTs to siponimod without washout had a good safety and tolerability profile with no unexpected findings. Subsequent analyses will include data on conversion to siponimod from infusible (natalizumab/ocrelizumab) DMTs.

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Imaging Poster Presentation

P0566 - Diffusion tensor imaging of the nucleus basalis of Meynert reveals associations with cognitive state in patients with multiple sclerosis (ID 1427)

Speakers
Presentation Number
P0566
Presentation Topic
Imaging

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.

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Imaging Poster Presentation

P0577 - Feasibility of thalamic atrophy measurement in clinical routine using artificial intelligence: Results from multi-center study in RRMS patients (ID 1058)

Abstract

Background

The thalamus is a key gray matter structure, and a sensitive marker of neurodegeneration in multiple sclerosis (MS). Previous reports have indicated that thalamic volumetry on clinical-quality T2-FLAIR images alone is fast and reliable, using artificial intelligence (AI).

Objectives

To investigate the feasibility of thalamic atrophy measurement using AI in patients with MS, in a large multi-center, clinical routine study.

Methods

DeepGRAI (Deep Gray Rating via Artificial Intelligence) is a multi-center (31 USA sites), longitudinal, observational, real-word, registry study that will enroll 1,000 relapsing-remitting MS patients. Brain MRI exams previously acquired at baseline and at follow-up on 1.5T or 3T scanners with no prior standardization are used, in order to resemble real-world situation. Thalamic volume measurement is performed at baseline and follow-up on T2-FLAIR by DeepGRAI tool and on 3D T1-weighted image (WI) and 2D T1-WI by using FIRST software.

Results

In this pre-planned interim analysis, 515 RRMS patients were followed for an average of 2.7 years. There were 487 (94.6%) T2-FLAIR, 342 (66.4%) 2D T1-WI and 176 (34.2%) 3D T1-WI longitudinal pair of MRI exams available for analyses. Estimation of thalamic volume by DeepGRAI on T2-FLAIR correlated significantly with FIRST on 3D-T1-WI (r=0.733 and r=0.816, p<0.001) and with FIRST on 2D-T1-WI (r=0.555 and r=0.704, p<0.001) at baseline and at follow-up. The correlation between thalamic volume estimated by FIRST on 3D T1-WI and 2D T1-WI was r=0.642 and r=0.679, p<0.001, respectively. The thalamic volume % change over the follow-up was similar between DeepGRAI (-0.75) and 3D T1-WI (-0.82), but somewhat higher for 2D T1-WI (-0.92). Similar relationship was found between the Expanded Disability Status Scale (EDSS) and thalamic volume by DeepGRAI on T2-FLAIR and by FIRST on 3D T1-WI at baseline (r=-0.214, p=0.01 and r=-0.287, p=0.001) and at follow-up (r=-0.298, p=0.001 and r=-0.291, p=0.001).

Conclusions

DeepGRAI provides feasible thalamic volume measurement on multi-center clinical-quality T2-FLAIR images. The relationship between thalamic atrophy and physical disability is similar using DeepGRAI T2-FLAIR and standard high-resolution research approaches. This indicates potential for real-world thalamic volume monitoring, as well as quantification on legacy datasets without research-quality MRI.

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Imaging Poster Presentation

P0617 - Predicting Disease Progression in Multiple Sclerosis from Clinical Routine T2-FLAIR MRI (ID 1670)

Speakers
Presentation Number
P0617
Presentation Topic
Imaging

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.

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Imaging Poster Presentation

P0636 - Relationship of real-world brain atrophy to MS disability using icobrain: 4 centre pilot study (ID 716)

Abstract

Background

To date, no studies have explored the relationship between brain atrophy and MS disability using differing MRI protocols and scanners at multiple sites.

Objectives

To assess the association between brain atrophy and MS disability, as measured by EDSS and 6-month confirmed disability progression (CDP).

Methods

In this retrospective study at 4 MS centres, a total of 1300 patients had brain MRI imaging assessed by icobrain. Relapse-onset MS patients were included if they had two clinical MRIs 12 (±3) months apart and ≥2 EDSS scores post MRI-2, the first ≤3 months from MRI-2, with ≥6 months between first and last EDSS. Volumetric data were analysed if the alignment similarity between two images was as good as that of same-scanner scan-rescan images (normalised mutual information ≥0.2). The percentage brain volume change (PBVC), percentage grey matter change (PGMC), FLAIR lesion volume change, whole brain volume, grey matter volume, FLAIR lesion volume and T1 hypointense lesion volume at MRI-2 were calculated. Ordinal mixed effect models were used to determine the association between these volumetric MRI measures and all EDSS scores post MRI-2. Cox proportional hazards models were used for the 6-month CDP outcome, using a subset of patients with ≥3 EDSS. Models were adjusted for proportion of time spent on disease-modifying therapy during MRIs ± whole brain/grey matter volume at baseline MRI.

Results

Of the 260 relapse-onset MS patients included, 204 (78%) MRI pairs were performed in the same scanner and 56 (22%) pairs were from different scanners. During the follow-up period (median 3.8 years, range 1.3-8.9), 29 of 244 (12%) patients experienced 6-month CDP. There was no evidence for association between annualised PBVC or PGMC and CDP or EDSS (p>0.05). Cross-sectional whole brain and grey matter volume (at MRI-2) tended to associate with CDP (HR 0.99, 95% CI 0.98-1.00, p=0.06). Every 1ml of whole brain or grey matter volume lost represented a 1% higher chance of reaching 6-month CDP. Only whole brain volume (at MRI-2) was associated with EDSS score (β -0.03, SE 0.01, p<0.001) and the slope of EDSS change over time (β -0.001, SE 0.0003, p=0.02). On average, every 33ml reduction of brain volume was associated with a 1 step increase in EDSS.

Conclusions

In this real-world clinical setting where a fifth of the brain atrophy analysis were performed on different scanners, we found no association between individual brain atrophy and MS disability. However, there was an association between cross-sectional whole brain volume with EDSS and slope of EDSS change.

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Imaging Poster Presentation

P0641 - Serum neurofilament light chain levels are associated with poorer thalamic perfusion in multiple sclerosis: cross-sectional DSC-PWI study (ID 1387)

Speakers
Presentation Number
P0641
Presentation Topic
Imaging

Abstract

Background

Both perfusion-based imaging (PWI) measures and serum neurofilament light chain levels (sNfL) have been associated with multiple sclerosis (MS) disability and different pathologies.

Objectives

To determine whether the perfusion and neurofilament biomarkers are correlated to each other or independently describe different MS processes.

Methods

3T MRI dynamic susceptibility contrast (DSC)-PWI and single molecule assay (Simoa)-based sNfL (in pg/mL) were utilized in 86 MS patients. Perfusion measures of mean transit time (MTT), cerebral blood volume (CBV) and cerebral blood flow (CBF) were derived for the regions of normal-appearing whole brain (NAWB), normal-appearing white matter (NAWM), gray matter (GM), deep GM (DGM) and thalamus. Normalized CBV and CBF (nCBV and nCBV) were adjusted with the corresponding NAWM measure. Age and sex-adjusted linear regression models determined associations between DSC-PWI measures and sNfL. False discovery rate (FDR)-adjusted p-values lower than 0.05 were considered statistically significant.

Results

After age and sex adjustment, thalamic MTT significantly and independently was associated with higher sNfL (standardized β=0.648, t-statistics=2.868, adjusted p-value=0.011) and explained additional 4.0% of sNfL variance. NAWM MTT was initially added in the model (adding additional 3.3%) but did not survive FDR correction. Similarly, after adjusting for age and sex effects, lower nCBV of the thalamus was associated with greater sNfL (standardized β=-0.221, t-statistics=-2.529, p=0.013, adjusted p-value=0.022). Correspondingly, lower nCBF of the thalamus was also associated with greater sNfL (standardized β=-0.346, t-statistics=-4.188, p<0.001, adjusted p-value=0.001).

Conclusions

Higher sNfL are associated with poorer PWI-based measures of the thalamus. Future longitudinal studies should determine their temporal relationship.

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Neuropsychology and Cognition Poster Presentation

P0789 - Benchmarks of meaningful improvement on neurocognitive tests (ID 1372)

Speakers
Presentation Number
P0789
Presentation Topic
Neuropsychology and Cognition

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.

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Observational Studies Poster Presentation

P0862 - Disability accrual in primary-progressive & secondary-progressive multiple sclerosis (ID 1232)

Abstract

Background

Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS.

Objectives

We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016).

Methods

Inclusion required adult-onset progressive MS; ≥ 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS ≤ 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if ≥ 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over ≥ 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS ≥ 7 (wheelchair required) was assessed (Kaplan-Meier).

Results

5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 ± 10.2, vs. 41.5 ± 10.7 [mean ± SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78–0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98–0.99); and higher in males (1.18; 1.12–1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71–0.87) but similar for PPMS-A (1.01; 0.93–1.10) and SPMS-N (0.94; 0.85–1.05). Sensitivity analyses corroborated these results. However, patients with SPMS-A reached EDSS ≥ 7 at younger ages (cumulative probability 30% by 57, vs. 64–66 for SPMS-N, PPMS-A, PPMS-N).

Conclusions

Progressive phase onset is later in SPMS than PPMS. Hazard of disability accrual during the progressive phase is lower in SPMS than PPMS. However, patients with SPMS-A reach wheelchair requirement younger than other progressive phenotypes, reflecting earlier progression onset versus SPMS-N, and greater disability at onset versus PPMS

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Observational Studies Poster Presentation

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.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1026 - Employment outcomes in multiple sclerosis (ID 852)

Speakers
Presentation Number
P1026
Presentation Topic
Patient-Reported Outcomes and Quality of Life

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.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1041 - Longitudinal Changes in Expanded Timed Get Up and Go (ETGUG) and its Association with Patient-Reported Outomes and Other Measures of Disability (ID 1748)

Presentation Number
P1041
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

The Expanded Timed Get Up and Go (ETGUG) is an objective and clinically useful measure of mobility which is predictive of falls. Previous research showed that ETGUG was a more sensitive predictor of disability, as measured by the Expanded Disability Status Scale (EDSS), than the Timed-25-Foot-Walk (T25FW).

Objectives

To evaluate correlations of absolute change of ETGUG, EDSS and T25FW in a longitudinal sample and to investigate associations between changes in ETGUG and changes in patient-reported outcomes (PROs).

Methods

Participants in this study are part of the New York State Multiple Sclerosis Consortium (NYSMSC), a 23-year longitudinal registry from MS centers throughout New York State. Participants with available data on the ETGUG, T25FW and EDSS on two visits or more were selected for this study (n=148). To investigate cross-sectional and longitudinal changes in ETGUG scores and its associations with EDSS, T25FW and PROs (as measured by the LIFEware system), Pearson correlation coefficient, chi-squared-, and paired-sample-t-tests were carried out.

Results

The average age of persons with multiple sclerosis (pwMS) in this study was 56.6 (11.0) years, with a disease duration of 21.1 (11.3) years. The majority was female (78.4%), with a mean duration between baseline and follow-up of 32.1 (SD=11.4) months. Baseline ETGUG scores were highly correlated to baseline scores of EDSS and T25FW (r=0.65 and r=0.86, respectively), as well as predictive of EDSS and T25FW at last follow-up (r=0.57 and r=0.60, respectively). Absolute change in ETGUG scores were correlated with absolute change in T25FW (r=0.71) and EDSS (r=0.19). Mean ETGUG scores showed a non-significant improvement from baseline (23.6 ±10.1 seconds) to follow-up (21.7±15.0 seconds), with 17.6% of pwMS worsening over time. Furthermore, pwMS who worsened in ETGUG scores were significantly more likely to report worsening in PROs as well (difficulties in getting up [p=.036], right upper- [p=<.001] and lower limb- problems [p=0.001]).

Conclusions

In the present study, we show that longitudinal changes in ETGUG scores are highly associated with other measures of disability, as well as PROs. Difficulty in walking remains one of the most bothersome limitations in pwMS. Our findings contribute to the ongoing pursuit to find accurate predictors of disability worsening.

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Pediatric MS Poster Presentation

P1082 - Therapeutic Response in Pediatric Neuromyelitis Optics Spectrum Disorder (ID 1820)

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition which can led to significant disability. Approximately 4% of the NMOSD cases are pediatric onset. At present, there are limited studies that aim at guiding physicians in their treatment choices for NMOSD in children.

Objectives

To evaluate the effect of different disease modifying therapies (DMT) with respect to attack prevention in children with NMOSD.

Methods

Cohort study that included 12 clinical centers participating in the US Network of Pediatric MS Centers. Cases were validated for NMOSD diagnostic criteria and classified via serostatus as AQP4+, MOG+, or double-seronegative (DS). Clinical data, including demographics, attack details, type of initial DMT (rituximab, mycophenolate mofetil, azathioprine, IVIg) and neurological visit data were extracted from charts, centrally collected in a database, and analyzed. Treatment response in the three serostatus subgroups was evaluated. Effect of DMTs on annualized relapse rate (ARR) was assessed by negative binomial regression.

Results

111 pediatric patients with NMOSD were identified: 80 AQP4+, 10 MOG+, 14 double seronegative (DS), and 7 with unknown serostatus (94 females and 17 males; 48 white, 47 African American, 13 other races). Mean follow-up duration was 1.9 years (SD±2.2). About 6% of patients were treatment-naive. First-line DMTs varied by serostatus: in the AQP4+ subgroup 42% used rituximab, 16% mycophenolate mofetil, 16% azathioprine, and 8% IVIg. Among MOG+ patients, 13% received rituximab, 13% azathioprine, 13% mycophenolate, and 38% IVIg. Within the DS group, rituximab was used in 21% of cases, azathioprine in 7%, mycophenolate in 21%, and IVIg in 21%. In the unknown serogroup, 33% received rituximab, 17% azathioprine, 0% mycophenolate, and 33% IVIg. The ARR calculated in all the serogroups was 0.25 (95% CI 0.13-0.46) for rituximab, 0.73 (95% CI 0.27-2.00) for azathioprine, 0.40 (95% CI 0.18-0.89) for mycophenolate, and 0.56 (95% CI 0.26-1.20) for IVIg. In the AQP4+ subgroup, the patients started on rituximab showed an ARR of 0.25 (95% CI 0.13-0.48), those on azathioprine an ARR of 0.76 (95% CI 0.24-2.39), those on mycophenolate an ARR 0.43 (95% CI 0.17-1.07), and those on IVIg an ARR of 0.63 (95% CI 0.26-1.55).

Conclusions

This retrospective study showed that rituximab is associated with a lowered annual relapse rate in pediatric NMOSD and in particular in the AQP4+ subgroup.

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Presenter Of 2 Presentations

Clinical Trials Poster Presentation

P0221 - Ocrelizumab treatment in patients with RRMS who had a suboptimal response with one or more prior disease-modifying therapies: CHORDS 2-year results (ID 1216)

Presentation Number
P0221
Presentation Topic
Clinical Trials

Abstract

Background

In the pivotal trials of ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis (RRMS; OPERA I, OPERA II), ≈75% of participants had no previous disease-modifying therapy (DMT).

Objectives

To report 2-year findings from the Phase IIIb CHORDS study (NCT02637856) investigating OCR in patients with RRMS who had a suboptimal response with previous DMT.

Methods

CHORDS enrolled patients who had a suboptimal response (≥1 relapse, ≥1 T1 gadolinium [Gd]-enhancing lesion or ≥2 new/enlarging T2 lesions) after ≥6 months of treatment with 1 to 3 previous DMTs. All participants received OCR 600 mg every 24 weeks for 96 weeks and were included in the intention-to-treat (ITT) population. Annualized relapse rate (ARR), changes in Expanded Disability Status Scale (EDSS) and safety were assessed in the ITT population. The primary endpoint was the proportion of patients free of any protocol-defined event (i.e. relapse, T1 Gd-enhancing lesion, new/enlarging T2 lesion, 24-week confirmed disability progression [CDP] on the EDSS) and was evaluated using a modified ITT (mITT) population, which imputed as having an event those patients who terminated early for lack of efficacy or death and excluded patients who discontinued for reasons other than an event.

Results

The ITT population included 608 patients with a mean (SD) time since diagnosis of 4.2 (3.03) years. The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%). In the mITT population (576 [94.7%]), 48.1% of patients were free of all protocol-defined events, and most experienced freedom from individual events (relapse, 89.6%; T1 Gd-enhancing lesions, 95.5%; new/enlarging T2 lesions, 59.5%; 24-week CDP, 89.6%) over 96 weeks. Similar results were observed for the primary endpoint in those who received 1 vs >1 prior DMT (50.9% vs 44.5%) as well as for individual events (relapse, 90.0% vs 89.2%; T1 Gd-enhancing lesion, 95.8% vs 95.1%; new/enlarging T2 lesion, 61.4% vs 57.1%; 24-week CDP, 90.9% vs 87.9%). The adjusted ARR over 96 weeks was 0.046. Most patients had stable (<1-point change; 61.5%) or improved (≥1-point decrease; 22.7%) EDSS scores. There were no deaths or new safety signals.

Conclusions

This analysis demonstrates the potential benefits of ocrelizumab treatment over 2 years in patients with RRMS who are relatively early in the disease course and have experienced suboptimal response on prior DMTs.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1041 - Longitudinal Changes in Expanded Timed Get Up and Go (ETGUG) and its Association with Patient-Reported Outomes and Other Measures of Disability (ID 1748)

Presentation Number
P1041
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

The Expanded Timed Get Up and Go (ETGUG) is an objective and clinically useful measure of mobility which is predictive of falls. Previous research showed that ETGUG was a more sensitive predictor of disability, as measured by the Expanded Disability Status Scale (EDSS), than the Timed-25-Foot-Walk (T25FW).

Objectives

To evaluate correlations of absolute change of ETGUG, EDSS and T25FW in a longitudinal sample and to investigate associations between changes in ETGUG and changes in patient-reported outcomes (PROs).

Methods

Participants in this study are part of the New York State Multiple Sclerosis Consortium (NYSMSC), a 23-year longitudinal registry from MS centers throughout New York State. Participants with available data on the ETGUG, T25FW and EDSS on two visits or more were selected for this study (n=148). To investigate cross-sectional and longitudinal changes in ETGUG scores and its associations with EDSS, T25FW and PROs (as measured by the LIFEware system), Pearson correlation coefficient, chi-squared-, and paired-sample-t-tests were carried out.

Results

The average age of persons with multiple sclerosis (pwMS) in this study was 56.6 (11.0) years, with a disease duration of 21.1 (11.3) years. The majority was female (78.4%), with a mean duration between baseline and follow-up of 32.1 (SD=11.4) months. Baseline ETGUG scores were highly correlated to baseline scores of EDSS and T25FW (r=0.65 and r=0.86, respectively), as well as predictive of EDSS and T25FW at last follow-up (r=0.57 and r=0.60, respectively). Absolute change in ETGUG scores were correlated with absolute change in T25FW (r=0.71) and EDSS (r=0.19). Mean ETGUG scores showed a non-significant improvement from baseline (23.6 ±10.1 seconds) to follow-up (21.7±15.0 seconds), with 17.6% of pwMS worsening over time. Furthermore, pwMS who worsened in ETGUG scores were significantly more likely to report worsening in PROs as well (difficulties in getting up [p=.036], right upper- [p=<.001] and lower limb- problems [p=0.001]).

Conclusions

In the present study, we show that longitudinal changes in ETGUG scores are highly associated with other measures of disability, as well as PROs. Difficulty in walking remains one of the most bothersome limitations in pwMS. Our findings contribute to the ongoing pursuit to find accurate predictors of disability worsening.

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