Background

Multiple-Sclerosis-Partners-Advancing-Technology-Health-Solutions (MSPATHS) is an international multicentre digital database that collects clinical information provided directly by patients together with standardized MRI and biomarkers.

Objectives

We identify a Benign multiple sclerosis (BMS) population using Patient-Determined-Disease-Steps (PDDS) as a proxy for EDSS. We describe its physical and non-physical characteristics, and explore the features that best discriminate BMS.

Methods

Cross-sectional study of MSPATHS patients (Feb 2019). In patients with disease duration ≥10 years, BMS was considered when PDDS score<2. We compared BMS and non-BMS in terms of (1)socio-demographic and clinical characteristics, (2)physical status (lower and upper extremity function by Neuro-QoL (LUEF-NQ) and neurological performance tests: walking speed test (WST), manual dexterity test (MDT), processing speed test (PST), contrast sensitivity test (CST)) and non-physical symptoms (anxiety, depression, fatigue, among other NQ domains), and (3)MRI (gadolinium enhancement and new T2 lesions). We built a random forest model to estimate the importance of each variable. Cohen’s d was used for descriptive statistics to categorize differences in small (d=0.2-0.5), medium (d=0.5-0.8) and large (d>0.8). A sensitivity analysis with a 1:1 matched cohort by disease duration was performed.

Results

From 15,257 patients included, 8,349 had a disease duration ≥10 years and 3,852 (46.1%) were classified as BMS. (1)BMS and non-BMS patients were similar for gender, age at disease onset and diagnosis, ethnicity, years of education and smoking status. Compared to non-BMS, BMS had small differences in disease duration (median, 17.2 (12,9-23,4) vs. 20.9 (15,1-28,8 years); d=0.39) but medium/large differences in (2)physical status (LUEF-NQ d=2.06 and 1.53, WST d=0.81, MDT d=0.97, PST d=0.82 and CST d=0.56), as well as, in all non-physical symptoms evaluated by NQ (anxiety d=0.53, depression d=0.69, fatigue d=0.84, stigma d=1.32, cognition d=0.69, social role satisfaction (SRS) d=1.11 and participation (SRP) d=1.19). (3)No differences were found on MRI activity. With 0.88 sensitivity and 0.86 specificity, LUEF-NQ was the most contributing variable for the random forest followed by stigma, SRP, WST, and SRS. The sensitivity analysis showed similar results.

Conclusions

PDDS seems to be a useful disability proxy to identify BMS when using digital technology. LUEF-NQ, stigma, SRP and SRS seem to better discriminate BMS.

Background

Rituximab (RTX) is an anti-CD20 monoclonal antibody, widely used as an off-label treatment for multiple sclerosis (MS). Despite well-known efficacy and safety, RTX regimen has not yet been standardized.

Objectives

We aimed to compare efficacy and safety data of two different rituximab doses at two large Catalan multiple sclerosis centres.

Methods

A two-centre ambispective study considering all MS patients that have received at least one RTX cycle until February 2020 was conducted. In Barcelona centre (BC), RTX regimen used was 2g intravenously (IV), at least during 3 cycles, followed by 1g every 6 months, while in Girona centre (GC), was 2g IV, at least the first cycle, followed by 500mg every 6 months. Patients were clinically followed every 6 months with lab tests, and brain MRI scans were performed at baseline and yearly thereafter. Baseline clinical, radiological and demographic characteristics were collected. Annual relapse rate (ARR), contrast-enhancing lesions (CELs) and new T2 lesions at one and third year on treatment, as well as EDSS changes at last follow-up visit, were evaluated. Also, the dynamics of CD19% lymphocytes and IG immunoglobulin (IgG) values in serum, as well as the incidence of adverse events (AE) were described.

Results

A total of 303 patients (249 at BC and 54 at GC) were included. Main reason to start RTX was clinical progression plus inflammatory activity (clinical, radiological or both) (45.8% BC vs 79.6% GC). No differences on age at RTX onset, gender and disease duration were found between both centres. At baseline, mean ARR was 0.37±0.6 (BC) vs. 0.33±0.5 (GC); median EDSS was 5.5 (1-9.0) (BC) vs. 6.0 (1-8.0) (GC); and proportion of MRI with CELs was 32.4% (BC) vs. 42.6% (GC). ARR decrease to 0.05 (87.5%, p<0.001) for BC vs. 0.03 (90.3%, p=0.018) for GC at first year, and to 0.08 (88.3%, p=0.016) vs. 0 (100%, p=0.172) at third year. Considering only progressive MS phenotypes, 79.4% vs. 71.4% of patients remained stable or improved the EDSS. Regarding MRI findings, percentages of patients with CELs and new T2 lesions (BC vs GC) were 2.7% vs. 8% and 19% vs. 16% at one year; and 0% vs. 0% and 12% vs. 0% at third year. AE incidence was higher at BC during the first year (14.8% vs 4.1%). No difference in the dynamics of CD19% lymphocytes was found, while IgG values decreased significantly in the BC cohort throughout the first 3 years.

Conclusions

In the treatment of multiple sclerosis, low doses of rituximab seem to offer similar effectiveness with better safety profile than high doses.

Background

Oligoclonal bands (OB) are part of the 2017 McDonald criteria but their determination is rater-dependent. Kappa free light chains (KFLC) are determined quantitatively and could be an alternative to OB, but a vendor-specific index cut-off is needed.

Objectives

To compare the proportion of patients with clinically isolated syndromes (CIS) and positive OB and a KFLC index equal or greater than 6.6 (KFLC-6.6, Leurs CE Mult Scler 2020) or 10.61 (KFLC-10.61, Gaetani L J Neuroimmunol 2020). To compare the diagnostic properties of OB, KFLC-6.6 and KFLC-10.61 for 2nd attack and 2017 MRI dissemination in space (DIS) and time (DIT).

Methods

MRIs were obtained 3-5 months after the CIS, at 1 year and every 5 years. OB were determined by isoelectric focusing combined with immunoblotting. We selected 228 patients with sufficient data to assess DIS and DIT, OB determination and enough remnant frozen samples to measure KFLC by turbidimetry (Optilite, The Binding Site). We compared the proportion of patients with positive OB, KFLC-6.6 and KFLC-10.61 and the 3-year diagnostic properties for the following outcomes: 2nd attack (n=179) and MRI DIS and DIT (n=192).

Results

Of all patients, 146 (64.0%) had OB, 147 (65.5%) KFLC-6.6 and 137 (60.1%) KFLC-10.61. In total, 130 (57.0%) had OB and KFLC-6.6, 16 (7.0%) only OB, 17 (7.5%) only KFLC-6.6 and 65 (28.5%) had neither. As for OB and KFLC-10.61, 122 (53.5%) had both, 24 (10.5%) only OB, 15 (6.6%) only KFLC-10.61 and 67 (29.4%) had neither. At baseline, the criteria were fulfilled by patients with OB, KFLC-6.6 and KFLC-10.61 as follows: DIS 109/135 (80.7%), 114 (84.4%) and 106 (78.5%); DIT 70/87 (80.5%), 78 (89.7%) and 74 (85.1%); DIS plus DIT 64/78 (81.2), 71 (91.0%) and 67 (85.9); DIS plus OB 109 (100.0%), 101 (92.7%) and 94 (86.2); and McDonald 111/130 (85.4%), 113 (86.9%) and 106 (81.5%). The diagnostic properties of OB, KFLC-6.6 and KFLC-10.61 for 2nd attack were sensitivity 77.8, 85.6 and 78.0; specificity 44.9, 48.3 and 51.7; and accuracy 61.5, 67.0 and 65.4. Results for MRI DIS plus DIT were sensitivity 81.8, 87.9 and 82.6; specificity 66.7, 70.0 and 73.3; and accuracy 77.1, 82.3 and 79.7.

Conclusions

KFLC-10.61 had the greatest specificity and KFLC-6.6 the best overall diagnostic properties. The results were probably due to the higher proportion of positive KFLC patients with DIT compared to those with positive OB, suggesting KFLC-6.6 could be used as an alternative to OB in the McDonald criteria.

Background

In the constantly evolving field of MS, personalized medicine is still one of the most important unmet need that requires further attention

Objectives

We aimed to develop a dynamic risk calculator to predict the long-term prognosis of MS in the context of a large MS Centre in Catalonia

Methods

This is an observational study based on data prospectively acquired from a deeply phenotyped CIS cohort from Barcelona. We first built a natural history baseline risk score (BRS) for predicting moderate disability, integrating baseline prognostic factors: Sex, age at CIS, CIS topography, number of T2 lesions, contrast-enhancing lesions (CEL) and oligoclonal bands. This BRS was designed as follows: For untreated patients, we built a Weibull model to estimate the median time to confirmed EDSS 3.0 and with these estimates we identified risk groups based on the median of the cut-offs of 2000 survival trees. Then we obtained the BRS of the full cohort. In patients with more than ten years of follow-up, we performed an inverse probability weighting to balance patients during their follow up for the propensity of being treated or lost to follow-up. The weights were estimated via a proportional hazards (PH) Cox model considering both baseline information (CIS year, BRS) and time-dependent (diagnosis status, new T2 lesions, CEL and cumulative number of relapses). Finally, a weighted PH Cox model was built to estimate the time to confirmed EDSS 3.0 considering the BRS and time-dependent events (new T2 lesions, cumulative number of relapses and first or second-line treatment use). Sensitivity analyses using other disability outcomes and different follow-ups were conducted.

Results

Of 956 patients, 577 (60.4%) were untreated before confirmed EDSS 3.0. Two BRS were obtained: low and high-BRS. Of 400 patients followed for more than ten years, 226 (56.5%) were low-BRS and 174 (43.5%) were high-BRS. High-BRS showed a HR=2.16 95%CI (1.16,4.02). Each new T2 lesion presented HR=1.04 95%CI (1.00,1.08) and each new relapse HR=1.46 95%CI (1.23,1.74). Being on second-line treatment showed a protective effect (HR=0.23 95%CI (0.06,0.94)) but no association was found for first-line treatments (HR=1.32 95%CI (0.67,2.60). Sensitivity analyses confirmed the association between BRS, new T2 lesions and the accumulation of relapses with the prognosis. However, treatment results were inconclusive.

Conclusions

Presenting a high-BRS doubles the risk of reaching moderate disability. Each new lesion and new relapse increses the risk by 4% and 46%, respectively; and second-line treatments seem to be protective. If validated, this risk calculator could be a crucial step to personalized medicine.

Background

Over 2 years in the CARE-MS trials (NCT00530348; NCT00548405), alemtuzumab (12 mg/day; baseline (BL): 5 days; 12 months later: 3 days) significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Alemtuzumab efficacy was maintained through a 4-year extension study (NCT00930553), wherein patients could receive additional 3-day courses (≥12 months apart, as needed for disease activity) or receive other disease-modifying therapy per investigator’s discretion.

Objectives

To evaluate post hoc the effects of alemtuzumab on brain atrophy over 6 years in CARE-MS patients without relapses and MRI disease activity.

Methods

Analysis included pooled CARE-MS patients with or without disease activity between BL and Year 1 or BL and Year 2. Absence of disease activity was defined as no BL gadolinium (Gd)-enhancing T1 lesions and no clinical relapses or MRI disease activity (new Gd-enhancing or new/enlarging T2 lesions) from Years 0-1 or Years 0-2 (Definition 1). A second definition had the additional criterion of no relapse within 60 days before BL (Definition 2). Brain atrophy was measured by brain parenchymal fraction (BPF); differences in the median annualized percent change in BPF were assessed using ranked ANCOVA adjusted for region and BL BPF.

Results

Compared with SC IFNB-1a, alemtuzumab reduced median annualized percent change in BPF in patients free of disease activity during Years 0-1 (Definition 1: -0.37% vs -0.61%, P=0.006; Definition 2: -0.36% vs -0.54%, P=0.024) or Years 0-2 (Definition 1: -0.27% vs -0.44%, P=0.014; Definition 2: -0.28% vs -0.41%, P=0.045). Median annualized percent change in BPF was reduced with alemtuzumab versus SC IFNB-1a in patients with disease activity in Years 0-1 (-0.61% vs -0.79%, P=0.005) or Years 0-2 (-0.40% vs -0.56%, P<0.0001). Over 6 years, brain volume loss (BVL) was slower in patients without disease activity who initiated alemtuzumab at core study BL (-1.66%) than in those who received SC IFNB-1a in the core studies and initiated alemtuzumab in the extension (-2.05%).

Conclusions

Brain atrophy was reduced with alemtuzumab compared with SC IFNB-1a in patients without disease activity over 2 years. A slower rate of BVL was maintained through Year 6 in patients without disease activity who received alemtuzumab in the core study compared with SC IFNB-1a, suggesting alemtuzumab may slow neurodegeneration associated with BVL.

STUDY SUPPORT: Sanofi.

Background

In 2017, a revision of the 2010 McDonald criteria for multiple sclerosis (MS) diagnosis in clinically isolated syndrome (CIS) patients has been proposed. However, its validation in a large multicenter cohort of CIS patients is still needed.

Objectives

To compare the performance of 2017 and 2010 revisions of the McDonald criteria with respect to MS development in a large multicentric cohort of CIS suggestive of MS.

Methods

Brain and spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination obtained ≤5 months from CIS onset and a follow-up brain MRI acquired ≤15 months from CIS onset were assessed in 626 CIS patients from 9 European MS centres. The occurrence of a second clinical attack (clinically definite [CD] MS) was recorded. Performances of the 2017 and 2010 revisions of McDonald criteria for dissemination in space (DIS), time (DIT) and DIS plus DIT, also including OCB assessment, were evaluated with a time-dependent receiver operating characteristic curve analysis. Median time to MS diagnosis for the different sets of criteria was estimated through Kaplan-Meier curves.

Results

At the last evaluation (median=61.9 months [IQR=39.1-102.5]), 319 (51%) of 626 patients had CDMS. At 36 months, for DIS, the 2017 MRI criteria had higher sensitivity (0.84 [95% CI=0.79-0.88] vs 0.77 [0.72-0.82]), lower specificity (0.33 [0.28-0.39] vs 0.40 [0.35-0.46]), and similar area under the curve values (AUC, 0.59 [0.55-0.62] for both). The 2017 DIS plus DIT MRI criteria had higher sensitivity (0.68 [0.63-0.74] vs 0.62 [0.56-0.68]), lower specificity (0.55 [0.49-0.61] vs 0.62 [0.56-0.68]), and similar AUC values (0.62 [0.58-0.66] for both). CSF-specific OCB assessment as part of the 2017 criteria revision, increased the sensitivity (0.81 [0.75-0.85]), decreased specificity (0.40 [0.34-0.46]) and preserved AUC values (0.60 [0.56-0.64]). Median time to MS diagnosis was earlier with the 2017 revision compared to the 2010 or CDMS criteria, especially with OCB assessment (2017 revision with OCBs=3.6 months [3.1-4.0], 2017 revision without OCB=11.6 months [7.8-13.5], 2010 revision=13.9 months [12.4-15.3], CDMS=56.3 months [43.8-76.0]).

Conclusions

The 2017 revision of the McDonald criteria showed overall similar accuracy to the 2010 McDonald criteria in predicting CDMS development. The suggested modifications are expected to simplify the clinical use of MRI criteria without reducing accuracy and allow an earlier diagnosis of MS.

Background

Synthetic MRI reduces acquisition time and could be an alternative to conventional sequences for the assessment of multiple sclerosis (MS).

Objectives

To perform a qualitative and quantitative comparison of conventional and synthetic MRI sequences to evaluate their value in the assessment of brain demyelinating lesions.

Methods

Twenty-seven RRMS patients (18 women), mean age of 44.0 years, median EDSS of 3.5 were examined in a 1.5T MRI scanner. A 2D QRAPMASTER sequence was added to the brain MRI protocol (proton density [PD] and T2w fast spin-echo, fast T2w FLAIR, and T1w spin-echo sequences). SyMRI software version 8.0.4 used QRAPMASTER images to generate synthetic images with the same TR, TE and TI used for conventional MRI.

Four raters performed a blinded qualitative analysis of the images in a random order to evaluate global image quality (GIQ), global image contrast, presence of flow artifacts in posterior fossa, contrast of lesions to white matter, and level of confidence for supratentorial and infratentorial lesion assessment. Moreover, the number of periventricular, juxtacortical, brainstem, and cerebellum lesions, and the contrast-to-noise ratio (CNR) between regions were evaluated.

Statistical analysis was performed in SPSS v. 25. Crosstabs were used to evaluate the degree of agreement between sequences for qualitative data. Wilcoxon signed rank test was used to evaluate differences for quantitative data.

Results

GIQ showed a predominance of better scores for conventional MRI. All other image quality parameters showed a degree of agreement similar or greater to the predominance of better scores for conventional MRI. There were no significant differences in the degree of agreement between pairs of raters in the assessment of conventional and synthetic MRI except between raters 1 and 2. However, we found a clear predominance of disagreement for all pairs of raters. Synthetic PD, T2w and T2w-FLAIR showed higher CNR than conventional sequences for most of the regions. Two raters found a greater number of brainstem lesions in conventional PD and one in synthetic T2w-FLAIR images. Three raters found a greater number of cerebellum lesions in conventional PD, and two of them in conventional T2w-FLAIR images.

Conclusions

Synthetic MRI obtained lower scores for some qualitative rater-related parameters while quantitative CNR data showed higher values. Synthetic MRI shows potential to be used as an alternative to conventional brain MRI sequences in the assessment of MS.

Background

Background: The ratio of T1- T2-weighted images (T1/T2) has been proposed as a biomarker of tissue integrity, although comparison with MRI-derived tissue metrics has not been perfomed.

Objectives

Objectives: In this study, T1/T2 has been compared to the T1/FLAIR, Phase-sensitive inversion recovery (PSIR), the fractional anisotropy (FA) and the orientation dispersion (ODI) in normal appearing grey, white matter and lesion mask, by using the structural similarity (SSIM) index. The SSIM is the product of 3 terms that take into account the luminance, the contrast and the structural information of the images compared. It ranges between [-1,1], with 1 indicating that the two images compared are identical.

Methods

Material and methods: MRIs of patients with a clinically isolated syndrome were included in this study. Images were acquired in a 3.0 T sytem (Trio, Siemens) using established acquisition protocols. The FA and ODI images were generated with the TBSS/FSL and NODDI/SPM toolboxes, respectively. The SSIM maps were calculated with the function implemented in Matlab. T1-weighted images were segmented with SPM12 and the lesion masks were generated from the FLAIR with the LST tool. Mean SSIM values were calculated over the normal-appearing grey (NAGM) and white (NAWM) matter, as well as in the lesion masks. The contribution of each term and the total SSIM were computed separately.

Results

Results: When T1/T2 images were compared to T1/FLAIR, in NAGM and NAWM the luminance, contrast and structural terms ranged between [0.81-0.99]; for the lesion mask, between [0.61, 0.92]. When T1/T2 was compared to FA, both the luminance and contrast terms ranged between [0.72, 0.92] in the three compartments; while the structural term ranged between [0.49, 0.61]. When T1/T2 was compared to ODI, the luminance term was quite high for the 3 masks [0.72, 0.93], intermediate for the contrast term [0.58, 0.67] and very low and negative [-0.19, -0.11] for the structural term. Finally, regarding the PSIR comparison, the structural term showed a high correspondence in the 3 compartments [0.72, 0.79], while the luminance and contrast terms were below 0.01 for the 3 compartments.

Conclusions

Conclusions: As expected, T1/T2 and T1/FLAIR are highly equivalent, in all aspects. When T1/T2 was compared to FA and ODI, a poor structural correspondence was found, whereas when T1/T2 was compared to PSIR, the structural correspondence was very high, suggesting that the anatomical features are reproduced in a similar way in both sequences. The SSIM index could be used as a measure to assess the equivalency between MRI sequences in a more thorough way.

Background

New T2 lesions count is routinely used for assessing disease activity in multiple sclerosis (MS), although their visual detection is challenging (low sensitivity, high variability).

Objectives

We assessed two different automatic decision-support systems to detect new T2 lesions in longitudinal brain MRIs of patients with MS.

Methods

The study included 100 MS patients with two MRI exams (median interval 12 months [range 3-27 months]; relapse free 85%). MRI scans were acquired on a 3T magnet following a standardized protocol (3D-FLAIR, 3D- MPRAGE, and 2D dual-echo T2-weighted sequences).

Two different automated methods were used: M1, based on an unsupervised approach that used intensity-derived features from the subtraction images together with deformation fields information obtained from the non-rigid registration between the two scans; and M2, a supervised approach based on the application of convolutional neural networks (CNN) trained to detect the presence of new T2 lesions in the follow-up scan. The outcomes of these automated tools were compared to the results of two operator-related methods based on visual analysis: the standard radiological report (O1); and revision of the MRIs by an expert observer non-blinded to the radiological report (O2). A “Gold Standard Outcome” (GOS) was created by consensus of two expert observers based on combined visual assessment of all the MRI images, the radiological reports, and the outcomes of the automated methods.

Results

GOS identified 104 new T2 lesions in 38 patients. Automated tools doubled the number of new T2 lesions (125 for M1; and 119 for M2) compared to operator-related methods (59 for O1 and 73 for O2). Specificity for detecting patients with at least one new T2 lesion was 100% for operator related methods while for automatic tools was 83% for M1 and 87% for M2. Sensitivity was higher with both automated tools (92.1% for M1; 97.4% for M2) compared to operator related methods (76.3% for O1, and 89.5% for O2).

Conclusions

The CNN model was more sensitive for detecting new T2 lesions and active patients, compared to standard and expert visual analysis, and to an unsupervised automated tool. However, visual supervision of the CNN model outcomes is still required due to its suboptimal specificity. Automatic tools, based on the application of CNN models are promising for detecting MRI disease activity, and shows potential to be used as an aid to the neuroradiological visual assessment in clinical practice.

Background

In multiple sclerosis (MS) the cervical spinal cord is often affected by demyelination and neuro-axonal injury, leading to irreversible tissue loss.

Objectives

To use voxel-wise analysis to evaluate the distribution and changes over time of cervical cord atrophy in MS patients from a multicentre dataset acquired at 7 European sites.

Methods

Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluation were obtained from 54 healthy controls (HC) and 110 MS patients (13 clinically isolated syndromes [CIS], 75 relapsing-remitting [RR] and 22 progressive [P]MS). A pipeline optimized for longitudinal analysis was used to co-register baseline and 1-year follow-up cervical cord scans to a cord template, obtained by averaging straightened HC images from all centers. Voxel-wise differences of cervical cord atrophy, their longitudinal changes and correlations with clinical variables were assessed using SPM12 and full factorial models (sex-, age-, center- and total cord volume-corrected).

Results

Compared to HC, MS patients exhibited significant (p<0.05, family-wise error [FWE] corrected) baseline cervical cord atrophy, mainly located in anterior, posterior and lateral cord regions at C1/C2, as well as in posterior regions between C4 and C6. While CIS patients showed a slight cord tissue expansion vs HC at posterior C4, RRMS presented significant clusters of cord atrophy vs CIS, mostly in lateral and posterior C2-C4 regions, and PMS showed widespread cord atrophy vs RRMS patients at C4-C5 and C7 levels. During the follow-up, a significant progression (p<0.05, FWE) of cord atrophy was detected in MS patients, predominantly in the posterior and lateral cord at C2, and between C4 and C6. Such pattern of cord atrophy progression was mainly driven by RRMS patients, while CIS patients did not show cord tissue loss at follow-up vs baseline, and PMS patients showed circumscribed tissue loss in posterior regions at C2 and C6. A strong relationship (p<0.05, FWE) was found between baseline clinical disability and baseline cord atrophy in the posterior and lateral cord at C2-C4. Also, baseline atrophy in the lateral cord at C3-C4 correlated with clinical disability at 1-year follow-up.

Conclusions

Voxel-wise analysis of cervical atrophy allowed to detect a differential involvement of cord levels and to characterize 1-year evolution of tissue loss across phenotypes. Cord atrophy was clinically relevant and contributed to explain follow-up clinical disability.

Background

People with MS present disruption of structural brain networks, but the differential characteristics of such changes among MS phenotypes and their clinical impact are not well elucidated.

Objectives

To characterize diffusion-based brain connectivity abnormalities in different MS phenotypes and their relation with disability in a large cohort of patients.

Methods

In this multicenter, retrospective, cross-sectional study, we collected clinical and brain MRI data from 344 patients with MS [median Expanded Disability Status Scale, EDSS 2.0 (range 0-7.0)] and 91 healthy volunteers (HV) from four MAGNIMS centers. Cognition was assessed with the Paced Auditory Serial Addition Test (PASAT) and Symbol Digits Modalities Test (SDMT) in 298 patients. We collected 3D-T1, FLAIR, diffusion-weighted images (DWI) and T2 or field maps acquisitions. FSL and ANTs packages were used to carry out DWI preprocessing and MRtrix software to generate connectivity matrices based on fractional anisotropy values. We computed six network measures (strength, global and local efficiency, clustering coefficient, assortativity and transitivity), and applied the ComBat tool to reduce inter-site variability. We calculated age-adjusted differences in graphs between groups using Mann-Whitney with FDR correction or Kruskal-Wallis with Dunn’s Test when necessary. Associations with clinical features were explored with Spearman’s rank correlation.

Results

Thirty-eight (11%) patients presented a clinically isolated syndrome (CIS), 262 (76%) had relapsing-remitting (RR) and 44 (13%) secondary progressive (SP) MS. CIS patients showed reduced global and local efficiency, clustering coefficient and transitivity compared to HV (corrected p<0.001), whilst RRMS did not differ from CIS patients. Compared with CIS and RRMS, patients with SPMS showed larger changes for the same previous graphs measures (corrected p<0.05), and lower strength than RRMS (corrected p=0.019).

In patients, reduced measures of strength, global and local efficiency, clustering and transitivity correlated with higher EDSS (rho:-0.12–-0.16, corrected p<0.034), lower PASAT (rho:0.26–0.30, corrected p<0.001) and worse SDMT scores (rho:0.28–0.32, corrected p<0.001).

Conclusions

Structural network integrity at the whole brain level is already widely reduced in people with MS from the earliest phases of the disease and becomes more abnormal in SPMS. Network modifications may contribute to the clinical manifestations of the disease.

Background

Mean rates of brain atrophy in healthy controls range from 0.05-0.5%, depending on age and technical factors, including scanner, acquisition sequences, and image analysis techniques. In MS PATHS (MS Partners Advancing Technology for Health Solutions), standardized MRIs are analyzed using a software prototype (MSPie, MS PATHS Image Evaluation) that incorporates a novel approach to calculate BPF. Normative ranges measured using MSPie are needed to distinguish age- and disease-related changes.

Objectives

To establish a normative reference for interpretation of brain parenchymal fraction (BPF) in individual MS patients relative to age-matched healthy volunteers (HV).

Methods

HV aged 21-60 were recruited at 6 MS PATHS sites to be age-, race-, and gender-matched to the MS PATHS cohort. HVs were imaged at baseline and once/year using 3T scanners (Siemens Healthcare, Erlangen, Germany) and standardized acquisitions (3DFLAIR and 3DT1), as in routine MRIs in MS PATHS. MRIs from UK Biobank supplemented the normative dataset past the age of 60. All MRIs were analyzed with MSPie to calculate BPF. BPF normative percentile were calculated for each age using quantile regression. Mean annualized rate of brain atrophy was estimated from HVs with follow-up MRIs. BPF percentiles were applied to the MS PATHS cohort. Mean Processing Speed Test (PST) z-scores were compared in MS patients stratified based on BPF percentiles.

Results

209 HVs were enrolled, 590 UKBiobank HVs were selected, and 9479 MS patients had at least one MRI. HV BPF values ranged from 0.855-0.895 in the 21-30 age group to 0.796-0.882 in the 61-73 age group, demonstrating accelerating and more variable atrophy with increasing age. For MS patients age 21-73 years (n=6791), mean age-adjusted BPF percentile was 27.8%, where BPF values fell above the 50^th%-ile in 23.4% (“mild MS”) and below the 25^th%-ile in 57.6% (“severe MS”). Mean PST z-scores differed in BPF-based mild MS vs. severe MS groups (-0.15 and -0.83; p<0.001). Mean annualized BPF change in HV was -0.08% (range: -0.71% to +0.57%) based on 71 subjects (mean age: 41.1 years) with >2 MRIs.

Conclusions

Incorporating normative reference data into MSPie will aid clinicians with interpretation of individual patients’ BPF in clinical practice and may enable patient stratification based on BPF and other predictors. Additional longitudinal normative data are being collected to contextualize disease progression as measured by BPF change over time.

Disclosures: MS PATHS is sponsored by Biogen.

Background

Clinical and imaging features of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may overlap with those of aquaporin 4-neuromyelitis optica spectrum disorder (AQP4-NMOSD) and relapsing remitting multiple sclerosis (RRMS). There is an unmet need for MRI biomarkers which reflect biological mechanisms involved in MOGAD and can help in the differential diagnosis.

Objectives

We aim to identify imaging features able to differentiate between non-acute MOG-antibody disease, AQP4-NMOSD and RRMS.

Methods

In this ongoing retrospective, cross-sectional MAGNIMS study, we analyzed data collected from 8 centers. All subjects (n=352) had brain and cervical cord 3T MRI. Quantification of MRI biomarkers included brain white matter lesions (WMLs), cortical lesions (CL), brain parenchymal fraction (BPF), white matter fraction (WMF), cortical and deep grey matter fractions (GMF) and cross-sectional cervical cord area (CSA) at C1-C2. Linear regression models were used to compare MRI measures between groups, corrected for age, sex, and centre. Statistical significance was considered when p was <0.05.

Results

91 patients with MOGAD (50F, mean age: 41yrs [±15]), 85 with AQP4-NMOSD (68F, 49yrs [±14]), 90 with RRMS (56F, 41yrs [±11]) and 87 healthy controls (HCs) (54F, 36yrs [±11.6]) were collected. The most common phenotypes at onset were optic neuritis and transverse myelitis in MOGAD (93%) and AQP4-NMOSD (87%). WMLs were detected in 57% MOGAD, 79% AQP4-NMOSD, all RRMS (100%) patients, and in 15% HCs. The mean lesion load and number of lesions were higher in RRMS than both MOGAD (p=0.007, p<0.001) and AQP4-NMOSD (p=0.001, p<0.001). At least one CL was seen in 8% patients with MOGAD (total n=8), 10% patients with AQP4-NMOSD (n=7), and in 69% patients with RRMS (n=150). All patient groups showed lower BPF than HCs, with lower WMF in MOGAD and RRMS than HCs (all p<0.01). Between groups, deep GMF was lower in RRMS than MOGAD (p<0.001) and AQP4-NMOSD (p=0.001). CSA was reduced in all disease groups when compared to HCs (all p<0.01) and lower in AQP4-NMOSD than RRMS (p=0.01).

Conclusions

This ongoing study indicates that MOGAD and AQP4-NMOSD share similar MRI features, and no specific MRI biomarker can distinguish between them. Patients with AQP4-NMOSD showed greater spinal cord atrophy than RRMS, and RRMS patients had a higher number of cortical lesions, and greater deep GM atrophy than AQP4-NMOSD and MOGAD. The next step is to investigate whether lesion distribution differs between the two antibody-mediated disease.

Background

Real-world evidence can be used to better characterize the course of multiple sclerosis (MS), care provision and outcomes in clinical practice. Magnetic resonance imaging (MRI) that occurs in the context of usual care is an important source of information that can inform clinical decision-making. Guidelines exist to enhance the clinical impact of routine MRI in MS, but it is unclear whether MRIs acquired as part of routine care in the United States adhere to these guidelines.

Objectives

To describe the clinical routine brain MRIs from patients with MS across different US imaging sites.

Methods

FlywheelMS is a novel patient-centered study that aims to extract and digitize health information not readily available in existing electronic health records of patients with MS. Up to 5,000 consenting adults with a confirmed MS diagnosis will be enrolled. Brain MRI data were retrieved, and summary statistics were computed to describe the sessions, imaging sites, scanner field strengths and slice thickness of T1-weighted and FLAIR (fluid-attenuated inversion recovery) images. Longitudinal acquisition consistency (i.e. MRIs acquired from the same center with the same scanner) was also assessed.

Results

Out of 2,389 patients enrolled, 1555 brain MRI data were retrieved from the first 492 patients (female, 81%; mean age at consent, 49±11 years). The mean number of MRI sessions per patient was 3.2±2.4, and data were captured between 1999 and 2018. Sessions were acquired at 598 different imaging sites, using mainly 1.5T scanners (61.3%), followed by 3T (32.7%) and lower field-strength magnets (3.4%; not available, 2.6%). The mean slice thickness of T1-weighted (3.1±1.7 mm) and FLAIR images (3.1±1.3 mm) was similar. Of the 352 patients (72%) that had more than one MRI session, 85 (24.1%) had consistent acquisition (i.e. same site/scanner), 153 (43.5%) had one site or scanner change, and 114 (32.4%) had more than one site and/or scanner change.

Conclusions

The novel, patient-centered approach of FlywheelMS can successfully extract imaging data from medical records of patients with MS across US imaging sites. These data will help us in describing the clinical routine MRI, determining the compliance to guidelines and understanding which measure (e.g. lesion volume and/or atrophy) could be potentially extracted from MRI data.

Background

Counselling and managing women with active Multiple Sclerosis (MS) during pregnancy and the postpartum period is a challenge. Alemtuzumab (ALZ) might be an option for patients with severe MS who desire pregnancy. However, data on relapse activity during and after pregnancy is scarce.

Objectives

Our objective was to describe our experience with ALZ treatment prescribed in highly active MS women with a pregnancy desire.

Methods

From all ALZ treated women (n=62), patients starting treatment because of a pregnancy desire were selected. Demographic, clinical, and radiological data before and during ALZ treatment as well as during and after pregnancy were collected.

Results

From 1^st September 2019, thirteen patients were identified with a mean age at ALZ onset of 33.9 years (SD 5.5), median disease duration of 12.0 years (IQR 12.5). The median number of relapses 1 year prior to ALZ onset was 2.0 (IQR 2.0) and 6 out of 10 patients (60%) had Gd-enhancing lesions at baseline MRI (median of 4.5 lesions; IQR 8.3). Only one patient was treatment naïve prior to ALZ onset, 5 patients (38%) were receiving fingolimod, 3 patients (23.1%) injectable therapies, and 3 patients (23,1%) other monoclonal antibodies. As of 1^st June 2020, 4 patients (30%) were still not pregnant, 8 patients (61.5%) have had a full-term pregnancy, and 1 patient (7.7%) was still pregnant. All 9 pregnant patients have received two cycles of ALZ with a median time from the last ALZ dose to pregnancy of 9 months (IQR 18). After 1-2 years ALZ treatment, and prior to the pregnancy, 4 out of 9 patients (44.4%) had at least one relapse and 3 (33.3%) patients had an active brain MRI either at 12 or 24 months after ALZ onset. During pregnancy, only 1 patient had a relapse during the first trimester. During the postpartum period, 2 out of 8 (25%) patients experienced a disease reactivation with a relapse occurring with a mean time of 42 days (SD 41) after delivery and a brain MRI showing a high number of Gd-enhancing lesions.

Conclusions

Alemtuzumab treatment in women with high disease activity and a pregnancy desire might be an option. However, it is warned that some patients could present a disease reactivation short after delivery. Thus, close monitoring is needed, especially in patients with a high disease activity during the preconception period.

Abstract

The indication of gadolinium (Gd)-enhanced T1-weighted sequences, especially in the monitoring and prediction of the efficacy of disease-modifying treatments has raised some controversy, given the evidence regarding the deposition of this element in deep grey matter structures, which is orders of magnitude more evident in patients receiving linear compared to macrocyclic chelates. Due to this evidence, the European Commission suspended in 2017, the use of linear gadolinium-based contrast agents (GBCAs) for central nervous system MRI examinations, and recommended that Gd should only be used if essential, and at the lowest possible dose. On the other hand, the US Food and Drug Administration (FDA) indicated that the retention characteristics of each agent should be considered when choosing a GBCA for patients who may be at higher risk for Gd retention, such as those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions. The FDA also stated that health care professionals should consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary, and are also urged to assess the necessity of repetitive GBCA MRIs in established treatment protocols. In MS, the policy of reducing GBCA use in MS patients in the pharmacovigilance setting is reasonable.

Gd-enhancing lesions are considered a marker of active inflammation at the time in which the scan is obtained. However, recognition of disease activity cannot rely exclusively on Gd-enhancing lesions, as this approach has a low sensitivity in detecting disease activity, due to the fact that median duration of contrast uptake in new T2 lesions is around 3 weeks, while the recommended interval between baseline and routine follow-up scans is much longer. Active T2 (new/enlarging) lesions, which reflect the permanent footprint from a previous focal inflammatory lesion that has occurred within the interval between two scans, are also considered a reliable marker of active inflammatory disease and may be superior to Gd-enhancing lesions in many clinical situations such as routine follow-up to detect subclinical disease activity, especially when the time gap between the two MRIs is longer than 3–6 months. The use of Gd should, therefore, be limited to cases where there is a need to confirm recent disease activity, particularly if a recent MRI is not available or not performed. On the other hand, the use of GBCAs seems to be unnecessary in the case of standard monitoring purposes for subclinical disease activity, as its detection can be based exclusively on the presence of active T2 lesions. This presentation will review the existing evidence in relation to the use of GBCAs for detecting disease activity, to finally establish a series of recommendations useful in clinical practice.

Abstract

The indication of gadolinium (Gd)-enhanced T1-weighted sequences, especially in the monitoring and prediction of the efficacy of disease-modifying treatments has raised some controversy, given the evidence regarding the deposition of this element in deep grey matter structures, which is orders of magnitude more evident in patients receiving linear compared to macrocyclic chelates. Due to this evidence, the European Commission suspended in 2017, the use of linear gadolinium-based contrast agents (GBCAs) for central nervous system MRI examinations, and recommended that Gd should only be used if essential, and at the lowest possible dose. On the other hand, the US Food and Drug Administration (FDA) indicated that the retention characteristics of each agent should be considered when choosing a GBCA for patients who may be at higher risk for Gd retention, such as those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions. The FDA also stated that health care professionals should consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary, and are also urged to assess the necessity of repetitive GBCA MRIs in established treatment protocols. In MS, the policy of reducing GBCA use in MS patients in the pharmacovigilance setting is reasonable.

Gd-enhancing lesions are considered a marker of active inflammation at the time in which the scan is obtained. However, recognition of disease activity cannot rely exclusively on Gd-enhancing lesions, as this approach has a low sensitivity in detecting disease activity, due to the fact that median duration of contrast uptake in new T2 lesions is around 3 weeks, while the recommended interval between baseline and routine follow-up scans is much longer. Active T2 (new/enlarging) lesions, which reflect the permanent footprint from a previous focal inflammatory lesion that has occurred within the interval between two scans, are also considered a reliable marker of active inflammatory disease and may be superior to Gd-enhancing lesions in many clinical situations such as routine follow-up to detect subclinical disease activity, especially when the time gap between the two MRIs is longer than 3–6 months. The use of Gd should, therefore, be limited to cases where there is a need to confirm recent disease activity, particularly if a recent MRI is not available or not performed. On the other hand, the use of GBCAs seems to be unnecessary in the case of standard monitoring purposes for subclinical disease activity, as its detection can be based exclusively on the presence of active T2 lesions. This presentation will review the existing evidence in relation to the use of GBCAs for detecting disease activity, to finally establish a series of recommendations useful in clinical practice.

Abstract

The indication of gadolinium (Gd)-enhanced T1-weighted sequences, especially in the monitoring and prediction of the efficacy of disease-modifying treatments has raised some controversy, given the evidence regarding the deposition of this element in deep grey matter structures, which is orders of magnitude more evident in patients receiving linear compared to macrocyclic chelates. Due to this evidence, the European Commission suspended in 2017, the use of linear gadolinium-based contrast agents (GBCAs) for central nervous system MRI examinations, and recommended that Gd should only be used if essential, and at the lowest possible dose. On the other hand, the US Food and Drug Administration (FDA) indicated that the retention characteristics of each agent should be considered when choosing a GBCA for patients who may be at higher risk for Gd retention, such as those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions. The FDA also stated that health care professionals should consider limiting GBCA use to clinical circumstances in which the additional information provided by the contrast is necessary, and are also urged to assess the necessity of repetitive GBCA MRIs in established treatment protocols. In MS, the policy of reducing GBCA use in MS patients in the pharmacovigilance setting is reasonable.

Gd-enhancing lesions are considered a marker of active inflammation at the time in which the scan is obtained. However, recognition of disease activity cannot rely exclusively on Gd-enhancing lesions, as this approach has a low sensitivity in detecting disease activity, due to the fact that median duration of contrast uptake in new T2 lesions is around 3 weeks, while the recommended interval between baseline and routine follow-up scans is much longer. Active T2 (new/enlarging) lesions, which reflect the permanent footprint from a previous focal inflammatory lesion that has occurred within the interval between two scans, are also considered a reliable marker of active inflammatory disease and may be superior to Gd-enhancing lesions in many clinical situations such as routine follow-up to detect subclinical disease activity, especially when the time gap between the two MRIs is longer than 3–6 months. The use of Gd should, therefore, be limited to cases where there is a need to confirm recent disease activity, particularly if a recent MRI is not available or not performed. On the other hand, the use of GBCAs seems to be unnecessary in the case of standard monitoring purposes for subclinical disease activity, as its detection can be based exclusively on the presence of active T2 lesions. This presentation will review the existing evidence in relation to the use of GBCAs for detecting disease activity, to finally establish a series of recommendations useful in clinical practice.