Displaying One Session

Poster Fri, Sep 11, 2020
Session Type
Poster
Date
Fri, Sep 11, 2020
Imaging Poster Presentation

P0573 - Evolution of Diffusely Abnormal White Matter and its relationship to Progression in Primary Progressive MS (ID 1817)

Speakers
Presentation Number
P0573
Presentation Topic
Imaging

Abstract

Background

Background: Diffusely abnormal white matter (DAWM) is associated with decreased axonal and myelin density, fibrillary gliosis, and inflammatory cell activation on histopathology, and has been linked to progression in secondary progressive MS (SPMS). However, few studies have focused on assessing DAWM in primary progressive MS exclusively. Hence, we aimed to characterize the longitudinal evolution of DAWM and its relationship with focal white matter lesions (FWML) and confirmed disability progression (CDP) in a PPMS population.

Objectives

Objectives: 1) To automatically segment and characterize the longitudinal evolution of FWML and DAWM in PPMS. 2) To assess associations of voxels of DAWM that transform into FWML at last visit with CDP (CDP=sustained increase in EDSS that persisted for 24 weeks).

Methods

Methods: The data included 1753 MRI scans of 376 PPMS participants, followed for 122 weeks, scanned at screening, weeks 06, 48, 96, and 122. FWML and DAWM were automatically segmented using a previously validated automated 2-weighted-intensity thresholding technique. All gadolinium enhancing and new white matter lesion voxels were excluded from the FWML mask, to capture the chronic component of FWML. DAWM voxels at screening, weeks 06, 48 and 96 that transformed into FWML at the last MRI scan (w122) were segmented.

Results

Results: As disease duration increased, PPMS participants showed volumes of chronic FWML that significantly increased (t=7.3; p<0.0001) but no significant changes in DAWM volumes. The voxels of DAWM in subsequent scans that transformed to FWML at the last visit significantly decreased as disease duration progressed (t=-8.8; p<0.0001) and were not significantly associated with CDP.

Conclusions

Conclusions: DAWM voxels show a dynamic transformation into FWML over time, with volumes of DAWM-to-FWML transformation in PPMS decreasing progressively as disease duration increases. These dynamic changes are similar to those observed in SPMS. However, unlike SPMS, where previous studies have shown an association between DAWM-to-FWML transformation and CDP, this group of PPMS participants did not show such an association. This finding would suggest that other factors, other than DAWM evolution, might have a stronger weight in disease progression in PPMS, compared to SPMS.

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Imaging Poster Presentation

P0574 - Expansion of chronic lesions associated with disease progression in RRMS patients. (ID 1062)

Speakers
Presentation Number
P0574
Presentation Topic
Imaging

Abstract

Background

It was suggested that slow-burning inflammation isassociated with lesion expansion and leads to progressive loss of axons and disability worsening. However, in vivo evidence linking lesion expansion with biomarkers of disease progression, particularly during relapsing-remitting stage of the disease, is lacking.

Objectives

To examine the incidence and extent of chronic white matter lesion expansion in relapsing-remitting MS (RRMS) patients followed for 5 yearsand to evaluate its relationship with clinical and imaging biomarkers of disease progression.

Methods

Pre- and post-gadolinium T1, FLAIR and diffusion tensor images were acquired from 33 patients. Lesion expansion was analysed between baseline and 48 months using custom-designed software written in Phyton. Percentage brain volume change (PBVC) was calculated using SIENA/FSL. Progression of clinical disability was assessed by EDSS. Progressive tissue damage inside chronic lesions was measured as an increase of Mean Diffusivity (MD).

Results

There were 569 lesions identified as chronic at baseline, of which 261 (46%) were expanding (total volume change:31320 mm3), 236 (42%) were stable (total volume change:1380 mm3) and 72 (12%) were shrinking (total volume change: -2664 mm3). In addition, 139 new free-standing and confluent lesions were detected (total volume:13867).

No association was found between change of volume in chronic lesions and the volume of new lesions (p=0.4). There was a significant increase in total brain lesion volume during the follow-up period (6680+/-5509 vs 7951+/-6315 mm3), the bulk of which was accounted for by an increase of chronic lesions group volume (67.3% or 855+/-1066 mm3), while only 32.7% (or 420+/-633 mm3) was attributable to new lesions.

There was significant negative correlation of chronic lesion volume change with the rate of brain atrophy (r=-0.57, p=0.001) and change of EDSS during the follow-up period (r=0.38, p=0.03). A strong positive correlation was also observed between the rate of chronic lesion volume change and an increase of MD inside the lesions during the follow-up period (r=0.75, p<0.001).

Conclusions

In RRMS patients the expansion of chronic white matter lesions dominates the process of total lesion load accumulation and is a significant contributing factor to the disease progression. Furthermore, our results suggest that low-grade inflammation at the lesion rim associated with significant degree of axonal loss both inside chronic lesions (MD increase) and in NAWM (brain atrophy). In addition, lack of correlation between an expansion of chronic lesion and volume of newly appearing lesions supports the notion that different mechanisms underpin the development of the new lesions and progressive changes in chronic pre-existing lesions.

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Imaging Poster Presentation

P0575 - Exploring demyelination and brain atrophy in multiple sclerosis using quantitative magnetic resonance imaging (ID 680)

Speakers
Presentation Number
P0575
Presentation Topic
Imaging

Abstract

Background

Conventional Magnetic Resonance Imaging (MRI) has a high sensitivity for detecting inflammatory disease activity of the brain, but is time-consuming, only semi-quantitative and rely on subjective assessments. On the contrary, the technique called ‘synthetic MRI’ (SyMRI) uses a single pulse sequence, can create contrast-weighted images from quantitative maps based on relaxometry and simultaneously provides automatic brain volume and myelin measurements. All this information is delivered after a single 6-minute scan and software with post-processing time less than 1 minute. Measuring the change in brain volume and myelin content in vivo could provide new insights into the relationship between two main pathological processes in multiple sclerosis (MS), demyelination and neurodegeneration and the impact of disease modifying treatments (DMTs) on these processes.

Objectives

The aim was to assess brain volume and myelin content over time in patients with newly diagnosed MS and in healthy control persons.

Methods

We prospectively included 116 patients newly diagnosed with relapsing-remitting (RR) MS, and 51 healthy control subjects (HC). All patients initiated DMT and were dichotomized into those with disease activity (relapse and/or new or enlarging lesions on MRI) (n=74) and those without disease activity (n=42) at follow up. The MRI was performed at baseline in both groups and in patients at 6, 12, 24 and 36 months, and in HC only at 24 months. Brain parenchymal fraction (BPF) and myelin parenchymal fraction (MyPF) of the brain were calculated via SyMRI software.

Results

At baseline, there was no significant difference between HC and newly diagnosed MS in BPF (89% and 89.1%, respectively, p=0.97), but HC had significantly lower MyPF than patients (14.1% and 14.9%, respectively, p<0.001). At 36 months follow-up, the mean change of BPF and MyPF in patients was -0.9% (±1.6) p<0.001 and 0.3 % (±1.3) p=0.022, respectively. Patients without disease activity had significantly higher MyPF compared with patients with disease activity during follow-up time (15.7% and 14.9%, respectively, p=0.009). At 24 month follow-up, BPF and MyPF were unchanged in HC compared to baseline (p=0.94 and p=0.44, respectively).

Conclusions

SyMRI showed the development of significant brain atrophy in RRMS after 3 years of follow-up and signs of increased demyelination in patients with disease activity. However, patients had unexpectedly higher MyPF than controls at baseline and the MyPF increased in stable RRMS at follow-up. This might indicate increased remyelination. However, the sensitivity of SyMRI to quantify the myelin fraction of the brain deserves further validation.

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Imaging Poster Presentation

P0576 - Exploring the Corticospinal Tract in Progressive Multiple Sclerosis: A Transcranial Magnetic Stimulation and Magnetic Resonance Imaging Study (ID 1446)

Speakers
Presentation Number
P0576
Presentation Topic
Imaging

Abstract

Background

Progressive multiple sclerosis (MS) phenotypes are associated with important clinical disability. Yet, moderate lesion burden is usually reported using conventional magnetic resonance imaging (MRI), suggesting other mechanisms at the basis of disability (e.g., motor cortical lesions, alteration of corticospinal tract (CST) function and integrity). Transcranial magnetic stimulation (TMS) permits a noninvasive exploration of corticospinal function. MRI allows a precise assessment of cortical (double inversion recovery (DIR) sequence) and CST structural integrity (diffusion tensor imaging (DTI)).

Objectives

This work aimed to assess the correlation between TMS and MRI-derived measures of CST and motor cortex. This might give complementary insight on neurophysiological and neuroanatomical characteristics of CST.

Methods

Adult patients with progressive MS were included. Patients were not included if they had a relapse in the last three months, change in MS treatments in the last two months, absence of motor evoked potentials, presence of contraindications for TMS/MRI performance, or presence of other neuropsychiatric diagnoses. TMS measures included short interval intracortical inhibition and facilitation. MRI protocol included DTI and DIR sequences to generate measures of CST integrity (volume, fractional anisotropy, apparent diffusion coefficient (ADC), axial diffusivity and radial diffusivity (RD)) and motor cortical lesions load. Correlation analysis was performed.

Results

Twenty-five patients completed the evaluations (13 females, mean age: 56 ± 11 years). Significant inverse correlations between percentages of intracortical facilitation and each of CST RD (p<0.01) and CST ADC (p<0.05) were observed.

Conclusions

High ADC and RD have been previously found among patients with MS and reflect high structural damage of the CST (demyelination as reflected by high RD, or both axon/myelin pathology as reflected by high ADC). In addition, low intracortical facilitation was previously suggested to reflect a deficient synaptic transmission and would hint towards an exhaustion of the compensatory mechanisms that are usually deployed to overcome the MS-related functional decline. The current findings would suggest a concomitant impairment of CST and intracortical facilitatory circuits that takes place at an advanced stage of MS. Intracortical facilitation and RD/ADC could constitute potential biomarkers to monitor disease evolution and response to interventions.

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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

P0578 - Five years functional connectivity reorganization without clinical or cognitive decline in MS (ID 755)

Speakers
Presentation Number
P0578
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) is a disease characterized radiologically by the accumulation of lesions in grey and white matter over time throughout the CNS. Accumulating evidence has demonstrated abnormal patterns of brain functional connectivity (FC) in MS patients as compared to healthy controls (HCs). A longitudinal approach that accounts for all alterations in FC following structural damage in MS is warranted to better understand the complex interplay between disease progression and FC reorganization.

Objectives

1) To assess fMRI-based FC anomalies in early MS 2) To determine the relation between FC changes and structural brain damage due to disease progression 3) To study the association between FC changes and cognitive and physical disability.

Methods

Structural MRI and resting-state fMRI were acquired from 76 early relapsing-remitting MS patients at baseline (average disease duration 71.7 months ± 63) and after five years. Ninety-four HCs matched for age and sex were included at baseline. Independent component analysis (ICA) and network modelling were used to measure FC. FC variation was related to expanded disability status scale, timed 25-foot walk test, 9 hole peg test and neuropsychological outcomes. Brain and lesion volumes were quantified using standard methods. We used the 25 independent components obtained from ICA to estimate the longitudinal stability of the brain functional connectome as a proxy for functional reorganization over time. We computed the stability of the brain functional connectome for each MS patient by vectorizing each participant’s whole-brain connectivity matrix. Then, we calculated the within subjects Spearman correlation coefficient between fMRI at baseline and follow-up, obtaining a measure of whole-brain connectome stability that is sensitive to all changes in FC in the follow-up period.

Results

The MS subjects (71% females, mean age 35.3 ± 7.3) were clinically and cognitively stable. Compared to HCs, FC abnormalities were detected within networks and in single connections, mainly in the default mode network and frontoparietal areas, in patients with early MS at baseline. Over time, FC was relatively invariable, but changes in FC were associated with progression of brain atrophy (ρ = 0.39, p = .06). No significant relationship with clinical and cognitive measures or lesion load was detected.

Conclusions

We used the stability of the brain functional connectome as a proxy for FC reorganization. Patients with MS showed altered FC in the early stages of the disease, with FC abnormalities being bidirectional (i.e. increased and decreased FC). Over time, changes in FC, independent of direction, could be related to progression of brain atrophy, which is associated with changes in clinical and cognitive functioning. Connectome stability enables fMRI data to be condensed into a proxy as a cross-sectional and longitudnal individual imaging marker.

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Imaging Poster Presentation

P0579 - FLAIR-only joint volumetric analysis of brain lesions and atrophy in clinically isolated syndrome (CIS) suggestive of MS (ID 395)

Speakers
Presentation Number
P0579
Presentation Topic
Imaging

Abstract

Background

MRI assessment in MS focuses on the presence of typical white matter (WM) lesions. Neurodegeneration characterised by brain atrophy is recognised in the research field as an important prognostic factor. It is not routinely reported clinically, in part due to difficulty in achieving reproducible measurements. Automated MRI quantification of WM lesions and brain volume could provide important clinical monitoring data. In general, lesion quantification relies on both T1 and FLAIR input images, while tissue volumetry relies on T1. However, T1-weighted scans are not routinely included in the clinical MS protocol, limiting the utility of automated quantification.

Objectives

We address this important translational challenge by assessing the performance of FLAIR-only lesion and brain segmentation, against a conventional approach requiring multi-contrast acquisition. We explore whether FLAIR-only grey matter (GM) segmentation yields more variability in performance compared with two-channel segmentation; whether this is related to field strength; and whether the results meet a level of clinical acceptability demonstrated by the ability to reproduce established biological associations.

Methods

We used a multicentre dataset of subjects with a CIS suggestive of MS scanned at 1.5T and 3T in the same week. WM lesions were manually segmented by two raters, ‘manual 1’ guided by consensus reading of CIS-specific lesions and ‘manual 2’ by any WM hyperintensity. An existing brain segmentation method was adapted for FLAIR-only input. Automated segmentation of WM hyperintensity and brain volumes were performed with conventional (T1/T1+FLAIR) and FLAIR-only methods.

Results

WM lesion volumes were comparable at 3T between ‘manual 2’, T1+FLAIR and FLAIR-only methods. For cortical GM volume, linear regression measures between conventional and FLAIR-only segmentation were high (1.5T: α=1.029, R2=0.997, standard error (SE)= 0.007; 3T: α=1.019, R2=0.998, SE=0.006). Age-associated change in cortical GM volume was a significant covariate in both T1 (p=0.001) and FLAIR-only (p=0.005) methods, confirming the expected relationship between age and GM volume for FLAIR-only segmentations.

Conclusions

FLAIR-only automated frameworks for segmentation of WM lesions and brain volumes were consistent with results obtained through conventional methods and had the ability to demonstrate biological effects in our study population. This could facilitate the integration of automated WM lesion volume and brain atrophy analysis as clinical tools in radiological MS reporting.

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Imaging Poster Presentation

P0580 - Focal inflammatory activity and lesion repair are associated with brain atrophy rates in MS patients (ID 1092)

Abstract

Background

The pathogenesis of neurodegeneration in multiple sclerosis (MS) is multifactorial and the determinants of brain atrophy rates are not completely understood.

Objectives

To investigate the association between annualized atrophy rate (AAR) of multiple brain measures (regional cortical thickness (CTh), volumes of basal ganglia, thalamus, white matter, gray matter, brain and brain parenchymal fraction (BPF)) and: (1) annualized rate of new and enlarging white matter lesions (WMLs); (2) annualized rate of resolved WMLs; (3) occurrence of progression independent of relapse activity (PIRA) during follow-up.

Methods

We included 1573 1.5T or 3T brain MRI scans from 378 patients of the Swiss MS Cohort Study (331 relapsing-remitting MS (RRMS), 27 clinically isolated syndrome (CIS), 11 secondary-progressive MS (SPMS), 9 primary-progressive MS (PPMS); 70% female; median age: 41.9 yrs; disease duration: 8.3 yrs; EDSS: 2.0; follow-up time: 4.0 yrs). Longitudinal changes in WMLs were obtained using an automated prototype (LeMan-PV). Brain volumes and CTh AARs were obtained using FreeSurfer longitudinal pipeline (v6.0) after WMLs filling. In patients fulfilling PIRA an EDSS progression had to be confirmed ≥6 months after the index event. Multivariable generalized linear models were used to model the association between AAR (dependent variable) and independent variables (1-3), correcting for age, sex, disease duration and baseline EDSS. p-values were adjusted for Bonferroni multiple comparison correction; for vertex-wise CTh analysis, Monte Carlo Z simulation was performed (cluster threshold p<0.05).

Results

We found positive associations between annualized rate of new and enlarging WMLs and (i) CTh AAR of 8 extensive clusters (bilateral frontal, temporal and occipital regions and right insula, all p<0.01) and (ii) AAR of: caudate bilaterally (p=0.02), white matter volume, brain volume and BPF (p<0.001 for all).

We also found a negative association between annualized rate of resolved WMLs and CTh AAR in 3 cortical clusters (right insula, precentral area and anterior cingulate region, all p<0.05); no associations with AAR of volumes emerged.

57 patients fulfilled PIRA whereas 295 experienced no EDSS progression events: no significant differences in AAR measures were found between these two groups.

Conclusions

In a large cohort of MS patients, with a median follow-up of 4 years, local radiological inflammatory and reparative activity were associated with AAR in multiple brain regions. PIRA did not seem to be related to increased AAR in any of the regions studied.

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Imaging Poster Presentation

P0581 - Gradient echo magnetic resonance imaging to detect central vein sign in patients with Multiple Sclerosis (ID 1528)

Speakers
Presentation Number
P0581
Presentation Topic
Imaging

Abstract

Background

Diagnostic criteria for multiple sclerosis (MS) have undergone several iterations in the past 20 years, resulting in increased sensitivity and earlier diagnosis, but also increased misdiagnoses due to reduced specificity. Biomarkers are needed to distinguish MS from its mimics and between MS subtypes. MS lesions in white matter (WM) typically form around a central vein, which can be visualized with FLAIR* imaging (Sati, et al, 2012). Central vein sign (CVS) presence on MRI can help differentiate MS from other diseases with WM T2-weighted hyperintensities and may increase the sensitivity and specificity of MS diagnosis.

Objectives

To apply MRI-based gradient echo plural contrast imaging (GEPCI) approach (Luo, et al, 2012) to generate FLAIR*-like images and detect CVS in patients with progressive MS (PMS) and relapsing remitting MS (RRMS). To quantitatively evaluate tissue damage in lesions with and without CVS using tissue-specific GEPCI R2t* metric (Xiang, et al, 2019).

Methods

MRI scans of PMS (n=39) and RRMS subjects (n=30) were analyzed for the CVS within WM lesions. Presence of CVS, lesion volume, and anatomic location were determined. To quantitatively evaluate the severity of brain-tissue damage in MS lesions, mean R2t* was calculated. R2t* is a quantitative measure that correlates with brain tissue cellular density and is decreased in areas of reduced tissue integrity. The proportion of total lesions with CVS was calculated, excluding confluent lesions and lesions with more than 1 central vein. Median proportions in PMS and RRMS subjects were compared using the Wilcoxon sign rank test. Individual lesion CVS status was examined using generalized linear models. Linear mixed models adjusted for age were used to evaluate predictors of mean R2t* in nonconfluent lesions with only one central vein of sufficient size. Associations of CVS and clinical data from time of MRI scan, including Expanded Disability Status Scale (EDSS), symbol digit modality test (SDMT), and multiple sclerosis functional composite (MSFC) were made using Spearman correlations.

Results

The PMS group had significantly higher EDSS scores and poorer performance on SDMT and MSFC than the RRMS group. There were no significant differences in total CVS and percentage of CVS per lesion between MS subtypes. Controlling for age, EDSS, and lesion volume did not increase the odds of either group having CVS. Lesions with CVS had lower R2t* (greater tissue damage). However, accounting for MS type, age, and lesion count reduced significance (p = 0.09). Mean R2t* was significantly lower in PMS than RRMS (p = 0.027) and declined with age (p = 0.023).

Conclusions

This study did not find that the presence of CVS could distinguish between patients with RRMS and PMS. Our data suggest that lesions with CVS have more tissue damage. Due to reduced significance after accounting for additional variables, further studies with more patients are needed.

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Imaging Poster Presentation

P0582 - High resolution functional mapping of upper and lower limb sensorimotor function in minimally disabled people with multiple sclerosis using 7T MRI (ID 1050)

Speakers
Presentation Number
P0582
Presentation Topic
Imaging

Abstract

Background

In multiple sclerosis (MS) upper and lower limbs can be affected, but impairments only moderately relate to each other. Previous motor task studies have focussed predominantly on imaging hand function at clinical field strengths, preventing the detection of subtle changes and differentiation of mechanisms underlying subtle motor impairment.

Objectives

To investigate functional brain changes related to upper and/or lower limb motor task performance in minimally disabled MS patients using ultra-high field MRI.

Methods

Twenty-eight MS patients and seventeen healthy controls underwent visually-guided force-matching fMRI tasks using either hand or foot. Task performance (force error and lag) and activation level during upper and lower limb movements were compared between groups. Correlations were assessed between task activation and behavioural performance.

Results

During lower limb force tracking, MS patients showed significantly (p<0.01) longer lag, higher force error, higher primary motor and premotor cortex activation and lower cerebellar Crus I/II activation, compared to controls. No differences were seen in upper limb performance or activation. Upper and lower limb task performance was related to the level of activation in cerebellar, visual and motor areas in MS patients.

Conclusions

Altered lower limb movements and brain activation with preserved upper limb function and activation in minimally disabled patients suggests partially divergent functional mechanisms underlying upper and lower limb disability.

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Imaging Poster Presentation

P0583 - High throughput lesion evaluation and quality control for incorporating quantitative imaging metrics into clinical practice (ID 1502)

Speakers
Presentation Number
P0583
Presentation Topic
Imaging

Abstract

Background

Automated multiple sclerosis lesion counts and volumes are poised to be salient clinical biomarkers of disease progression; however, algorithmic variability and low expert agreement prevents widespread adoption in clinical practice. Because every method has a non-negligible error rate, visual quality control (QC) is required before a clinical decision can be made. QC is a bottleneck to the use of automated lesion count and volume metrics in the clinic. A method is needed to 1) quickly evaluate experts and non-experts to understand and resolve disagreements, and 2) quickly QC the output of automated lesion segmentation methods.

Objectives

To evaluate the feasibility of a web application called braindr (Keshavan et al., 2019) for high-throughput QC of automated lesion segmentation by measuring the 1) intra-rater reliability, 2) the inter-rater reliability, and 3) to characterize the types of lesions that are disagreed upon.

Methods

3D T1 and FLAIR images from 32 subjects were registered, N4 bias field corrected, and z-scored. Subtraction images (Z_FLAIR-Z_T1) were thresholded at varying levels. A triplanar image of each resulting segmentation (called a potential lesion, PL) was generated, resulting in over 80,000 individual PL’s needing QC, which simulates a high-throughput scenario with a high error rate. Expert and non-expert raters were asked to pass or fail PLs based on the 2D triplanar image on the app. We measured variability between and within raters by calculating the intraclass correlation coefficients (ICC).

Results

1) Feasibility: 14,973 PLs were labelled by 5 raters. The raters were a neuroradiologist (MI), a general neurologist (BD), 2 experienced technicians (AK, KL), and 1 beginner (MB). 2) Intra-rater reliability (ICC(1,1)) : a) neuroradiologist: 0.97, b) beginner: 0.90, c) experienced techs: 0.87, 0.85, and d) neurologist: 0.84. 3) Inter-rater reliability for an average rating ICC(2,k) = 0.92, and individual ICC(2,1) = 0.74. 4) Disagreements occurred more frequently on PL’s in the brainstem, cerebellum, hippocampal, and basal ganglia.

Conclusions

We simultaneously evaluated raters, and QC’d lesions from an automated method using a quick, scalable, web application. This enables us to 1) improve expert agreement on lesion identification, 2) develop better quality education materials for experts and non-experts alike, 3) train new raters quickly, and 4) ensure the quality of the measurements at scale.

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Imaging Poster Presentation

P0584 - Histological analysis of slowly expanding lesions in multiple sclerosis: case report (ID 878)

Speakers
Presentation Number
P0584
Presentation Topic
Imaging

Abstract

Background

Slowly expanding lesions (SELs) can be detected on conventional in vivo brain magnetic resonance imaging (MRI). Previous studies suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. Histopathological characterization of SELs are still not fully investigated.

Objectives

To characterize SEL regions using in vivo MRIs and postmortem brain tissue, and compare the difference between SEL and non-SEL regions.

Methods

We identified an autopsy case with secondary progressive MS (male, age=51 years, disease duration=23 years), who had standardized in vivo MRIs. The interval between the last in vivo MRI and death was 7 weeks. From the last two years of in vivo MRIs, T2 lesions were segmented, and the Jacobian determinants of nonlinear registration between baseline and follow-up scans were calculated. SELs were identified as regions with small local constant and concentric expansion from baseline lesions. We identified 11 regions-of-interest (ROI): 10 T2 lesions (3 SELs and 7 non-SEL) and 1 normal-appearing white matter (NAWM). Using a custom brain cutting box with MRI-visible markers, the in vivo ROIs were localized on the corresponding brain slice. The ROIs were blocked and stained for proteolipid protein, SMI-31/32, and MHC class II. We then evaluated myelin status, axonal diameter, axonal loss, and inflammatory activity in ROIs.

Results

The NAWM region was myelinated, the axonal diameter was 0.74 um, and axonal density was 23.4%. In the SEL regions, the mean axonal diameter was 1.11 um, and mean axonal density was 17.5%. In non-SEL regions, the mean axonal diameter was 0.84 um, and mean axonal density was 15.7%.

Two SEL and 4 non-SEL regions were demyelinated. The demyelinated SEL regions had activated microglia at the lesion edge and were compatible with chronic active lesions. Three demyelinated non-SEL regions also had activated microglia at the edge. One demyelinated non-SEL region was a chronic inactive lesion. No microglia activity was observed in any of the myelinated non-SEL regions. In the myelinated SEL region, the density of activated microglia was higher compared to NAWM.

Conclusions

Not all SEL regions in T2 lesions were demyelinated. SEL also had greater axonal diameters suggesting of axonal swelling. In this case report, all of the demyelinated SEL regions had activated microglia at the lesion edge.

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Imaging Poster Presentation

P0585 - Hurst exponent as an imaging biomarker of impairment in multiple sclerosis (ID 1426)

Speakers
Presentation Number
P0585
Presentation Topic
Imaging

Abstract

Background

Hurst Exponent (HE) is a scalar measurement of long-term temporal memory of a time series. The HE has been found in previous studies to be an effective means of measuring the long-range temporal dependence of brain activity as measured by fMRI. We hypothesize that the HE can be associated with impairment in Multiple Sclerosis (MS), therefore can be an imaging biomarker of MS.

Objectives

The primary goal of the study is to assess how well HE measurements can distinguish MS patients from healthy controls (HC), as well as MS patients with impairment from those without impairment. The second objective was to identify which brain regions’ HE alterations are associated with impairment in MS.

Methods

Fifteen HC (age: 43.66±8.64, 53% female) and 76 MS patients (age:45.28±11.46 years, 65% female, disease duration:12.29±7.25 years) were included in our study; 23 had EDSS2 at study baseline. Logistic ridge regression (LR) was used to classify two groups: (1) HC vs MS patients and (2) MS patients with vs without impairment. The classification tasks were performed using HE measurements in 86 cortical and subcortical regions. Five-fold cross-validation was used to train, validate, and test the model, with 10 outer loop repetitions. Area Under ROC curve (AUC) over the folds was used to assess classification performance.

Results

HE was found to be significantly higher in the non-impaired group compared to the impaired group in the right superior frontal gyrus (corrected p-value=0.025). The classification of HC vs MS had an AUC of 0.65 (IQR:0.18), while the task of classifying MS patients by impairment level had an AUC of 0.63 (IQR: 0.12). For the classification of HC vs MS, the regions that were the most predictive were in deep gray matter. Lower HE in the left amygdala, left thalamus and left putamen, and higher HE in the left hippocampus was associated with MS. For the classification of impairment level in MS, deep gray matter regions were also important, as were HE in the frontal lobe. Lower HE in the left caudate, right and left amygdala, and left superior frontal and higher HE in the right ventral DC were associated with more impairment in MS.

Conclusions

HE was found to be moderately discriminative between HC and MS and within impairment levels in MS. HE in subcortical and superior frontal regions were found to be important biomarkers of impairment severity in MS, as well as in distinguishing MS patients from HC. Further research is necessary to identify the mechanism driving these differences.

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Imaging Poster Presentation

P0586 - Impact of Cladribine Tablets on Brain Volume Protection in Highly Active MS (ID 1173)

Speakers
Presentation Number
P0586
Presentation Topic
Imaging

Abstract

Background

Brain volumetry is an accepted monitoring tool for the diffuse, not relapse-related inflammatory activity in MS. As thalamus volume turned out to be most affected by the atrophic process in MS, a special focus is put on this region.

Objectives

We present first data from our ongoing study, addressing the effect of Cladribine Tablets on global and regional brain atrophy.

Methods

45 consecutive patients with highly active MS from our observational study are presented (mean age 39 y, mean EDSS 2.1, 31 female, 14 male). Clinical and brain MRI evaluations were carried out at baseline prior to Cladribine treatment and repeated after 6 and 12 months following Cladribine treatment initialization. All images were acquired with the same 3T Philips Achieva scanner using the same 3D MPRAGE protocol. Global and regional brain volumes were derived using a previously described atlas based volumetry approach implemented in SPM12 in cooperation with jung diagnostics. Quantified parameters include brain parenchymal volume (BPV), grey matter volume (GMV), white matter volume (WMV), Corpus callosum volume (CCV) and thalamus volume (THV). All atrophy parameters of the single subjects were tested against the normative database. All volumes were tranformated to age-corrected z-volumes. Z<-1.96 means significant atrophy. 0.0 equals the mean of the normative database.

Results

As expected, at baseline the regional brain volumetry revealed the highest pretreatment mean loss in THV, e.g. the highest sensitivity for the atrophic process in thalamus (z= -1.64), followed by CCV (z=-1.22), WMV (z=-1.67) and GMV (z=-0.54). 6 and 12 months after Cladribine initialization the z-differences from baseline to first visit and second visit to third visit were for BPV +0.21, -0.11; GMV +0.18, +0.01; WMV +0.07, -0.18; THV +0.21, +0.06; CCV +0.13, +0.02. GMV, THV and CCV are fully protected by Cladribine tablets for the entire first treatment year. For WMV and BPV respectively there is a slight trend to volume reduction. The z-difference in the second half of the first treatment year equals an estimated annual volume loss of age-corrected 0.2% which is still an excellent effect.

Conclusions

From the first data of this ongoing study can be concluded that the first treatment period with Cladribine tablets fully protects GMV including the highly sensitive thalamus. With the exception of CCV with good protection, the effect of Cladribine on WMV seems to decrease in the second half of the first treatment year.

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Imaging Poster Presentation

P0587 - Impact of siponimod on myelination as assessed by MTR across SPMS subgroups: Post-hoc analysis from the EXPAND MRI substudy (ID 1588)

Speakers
Presentation Number
P0587
Presentation Topic
Imaging

Abstract

Background

Changes in magnetization transfer ratio (MTR) are a marker of changes in myelin density and associated tissue integrity in the brain. Siponimod improved MTR recovery in lesions and demonstrated a significant effect on MTR decrease in normal-appearing brain tissue (NABT) and cortical grey matter (cGM) with a more pronounced effect on normal-appearing white matter (NAWM) in the overall EXPAND secondary progressive multiple sclerosis (SPMS) population, as reported previously.

Objectives

To investigate the effect of siponimod vs placebo (PBO) on MTR changes in NABT, cGM, and NAWM in subgroups of SPMS patients.

Methods

This prospective MTR substudy assessed the effect of siponimod versus PBO on median normalized MTR (nMTR) in NABT, cGM and NAWM assessed by absolute change from baseline (BL) to Month (M) 24 using repeated measures models. Patient subgroups were defined by: disease history and severity (age [≤45/>45 years], disease duration [≤15/>15 years], Expanded Disability Status Scale (EDSS) score [≤5.5/≥6.0], Symbol Digit Modalities Test score (≤43/>43); and inflammatory disease activity (active/non-active SPMS, with/without relapse in 2 years before screening, with/without gadolinium-enhancing lesions). Data from the per-protocol set (n=443) are presented.

Results

The subgroup analysis indicated that absolute changes from BL in median nMTR for NAWM ranged from –0.124 to –0.034 in the PBO group and from –0.016 to 0.040 in the siponimod group, which corresponds to 79–198% attenuation in median nMTR decrease versus PBO across all the subgroups studied (all p<0.05 except EDSS≥6 subgroup, p=0.064). The results were consistent for NABT (70–170%) and cGM (44–188%) although slightly less pronounced (p>0.05 for some subgroups). In the active SPMS subgroup, siponimod attenuated median nMTR decrease across NABT, cGM and NAWM by 91–109% (p<0.01 all); and in the non-active SPMS subgroup by 170–198% (p=0.0151 for NAWM, p>0.05 for NABT, cGM).

Conclusions

Over 24 months, siponimod attenuated the decrease in median nMTR in brain tissues across the patient subgroups characterized by disease activity and severity. The effect of siponimod was most pronounced in NAWM. These data support preclinical studies of siponimod, showing direct beneficial CNS effects on myelination.

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Imaging Poster Presentation

P0588 - Implementation strategy of an international standardized MRI protocol for the diagnosis and follow-up of MS patients (ID 1905)

Speakers
Presentation Number
P0588
Presentation Topic
Imaging

Abstract

Background

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines.

Objectives

The goal is to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination and implementation.

Methods

The CMSC convened an expert panel in October 2019 to update the standardized MRI protocol. Conference attendees included neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Representatives from CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocol, gadolinium, diffusion weighted imaging, and the central vein sign.

Results

95 neurologists completed the survey. 34% use the CMSC protocol. 48% use a standardized MRI protocol but are uncertain if it is similar to CMSC guidelines. 51% continue to use gadolinium for routine imaging. 58% wanted the central vein sign to be included in the diagnostic work up of MS. 87% were interested in monitoring brain volume and 10% were doing it routinely. The panel worked to harmonize CMSC and MAGNIMS MRI protocols so the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences and exam cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use.

Conclusions

The international expert group developed revised clinical MRI guidelines with the vision and action plans for them to be universally useful and useable and become the standard of care for patients with MS.

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Imaging Poster Presentation

P0589 - Implications of registration of white matter structures for MS connectome analysis (ID 1945)

Speakers
Presentation Number
P0589
Presentation Topic
Imaging

Abstract

Background

To assess the connectome disruption in patients with multiple sclerosis (MS), methods have been developed that utilise connectomes derived from healthy controls (HC) which require the accurate registration of white matter structures from patients with MS onto HCs whole brain streamline tractograms.

MRI T1 based image registration may be inaccurately mapped to HC derived tractograms due to the lack of information within the relatively homogenous T1 signal of white matter.

Fibre orientation distributions (FODs), created by the constrained spherical deconvolution (CSD) model of white matter diffusion data, have the potential to improve white matter registration as it holds information of all fibre directions for each voxel.

Objectives

Here we compare the accuracy and utility of FOD-based, T1-based and FA-based registration of white matter tracts in MS.

Methods

10 MS patients and 10 age matched healthy controls underwent 3T MRI scanning including 1mm 3D T1 and single shell diffusion weighted imaging. FOD maps were created using CSD algorithm designed for single shell data. Tensor and FA maps were created.

Non-linear registration was undertaken directly from each patient to each control (ie. 100 warps) with ANTs using T1 and FA images, and through an MNI template intermediary.

Registration was performed directly from each patient to controls using FOD maps using MRtrix3 FOD-based registration, as well as through a custom population FOD template.

Each registration method was assessed in transforming three white matter tracts, corticospinal tracts (CST), anterior thalamic radiations (ATR) and optic radiations (OR), from patients to controls. The resultant transformed segmentations from each registration method was compared to the control segmentation by calculating its Dice coefficient.

Further to this each method was assessed using a tract segmentation that had the cortical ribbon and juxtacortical tract removed.

Statistically significant differences were assessed by non-parametric Kruskal-Wallis test with Dunn’s post hoc testing.

Results

For combination of all tracts, the highest Dice coefficients were with direct FA (median = 0.727, IQR 0.06215) and direct T1 (median = 0.72185, IQR 0.056525) with no significant difference found.

For combination of all cropped tracts, the highest Dice coefficients were with FOD population template (median = 0.7673, IQR 0.0468), direct FOD (median = 0.76565, IQR 0.050175) and direct FA registration (median = 0.7626, IQR 0.060025) with no significant difference found.

When utilising an intermediary template, both T1 and FA based methods performed worse, whereas the FOD population template performed similarly.

Conclusions

FA and T1 based registration outperformed FOD based, despite more white matter information. This was driven by poorer juxtacortical registration in the FOD based method. This is important in the analysis of MS due to the high prevalence of juxtacortical lesional pathology.

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Imaging Poster Presentation

P0590 - Improved detection of clinically relevant MRI findings in Multiple Sclerosis radiology reports using FDA-approved quantitative software (ID 1501)

Speakers
Presentation Number
P0590
Presentation Topic
Imaging

Abstract

Background

Quantitative metrics such as lesion count and brain volume can provide objective data of disease progression in Multiple Sclerosis (MS). However, implementing FDA-approved quantitative software in clinical practice requires significant effort and investment. It has not yet been established if quantitative software can consistently improve the detection of clinically relevant MRI findings in MS-specific radiology reports.

Objectives

To characterize clinically relevant findings in MS-specific radiology reports generated by a neuroradiologist after visual interpretation of images alone and with FDA-approved software.

Methods

26 patients with MS who had MRIs performed between 2013-2017 were retrospectively selected from an anonymized database. Each patient had 2 MRIs (average 1 year apart) consisting of 3D T1 and T2 FLAIR sequences. Images were processed using FDA-approved software (NeuroQuant and LesionQuant 3.0.1) to generate lesion count and brain volume data and a color-coded map that highlighted lesion changes between MRI timepoints.

A neuroradiologist visually compared MRIs in each patient and reported the number of new, enlarging, shrinking, and enhancing lesions, and provided an assessment of brain atrophy in a qualitative report (qual). To avoid recall bias, cases were randomized and re-anonymized, and one month later, the neuroradiologist used the post-processed data and images to generate a second quantitative report (quant). Interpretation time was recorded during both sessions. Two neuroimaging experts coded differences in the reports and verified lesion accuracy.

Results

Upon review of qual reports, a total of 44 new, 10 enlarging, and 5 shrinking T2 lesions and 3 enhancing lesions were reported, compared with 50 new, 15 enlarging, 8 shrinking, and 3 enhancing lesions on quant reports. Of the 13 cases that reported differences in lesion counts, one additional new lesion, on average, was detected in quant reports (SD= 2.4). Brain atrophy descriptions changed with the addition of quantitative metrics in 7 cases, where 5 cases were upgraded and 2 cases were downgraded in severity. No significant difference (p=.16, paired t-test) was found in interpretation time (qual 12.3 minutes; quant 11.4 minutes).

Conclusions

The use of FDA-approved quantitative software improved the detection of clinically relevant neuroimaging findings in MS patients, without adding time to image interpretation, suggesting its potential value in clinical practice.

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Imaging Poster Presentation

P0591 - In vivo cortical lesions detection as an early hallmark of multiple sclerosis. (ID 901)

Abstract

Background

Ultra-high field MRI highlighted the crucial role of cortical injury in multiple sclerosis (MS). Cortical pathology is frequent in MS, and seems to be more pronounced in progressive stages of the disease. One aspect of cortical pathology is represented by focal cortical lesions (CL).

Pioneering studies demonstrated the high frequency of CL in MS, their independence from white matter injury and their clinical relevance, particularly for cognitive impairment. Nevertheless, very few is known about their presence from the onset of the disease, their dynamics of apparition, neither the differential impact of intracortical (IC) and leukocortical (LC) lesions in early MS.

Objectives

The present study aims to assess the prevalence, the topography and the clinical counterpart of cortical lesions in patients included in the first year of MS.

Methods

16 MS patients in the first year of their disease course and 12 matched controls were included. All subjects underwent a 7T brain MRI scan designed to maximize the accuracy of CL detection (sequences: MP2RAGE, FLAIR, FLAWS with 600μm3 isotropic resolution and T2*/QSM with 600μm2 in-plane resolution and thickness of 600μm, total acquisition time 58 min). EDSS and MSFC were performed by rated physicians.

Radiological analysis: a cortical lesion was considered in case of signal change with identifiable boundaries compared to adjacent cortex on MP2RAGE, confirmed by at least one other sequence (FLAIR, FLAWS and T2*/QSM), excluding anatomical structure (eg vessels). CL were divided into two groups according to their location: leukocortical when the lesion extended across both white matter (WM) and grey matter (GM) and intracortical when the lesion is exclusively located within the GM. WM lesions were depicted on MP2RAGE and FLAIR sequences with a 3 mm minimal size.

Statistical analysis: patients and lesions descriptive data were presented with means and standard deviation (SD). Spearman correlations were performed between cortical and WM lesions count and clinical evaluations.

Results

Patients' caracteristics: 13 females, 3 males; mean age = 33 yo (SD = 9); mean disease duration = 6 months (SD = 3); mean EDSS = 0.28 (SD=0.51); mean relapse = 1.68 (SD = 1.01).

399 cortical lesions were detected in 14 patients (mean = 11.68, SD = 12.32). Among them 211 LC lesions were seen in 11 patients and 187 IC lesions in 14 patients. Mean number of WM lesions was 27 (SD = 27.45), mean volume was 2.15 mL (SD = 2.75). LC lesions were significantly correlated with WM lesions (ρ=0.91, p<.001). In opposite, IC lesions were not correlated with WM lesions (ρ=0.49, p=0.05) nor LC lesions (ρ=042, p=0.09). No lesions were seen in controls.

No correlations were found between cortical lesions and EDSS nor MSFC.

Conclusions

We evidenced that the prevalence of cortical lesions is very high at the earliest stage of MS and is not correlated with white matter impairment. This study confirms the accuracy of MP2RAGE to depicit these lesions.

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Imaging Poster Presentation

P0592 - In-clinic performance of MSPie, an image analysis prototype for automated MRI quantitative point-of-care metrics in MS (ID 1310)

Abstract

Background

Automated and reproducible measures of MS severity and subclinical inflammatory activity and neurodegeneration in routine practice could support therapeutic decisions and accelerate research. Toward this goal, we developed and validated a software prototype, MSPie (MS PATHS Image Evaluation). MSPie runs on syngo.via Frontier (Siemens Healthcare, Erlangen, Germany) and processes standardized T2 FLAIR and T1-weighted MRIs to quantify brain parenchymal fraction (BPF), T2 lesion volume, and #new/enlarging T2 lesions (NET2L). Results are reviewable by radiologists through an interface that displays current, prior, and subtraction images, as well as overlays of brain and lesion segmentations, and allows +/- corrections of NET2L.

Objectives

To assess an image analysis prototype integrated into radiological practice to generate quantitative brain volume and lesion measurements at the point of care.

Methods

MSPie was installed at 2 MS Partners Advancing Technology and Health Solutions (MS PATHS) institutions. 3 neuroradiologists per institution used MSPie to review 40 longitudinal pairs of routine MS PATHS MRIs. For each case, radiologists performed a visual assessment of the brain segmentation used for BPF, manually corrected NET2L if needed, approved or rejected the results, and completed a performance evaluation survey.

Results

MSPie performance was assessed in 240 cases. Radiologists accepted MSPie-generated BPF and lesion results for 230/240 cases (96%). 38.8% of cases required corrections of false positive (FP) or false negative (FN) NET2L, with a mean of 2.5 (FP+FN) NET2L per case. In 94% of cases, NET2L FP+FN was £3, a prespecified design target based on radiologists’ input. MSPie detected 221/229 true NET2L, yielding a sensitivity of 96.2%. In 18% of cases, radiologists reported MSPie-detected NET2L they would have missed. Mean performance ratings on a scale of 1(poor) to 5(excellent) were: 3.9 for overall performance; 3.9 for brain segmentation; 3.9 for T2 lesion segmentation.

Conclusions

Incorporation of brain volume and T2 lesion quantification into MS imaging practice is feasible. MSPie demonstrated a high sensitivity for disease activity, detecting some NET2L that might have been missed by radiologists. MSPie achieved the prespecified target rate of acceptable false positive NET2L. MSPie might allow neuroradiologists to provide quantitative brain atrophy and T2 lesion metrics in clinical practice and to increase their diagnostic precision.

Disclosures: MS PATHS is sponsored by Biogen.

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Imaging Poster Presentation

P0593 - Increased perfusion and microstructural damage precede demyelination in newly forming MS lesions (ID 1802)

Speakers
Presentation Number
P0593
Presentation Topic
Imaging

Abstract

Background

Microstructural alterations in the Normal-Appearing White Matter (NAWM) preceeding the onset of a new lesion have been described using advanced MRI in patients with MS. However, the biological substrate of these alterations remains poorly understood due to the lack of specificity of the MRI signal. We have previously shown that Positron Emission Tomography (PET) with 11C-PIB has the potential to quantify myelin content changes in WM lesions. Interestingly, dynamic 11C-PIB PET acquisitions, including early frames, enable the estimation of regional brain perfusion too.

Objectives

To characterize whether perfusion changes, microstructural damage and demyelination could precede lesion appearance on T2-weighted (T2-w) MRI images.

Methods

Longitudinal dynamic 11C-PIB PET and 3T MRI, including diffusion weighted and magnetization transfer imaging, were acquired in 19 active patients with relapsing-remitting MS. Following baseline scans, patients underwent a second evaluation after 1-2 month (n= 10) or after 3-4 months (n=9). Prelesional areas were defined as the baseline NAWM areas which became hyperintensities on the second T2-w image. Logan reference graphical analysis and simplified reference tissue model were respectiveley used to generate voxelwise maps of Distribution Volume Ratio (DVR), and relative delivery (R1) from 11C-PIB images. Myelin content, reflected by DVR, and perfusion, measured by R1, were extracted for each prelesional area and the corresonding contralateral area in the NAWM. Magnetization transfer ratio (MTR), fractional anisotropy (FA), radial and axial diffusivity (RD and AD) were calculated in the same areas. Paired t-test were used to test differences in DVR, R1, MTR, FA, RD and AD between the prelesional and its contralateral areas.

Results

We identified 77 prelesional areas. In the subgroup of patients with a 1-2 months follow-up, prelesional areas (45 out of 77) showed a higher perfusion (8.5%, p=0.03), increased RD (4.2%, p=0.003), lower MTR (-1.2%, p=0.008) and reduced FA (-6.2%, p=0.008), compared to contralateral NAWM areas, while no difference was detected in DVR (p=0.4). No statistical differences were found in the subgroup of patients with a follow-up of 3-4 months.

Conclusions

One-two months before becoming hyperintense on T2-w MRI, prelesional areas are characterized by an increased perfusion associated with microstructural changes, but not by demyelination.

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Imaging Poster Presentation

P0594 - Interpreting brain parenchymal fraction by comparison to healthy volunteers: Initial results from the MS PATHS normative sub-study (ID 1646)

Abstract

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 50th%-ile in 23.4% (“mild MS”) and below the 25th%-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.

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Imaging Poster Presentation

P0595 - Investigating the relation between global structural network measures and serum neurofilament light in multiple sclerosis (ID 1325)

Speakers
Presentation Number
P0595
Presentation Topic
Imaging

Abstract

Background

Neurofilament light polypeptide (NfL) is a neurofilament protein highly expressed in myelinated axons. Increased serum NfL (sNfL) concentration indicates the presence of axonal damage in patients with multiple sclerosis (MS). Until now, the potential effects of this axonal damage on brain connectivity have never been investigated.

Objectives

We studied the relationship between active inflammation measured by sNFL and structural connectivity alterations detectable by global network metrics estimated with diffusion MRI.

Methods

Diffusion MRI, T1-weighted and FLAIR sequences were acquired on 74 patients (44F, 44.9±14.6yrs, 50 relapsing-remitting and 24 progressive) and sNfL levels were measured from blood samples in the same session. Volume of white-matter lesions was computed on FLAIR with an automatic in-house tool. To build the connectomes we 1) performed deterministic tractography on diffusion MRI, 2) segmented the grey matter in 85 regions using T1 images, and 3) quantified the connection strength of each pair of regions by counting the streamlines between them. From each connectome we extracted 5 global metrics: Density (ratio between actual and possible connections), Efficiency (capability of transferring and processing information); Modularity (network segregation); Clustering Coefficient (degree to which nodes tend to cluster together); Mean Strength (average of the sum of the edge weights connected to a node). Since discrepancies in density may affect other metrics, we first tested its correlation with sNFL, then we performed partial correlations of the last 4 metrics with sNFL using age, sex and density as covariates.

Results

We found negative correlation between density and sNfL (R=-0.252 p=0.05) indicating that high axonal damage is associated with reduced number of connections. Efficiency and mean strength showed a strong anti-correlation with sNfL (R=-0.325 p=0.011 and R=-0.475 p<0.001), while modularity and clustering coefficient seemed not related to axonal damage (R=0.183 p=0.162 and R=-0.215 p=0.099). Finally, a positive association with sNfL was found for both the lesions volume and the Expansion Disability Status Scale (p=0.011 R=0.323 and p=0.038 R=0.267), confirming previous results.

Conclusions

We showed that high values of sNfL are associated with global connectivity damage (reduced number of connections, efficiency and mean strength) confirming the utility of network-based connectivity metrics to assess MS disease impact.

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Imaging Poster Presentation

P0596 - Investigation of lesion volume dynamics in MS patients as detected by Voxel-Guided Morphometry – A multi center study (ID 1485)

Speakers
Presentation Number
P0596
Presentation Topic
Imaging

Abstract

Background

Chronic active lesions (‘smoldering lesions’) in MS patients have recently gained increasing interest as possible markers of MS activity. Yet there is no in vivo marker to detect these lesions and characterize their structural dynamics.

Objectives

Our objective was to detect chronic active lesions in MS patients and characterize their intraindividual volume dynamics over time.

Methods

581 MRI datasets in 200 relapsing-remitting MS patients (2 - 5 per individual) from a 3-year multi-centre observational INSPIRATION-MRI study were investigated using Voxel-Guided-Morphometry (VGM), a method for intraindividual detection and quantification of structural changes in volumetric MRI scans (T1 – weighted MPRAGE-sequence) over time. Chronic active lesions were identified and differentiated into chronic shrinking vs. chronic enlarging lesions.

Results

Intervals between consecutive scans varied between 53 and 1199 days, mean = 443 days. Overall, individual MRI scan intervals varied between 53 (2 scans) and 1360 (3 scans) days. In total, 2419 active lesions were identified, characterized and quantified, corresponding to a mean active lesion load of 12 lesions per patient. In chronic shrinking lesions, mean volume change was -33% (from -11% to -59%), in chronic enlarging lesions mean volume change was +53% (from 29% to 425%). We found a mean annual volume decrease for white matter of 0.17% and gray matter of 0.12%. 31 patients exclusively demonstrated chronic enlarging lesions, in 16 patients only chronic shrinking lesions were detected, and 119 patients were found to have a mixture of both types of active lesions. In 34 patients, no active lesions were identified.

Conclusions

Chronic active lesions were detected in 83% of the investigated patients using Voxel-Guided-Morphometry in longitudinal 3D-MRI datasets. As these chronic active lesions are supposed to represent MS activity with corresponding brain tissue damage also in patients who do not demonstrate new contrast-enhancing lesions, they might be regarded as an additional biomarker for MS activity. The relationship between chronic active brain tissue lesions and clinical MS progression needs to be further investigated.

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Imaging Poster Presentation

P0597 - Lesional myelin repair, as measured with positron emission tomography, effectively protects the integrity of surrounding tissues (ID 1889)

Speakers
Presentation Number
P0597
Presentation Topic
Imaging

Abstract

Background

In multiple sclerosis (MS), pathological changes are not limited to lesions, but extensively involve normal-appearing tissues, being more pronounced in perilesions. Histological studies have shown that the pathological changes affecting perilesions mainly result from the ongoing damage in demyelinating lesions. Similarly, the structural integrity of perilesions could depend on the extent of myelin repair at the lesional level, which can be explored in vivo by positron emission tomography (PET) with 11C-PiB.

Objectives

To assess in a longitudinal study whether myelin content changes in white matter lesions, measured with 11C-PiB PET, influence the microstructural integrity of the surrounding perilesions over time, explored by diffusion tensor imaging and magnetization transfer (MT)-derived metrics.

Methods

Nineteen patients with MS underwent a longitudinal PET/MRI study. Voxel-wise maps of 11C-PiB distribution volume ratio, reflecting myelin content, were used to calculate for each patient in each non-enhancing lesion 3 indices of myelin content change: the percentage of demyelinated voxels at baseline, and the percentage of demyelinating and remyelinating voxels over the follow-up. From each 3 mm-thick perilesional area surrounding lesions, the change over time (delta) of fractional anisotropy (FA), mean diffusivity (MD) and MT ratio (MTR), reflecting microstructural damage, was calculated. Associations between the indices of myelin content change and the delta FA, MD, and MTR in perilesions were assessed using multivariate linear regressions. Perilesions were classified in “improving” or “worsening” according to the sign of the change of the microstructural parameters and a multivariate logistic regression was used to test which PET-derived index was independently associated with perilesion class.

Results

A higher percentage of demyelinated voxels at baseline and of demyelinating voxels over the follow-up inside lesions were associated with a more severe microstructural damage developing over time in perilesions (p<0.001). Conversely, a higher percentage of remyelinating lesional voxels correlated with a more preserved perilesional microstructure at the follow-up (p<0.001). The percentage of remyelinating voxels inside lesions was the only independent predictor of perilesion improvement (p=0.001). We found that at least 43% of the demyelinated volume had to remyelinate to predict a favorable evolution of the microstructure of perilesional tissue (AUC=0.8).

Conclusions

Lesional remyelination effectively protects the integrity of surrounding tissues over time, possibly by reducing the extent of Wallerian degeneration and rescuing damaged axons.

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Imaging Poster Presentation

P0598 - LesionQuant for assessment of MRI in multiple sclerosis- a promising supplement to the visual scan inspection  (ID 670)

Speakers
Presentation Number
P0598
Presentation Topic
Imaging

Abstract

Background

Quantitative measurements of lesion volume, lesion count, distribution of lesions and brain atrophy have a potentially significant value for evaluating disease progression in multiple sclerosis (MS).

Objectives

We wanted to investigate whether utilizing a software designed for evaluating MRI data in MS would be more sensitive and clinically useful compared to the visual neuro-radiological evaluation.

Methods

A group of 56 MS patients (mean age 35 years, 70 % females and 96 % relapsing-remitting MS) was examined with brain MRI one and five years after being diagosed with MS. The T1 and FLAIR brain MRI sequences for all patients were analyzed using the LesionQuant (LQ) software. The resulting LQ output was compared with data from structured visual evaluations of the MRI scans performed by a neuro-radilogist, includning assessements of atrophy and lesion count. Correlations with clinical tests, like the timed 25- foot walk test (T25-FW), were performed to explore additional value of LQ analyses compared to visual assessments.

Results

Lesion count assessments by LQ and by the neuro-radiologist were significantly correlated one year (cor=0.92, p=2.2x10¯16) and five years (cor=0.84, p=2.7x10¯16) after diagnosis. LQ detected a reduction in whole brain percentile >10 in 10 patients across the time-points, whereas the neuro-radiologist assessment identified six of these. The neuro-radiologist additionally identified five patients with increased atrophy in the follow-up period, all of them displayed decreasing low whole brain percentiles (median 11, range 8-28) in the LQ analysis. A significant positive correlation was identified between lesion volume measured by LQ and test performance of T25-FW both at one year (t=3.08, p=3.2x10¯3) and five years (t=3.72, p=4.8x10¯4) after diagnosis, while we found no association between visual inspection and the clinical tests.

Conclusions

For the number of MS lesions at both time-points, we demonstrated strong correlations between the assessments done by LQ and the neuro-radilogist. Lesion volume evaluated with LQ correlated with T25-FW performance. LQ-analyses were more sensitive in capturing brain atrophy than the visual neuro-radiological evaluation. In conclusion, LQ seems like a promising supplement to the evaluation performed by neuro-radiologists, providing an automated tool for evaluating lesions and brain volume in MS patiens in both a longitudinal and cross-sectional setting.

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Imaging Poster Presentation

P0599 - Linking microstructural integrity and motor cortex excitability in multiple sclerosis (ID 1151)

Speakers
Presentation Number
P0599
Presentation Topic
Imaging

Abstract

Background

Motor skills are commonly impaired in patients with multiple sclerosis (MS) as a consequence of gray (GM) and white matter (WM) pathology and cortical excitability abnormalities.

Objectives

We hypothesized that microstructural characteristics of motor regions as assessed with the neurite orientation dispersion and density imaging (NODDI) model predict motor cortical excitability that is frequently altered in MS. Further, we evaluated pathological microstructure alterations in motor WM tracts of MS patients compared to healthy controls (HC) using NODDI in comparison to the diffusion tensor imaging (DTI) parameter fractional anisotropy (FA).

Methods

We applied advanced diffusion imaging in 50 MS patients and 49 age-matched HC. As excitability maker, we assessed resting motor thresholds using non-invasive transcranial magnetic stimulation. For quantification of microstructural integrity of the motor system, neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (IVF) and FA averaged within left primary motor cortex as the stimulation site were considered. We applied hierarchical regression modeling to evaluate the prediction of the resting motor threshold by NDI, ODI, IVF and FA in MS patients and HC. Cognitive-motor performance quantified by the Nine Hole Peg Test and Trail Making Test part A (TMT-A) and part B (TMT-B) was regressed on the diffusion parameters in a subsample of 44 MS patients. In the WM, we applied tract-based spatial statistics with the threshold-free cluster enhancement (TFCE) method within motor tracts comparing MS patients and HC. We tracked contributions of NDI and ODI to FA and evaluated if the NODDI model detects additional pathological alterations.

Results

A hierarchical regression revealed that lower NDI suggestive for axonal loss in the GM significantly predicted higher motor thresholds, i.e. reduced excitability in MS patients (F(1,48) = 7.493, p = .009). Lower NDI was indicative for decreased performance in TMT-A (F(1,42) = 8.102; p = .007) and TMT-B (F(1,42) = 7.390; p = .009). Microstructural abnormalities of the interconnected WM tracts were characterized by lowered FA, decreased NDI and increased ODI in MS (all TFCE-corrected p < .05). NDI exclusively (56%) and in overlap with FA (19%) accounted for the largest amount of differences, followed by ODI alone (9%).

Conclusions

Our work shows that lower neurite density in primary motor cortex is linked to decreased motor cortical excitability and decreased cognitive-motor performance in MS patients. Lower neurite density and higher orientation dispersion are characteristic in the WM of MS patients compared to HC. Our results suggest that these markers are more sensitive to pathological alterations than the classical DTI measure FA. This work outlines the potential of microstructure imaging using advanced biophysical models to forecast neurodegeneration and excitability alterations in neuroinflammation.

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Imaging Poster Presentation

P0600 - Longitudinal evolution of cortical lesions in an Italian cohort of multiple sclerosis patients (ID 731)

Speakers
Presentation Number
P0600
Presentation Topic
Imaging

Abstract

Background

Cortical lesions (CLs) have recently acquired a great relevance in multiple sclerosis (MS), both at diagnosis and during the monitoring of the disease, because of their impact on long-term prognosis. However, there is still limited knowledge about the evolution of CLs in time.

Objectives

The aim of the present observational study was to investigate, retrospectively, the longitudinal evolution of CLs number in comparison to FLAIR-T2 hyperintense white matter lesions (WMLs) in a cohort of MS patients in a single MS centre.

Methods

We included all consecutive patients with a relapse-onset MS referred to MS centre of Parma (Italy) who performed at least two MRI scans including double inversion recovery sequences from 2014 to 2019, collecting demographic, clinical and MRI data.

Results

We included 140 MS patients, 67.9% female, with the following characteristics at first MRI: relapsing-remitting (RR) course in 84.3% and secondary progressive (SP) in 15.7% of cases, mean age 40.1±10.49 years, mean disease duration 169.7±100.75 months, mean EDSS 2.5±1.30, mean number of WMLs 24.8±16.50 and of CLs 2.5±2.87. After a mean follow-up of 51.8±8.32 months we observed a conversion to SP phase in 2.1% and a 3-mo-confirmed EDSS progression in 13.6% of patients, with a mean EDSS of 2.6±1.48 and mean number of relapses of 1.1±1.95. During the follow-up only 3.6% of patients did not take any therapy, while 47.1% and 49.3% were on a first-line and a second-line disease-modifying treatment (DMT), respectively. Occurrence of ≥1 new WML or CL appeared in 37.9% and 12.9% of cases, respectively, with a mean number of new WMLs of 1.8±5.58 and new CLs of 0.2±0.6. New CLs never appeared without concomitant WMLs, but 44.4% of cases with new CLs occurred in patients with 1-2 new WMLs and 26.7% of patients with 1-2 new WMLs had ≥1 new CL. At multivariate analysis the risk of occurrence of new CLs was higher in patients with a higher number of new WMLs at last MRI (OR 1.44, CI95% 1.17-1.78, p=0.001) and lower in those who remained RR (OR 0.04, CI95% 0.002-0.76, p=0.03).

Conclusions

In our cohort we observed an overall low MRI activity, probably related to the high percentage of patients on DMT. New CLs appeared in a small percentage of patients and were strictly related to new WMLs. Nevertheless, they added clinical relevance to a consistent proportion of cases characterised by otherwise minimal MRI activity, with important implications for therapeutic switch.

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Imaging Poster Presentation

P0601 - Longitudinal functional modularisation and causality dynamics during de- and remyelination (ID 1715)

Abstract

Background

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), one of its pathophysiological hallmarks is demyelination, which is known to be involved in neurodegenerative mechanisms.

Objectives

Modular architecture and its dynamic adaptation could play a critical role in achieving flexible alterations of cerebral network architecture during de- and remyelination which is still not fully elucidated.

Methods

We address dynamic adaptation to cuprizone model of general de- and remyelination and ask if network community organization can relate to the longitudinal time events. To start with baseline and then by introducing cuprizone into the diet of mice we induced full CNS demyelination by targeting oligodendrocytes, over a period of 5 weeks (two time points). A subsequent myelin synthesis was allowed over reintroduction of normal food (two time points). To identify the modular organization the resting state fMRI within the graph theory framework was analyzed from each of the five time points. The dynamic network reconfiguration was estimated by flexibility as parameter of modularity allegiance and effective connectivity analyses were applied to test the causality of network dynamics between the identified modules.

Results

We found six modules namely default mode network (DMN), hippocampus, thalamus, lateral cortical network, basal forebrain and ventral mid brain. Interestingly the dynamics of de- and remyelination was mirrored by an initial significant increase in flexibility values and a return to baseline in the hippocampus (F(4, 80) = 22.8, p < 0.001), DMN (F(4, 80) = 36.5, p < 0.001) and thalamus (F(4, 80) = 24.5, p < 0.001). The other three networks showed a reversed pattern. The strength of connections from the hippocampus to DMN was associated with the behavioral indicators of memory novel object recognition (NOR) (r2 = 0.3854, p < 0.001) and thalamus to hippocampus to locomotor activity (r2 = 0.3144, p < 0.001).

Conclusions

Taken together, our fMRI modular analyses showed that global modularity and flexibility partially compensate for demyelination. Dynamics of compensation could be identified as modular specific (i.e. hippocampus, thalamus and DMN) at different intermediate time points, supporting the hypothesis that altered thalamocortical connectivity is an early pathological hallmark of the disease. Causality dynamics also provide biomarkers for evaluating the course of MS and disease dynamics.

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Imaging Poster Presentation

P0602 - Long-lasting effects of optic neuritis on anatomical and functional visual network patterns (ID 1326)

Speakers
Presentation Number
P0602
Presentation Topic
Imaging

Abstract

Background

The brain's ability to adapt in response to damage is debated in multiple sclerosis (MS) literature. In a previous work, we have shown that following the acute damage caused to the visual system by an episode of optic neuritis (ON), the functional visual network experiences changes that are associated with the specific neurologic deficit, all within the limits of the underlying disease pathophysiology.

Objectives

To examine whether the changes associated with ON in the structural and functional networks, can still be discerned in progressive MS patients, even years after the acute insult.

Methods

Forty-eight progressive MS patients, with and without prior ON (MS-ON and MS-nON, respectively; nMS-ON = 21, nMS-nON = 27), underwent structural and functional magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and resting state fMRI (RS-fMRI). Anatomical and functional visual networks were defined using 50 visual regions-of-interest. Data were analyzed using graph theory-based methods and weighted network metrics were extracted, including density, strength, global and local efficiency, and modularity.

Results

Preliminary results have shown that while no functional metrics were significantly different between the two groups, anatomical global efficiency and density were significantly higher for the MS-nON group, despite no significant difference in lesion load between the groups.

Conclusions

The anatomical networks of the MS-ON group appear to be more damaged than those of the MS-nON group, while the functional networks appear to function to the same degree. Anatomical connectivity seems influenced by the long- standing distal damage to the optic nerve, suggesting trans-synaptic effects. However, despite our previous study having shown possibly-adaptive functional changes in the visual network following acute ON, our current results suggest that even if the MS brain has the ability to respond and adapt to insult in the early stages of the disease, this ability is nullified in progressive patients.

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Imaging Poster Presentation

P0603 - MAGNON – Implementation and Contribution of Lublin Criteria and quantitative MRI-Analysis for daily clinical routine of MS Patients (ID 318)

Speakers
Presentation Number
P0603
Presentation Topic
Imaging

Abstract

Background

The revised Lublin criteria (Lublin et al. 2014) provide a detailed definition of individual patient status in secondary progressive multiple sclerosis (SPMS), where patients are assessed annually based on progression and activity (MRI and/or relapse). So far, the revised criteria were applied to SPMS patients only in a small number of studies (Perez et al. EP1344 ECTRIMS 2017). The same is true for quantitative and standardized MRI analyses, which are often implemented in clinical trials, but are not part of standard routine care in patient management, although projects like QUANTUM clearly showed a benefit of quantitative and standardized MRI analysis in routine care (Schippling et al. P508 ECTRIMS 2018).

Objectives

MAGNON aims to evaluate if access to standardized quantification of MRI data and assessment of MS patients based on the Lublin criteria provides additional benefit for neurologists working in day-to-day MS patient management.

Methods

Approximately 3.600 MRI studies of patients with transitioning relapsing remitting MS (RRMS) or SPMS will be provided by 100 centers in Germany. Physicians are asked to categorize their patients according to the revised Lublin criteria. Standardized MRI data (3D T1 gradient-echo sequence and 2D/3D FLAIR) are analysed by means of a centralised automatic processing pipeline (Biometrica MS®, jung diagnostics GmbH). The analysis comprises a volumetric quantification of brain and thalamic volumes as well as T2 lesion volume and number. Percentage brain volume change is computed (using an optimized SIENA pipeline) when follow-up scans are available. The results are visualised and provided to the participating physicians as a report. The value of standardized MRI analysis and the impact on patient assessment, including potential changes in Lublin classification, will be evaluated.

Results

MAGNON will start in the first half of 2020 and design of the project as well as the first baseline data will be presented.

Conclusions

In the near future, an increasing implementation of Lublin criteria and quantitative MRI analysis in routine clinical practice is expected. Quantification of lesion volume as well as brain and thalamic atrophy on routine MRI may facilitate the individual assessment of disease activity and progression according to the Lublin criteria and provide additional information for individual patient management.

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Imaging Poster Presentation

P0604 - Mild Gray Matter Atrophy in Patients with Longstanding Multiple Sclerosis and Favorable Clinical Course  (ID 1263)

Speakers
Presentation Number
P0604
Presentation Topic
Imaging

Abstract

Background

Understanding whether multiple sclerosis (MS) can have a favorable course is still challenging. However, a small group of patients who are not disabled after many years of disease can be identified. The mechanisms responsible for this ‘benign’ clinical course remain unclear, likely due to the lack of long-term studies.

Objectives

To assess brain damage in multiple sclerosis patients with no or minimal disability after a longstanding clinical course.

Methods

We compared 13 patients with long-term benign clinical course (LT-BMS, age >55 years, disease duration >30 years, Expanded Disability Status Scale [EDSS] <3.0) and 27 non-benign MS (non-BMS) patients (age >55 years, EDSS >3.0). MRI scans were retrospectively assessed (mean follow-up: 11 years, mean scan per patient: 3). Comparisons of brain volumes (BV) and total T2-lesion volume (LV) changes between the two groups were performed using a mixed effect model. Lesion probability maps (LPMs) of both groups were compared using a nonparametric permutation test.

Results

Patients with LT-BMS showed less over-time decrease in global BV (p=0.02) and grey matter (GM) volume (p<0.001) than non-BMS. Lower atrophy was seen in LT-BMS with no or mild cognitive impairment. By contrast, there was no over-time difference between patient groups in T2-LV accumulation and lesion frequency across brain.

Conclusions

Global brain and GM atrophy changes were mild in this unique patient group with long-standing and no or minimal physical and cognitive disability. These results support the relevant role of GM atrophy in characterizing MS patients who may have favorable long-term disease evolution.

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Imaging Poster Presentation

P0605 - More dynamic functional network switching in cognitively declining multiple sclerosis patients (ID 777)

Speakers
Presentation Number
P0605
Presentation Topic
Imaging

Abstract

Background

Cognitive impairment in multiple sclerosis (MS) is strongly related to functional network dysfunction. In the absence of MS, optimal cognitive functioning of an individual is ensured by dynamically adapting the configuration of the functional network as needed. How these dynamic patterns are altered in MS remains unclear.

Objectives

Our aim was to investigate the dynamic reconfiguration of cognitively relevant brain networks in MS, to identify specific brain network patterns related to progression of cognitive impairment.

Methods

Resting-state functional MRI (rs-fMRI) and cognitive scores were acquired from 230 patients with MS and 59 matched healthy controls, at baseline and at 5 year follow-up. Seven cognitive domains were examined with the expanded Brief Repeatable Battery of Neuropsychological tests. A sliding-window approach was used on the rs-fMRI data, for which brain regions were assigned to one of seven classic literature-based resting-state networks based on connectivity patterns at that point in time. How regions switched between networks was described using measures of promiscuity (number of networks switched to), flexibility (number of switches), cohesion (switches with another region), and disjointedness (independent switches). Linear mixed models were used for baseline and longitudinal analyses, controlling for age, sex, and education.

Results

At baseline, 42% of patients showed cognitive impairment (CI) (18% Mild CI, ≥2 tests Z<-1.5; 23% severe CI, ≥2 tests Z<-2) and 28% of patients declined over time (≥2 tests yearly reliable decline>0.25). At baseline, CI patients showed increased promiscuity, flexibility and cohesion (i.e. more switching between networks) compared to preserved patients. Patients displaying cognitive deterioration showed increases in cohesion over time. Higher baseline cohesion was related to less gray matter volume, and more white matter integrity loss and lesion volume. Within cognitive domains, cohesion was inversely related to verbal memory, information processing speed, and working memory.

Conclusions

In patients with MS, increased switching between brain networks was related to cognitive impairment and structural damage. Cohesion particularly increased over time in patients showing cognitive decline, indicating that switching together with other regions might be particularly more common. These results provide support for the hypothesis of a progressive destabilization of the functional brain network in MS.

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Imaging Poster Presentation

P0606 - MRI changes over the disease course in a large multiple sclerosis clinical cohort (ID 1318)

Speakers
Presentation Number
P0606
Presentation Topic
Imaging

Abstract

Background

Quantitative MRI measures are proposed as biomarkers of disease course and therapeutic response. Understanding the evolution of these metrics is key for interpretation of change in clinical practice.

Objectives

To describe longitudinal changes in T2 lesion volume (T2LV), whole brain (WBF) and gray matter (GMF) fraction, and thalamic volume (TV) over the disease course in a large multiple sclerosis (MS) cohort.

Methods

Demographics, disease history, and MRI were collected from MS patients at a single site. Patients with ≥2 MRI assessments were included. T2LV, WBF, GMF, and TV annualized rate of change and raw values compared to the first available scan were analyzed. Multivariate mixed-effects models were used to evaluate longitudinal MRI changes, adjusting for age at disease onset, sex, and patient-determined disease steps category (PDDS) with a random intercept for patient and an autoregressive covariance structure. For each outcome, three models were generated: a linear model, a second-order B-spline model, and a third-order B-spline model were tested for nonlinearity in the relationship between MRI outcome and disease duration and were compared based on Akaike Information Criterion.

Results

1012 patients were included (69.2% female, 72.9% relapsing-remitting MS, mean ± SD age at disease onset 34.4±10.3, age at baseline MRI 43.8±11.1, disease duration 9.4±5.8 years, mean number of MRIs 3.1±1.2, median [IQR] PDDS 1.0 [0.0-3.0]). Male sex (B=4.9) and PDDS>3 (B=7.0) were associated with greater T2LV accumulation over the disease course (best fit: linear model). T2LV annualized rate of change peaked at 5-6 years of disease duration (rate 9%/year) (best fit: third-order B spline). Male sex, older age, and PDDS>3 were associated with lower WBF, TV (best fit: linear model), and GMF (best fit: second-order B spline), all p<0.05. No non-linear effect of disease duration on WBF, TV, and GMF were observed. There was no statistically significant change in the annualized rate of change of WBF, TV, and GMF over the disease course.

Conclusions

The dynamics of T2LV accumulation are variable throughout the disease course, whereas the rate of change of WBF, TV, and GMF were more stable. These results suggest T2LV accumulation reflecting focal lesion activity predominates early in the disease while WBF, TV, and GMF loss reflecting underlying neurodegeneration is present at disease onset and continues throughout the course.

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Imaging Poster Presentation

P0607 - MRI Characterization of Damage in and Around Lesions in Pediatric MS and MOG-Associated Disorders (ID 1847)

Abstract

Background

Multiple sclerosis (MS) and MOG-associated disorders (MOGad) are characterized by hyperintense white matter (WM) lesions on T2/FLAIR MRI. Conventional imaging is sensitive but does not inform on the specific pathological substrate. Magnetization transfer saturation provides a good myelin measure, and multishell diffusion is sensitive to the axon + myelin assembly. Together, these can be modelled to estimate myelin volume fraction (MVF), axonal volume fraction (AVF) and imaging g-ratio.

Objectives

To quantify gradients of damage to axons and myelin in lesions and surrouding normal appearing white matter, in pediatric MS and MOGad.

Methods

15 MS [67% females (F), mean (range) age [years (y)]: 17y (14-18), disease duration (DD) 3y (0-6), time from last relapse (TLR) 2y (0-6)] and 7 MOGad [86% F, 13y (8-18), DD 3y (0-6), TLR 1y (0-3), 6/7 relapsing] participants received 3T brain MRI. MVF, AVF and g-ratio were computed according to established procedures. T2 lesions were segmented according to standardized pipelines and WM masks by multi-atlas segmentation. Euclidean distance transforms labelled voxels in normal-appearing WM with the distance to the nearest lesion voxel, and voxels inside lesions with the distance to the nearest non-lesional WM voxel. Mean MVF, AVF and g-ratio were computed on each isodistant surface. Data were modeled using linear mixed models with distance, diagnosis, and their interaction. Knots were used at 0 and 2mm distance.

Results

MVF decreased towards the center of lesions (MOGad: -0.03/mm; MS: -0.05/mm; p values (ps)<0.002; difference n.s.) as did AVF (MOGad: -0.03/mm; MS: -0.01/mm; ps<0.0002; difference p=0.02); this graded damage extended to 2mm outside lesions. Beyond this, AVF continued to increase (MOGad: 0.001/mm; MS: 0.0003/mm; ps<10-6; difference p<10-6). Inside lesions, g-ratio increased towards the center in MS (0.03/mm, p<10-6) and decreased in MOGad (p=0.15; MOGad-MS difference p<10-4). G-ratio rose with distance outside lesions (MOGad: 0.001/mm; MS: 0.0004/mm; ps<10-4; difference p<10-5). AVF and g-ratio were similar between groups (within 2%) at 20mm from lesions; MVF was higher in MS (14%, p=0.08).

Conclusions

MS and MOGad showed myelin and axonal loss of decreasing severity with distance from lesion center, and this damage extended outside visible lesions. However, MOGad exhibited more severe axonal loss within and near lesions. The corresponding decreasing g-ratio relative to MS may indicate preferential loss of small axons in MS, or relatively better remyelination in MOGad.

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Imaging Poster Presentation

P0608 - MRI-based clustering of MS patients in the perspective of personalized medicine (ID 1075)

Speakers
Presentation Number
P0608
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) patients have heterogeneous clinical manifestations, natural history, and treatment response, due to heterogeneous underlying pathophysiological differences.

Objectives

To find clusters of MS patients with homogeneous underlying pathophysiology, as determined by advanced MRI techniques.

Methods

One-hundred-and-fifteen MS (57 relapsing-remitting, 12 primary- and 46 secondary-progressive) patients, and 44 age- and sex-matched healthy controls (HC) underwent brain and cervical cord 3T MRI with pulse sequences for assessing lesions, atrophy, and microstructural damage (with diffusion-tensor metrics). A complete neurological assessment, with rating of Expanded Disability Status Scale (EDSS) was also performed. Clusters of MS patients were identified with hierarchical clustering on age- and sex-adjusted MRI variables.

Results

Five clusters of MS patients were identified: “early”; “intermediate-cord”, “intermediate-cortical”, “intermediate-late-lesion”; and “late”. “Early” patients showed similar MRI metrics vs HC (except lesions), low EDSS and short disease duration (DD). “Intermediate” groups had altered MRI metrics, higher EDSS and longer DD, compared to “early” (p<0.01). “Intermediate-cord” patients were characterized by high cord T2-lesion volume (LV) (p<0.001 vs all but “late” groups), and “intermediate-cortical” by low cortical thickness (p<0.001 vs all but “intermediate-late-lesion” and “late” groups). “Intermediate-late-lesion” patients showed higher brain T2-LV and deep grey matter (GM) atrophy, but also a longer DD, compared to all but “late” groups (p<0.01). “Late” patients had higher EDSS and DD, compared to “intermediate-cord” and “intermediate-cortical” (p<0.01); and worst corticospinal-tract diffusion-tensor metrics and cord/brain atrophy (p<0.01 vs all). “Intermediate-cord” patients could be divided into 2 groups with similar DD characterized by different cord GM atrophy and cortical thickness (p<0.01), the more impaired one including mostly progressive phenotypes and higher EDSS.

Conclusions

MRI-based clustering of MS patients is feasible. It contributes to demonstrate disease heterogeneity and in the future it may be useful for personalized medicine. “Intermediate-cord” patients may be the best target to study neuroprotective and regenerative strategies.

Funding: Partially supported by grants from Fondazione Italiana Sclerosi Multipla (FISM/2018/R/16).

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Imaging Poster Presentation

P0609 - Multimodal MRI of the Brain to Improve Prediction of Disease Progression in Multiple Sclerosis (ID 1428)

Speakers
Presentation Number
P0609
Presentation Topic
Imaging

Abstract

Background

One of the challenges in multiple sclerosis (MS) research is to improve prediction of disease progression. While information from conventional MRI of the brain is essential in the diagnosis of MS, it only allows prognosis to some extent. Given the complexity of the disease, a combined analysis of structural and functional MRI changes appears more promising to identify markers associated with disease progression.

Objectives

We thus investigated how multimodal MRI can contribute to predicting disease progression in a single-centre cohort of patients with MS (PwMS).

Methods

We analyzed multimodal MRI-data from 123 PwMS (71 women; age (years): M=37.2, SD=10.4; nCIS=16; nRRMS=98; nPMS=9). All patients had undergone clinical and 3T MRI evaluations between 2015 and 2016 (baseline, BL) and clinical re-evaluations 2 years later (SD=1.0; follow-up, FU). Brain-volume, T2 lesion load, fractional anisotropy (FA) and resting-state functional connectivity (rsFC) of the default-mode (DMN) and sensorimotor network (SMN) at BL were correlated with the patients’ disease severity score progression (absolute Expanded Disability Status Scale (EDSS) score change from BL to FU).

Results

Across the entire cohort, median EDSS scores were significantly higher at FU (Med=1; IQR=2.5) than at BL (Med=1; IQR=2; p=0.04), with a low rate of disease severity score progression (assessed by EDSS BL – EDSS FU/ FU duration; Med = 0; IQR = 0.5). Neither normalized brain volume (NBV) nor T2 lesion load, extracted mean scores of whole brain FA or rsFC within DMN or SMN significantly correlated with disease severity score progression. Whole brain voxel-based analyses (controlled for age and disease duration) indicated trends for decreased FA within the corpus callosum (CC) and the corticospinal tract (CST) and decreased rsFC within the anterior cingulate cortex (ACC) and the hand motor area to be associated with disease progression. Subsequent ROI analyses revealed a significant decrease in mean FA in the CC genu (p=0.024), the CC forceps minor (p=0.020) and right CST (p=0.020) related to disease progression. Moreover, ROI analyses showed a decrease in mean rsFC in the left hand motor area (p=0.012) and the ACC (p=0.005) with increased disease progression.

Conclusions

Our results show that even within a relatively low rate of clinical disease progression over short term FU, subtle microstructural and functional changes may represent more sensitive predictors compared to gross morphological measures obtained from conventional MRI.

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Imaging Poster Presentation

P0610 - Multiparametric MRI investigation of enlarging and shrinking MS lesions (ID 1876)

Speakers
Presentation Number
P0610
Presentation Topic
Imaging

Abstract

Background

Background: After cessation of contrast enhancement MS lesions may show enlargement or shrinkage on T1w MRI. The presence of hypointense lesion rims on susceptibility weighted MRI may be associated with ongoing inflammation and tissue damage/rearrangement. The relationship of enlarging and shrinking MS lesions on T1w MRI to hypointense rims on SWI is therefore of interest.

Objectives

Objective: To investigate enlarging and shrinking non-enhancing multiple sclerosis (MS) lesion characteristics using a novel multimodal magnetic resonance imaging (MRI) approach.

Methods

Methods: Two high-resolution 3 D T1-weighted 3T MRI datasets obtained 12 months apart were analyzed in 67 MS patients. Non-enhancing enlarging and shrinking lesions were identified by voxel guided morphometry (VGM) demonstrating regional volume changes as compared to stable lesions without volume change. In addition the presence of hypointense lesion rims on susceptibility-weighted imaging (SWI) was evaluated. In order to estimate tissue damage within lesions, T1 signal intensity (SI) ratios and the apparent diffusion coefficient (ADC) were analyzed.

Results

Results: Forty-three patients demonstrated chronic enlarging and/or shrinking lesions (active T1 lesions), while in 24 patients exclusively stable lesions were seen. Overall, we identified 444 chronic MS lesions (109 enlarging, 67 shrinking, 268 stable lesions). Chronic-enlarging/shrinking lesions were more frequently associated with hypointense rims compared to stable lesions (p < 0.05). Both, chronic-enlarging/shrinking lesions showed a stronger decrease of the T1 SI ratio and, conversely, an increase in ADC values at follow-up in comparison to stable lesions. Patients with enlarging or shrinking lesions had longer disease durations, higher EDSS scores, larger T2 lesion volumes and lower normalized brain volumes than patients without such lesions (p < 0.05).

Conclusions

Conclusion: Enlarging and shrinking lesions on T1w MRI frequently show hypointense rims on SWI. Those lesions are linked to progressive white matter damage and may indicate sustained inflammation and may therefore indicate low grade inflammatory changes, that could be a valuable marker of disease activity.

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Imaging Poster Presentation

P0611 - Neurite density explains cortical T1-/T2-weighted ratio in multiple sclerosis (ID 1090)

Speakers
Presentation Number
P0611
Presentation Topic
Imaging

Abstract

Background

Cortical damage is clinically relevant in multiple sclerosis (MS), however reliable MRI markers for its monitoring are still an unmet need. Ratio of T1-weighted (T1w) and T2-weighted (T2w) sequences (i.e., T1w/T2w-ratio) has been suggested as a feasible MRI measure to assess cortical abnormalities in patients with MS (PwMS), but its histopathological substrate has yet to be definitively elucidated.

Objectives

To define the histopathological substrate of T1w/T2w-ratio in normal-appearing and demyelinated cortices of PwMS by performing a combined post-mortem MRI/histopathology study.

Methods

Fifteen PwMS and ten age- and sex-matched non-neurological controls (nNC) underwent post-mortem in situ 3T MRI with 3D T1w and T2w sequences, followed by brain dissection.

One hundred and five paraffin embedded tissue blocks (49 from PwMS, 56 from nNC) were collected. Tissue regions were matched to T1w/T2w-ratio maps to obtain regional cortical T1w/T2w-ratio. Using immunohistochemistry and silver staining, cortical density of myelin, microglia, neurons, glial cells and neurites were evaluated. Correlates of T1w/T2w-ratio alterations with histological markers were assessed through linear mixed-effects models.

Results

Twenty-six cortical lesions (85% subpial) were found in 24/49 (51%) cortical regions from PwMS. Compared to nNC’s cortex, both PwMS’ normal-appearing and demyelinated cortices had a significantly lower T1w/T2w-ratio (p=0.045 and 0.001). In PwMS, demyelinated cortex showed a significant lower T1w/T2w-ratio compared to normal-appearing cortex (p=0.007). In PwMS, neurite density was significantly lower in both normal-appearing and demyelinated cortices compared to nNC (p=0.041 and 0.001), and in demyelinated vs. normal-appearing cortex (p=0.048). Demyelinated cortex showed also significant lower myelin density compared to normal-appearing cortex in both nNC and PwMS (p<0.001). Regarding the pathological substrate, T1w/T2w-ratio was positively associated with neurite density (β=3.464×10-2, p=0.004), whereas only a trend for myelin density was found (p=0.082).

Conclusions

Both demyelination and neurite loss were found in the cortex of PwMS. By evaluating several histopathological markers in nNC and PwMS (in normal-appearing and demyelinated cortices), T1w/T2w-ratio was found to be sensitive to MS cortical damage and more specific to neurite than myelin density. T1w/T2w-ratio could be useful to investigate cortical damage in MS.

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Imaging Poster Presentation

P0612 - New cortical lesions are rare in an MS cohort with stable white matter lesions: a 7T multicontrast longitudinal study (ID 1866)

Speakers
Presentation Number
P0612
Presentation Topic
Imaging

Abstract

Background

Cortical lesions are common and often extensive in MS, and have been associated with worse disability and progressive disease. There is limited evidence that cortical lesions continue to form in progressive phases of the disease, when new white matter lesion formation is minimal, perhaps offering an explanation for worsening disability in progressive MS.

Objectives

We longitudinally characterized cortical lesions in an MS cohort with stable white matter lesion burden in the year prior to enrollment to determine whether new cortical lesions are more frequent in people with worsening disability.

Methods

45 adults with MS (30 relapsing remitting (RR), 13 secondary progressive (SP), and 2 primary progressive (PP)), underwent 7T brain MRI (T2*w and MP2RAGE, each with 0.5mm isometric resolution), 3T brain and spine MRI, and clinical evaluation annually for 1 year. Cortical lesions were segmented manually on 7T images and categorized as leukocortical, intracortical, or subpial. White matter and spinal cord lesion burden were also determined.

Results

At baseline, 93% of individuals (42/45) had at least 1 cortical lesion. Median cortical lesion number was higher in progressive MS (median 55, interquartile range (IQR) 96, range 2–177) than RRMS (median 15, IQR 21, range 0–108; p<0.01). Cortical lesion volume correlated with physical and cognitive measures of disability. There was only a weak correlation between subpial and white matter lesion volume (r=0.35, p<0.05). During 1 year of follow-up, 6 people (4 RR, 2 SP) developed 1 new cortical lesion each. 4 of the 6 new cortical lesions were leukocortical, 1 was intracortical, and 1 was subpial. 5 people developed new white matter lesions, none of whom developed a new cortical lesion. In 2 people, we observed white matter lesions expand into the cortex. 3/6 people with new cortical lesions were on highly effective disease-modifying therapy during the follow up period. There was no difference in new cortical lesion or new white matter lesion number in people with stable vs worsening disability.

Conclusions

Using sensitive 7T MRI techniques, cortical lesions are detected in almost all MS cases. Cortical lesions are associated with worse and progressive disability and may form independently from white matter lesions. New cortical lesions appear to form infrequently in people with stable white matter lesions, however current disease-modifying therapies may not be completely effective at stopping cortical lesion formation.

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Imaging Poster Presentation

P0613 - Ocrelizumab Reduces Regional Brain Atrophy in Relapsing Multiple Sclerosis as Assessed by Longitudinal Deformation-based Morphometry (ID 1228)

Speakers
Presentation Number
P0613
Presentation Topic
Imaging

Abstract

Background

Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (MS). It has been reported that OCR reduces brain atrophy in MS patients, however, a voxel-based approach has never been reported.

Objectives

To identify brain regions where atrophy is modified by the OCR treatment in Relapsing MS (RMS), using a fully automatic, voxel-based approach.

Methods

We applied longitudinal deformation-based morphometry (L-DBM) using the Advanced Normalization Tools (ANTs) to T1-weighted 3D MPRAGE brain MRI (voxel=1x1x3 mm3​ ​) from two clinical trials of OCR for RMS (Opera I: NCT01247324 and Opera II: NCT01412333). For each MRI visit, a Jacobian map was derived based on the deformation generated by registering the scan to a Single-Subject Template (SST) constructed for the same patient. Jacobian maps in patient SSTs were mapped to a population brain template for group analysis. Patients were included if MRI data were available for all visits (baseline, Weeks 24, 48, and 96) and the images were of sufficient quality to be successfully processed through the L-DBM pipeline (683 in the OCR arm, 580 in the active control arm of Interferon beta-1a). Voxelwise ANOVA was iterated over the whole brain to detect an interaction between Treatment and Time (​p​<0.01 with familywise error correction). Post-hoc analysis was done with mean Jacobian of identified regions, including Linear Mixed Effect (LME) analysis.

Results

Voxelwise ANOVA identified one cluster of voxels in the brain (besides the ventricles) that were contained within parts of thalamus, brainstem, and cerebellum. From the analysis of mean Jacobian of this cluster region, the percent volume reduction from baseline was significantly smaller in the treatment arm than the control arm at every follow-up visit (​p​<0.0001, ​t​>8.0, relative difference>75%). LME analysis of the mean Jacobian of the cluster region confirmed that there was a strong interaction between Treatment and Time (​F​=18.35), for which age and sex were controlled.

Conclusions

L-DBM has identified several brain structures where atrophy was modified by the OCR treatment in RMS. The L-DBM analysis was performed at the voxel level and these regional findings are consistent with previous reports. Localization of the treatment-responsive brain structures may have an implication for future assessment of clinical outcomes in MS.

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Imaging Poster Presentation

P0614 - Perilesional neurodegenerative injury in MS: relations with focal lesions and disability (ID 1849)

Speakers
Presentation Number
P0614
Presentation Topic
Imaging

Abstract

Background

Chronic black holes (cBHs), characterized by severe myelin and axonal loss, are associated with higher disability levels in patients with multiple sclerosis (MS). However, whether cBHs impact perilesional tissue via retrograde and/or antegrade degeneration and how this remote pathology affects patient disability has not been investigated in vivo. Novel MRI techniques, such as selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment microscopic diffusion MRI spherical mean technique (SMT) have the potential to more accurately assess myelin and axonal injury in vivo, thus allowing us to measure remote tissue injury and its impact on patient clinical disability.

Objectives

To compare the macromolecular-to-free pool size ratio (PSR), derived from SIR-qMT, and apparent axonal volume fraction (Vax), from SMT, values among cBHs, perilesional normal-appearing white matter (NAWM) and contra-lateral (distant) NAWM and test associations of these measures with disability in vivo.

Methods

Eighteen MS patients underwent 3T MRI consisting of clinical protocols, SIR-qMT and SMT. Regions of interest (ROIs) were manually placed on CBHs, perilesional NAWM and distant NAWM areas; PSR/Vaxwere calculated and compared using a mixed effects model. Pearson correlation analyses tested the associations between PSR/Vax values and patient clinical and MRI metrics.

Results

Compared to perilesional NAWM, both PSR (-43.3%, p<0.001) and Vax (-29.7%, p<0.001) values were reduced in cBHs and increased in distant NAWM (10.2%, p<0.001 for PSR and 20%, p<0.001 for Vax). A strong correlation was seen for cBH and perilesional NAWM Vaxvalues (rho=0.63 p<0.001). No significant associations were seen between PSR/Vaxvalues and other clinical or MRI metrics of disease apart from cBHs PSR, which correlated with the EDSS score (rho=-0.63, p=0.03). There was a trend for decreasing PSR and Vaxvalues in all regions with worsening disease phenotype.

Conclusions

Our results show that myelin and axonal integrity, detected by PSR and Vax, are reduced in perilesional NAWM, as a function of the degree of focal cBH axonal injury. This is indicative of an ongoing anterograde and retrograde degeneration and suggests that preventing cBH development is a key factor for preserving NAWM integrity in surrounding tissue. PSR and Vaxlargely failed to capture associations with clinical and MRI characteristics. However, the trends observed with disease phenotypes suggest that longitudinal assessment of a larger cohort may indeed unravel the impact of this pathology on disease progression.

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Imaging Poster Presentation

P0615 - Physical disability is related to resting-state network atrophy and altered MEG-based functional network topology in multiple sclerosis. (ID 1350)

Speakers
Presentation Number
P0615
Presentation Topic
Imaging

Abstract

Background

Clinical disability in multiple sclerosis (MS) is insufficiently explained by structural damage as measured with standard magnetic resonance imaging (MRI) measures. More advanced measures of brain network atrophy and functional network changes might better explain symptoms and clinical deterioration.

Objectives

To investigate the relevance of functional network alterations in addition to network atrophy for explaining physical disability in MS.

Methods

In this cross-sectional study 143 MS patients and 36 healthy control participants underwent resting-state magnetoencephalography (MEG) and structural MRI. Functional connectivity between regions was estimated using the phase lag index, from which the minimum spanning tree (MST) was constructed, representing the backbone of the functional network. The topology of the MST was described using the so-called tree hierarchy (MST-Th). Gray matter (GM) volume was calculated within literature-based resting-state network maps (i.e. visual, sensorimotor, dorsal attention, ventral attention, limbic, fronto-parietal, default mode, deep gray matter, and cerebellar networks). Physical disability was quantified with the Expanded Disability Status Scale (EDSS), Nine Hole Peg Test (9HPT) and Timed 25-Foot Walk Test (TWT). Network atrophy and topology were compared between groups and related to disability.

Results

Atrophy was apparent in all resting-state networks. All volumes correlated positively (p<.001) with EDSS and 9HPT: Spearman’s ρ between .289 and .567, highest correlations for sensorimotor, default mode, fronto-parietal and dorsal attention networks. EDSS correlated negatively with MST-Th in the lower alpha band (α1) (p < 0.008), while 9HPT correlated negatively with MST-Th in the upper and lower alpha, gamma, delta and theta bands (p <0.05), indicating a less efficient network relating to worse disability. TWT was related to atrophy in all networks, but not network topology. Together, MST-Th-α1, age, cerebellar and fronto-parietal atrophy explained 36% of EDSS variance, while 19% of 9HPT variance was explained by deep GM atrophy and MST-Th-α1. Lesion volume had no added significant effect on variance.

Conclusions

These results suggest that more advanced measures of network atrophy and functional network topology can explain a significant degree of disability variance in MS. In addition, mobility scores were not related to network changes, which could imply different underlying pathological substrates compared to those that underlie upper limb dexterity.

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Imaging Poster Presentation

P0616 - PiB-PET and MRI myelin water fraction provide complementary information about myelin (ID 1474)

Speakers
Presentation Number
P0616
Presentation Topic
Imaging

Abstract

Background

Myelin water imaging can isolate the magnetic resonance imaging (MRI) signal from myelin water, providing a quantitative measure associated with myelin, termed the myelin water fraction (MWF), which has been validated in histopathologic studies. The amyloid tracer 11C Pittsburg compound B (PiB) also has an affinity for myelin and its binding can be reduced in MS lesions compared to normal-appearing white matter (NAWM). We sought to determine whether these myelin-sensitive techniques provide overlapping or complementary information in MS.

Objectives

To determine (1) whether MWF and PiB binding are decreased in lesions compared to NAWM and (2) if there is a correlation between MWF andPiB binding.

Methods

Eleven participants (5 relapsing-remitting MS, 3 secondary progressive MS, 3 primary progressive MS) were scanned on a 3T Philips MRI scanner, and on a Siemens HRRT PET scanner with an injection of 18 mCi 11C PiB. Two RRMS participants were treated with glatiramer acetate 40 mg subcutaneously three times per week. MRI scans included structural scans for tissue segmentation and a myelin water sequence for MWF calculation. PIB binding was quantified with the Logan method-derived non-displaceable binding potential (BPND) using healthy grey matter from cerebellum as reference region. Lesion masks included all lesions within the imaging volume. Regional mean values of MWF and BPND were determined for NAWM and lesions.

Results

Lesions showed a 38% decreased MWF and a 23% decreased BPND compared to NAWM (MWF: lesions=0.08±0.01 vs NAWM=0.13±0.02, p<0.0001; BPND: lesions=0.91±0.08 vs NAWM=1.18±0.07, p<0.0001). A correlation was found between MWF and BPND when including both NAWM and lesions (r=0.73, p=0.0001). However, there was no correlation when fitting for NAWM or lesions alone (NAWM: r=-0.51, p=0.06; lesions: r=0.39, p=0.23).

Conclusions

In this pilot study, lesions showed a decrease in both myelin water and PiB binding as expected in demyelinated tissue. The partial correlation between MWF and PIB BPND suggests that each technique might have different sensitivity for detecting the severity of demyelination in heterogeneously affected tissue. PIB BPND values in NAWM were relatively homogenous. PIB BPND was good at discriminating between NAWM and lesions. MWF showed more subtle differences in myelination in NAWM and lesions. PET-PiB imaging and MWF appear to provide reliable measures of myelin abnormality in MS lesions. MWF may be able to provide additional information on the heterogeneity of demyelination in lesions and NAWM.

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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

P0618 - Prednisolone treatment during the first episode in multiple sclerosis is associated with cortical thinning in the right medial orbitofrontal cortex. (ID 1923)

Speakers
Authors
Presentation Number
P0618
Presentation Topic
Imaging

Abstract

Background

Steroid treatment is a first-line therapy in acute multiple sclerosis (MS) episodes. While it is well-established that there is an inverse relationship between serum steroid-levels and decreases of cortical thickness (CT), little is known about the effects of steroid treatment during MS relapses on CT.

Objectives

In this study, we investigated whether CT changes occur in MS patients following steroid treatment after the first clinical episode in MS in a retrospective design. Additionally, we aimed to assess whether such effects were sustained.

Methods

T1-weighted magnetic resonance (MR) images were acquired from 8 MS patients during their first clinical episode (7 females, median age 27 years). At the time of that baseline scan, all patients were within 5 days of onset of prednisolone treatment (1000mg/day i.v.; steroid treatment was stopped after these 5 days). A first follow-up scan was acquired 4 weeks later. To check for sustained effects on CT (post-hoc), a second follow-up scan, 8 weeks after baseline, was acquired. Additionally, data from 8 age- and sex-matched healthy controls (HC) was acquired (baseline and 4 weeks later).

CT maps from all subjects were generated individually and parceled into 68 regions using the Desikan-Killiany atlas. We used a repeated measures analysis of variance to test for significant differences of CT changes between MS and HC over time. Family-wise error-corrected p-values (pFWER) were calculated using a Monte-Carlo permutation procedure. Since the ANOVA yielded a significant interaction for one region, we investigated post-hoc whether that effect was still observable another four weeks after the first follow-up. To test for this effect, we used a paired t-test to compare mean CT levels of that region within the patient group between 4 and 8 weeks after treatment, as well as baseline vs. 8 weeks after treatment.

Results

The ANOVA showed a significant interaction of group x time for the medial orbitofrontal cortex (mOFC) of the right hemisphere (F = 21.956 , pFWER = 0.011), with MS patients showing a decrease of mean CT within that region over time. No main effects were observed. A post-hoc paired t-test comparing the CT means within the mOFC at a second follow-up scans eight weeks after baseline revealed no significant difference between follow-up 1 and follow-up 2 (t7 = -0.9841, p = 0.3578) and approached significance for the comparison between baseline and follow-up 2 (t7 = 2.3513, p = 0.0510).

Conclusions

Our results provide first evidence that steroid treatment during the first acute episode in MS was associated with cortical thinning in the mOFC, which tended to reverse after eight weeks of steroid-free treatment. Although these results need to be further validated in a larger cohort, our results suggest that steroid treatment potentially associates to atrophy in the medial orbitofrontal cortex; an effect which – if validated – should be taken into account for MS therapy.

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Imaging Poster Presentation

P0619 - Prefrontal Metabolism Explains Processing Speed Ability in Multiple Sclerosis: A Calibrated fMRI study (ID 1385)

Speakers
Presentation Number
P0619
Presentation Topic
Imaging

Abstract

Background

Cognitive processing speed deficits are common in multiple sclerosis (MS). Despite this, the exact neural mechanism underlying slowed information processing speed remains unknown. Furthermore, functional magnetic resonance imaging (fMRI) using only blood-oxygen-level-dependent signal may not be sensitive to MS-related metabolic changes affecting processing speed ability. Previous work has shown that cerebral metabolism in motor and visual areas are associated with performance on motor and visual tasks, however, it is unknown if task-based metabolism in the dorso-lateral prefrontal cortex (dlPFC), a region known to be involved in processing speed, is related to the slowed processing speed observed in MS.

Objectives

We aim to assess whether metabolism in the dlPFC, a processing speed region, is associated with MS-related processing speed deficits.

Methods

MS and healthy control (HC) participants who met inclusion criteria were scanned using a 3T MRI scanner with a dual­echo calibrated fMRI (cfMRI) sequence which provided near­simultaneous measures for both cerebral blood flow (CBF) and BOLD signal. During imaging, participants performed a block-design digit-symbol substitution task (DSST) that required the viewing of a digit-symbol pairing key and responding as to whether a probe digit-symbol pair matched the key as fast as they could using button boxes. A hypercapnia gas challenge involving periodic inhalation of room air (4 min) and 5% CO2 (6 min) permitted measures of cerebral metabolic rate of oxygen (CMRO2). Data were preprocessed and average percent signal change from baseline was calculated in each voxel providing BOLD and CBF time series. The anatomical region of interest (ROI) was defined as dlPFC after Freesurfer cortical parcellation. Regression analyses were performed controlling for ROI size to assess whether BOLD, CBF, or CMRO2 could explain variability in processing speed ability.

Results

An independent-samples t-test showed that the MS group had a significantly higher response time (RT) for the DSST (t[50]=3.12, p=.003) compared to HCs. Within the MS group, regression analyses using RT for correct trials as the dependent factor were not significant for BOLD and CBF PSC but was significant for CMRO2 (R2=.170, p=.053) after controlling for number of voxels within the ROI. No regression analyses were significant within the HC group.

Conclusions

Our analyses suggest that metabolism, not BOLD or CBF, in dlPFC, a region known to involved in processing speed, explains MS-related slowed processing speed.

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Imaging Poster Presentation

P0620 - QSM detects greater rate of reduction in lesion magnetic susceptibility in patients treated with Dimethyl Fumarate over Glatiramer Acetate treatment (ID 1783)

Abstract

Background

Chronic active multiple sclerosis (MS) lesions, characterized by a hyperintense rim (rim+) on quantitative susceptibility mapping (QSM), have been shown to contain iron-enriched, activated microglia and macrophages. QSM is a potential biomarker to monitor treatments directed toward the CNS inflammation. Studies have suggested that dimethyl fumarate (DMF) may reduce the pro-inflammatory innate immune response in the CNS. A comparison to other disease modifying therapies (DMTs) is warranted to evaluate this potential benefit.

Objectives

To determine if dimethyl fumarate (DMF) reduces the iron load, as measured on QSM, in chronic active MS lesions at a greater rate than glatiramer acetate (GA) treatment.

Methods

Sixty-one patients (41 female, 20 male, mean age: 42.1 years +/- 10.9 and EDSS 0.82 +/- 1.2), were considered for this analysis. Fifty-six patients had relapsing-remitting MS and 5 had clinically-isolated syndrome; 37 patients were treated with DMF and 24 with GA. The two treatment groups had similar baseline clinical characteristics; however, DMF patients had less time on treatment as compared to GA (3.86 +/- 1.75 years vs 5.99 +/- 2.67 years, p<0.001). Patients had a QSM scan prior to treatment and a minimum of two on-treatment QSM MRIs. Lesions were classified as rim+ or rim- negative based upon a review of two independent reviewers. To compare longitudinal QSM change in the rim+ lesions among treatment groups, a linear mixed effects model was utilized.

Results

At baseline, patients treated with GA had more QSM rim+ lesions (9.4%) as compared to those starting DMF (4.5%), p=0.0004, however the number of patients having at least one rim+ lesion was similar (16 vs 18 patients) among the treatment groups. DMF patients with rim+ lesions had a longer disease duration as compared to rim+ GA patients (8.15 +/- 6.82 vs 3.55 +/- 4.85 years, p= 0.032). In the subset of patients with QSM rim+ lesions, there was a significantly larger decrease in susceptibility in rim+ lesions with DMF treatment as compared to GA, p< 0.0009. There was minimal reduction of susceptibility in rim- lesions, which was similar among treatment groups; all patients (p=0.92) and QSM rim+ only patients (p=0.11).

Conclusions

This study suggests that DMF reduces the iron load in rim+ MS lesions at a greater rate than GA. These results support QSM to evaluate the effectiveness of various DMTs on the CNS innate immune response in chronic active MS lesions.

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Imaging Poster Presentation

P0621 - q-Space Myelin Map imaging for longitudinal analysis of remyelination in multiple sclerosis patients treated with dimethyl fumarate (ID 334)

Speakers
Presentation Number
P0621
Presentation Topic
Imaging

Abstract

Background

[Background]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). However, there is a lack of appropriate methods to monitor CNS myelin in daily practice. We successfully developed a novel imaging method, titled q-space Myelin Map (qMM). The qMM accurately depicted myelin status in a pilot clinical study of patients with MS, suggesting that it may be useful in detecting remyelinated lesions.

Dimethyl fumarate (DMF) has demonstrated its sustained efficacy on relapses and disability progression in patients with relapsing-remitting MS (RRMS). However, limited reports exist to indicate the potential for remyelination with DMF.

Objectives

[Objective]

To report the interim results of the efficacy of DMF on qMM recovery, which suggests remyelination activity, in patients with RRMS.

Methods

[Methods]

Nineteen RRMS patients were registered and 14 of those were evaluated as of February 2020. After initiating DMF, a longitudinal analysis of qMM was performed with 3-12 month intervals to detect q-MM supported remyelination and demyelination. The expanded disability status scale (EDSS) assessment and the qMM analysis were performed independently by board-certified neurologists. The study was approved in advance by the ethics committee of Keio University School of Medicine (#20170311).

Results

[Results]

A total of 14 patients were included in the analysis. The age and EDSS at baseline (mean ± standard deviation) were 37.6±10.2 years and 1.9±1.5, respectively. Prior disease-modifying therapies included glatiramer acetate (n=1), fingolimod (n=10) and natalizumab (n=1); two patients were treatment-naïve. Mean time to start DMF after MS onset was 80.1±95.9 months and DMF treatment duration was 23.1±9.4 months. Three patients discontinued DMF: reasons were disability progression (n=1), new MRI lesion (n=1) and entry of another clinical trial (n=1). One patient interrupted DMF due to pregnancy (n=1). Out of the 14 patients, 6 (42.9%) had presence of remyelination. Of those 6 patients, 3 had presence of remyelination only while 3 also had presence of demyelination. No patients were detected with demyelination only. In all 6 cases of remyelination, the remyelination was detected in the first year of DMF treatment.

Conclusions

[Conclusions]

The qMM successfully visualized remyelination activity in MS patients treated with DMF. The association between qMM-supported remyelination and disease progression should be further investigated in a larger population.

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Imaging Poster Presentation

P0622 - Quanitifying the T1 hypointensity of MS lesions (ID 1063)

Speakers
Presentation Number
P0622
Presentation Topic
Imaging

Abstract

Background

Within multiple sclerosis (MS) lesions, T1 weighted hypo-intensity correlates with pathological markers of irreversible damage, including axonal degeneration. Studies have found that T1 “black holes” have a higher correlation with clinical disability than do T2 weighted lesions, and that measurable T1 signal drop out occurs within slowly enlarging lesions or chronic active lesions, as opposed to inactive lesions, suggestive of ongoing axonal degeneration.

To perform this quantitative analysis two pre-processing steps are necessary. The first is correction of low frequency intensity nonuniformity present in image data, also known as bias fields. The second is normalisation of the signal between subjects and timepoints. Both of these steps need to maintain representative contrast between pathological and normal appearing white matter (NAWM) to provide accurate results. Validation of these methods within the MS context is needed to support their use as a biomarker in MS.

Objectives

To assess the accuracy N34 bias correction on maintaining accurate MS lesion contrast

To assess the accuracy of Freesurfer normalization tool6 in maintaining accurate relative signal intensity

Methods

21 relapsing MS and 26 progressive MS subjects had MRI brain scans with 1mm3 3D T1 fast spoiled gradient echo (FSPGR), and 0.6 x 0.46mm2 FLAIR sequences. FLAIR images were resampled and linearly registered to the T1 using FLIRT. MS lesions were segmented from the FLAIR using JIM software.

To calculate an accurate measure of local tissue contrast between MS lesions and surrounding NAWM, the lesion segmentations were dilated and masked for white matter segmentation. The lesion mask was then subtracted from the segmentation to create an edge of NAWM surrounding the lesion. The measure of raw local tissue contrast was taken as the T1 value of

lesion core / lesion edge

N3 bias correction was done with the Freesurfer command mri_nu_correct.mni. Normalization of the T1 sequences was undertaken with Freesurfers mri_normalize which imposes a hard ceiling effect on the white matter peak found, creating an homogenous NAWM intensity of 110 and CSF intensity of ~35.

Correlations of each MS lesion between the bias field corrected and local tissue contrast was explored. Correlations between the bias field corrected and normalized values was explored.

Results

A total of 2401 lesions were analysed. N3 bias corrected T1 images correlated with local tissue contrast of the raw T1 images with an R2 = 0.7556. Normalized T1 images correlated with N3 bias corrected images with an R2 = 0.9415. Average MS lesion normalized T1 intensity was similar between relapsing MS and progressive MS cohorts (82.927 vs 82.793, p = 0.42).

Conclusions

In this analysis T1 intensity was able to be corrected for bias fields and normalized to a set range with reasonable accuracy in maintaining lesion contrast. This supports the use of these methods as a biomarker in quantifying the T1 signal within MS lesions.

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Imaging Poster Presentation

P0623 - Quantifying Cervical and Thoracic Cord Atrophy in Multiple Sclerosis  (ID 1478)

Speakers
Presentation Number
P0623
Presentation Topic
Imaging

Abstract

Background

Spinal cord atrophy contributes to disability in multiple sclerosis (MS), and its quantification along the entire spinal cord may be important to fully characterize the disease.

Objectives

We sought to characterize atrophy of the entire spinal cord in various multiple sclerosis phenotypes and determine its clinical correlates in a cross-sectional study. Further, we sought to evaluate its evolution in a longitudinal study of relapsing remitting MS (RRMS).

Methods

Axial T1-weighted images perpendicular to cord edge were automatically reformatted at each point along the cord. Spinal cord cross‐sectional area (SCCSA) were calculated from C1-T10 vertebral body levels and profile plots were compared across phenotypes. Average values from C2-3, C4-5, and T4-9 regions were compared across phenotypes and correlated with clinical scores, then categorized as atrophic/normal based on z-scores derived from controls, to compare clinical scores between subgroups. In the subset of relapsing-remitting cases with longitudinal scans, cases showing clinical progression (progressive-disability group) were defined as those in whom change in EDSS was ≥ 1 , while all other cases were grouped as having stable-disability. A random coefficient model for longitudinal data was applied to evaluate the change of regional-SCCSA variables over time, including in the model the disability group (progressive vs. stable), age, and the interaction between disability group and age.

Results

The cross-sectional study consisted of 149 adults with RRMS, 49 with secondary-progressive MS, 58 with primary-progressive MS and 48 healthy controls. The longitudinal study included 78 RRMS cases. Compared to controls, all MS groups had smaller average regions except RRMS in T4-9 region. Measures from all regions of the RRMS cohort correlated with clinical measures, whereas the progressive cohorts had fewer clinical correlates. In the RRMS cohort, 23% of cases had at least one atrophic region, whereas in progressive MS the rate was almost 70%. Longitudinal analysis demonstrated a correlation between disability and cervical cord thinning, as the random coefficient model showed a significant interaction between groups (stable- vs. progressive-disability) and age for cervical regional-SCCSA variables, indicating that the rate of decrease in regional-SCCSA with age in the progressive disability group was significantly higher than that in the stable disability group (0.62 mm2/year vs. 0.07 mm2/year for C2–3, p=0.0015; 0.72 mm2/year vs. 0.29 mm2/year for C4–5, p=0.0038).

Conclusions

Spinal cord atrophy was demonstrated in all MS phenotypes, with SCCSA from all regions showing significant correlations with all clinical parameters in RRMS cohort. Longitudinal changes in the cervical regions were significantly higher in RRMS subjects showing clinical progression than those who did not. SCCSA is therefore a potential imaging marker for disease progression.

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Imaging Poster Presentation

P0624 - Quantitative multiparametric 3T-MRI of postmortem multiple sclerosis whole brains (ID 1583)

Abstract

Background

Postmortem MRI provides precious insights into the relation of MRI metrics to pathoanatomical features of multiple sclerosis (MS) and can help to understand the basis of damage and repair.

Objectives

To investigate the respective features of MS lesions in the cortex and in the white matter using multiparametric postmortem MR imaging at 3T and identify discriminant characteristics of white matter lesion subgroups.

Methods

We scanned three fixed brains of secondary-progressive MS patients (mean disease duration 15.3 years) on a standard clinical 3T-MRI scanner with following sequences: Magnetization Transfer Saturation (MTsat), T1-relaxometry (T1-rt), Myelin Water Fraction (MWF) and Diffusion Tensor - Fractional Anisotropy (DTI-FA). We compared these metrics between (i) cortical lesions (CL, n=118) and normal-appearing grey matter (NAGM, n=186) and (ii) white matter lesions (WML, n=140) and normal-appearing white matter (NAWM, n=53) using a Mann-Whitney U test. Then, we analyzed the differences between different subgroups of WML (periventricular lesions -PVL-, n=38, WM part of leukocortical lesions -WMLCL-, n=36, subcortical lesions -SCL-, n=66, and areas of “dirty white matter” -DWM-, n=15) by performing a Kruskal-Wallis test and a Mann-Whitney U tests for direct comparison. Bonferroni correction for multiple-testing was applied.

Results

CL exhibited lower MTsat (p<0.001), higher T1-rt (p<0.001) and MWF (p<0.01) than normal appearing cortical tissue. WML showed lower MTsat (p<0.001), higher T1-rt (p<0.001), and lower MWF (p<0.001) than normal appearing white matter. DTI-FA did not differ between CL/WML and NAWM/NAGM. MTsat values were lower in the PVL (p<0.001) and higher in the DWM (p<0.001) in comparison to all other lesion subgroups. T1-rt were higher in PVL (p<0.001) compared to the other lesion subgroups. MWF values were higher in DWM and SCL (p<0.01), not statistically different between PVL and WMLCL. DTI-FA values were lower in WMLCL in comparison to all other subgroups (p<0.01) and did not differ between the other categories.

Conclusions

Postmortem MRI metrics in WML/CL as well as in different subgroups of WML, are compatible with myelin damage and tissue destruction. Interestingly, MWF was higher in CL than in NAGM, which might correspond to a predominance of “myelin blistering” pathology in the cortex. Ongoing work aims to directly correlate our findings with detailed histopathological characterization including electron microscopy of myelin damage.

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Imaging Poster Presentation

P0625 - Quantitative Susceptibility Mapping in the cortical ribbon of MS patients and its dependence on cortical thinning. (ID 1142)

Speakers
Presentation Number
P0625
Presentation Topic
Imaging

Abstract

Background

Neuropathological examinations of multiple sclerosis (MS) brains indicate sub-pial cortical grey matter (GM) demyelination and damage occurring according to a “surface-in” gradient related to elevated levels of inflammation compartmentalized in sub-arachnoid spaces and meninges. Quantitative susceptibility mapping (QSM) is an MRI technique sensitive to changes in iron or myelin.

Objectives

To test the ability of QSM to detect and localize alterations in cortical iron/myelin content in MS and to investigate possible QSM alterations possibly caused by cortical thinning.

Methods

A group of 105 RR-MS patients (40.7±10.2 y mean±std; m:f 13:92; EDSS median 2 (0 - 6)) and 21 matched healthy controls (HC; 39.5±10.5 y; m:f 8:13) were examined by using 3T MRI 3D-EPI (0.5x0.5x0.5mm), 3D T1w (1x1x1mm) and a 3D FLAIR sequence (1x1x1mm). QSM was computed using a total generalized variation algorithm. T1 lesion filled images were analyzed with Freesurfer to reconstruct WM/GM and pial surfaces. QSM was sampled across the entire cortex with steps of 25% of cortical volume (0%: WM/GM, 100%: pial surface) and projected to the 32k vertices Conte-69 template. Group-wise QSM differences were performed by a permutation-based ANOVA test employing threshold-free cluster enhancement to correct for multiple comparisons (p<0.05 FWE corrected). A vertex-wise cortical thickness (CTh) regressor was used to investigate the impact of cortical thinning on QSM alterations.

Results

Significant differences in QSM showing higher susceptibility in RR-MS than HC were present in majority in cerebral sulci (21, 55 and 55% at 25, 50 and 75%) compared to gyri (9, 37, 38% at 25, 50 and 75%) and in the outer portion of the cortex compared to the inner cortex. The percentage of vertices significantly altered was higher in the outer layer (75%) respect to the inner ones (25%) in several regions, including portions of temporal and parietal lobes, precuneus and para- and post-central sulcus. The use of the CTh regressor, showed significant alterations in the same regions, and revealed further alterations of the cingulate cortex.

Conclusions

Surface analysis of QSM exhibits the presence of increase susceptibility in the cortex of MS patients compared to HC: the alterations are more extended in the outer layers of the cortical ribbon than the inner ones, supporting the hypothesis of a “surface-in” gradient of iron/myelin alterations in the cortex of MS patients. Moreover, these differences were not entirely explained by the presence of cortical thinning.

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Imaging Poster Presentation

P0626 - Quantitative Susceptibility Mapping at 7 Tesla detects ongoing active lesions in relapse-free RRMS patients (ID 1540)

Abstract

Background

Microglia are iron-rich cells, found surrounding multiple sclerosis (MS) lesions in areas of active inflammation. Quantitative Susceptibility Mapping (QSM) can detect this increased iron and thus could be a novel MRI biomarker for microglia-associated inflammation in the brain. The proportion of patients with active inflammation is currently unknown, as is the proportion of MS lesions seen on conventional MRI sequences that are active across patients. Ultra-high field MRI (7 Tesla +) provides superior signal to noise and susceptibility contrast making it the optimal method for detecting iron in MS lesions and tracking active inflammation.

Objectives

To compare the number of lesions with positive QSM signal indicating active inflammation with lesion size and number in patients with relapsing-remitting MS (RRMS) using 7T MRI.

Methods

21 people with RRMS (mean ± SD age = 42 ± 11 yrs; sex: 2m/19f; mean ± SD disease duration = 5.5 ± 3.2 yrs; all EDSS < 4; no relapses in previous 12 months) were scanned using MP2RAGE anatomical and multi-echo gradient echo sequences on a Siemens 7T MAGNETOM MRI scanner. MP2RAGE was used to identify lesions and then co-registered to QSM (calculated from gradient echo phase images using an in-house pipeline). The number of lesions with an average QSM value over 0 (QSM+), indicating the presence of iron associated with active inflammation, were compared to the total number and total volume (log10 transformed) of lesions across patients using linear regression.

Results

The number of lesions in patients ranged from 3 to 92 (mean ± SD = 33 ± 25) and volumes ranged from 26 to 14505 mm3 (mean ± SD = 2554 ± 3445 mm3). Across all patients, the average proportion of QSM+ lesions was 0.61 (95% CI = 0.50-0.72, R2=0.87, p<0.0001), and for each log10 cubic millimeter change in the lesion volume, there were an additional 15 QSM+ lesions (95% CI = 7.0-24, R2=0.43, p=0.0012). There were no associations between the proportion of QSM+ lesions and any disease or demographic variables.

Conclusions

Irrespective of disease severity or duration, the proportion of QSM+ lesions was highly consistent. Based on the assumption that QSM+ lesions are undergoing active inflammation, our results indicate that around ~60% of lesions in RRMS patients could be active.

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Imaging Poster Presentation

P0627 - Quantitative T1 changes relate to infratentorial pathology in early multiple sclerosis. (ID 1844)

Abstract

Background

The presence of infratentorial lesions early in the disease has been shown to have prognostic value for future disability in multiple sclerosis (MS). Quantitative imaging metrics such as T1 relaxometry might contribute to understanding the relationship between supratentorial (ST), infratentorial (IT), and spinal cord (SC) pathology.

Objectives

Our aim was to explore the association between ST, IT and SC pathology and microstructural tissue alterations assessed with T1 relaxometry in T2-hyperintense lesions as well as cerebral and cerebellar normal-appearing white matter (NAWM) in patients with recently diagnosed MS with- and without IT lesions.

Methods

Microstructural tissue alterations were assessed in 42 patients (mean age 33.6±8.0 years, median MS duration 0.2 years (0-2.3)) as deviations from normative T1 times, both obtained from the MP2RAGE sequence at 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The normative T1 values were voxel-wise modelled via a study-specific atlas based on spatially normalized data from 102 healthy individuals (21-59 years). Relationship between normalized IT volumes (mesencephalon, pons, medulla oblongata, cerebellum), SC volume, ST and IT lesion loads estimated by the Morphobox prototype, Scanview and LemanPV prototype, respectively and the deviations from normative T1 times expressed as z-score-derived metrics (volumes and means of voxels with z-scores above z-score 2 and below z-score 2) in lesions, cerebral and cerebellar NAWM were studied by partial correlations adjusted for age and brain lesion volume.

Results

Patients with IT lesions (n=23, 33.0±8.5 years) had larger lesion load, higher volumes of voxels with positive z-scores (> 2), higher mean of z-scores above 2 in lesions, and larger thalami than patients without IT lesions (n=19, 34.3±7.7 years). The remaining volumes and z-scores derived metrics did not differ between groups. Cerebellar volume correlated negatively with volume of voxels with negative z-scores (< 2) in cerebellar NAWM (partial correlation coefficient r=-.437, p=.005) only in patients with IT lesions. In patients without IT lesions, SC and pons volumes correlated negatively with volume of voxels with positive z-scores corresponding to areas of supratentorial T2 lesions (SC: r=-.669, p=.003, pons: r=-0.606, p=0.01).

Conclusions

Microstructural alterations identified as T1 z-scores relate differently to IT and SC volumes in MS patients with and without IT lesions. In the presence of IT lesions, changes in cerebellar NAWM (T1 shortening relative to healthy controls) are associated with lower cerebellar volume. In the absence of IT lesions, the association of cerebellar NAWM and cerebellar volume is not present. In patients without IT lesions, microstructural alterations in ST lesions (T1 prolongation) that might indicate the extent of tissue damage in lesions, are associated with lower pontine and SC volumes regardless of the T2 lesion load.

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Imaging Poster Presentation

P0628 - Quantitative T1 deviations in brain lesions and NAWM improve the clinico-radiological correlation in early MS (ID 763)

Abstract

Background

Although conventional MRI acquisitions are of essence in the monitoring of MS, they show low specificity towards the microstructural nature of tissue alterations and exhibit rather low correlations with clinical metrics (“clinico-radiological paradox”). Conversely, recent advances in brain relaxometry allow characterizing microstructural alterations on a single-subject basis; the question yet remains whether such quantitative measurements can help bridging the gap between radiological and clinical findings.

Objectives

This study investigates whether automatically assessed alterations of T1 relaxation times in brain lesions and normal-appearing white matter (NAWM) improve clinico–radiological correlations in early MS with respect to conventional measures.

Methods

102 healthy controls (65% female, [21-59] y/o) and 50 early-MS patients (76% female, [19-52] y/o) underwent MRI at 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The employed 3D protocol comprised MPRAGE, FLAIR (both used for lesion segmentation as in [Fartaria et al., 2017, MICCAI]), and MP2RAGE for T1 mapping.

After the healthy controls’ data were spatially normalized into a study-specific template, reference T1 values in healthy tissues were established by linear, voxel-wise modelling of the T1 inter-subject variability [Piredda et al., MRM, 2020]. In the MS cohort, T1 deviations from the established references were calculated as z-score maps.

Correlations between the EDSS and conventional measures, i.e. lesion volume and count, were compared against correlations with z-score-derived metrics in lesions and NAWM, namely the volume of voxels exceeding a given z-score threshold.

Results

Correlations between EDSS and lesion volume and count were found to be 0.23 and 0.18, respectively. Higher correlations were found between EDSS and the volume of voxels exceeding an absolute z-score threshold of 2, both in lesions and NAWM, with ρ=0.3 and ρ=0.33, respectively. Correlation further improved when considering only negative z-scores, ρ=0.36 for lesions and ρ=0.39 for NAWM. The highest correlation was found when considering absolute z-scores in the occipital lobe NAWM, ρ=0.47.

Conclusions

Microstructural alterations identified as T1 z-scores were found to improve clinico–radiological correlation in comparison to conventional measures (lesion volume and count). Of notice, negative z-scores (i.e. abnormal T1 shortening), which may be due to an increase in iron content, appear to be a potential predictor for the clinical state of an early MS patient.

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Imaging Poster Presentation

P0629 - QUANTUM – Quantitative and standardized imaging in daily clinical routine of multiple sclerosis patients (ID 1093)

Speakers
Presentation Number
P0629
Presentation Topic
Imaging

Abstract

Background

Magnetic resonance imaging (MRI) analyses play a key role both in treatment monitoring of patients with multiple sclerosis (MS). In MS clinical trials MRI analyses are carried out based on highly standardized protocols, comparable standards are yet to be implemented in routine clinical practice.

Objectives

To evaluate whether standardization of MRI acquisition, volumetric quantification and computerized lesion evaluation of MRI data provides an additional benefit to neurologists working in day-to-day MS patient management.

Methods

From July 2016 until December 2019 297 neurological centers across Germany participated in the QUANTUM project. In total 9,000 MRI data sets from 6.718 MS patients were acquired from 183 radiological centers which all underwent a qualification procedure. Standardized MRI data (3D T1 gradient-echo sequence and 2D/3D FLAIR) were analyzed by a centralized automatic processing pipeline (Biometrica MS®, jung diagnostics GmbH). The analysis comprises volumetric quantification of brain volume, as well as T2 lesion load and number. Percentage brain volume change (using an optimized SIENA pipeline) and T2 lesion activity were computed if follow-up scans were available. The results were visualized and provided to the participating physicians as a report. The benefit and feasibility were evaluated using questionnaires.

Results

Analysis of 8087 questionnaires revealed a good acceptance and usability of the QUANTUM reports. 70% of neurologists reported a strong/very strong correlation between the quantitative MRI parameters and the clinical evaluation of MS patients. More than 74% of neurologists were able to use the report to better classify the patient's disease activity. They rated the additional benefit of the quantitative MRI parameters as high/very high in terms of achieving all four NEDA criteria. 24.4% of the neurologists weighted MRI as more important for therapy decision making than at the beginning of the project. The full data set will be available for presentation.

Conclusions

With QUANTUM standardization of MRI acquisition and MRI evaluation was transferred into daily clinical practice. Volumetric quantification and computerized lesion evaluation can be provided reliably if standardized MRI protocols are used. Quantification of lesion load and volume and visualization of MRI abnormalities might be beneficial for the use of MRI data by neurologists in general and support the individual patient management.

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Imaging Poster Presentation

P0630 - Racial/ethnic disparities in volumetric MRI correlates of clinical disability between Hispanic/Latino and Caucasian multiple sclerosis patients (ID 564)

Speakers
Presentation Number
P0630
Presentation Topic
Imaging

Abstract

Background

Magnetic resonance imaging (MRI)-based measures have been established as robust, non-invasive, in vivo biomarkers of disease. Although the relationship between quantitative regional MRI volume measures and selected aspects of clinical disability in MS has been described, characterization of specific trends by race/ethnicity is lacking.

Objectives

To characterize racial disparities in disability-specific patterns of MRI-based volumetric measures between Hispanic and non-Hispanic Caucasian individuals with MS and explore the relevance of regional brain volumetric measures as predictors of clinical disability progression.

Methods

MRI from 94 Hispanic and 94 Caucasian MS patients was analyzed using automatic and manual brain segmentation techniques. Scans were done between January 2010 and December 2019 on a single 3.0-Tesla scanner using a standardized imaging protocol. Whole brain, cortex, white matter, basal ganglia, thalamus, corpus callosum, lateral ventricular, and T2 lesion volumes were measured and compared with the extent of neurological impairment as measured by Expanded Disability Status Scale (EDSS) scores at baseline and in subsequent follow-up visits. Cox proportional hazard regression models determined the predictive value of baseline MRI metrics for sustained EDSS progression in a time-to-event analysis.

Results

At baseline, Hispanic patients had a higher median EDSS score (median [IQR], 2.0; [1.0–3.5]) compared to Caucasians (median [IQR], 1.0 [0.0–2.0]). In addition, Hispanics were found to develop more rapid accumulation of clinical disability and an increased risk of requiring assistance to ambulate (hazard ratio (HR), 9.7; 95% confidence interval (CI), 2.8–32.5). T2 lesion volume was associated with EDSS in Hispanics (rs = .38, p < .001), and white matter volume was moderately correlated with disability in Caucasians only (rs = -.41, p < .001). The association between normalized thalamic volume and EDSS scores was moderate in both (rs = -.42, P < .001 in Hispanics and rs = -.32, P = .002 in Caucasians). Baseline thalamic volume was the best predictor of sustained disability worsening in both. Patients with thalamic volumes below the mean had a higher risk for progression, with greater risk in Hispanics (HR, 7.9; 95% CI, 3.5–17.9) compared to Caucasians (HR, 3.0; 95% CI, 1.5–6.4).

Conclusions

Quantitative MRI assessment of brain and lesion volume is a useful tool to explore the influence of race on clinical disease expression in multiple sclerosis. Racial disparities in baseline volumetric MRI correlates of clinical disability suggest a burgeoning trend of possibly differentially regulated pathophysiologic processes through which race-dependent disparities may manifest. The confounding impact of race and ethnicity on brain volumetric measures may affect the interpretation of outcome measures in clinical MS studies and should be controlled in randomized clinical trials.

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Imaging Poster Presentation

P0631 - Recommendations for the coordination of Neurology and Neuroradiology departments in the management of patients with multiple sclerosis (ID 314)

Abstract

Background

Magnetic resonance imaging (MRI) is widely used for the diagnosis and follow-up of patients with multiple sclerosis (MS). It is considered the most reliable and accurate paraclinical tool to evaluate disease activity and progression due to the high sensitivity to detect demyelinating lesions. Coordination between Neurology and Neuroradiology departments is essential to ensure that radiological studies are effectively performed and interpreted. However, in clinical practice, this coordination can be improved to maximize MS management and care.

Objectives

To establish a set of organizational recommendations focused on the coordination between neurologists and neuroradiologists to improve MS management in clinical practice.

Methods

A panel of 17 experts, including neurologists and neuroradiologists, from eight Spanish academic hospitals participated in the study. The Consensus Recommendation Guideline was conducted in four phases: 1) definition of the scope and methodology of the study; 2) review of the literature on good practices or recommendations in the use of MRI in MS; 3) discussion of drafted recommendations to achieve a consensus between the authors; 4) formalization and validation of the contents in a set of recommendations.

Results

We provide nine recommendations to improve the coordination between Neurology and Neuroradiology departments, which can be summarized as follows: 1) standardize the MRI requests, reports and schedules, 2) create shared protocols for MRI studies, 3) establish multidisciplinary working committees and coordination sessions, and 4) generate formal communication channels to improve the coordination between professionals from both departments. These recommendations are based on the available scientific evidence, international good practice guidelines and the experience of the panel experts.

Conclusions

We propose a series of recommendations expected to serve as a functional guide to implement improvements in the coordination between neurologists and neuroradiologists that will ultimately lead to improve the diagnosis and follow-up of MS patients.

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Imaging Poster Presentation

P0632 - Reduced brain integrity slows down and increases low alpha power in multiple sclerosis (ID 891)

Abstract

Background

In multiple sclerosis, the interplay of neurodegeneration, demyelination and inflammation leads to changes in neurophysiological functioning.

Objectives

This study aims to characterise the relation between reduced brain volumes and spectral power in multiple sclerosis patients and matched healthy subjects.

Methods

During resting-state eyes closed, we collected magnetoencephalographic data in 67 multiple sclerosis patients and 47 healthy subjects, matched for age and gender. Additionally, we quantified different brain volumes (white matter, cortical and deep grey matter, FLAIR lesion load and volume of black holes) and calculated the power spectral density. Instead of using the traditionally used frequency bands, we calculated the source reconstructed power spectral density in frequency bins of 0.25 Hz (range: 0-40 Hz) and corrected for multiple comparisons through permutation testing.

Results

First, a principal component analysis (PCA) of brain volumes demonstrates that atrophy can be largely described by two components: one overall degenerative component that is indicative of brain integrity and correlates strongly with different cognitive tests, and one component that mainly captures degeneration of the cortical grey matter that strongly correlates with age. As the first PC was observed both when performing the PCA on the full cohort and on the two subcohorts, we denote this component as an index of brain integrity. Logically, this component was more strongly expressed in the MS cohort.

Next, a multimodal correlation analysis indicates that reduced brain integrity is accompanied by increased alpha1 power in the temporoparietal junction (TPJ). Patients showing this local increase in alpha-peak also scored significantly worse on different cognitive tests and reduced thalamic volumes. The increase in alpha1-power comes from both a slowing of the main alpha-peak and an increase in power.

Conclusions

MS patients with reduced brain integrity demonstrated increased alpha1 power in the TPJ and impaired cognitive functioning.

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Imaging Poster Presentation

P0634 - Relationship Between Cognitive Functioning and 7T Thalamic Imaging Metrics in Fingolimod-Treated MS Patients and Healthy Controls (ID 700)

Speakers
Presentation Number
P0634
Presentation Topic
Imaging

Abstract

Background

Cognitive dysfunction is common in multiple sclerosis (MS) and can impair processing speed, episodic memory, and executive function. Magnetic resonance imaging (MRI) studies have demonstrated associations between several MRI metrics and cognitive functioning in MS, including thalamic volume and brain parenchymal fraction. Fingolimod is an MS therapy that demonstrated reduced brain volume loss across several clinical trials.

Objectives

Determine the relationship between cognitive function in fingolimod-treated relapsing-remitting MS patients and 7 tesla (7T) MRI measures.

Methods

We recruited fingolimod-treated MS patients and healthy controls to be followed for 12 months. Participants underwent 7T brain MRI and cognitive testing including the symbol digit modalities test (SDMT), selective reminding test (SRT), and the trail making, color, and verbal subtests of the Delis-Kaplan Executive Function System (DKEFS) at baseline, 6 months, and 12 months. Mixed effects linear regression models were used to determine the relationship between MRI metrics and neurometric test performance, fitting values from all 3 time points. Rates of change in MRI metrics and neurometric test performance were compared between patients and controls using two-sample t-tests.

Results

We enrolled 15 MS patients with mean age 42.4 years (SD=5.6), mean disease duration 8.5 years (SD=4.1), and median expanded disability status scale 3 (IQR=1.5-3.5). Five controls were enrolled with mean age 41.5 (SD=6.6) years. Controls performed better than patients on all psychometric tests, but this was only significant for tests of orthographic knowledge (DKEFS letter fluency) and long-term storage (SRT). When MRI metrics were used to predict neuropsychological test performance over time in patients, thalamic volume was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and inhibitory control (DKEFS Color Inhibition). Thalamic myelin density was a significant predictor of visuospatial memory (BVMTR), long-term storage (SRT), and semantic knowledge (DKEFS Verbal Category Fluency). When changes in neuropsychological testing performance and MRI metrics were compared for patients and controls from 0-6 months, and from 0-12 months, none of the differences between patients and controls were significant.

Conclusions

Thalamic volume and myelin density are associated with measures of cognitive function. 7T MRI of the thalamus may be useful as a clinical trial measure to predict cognitive effects.

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Imaging Poster Presentation

P0635 - Relationship between mood disturbance and cerebellar volume and structural connectivity in multiple sclerosis  (ID 1068)

Speakers
Presentation Number
P0635
Presentation Topic
Imaging

Abstract

Background

Recent examinations of the cerebellum have found relationships to higher level processes (i.e., cognition, mood). Mood disturbance is highly prevalent in multiple sclerosis (MS), yet, most studies examining the role of the cerebellum in MS have focused on disability or cognitive functioning, despite cerebellar changes being linked to mood disturbance (e.g., depression) in other clinical populations.

Objectives

The aim of the current study is to examine the relationship between cerebellar gray matter volume and white matter connectivity and mood in persons with MS.

Methods

Forty-eight participants were divided into three groups: MS with depression (MS+D; N=22), MS without depression (MS-D; N=11), and Depression without MS (D-MS; N=15). Each participant completed self-report mood questionnaires (Beck Depression Inventory-Fast Screen; Chicago Multiscale Depression Inventory; Apathy Evaluation Scale; Depression Proneness Rating Scale). Multi-shell diffusion MRI and structural data (T1, T2 FLAIR) were collected. Deterministic tractography was performed and structural connectivity (i.e., graph theory) analyses were conducted within the cerebellum. Five graph theory metrics were calculated- density, clustering coefficient, path length, small worldness, global efficiency- for number of normalized streamlines and quantitative anisotropy (QA). Gray matter volume (mm3) was calculated for the anterior and posterior cerebellum and 16 separate cerebellar lobules. Whole brain lesion volume was also calculated. Analyses of variance (ANOVA) determined group differences for self-report and brain measures. The two MS groups were also combined to conduct ridge regression analyses for brain metrics vs. mood severity.

Results

Significant differences were observed between groups on all mood measures. MS+D and MS-D had significantly greater whole brain lesion volumes than D-MS. After correcting for multiple comparisons, MS+D had significantly lower streamline clustering coefficients and global efficiency compared to MS-D. MS+D showed significantly decreased volume in lobules I-IV, Vermis Crus II, and lobule VIIIb when compared to MS-D or D-MS, though they did not survive Bonferroni correction. The combined MS group showed less efficient connectivity (clustering, global efficiency) to be related to greater depression severity/proneness and apathy. Similarly, greater atrophy within the anterior cerebellum, Vermis Crus II, I-IV, lobule VIIIb, Vermis IIIb, and Vermis IX were related to depression severity/proneness and apathy.

Conclusions

This study is among the first to examine mood in persons with MS through a cerebellar volumetric and structural connectivity lens. Results provide evidence for the contribution of cerebellar atrophy and structural network disruption to the presence and severity of mood disturbance in MS. These results have important implications for future research and clinical interventions.

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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

P0637 - Relevance of NODDI to characterise in vivo the microstructural abnormalities of multiple sclerosis cortex and cortical lesions: a 3T study (ID 1087)

Speakers
Presentation Number
P0637
Presentation Topic
Imaging

Abstract

Background

In multiple sclerosis (MS), cortical damage is a relevant predictor of clinical disability, but MRI measures more specific to cortical pathology are needed. Neurite orientation dispersion and density imaging (NODDI) model is a multi-compartment diffusion model to better evaluate the complexity of brain microarchitecture.

Objectives

To characterize, using NODDI, the microstructural abnormalities of normal-appearing cortex (NA-cortex) and cortical lesions (CLs) and their relations with disease phenotypes and clinical disability in a relatively large cohort of MS patients.

Methods

Brain 3D T1-weighted, FLAIR, double inversion recovery (DIR) and diffusion-weighted (DW) sequences were acquired from 164 MS patients (94 relapsing-remitting [RR], 70 progressive [P] MS) and 51 healthy controls (HC). The cortex was segmented from 3D T1-weighted sequence, whereas CLs were quantified on DIR. CLs and NA-cortex masks were then transformed into DW space. Using NODDI, intracellular volume fraction (ICV_f), representing neurite density, extracellular volume fraction (ECV_f) and orientation dispersion index (ODI), reflecting neurite orientation variability, were assessed in NA-cortex and CLs. Between-group comparisons and correlations with clinical and structural MRI measures were investigated.

Results

One hundred and twelve (68.3%) MS patients had ≥1 CL. MS NA-cortex had a significant lower ICV_f vs HC NA-cortex (p=0.001). CLs showed a significant increased ECV_f (p<0.001) and decreased ICV_f and ODI compared to NA-cortex of HC (p<0.001) and MS (p=0.035 and <0.001). Compared to RRMS, PMS had a significant decreased NA-cortex ICV_f (p=0.024). Higher burden of CLs (p<0.001) were found in PMS vs RRMS, without microstructural differences. In MS patients, NA-cortex ICV_f, ECV_f and ODI were significantly correlated with disease duration, EDSS, white matter lesion volumes, CL volumes and whole brain and gray matter atrophy (r from -0.37 to 0.71, p from <0.001 to 0.048).

Conclusions

A significant neurite loss occurs in MS NA-cortex, being more severe with longer disease duration, higher disability and PMS. CLs show a further reduction of neurite density, together with an increased extracellular space, possibly due to inflammation and gliosis, and a reduced ODI suggestive of increased tissue coherence and simplification of neurite complexity. NODDI is reliable and clinically relevant to investigate in vivo the heterogeneous pathological processes affecting MS cortex.

Funding. This study is supported by a senior research fellowship FISM – Fondazione Italiana Sclerosi Multipla – cod. 2019/BS/009 and financed or co-financed with the ‘5 per mille’ public funding.

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Imaging Poster Presentation

P0638 - Role of Gadolinium-based contrast agents to detect subclinical disease activity in clinically stable patients in the Swiss MS Cohort Study (ID 821)

Abstract

Background

Gadolinium (Gd)-based contrast agents are widely used to assess disease activity and treatment response by MRI in multiple sclerosis (MS). There is, however, increasing concern about their safety as their repeated administration may lead to brain parenchymal accumulation, while preclinical models suggest that they induce mitochondrial toxicity and neuronal cell death. Moreover, recent reports have demonstrated that three-dimensional (3D) T2-weighted Fluid-Attenuated-Inversion-Recovery (FLAIR) is highly sensitive in detecting new or enlarging MS lesions.

Objectives

To explore whether the presence of contrast enhancing lesions (CEL) based on Gd injection is more sensitive in detecting lesional activity in clinically stable MS patients in comparison to the analysis of new or enlarging MS lesions by 3D FLAIR.

Methods

MS patients being part of the observational, multicenter Swiss Multiple Sclerosis Cohort Study (SMSC) with contrast enhanced T1-weighted (T1w) images were included. Clinical stability was defined as no relapse and no Expanded Disability Status Scale (EDSS) increase during at least twelve months prior to MRI. Presence of CEL was assessed on contrast enhanced T1w images. Presence of new or enlarging T2w lesions was assessed manually on 3D FLAIR in an independent analysis by a different investigator in clinically stable MS patients presenting with CEL.

Results

3930 MRI scans (3.0 Tesla n=1497 (38%)) in 1057 participants (685 women, median age 42.0 years, 941 with relapsing MS, 116 with progressive MS, median EDSS 2.0 (range 1.5-3.5), median disease duration 7.4 years) were included.

Of 2620 MRI scans (66.7%) acquired in clinically stable conditions 46 (1.8%) demonstrated CEL. In all of these, new or enlarging T2w lesions were detectable by 3D FLAIR when a previous MRI was available for comparison (previous MRI available in 29/46; median number of new or enlarging T2w lesions: 3 (range 1-41, total number 176); median number of CEL: 1 (range 1-4, total number 47)).

Conclusions

In our large cohort from clinical practice, the assessment of new or enlarging lesions by 3D FLAIR was equally sensitive as the quantification of CEL to detect disease activity in clinically stable MS patients, challenging current practice of the use of Gd-enhanced MRI for monitoring of MS in clinical routine.

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Imaging Poster Presentation

P0639 - Sensorimotor cerebellar functional connectivity changes as compensatory  mechanisms of structural damage in patients with MS and no disability (ID 1777)

Speakers
Presentation Number
P0639
Presentation Topic
Imaging

Abstract

Background

The cerebellum plays a relevant role in both motor and cognitive function due to the high number of cerebellar connections with the brain and spinal cord. Alterations in cerebellar functional connectivity may modulate the relationship between brain structural damage and clinical impairment in multiple sclerosis.

Objectives

To investigate whether resting-state functional connectivity changes of the sensorimotor cerebellum represent adaptive neuroplastic mechanisms to reduce the effects of structural damage on physical disability in patients with multiple sclerosis and no disability.

Methods

A total of 144 multiple sclerosis patients with a score of ≤1.5 on the Expanded Disability Status Scale and 98 healthy subjects were selected from the Italian Neuroimaging Network Initiative database and included in this study. Both patients and healthy subjects underwent multimodal 3T-MRI including functional MRI at rest. After parcellation of the cerebellum, the sensorimotor cerebellum (lobules I-V + VIII) was identified and used as a seed for resting-state functional connectivity analysis.

Results

In patients, brain areas with decreased and increased sensorimotor cerebellar functional connectivity were found to coexist with respect to healthy subjects. Areas of decreased cerebellar functional connectivity, i.e. the lingual gyrus, insula, and precentral and postcentral gyri, negatively correlated with T2 lesion load and white matter atrophy. Areas of increased cerebellar functional connectivity, i.e. the posterior cerebellum, nucleus accumbens, prefrontal cortex, cingulate/paracingulate gyri, and precuneus, positively correlated with T2 lesion load and cerebellar and thalamic atrophy. Areas of increased cerebellar functional connectivity with the cingulate gyrus and precuneus negatively correlated with global grey and white matter atrophy.

Conclusions

In patients with multiple sclerosis, the sensorimotor cerebellum extensively reorganizes its functional links with other brain regions. Areas of decreased cerebellar functional connectivity related to white matter damage are present even in the absence of clinical manifestations and may represent a preclinical condition. Areas of increased cerebellar functional connectivity related to both lesion burden and thalamic or cerebellar atrophy likely represent a compensative reorganization of brain circuits. Lastly, global atrophy may influence functional connectivity changes in posterior cortical areas.

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Imaging Poster Presentation

P0640 - Sensorimotor network dynamics predicts loss of upper and lower limb function in people with multiple sclerosis (ID 1048)

Speakers
Presentation Number
P0640
Presentation Topic
Imaging

Abstract

Background

Both upper and lower limb disability is common in multiple sclerosis (MS), but do not always occur together, suggesting partially independent underlying mechanisms. Physical disability strongly relates to brain network disturbances in MS, yet network mechanisms underlying upper and lower disability progression remain unclear.

Objectives

To investigate the relationship between upper and lower limb progression and functional sensorimotor network changes in MS.

Methods

Longitudinal data was included from a prospectively acquired cohort, with baseline data collected between 2008 and 2012 and follow-up assessments between 2014 and 2017. Participants underwent MRI and dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) tests at baseline and after 5 years. Patients were stratified into progressors (>20% decline) or non-progressors for both tests. Measures of network efficiency were calculated from resting-state functional MRI data using both static (i.e. calculated on the entire scan) and dynamic (i.e. fluctuations during the scan) approaches and compared between patient groups. Multiple logistic regression was used to identify independent predictors of upper and lower limb progression and baseline connectivity patterns.

Results

This study included 214 people with MS (age 47±11; 149 women) and 58 healthy controls (age 46±10; 31 women). Compared to respective non-progressors, upper limb progression (n=24) was related to higher dynamic efficiency of the right premotor cortex, somatosensory cortex and thalamus, while lower limb progression (n=37) was related to higher dynamic efficiency of the right supplementary motor area at baseline (p<0.05). Logistic regression showed that dynamic efficiency of the thalamus and supplementary motor area best predicted upper and lower limb progression respectively, independent of the severity of structural damage (p<0.01). Both areas displayed widespread higher dynamic connectivity in progressing compared to non-progressing patients at baseline (p<0.05).

Conclusions

Disability progression can be predicted by the severity of fluctuations (i.e. higher dynamics) in the efficiency of the sensorimotor network. The dynamic behavior of the thalamus and supplementary motor area were respectively related to upper and lower limb progression, possibly indicating different mechanisms underlying these types of progression in MS.

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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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Imaging Poster Presentation

P0642 - Spatial distribution of cortical lesions in multiple sclerosis correlates to clinical and cognitive decline (ID 818)

Speakers
Presentation Number
P0642
Presentation Topic
Imaging

Abstract

Background

Cortical lesions are of eminent clinical relevance in patients with multiple sclerosis (MS), since they have been associated with clinical decline and disease progression. Heretofore, cortical lesions were commonly assessed at a whole-brain level, and were found to correlate with EDSS. However, there is no evidence on correlations between the spatial distribution of cortical lesions and cognition. We hypothesize that the distribution of cortical lesions contributes to explaining the variance of both clinical and cognitive decline.

Objectives

To further elucidate the spatial distribution of cortical lesions and assess their association with clinical and cognitive decline.

Methods

One-hundred-fourteen patients (59 RRMS, 37 SPMS, 16 PPMS, mean age 54.49 ±8.99, 76 female) underwent MRI (double inversion recovery (DIR) and 3D-T1), and neuropsychological assessment (BRB-N, Stroop, Memory comparison task). Raw cognition data were converted to Z-scores based on the control scores, and averaged over the domains. For each patient, cortical lesions were identified and delineated on DIR. The extent of lesioned cortex was measured and cortical lesion maps were generated to enable vertex-wise cortical lesion probability maps and correlations using FreeSurfer.

Results

Cortical lesions were preponderantly situated in frontal and temporal lobes, as well as in the motor and anterior cingulate cortex. Significant clusters of vertex-wise correlations between cortical lesions and EDSS were primarily found for the motor cortex. Significant clusters of vertex-wise correlations between cortical lesions and cognition were primarily found for the frontal and temporal lobe.

Conclusions

The presence of frontal and temporal cortical lesions specifically predicted cognitive decline, while cortical lesions in the motor cortex were related to physical functioning. This confirms the hypothesis that the spatial distribution of cortical lesions contributes to explaining the variance of both clinical and cognitive decline. Further studies should investigate whether the location of cortical lesions is relevant to specific cognitive functions (e.g., memory or executive functioning).

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Imaging Poster Presentation

P0644 - Spinal cord atrophy in a primary progressive multiple sclerosis trial: improved sample size using GBSI (ID 686)

Speakers
Presentation Number
P0644
Presentation Topic
Imaging

Abstract

Background

Spinal cord atrophy is a common feature of multiple sclerosis (MS), can be detected in vivo using MRI, and is one of the main substrates of disease progression. In our previous studies, we have adapted the boundary shift integral (BSI) technique developed for the brain, to be applied to the spinal cord, obtaining the first registration-based method for longitudinal assessment of spinal cord atrophy.

Objectives

We aim to 1) compare spinal cord atrophy measurements using segmentation- and registration-based methods, with possible implications for clinical trial design (e.g., measurement variability, image noise floor); 2) compare spinal cord atrophy measurements obtained from routine brain (C1-2) and dedicated spinal cord MRI (C1-2 and C2-5), using segmentation- and registration-based methods; 3) explore possible clinical correlates, also in relation to conventional brain MRI measures; and 4) explore possible treatment effect.

Methods

We included 220 primary-progressive multiple sclerosis patients from a phase 2 clinical trial, with baseline and week-48 3DT1-weighted MRI of the brain and spinal cord (1x1x1mm3), acquired separately. We obtained segmentation-based cross-sectional spinal cord area (CSA) at C1-2 (from both brain and spinal cord MRI) and C2-5 levels (from spinal cord MRI) using DeepSeg, and, then, we computed corresponding GBSI.

Results

Depending on the spinal cord segment, we included 67.4-98.1% patients for CSA measurements, and 66.9-84.2% for GBSI. Spinal cord atrophy measurements obtained with GBSI had lower measurement variability, than corresponding CSA. Looking at image noise floor, the lowest median standard deviation of the MRI signal within the cerebrospinal fluid surrounding the spinal cord was found on brain MRI at C1-2 level. Spinal cord atrophy derived from brain MRI was related to corresponding measures from dedicated spinal cord MRI, more strongly for GBSI than CSA. Spinal cord atrophy measurements using GBSI, but not CSA, were associated with upper and lower limb motor progression. No treatment effect was detected for any spinal cord atrophy measurements.

Conclusions

Notwithstanding reduced measurement variability, clinical correlates, and possibility of using brain acquisitions, spinal cord atrophy using GBSI should remain a secondary outcome measure in MS studies, until further advancements increase the quality of acquisition and reliability of processing.

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Imaging Poster Presentation

P0645 - Spinal cord pathology in a large cohort of MS patients with different levels of disability and MS phenotypes (ID 865)

Abstract

Background

SC pathology occurs early in the course of MS. However, few studies have investigated the relationship between lesions, diffuse changes and mean upper cervical cord area (MUCCA) in MS patients with different levels of disability in detail.

Objectives

To explore spinal cord (SC) pathology in multiple sclerosis (MS) patients with different levels of disability and MS phenotypes.

Methods

638 MS patients with different degrees of disability and 102 healthy controls (HC) underwent MRI on a 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). The MRI protocol comprised transversal 3D-T2WI for MUCCA, sagittal T2WI-Fat-Sat and PDWI for SC pathology, and 3D-MPRAGE for regional brain volume (BV). MUCCA was measured automatically between the C3 and C4 vertebra (ScanView.cz). Global and regional BVs were estimated by the fully automated MorphoBox prototype (Siemens Healthcare, Erlangen, Germany). Diffuse changes, number and location of SC lesions were assessed manually. Patients and HC were matched by sex and age using propensity scores. MUCCA, regional BVs and SC pathology were compared among matched subgroups of: 54 patients with mild disability (EDSS=<1.5), 54 patients with mild-to-moderate disability (EDSS 2-3.5), 54 patients with severe disability (EDSS 4-4.5), 54 patients with very severe disability (EDSS>=5), 18 primary progressive (PP) patients, and 54 controls from the HC group. ANOVA test was used for between-group comparison.

Results

There was a trend of lower MUCCA with higher disability level. Mean MUCCA was 76.5±10.8 mm2 invery severe, 80.1±9.6 mm2 in severe, 85.7±8.0 mm2 in moderate, 85.6±8.5 mm2 in mild disability, and 90±7.7 mm2 in HC groups. There was a significant difference in MUCCA between HC and mild disability group (p<0.001). SC pathology was prominent in 64.1% of the patients with mild disability, compared to 90.4% patients with very severe disability. The percentage of diffuse changes varied greatly between the groups, with prevalence increasing almost four times between patients with mild and very severe disability.

Conclusions

SC pathology is present in all disability MS groups. MUCCA differentiated between patients with mild disability and healthy controls, suggesting that it may be promising for the implementation in diagnostic protocols. The evaluation of diffuse changes can help to predict disability. Low MUCCA together with prominent diffuse changes could help differentiate PP MS from other MS phenotypes.

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Imaging Poster Presentation

P0646 - Structural constraints of functional connectivity drive cognitive impairment in the early stages of multiple sclerosis (ID 1161)

Speakers
Presentation Number
P0646
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) is associated with brain dysconnectivity that leads to changes in network organisation. However, given the inconsistent results obtained by studies of structural and functional connectivity, the relationship between the structural and functional deficits in MS is unclear.

Objectives

This study explored structure-function relationships during the early stages of MS and their role in cognitive performance.

Methods

Patients were enrolled after their first neurological episode suggestive of MS and followed for 5 years. Healthy controls matched for age, sex and level of education were followed-up in parallel.

The evolution of structural and functional brain networks was investigated, and structural-functional coupling was assessed. Clinical and cognitive status was determined at each follow-up visit. The association between brain network parameters and cognitive performance was assessed using linear mixed-effects models.

Results

The study included 32 patients (25 females) and 10 healthy controls. The mean (SD) age of the patients was 37.7 (10.4) years. Both structural and functional reorganisation was observed during the disease course. Structural clustering coefficient was significantly increased after 5 years whereas characteristic path length decreased, indicating strengthened short-distance connections and the loss of long-range connections. By contrast, functional connections and related path lengths were decreased after 5 years, suggesting stronger local short-distance connections. Structural-functional coupling had increased significantly after 5 years, indicating greater constraint of functional connectivity by direct anatomical connections. This structural-functional coupling was the only parameter associated with cognitive and clinical status, with stronger coupling associated with a decline in both domains.

Conclusions

Our findings provide novel biological evidence that MS leads to less dynamic brain function in relation to the underlying anatomy of the brain. The collapse of this network leads to both cognitive impairment and clinical disability.

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Imaging Poster Presentation

P0647 - Studying intralesional axonal damage in MS white matter lesions with diffusion MRI biophysical models (ID 694)

Abstract

Background

Advanced diffusion-weighted MRI (DW-MRI) sequences, in combination with biophysical models, provide new information on the microstructural properties of the tissue.

Objectives

To investigate the differences in intra-axonal signal fraction (IASF) between perilesional normal-appearing white matter (pl-NAWM), white matter lesions (WML) without (rim-) and with paramagnetic rim (rim+) comparing eight biophysical diffusion models.

Methods

The study included 102 MS patients: RRMS: 66%, SPMS: 18%, PPMS: 16%, mean age 46±14; female 64%, disease duration 12.16±18.18 yrs, median EDSS: 2.5.

DW-MRI data were acquired with 1.8mm isotropic resolution and b-values [0, 700, 1000, 2000, 3000] s/mm2.

Lesion masks were generated with a deep-learning-based method and manually corrected if required; pl-NAWM was defined as a region of 3-voxels around each WML; 225 paramagnetic rim lesions were manually identified based on 3D EPI and 2330 were labelled as rim-.

The following microstructural models were applied: Ball and Stick, Ball and Rockets, AMICO-NODDI, SMT-NODDI, MCMDI, NODDIDA, CHARMED, Microstructure Bayesian approach.

Delta (WML - pl-NAWM) was calculated for each WML, and one-side Mann Whitney U was used to compare the delta between models, followed by Bonferroni to correct for multiple testing.

Mean difference and Cohen's d was used to assess differences between lesions with extensive axonal damage (rim+) and other WML (rim-).

Results

All models applied in this study reported low IASF in rim+ WML, medium IASF in rim- WML and relatively high IASF in pl-NAWM. However, a broad spectrum of IASF values was identified from the different models: relatively simple models such as Ball and Stick and CHARMED, showed low delta IASF within lesions, while MCMDI models reported the highest significant difference compared to other models (p<0.0001). The comparison between WML and pl-NAWM mean IASF across models showed that MCDMI exhibited the highest difference (mean 0.13, Cohen’s d 1.34). AMICO-NODDI and SMT-NODDI showed close results (mean difference 0.12/0.12 and Cohen’s d 1.46/1.51).

The models best discriminating IASF between rim+ and rim- lesions were MCMDI and NODIDDA (mean 0.08/0.07, Cohen’s d -0.69/-0.70).

Conclusions

We compared eight WM diffusion models for assessment of intralesional axonal damage in MS patients. The comparison between WML and pl-NAWM showed that robustness of the method, identified with SMT-based and NODDI-based models, it is crucial. For the comparison between lesions with a high level of damage (rim +) and other WML, the diffusivity estimation appeared to play an important role. The method which appeared both robust and able to estimate the diffusivity of the tissue was MCMDI, which performed best in both cases.

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Imaging Poster Presentation

P0648 - The central vein sign as a biomarker for MS in the infratentorial brain (ID 920)

Speakers
Presentation Number
P0648
Presentation Topic
Imaging

Abstract

Background

The central vein sign (CVS) is a novel imaging biomarker for the differential diagnosis of multiple sclerosis (MS). In studies at 7.0 tesla MRI, the percentage of supratentorial white matter lesions (WMLs) with CVS vary between 80% to 100% in MS patient brains. Similar results were reported at 3.0 tesla (3T) MRI in optimized sequences, such as T2*-weighted 3D echo-planar-imaging sequence and SWAN-venule. The value of the CVS for infratentorial brain remains unknown.

Objectives

The aim of this study was to determine the proportion of WMLs positive for the CVS in the brainstem and cerebellum of MS patients.

Methods

We included subjects with clinically defined MS, that showed at least one infratentorial lesion larger than 3 mm in 3D-FLAIR. Patients were scanned in a 3T MRI system (GE Medical Systems, discovery MR750) using a 32-channel coil array. MRI included 3D T2-weighted FLAIR and post-contrast SWAN-venule: [FOV = 22 cm x 16 cm; number of slices= 126; voxel resolution, 0.4 mm x 0.4 mm x 0.8 mm; TR = 47 msec; TE = 28 msec; flip angle (FA) = 8 degrees; ETL = 9; AT = 7.38 min]. The CVS, defined as a thin hypointense line or a hypointense small dot visualized in two planes, was recorded on SWAN-venule by two trained raters.

Results

Thirty MRIs were analyzed, three were excluded for motion artefacts. A total of 91 focal lesions were detected in FLAIR, 22 in the cerebellum and 69 in brainstem. Out of 91 lesions, 83 (91%) were visible in SWAN-venule and 83% were positive for the CVS.

Conclusions

The infratentorial brain is a cardinal compartment for MS diagnosis, SWAN-venule detects infratentorial WMLs and highlights the CVS in most plaques at 3.0 T MRI. The CVS could be used to discriminate MS lesions from its radiological infratentorial mimics.

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Imaging Poster Presentation

P0649 - The Central Vein Sign discriminates multiple sclerosis from its radiological mimics in the clinical setting (ID 1503)

Presentation Number
P0649
Presentation Topic
Imaging

Abstract

Background

The “central vein sign” (CVS) in white matter lesions (WMLs) is a current radiological biomarker of multiple sclerosis (MS). Using magnetic susceptibility-based sequences, the CVS was observed in 80-100% of lesions at 7.0 tesla Magnetic Resonance Imaging (MRI) in the research setting. Recently, similar detection rate was reported at 3.0 Tesla (3T) MRI in the clinical setting using susceptibility-weighted angiography (SWAN)-venule sequence. Some data suggest that using 3D T2*EPI/ FLAIR*, the CVS may be useful to differentiate MS from other neurological diseases with focal WMLs.

Objectives

The objective of our study was to determine if the CVS detected in SWAN-venule at 3T MRI discriminates MS from its radiological mimics.

Methods

Subjects were scanned on a 3T MRI system (Discovery MR750, GE, Milwaukee, USA) using a 32-channel head coil. We performed post-contrast 3D-FLAIR and SWAN-venule sequences [FOV = 22 cm x 16 cm; number of slices= 126; voxel resolution, 0.4 mm x 0.4 mm x 0.8 mm; TR = 47 msec; TE = 28 msec; flip angle = 8° ; ETL = 9; AT = 7.38 min]. MRIs with focal supratentorial WMLs visible in FLAIR, larger than 3 mm and smaller than 15 mm, were included. The CVS, defined as a thin hypointense line or a hypointense small dot centering a WML, was recorded blinded to the diagnosis on SWAN-venule by one junior neuroradiologist and two trained MS raters.

Results

Twenty people with MS and 24 subjects with non-MS WMLs: 9 migraine, 6 Neuromyelitis Optica spectrum disease (NMOs), 5 Susac Syndrome (SS), and 4 with other vascular diseases (2 primary angiitis of the central nervous system, 1 small vessels disease, and 1 Lupus), were included. A total of 380 WMLs were detected in the MS group, and 427 WMLs in the non-MS group (215 migraine, 52 NMOs, 83 SS, and 77 in other vascular diseases). The CVS was detected in 86% of MS WMLs compared to 23% of WMLs of other diseases (25% of migraine, 21% of NMOs, 22% of other vascular diseases).

Conclusions

The use of SWAN-venule sequence for the identification of CVS on 3T MRI helps differentiate MS WMLs from other WMLs that mimic MS.

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Imaging Poster Presentation

P0650 - The contribution of cortical lesions to fatigue  and depression in relapsing remitting multiple sclerosis. (ID 1163)

Speakers
Presentation Number
P0650
Presentation Topic
Imaging

Abstract

Background

Despite the high prevalence and debilitating nature of fatigue and depression in Relapsing-Remitting Multiple Sclerosis (RRMS), the underlying pathophysiology is still far from being fully understood. While several findings highlighted the contribution of white matter lesion load (WMLL) and brain atrophy, the role of cortical lesions (CL) has been only marginally assessed.

Objectives

To investigate: i) the contribution of CL volume to fatigue and depression; ii) the relative role of total CL volume (tCLV), intracortical lesion volume (ICLV) and juxtacortical lesion volume (JCLV).

Methods

Sixty-five RRMS patients underwent: i) clinical evaluation including the Expanded Disability Status Scale (EDSS), ii) assessment of fatigue and depression trough the Modified Fatigue Impact Scale (MFIS) and the Beck Depression Inventory (BDI), iii) a 3T–MRI protocol including Double-Echo (DE) and 3D–Double Inversion Recovery (DIR) imaging to identify WMLL and CL. Correlation analyses were run between WMLL, CL and MFIS, and BDI. A multiple linear regression model was applied to evaluate the contribution of CL to MFIS and BDI, controlling for clinico-demographic data and WMLL.

Results

The correlation analysis showed that tCLV and JCLV correlated with MFIS (rho= 0.31, p=0.007; rho= 0.28, p=0.01 rispectively) and BDI (rho= 0.24, p=0.03 and rho= 0.23, p=0.04, rispectively), while ICLV or WMLL did not correlate with neither MFIS nor BDI. Regression analysis did not reveal any CL volume as a significant predictor of fatigue or depression.

Conclusions

Although CL volume is not a significant independent predictor of fatigue and depression, our study shows a significant role of CL volume in determining these symptoms in RRMS.

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Imaging Poster Presentation

P0651 - The effects of amiloride, fluoxetine and riluzole over 96 weeks on metabolic markers of brain injury in secondary progressive multiple sclerosis. (ID 1206)

Abstract

Background

MS-SMART is a recently reported phase 2b randomised placebo controlled multi-arm study of the neuroprotective potential of amiloride, fluoxetine and riluzole in secondary progressive multiple sclerosis [NCT01910259]. No change in atrophy rate was observed in any arm compared to placebo. We obtained brain metabolic data using proton magnetic resonance spectroscopic imaging (MRSI) at baseline and 96 weeks to explore postulated candidate drug mechanisms of action for the three interventions. Fluoxetine has previously shown an increase in total N-acetyl aspartate plus N-acetyl aspartyl glutamate [tNAA]; myoinositol was also examined as a marker of astrogliosis. Amiloride blocks the acid sensing ion channel-1 receptor that mediates sodium and calcium and therefore could increase neuroaxonal integrity (tNAA). It is known that riluzole decreases glutaminergic transmission.

Objectives

MRSI data at baseline and then 96 weeks was used to interrogate drug specific effects of fluoxetine on tNAA and myoinositol (mIns); riluzole on Glx (glutamate + glutamine); and amiloride on tNAA levels, all compared to placebo.

Methods

108 participants from the MS-SMART trial were included and had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR =35/2000ms) at 3T. Metabolite levels and ratios to creatine (tCr) were determined for normal appearing white matter (NAWM) and grey matter (GM) with LCModel using an unsuppressed water scan as the internal reference. Multiple regression models adjusting for age, sex and baseline Expanded Disability Status Scale (EDSS) were used.

Results

Mean age of the entire cohort was 55 (sd 7.1) years, 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (range 4.0-6.5) and median T2 lesion volume 9.0mL (IQR 6.0).

In the fluoxetine arm, there was no significant change in tNAA (or tNAA/Cr) in NAWM or GM; mIns/tCr (but not mIns) was lower at 96 weeks (β = -0.21, 95% CI [-0.40 to -0.02], p = 0.03) in NAWM (but not GM).

In the riluzole arm, there was a reduction in GM Glx (β = -0.25, 95% CI [-0.47 to -0.04], p = 0.02) and Glx/tCr (β = -0.29, 95% CI [-0.50 to -0.08], p = 0.007), but no change was seen in NAWM.

In the amiloride arm, there was no change in tNAA (or tNAA/tCr) in NAWM or GM.

Conclusions

Neither fluoxetine nor amiloride had any effect on proposed measures of neuroaxonal integrity in NAWM or GM as reflected in tNAA levels. There was a fluoxetine reduction in NAWM mIns/tCr perhaps reflecting some decrease in astrogliosis. Riluzole decreased GM Glx levels as anticipated. However, despite these target effects for these drugs, ultimately they did not translate into a reduction in atrophy rate in the trial.

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Imaging Poster Presentation

P0652 - The relationship among leptomeningeal enhancement clinical, radiological activity and cerebrospinal fluid markers (ID 1593)

Speakers
Presentation Number
P0652
Presentation Topic
Imaging

Abstract

Background

Meningeal inflammation is a progressively recognized finding in multiple sclerosis (MS). The real prevalence of leptomeningeal enhancement (LME) in different stages of MS and its association with neurodegeneration is still a matter of debate.

Objectives

To assess the in-vivo prevalence of LME in relapsing-remitting MS (RRMS) and to evaluate the association with clinical/radiological activity and cerebrospinal fluid (CSF) markers.

Methods

This is an ongoing observational study. LME was assessed by two blinded neurologists on a 3D 1x1x1 mm3 Fluid-Attenuated-Inversion-Recovery (FLAIR) acquired 20 minutes post gadolinium (TR 6000 ms; TE 356 ms; Fat suppressed). LME was defined as signal intensity within the subarachnoid space greater than that of brain parenchyma and brighter on postcontrast scans. MRI activity was defined as at least 1 gadolinium enhancing and/or new/enlarging T2 lesions. Differences in terms of clinical, radiological, CSF metrics between patients with and without LME were tested with ANOVA, chi square and binary logistic regression analysis as appropriate.

Results

38 RRMS patients were included in the analysis: [65,2% female, mean age 37,8±10.1 years mean disease duration 10,1±9.2 years, median Expanded-Disability-Status-Scale (EDSS) 2 (0-6,5)]. 78,3% of patients had MRI activity in the previous 2 years: among them 17,4% had uniquely radiological activity and 60,9% had clinical relapses (experiencing disease progression in 17,4 % of cases), 26.1% had ongoing MRI activity. LME was found in 37% of patients, median number 1 (range 1-3). No difference in EDSS, age and disease duration was found between patients with or without nodules. LME prevalence was higher in patients with previous MRI activity (P=0.047). Multivariable models adjusted for baseline EDSS exploring predictive value of clinical progression, previous MRI activity, ongoing MRI activity show that previous MRI activity was the only variable associated with LME (p=0.002). CSF parameters had no predictive value for LME development nor any association was found between presence of oligoclonal bands and LME.

Conclusions

LME was found in a discrete proportion of RRMS patients and it was associated with previous, but not ongoing, radiological activity. A prospective clinical evaluation is needed in order to assess the prognostic value of our findings.

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Imaging Poster Presentation

P0653 - The value of grey matter microglial activation measurement by TSPO-PET in predicting clinical disease progression in multiple sclerosis (ID 1431)

Speakers
Presentation Number
P0653
Presentation Topic
Imaging

Abstract

Background

Conventional MRI has limitations when it comes to characterizing the grey matter pathology of MS. PET (positron emission tomography) imaging, on the other hand, can provide more precise information at the cellular level. [11C]PK11195 is a first generation translocator protein (TSPO) radioligand that has been used to study innate immune cell activation status in multiple sclerosis brain in vivo.

Objectives

Our aim was to analyse the MRI volumes and [11C]PK11195 signal of MS brain grey matter regions and to investigate how these variables connect with disability progression.

Methods

MRI (3 or 1.5 tesla) and [11C]PK11195 PET data from 71 MS patients and 18 healthy controls were examined for regional grey matter BPF (brain parenchymal fraction) and [11C]PK11195 DVR (distribution volume ratio). The following regions of interest were chosen: cerebral cortex, thalamus, caudate, putamen and pallidum. EDSS (Expanded Disability Status Scale) was available at baseline and after 3.4 ± 1.1 (mean ± SD) years of follow-up. The imaging variables were compared between MS patients and healthy controls, and forward type stepwise logistic regression was used to assess the best variables predicting disease progression.

Results

MS patients had lower BPF in the cortex, thalamus and caudate (P < 0.05) compared to controls. MS patients had higher [11C]PK11195 DVR in the thalamus and pallidum (P = 0.01 and P = 0.0099 respectively) compared to controls. Patients with EDSS progression (EDSS increase ≥ 1.0 at follow-up; or ≥ 0.5, if EDSS at baseline was ≥ 6.0) had lower BPF in the thalamus and caudate (P = 0.045 and P = 0.034 respectively) and higher DVR in the thalamus (P = 0.014) compared to patients with no EDSS progression. In the forward type stepwise logistic regression model DVR in the thalamus was the only measured imaging variable that remained a significant predictor of disease progression.

Conclusions

There are regional differences in [11C]PK11195 binding and atrophy in grey matter areas of the MS brain. [11C]PK11195 signal in the thalamus seems to have potential in predicting future MS disease course.

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Imaging Poster Presentation

P0654 - Time course of hippocampal functional connectivity in relation with memory performances at the early stage of multiple sclerosis (ID 1162)

Speakers
Presentation Number
P0654
Presentation Topic
Imaging

Abstract

Background

Multiple sclerosis (MS) is frequently associated with memory impairment. Nevertheless, the pathophysiology of memory impairment in MS is still unclear. Most studies now agree on hippocampal involvement. However, whether functional reorganization could help compensate and mitigate memory deficit is a matter of debate.

Objectives

This study aimed to identify the patterns of functional connectivity between the hippocampus and the rest of the brain and their possible relevance to memory performances at the early stage of MS. We hypothesized that functional reorganization could compensate for structural damage, allowing a delay in memory impairment appearance.

Methods

Patients were enrolled after their first neurological episode suggestive of MS in a prospective longitudinal study, along with matched healthy controls, and followed over 5 years. Verbal and visual memory scores were assessed. We used a multimodal approach, combining in vivo structural measures – i.e. hippocampal volume and connectivity – and functional measures – i.e. rs-fMRI connectivity. The association between network parameters and cognitive performance was assessed using linear mixed-effects models.

Results

This study included 32 patients and 10 healthy controls. The mean (SD) age of the patients was 37.7 (10.4) years. Verbal memory scores decreased significantly over time, whereas visuospatial memory performances were maintained.

Hippocampal volume of patients decreased significantly over time, indicating an increase in tissue alteration with the evolution of the pathology. Structural shortest path length of the hippocampus significantly decreased after 5 years along with an increase in hippocampus’ connections, indicating strengthened short-distance connections.

As for the functional network, the hippocampus showed a significant increase in the number of connections after 5 years, with a decrease of its shortest path length, suggesting stronger local short-distance connections.

Hippocampal volume loss was associated with worse verbal memory, while the hippocampus functional shortest path length significantly explained visual memory performances.

Conclusions

Our study demonstrated an important interplay between hippocampal-related structural and functional networks in explaining cognitive performances in the early stages of MS. As the structural damage increases, functional reorganization is able to maintain visual memory performances with strengthened short-distance connections.

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Imaging Poster Presentation

P0655 - Tissue destruction and blood-brain barrier breakdown in chronic-active vs. inactive MS lesions by 7T MP2RAGE and susceptibility MRI (ID 996)

Speakers
Presentation Number
P0655
Presentation Topic
Imaging

Abstract

Background

Recent imaging data in multiple sclerosis (MS) suggests that chronic-active lesions and inactive lesions can be differentiated based on the presence of paramagnetic rims on gradient-echo (GRE). At autopsy, chronic-active lesions show significant demyelination, oligodendrocyte loss, and outer rims of iron laden macrophages and activated microglia. Confirmation of the destructive nature of these lesions on MRI would provide in vivo evidence of their consequences. Further, evidence of local blood-brain barrier (BBB) breakdown in these lesions would provide further validation of their chronic-active state, along with suggesting a possible opportunity for therapeutic intervention.

Objectives

We aimed to determine if white matter lesions (WMLs) with paramagnetic rims show greater alterations in multiple signal characteristics, including our novel metric for BBB breakdown, Magnetization prepared 2 rapid gradient echo (MP2RAGE) ΔT1 mapping.

Methods

MP2RAGE and GRE images of the brain were acquired on 36 participants with MS on a 7T MRI before and after contrast. GRE images were processed for R2* and quantitative susceptibility maps (QSM). MP2RAGE was processed for T1 mapping and all images were registered to the pre-contrast T1-weighted (T1-w) image. ΔT1 maps were created by subtracting pre and post-contrast T1 maps. All WMLs were masked on T1-w and masks were separately created for lesions with visible paramagnetic rims on QSM. T1, ΔT1, χ (from QSM), and R2* values were compared across lesion types using a linear mixed effects model and Wilcoxon rank sum testing.

Results

Mean pre-contrast T1 was significantly higher in rimmed lesions (2.323, SE = 0.03964) compared to non-rimmed lesions (2.113, SE = 0.05791; p<0.001). Mean and median ΔT1 values were not significantly different in non-rimmed lesions versus rimmed lesions. Median pre-contrast χ values were significantly smaller in rimmed lesions (-0.00581, SE = 0.00277) versus non-rimmed lesions (-0.01298, SE = 0.003332; p = 0.011). Pre-contrast median R2* was significantly lower in rimmed lesions (24.55, SE = 0.8378) versus non-rimmed lesions (28.04, SE = 0.8919; p<0.001).

Conclusions

Elevated T1 and reduced χ and R2* in rimmed lesions in this study are confirmatory of greater demyelination and tissue destruction in this lesion subtype. The lack of significant difference in ΔT1 values suggests that there is no evidence of additional BBB breakdown in chronic-active lesions as measured on MRI.

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Imaging Poster Presentation

P0656 - Unraveling deep grey matter atrophy, iron and myelin changes in Multiple Sclerosis (ID 1287)

Abstract

Background

Modifications of magnetic susceptibility, seemingly reflecting iron accumulation/depletion, have been consistently demonstrated in subcortical gray matter (GM) of MS patients, but some questions remain unanswered regarding the underlying neurobiological processes and their clinical relevance.

Objectives

to disentangle the contribution of atrophy, iron and myelin changes to deep GM (DGM) damage in MS, simultaneously exploring their relationship with clinical disability through the application of quantitative susceptibility mapping (QSM) and longitudinal relaxation rate (R1) relaxometry.

Methods

In this cross-sectional study, 91 patients and 55 healthy controls were imaged with 3T MRI to compute QSMs and R1 maps, from which iron and myelin concentration maps were estimated by applying an external model. Modifications of DGM iron and myelin (mean concentration-dependent from atrophy and total content-independent from atrophy) were investigated at both global and regional levels. Significantly altered MRI features were tested as disability predictors in hierarchical linear regression models.

Results

Compared to controls, MS patients showed reduced thalamic(p<0.001) and increased pallidal(p<0.001) iron concentrations. No differences emerged regarding total myelin or iron content in the basal ganglia, while actual iron depletion was found in the thalamus(p<0.001). At the voxel-based analysis, patients showed increased iron concentration in the basal ganglia(p≤0.001) and reduced iron and myelin local content in thalamic posteromedial regions(p≤0.004), corresponding to reduced iron and myelin content in the pulvinar(p≤0.001) at the subnuclei analysis. Thalamic volume(B=-0.341,p=0.02), iron concentration(B=-0.379,p=0.005) and content(B=-0.406,p=0.009) significantly predicted disability, as well as pulvinar iron(B=-0.415,p=0.003) and myelin(B=-0.406,p=0.02) content, independently of atrophy.

Conclusions

Quantitative MRI suggests an atrophy-related iron increase within the basal ganglia of MS patients, along with an absolute reduction of thalamic iron and myelin, which correlates with disability. Atrophy-independent depletions of thalamic iron and myelin may represent clinically relevant, sensitive markers of subcortical GM damage.

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Imaging Poster Presentation

P0657 - Utility of Gadolinium in Multiple Sclerosis Radiographic Monitoring (ID 1753)

Speakers
Presentation Number
P0657
Presentation Topic
Imaging

Abstract

Background

Magnetic resonance imaging (MRI) is frequently utilized to assess activity of disease in multiple sclerosis (MS). Repeated gadolinium-based contrast agent use has been shown to deposit in the brain by a dose-dependent fashion. As a result, the Food and Drug Administration issued a warning regarding gadolinium use and has prompted the reexamination of its utility in clinical practice.

Objectives

To evaluate gadolinium utility in brain MRIs for routine monitoring of asymptomatic MS in an academic neurology clinic.

Methods

Retrospective chart review identified patients diagnosed with MS seen at the Landon Center of the University of Kansas Health System who had a MRI brain performed from December 16, 2016 to December 16, 2017. Data was collected regarding demographics, MS history, MRI ordered (with and/or without gadolinium), MRI results, and treatment decisions.

Results

Two-hundred forty charts were reviewed to date, identifying 124 completed MRIs in the study timeframe. All but 2 were ordered with gadolinium. Average age was 41.0 with 69.0% female and 85.2% with relapsing remitting MS. MRIs were then subdivided into the following indications: asymptomatic monitoring (n=85), diagnostic (n=15), and symptomatic (n=15). Of the monitoring MRIs, 79 (93%) had prior MRIs available for comparison, 19 (22.4%) had a new nonenhancing lesion, 10 (11.8%) had an enhancing lesion, and 22 (25.9%) had either a new nonenhancing or enhancing lesion. Of those who had radiographic progression of MS, 59% had a change in MS disease modifying therapy at follow up visit (RR 34.4, 95% CI 5.9-196.7; p=0.001). There were 17 (26.2%) enhancing lesions identified of 65 new nonenhancing or enhancing lesions. By direct comparison of unenhanced sequences, only 4.7% (n=3) of new lesions were not apparent without the aid of contrast, though each of these MRIs had other evidence of progression (total of 4 enhancing, 3 new nonenhancing lesions). In those without an available prior comparison MRI (n=6), none had enhancing lesions.

Conclusions

Preliminary results show gadolinium was useful in identifying only 4.7% additional lesions on asymptomatic monitoring MRIs and was not of additional benefit in identifying overall radiographic progression by MRI study nor in those without a prior comparator. Further data collection is planned to verify these initial trends.

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Imaging Poster Presentation

P0658 - Vascular Disease Risk Factors in Multiple Sclerosis (ID 1867)

Speakers
Presentation Number
P0658
Presentation Topic
Imaging

Abstract

Background

VDRF, such as hyperlipidemia, hypertension, obesity, diabetes, and heart disease, appear to significantly increase the risk of disability progression in MS, however the underlying mechanisms are not well understood.

Objectives

To determine if the presence of VDRF affects the disease progression and brain phosphate metabolism in people with MS.

Methods

This is a 3-year prospective, observational, single-site, study with two arms (MS subjects with and without VDRF). We collect 7T MRI brain data at baseline, 12, 24 and 36 months (V1, V2, V3 and V4 visits, respectively) and clinical and biomarkers data every 6 months. Outcome measures include changes in: 1) high energy phosphate metabolites in cerebral gray matter assessed by 31P 7T MR imaging (MRSI) and 2) brain parenchymal volume, 3) clinical impairment, disability, and quality of life.

Results

We preformed cross-sectional and longitudinal analyses of MRI data (52 V1 and 37 V3 subjects). Mean age/gender was 54.6 years with 71% female) (+VDRF, N=29, mean age 56.3 years, 83% female) and -VDRF, N=23, mean age 52.4 years; 57% female) at baseline. We analyzed a volume of interest in the occipital region for changes in phosphate metabolites (V1 and V3) using 7T MRSI. We observed decrease in Adenosine triphosphate (ATP) to total phosphate signal ratio in +VDRF subjects by 3.3% (P<0.05) compared with -VDRF. +VDRF subjects showed a larger reduction in parenchymal volume fraction (0.01544, P=0.025) over time (between V1 and V3) compared to ‑VDRF (0.00423). No significant group differences in temporal changes in phosphate metabolites are seen. Additional analyses are underway.

Conclusions

This is the first study to assess brain metabolism and volume in MS patients with and without VDRF. +VDRF MS subjects have significantly reduced brain ATP compared with -VDRF. ATP depletion may reflect mitochondrial dysfunction and contribute to MS disease progression as suggested by the increased brain atrophy in those with VDRF.

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Imaging Poster Presentation

P0659 - White matter tracts that overlap with hubs are preferentially protected against multiple sclerosis pathology (ID 926)

Speakers
Presentation Number
P0659
Presentation Topic
Imaging

Abstract

Background

The thalamus and the putamen, highly-connected brain areas (hubs), are vulnerable to MS-induced atrophy. Here we investigate if white matter (WM) tracts that pass through hubs have different susceptibility to MS pathology, due to anterograde and retrograde neurodegeneration, compared to tracts do not pass through these hubs. We use the apparent intra-axonal volume fraction (Vax) derived from the multi-compartment diffusion MRI spherical mean technique (SMT) as well as the neurite density index (NDI) and isotropic volume fraction (IVF) derived from the neurite orientation dispersion and density imaging (NODDI) coupled with high-resolution tractography to assess the degree of tract-specific axonal integrity.

Objectives

(1) To compare tract-specific lesion burden, Vax, NDI and IVF between WM tracts that overlap with either the thalamus or the putamen (hub+ tracts) and those that do not (hub- tracts); and (2) to assess the relationship between these MRI metrics and those of physical impairment, as measured by the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk test (T25FW).

Methods

EIghteen patients underwent 3T MRI inclusive of T1- and T2-weighted sequences, SMT and NODDI. Using probabilistic tractography, we reconstructed 49 WM tracts, 12 hub+ tracts and 37 hub- tracts. Using T-tests, we compared the following MRI metrics between hub+ and hub- tracts: T1 and T2 lesion burden (calculated as percentage of tracts occupied by T1 and T2 lesions) as well as whole tract and normal-appearing WM (NAWM) average NDI, IVF and Vax values. Spearman correlation assessed the relationship between these MRI metrics and those of clinical impairment.

Results

Hub+ tracts had a lower mean %T1 lesions (0.86 vs. 1.99) and %T2 lesions (2.90 vs. 5.42), as well as higher whole tract NDI (0.61 vs. 0.57), NAWM NDI (0.61 vs. 0.58), whole tract Vax (0.49 vs 0.44) and NAWM Vax (0.50 vs. 0.44), all significant at the p<0.001 level. Stronger correlations were seen between clinical measures and hub+ tracts compared to hub- tracts, with the strongest correlation for %T1 lesions and the T25FW (r= -0.59, p<0.0001).

Conclusions

WM tracts that overlap with the thalamus and the putamen have a higher degree of axonal integrity and lower lesional burden, suggesting a protective role of hubs. However, given the ramifications of disease present at the level of hub+ tracts, disease here retains a major impact on disability. If confirmed, our data suggest the role of disease location in relation to hubs as guidance for treatment personalization, considering more aggressive approaches for patients presenting with MRI changes in hub+ fiber tracks.

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Imaging Poster Presentation

P0660 - Yield and potential value of spinal cord MRI surveillance in treated relapsing multiple sclerosis   (ID 1496)

Presentation Number
P0660
Presentation Topic
Imaging

Abstract

Background

Periodic brain magnetic resonance imaging (MRI) monitoring is recommended to assess subclinical disease activity in patients with multiple sclerosis (MS) who are on disease modifying therapies (DMTs). However, it is unclear whether spinal cord MRI surveillance is also useful.

Objectives

To determine how frequently follow-up MRI of the cervical or thoracic spine revealed asymptomatic new (T2 hyperintense or T1 gadolinium-enhancing) lesions in patients with MS on DMTs.

Methods

This was a retrospective medical record review. Patients with relapsing MS aged 18–60 years, on DMT, with MRI of the brain, cervical and thoracic spine, seen in our MS clinic in the past 5 years were included.

Results

One hundred and ten patients were included. Seventy-four percent were female and 92% were Caucasian. Median age at MS diagnosis was 37 years (range 19-56) and the median disease duration at the time of first MRI in the study was 0.7 years (range 0-20). Median follow up time was 3 years (range 1- 10). At least one new asymptomatic lesion was detected in the brain MRI in 31% of the patients. Nine patients (8%) developed at least one new asymptomatic cervical cord lesion. None developed asymptomatic new lesions in the thoracic spine.

Conclusions

A small proportion of patients developed asymptomatic cervical cord lesions and none of the patients developed asymptomatic thoracic lesions. Given that spinal cord lesions are associated with worse prognosis in the first years after MS diagnosis, cervical spine MRI might be useful in surveying asymptomatic new lesions, but thoracic spinal cord MRI does not appear to add significant value to MS monitoring.

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Internet and Social Media Poster Presentation

P0661 - A 164 second multi-format film successfully conveys the importance of early intervention in MS (ID 1031)

Speakers
Presentation Number
P0661
Presentation Topic
Internet and Social Media

Abstract

Background

Early treatment in MS is a complex concept to convey to a naïve audience as it often needs to be considered in the absence of symptoms. There are risks involved and other life priorities to contemplate.

Objectives

To address the importance of early intervention, a film was created conveying the results of non-action. The film was produced to appeal to a broad, modern audience: short duration (164 seconds), conceptual, without dialogue and accessible across multi-formats. We assessed its success at delivering the message to people with MS (pwMS) and a general population (GP).

Methods

Three populations were included: pwMS from the UK MS Register, pwMS from outpatient clinics and a GP (Ethical approval ref: 19/LO/0282). Based upon industry standard, pre-specified outcomes were 50% viewer retention (viewing for ≥30 seconds) and 50% understanding of the concepts. The film was embedded into a website, participants were asked to review the film and the four concepts were explained. Participants answered questions about the concepts and were asked for their opinion utilising free commentary and evaluated using thematic analysis.

Results

In the MS Register population 757/959 (78.9%) pwMS had total self-perceived understanding (4/4 concepts) versus 29/42 (69%) in pwMS from outpatients and 136/149 (91%) in the GP. Understanding in all cohorts were significantly above the expected outcomes (p<0.0001) and was highest in the GP compared to pwMS (p>0.0001) In the total population 714/1150 (62%) watched ≥30 seconds with an average viewing duration of 156/164 seconds (95%), significantly above the pre-specified outcome percent (p<0.0001). Nine-hundred and eighteen of 959 (96%) provided optional free text commentary about the film. Six-hundred and ten of 918 (66%) acknowledged the role of early intervention and of taking action. In a multivariate analysis with understanding as the factor, pwMS without degree-level education and who commentated neutrally/positively, were independently associated with increased understanding of the film.

Conclusions

As part of a preventative medicine strategy, a short duration, targeted film can successfully convey the importance of early intervention to both pwMS and a GP.

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Internet and Social Media Poster Presentation

P0662 - How patients utilize online data sources to engage with the Multiple Sclerosis (MS) community and search for information on their condition (ID 321)

Speakers
Presentation Number
P0662
Presentation Topic
Internet and Social Media

Abstract

Background

The internet and social media have become an increasingly accessible source of information for MS patients; allowing them to not only expand their knowledge of MS but also connect with fellow sufferers and hence feel part of a community.

Objectives

To assess how use of online information and social media impacts patients’ MS management, in the 5EU (UK/Germany/France/Italy/Spain) and the United States (US).

Methods

The Ipsos MS syndicated Patient Community gathered qualitative patient perceptions via an online community platform; collected via a PC, tablet or app in the 5EU (UK/ Germany/ France/ Italy/ Spain) and US in 9/2019. Patients were recruited from a specific MS patient panel and were taking a range of disease-modifying treatments (DMTs) of varying treatment status and MS types.

Results

229 MS patients participated in the MS syndicated Patient Community (n=178/51 5EU/US). Patients typically use official MS specific websites to search for facts seeing these as credible sources whilst Facebook groups are the main social media platform used to engage with other patients, gain first-hand experiences and share support. Patients typically research only at key milestones in their journey; primarily when they are waiting for a diagnosis, when first starting or switching DMT or when suffering from a significant symptom or relapse. Additionally, patients are more likely to research if they feel listened to by their Healthcare Professionals (HCPs) as being able to discuss their online findings provides an incentive to be proactive in their MS management. Patient awareness of the European/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) is low; 63.1% of patients have never heard of ECTRIMS/ACTRIMS and many are not aware of key topics and new developments presented, although most have a strong interest to learn.

Conclusions

Patients are less proactive in researching about MS if they feel they are stable on treatment or if there is little HCP engagement to discuss what they have read online. The low awareness of ECTRIMS/ACTRIMS suggests that HCPs are not sharing what they have learned as well there being a lack of patient-friendly conference news. Whilst there is a lot of focus on both pharma and HCPs having a patient-centric approach, additional investigation is needed to identify how to promote an active patient researcher mindset thereby empowering patients to take charge of their MS management.

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Internet and Social Media Poster Presentation

P0663 - Real-time internet-based teleconsultations for neurological follow-up of patients with multiple sclerosis: an interim feasibility analysis (ID 1703)

Speakers
Presentation Number
P0663
Presentation Topic
Internet and Social Media

Abstract

Background

Classic health care (HC) models are currently being challenged by the ‘coronavirus disease of 2019’ (COVID-19) pandemic for which social isolation and unprecedented mobility restrictions have been deployed as essential measures of constrain. Digital communication services have the potential to preserve and improve access to specialized medical facilities in a cost- and time-efficient manner. Nonetheless, studies on live interaction between patients with multiple sclerosis (MS) and HC providers for neurological follow-up are still scarce. In a recent pilot project, we have shown that individual real-time audiovisual teleconsultations (TCs) over the internet are feasible and highly appreciated in patients with MS, but compliance and technical reliability over time remain to be demonstrated.

Objectives

To evaluate feasibility of real-time audiovisual TCs over the internet for neurological follow-up of patients with MS.

Methods

Thirty patients with MS presenting at a specialized center in Belgium were recruited for this ongoing study, and scheduled to receive 4 TCs over the course of 12 months. Patients were provided a unique hyperlink by mail in advance, leading them automatically and directly to the virtual waiting room, where they could accept or decline our incoming call. All TCs are performed by a trained HC professional with the intention to keep the conversation similar to what is usually discussed during a classic face-to-face MS consultation. The approach will be considered feasible if at least 80% of the planned TCs can be successfully completed at the foreseen moment. We present the results of an interim analysis (July 8, 2020), when at least 2 TCs were executed in each participant. Patient satisfaction (technical quality, convenience, quality of care and added value) was evaluated via telephone by means of 5-point Likert scales containing the categories very unsatisfied, unsatisfied, neutral, satisfied and highly satisfied.

Results

Three participants dropped out of the study due to loss of interest (2) or a broken device (1). Sixty of the 75 scheduled TCs were successfully completed (80%). Failures were due to patients not responding (7/56) or technical issues (8/56). Out of the 27 active participants, 24 responded to the telephone call for satisfaction analysis. Rates of patients declaring themselves satisfied or highly satisfied regarding the TCs were 19/24 for technical quality, 23/24 for convenience, 22/24 for quality of care and 21/24 for added value.

Conclusions

Real-time audiovisual TCs over the internet appear to be feasible and well-received in patients with MS. Full completion of this trial is expected early next year. Incorporation of digital communication services in routine MS practice is expected to improve access to specialized care, particularly in dire times such as the current COVID-19 crisis.

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Internet and Social Media Poster Presentation

P0664 - Smartphone based Symbol Digit Modalities Test reliably measures cognitive function in multiple sclerosis patients (ID 1822)

Speakers
Presentation Number
P0664
Presentation Topic
Internet and Social Media

Abstract

Background

Neurological examination is a powerful tool for diagnosing and measuring progression of neurodegenerative diseases. However, examinations are resource intensive and thus not practical for comprehensive measurement of neurological disability in chronic diseases. A remote digital solution may be more practical and particularly relevant now due to the ongoing COVID-19 pandemic.

Objectives

To clinically validate a digital adaptation of the Symbol Digit Modalities Test (SDMT) developed as part of a smartphone test suite replicating aspects of a neurological exam.

Methods

Participants consisted of healthy volunteers (HV; n=39) and multiple sclerosis (MS; n=154) patients, with a longitudinal subcohort that performed tests at home (n=15). During clinic visits, the smartphone test suite was administered alongside a full neurological exam. The smartphone SDMT featured randomization of symbol-digit code and testing sequence. The subjects also underwent written SDMT and brain MRI.

Results

Performance differed significantly between HV and MS cohorts (p<.0001). Performance on smartphone and written SDMT had strong evidence of association (R2=0.71, concordance coefficient CCC=0.69, p<.0001). Smartphone SDMT had higher criterion validity than written SDMT measured by correlation with T2 lesion load and brain atrophy. Correlations with NeurEx subdomains identified neurological functions involved in performance of each of the 3 functional cognitive tests. Correcting for these contributing non-cognitive disabilities generated linear regression models strongly predicting the amount of MS-related brain injury measured by volumetric MRI (R2 = 0.75, p < 0.0001 vs R2 = 0.62, p < 0.0001). Of the longitudinal cohort, 87% of patients demonstrated practice effects measured by non-linear regression. Averaging multiple sequential post-learning results significantly decreased threshold for identifying true test deteriorations on a patient level.

Conclusions

Smartphone SDMT allows for less resource intensive remote administration. The clinometric properties of smartphone SDMT compare to or outperform written SDMT. This study expands the validation of multiple neurological tests administered via smartphone and bring us closer to a patient-autonomous neurological examination.

Acknowledgments: The research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID).

Notice: This study involved patients and was approved by NIAID IRB.

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Internet and Social Media Poster Presentation

P0665 - Social Listening: Digital Profile of the Multiple Sclerosis Patient in Mexico (ID 1242)

Presentation Number
P0665
Presentation Topic
Internet and Social Media

Abstract

Background

It is widely known that Multiple Sclerosis (MS) patients consult social media platforms to understand the disease, look for emerging treatments or social support. However, to date, there is not a defined Digital Profile (DP) of the patient with MS in Mexico. The understanding of this DP could improve the doctor-patient relationship.

Objectives

Discover how patients live MS and Secondary Progressive Multiple Sclerosis (SPMS) in Mexico by understanding their Digital Profile by using different Social Listening tools.

Methods

We applied a “Social Listening” method: This methodology basis is the implementation of Artificial Intelligence, which characterizes by the combination of algorithms to understand the DP of the MS patient in Social Media. The tools used are “Social Studio”, “The Moments Tool – Search Insights”, “Sysomos 2018” and “BNN Insights”.

Results

We collected data from 80 000 users between 18 to 65 years old, in which 68% of the users were women, and 32% were men. As for the marital status, 46% of the patients are married, 35% single, 15% in a relationship, and 4% engaged. As a disease, MS has less amount of Google search results (23,400 results) compared to other pathologies such as diabetes (6, 800, 000 results) or HIV (3, 780, 000 results). Moreover, only 10% of the MS results relate to SPMS. Listening shows 4, 200 mentions of MS in the last six months, only seven mentions for SPMS. We found that many MS patients are not writing about their struggle, furthermore their friends and family that share their stories. We analyzed the digital conversation of the four main topics we found: diagnosis, treatment, physicians, and pain management, as well as the synergy of the searches of the words “Multiple Sclerosis”. The social media groups are mainly composed of patients, caregivers, families, and friends; many of the social media group administrators work in associations regarding MS.

Conclusions

This work unveils a new vision about the way we know MS patients from an unexplored point of view inmedicine. This information gives the physician value to have a better understanding of the patient and the challenges of the disease, by analyzing the use that patients make of their digital tools.

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Internet and Social Media Poster Presentation

P0666 - Telemedicine in/outside the pandemic: a survey about satisfaction of this tool in a cohort of multiple sclerosis patients and their neurologists (ID 1810)

Speakers
Presentation Number
P0666
Presentation Topic
Internet and Social Media

Abstract

Background

Telemedicine is a live communication between patients and physicians through different technological tools. It became fundamental during COVID-19 pandemic to keep on taking care of patients in more medical fields than before. Given the chance for telemedicine to become a pivotal part of neurological routine practice, we investigated patients and neurologists satisfaction about this tool.

Objectives

This survey aimed to understand satisfactionabout telemedicine during pandemic and its possible use in the future outside pandemic

Methods

We administered a brief survey to a cohort of Multiple Sclerosis (MS) patients and their neurologists at MS center of San Raffaele Hospital, Milan. Demographic and clinical data (EDSS, treatment) were collected.

Results

151 patients filled out the survey: 75% females; mean age 42.2yy (18-73); median EDSS 1.5 (0-7). Treatments were almost equally distributed across first and second-line drugs (10% interferon, 10% glatiramer acetate, 14% teriflunomide, 22% dimethylfumarate, 23% fingolimod, 3% cladribine, 8% alemtuzumab, 10% ocrelizumab).

87% of patients appreciated telemedicine during pandemic; 10% had a positive opinion but with a need for traditional evaluations, while 3% were not satisfied.

Considering the possible routine use of telemedicine outside the pandemic, 82% firmly stated the importance of traditional evaluations. In particular, 44% would alternate in person and remote visits, while 38% strongly preferred traditional ones. Among the latters, the main reasons were the need for human empathy with the neurologist and the feeling that traditional evaluations may lead to better clinical outcomes. The remaining 18% would always use telemedicine except in the case of acute events. Neurologists and residents (n=18) were inquired about telemedicine: no one would use it as the only tool, 33% would alternate it with traditional practice and 67% would use it only in special contexts.

Conclusions

In our survey, both patients and neurologists recognized the importance of telemedicine during a pandemic. Patients more than physicians seemed ready to use it in everyday clinical practice. These data may be biased by a still ongoing patients fear and physicians lack of confidence in this multifaceted tool. The pandemic spurred the development of institutional telematic platforms capable of providing legal protection and traceability of visits and communication between patients and physicians. So far, we can conclude that telemedicine is a useful tool to overcome space-time limits, giving the best care to all patients in any condition. However, it cannot replace but only integrate traditional medicine.

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Internet and Social Media Poster Presentation

P0667 - The Dutch MS Patient Voice Survey: The search for information. (ID 1745)

Speakers
Presentation Number
P0667
Presentation Topic
Internet and Social Media

Abstract

Background

Shared decision-making is a key aspect in healthcare and patients are motivated to take ownership of their own lifestyle changes. Informing patients with multiple sclerosis (MS), sharing knowledge, and coaching are the key objectives of patient advocacy organizations. Gathering patient insights on disease burden and interests will help patient organizations and other stakeholders to support MS patients in the Netherlands.

Objectives

The Dutch MS Patient Voice Survey aims to obtain insights in the role and use of different media and topics of interest split by MS phenotype and patients age.

Methods

From June until August 2019, 1029 MS patients participated in this on-line survey. Dutch patient advocacy organizations, MS association Netherlands and the National MS Foundation, invited participants to fill in the survey. The survey consist of three parts: 1. characteristics of disease phenotype and activity, 2. influence of the disease on daily life, and 3. information gathering and needs. Results from the Part 3 is reported in this abstract.

Results

Of the 1029 participants, 75% were female, 25% male. The participants were split by reported phenotype: clinically isolated syndrome/Benign (CIS/B) 4%, relapsing-remitting MS (RRMS) 45%, primary-progressive MS (PPMS) 18%, secondary-progressive MS (SPMS) 23%, and not reported 10%. Participants showed the highest interest in information about new treatments (75%), MS as a disease (64%), and lifestyle (51%). Topics of interest were influenced by age and did not vary by phenotype. Younger patient were most interested in MS and work, pregnancy and children while elderly patients have a high interest in how to stay mobile. 80% to 85% of the patients spend more than one hour a day online. There is a significant correlation between age and time spend online. Facebook is most frequent used (41%), mainly by younger patients. Snapchat is only use by 7% of the patients. Of the MS patients, 78% read daily newspapers and 39% read magazines (weekly or monthly).

Conclusions

Online information is an important source of information, especially Facebook. MS patient organizations, healthcare professionals and other stakeholders should keep in mind that some online information is not fact-checked and might misinform patients, which could influence their behavior. Most MS patients read local newspapers. Topics of interest depend mainly on age, suggesting that information should be tailored to patient age groups to fit their specific information needs.

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Internet and Social Media Poster Presentation

P0668 - Understanding Multiple Sclerosis Massive Open Online Course: Closing The Gap On Information Asymmetry (ID 1723)

Speakers
Presentation Number
P0668
Presentation Topic
Internet and Social Media

Abstract

Background

A key market failure in health economics is the concept of information asymmetry between the consumer and supplier where the level of knowledge and expertise is weighted to the supply-side (healthcare provider). In the information-age and the ensuing knowledge economy, people with multiple sclerosis and their carers (consumers) may become more empowered in their negotiated relationship with healthcare providers (physicians, allied-health professionals) after undertaking a fit-for-purpose Massive Open Online Course (MOOC).

Objectives

We aimed to establish if our fit-for-purpose Understanding Multiple Sclerosis MOOC closed the information asymmetry gap for people with MS and their carers.

Methods

We gathered qualitative data from people with MS and their carers (consumers), and healthcare professionals (suppliers) who undertook our Understanding MS Massive Open Online Course (MOOC) through course discussion boards and a feedback survey. We postulated that qualitative research methods would establish if our fit-for-purpose MOOC closed the information asymmetry gap among the MOOC cohort. Our study used the pre-existing health economics theory of information asymmetry to inform qualitative inductive and deductive theory building about the information disseminated through our MOOC. Socio-demographic data were also analysed.

Results

N=5,500 people consented to participate in the study with a range of 200-345 people responding to each discussion question and over 1,200 participants providing free-text responses on the course feedback survey. We found that consumers were more likely to post in discussion boards and were more likely to report knowledge gain than providers. We also identified key information sources for consumers, including MS societies and public-facing text and video blogs.

Conclusions

Our study indicates that information provision through online learning platforms such as the Understanding MS MOOC can operate to close the information asymmetry gap.

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Internet and Social Media Poster Presentation

P0669 - Using WebEx Technology to Increase Knowledge and Awareness About Multiple Sclerosis via Documentary Film “When We Walk” as an Educational Intervention (ID 1788)

Speakers
Presentation Number
P0669
Presentation Topic
Internet and Social Media

Abstract

Background

Multiple Sclerosis (MS) is an autoimmune disease with no known cure that attacks the protective coverings of nerves which results in a communication malfunction between the body and central nervous system. Common symptoms include numbness, fatigue, impaired coordination, and muscle spasms. About 1 million adults live with MS in the US (National Multiple Sclerosis Society [NMSS], 2019).

Objectives

(1) To increase knowledge and awareness about MS through documentary film using WebEx technology (2) Increase awareness of national, state, and local MS resources.

Methods

A pre-experimental, posttest only research design assessed the impact of using WebEx technology to increase knowledge and awareness about MS and available resources. WebEx is an online video conferencing technology used to conduct online meetings and webinars, including screen share and chat functions. Participants viewed a 2019 documentary film, “When We Walk,” about a filmmaker’s personal experience with primary progressive MS, followed by a 30-minute virtual panel discussion. Participants could also post questions in the chat function during the film screening and panel discussion. Five panelists included two persons living with MS, an NMSS MS Navigator Program representative, UNC Charlotte ADA Coordinator, and a local neurologist. Nineteen of the 29 participants (65.5%) completed a confidential 24-item post-event electronic survey (via Qualtrics).

Results

Results. The majority of participants were female (n=17; 89.47%) and between the ages of 45 to 64 years old (n=13; 68.52%). Participants included 3 persons of color (Hispanic/Latino; Black/African American; African) (16.66%), 14 Caucasians (77.78%), and 1 other ethnicity (5.56%). Participants were highly educated: trade/technical/vocational training (n=1), Associates degree (n=1), Bachelor's degree (n=6), Master’s degree (n=6), Doctoral or Professional degree (n=5). Twelve participants were affiliated with UNC Charlotte (63.15%) and 7 participants reported other affiliations.

The overwhelming majority of participants (n=18; 94.74%) “agreed” or “strongly agreed” that “participation in the MS documentary screening and panel discussion increased my knowledge of MS and its related symptomatology”. Eighteen participants (94.74%) “agreed” or “strongly agreed” “participation in the MS film screening and panel discussion increased my knowledge of available resources at UNC Charlotte and the surrounding area”. All participants “agreed” or “strongly agreed” that “the virtual event met my expectations”. Seventeen participants (94.44%) rated the “When We Walk” film screening and panel experience as “excellent.”

Conclusions

Conclusions. The results of this virtual educational intervention suggest that WebEx is an effective virtual technology as is the use of documentary film and panel discussion to increase participant knowledge and awareness of MS and available MS resources.

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Microbiome Poster Presentation

P0670 - Ecological and functional alterations of the gut microbiome in different stages of multiple sclerosis (ID 1118)

Speakers
Presentation Number
P0670
Presentation Topic
Microbiome

Abstract

Background

Multiple sclerosis (MS), an autoimmune disease of the central nervous system, generally starts as relapsing remitting form (RRMS), but often shifts into secondary progressive MS (SPMS). SPMS represents a more advanced stage of MS, characterized by accumulating disabilities and refractoriness to medications.

Objectives

The aim of this study was to clarify the microbial and functional differences in gut microbiomes of the different stages of MS.

Methods

Here, we compared gut microbiomes of patients with RRMS (n = 62), SPMS (n = 15), and two closely related disorders; atypical MS (n = 21) and neuromyelitis optica spectrum disorder (n = 20) with healthy controls (HC; n = 55) by 16S rRNA gene and whole metagenomic sequencing data from fecal samples and by fecal metabolites.

Results

Each patient group had a number of species having significant changes in abundance in comparison with HC, including short chain fatty acid (SCFA) producing bacteria reduced in MS. Changes in some species had close association with clinical severity of the patients. A marked reduction in butyrate and propionate biosynthesis and corresponding metabolic changes were confirmed in RRMS compared with HC (p = 0.0007 and p = 0.003, respectively). Although bacterial composition analysis showed limited differences between the patient groups, metagenomic functional data disclosed an increase in microbial genes involved in DNA mismatch repair in SPMS as compared to RRMS. Together with an increased ratio of cysteine persulfide to cysteine in SPMS revealed by sulfur metabolomics (p = 0.0152), we postulate that excessive DNA oxidation could take place in the gut of SPMS.

Conclusions

Thus, gut ecological and functional microenvironments were significantly altered in the different stages of MS. In particular, reduced SCFA biosynthesis in RRMS and elevated oxidative level in SPMS were characteristic (Takewaki et al., PNAS. under review).

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Microbiome Poster Presentation

P0671 - Exploring the gut microbiome in multiple sclerosis via the international MS Microbiome Study (iMSMS) (ID 1532)

Abstract

Background

The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.

Objectives

The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.

Methods

A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.

Results

This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.

Conclusions

Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.

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Microbiome Poster Presentation

P0672 - Human commensal Prevotella histicola ameliorates disease in an animal model of multiple sclerosis  as effectively as interferon-beta (ID 1205)

Speakers
Presentation Number
P0672
Presentation Topic
Microbiome

Abstract

Background

We and others have shown that multiple sclerosis (MS) patients have distinct gut microbiota compared to healthy control (HC) with a lower abundance of Prevotella. Additionally, the abundance of Prevotella increased in patients receiving disease-modifying therapies (DMTs) such as Copaxone and/or Interferon-beta (IFNβ). We have previously identified a specific strain of Prevotella (Prevotella histicola), which can suppress disease in Human leukocyte antigen-HLA-DR3.DQ8 transgenic mice, a preclinical animal model of MS. Since Interferon-β-1b [IFNβ (Betaseron)] is a major DMTs used in MS patients. We hypothesized that treatment with the combination of P. histicola and IFNβ would have an additive effect on the disease suppression.

Objectives

We investigated whether a combination of P. histicola and IFNβ is more effective than either drug alone utilizing an animal model of MS, experimental autoimmune encephalomyelitis (EAE), in HLA-DR3.DQ8 transgenic mice.

Methods

HLA-DR3.DQ8 transgenic mice (8 to 12 weeks old) were immunized subcutaneously in both flanks with proteolipid protein-PLP91–110/CFA/PTX. Mice were divided into four groups treated with IFNβ alone (10,000 IU), live P. histicola alone (108 CFUs), and combination of P. histicola plus IFNβevery alternate day for a total of seven doses. Mice in the control group were orally gavaged with TSB media. All mice were evaluated for EAE scores till the duration of the experiment. CNS pathology, pro-inflammatory cytokines, and anti-inflammatory CD4+Foxp3+ regulatory T cells (Treg) were analyzed after treatments. All experiments were approved by the Institutional Animal Care and Use Committee at the University of Iowa.

Results

We observed that treatment with P. histicola suppressed disease as effectively as IFNβ. Surprisingly, the combination of P. histicola and IFNβ was not more effective than either treatment alone. P. histicola alone or in combination with IFNβ increased the frequency and number of CD4+FoxP3+ regulatory T cells in the gut-associated lymphoid tissue. Treatment with P. histicola alone, IFNβ alone, and in the combination decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4+ T cells in the CNS. Additionally, P. histicola alone or IFNβ alone or the combination treatments resulted in milder CNS pathology.

Conclusions

Our study indicates that the human gut commensal P. histicola can suppress disease as effectively as commonly used MS drug IFNβ and may provide an alternative treatment option for MS patients.

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Microbiome Poster Presentation

P0673 - Induction of human IL-10 and protection against murine EAE by a manufactured human gut derived microflora antigen  (ID 734)

Speakers
Presentation Number
P0673
Presentation Topic
Microbiome

Abstract

Background

The intestinal microbiota and products are pivotal regulators of the immune system at local and systemic levels. We have shown that a purified form of polysaccharide-A (PSA) produced by the intestinal Gram-negative Bacteroides fragilis @ 100 μg once every three days conferred protection against the central nervous system (CNS) inflammatory demyelination induced in the experimental autoimmune encephalomyelitis (EAE) murine model of multiple sclerosis.

Objectives

To determine if a GMP manufactured PSA could induce immune protection against murine EAE and indicators of immune regulation by human PBMC in vitro.

Methods

PSA was prepared in a GMP commercial facility and compared by immune assay and NMR spectroscopy to the purified PSA previously reported to protect against EAE (Ochoa-Reparaz et. al. Mucosal Immunol 2010). Manufactured PSA was administered using the C57BL/6 model of EAE. A control (PBS) and two dose range (100 and 300μg) of PSA were administered per os once 3 days before and every 3 days post disease induction in ten-week-old female C57BL6 mice (n = 12 per group). Treatment was carried out q3 days for a 30-day period. The body weight changes, EAE clinical scores, and other disease parameters such as disease onset, cumulative scores, and severity scores were compared among groups.

Results

There was no evidence of clinical adverse events to oral treatment with PSA and moreover no effect on the body weight of mice. The treatment with PSA-100 was protective against EAE when compared to PBS control (Area under curve: p = 0.0218). The level of protection was not statistically improved by the oral administration of 300 mg PSA. Protection with PSA-100 was evidenced by the reduced overall severity of disease (p < 0.0001), mortality rate (5/12 mice in PBS-treated. vs. 0/12 in PSA-treated) cumulative EDSS scores (p = 0.0212), and severity indexes (p = 0.0196). The manufactured PSA was then used in a human PBMC stimulation study. Earlier studies indicated that PSA amplifies the conversion to human IL-10 secreting Foxp3 T regulatory cells (Burgess J. et. al Ann Clinical Translational Neurol 2017). Upon exposure to the manufactured PSA, in vitro isolated T cell/DC produced substantial increases in IL-10 production in both HC (p=0.0011) and untreated MS (p=0.0039) as measured by ELISA. Further, there was no PSA haplotype restriction to human IL-10 production as measured by ELISPOT using 20 healthy PBMC donors of known HLA haplotype.

Conclusions

These studies recapitulate our previous reports demonstrating a robust regulatory effect by a native gut commensal antigen isolated from B. fragilis with a commercially prepared biosimilar molecule. The manufactured PSA shared biochemical and immunologic properties consistent with native molecule. These studies suggest a novel class of oral therapy for treating CNS demyelinating disease in humans can be achieved via induction of immune regulation by a single microbial antigen derived from the gut microbiome

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Microbiome Poster Presentation

P0674 - “Lactobacillus species differentially alter CNS autoimmunity via distinct immunomodulatory genomic loci and modulation of gut microbial composition.” (ID 1561)

Speakers
Presentation Number
P0674
Presentation Topic
Microbiome

Abstract

Background

The etiology of multiple sclerosis (MS) is complex, multifactorial, and polygenic with approximately 30% of disease susceptibility attributed to genetics, and only modest increase in risk attributed to any singular allele. The remaining 70% of risk is attributed to environmental influences, including diet, vitamin D intake, smoking, and stress, all of which can contribute to an imbalance in the gut microbiome as a central emerging risk factor. Recent studies have shown that MS patients harbor altered gut microbial content as compared to healthy controls, including depletion of the Lactobacillus genus, however the mechanism by which these changes impact disease pathogenesis remains unclear.

Objectives

The purpose of this study was to identify commensal members of the gut microbiome sufficient to alter CNS autoimmunity and begin to discern their mechanism of action.

Methods

Using a multipronged approach involving gut microbiome transplantation and colonization of germ-free mice, commensal microbiota associated with exacerbation of a murine model of MS, experimental autoimmune encephalomyelitis (EAE) where identified bioinformatically upon 16S sequencing. Commensal isolation and colonization studies were used to validate computational predications coupled with mechanistic studies utilizing immune profiling strategies and whole genome sequencing of bacterial isolates.

Results

We demonstrate that disparate gut microbiomes in genetically identical hosts confer differential susceptibility to EAE correlating with the abundance of several commensal Lactobacillus species, including Lactobacillus reuteri (L. reuteri), which unexpectedly is associated with exacerbation of neuroinflammation. Functionally, colonization with L. reuteri was sufficient to exacerbate EAE and elicit higher proportions of CD4+ effector T cells and higher GM-CSF production by CD4+ and CD8+ T cells in the CNS during chronic EAE. Mechanistically, whole genome sequencing of commensal Lactobacillus isolates, including L. reuteri, revealed alterations in the enzymatic machinery necessary to catabolize dietary tryptophan into indole derivatives with known immunomodulatory capacity, as well as species-specific bacteriocin production, with the capacity to shape the peripheral immune system and alter gut microbiome community structure. Consistent with the latter, we show that introduction of L. reuteri significantly remodels existing gut microbial communities.

Conclusions

These data highlight the need for further mechanistic study of host-microbe interactions as dictated by bacterial species-specific differences in commensal microbiota to discern their role in MS pathogenesis.

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Microbiome Poster Presentation

P0675 - Multi-OMICS of the host-gut microbiome dynamics in multiple sclerosis (ID 1719)

Speakers
Presentation Number
P0675
Presentation Topic
Microbiome

Abstract

Background

Gut microbiome changes have been described in multiple sclerosis (MS) patients compared to healthy controls (HCs). Evidence from studies on germ-free animals led to the hypothesis that the gut microbiome is involved in shaping the nature of the autoimmune response. Systematic studies with the aim to investigate a possible correlation between gut microbiome composition, peripheral immune-metabolic profiles, disease course and response to therapy are lacking.

Objectives

The main goal of this study was to test the hypothesis that the gut microbiome is correlated with the peripheral immune-metabolic profile and it influences MS disease course and response to therapy.

Methods

Thirty untreated MS patients and 24 age- and gender-matched HCs were enrolled at the John L Trotter MS Center at Washington University School of Medicine. Stoll and blood samples were collected at baseline before treatment and at 6 months after starting treatment. Stool samples were subjected to 16S rRNA gene sequencing and Whole Genome Shotgun Sequencing using the Illumina Miseq platform. Immunophenotyping was performed on whole blood samples by flow cytometry to characterize T, B, NK and myeloid cells.

Results

Considering both the MS and the control groups we found that body mass index and peripheral immune profile accounted for 4% and 3% of total variance in the microbiome composition (p=0.03). Differential microbiome abundance analysis performed at baseline demonstrated a significant decrease of Fecalibacterium species in MS compared to HCs. Moreover, the MS group presented alteration in fungi composition in the gut flora with higher abundance of Saccharomices and Aspergillus compared to the HCs group. Interestingly, in HCs we found a correlation between microbiome composition and peripheral blood immunophenotype, that was lost in MS subjects. Analyzing specific immune profiles in the MS group, we observed a strong correlation between Bacteroides and B cells, Alistipes and CD8+ naïve T cells and Lachnospiracee and Th1 memory cells.

Conclusions

We obtained preliminary results on an integrated multi-omics approach to identify new potential biomarkers to predict MS disease course, progression and response to therapy.

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Microbiome Poster Presentation

P0676 - Ocrelizumab impacts IgA coating of immunomodulatory gut bacteria in multiple sclerosis patients (ID 1887)

Speakers
Presentation Number
P0676
Presentation Topic
Microbiome

Abstract

Background

The mechanisms by which B-cell depletion ameliorates multiple sclerosis (MS) have not been fully delineated. Gut bacteria and their metabolites are important regulators of the systemic immune response, and early work demonstrated dysbiosis in MS. Dysregulation of immunomodulatory bacteria may contribute to the pathologic immune response in MS. We hypothesized that ocrelizumab, a B-cell depleting monoclonal antibody used to treat MS, would normalize the phenotype of gut bacteria, promoting an anti-inflammatory immune milieu.

Objectives

To characterize the taxonomic and functional shifts in the gut microbiota of MS patients induced by B-cell depletion.

Methods

We enrolled untreated, new onset MS patients and obtained longitudinal samples of paired blood and stool. We also recruited healthy controls. To date, 11 healthy controls, 16 baseline MS, 8 1-month, 9 6-month and 3 12-month post-ocrelizumab samples have been sequenced. Recruitment and follow up are ongoing; updated numbers will be presented. Gut microbiota were characterized using high-throughput long amplicon sequencing of the 16S-ITS-23S rRNA operon, allowing increased bacterial taxonomic resolution. We also performed IgA-Seq, a technique differentiating immune-reactive (IgA-coated) bacteria from those not eliciting an immune response (IgA-uncoated). IgA coating index (ICI) was calculated by dividing the IgA-coated bacteria by the uncoated fraction. Intestinal inflammation was measured using lipocalin-2 ELISA.

Results

Alpha and beta-diversity in the fecal microbiome of untreated MS patients appeared similar to that of healthy controls. B-cell depletion was not associated with changes in overall alpha or beta diversity. Analysis of composition of microbiomes (ANCOM) comparing all MS to healthy samples indicated enrichment of Monoglobus species. There was concurrent elevation of the ICI for Monoglobus. B-cell depletion was associated with trends for individual-level reductions in ICI for organisms that were highly coated at baseline. Fecal lipocalin-2 was significantly increased in MS patients and decreased after B-cell depletion.

Conclusions

Untreated MS patients exhibit increased intestinal inflammation. Moreover, a subset of immunomodulatory gut bacteria recognized as pathogenic by the immune system of untreated MS patients (e.g. with high levels of IgA coating) is less targeted by the immune system after B-cell depletion. This could impact differentiation of circulating immune cells and contribute to the efficacy of B-cell depletion in MS.

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Microbiome Poster Presentation

P0677 - Possible association between miRNAs and gut microbiota in pathogenesis of Multiple sclerosis (ID 1624)

Speakers
Presentation Number
P0677
Presentation Topic
Microbiome

Abstract

Background

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of CNS, involving interplay of multiple genetic and environmental factors, which leads to a chronic activation of the immune cells targeting CNS autoantigen. Involvement of microbiota has been correlated with the pathogenesis of MS, further mechanistic analyses are needed. Circulating extracellular vesicles(EVs) including exosomes play an important role in many signaling pathway by regulating gene expression, and the role of exosomal microRNA in MS has been demonstrated in our previous study (Kimura et al. Nature Comm 2018). Here we explored if extracellular vesicles including exosomes can be a communication tool between gut microbiota and the host immune system.

Objectives

Role of gut microbiome in generation of circulating exosomes and miRNAs.

Elucidate the relationship between circulating miRNA and gut microbiota in the pathogenesis of MS, using EAE model.

Methods

We generated gut microbiome dysbiosis model mice by oral administration of non-absorbing antibiotics cocktail (ABX) containing kanamycin, vancomycin and colistin. The model mice were subjected to Experimental autoimmune encephalomyelitis (EAE) by injecting MOG35-55 peptide in CFA. Exosome concentrations in the sera were quantified using enzymatic analysis. MOG tetramer35-55 reactive CD4+ T cells (%) were evaluated for lymphocytes isolated from the CNS, spleen and blood. For cell-free miRNA analysis, total RNA was isolated from the plasma by a Plasma/Serum. Circulating and exosomal RNA Purification kit and miRNA expression analysis was performed by a DNA chip of mouse miRNAs and TaqMan miRNA assay.

Results

Dysbiosis of gut microbiome was shown to ameliorate signs of EAE, along with a notable reduction in the migration of total T cells and MOG tetramer35-55 reactive CD4+ T cells to the CNS. We also revealed substantial changes in the circulating exosome and significant decreases in the expression of exosomal miRNAs, including miR-21a-5p, miR-146-5p, and miR-223-3p. Notably, these miRNAs can directly bind to the 3` UTR region of major genes that controls the T cell migration to the CNS in EAE. The results indicate that gut microbiome would significantly influence the T cell trafficking through exosomal miRNAs in EAE.

Conclusions

Our data support that exosomes and exosomal miRNAs could be the major source of communication between gut microbiome and host immune response.

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Microbiome Poster Presentation

P0678 - Selected Clostridia strains increase responses related to interferon beta signaling and butyrate levels in experimental autoimmune encephalomyelitis (ID 1576)

Presentation Number
P0678
Presentation Topic
Microbiome

Abstract

Background

MS patients show a significant decrease in Clostridia clusters XIVa and IV in the gut microbiome. We have previously reported that a mixture of human gut-derived 17 Clostridia strains, which belong to Clostridia clusters XIVa, IV, and XVIII, improved the clinical outcome of experimental autoimmune encephalomyelitis (EAE) mice as a therapeutic approach. The clinical improvement was related to lower histopathological signs in the central nervous system (CNS) and to an enhanced immunoregulatory response of regulatory T (Treg) cells in the periphery.

Objectives

We aimed to study in depth the mechanism of action of the treatment with Clostridia strains in Experimental Autoimmune Encephalomyelitis

Methods

In two independent experiments, myelin oligodendrocyte glycoprotein (MOG)-immunized C57BL6/J mice were treated with Clostridia strains (n=15) or vehicle (n=15) via oral gavage from 13-14 days post-immunization (dpi) until the end of the experiment (28 dpi). At 28 dpi, spleens and spinal cords were collected to perform transcriptome studies and serum was collected to determine the short-chain fatty acid (SCFA) levels. In three independent experiments, MOG-immunized C57BL6/J mice were orally gavaged with butyrate (n=19) or vehicle (n=18) from 13-15 dpi until 28 dpi. Then, spinal cords were collected to perform histopathological studies.

Results

Therapeutic administration of Clostridia strains ameliorated EAE clinical course, as previously reported. Transcriptome studies revealed increased antiinflammatory responses related to interferon beta in the periphery and lower activation, differentiation, and proliferation of immune cells in the CNS. Higher levels of the immunomodulatory SCFA butyrate were detected in the serum of Clostridia-treated mice. Therefore, we studied the therapeutic effect of butyrate on EAE. We observed a slight therapeutic impact on EAE clinical course that was connected to a noticeable improve concerning axonal damage and a tendency to lower demyelination, inflammation, and astrogliosis in the CNS.

Conclusions

Clostridia strains perform their therapeutic effect on EAE enhancing the immunoregulatory response of Treg cells and antiinflammatory responses related to interferon beta signaling pathway in the periphery. The beneficial outcome exerted by the oral administration of the 17 Clostridia strains was not exclusively related to the production of the SCFA butyrate.

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Microbiome Poster Presentation

P0679 - The gut microbiota: a case-control study of children with multiple sclerosis, monophasic acquired demyelinating syndromes and unaffected controls (ID 102)

Abstract

Background

The gut microbiota may influence multiple sclerosis (MS) onset. Pediatric MS offers the opportunity to examine pathological processes close to risk acquisition.

Objectives

To examine the gut microbiota from stool samples of persons with pediatric onset MS, or monophasic acquired demyelinating syndromes (ADS) and unaffected controls in a case-control study.

Methods

Persons ≤21 years old with symptom onset <18 years of age with either MS (McDonald criteria) or ADS were eligible, as were unaffected controls with no known neurological or immune-mediated condition (migraine, asthma/allergies were permissible) were enrolled via the Canadian Pediatric Demyelinating Disease Network. Stools were collected between Nov/2015–Mar/2018, shipped on ice, and stored at -80°C. The 16S ribosomal RNA gene (V4 region) was amplified from extracted DNA and sequenced via the Illumina MiSeq platform. Amplicon sequence variants were used to compare the gut microbiota by disease status (MS/ADS/controls). The MS cases were also compared by disease-modifying drug (DMD) status (exposed/naïve). Negative binomial regression was used for genus-level analyses, with rate ratios adjusted (aRR) for age and sex.

Results

Of the 32/41/36 included MS/ADS/control participants, 24/23/21 were girls, averaging age 16.5/13.8/15.1 years at stool sample, respectively. The MS/ADS cases were 14.0/6.9 years at symptom onset. The 3 groups (MS/ADS/controls) were relatively similar for: body mass index (median: 22.8/19.7/19.9), presence of constipation (number of participants with a Bristol Stool Scale score of 1 or 2=8/9/7) and diet (% caloric intake for fat (median)=34/35/34 and for fibre (median)=9/10/11 g/day). Nine MS cases (28%) were DMD naïve. Gut microbiota diversity (alpha and beta) did not differ by disease (MS/ADS/controls), or DMD status (all p>0.1), while taxa-level findings did. For example, relative abundance of the Proteobacteria, Sutterella was depleted for MS cases vs controls and MS vs ADS cases (aRR:0.13;95%CI:0.03–0.59 and 0.21;95%CI:0.05–0.98), but did not differ for the ADS cases vs controls or by DMD status for the MS cases (all p>0.1). Several of the butyrate-producing genera within the Clostridia class (Firmicutes phylum) —Ruminococcaceae UCG−003, Lachnospiraceae UCG−008 and UCG−004—exhibited similar patterns.

Conclusions

Gut microbiota diversity was similar for individuals with pediatric MS relative to either monophasic ADS or unaffected controls. However, at the taxa-level, differences were observed which differentiated the MS cases from the monophasic ADS cases and controls.

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Microbiome Poster Presentation

P0680 - The role of gut microbiota in the Egyptian relapsing remitting multiple sclerosis patients. (ID 1599)

Speakers
Presentation Number
P0680
Presentation Topic
Microbiome

Abstract

Background

The gut microbiota assumed to play an essential role in the pathogenesis of MS. It is thought to be involved in modulating the host’s immune system, modifies the integrity and function of the blood brain barrier, triggers autoimmune response, and interacts directly with different cell types present in the CNS, which lead to demyelination at the end. MS has several clinical variants, among which the most frequent is relapsing–remitting MS (RRMS).

Objectives

to assess the role of gut microbiota among the Egyptian RRMS patients and to discover the abundance and diversity of gut microbiota in the patients and healthy age- and sex- matched control group.

Methods

In our cross-sectional study, 40 cases of RR-MS patients (diagnosed according to the McDonald criteria 2017), were consecutively recruited from inpatients ward at the department of Neurology, Assiut University Hospitals, Assiut, Egypt. Together with 30 age and sex matched healthy control subjects. Detailed history, thorough neurologic examinations, MRI brain and whole spine with contrast, CSF analysis, Evoked potentials, complete Laboratory investigations and Expanded Disability Status Scale (EDSS) were carried out for each patient. Stool sample processing and DNA extraction, concentration and copy number of bacterial organisms were estimated for Patients and control groups.

Results

The mean age of the patients was 31.4 ± 8.8, 75% of them were women. The mean disease duration was 29.90 ± 25.79 months. The mean EDSS score was 3.43 ±1.35. There were significant increased Copy number of Desulfovibrio, Actinobacteria, Firmcutes, and Lactic acid bacteria in the patients with RRMS in comparison with control group, in the contrary a significant lower level of Copy number of Clostridium cluster IV group in RR-MS in comparison with control group were found. The other species of gut microbiota showed no significant differences between groups. Patients who had EDSS 3.5 had significant higher copy number of Actinobacteria, Bacteroidetes, and Bifidubacterium, in comparison with patients who had EDSS > 3.5. A significant correlation between EDSS scoring and copy number of Bifidubacterium only with P= 0.04. There was a significant negative correlation between duration of illness and copy number of three species; Firmcutes, Akkermansia, and Lactic acid bacteria (r= - 0.42; P = 0.01, r= - 0.33; P = 0.04, r= - 0.64; P = 0.004 respectively)

Conclusions

The present study demonstrated that the Egyptian RRMS patients had a distinct fecal microbiome compared to healthy controls, with specific changes in certain gut microbes richness among RRMS patients compared to controls.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0681 - A severe case of tetraparesis with conus involvement in neuromyelitis optica spectrum disorder (ID 1038)

Speakers
Presentation Number
P0681
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is a severe neuroinflammatory disorder primarily affecting the optic nerves and spinal cord. It is associated with a variety of clinical phenotypes and radiological features that can make diagnosis challenging.

Objectives

We present an atypical and diagnostically challenging case of NMOSD with severe tetraparesis and conus involvement.

Methods

This is a case report detailing the complex clinical presentation, workup, and treatment of a patient who was ultimately diagnosed with NMOSD.

Results

A previously healthy 46-year-old woman presented to the emergency room with 2 weeks of unidentifiable nausea/vomiting after a recent ear infection. Shortly after discharge, she returned to the hospital with complaints of worsened generalized weakness and no longer being able to walk. Over the next few days, she became flaccid with 0/5 strength in all 4 extremities. Magnetic resonance imaging (MRI) of the brain showed several nonenhancing lesions in the hypothalamic, anterior medial thalamic, right posterior pontine, and right middle cerebellar peduncular regions. MRI spine showed extensive enhancing lesions in the upper cervical cord and conus medullaris with leptomeningeal enhancement. Cerebrospinal fluid (CSF) studies were notable for lymphocytic-predominant pleocytosis with negative oligoclonal bands and negative cytology. Serum and CSF autoimmune panels were negative. Infectious and malignancy workup was negative. Cell-based assay testing for myelin oligodendrocyte glycoprotein (MOG-Abs) and aquaporin-4 (AQP4-Abs) antibodies were negative. Workup was negative for systemic signs of sarcoidosis or malignancy. She was treated with 5 days of intravenous steroids followed by intravenous immunoglobulin (IVIG) without improvement. She then underwent plasma exchange for 5 sessions. Within a week after completion, her strength gradually improved such that she was antigravity with 4/5 strength in all extremities by discharge to rehab. Because it was unclear if this was a monophasic event, a tentative diagnosis of atypical acute disseminated encephalomyelitis (ADEM) was made. Three months later, she developed muscle spasms in her right arm and was found to have a new enhancing lesion in the right spinal cord at C2. Repeat testing was sent and her AQP4-Ab test returned positive, leading to a final diagnosis of NMO.

Conclusions

This is a complex case with multiple differential diagnoses, including NMO, atypical ADEM, neurosarcoidosis, or lymphoma. Conus involvement is unusual for NMO and tend to be associated more with MOG-Abs compared to AQP4-Abs. Though cell-based assays have high sensitivities (90-94%), testing should be repeated on negative values if clinical suspicion is high.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0682 - Aggressive and fulminant course of Anti-myelin oligodendrocyte glycoprotein antibody associated disease in a solid organ receptor (ID 1514)

Speakers
Presentation Number
P0682
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Anti-myelin oligodendrocyte glycoprotein (MOG) antibody (ab)-associated disease or MOG-IgG-associated encephalomyelitis (MOG-EM) was previously considered a benign entity but mounting evidence shows there are patients who experience severe and frequent relapses and ultimately acquire significant neurological disability.

There are some evidence about (MOG-EM) in hematopoietic receptors, with good prognosis, but these information is limited in solid organ receptors.

Objectives

To describe a case of MOG EM with aggressive course treated with steroids, azathioprine and rituximab in a solid organ receptor

Methods

We report a case of MOG EM with aggressive course treated with steroids, azathioprine and rituximab in a kidney organ recipient.

Results

He was diagnosed with a haemolytic uremic syndrome during his childhood, so he progressed to end stage kidney failure. At age of 20 he received a kidney transplant from his mother and a second new transplant at age 29 was indicated due to solid organ rejection. In the following months, a malign mammary nodule appeared so he was under tamoxifen for the next year. At 38 yo, he presented to the emergency department referred a 15-days-history of bilateral optic neuritis(ON) without other focal signs at the neurological exam and under treatment with deltisone, cyclosporine and micofenolate for immunosuppression, enalapril, and lovastatine. Acute renal failure was detected due to kidney confirmed through biopsy. Brain MRI and Lumbar puncture were made, CSF, Anti aqp4 and Anti Mog were unremarkable and treated with methylprednisolone and plasmapheresis. The diagnosis was atypical ON by inmunosupression drugs in the context of decreased glomerular filtrate. His visual acuity improved in the consecutives months. Against he received methylprednisolone and plasmapheresis. Throated out others causes, Azathioprine was started.

A new relapse was presented in few days, showing a long extensive transverse myelitis (LETM) at dorsal levels appeared, without supratentorial lesions; CSF with increased proteins levels, against infectious causes was dismissed, MOG-Ab were positive in CSF and plasma. Steroids, plasmapheresis and rituximab were started. Two months after encephalopathy signs appeared. A new MRI showed acute supratentorial lesion and LETM at cervical levels. A pulmonary sepsis appeared like a complication an instable haemodynamic, so we had a wide range of treatment. The patient died few days after.

Conclusions

MOG EM is a heterogenous sometimes severe disease. We report an aggressive and fulminant form in a previous immunosuppressive patient. We discuss the presence of Anti MOG disease as comorbidity in association to other immunological conditions. The aim of this report is increased the experience in this condition

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0683 - Altered resting state dynamic functional connectivity of precuneus contributes to cognition and depression in neuromyelitis optica spectrum disorders (ID 887)

Speakers
Presentation Number
P0683
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

In neuromyelitis optica spectrum disorders (NMOSD), cognitive impairment (CI) is nowadays considered as a unique relapse-unrelated manifestation of the disease. As a proof-of-concept, anti-aquaporin4 (AQP4)-IgG seems to inhibit neuronal plasticity and long-term potentiation. Structural and functional MRI (fMRI) studies have disclosed an association with damage of the precuneus (PCUN) and cognitive impairment (CI) in several neurological conditions.

Objectives

To explore the role of dynamic functional connectivity (dFC) of the PCUN at resting state (RS) to explain cognitive alterations in NMOSD patients.

Methods

3.0 T RS fMRI were acquired from 27 AQP4-positive NMOSD patients and 30 age- and sex-matched healthy controls (HC). Patients underwent an extensive neuropsychological evaluation including the assessment of global and domain-specific cognitive impairment index (CII) and Beck Depression Inventory II (BDI-II) scores. DFC of the left (L) and right (R) PCUN was assessed by means of sliding-window seed-voxel correlation analysis. Standard deviation of dFC across windows was used as a measure of dynamicity (the higher the better). Age- and sex-adjusted between-group dFC comparisons and correlations with cognitive scores were assessed using SPM12 and full-factorial models. A p value <0.001 was considered statistically significant.

Results

Compared to HC, NMOSD patients had reduced L-PCUN dFC with caudate nucleus, rectus, olfactory bulb and occipital inferior gyrus and increased dFC between the L-PCUN and the middle temporal gyrus and between the R-PCUN the middle occipital gyrus. Global CII positively correlated with higher L-intra-PCUN dFC, as well as with higher dFC between the L-PCUN and the middle temporal and middle frontal gyrus and between the R-PCUN and the middle cingulate gyrus. Impairment of information processing speed (IPS, 59.2%) and depression (63.0%) were the most common cognitive alterations. The IPS index positively correlated with a higher L-intra-PCUN-dFC, and a higher dFC between the R-PCUN and the middle cingulate gyrus. The BDI-II score positively correlated with a higher dFC between the R-PCUN and the middle frontal gyrus.

Conclusions

The assessment of PCUN dFC supports the role of PCUN in NMOSD cognitive dysfunction. We observed a protective effect of higher dynamic connections with limbic regions for cognitive performance, while those with the frontal lobe were detrimental for depressive symptoms.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0684 - Anti-IL-6 receptor antibody prevents blood-brain barrier disruption in mice with experimental autoimmune encephalomyelitis (EAE) (ID 717)

Speakers
Presentation Number
P0684
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Breakdown of blood-brain barrier (BBB), which strictly regulates the entry of immunoglobulin (IgG) and lymphocyte into the central nervous system, is essential to pathogenesis in autoimmune encephalomyelitis such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD). IL-6 increases in serum and cerebrospinal fluid (CSF) in NMOSD patients and its level has been reported to correlate with CSF/serum ratio of albumin, a surrogate marker of BBB function. It is possible that IL-6 are involved in pathogenesis of NMOSD in terms of T and B cells, but roles of IL-6 signal inhibition on BBB function remain unknown.

Objectives

In this study, we examined the effects of anti-IL-6 receptor antibody on BBB function in EAE mice as a CNS autoimmune disease model in which IL-6 concentration in the CNS dramatically increases.

Methods

EAE was induced in female C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein 35–55 emulsified in adjuvant (Day 0). Pertussis toxin was administered at Days 0 and 2. Control mice were treated with complete Freund's adjuvant and saline alone. Mice were sequentially scored for clinical symptoms of EAE. Anti-IL-6 receptor antibody was intraperitoneally administered on Day 7. On Day 15 or 16, spinal cord, spleen and serum were harvested for immunohistochemistry, flow cytometry and transendothelial electrical resistance (TEER) studies.

Results

Immunohistochemical analysis showed that leakages of albumin and IgG into the spinal cord, which mean BBB permeability, in vehicle-treated EAE mice were higher than those in control mice. The number of CD4-positive T cells also markedly increased in the spinal cord of vehicle-treated EAE mice. Anti-IL-6 receptor antibody significantly reduced those changes in accordance with the prevention of clinical symptoms in EAE mice. It seems that these effects of anti-IL-6 receptor antibody are not only dependent on the inhibition of immune response because anti-IL-6 receptor antibody did not affect T cell differentiation in splenocytes of EAE mice. In addition, the serum of vehicle-treated EAE mice significantly decreased endothelial TEER value of cultured mouse primary endothelial cells, an indicator of permeability, and anti-IL-6 receptor antibody significantly prevented it in vitro.

Conclusions

These results suggest that anti-IL-6 receptor antibody can inhibit the BBB breakdown at least partly by direct effect on the endothelial permeability in EAE mice.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0685 - AQP4-IgG and MOG-IgG related optic neuritis – prevalence, optical coherence tomography findings, visual outcomes: systematic review and meta-analysis (ID 860)

Speakers
Presentation Number
P0685
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Optic neuritis (ON) is a cardinal manifestation of multiple sclerosis (MS), aquaporin-4 (AQP4)-IgG, and myelin oligodendrocyte glycoprotein (MOG)-IgG associated disease. However, the prevalence of AQP4-IgG seropositivity and MOG-IgG seropositivity in isolated ON is unclear, and studies comparing visual outcomes and optical coherence tomography (OCT)-derived structural retinal measures between MS-ON, AQP4-ON, and MOG-ON eyes are limited by small sample sizes.

Objectives

1) To assess the prevalence of AQP4-IgG and MOG-IgG seropositivity among patients presenting with isolated ON; 2) To compare visual outcomes and OCT measures between AQP4-ON, MOG-ON, and MS-ON eyes.

Methods

In this systematic review and meta-analysis, a total of 65 eligible studies were identified by Pubmed search. Statistical analyses were performed with random-effects models.

Results

In adults with isolated ON, AQP4-IgG seroprevalence was 4% in non-Asian and 27% in Asian populations, whereas MOG-IgG seroprevalence was 8% and 20% respectively. In children, AQP4-IgG seroprevalence was 0.4% in non-Asian and 15% in Asian populations, whereas MOG-IgG seroprevalence was 47% and 31% respectively. AQP4-ON eyes had lower peri-papillary retinal nerve fiber layer (pRNFL; -11.7μm, 95% CI: -15.2 to -8.3μm) and macular ganglion cell + inner plexiform layer (GCIPL; -9.0μm, 95% CI -12.5 to -5.4μm) thicknesses compared with MS-ON eyes, but these measures did not differ between AQP4-ON and MOG-ON eyes (pRNFL: -1.9μm, 95% CI: -9.1 to 5.4μm; GCIPL: -2.6μm, 95% CI: -8.9 to 3.8μm). Similar to AQP4-ON, pRNFL (-11.2μm, 95% CI -21.5 to -0.9μm) and GCIPL (-6.1μm, 95% CI -10.8 to -1.3μm thicknesses were lower in MOG-ON compared to MS-ON eyes. Visual outcomes were worse in AQP4-ON compared to both MOG-ON (mean logMAR difference: 0.60, 95% CI 0.39 to 0.81) and MS-ON eyes (mean logMAR difference: 0.68, 95% CI 0.40 to 0.96), but were similar in MOG-ON and MS-ON eyes (mean logMAR difference: 0.04, 95% CI: -0.05 to 0.14).

Conclusions

AQP4-IgG and MOG-IgG associated disease are important diagnostic considerations in adults presenting with isolated ON, especially in Asian populations. Furthermore, MOG-IgG seroprevalence is especially high in pediatric isolated ON, in both non-Asian and Asian populations. Despite a similar severity of GCIPL and pRNFL thinning in AQP4-ON and MOG-ON, AQP4-ON is associated with markedly worse visual outcomes.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0686 - Aquaporin-4 antibody seroreversion in patients with neuromyelitis optica spectrum disorder treated with rituximab. (ID 1883)

Speakers
Presentation Number
P0686
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

The mechanism of action (MOA) of anti B-cell therapies in CNS demyelinating disorders associated with Aquaporin-4 antibody (AQP4-Ab) neuromyelitis optica spectrum disorders (NMOSD) is unknown. Restoration of immune tolerance by blocking self-antigen presentation by autoreactive B to T cells and return to immune homeostasis has been postulated as a MOA.

Presence of AQP4-Ab is a marker of breakdown of immune tolerance in NMOSD while their disappearance after initial positivity could signify restoration of immune homeostasis. The outcome of AQP4-Ab in NMOSD treated with rituximab has not previously been examined.

Objectives

To examine the evolution of AQP4-Ab status in a cohort of patients with CNS demyelinating disorders that were treated with rituximab.

Methods

Retrospective study of consecutive patients with recurrent optic neuritis or transverse myelitis treated with rituximab between 2006 and 2020. The data on AQP4-Ab status were obtained by chart review.

Results

A total of 51 patients who were on long-term monotherapy with rituximab 1 gm IV every 6 months were identified. All were clinically stable. All serology was obtained by commercial laboratories as reported in the respective clinical records. Twenty-nine patients were AQP4-Ab positive (57%) at some time using the ELISA or more recently, the cell-based assay. In 23 patients re-testing for serological status was undertaken at varied intervals. Serostatus changed in 10 patients with 4 patients previously seronegative now becoming seropositive, and 6 patients who were seropositive becoming seronegative. In some subjects where seroreversion occurred, when titers were reported, a decrease in titer over time occurred before becoming seronegative.

Conclusions

AQP4-Ab reactive status can revert to non-reactivity on rituximab therapy in some patients. The seroconversion, however, was not a marker for response to rituximab as a favorable clinical response was also observed in persistently seropositive patients as well. This previously unrecognized observation suggests that the change in AQP4-Ab status from positive to negative on rituximab therapy can be used as a potential marker to guide future randomized discontinuation trials of rituximab in a select group of clinically stable patients.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0687 - Aquaporin-4 neuromyelitis optica spectrum disorder in a 5-year-old girl presenting with neuropsychiatric symptoms (ID 363)

Speakers
Presentation Number
P0687
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare autoimmune inflammatory condition that affects the central nervous system and a majority of cases have antibodies directed against the aquaporin-4 (AQP4) water transport channel. AQP4-NMOSD is exceedingly rare in young children. A predominantly neuropsychiatric manifestation in young children is not a commonly reported phenotype.

Objectives

To report a case of severe aquaporin-4 NMOSD in a young child presenting with neuropsychiatric symptoms and lethargy.

Methods

A case report with information obtained from the medical records and from providers involved in the care of this child.

Results

A 5-year-old previously healthy African American girl presented with subacute onset lethargy and psychiatric symptoms, including visual hallucinations, delusions, paranoia, and disinhibition. She was initially seen 2 weeks after symptom onset and was diagnosed with presumed viral meningitis. Lumbar puncture at that time was remarkable for leukocytosis (WBC 17, 98% lymphocytes) but cultures were negative. She represented 3 weeks after symptom onset, with repeat CSF studies showing worsening leukocytosis (WBC 80, 94% lymphocytes). MRI brain was significant for hyperintense signal changes within the medial thalami, hypothalamus, and central optic pathway. MRI of the cervical and thoracic spine were normal. She continued to decline with severely impaired arousal and acute respiratory failure requiring intubation and mechanical ventilation. Her clinical presentation was suspicious for NMOSD and she was treated with high dose pulse steroid therapy and plasma exchange. Testing prior to initiation of treatment showed that her AQP-4 antibodies were negative in the serum (via cell based assay and flow cytometry testing) but positive in the CSF (via indirect immunofluorescence). She was started on maintenance therapy with rituximab, with complete resolution of symptoms at follow-up, 4 months after discharge.

Conclusions

To our knowledge, this is one of the youngest reported cases of AQP4-NMOSD and the first reported case of a child with AQP4-NMOSD who initially presented with behavioral concerns and neuropsychiatric symptoms. She was also found to be negative for serum AQP4 antibodies but tested positive for CSF AQP4 antibodies. This emphasizes the need to consider CSF testing for AQP4 antibodies should the serum test be negative in cases of high suspicion, contrary to current literature suggesting higher sensitivity with serum testing.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0688 - Area postrema syndrome and longitudinally extensive transverse myelitis in a patient with prostatic adenocarcinoma and Aquaporin-4 antibodies. (ID 1872)

Speakers
Presentation Number
P0688
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is not defined as a “classical” paraneoplastic neurological syndrome (PNS), however there are growing evidences that NMOSD may be associated with cancer.

Objectives

The aim of the present report is to describe the clinical presentation of a patient with NMOSD of probable paraneoplastic origin.

Methods

A 79-years old man presented with acute onset of mild dysphagia associated with intractable hiccups and vomiting one month after radiotherapy for prostatic adenocarcinoma (cT2N0M). Two weeks later, he developed subacute lower-limb weakness and hypoesthesia that rapidly spread involving the trunk and upper limbs. MRI showed an extensive T2 hyperintense, tumefactive spinal cord lesion, extending from C2 to the conus and similar lesion in the area postrema. Cerebrospinal fluid analysis showed increased cell count (mononuclear cells) and protein concentration. He resulted positive for Aquaporin-4-IgG (AQP4) antibodies on serum. He was treated with intravenous steroids with mild improvement.

Results

Our patient fulfills the criteria for a “probable PNS”, according to PNS diagnostic criteria, since NMOSD is a “non-classical” PNS and cancer occurred within two years from the diagnosis. It has been recently highlighted that older male patients (>45 years) presenting with longitudinally extensive transverse myelitis or patient with an “area postrema” syndrome at onset have higher risk for neoplasm associated NMOSD. Appropriate tumor screening should be always performed in patients with the aforementioned clinical features.
Since prostatic cells express AQP4, we hypothesize that AQP4-IgG could be part of the immune response against cancer cells or alternatively that radiotherapy could have led to a break of tolerance against AQP4, given the close temporal relationship with disease onset.

Conclusions

Paraneoplastic NMOSD is a rare disease that is becoming more frequently recognized. Further studies should elucidate the immunological relationship between cancer and AQP4-IgG.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0689 - Autoimmune comorbidity increases healthcare cost burden in patients with NMOSD in the United States: a retrospective commercial claims analysis   (ID 1053)

Speakers
Presentation Number
P0689
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the central nervous system that may be associated with specific comorbidities, including autoimmune disease (AID) or nonautoimmune conditions. This study assessed real-world healthcare utilization and cost of illness in patients with NMOSD and overlapping AID.

Objectives

To evaluate the cost of illness in patients with NMOSD with overlapping AID compared with controls without NMOSD (non-NMOSD) and NMOSD without comorbid AID in US commercial claims databases.

Methods

Methods

Claims data from the Truven Health MarketScan Commercial and Medicare Supplemental Databases were analyzed between 2014 and 2018. Patients were identified as having NMOSD if they had ≥1 inpatient or ≥2 outpatient claims for NMOSD diagnosis ≥60 days apart or ≥2 claims for transverse myelitis diagnosis in combination with ≥1 claim for optic neuritis ≥6 months apart. Continuous enrollment ≥6 months before and ≥1 year after the first claim (index date) was required. Non-NMOSD controls were matched 5:1 to patients with NMOSD. Total costs stratified by AID in consumer price index–adjusted 2019 US dollars within 12 months post–index date were calculated for each patient.

Results

In the NMOSD group, 31/162 patients (19.1%) had AID compared with 40/810 matched non-NMOSD controls (4.9%), with 8/162 (4.9%) in the NMSOD group having multiple AIDs vs 5/810 (0.6%) in matched non-NMOSD controls. These included systemic lupus erythematous (SLE; 5.6% vs 0.4%; p<0.001), rheumatoid arthritis (RA; 4.3% vs 0.9%; p=0.004), Sjögren syndrome (SS; 3.1% vs 0.1%; p<0.001), and autoimmune encephalitis (AE; 2.5% vs 0%; p<0.001). Total median [IQR] costs per patient during the post-index follow-up period were significantly higher for patients with NMOSD and AID ($68,386 [$23,374–$160,863]) than both matched non-NMOSD controls with AID ($17,215 [$6,715–$31,442]; p<0.001) and NMOSD without AID ($23,905 [$8,633–$67,252]; p=0.022). This trend held across all settings, including inpatient care, outpatient care, outpatient emergency room services and pharmacy expenses.

Conclusions

Patients with NMOSD and comorbid AID incurred significantly higher costs associated with healthcare resource utilization compared with matched non-NMOSD controls and patients with NMOSD who did not have AID. These results demonstrate a higher cost burden associated with overlapping AID (primarily SLE, RA, SS and AE) in patients with NMOSD and a need to identify more cost-efficient, integrated therapeutic approaches to address the overlap of NMOSD and other serious, debilitating AID.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0690 - Autologous hematopoietic stem cell transplantation in a pediatric patient with aquaporin-4 neuromyelitis optica spectrum disorder (ID 1237)

Speakers
Authors
Presentation Number
P0690
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

NMOSD is an autoimmune condition commonly involving the optic nerve and spinal cord. Pediatric onset NMOSD is rare, representing 3% of cases, with a mean age of onset of 10 years. Presenting features in these patients include optic neuritis, myelitis, brainstem, diencephalic, and cerebral syndromes. Acute treatments include plasma exchange (PLEX) and steroids. Early initiation of immunosuppression is critical to prevent relapses and disability. In adults with refractory NMOSD, autologous hematopoietic stem cell transplant (AHSCT) has been utilized as a salvage therapy. We report the first case to our knowledge of a child with AQP4 NMOSD receiving AHSCT.

Objectives

We report a child with an early and severe manifestation of an AQP-4 positive NMOSD who had a refractory course despite aggressive immunotherapy and underwent AHSCT.

Methods

Case report featuring clinical presentation, laboratory, neuroimaging, discussion of medical decision-making and specific treatment protocol used for AHSCT.

Results

A 2 year old girl presented with left hand weakness and abnormal gait and was found to have abnormalities in the dorsal medulla and longitudinally extensive myelitis. She was diagnosed with NMOSD based on positive CSF and serum AQP-4 antibody.

She has had highly active disease with 7 hospitalizations (5 of which she received PLEX) for exacerbations involving holocord edema, bilateral optic neuritis, parenchymal brain lesions, area postrema syndrome, and hypothalamus.

She was initially placed on rituximab but had rapid B cell repopulation. She was transitioned to mycophenolate mofetil (MMF), titrated up to 85 mg/kg/day, but still relapsed, even when Tocilizumab 8 mg/kg monthly was added on to MMF. While her attacks continued to be partially responsive to acute therapies, serial imaging revealed increasing myelomalacia and optic nerve atrophy.

She later underwent a myeloablative AHSCT with conditioning using rituximab, cyclophosphamide, and rabbit thymoglobulin without significant complication. Her home MMF, prednisone, and Tocilizumab were discontinued prior to transplant. A week after full engraftment of stem cell transplant, she started to have worsening visual symptoms and was found to have enhancing lesion of the optic chiasm with elevated anti-AQP4 titers at > 1:100,000. She then received PLEX and IV steroids with significant clinical improvement. She has since had no further NMOSD exacerbations and had a recent admission for febrile neutropenia.

Conclusions

AHSCT has been increasingly utilized in refractory cases of adult NMOSD, showing good efficacy, tolerability, and potential for enduring disease remission. We present this case to highlight its first use to our knowledge in pediatric NMOSD, unfortunately complicated by a relapse shortly after engraftment and subsequent hospitalization for febrile neutropenia. The long-term efficacy and safety of this treatment in children requires further investigation.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0691 - Autologous Hematopoietic Stem Cell Transplantation in Neuromyelitis Optica – Year 5 Update (ID 1042)

Speakers
Presentation Number
P0691
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis Optica Spectrum Disorder (NMO/NMOSD) is an immune astrocytopathy characterized by disabling attacks of optic nerves, spine, the area postrema, hypothalamus and other CNS regions. Although new, targeted therapies have recently been approved, they require indefinite use, with data limited essentially to positive aquaporin-4 (AQP4) patients. As well, many patients may not have access to such agents and still rely on older, harsher immunosuppressants. The immunological features of NMO/NMOSD, coupled with its severity, make it an ideal candidate for trials of autologous hematopoietic stem cell transplantation (AHSCT), with the goal of disease remission and freedom from long-term treatment. Several small studies, with a variety of transplant regimens, have been presented thus far, with mixed results.

Objectives

To determine if NMO/NMOSD patients who have failed standard immune maintenance therapy, experience a reduction in relapse and disability without need for immune therapy after AHSCT.

Methods

Starting in 2010, patients were eligible and enrolled if they met Wingerchuk 2006 criteria for NMO, aged 18-65, with => 1 relapse in 12 months or => 2 in 24 months despite immunotherapy and EDSS < 6.5. Patients underwent non-ablative stem cell mobilization and infusion using cyclophosphamide (200mg/kg - divided as 50mg/kg/day over days -5 to -2), ATG and rituximab. The primary endpoint was a 50% reduction in relapse rate at year 3 (secondary at year 5). Additional outcomes included annualized relapse rate (ARR), EDSS, MRI, AQP4 serostatus, and optical coherence tomography over 5 years. Ten subjects were to be enrolled to provide 80% power.

Results

Between 2010-2015, 3 patients were enrolled and underwent AHSCT. A 28F, AQP4-, was transplanted in 2011. Her ARR dropped from 5 to 0 at both year 3 and 5, with her EDSS dropping from 4.0 to 2.0. A 36F, AQP4+, transplanted in 2012, had a reduction in her ARR from 4 to 0.67 at year 3, and 0.5 at year 5, with her EDSS dropping from 4.5 to 3.0 throughout the trial. She was treated with MMF after her two mild post-transplant relapses. The final patient, a 39M, AQP4+ was transplanted in 2014. He had a precipitous decline with an ARR increasing from 1.3 to 2 at year 3 and 5, and an EDSS increasing from 3.5 to 7.5 at year 3, with death from NMO at year 3.5. As well, both seropositive patients remained seropositive after transplant. The trial was closed in 2016 due to challenges in recruitment.

Conclusions

While the small cohort size limits interpretation, two of three patients had a marked improvement in their NMO activity and disability after AHSCT. Regimen selection and patient features may speak to the success and failures in this trial and other published studies, but it appears that AHSCT in NMO/NMOSD is a viable option worthy of further study and refinement.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0692 - Benefit of eculizumab for a broad range of patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: findings from PREVENT (ID 408)

Abstract

Background

Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in neuronal injury. The terminal complement inhibitor eculizumab is the first treatment approved for use in patients with AQP4 immunoglobulin G-positive NMOSD, based on PREVENT data.

Objectives

To determine whether the beneficial effect of eculizumab in reducing relapse risk in patients with NMOSD is associated with time since diagnosis, relapse history, disability burden or prior immunosuppressant therapy (IST) use, based on data from the phase 3 trial PREVENT (NCT01892345)

Methods

In PREVENT, patients received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo, with stable-dose concomitant IST (except rituximab and mitoxantrone) permitted. PREVENT was not powered for subgroup analyses; post hoc descriptive analysis was performed on subgroups defined by time since diagnosis, total number of historical relapses, baseline Expanded Disability Status Scale (EDSS) score and prior IST use.

Results

The proportions of patients experiencing an adjudicated relapse were lower with eculizumab than with placebo in all subgroups. Proportions for eculizumab and placebo, respectively, were: 2/31 versus 6/12 for < 1 year since diagnosis and 1/65 versus 14/35 for ≥ 1 year since diagnosis; 1/39 versus 10/24 for 2–4 historical relapses and 2/57 versus 10/23 for ≥ 5 historical relapses; 0/14 versus 3/6 for baseline EDSS scores ≤ 2.0 and 3/82 versus 17/41 for baseline EDSS scores ≥ 2.5 to ≤ 7.0; 0/15 versus 2/5 for no prior IST use (except corticosteroids alone); and 3/81 versus 18/42 for prior IST use. Relapse-risk reductions were consistent and statistically significant in all subgroups.

Conclusions

The data from this post hoc subgroup analysis suggest that eculizumab reduced relapse risk in PREVENT compared with placebo, regardless of time since NMOSD diagnosis, relapse history, disability burden or prior IST use.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0693 - Brainstem and cerebellar involvement in MOG-IgG Associated Disorder versus Aquaporin-4-IgG and Multiple Sclerosis (ID 1244)

Speakers
Presentation Number
P0693
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Brainstem and cerebellar involvement are recognized to occur in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) and the clinical syndrome can be severe. However, data on brainstem and cerebellar involvement in MOGAD is limited.

Objectives

To determine the frequency and characteristics of brainstem/cerebellar involvement in MOGAD versus aquaporin-4-IgG-seropositive-neuromyelitis-spectrum-disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS).

Methods

In this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients and included those with: 1) characteristic MOGAD phenotype; 2) MOG-IgG seropositivity by live-cell-based-assay; 3) brainstem/cerebellar MRI lesion(s). We compared clinical, MRI and cerebrospinal fluid (CSF) characteristics of symptomatic brainstem/cerebellar attacks in MOGAD to AQP4-IgG-NMOSD (n=30) and MS (n=30).

Results

Brainstem/cerebellum involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) had accompanying brainstem/cerebellum symptoms/signs. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2–65) was younger than MS at 36 (19–65) and AQP4-IgG-NMOSD at 45 (6–72)(P<.05). Isolated brainstem/cerebellar attacks in MOGAD (9/39[23%]) were less frequent than MS (22/30[73%]; p<0.05) but not significantly different from AQP4-IgG-NMOSD (14/30[47%]; p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favored MOGAD (17/37[46%]) over MS (3/30[10%]; P<0.05) and AQP4-IgG-NMOSD (3/30[10%]; p<0.05), while diffuse medulla, pons or midbrain MRI-lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. CSF oligoclonal bands were similarly rare in MOGAD (2/30[7%]) and AQP4-IgG-NMOSD (1/22[5%]; p>0.99) but common in MS (17/22[77%]; p<0.05). Expanded-disability-status-scale-score (EDSS) and brainstem/cerebellar functional-system-scores (FSS) at nadir and recovery did not significantly differ between the groups.

Conclusions

Brainstem/cerebellar involvement is common in MOGAD but usually occurs as a component of a multifocal CNS attack rather than in isolation. We identified clinical, CSF, and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0694 - Burden of autoimmune comorbidity in patients with NMOSD in the United States revealed by retrospective commercial claims analysis (ID 1051)

Speakers
Presentation Number
P0694
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition of the central nervous system that may be associated with concomitant autoimmune disease (CAID), such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), as well as nonautoimmune conditions (CnAID).

Objectives

To evaluate the burden of CAID in patients with NMOSD compared with controls without NMOSD (non-NMOSD) in US commercial claims databases.

Methods

Claims data from the Truven Health MarketScan Commercial and Medicare Supplemental Databases were analyzed between 2014 and 2018. Patients were identified as having NMOSD if they had ≥1 inpatient or ≥2 outpatient claims for NMOSD diagnosis ≥60 days apart or ≥2 claims for transverse myelitis diagnosis in combination with ≥1 claim for optic neuritis ≥6 months apart. Continuous enrollment ≥6 months before and ≥1 year after the first claim (index date) was required. Non-NMOSD controls were matched 5:1 to patients with NMOSD. The Charlson Comorbidity Index (CCI) was assessed during a 6-month baseline period prior to NMOSD diagnosis and at 12 months post-index. Comorbidities during the 12-month follow-up period were evaluated.

Results

A total of 162 patients with NMOSD (mean [SD] age, 43.3 [18] years) and 810 non-NMOSD controls (mean [SD] age, 43.3 [18] years) were evaluated. Mean (SD) 6-month baseline and 12-month follow-up CCI scores were 0.96 (1.77) and 1.62 (2.53) for patients with NMOSD vs 0.34 (0.91) and 0.52 (1.31) for non-NMOSD controls, respectively (p<0.001). CAID occurred in 19.1% vs 4.9% (p<0.001) of NMOSD patients vs non-NMOSD controls. SLE (5.6% vs 0.4%; p<0.001), RA (4.3% vs 0.9%; p=0.004), Sjögren syndrome (3.1% vs 0.1%; p<0.001) and autoimmune encephalitis (2.5% vs 0%; p<0.001) occurred at significantly higher prevalence in patients with NMOSD. Reports of type 1 diabetes (1.9% vs 1.4%) and myasthenia gravis (1.2% vs 0.1%) were not significantly different between the NMOSD and non-NMOSD groups in this study cohort.

Conclusions

Patients with NMOSD had significantly higher CCI scores and CAID prevalence compared with controls. Consistent with previous studies, these results highlight the significant CAID burden in NMOSD. Moreover, these data suggest immune dysfunction common to multiple autoimmune diseases and underscore the need to identify efficacious therapies with distinct mechanisms of action to address the concomitant burden of NMOSD and other debilitating CAIDs.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0695 - Burden of disease in patients with neuromyelitis optica spectrum disorder: insights from the CIRCLES study cohort (ID 802)

Speakers
Presentation Number
P0695
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

In patients with neuromyelitis optica spectrum disorder (NMOSD), relapses may result in cumulative neurological damage and disability. Disease burden may include pain, sensory, cognitive and visual impairment, bowel/bladder dysfunction, weakness or paralysis, and necessitate caregiver support. Prior to 2019, no therapies had received regulatory approval for NMOSD. Thus, off-label immunosuppressive therapies (IST) were commonly used for maintenance therapy. CIRCLES is a prospective, longitudinal, cross-sectional study of disease epidemiology and treatment in North American patients with NMOSD.

Objectives

This study analyzed real-world disease burden in North American patients with NMOSD enrolled in the CIRCLES study from 2013 to 2019.

Methods

Of 629 CIRCLES participants, 523 (83.1%) with anti-aquaporin-4 immunoglobulin G-positive (AQP4-IgG+) NMOSD were assessed for disease burden, including vision loss, paralysis, annual relapse rate (ARR) relative to mobility level, and steroid side effects.

Results

Baseline assessment of disability indicated at least partial (136/523, 26.0%) or complete (55/523, 10.5%) dependence on caregiver support. Among patients on off-label maintenance IST and having ≥60 days of on-study follow-up (n = 469), 136 (29.0%) experienced a total of 209 on-study relapses. The unadjusted ARR (95% confidence interval [CI]) by mobility level was 0.17 (0.14–0.20), 0.21 (0.16–0.27), and 0.24 (0.16–0.34) for independent, partially dependent, and completely dependent patients, respectively. Side effects from steroids were assessed in 429 respondents, of whom, 35 (8.2%) had gastroesophageal reflux disease, 30 (6.9%) had depression/anxiety, and 28 (6.5%) had osteoporosis. Of 77 patients with on-study relapses and vision assessment, 24 (31.2%) had vision loss (unadjusted ARR, 0.18 [CI, 0.13–0.24]; P > 0.05 vs. no relapses). Furthermore, of 129 patients with on-study relapses and paralysis assessment, 68 (52.7%) had partial or complete paralysis (unadjusted ARR, 0.23 [CI, 0.19–0.27]; P = 0.03 vs. no relapses).

Conclusions

NMOSD imposes significant disease burden, including vision loss and paralysis resulting in dependence on caregiver support in over one-third of patients. Despite the use of off-label maintenance ISTs, a substantial proportion of patients with NMOSD continue to experience relapses, disability, and neurological damage. These findings underscore the need for safe, effective, and well-tolerated treatments for preventing relapses.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0696 - Characteristics of Myelin Oligodendrocyte Glycoprotein Antibody Positive Children with Demyelinating Disorders (ID 1565)

Speakers
Presentation Number
P0696
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Myelin oligodendrocyte glycoprotein (MOG) antibodies (ab) are detected in approximately 1/3 of children with demyelinating disease at onset; presentations commonly overlap with optic neuritis, neuromyelitis optica spectrum disorder (NMOSD) or acute disseminated encephalomyelitis. Serum MOG-ab titers have unclear relevance to disease course, and optimal treatment strategy is unknown.

Objectives

We aimed to characterize children with CNS demyelinating disorders who tested positive for MOG-ab. We also aimed to evaluate the relevance of serum MOG-ab titers for diagnosis, risk and severity of subsequent demyelinating events. Finally, we aimed to evaluate treatment strategies for MOG-ab positive children.

Methods

This retrospective study evaluated children with demyelinating disorders with onset before 18 years of age seen at the University of California, San Francisco who tested positive for MOG-ab (tested by live cell-based fluorescent activated cell sorting assay at Mayo Clinic) between October 2006-June 2020. Demographic information, clinical presentation at onset, MRI, CSF, brain biopsy, and treatment data were collected by chart review.

Results

Sixty children were included (mean onset age 8.2 years; 53% female; 72% white; 40% Hispanic or Latino). The most common clinical localization at onset included optic nerve (ON) (53%) and/or brainstem/cerebellum (42%). 83% of initial events were severe. Median EDSS assessed within 6 months of onset was 1.5 (range 0-4). 81% of initial brain MRIs had T2 bright lesions and 61% had gadolinium-enhancing lesions; T2 bright lesions were most commonly seen in subcortical areas (50%) and/or brainstem/cerebellum (33%). Oligoclonal bands were positive in 17% of initial CSF. 57% had initial serum MOG-ab titers ≥1:100 (median time from onset to first titer 15.4 months). Titers ≥1:320 were only observed within 2 months of an event (disease onset or relapse). While 38% had no relapses (mean follow-up 1.42 years), those who did had a median of 2 relapses (mean follow-up 3.83 years). The most commonly used treatments were interferon beta (28%) and rituximab (27%). Brain biopsy was performed in 2 patients and showed overt demyelination and prominent infiltration of monocyte lineage and polymorphonuclear cells.

Conclusions

The most common clinical onset localizations in MOG-ab positive children were ON and brainstem/cerebellum. Higher MOG-ab titers were only observed close to a clinical event.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0697 - Child with MOG antibodies, synringomyelia and MRI mimicking Langerhansian hystiocytosis (ID 1912)

Speakers
Presentation Number
P0697
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Myelin oligodendrocyte glycoprotein antibody (MOG-ab) associated diseases are a distinct nosological entity among central nervous system (CNS) inflammatory diseases such as multiple sclerosis and AQP4-ab neuromyelitis optica spectrum disorder(NMOSD). In children, the clinical spectrum encompasses different phenotypes. Acute disseminated encephalomyelitis (ADEM) remains the most common clinical presentation particularly in young children. Optic neuritis, longitudinaly extensive transverse myelitis and brainstem involvment are the other frequent phenotypes.

Objectives

To report a case of young child with MOG antibodies associated with relapsing disease with syringomyelia and brain MRI lésions mimicking langerhansian histyocytosis.

Methods

A 6 year old girl presented with rapidly progressive balance disorder wich occured few days after viral nasopharyngitis. neurological examination found a statokinetic cerebellar syndrom and moderate visual loss in one eye. In her medical history, the mother described the occurence two years ago of acute bilateral legs weakness and bladder dysfunction with viral infection two weeks earlier. The recovery was complete and spontaneous.The child had follow up since there in neurosurgery because MRI showed syringomyelia evocating lesion.

we performed brain MRI, lumbar puncture, serological and immunological assessment.

Results

Brain MRI found bilateral symetrical cerebellar T2/Flair lesions with gadolinium enhancement, periventricular non specific lésions were also found. Aspect of lesion evocated langerhansian neurohystiocytosis. no evidence of cutaneous or viceral hystiocytosis was found. MOG-ab were positive. IgG olioclonal bands were present in cerebrospinal fluid. the patient recovered after metylprednisolone infusions.

Conclusions

Syringomyelia is described in few cases of AQP4-ab NMOSD, but not in MOG-ab associated diseases. Also, in children with MOG ab, brain MRI usually show ADEM like or brainstem lesions. it is to our knowledge the first case of MOG-ab with these two particular MRI presentations (syringomyelia and neurohystiocytosis mimicking lesions).

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0698 - Clinical and MRI correlates of autonomic dysfunction in neuromyelitis optica spectrum disorder (ID 279)

Speakers
Presentation Number
P0698
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Dysautonomia is common and associated with disease disability or activity in multiple sclerosis. However, in neuromyelitis optica spectrum disorder (NMOSD), the clinical and MRI correlates of autonomic dysfunction are unknown.

Objectives

The aim of this study was to investigate the relationship of autonomic dysfunction and clinical findings in patients with NMOSD.

Methods

A total of 27 patients (mean age, 44.4±12.26 years; female: male=22:5) were enrolled in this study. For the assessment of autonomic dysfunction, hear rate variability (HRV) and blood pressure (BP) measurement to deep breathing, Valsalva maneuver or head tilt-table test, with quantitative sudomotor axon reflex test (QSART) were used and interpreted in the form of the composite autonomic scoring scale (CASS). Clinical and radiological correlates with autonomic profiles were analyzed.

Results

Among the 27 patients, 74.1% (N=20) showed autonomic dysfunction, involving the adrenergic, cardiovagal, and sudomotor domains. Demographics and MRI findings were associated with each index of CASS. The number of attacks showed the association with cardiovagal index (B=0.197, S.E. 0.070, 95% CI 0.051-0.342, p=0.010), corticospinal tract lesion with adrenergic index (B=2.780, S.E. 0.970, 95% CI 0.783-4.777, p=0.008), the involvement of brain and/or spinal cord with total CASS score (B=1.258, S.E. 0.566, 95% CI 0.081-2.434, p=0.037) and male gender with sudomotor index (B=1.317, S.E. 0.425, 95% CI 0.376-2.259, p=0.008). In multivariable analysis, delayed pressure recovery time in the Valsalva maneuver, onset age, and disease activity showed a significant positive association with EDSS score (B=2.177, S.E. 0.758, 95% CI 0.553-3.802, p=0.011; B=0.061, S.E. 0.023, 95% CI 0.014-0.107, p=0.013; B=1.369, S.E. 0.593, 95% CI 0.142-2.596, p=0.030, respectively).

Conclusions

Cardiovascular and sudomotor autonomic dysfunction are common in NMOSD. Several clinical and MRI characteristics of patients may warrant the investigation of autonomic dysfunction and its proper management.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0699 - Clinical and radiological features of a hospital cohort of Neuromyelitis optica. (ID 324)

Speakers
Presentation Number
P0699
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing autoimmune inflammatory disorders of the central nervous system. Hallmark features of NMOSD include acute attacks of bilateral or rapidly sequential optic neuritis or transverse myelitis. Attacks most often occur over days, with variable degrees of recovery over weeks to months

Other suggestive symptoms include episodes of intractable nausea, vomiting, hiccups, excessive daytime somnolence or narcolepsy, reversible posterior leukoencephalopathy syndrome, neuroendocrine disorders, and seizures

The discovery of AQP-4 antibodies supposed a breakthrough for understanding NMOSD. Recently, MOG antibodies have been also related to this entity. However, about 10-50% of NMOSD patients are still seronegative. These patients are a heterogeneous subgroup that may be associated with other autoantibodies

Objectives

To identify main clinical and radiological characteristics

To recognize differences between seropositive and seronegative NMOSD patients

To evaluate safety and effectiveness of Rituximab

Methods

We presented 12 patients diagnosed of NMOSD according revised consensus criteria published in 2015 at Unit of Neuroimmunology and Multiple Sclerosis Unit of Girona, Spain

The data were collected during the course of clinical care. We focused on medical history, neurologic symptoms, MRI features, CSF findings

Rituximab response was assessed using the annualized relapse rate (ARR)

Results

Disease-onset form: optic neuritis 7 (58,3%) 1 of them had bilateral optic neuritis; myelitis 4 (33,3%); brainstem syndrome 1 (8,3%)

Abnormal laboratory findings: 2 patients had positivity for lupus anticoagulant, 1 for TPO-Ab and 1 for ANAs

8 patients were seronegative NMOSD

6 patients (50%) had cognitive impairment

CSF findings: 8 patients had CSF abnormalities include pleocytosis and elevated protein levels. Oligoclonal bands were positive in 4 patients

4 patients were positive for antibodies: AQP-4= 2 / MOG= 2

MRI findings: 4 patients had brain MRI abnormalities that matched with NMOSD pattern, rest of patients had normal or unspecific MRI. Longitudinally extensive spinal cord lesions were observed in 7 patients. Cervical and thoracic segments were most affected

4 patients had positivity for other antibodies. 3 of them are seronegative NMOSD

Of 4 seropositive patients, 3 had cognitive impairment

Of 4 patients with presence of CSF oligoclonal bands, 3 were seronegative NMOSD

ARR before Rituximab: 1,25 and ARR after Rituximab: 0,27

No patient had serious adverse events after Rituximab treatment. Rituximab was discontinued in 1 patient due to an allergic reaction

Conclusions

Seronegative NMOSD has a prevalence up to 60% and it could be related with presence of other serum antibodies and with positivity for CSF oligoclonal bands

Cognitive impairment is frequent in NMOSD and can be more prevalent in seropositive patients

Rituximab is safe and effective to reduce ARR

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0700 - Clinical characteristics of neuromyelitis optica spectrum disorder and multiple sclerosis in Iranian pediatric patients (ID 552)

Speakers
Presentation Number
P0700
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Patients with Neuromyelitis optica spectrum disorder (NMOSD) and Multiple sclerosis (MS) usually experience first symptoms between 20 to 40 years of age. However, the onset of these disease rarely can occur in pediatrics population. Few data are available for patients with pediatric onset of NMOSD (PO-NMOSD) and MS (POMS).

Objectives

To survive the clinical characteristics, outcome, and predictive factors of disability in PO-NMOSD, and compared to patients with POMS.

Methods

This retrospective follow up study was performed evaluating 18 patients with PO-NMOSD and 144 PMS patients presenting at MS clinic, Kashani Hospital, affiliated to the Isfahan University of Medical Sciences, Isfahan, Iran. All cases were ascertained and diagnosed by a neurologist with subspecialty training in MS and NMOSD.

Results

In PO-NMOSD group, female to male ratio was 8.0:1; the mean age of onset was 14.77±2.23; age at last visit was 21.06±5.42; and median (IQR) follow-up was 6.0 (3.0, 11.0). The mean of first and last EDSS were 2.47±1.16 and 2.11±2.01; twelve (66.6%) patients had relapsing course; the median of first inter-attack was 3.0 (1.0, 4.0); and a total of 38 attacks (2.11 attack per patient) were recorded. Up to now, five (27.8%) patients reach EDSS ≥3. Three patients received azathioprine and other were treated by rituximab. For individuals with POMS, female/male ratio was 3.5:1; the mean age of onset was 14.84±2.35; age at last visit was 24.08±7.29; and median follow-up was 8.0 (4.2, 14.0). The mean of first and last EDSS were 1.68±1.20 and 1.44±1.85; no patient had primary progressive course and 20 (13.8%) patients converted to secondary progressive course; the median of first inter-attack interval was 2.0 (1.0, 4.0); and a total of 317 attacks (2.20 attacks per patient) were recorded. Until now, 34 (23.6%) patients reach EDSS ≥3. Most patients received beta interferon (47), fingolimod (23), and rituximab (23). There was statistically significant difference between the groups in the term of first EDSS score (p=0.019). In both groups, multivariate analysis shows significant association between the age at last visit, firs EDSS, disease duration with higher EDSS score at last appointment. The survival curves showed that PO-NMOSD patients reach to EDSS ≥3 earlier than POMS, though the difference was not statistically significant.

Conclusions

Patients with pediatric onset NMOSD and MS show specific features and prognosis, which should be taken in consideration for the diagnosis and treatment.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0701 - Clinical characteristics of Neuromyelitis optica spectrum disorder Peruvian patients: a government-run tertiary level neurological center cohort (ID 1567)

Presentation Number
P0701
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon antibody-mediated disease of the central nervous system. It’s characterized by severe demyelination and axonal damage predominantly targeting optic nerves and spinal cord. The reported incidence and prevalence of NMOSD are dependent on geographical location and ethnicity. There are only case reports of the disease in Peru, but no study reported epidemiological or clinical data.

Objectives

We aim to describe the principal clinical characteristics of Peruvian patients with positive (P-NMOSD) and other (O-NMOSD) aquaporin-4 antibody serostatus (negative, N-NMOSD, or unknown, U-NMOSD) at disease onset.

Methods

We retrospectively reviewed medical records and applied 2015 NMOSD diagnostic criteria to all NMOSD patients who were diagnosed at the Instituto Nacional de Ciencias Neurológicas between 2013 and 2018. Mean and percentages were used to describe the variables. Data between groups were compared by Fisher’s exact test and Mann-Whitney U test for categorical and continuous data, respectively.

Results

We included 23 P-NMOSD, 35 O-NMOSD patients (14 N-NMOSD and 21 U-NMOSD). Mean age at onset was 46.78 years (P-NMOSD 53.35 and O-NMOSD 42.46, p=0.0135). No differences in sex, number of relapses, time to diagnosis and initial syndromes were observed between groups. Regarding the presence of core clinical characteristics, we found differences in the presence of acute myelitis and symptomatic cerebral syndrome. When the spinal cord was affected, differences between groups were found regarding longitudinal extensive transverse myelitis and dorsal spinal cord involvement. Simultaneous optic neuritis and acute myelitis was the first presentation in 4% of P-NMOSD and 20% of O-NMOSD patients (p=0.094).

Conclusions

We described the first cohort of Peruvian NMOSD patients. Clinical characteristics were similar to other studies. P-NMOSD patients were older than O-NMOSD. O-NMOSD had more involvement of spinal cord compared with P-NMOSD with dorsal spinal cord involvement and presence of longitudinal extensive transverse myelitis.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0702 - Clinical characteristics of neuromyelitis optica spectrum disorders in a Spanish population. (ID 345)

Speakers
Presentation Number
P0702
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Neuromyelitis optica-spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS). It may be reccurent in time. It preferably affects the optic nerve and spinal cord . Several antibodies like aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody have been involved in its pathophisiology. Currently, there is several immunomodulatory treatments that seem effective stopping disease progression. Thus, made a early diagnostic is essentially in the prognosis of the disease.

Objectives

To describe the baseline characteristics of Southwestern-european population cohort of patients diagnosed with NMOSD

Methods

Retrospective observational study in patients diagnosed with NMOSD from January 2015 to May 2020 at Virgen Macarena Hospital, Seville, Spain. Demographic/disease characteristics, previous DMTs, adverse events, changes in disability, and cerebral MRI findings were collected at enrolment.

Results

16 patients were diagnosed with NMOSD in accordance with 2015 International Panel for NMO Diagnosis criteria. All of them were womens. Average age 49 (10.6,SD). Mean time since clinical onset was 6,34 years (3.7,SD) Diagnostic delay was 3 years (3,SD). 11 patients were AQP4 antibody positive by indirect inmunofluorescence (IIF) assay (69%). 5 of patients were AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies seronegative (31%). 3 patiens had oligoclonals bands in LCR (19%)

Mean EDSS increased from 4 to 4.1 after a mean follow-up of 3.34 years.

7 patients are treated with Rituximab (RTX)(44%), 6 patients with Azathioprine (AZT) (38%), 1 patients receive intravenous inmunoglobuline(6%) and two patients have not maintenance treatment (13%). One patient has presented one clinical relapse since current treatment administration(6%) Mean 2.98 years.

Longitudinally extensive transverse myelitis (LETM) was responsible for clinical onset in 8 patients (50%). 6 patients (37,5%) sought medical attention for first time due to Unilateral optic Neuritis, 1 patient had LETM and optic neuritis and 1 patient presented a isolated area postrema syndrome (intractable hiccups and vomiting).

Conclusions

Our sample presents similar characteristics than other populations published. The current inmunotherapy agents seem to be a safe and effective treatment for control disease progression. Thus, an acute and early diagnostic would be related with a better outcome.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0703 - Clinical, radiological features and management of twenty patients diagnosed with anti-MOG demyelinating syndrome in a tertiary referral centre. (ID 1857)

Speakers
Presentation Number
P0703
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

Background

Myelin Oligodendrocyte Glycoprotein (MOG) – antibody demyelinating disease has emerged as a distinct clinical entity in recent years. Prevalence is also likely higher than previously recognized. MOG antibody testing is standard of care in new presentations, however a significant population remains undiagnosed. Identifying this cohort requires clinical vigilance.

Objectives

To characterize the clinical course, treatment and outcomes in 20 patients diagnosed with MOG demyelinating syndrome between 2018 and 2020.

Methods

We evaluated clinical phenotype, demographic data, historical episodes and radiological findings in 20 patients attending the demyelination clinic in our institution who tested positive for myelin oligodendrocyte glycoprotein between 2018 and 2020. This patient cohort included new presentations with optic neuritis and myelitis and patients with a previous diagnosis of multiple sclerosis and chronic relapsing idiopathic optic neuropathy.

Results

52% of the cohort were female. The median age at diagnosis was 35 years, however the median age at initial clinical presentation was 22.5 years (age range 4-60). 70% had optic neuritis as their initial presenting complaint. 95% had clinical or radiological evidence of optic neuritis during their clinical course. ADEM had occurred in 3/4 patients who had presented before the age of 10. Recurrence was common - 75% of the cohort had subsequent clinical episodes. 65% of those with recurrence had a second event within six months of presentation. The longest duration between first and second clinical episodes was 25 years. 60% of the cohort had CSF sampling and OCBs were negative in all cases. Long term antibody positivity despite clinical and radiological quiescence was common. Radiological features included retrobulbar high signal of the optic nerves, chiasmal atrophy, leptomeningeal enhancement and spinal cord lesions. Resolution of radiological features was common.

Conclusions

MOG antibody associated demyelination frequently presents with optic neuritis. Recurrence is common and can occur many years after the initial presentation, making long term management challenging. There is an excellent response to steroids in the acute phase. Asymptomatic optic nerve lesions and cord lesions do occur, and imaging of the neuraxis at presentation should be considered. Consideration should be given to MOG antibody testing in patients transitioning to adult MS services from the paediatric population. The role of longer-term immunosuppression in the cohort is typically reserved for those with recurrence.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0704 - Cortical involvement  in MOG IgG–positive patients : a multicenter MRI study (ID 1853)