Association of retinal vessel pathology and brain atrophy in relapsing-remitting multiple sclerosis.

Background: Optical coherence tomography angiography (OCTA) allows non-invasive assessment of retinal vessel structures. Thinning and loss of retinal vessels is evident in eyes of patients with multiple sclerosis (MS) and might be associated with a proinflammatory disease phenotype and worse prognosis. We investigated whether changes of the retinal vasculature are linked to brain atrophy and disability in MS. Material and methods: This study includes one longitudinal observational cohort (n=79) of patients with relapsing-remitting MS. Patients underwent annual assessment of the expanded disability status scale (EDSS), timed 25-foot walk, symbol digit modalities test (SDMT), retinal optical coherence tomography (OCT), OCTA, and brain MRI during a follow-up duration of at least 20 months. We investigated intra-individual associations between changes in the retinal architecture, vasculature, brain atrophy and disability. Eyes with a history of optic neuritis (ON) were excluded. Results: We included 79 patients with a median disease duration of 12 (interquartile range 2 - 49) months and a median EDSS of 1.0 (0 - 2.0). Longitudinal retinal axonal and ganglion cell loss were linked to grey matter atrophy, cortical atrophy, and volume loss of the putamen. We observed an association between vessel loss of the superficial vascular complex (SVC) and both grey and white matter atrophy. Both observations were independent of retinal ganglion cell loss. Moreover, patients with worsening of the EDSS and SDMT revealed a pronounced longitudinal rarefication of the SVC and the deep vascular complex. Discussion: ON-independent narrowing of the retinal vasculature might be linked to brain atrophy and disability in MS. Our findings suggest that retinal OCTA might be a new tool for monitoring neurodegeneration during MS.

Regulation of the programmed cell death protein 1/programmed cell death ligand 1 axis in relapsing-remitting multiple sclerosis.

The programmed cell death protein 1/programmed cell death ligand 1 axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases, while its role in multiple sclerosis is unclear. Here, we aimed to analyse expression patterns of programmed cell death protein 1 and programmed cell death ligand 1 on peripheral blood mononuclear cells and their soluble variants in multiple sclerosis patients and controls, to determine their correlation with clinical disability and disease activity. In a cross-sectional study, we performed in-depth flow cytometric immunophenotyping of peripheral blood mononuclear cells and analysed soluble programmed cell death protein 1 and programmed cell death ligand 1 serum levels in patients with relapsing-remitting multiple sclerosis and controls. In comparison to control subjects, relapsing-remitting multiple sclerosis patients displayed distinct cellular programmed cell death protein 1/programmed cell death ligand 1 expression patterns in immune cell subsets and increased soluble programmed cell death ligand 1 levels, which correlated with clinical measures of disability and MRI activity over time. This study extends our knowledge of how programmed cell death protein 1 and programmed cell death ligand 1 are expressed in the membranes of patients with relapsing-remitting multiple sclerosis and describes for the first time the elevation of soluble programmed cell death ligand 1 in the blood of multiple sclerosis patients. The distinct expression pattern of membrane-bound programmed cell death protein 1 and programmed cell death ligand 1 and the correlation between soluble programmed cell death ligand 1, membrane-bound programmed cell death ligand 1, disease and clinical factors may offer therapeutic potential in the setting of multiple sclerosis and might improve future diagnosis and clinical decision-making.

Prognostic value of spinal cord lesion measures in early relapsing-remitting multiple sclerosis.

BACKGROUND: Spinal cord (SC) lesions have been associated with unfavourable clinical outcomes in multiple sclerosis (MS). However, the relation of whole SC lesion number (SCLN) and volume (SCLV) to the future occurrence and type of confirmed disability accumulation (CDA) remains largely unexplored. METHODS: In this monocentric retrospective study, SC lesions were manually delineated. Inclusion criteria were: age between 18 and 60 years, relapsing-remitting MS, disease duration under 2 years and clinical follow-up of 5 years. The first CDA event after baseline, determined by a sustained increase in the Expanded Disability Status Scale over 6 months, was classified as either progression independent of relapse activity (PIRA) or relapse-associated worsening (RAW). SCLN and SCLV were compared between different (sub)groups to assess their prospective value. RESULTS: 204 patients were included, 148 of which had at least one SC lesion and 59 experienced CDA. Patients without any SC lesions experienced significantly less CDA (OR 5.8, 95% CI 2.1 to 19.8). SCLN and SCLV were closely correlated (rs=0.91, p<0.001) and were both significantly associated with CDA on follow-up (p<0.001). Subgroup analyses confirmed this association for patients with PIRA on CDA (34 events, p<0.001 for both SC lesion measures) but not for RAW (25 events, p=0.077 and p=0.22). CONCLUSION: Patients without any SC lesions are notably less likely to experience CDA. Both the number and volume of SC lesions on MRI are associated with future accumulation of disability largely independent of relapses.

Retrospective cohort study to devise a treatment decision score predicting adverse 24-month radiological activity in early multiple sclerosis.

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory disease affecting about 2.8 million people worldwide. Disease course after the most common diagnoses of relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) is highly variable and cannot be reliably predicted. This impairs early personalized treatment decisions. Objectives: The main objective of this study was to algorithmically support clinical decision-making regarding the options of early platform medication or no immediate treatment of patients with early RRMS and CIS. Design: Retrospective monocentric cohort study within the Data Integration for Future Medicine (DIFUTURE) Consortium. Methods: Multiple data sources of routine clinical, imaging and laboratory data derived from a large and deeply characterized cohort of patients with MS were integrated to conduct a retrospective study to create and internally validate a treatment decision score [Multiple Sclerosis Treatment Decision Score (MS-TDS)] through model-based random forests (RFs). The MS-TDS predicts the probability of no new or enlarging lesions in cerebral magnetic resonance images (cMRIs) between 6 and 24 months after the first cMRI. Results: Data from 65 predictors collected for 475 patients between 2008 and 2017 were included. No medication and platform medication were administered to 277 (58.3%) and 198 (41.7%) patients. The MS-TDS predicted individual outcomes with a cross-validated area under the receiver operating characteristics curve (AUROC) of 0.624. The respective RF prediction model provides patient-specific MS-TDS and probabilities of treatment success. The latter may increase by 5-20% for half of the patients if the treatment considered superior by the MS-TDS is used. Conclusion: Routine clinical data from multiple sources can be successfully integrated to build prediction models to support treatment decision-making. In this study, the resulting MS-TDS estimates individualized treatment success probabilities that can identify patients who benefit from early platform medication. External validation of the MS-TDS is required, and a prospective study is currently being conducted. In addition, the clinical relevance of the MS-TDS needs to be established.

Lesion location across diagnostic regions in multiple sclerosis.

BACKGROUND: Lesions in the periventricular, (juxta)cortical, and infratentorial region, as visible on brain MRI, are part of the diagnostic criteria for Multiple sclerosis (MS) whereas lesions in the subcortical region are currently only a marker of disease activity. It is unknown whether MS lesions follow individual spatial patterns or whether they occur in a random manner across diagnostic regions. AIM: First, to describe cross-sectionally the spatial lesion patterns in patients with MS. Second, to investigate the spatial association of new lesions and lesions at baseline across diagnostic regions. METHODS: Experienced neuroradiologists analyzed brain MRI (3D, 3T) in a cohort of 330 early MS patients. Lesions at baseline and new solitary lesions after two years were segmented (manually and by consensus) and classified as periventricular, (juxta)cortical, or infratentorial (diagnostic regions) or subcortical-with or without Gadolinium-enhancement. Gadolinium enhancement of lesions in the different regions was compared by Chi square test. New lesions in the four regions served as dependent variable in four zero-inflated Poisson models each with the six independent variables of lesions in the four regions at baseline, age and gender. RESULTS: At baseline, lesions were most often observed in the subcortical region (mean 13.0 lesions/patient), while lesion volume was highest in the periventricular region (mean 2287 µl/patient). Subcortical lesions were less likely to show gadolinium enhancement (3.1 %) than juxtacortical (4.3 %), periventricular (5.3 %) or infratentorial lesions (7.2 %). Age was inversely correlated with new periventricular, juxtacortical and subcortical lesions. New lesions in the periventricular, juxtacortical and infratentorial region showed a significant autocorrelative behavior being positively related to the number of lesions in the respective regions at baseline. New lesions in the subcortical region showed a different behavior with a positive association with baseline periventricular lesions and a negative association with baseline infratentorial lesions. CONCLUSION: Across regions, new lesions do not occur randomly; instead, new lesions in the periventricular, juxtacortical and infratentorial diagnostic region are associated with that at baseline. Lesions in the subcortical regions are more closely related to periventricular lesions. Moreover, subcortical lesions substantially contribute to lesion burden in MS but are less likely to show gadolinium enhancement (than lesions in the diagnostic regions).

Percentage brain volume change in multiple sclerosis mainly reflects white matter and cortical volume.

Brain atrophy in multiple sclerosis (MS), as measured by percentage brain volume change (PBVC) from brain magnetic resonance imaging (MRI), has been established as an outcome parameter in clinical trials. It is unknown to what extent volume changes within different brain tissue compartments contribute to PBVC. We analyzed pairs of MRI scans (at least 6 months apart) in 600 patients with relapsing-remitting MS. Multiple regression revealed that PBVC mainly reflects volume loss of white and cortical gray matter, while deep gray matter and white matter lesions were less represented. Our findings aid the interpretation of PBVC changes in MS.

Somatosensory evoked potentials and magnetic resonance imaging of the central nervous system in early multiple sclerosis.

BACKGROUND: Somatosensory evoked potentials (SSEP) are still broadly used, although not explicitly recommended, for the diagnostic work-up of suspected multiple sclerosis (MS). OBJECTIVE: To relate disability, SSEP, and lesions on T2-weighted magnetic resonance imaging (MRI) in patients with early MS. METHODS: In this monocentric retrospective study, we analyzed a cohort of patients with relapsing-remitting MS or clinically isolated syndrome, with a maximum disease duration of two years, as well as with available data on the score at the expanded disability status scale (EDSS), on SSEP, on whole spinal cord (SC) MRI, and on brain MRI. RESULTS: Complete data of 161 patients were available. Tibial nerve SSEP (tSSEP) were less frequently abnormal than SC MRI (22% vs. 68%, p < 0.001). However, higher EDSS scores were significantly associated with abnormal tSSEP (median, 2.0 vs. 1.0; p = 0.001) but not with abnormal SC MRI (i.e., at least one lesion; median, 1.5 vs. 1.5; p = 0.7). Of the 35 patients with abnormal tSSEP, 32 had lesions on SC MRI, and 2 had corresponding lesions on brain MRI. CONCLUSION: Compared to tSSEP, SC MRI is the more sensitive diagnostic biomarker regarding SC involvement. In early MS, lesions as detectable by T2-weighted MRI are the main driver of abnormal tSSEP. However, tSSEP were more closely associated with disability, which is compatible with a potential role of tSSEP as prognostic biomarker in complementation of MRI.

Multiple sclerosis lesions and atrophy in the spinal cord: Distribution across vertebral levels and correlation with disability.

BACKGROUND: The vast majority of magnetic resonance imaging (MRI) studies on multiple sclerosis (MS) covered the spinal cord (SC), if at all, incompletely. OBJECTIVE: To assess SC involvement in MS, as detectable by whole SC MRI, with regard to distribution across vertebral levels and relation to clinical phenotypes and disability. METHODS: We investigated SC MRI with sagittal and axial coverage. Analyzed were brain and SC MRI scans of 17 healthy controls (HC) and of 370 patients with either clinically isolated syndrome (CIS, 27), relapsing remitting MS (RRMS, 303) or progressive MS (PMS, 40). Across vertebral levels, cross-sectional areas were semiautomatically segmented, and lesions manually delineated. RESULTS: The frequency of SC lesions was highest at the level C3-4. The volume of SC lesions increased from CIS to RRMS, and from RRMS to PMS whereas lesion distribution across SC levels did not differ. SC atrophy was demonstrated in RRMS and, to a higher degree, in PMS; apart from an accentuation at the level C3-4, it was evenly distributed across SC levels. SC lesions and atrophy volume were not correlated with each other and were independently associated with disability. CONCLUSION: SC lesions and atrophy already exist at the stage of RRMS in the whole SC with an accentuation in the cervical enlargement; SC lesions and atrophy are more pronounced in the stage of PMS. Both contribute to the clinical picture but are largely independent.

Gray matter atrophy in relapsing-remitting multiple sclerosis is associated with white matter lesions in connecting fibers.

BACKGROUND: Lesions of brain white matter (WM) and atrophy of brain gray matter (GM) are well-established surrogate parameters in multiple sclerosis (MS), but it is unclear how closely these parameters relate to each other. OBJECTIVE: To assess across the whole cerebrum whether GM atrophy can be explained by lesions in connecting WM tracts. METHODS: GM images of 600 patients with relapsing-remitting MS (women = 68%; median age = 33.0 years, median expanded disability status scale score = 1.5) were converted to atrophy maps by data from a healthy control cohort. An atlas of WM tracts from the Human Connectome Project and individual lesion maps were merged to identify potentially disconnected GM regions, leading to individual disconnectome maps. Across the whole cerebrum, GM atrophy and potentially disconnected GM were tested for association both cross-sectionally and longitudinally. RESULTS: We found highly significant correlations between disconnection and atrophy across most of the cerebrum. Longitudinal analysis demonstrated a close temporal relation of WM lesion formation and GM atrophy in connecting fibers. CONCLUSION: GM atrophy is associated with WM lesions in connecting fibers. Caution is warranted when interpreting group differences in GM atrophy exclusively as differences in early neurodegeneration independent of WM lesion formation.

Cognitive impairment in early MS: contribution of white matter lesions, deep grey matter atrophy, and cortical atrophy.

BACKGROUND: Cognitive impairment (CI) is a frequent and debilitating symptom in MS. To better understand the neural bases of CI in MS, this magnetic resonance imaging (MRI) study aimed to identify and quantify related structural brain changes and to investigate their relation to each other. METHODS: We studied 51 patients with CI and 391 patients with cognitive preservation (CP). We analyzed three-dimensional T1-weighted and FLAIR scans at 3 Tesla. We determined mean cortical thickness as well as volumes of cortical grey matter (GM), deep GM including thalamus, cerebellar cortex, white matter, corpus callosum, and white matter lesions (WML). We also analyzed GM across the whole brain by voxel-wise and surface-based techniques. RESULTS: Mean disease duration was 5 years. Comparing MS patients with CI and CP, we found higher volumes of WML, lower volumes of deep and cortical GM structures, and lower volumes of the corpus callosum (all corrected p values < 0.05). Effect sizes were largest for WML and thalamic volume (standardized ß values 0.25 and - 0.25). By logistic regression analysis including both WML and thalamic volume, we found a significant effect only for WML volume. Inclusion of the interaction term of WML and thalamic volume increased the model fit and revealed a highly significant interaction of WML and thalamic volume. Moreover, voxel-wise and surface-based comparisons of MS patients with CI and CP showed regional atrophy of both deep and cortical GM independent of WML volume and overall disability, but effect sizes were lower. CONCLUSION: Although several mechanisms contribute to CI already in the early stage of MS, WML seem to be the main driver with thalamic atrophy primarily intensifying this effect.

Deep-Learning Generated Synthetic Double Inversion Recovery Images Improve Multiple Sclerosis Lesion Detection.

OBJECTIVES: The aim of the study was to implement a deep-learning tool to produce synthetic double inversion recovery (synthDIR) images and compare their diagnostic performance to conventional sequences in patients with multiple sclerosis (MS). MATERIALS AND METHODS: For this retrospective analysis, 100 MS patients (65 female, 37 [22-68] years) were randomly selected from a prospective observational cohort between 2014 and 2016. In a subset of 50 patients, an artificial neural network (DiamondGAN) was trained to generate a synthetic DIR (synthDIR) from standard acquisitions (T1, T2, and fluid-attenuated inversion recovery [FLAIR]). With the resulting network, synthDIR was generated for the remaining 50 subjects. These images as well as conventionally acquired DIR (trueDIR) and FLAIR images were assessed for MS lesions by 2 independent readers, blinded to the source of the DIR image. Lesion counts in the different modalities were compared using a Wilcoxon signed-rank test, and interrater analysis was performed. Contrast-to-noise ratios were compared for objective image quality. RESULTS: Utilization of synthDIR allowed to detect significantly more lesions compared with the use of FLAIR images (31.4 ± 20.7 vs 22.8 ± 12.7, P < 0.001). This improvement was mainly attributable to an improved depiction of juxtacortical lesions (12.3 ± 10.8 vs 7.2 ± 5.6, P < 0.001). Interrater reliability was excellent in FLAIR 0.92 (95% confidence interval [CI], 0.85-0.95), synthDIR 0.93 (95% CI, 0.87-0.96), and trueDIR 0.95 (95% CI, 0.85-0.98).Contrast-to-noise ratio in synthDIR exceeded that of FLAIR (22.0 ± 6.4 vs 16.7 ± 3.6, P = 0.009); no significant difference was seen in comparison to trueDIR (22.0 ± 6.4 vs 22.4 ± 7.9, P = 0.87). CONCLUSIONS: Computationally generated DIR images improve lesion depiction compared with the use of standard modalities. This method demonstrates how artificial intelligence can help improving imaging in specific pathologies.

Prognostic value of white matter lesion shrinking in early multiple sclerosis: An intuitive or naïve notion?

BACKGROUND AND PURPOSE: New or enlarging T2-hyperintense white matter lesions (WML) are associated with clinical disease progression in multiple sclerosis (MS). The prognostic value of WML shrinking is unclear. Assuming that waning of acute inflammation and repair processes would be the main drivers of WML shrinking, we aimed to assess the prognostic value of WML shrinking in early MS. METHODS: We retrospectively analyzed a cohort of 144 early MS patients with three brain MRI scans at baseline and after 1 and 3 years available. All patients were therapy naïve at baseline and 70.5% of them treated with disease modifying drugs at year 1. We determined the volume of WML shrinking between MRI scans, total WML volumes, number of gadolinium-enhancing and new WML, white matter (WM) and gray matter volumes at each MRI scan. Clinical disability was measured by Expanded Disability Status Scale. We performed the correlation analyses of WML shrinking with other MRI parameters and clinical outcome. RESULTS: White matter lesions shrinking was highly variable between patients and correlated with the initial number of gadolinium-enhancing WML and with WM volume decrease. WML shrinking was not associated with clinical outcome. CONCLUSION: We found no indication of a prognostic value of WML shrinking in early MS patients. WML shrinking seems to be related to waning of acute inflammation.

Automated segmentation of changes in FLAIR-hyperintense white matter lesions in multiple sclerosis on serial magnetic resonance imaging.

Longitudinal analysis of white matter lesion changes on serial MRI has become an important parameter to study diseases with white-matter lesions. Here, we build on earlier work on cross-sectional lesion segmentation; we present a fully automatic pipeline for serial analysis of FLAIR-hyperintense white matter lesions. Our algorithm requires three-dimensional gradient echo T1- and FLAIR- weighted images at 3 Tesla as well as available cross-sectional lesion segmentations of both time points. Preprocessing steps include lesion filling and intrasubject registration. For segmentation of lesion changes, initial lesion maps of different time points are fused; herein changes in intensity are analyzed at the voxel level. Significance of lesion change is estimated by comparison with the difference distribution of FLAIR intensities within normal appearing white matter. The method is validated on MRI data of two time points from 40 subjects with multiple sclerosis derived from two different scanners (20 subjects per scanner). Manual segmentation of lesion increases served as gold standard. Across all lesion increases, voxel-wise Dice coefficient (0.7) as well as lesion-wise detection rate (0.8) and false-discovery rate (0.2) indicate good overall performance. Analysis of scans from a repositioning experiment in a single patient with multiple sclerosis did not yield a single false positive lesion. We also introduce the lesion change plot as a descriptive tool for the lesion change of individual patients with regard to both number and volume. An open source implementation of the algorithm is available at http://www.statistical-modeling.de/lst.html.

Accuracy of Unenhanced MRI in the Detection of New Brain Lesions in Multiple Sclerosis.

Background Administration of a gadolinium-based contrast material is widely considered obligatory for follow-up imaging of patients with multiple sclerosis (MS). However, advances in MRI have substantially improved the sensitivity for detecting new or enlarged lesions in MS. Purpose To investigate whether the use of contrast material has an effect on the detection of new or enlarged MS lesions and, consequently, the assessment of interval progression. Materials and Methods In this retrospective study based on a local prospective observational cohort, 507 follow-up MR images obtained in 359 patients with MS (mean age, 38.2 years ± 10.3; 246 women, 113 men) were evaluated. With use of subtraction maps, nonenhanced images (double inversion recovery [DIR], fluid-attenuated inversion recovery [FLAIR]) and contrast material-enhanced (gadoterate meglumine, 0.1 mmol/kg) T1-weighted images were separately assessed for new or enlarged lesions in independent readings by two readers blinded to each other's findings and to clinical information. Primary outcome was the percentage of new or enlarged lesions detected only on contrast-enhanced T1-weighted images and the assessment of interval progression. Interval progression was defined as at least one new or unequivocally enlarged lesion on follow-up MR images. Results Of 507 follow-up images, 264 showed interval progression, with a total of 1992 new or enlarged and 207 contrast-enhancing lesions. Four of these lesions (on three MR images) were retrospectively detected on only the nonenhanced images, corresponding to 1.9% (four of 207) of the enhancing and 0.2% (four of 1992) of all new or enlarged lesions. Nine enhancing lesions were not detected on FLAIR-based subtraction maps (nine of 1442, 0.6%). In none of the 507 images did the contrast-enhanced sequences reveal interval progression that was missed in the readouts of the nonenhanced sequences, with use of either DIR- or FLAIR-based subtraction maps. Interrater agreement was high for all three measures, with intraclass correlation coefficients of 0.91 with FLAIR, 0.94 with DIR, and 0.99 with contrast-enhanced T1-weighted imaging. Conclusion At 3.0 T, use of a gadolinium-based contrast agent at follow-up MRI did not change the diagnosis of interval disease progression in patients with multiple sclerosis. © RSNA, 2019 See also the editorial by Saindane in this issue.

The Trail Making test: a study of its ability to predict falls in the acute neurological in-patient population.

OBJECTIVE: To determine whether tests of cognitive function and patient-reported outcome measures of motor function can be used to create a machine learning-based predictive tool for falls. DESIGN: Prospective cohort study. SETTING: Tertiary neurological and neurosurgical center. SUBJECTS: In all, 337 in-patients receiving neurosurgical, neurological, or neurorehabilitation-based care. MAIN MEASURES: Binary (Y/N) for falling during the in-patient episode, the Trail Making Test (a measure of attention and executive function) and the Walk-12 (a patient-reported measure of physical function). RESULTS: The principal outcome was a fall during the in-patient stay ( n = 54). The Trail test was identified as the best predictor of falls. Moreover, addition of other variables, did not improve the prediction (Wilcoxon signed-rank P < 0.001). Classical linear statistical modeling methods were then compared with more recent machine learning based strategies, for example, random forests, neural networks, support vector machines. The random forest was the best modeling strategy when utilizing just the Trail Making Test data (Wilcoxon signed-rank P < 0.001) with 68% (± 7.7) sensitivity, and 90% (± 2.3) specificity. CONCLUSION: This study identifies a simple yet powerful machine learning (Random Forest) based predictive model for an in-patient neurological population, utilizing a single neuropsychological test of cognitive function, the Trail Making test.