In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0–6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings.

IMPORTANCE Clinical outcome in multiple sclerosis was suggested to be driven by not only remyelination but also adaptive reorganization. This mechanism needs to be further understood. OBJECTIVE To explore anatomical and functional visual networks in patients with optic neuritis (ON) to assess the relative weight of each connectivity modality to expedite visual recovery.

BackgroundDiffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage.ObjectiveTo evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs).MethodsTwenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs.ResultsAbsolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p < 0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R2 for CSD-PROB (AUC = 0.812; R2 = 0.282) and JHU-TBSS (AUC = 0.756; R2 = 0.262), compared to CON-PROB (AUC = 0.742; R2 = 0.179) and JUEL-TBSS (AUC = 0.719; R2 = 0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUC = 0.796; R2 = 0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods.ConclusionsAll DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false-positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question.

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Background: Over the last few years there has been growing interest in use of visual measures as useful tools for multiple sclerosis (MS) prognosis and tracking. Optic neuritis (ON) being a prevalent and often-presenting symptom of the disease, as well as the high occurrence rate of posterior visual system damage independent of ON (optic radiation lesions), make the visual system a prime candidate for such endeavors. However, while the visual system makes for a convenient model in early stages of MS, processes which may be true in those stages may drastically change as the disease progresses, due to accumulated disease load. Here, we examine whether vision-related tools reflect demyelinative and axonal damage of the visual pathways and may be used for assessment in the clinical setup in progressive multiple sclerosis (MS) patients, in whom disease load may alter the early stage picture. Methods: Forty-eight progressive MS patients, with and without prior optic neuritis (ON), underwent a battery of behavioral tests, visual evoked potential (VEP) tests, optical coherence tomography (OCT), and structural MRI scans, at two time-points. Data were analyzed for stability between visits and for correlation between behavioral and electrophysiological data. Results: All measures were stable between visits. Significant differences were found in all measures between the affected and fellow eyes of ON patients and in VEP latencies between the affected and non-ON eyes. Motion perception differentially correlated with latencies of both ON eyes and with the non-ON eyes. Retinal nerve fiber layer thickness correlated with the latencies of non-ON eyes but not of either ON eye. No difference in lesion load was found between the ON and non-ON patients. Conclusions: ON still leaves its mark in the patient's visual system over time, with all visual measures of the affected eyes notably reduced compared to fellow eyes. Motion perception, reflecting myelination level along the visual pathway, shows its usefulness also in progressive MS. In the non-ON eyes, axonal loss appears to explain prolonged latencies, unlike in ON eyes, where demyelination appears to be the main mechanism. Lastly, the visual measures assessed herein are applicable as valid assessment tools in therapeutic studies.

ObjectiveTo differentiate between visual cortical network topology changes following optic neuritis (ON) stemming from different inflammatory disease types, we used mathematical graph theory-based tools to analyze functional imaging data. MethodsSixty-two patients were recruited into this cross-sectional study, 23 of whom had neuromyelitis optica spectrum disorder (NMOSD) with ON, 18 with clinically isolated syndrome (CIS)-ON, and 21 with other CIS episodes. Twenty-six healthy controls (HCs) were also recruited. All participants underwent resting-state functional MRI. Visual networks were defined using 50 visual regions of interest. Analysis included graph theory metrics, including degree, density, modularity, and local and global efficiency. ResultsVisual network density shows decreased connectivity in all patient groups compared with controls. A higher degree of connections is seen in both ON groups (CIS and NMOSD) compared with the the non-ON group. This pattern is most pronounced in dorsal-lateral regions. Information transfer efficiency and modularity were reduced in both CIS groups, but not in the NMOSD group, compared with the HC group. ConclusionsVisual network density appears affected by the neurologic deficit sustained (ON), and connectivity changes are more evident in dorsal-lateral regions. Efficiency and modularity appear to be associated with the specific disease type (CIS vs NMOSD). Thus, topological cortical changes in the visual system are associated with the type of neurologic deficit within the limits set on them by the underlying pathophysiology. We suggest that cortical patterns of activity should be considered in the outcome of the patients despite the localized nature of ON. Complex network analysis is based on graph theory, a mathematical approach to networks. Briefly, the method requires definition of brain regions as nodes and the search for connections, or edges, between those nodes. These connections, anatomic or functional, can then be thresholded and binarized into connectivity matrices, representing the existence or lack of connection between any 2 nodes in the network. From these matrices, various measures can be extracted to quantify network topology and organization (figure 1).Glossary CIS = clinically isolated syndrome; EDSS = Expanded Disability Status Scale; FEF = frontal eye field; FLAIR = fluid-attenuated inversion recovery; HC = healthy control; NMOSD = neuromyelitis optica spectrum disorder; nON = nonoptic neuritis; ON = optic neuritis; ROI = region of interest; RS-fMRI = resting-state functional MRI.

Posterior cortical atrophy (PCA), a localized neurodegenerative syndrome involving the occipito-parietal cortices, can serve as a good model to elaborate on the consequence of a localized damage on the anatomical and functional connectivity within an affected system. Ten PCA patients and 14 aged-matched controls were enrolled. Structural connectivity was measured via Diffusion Tensor Imaging (DTI) and probabilistic tractography. The optic tracts and radiations and the splenial fibers were delineated and their microstructural properties were evaluated. Functional connectivity was measured by resting state functional MRI (rsfMRI). Voxel-based morphometry (VBM) was used to assess atrophy. Dorsal stream visual functions were tested and correlation between these behavioral data, volume measures, white matter integrity and connectivity were examined. Impaired white matter integrity was evident in patients' optic radiations and occipito-callosal fibers, in the segments located in close proximity to the occipital cortex, suggesting a localized damage. Degeneration did not proceed to the optic tracts, opposing trans-synaptic changes. rsfMRI revealed reduced connectivity within the visual network and between the visual and other related areas such as the frontal eye field. Correlations were found between grey matter volume and spatial perception abilities and between the integrity of the affected fibers and motion perception. White matter involvement in PCA seems to be grey matter dependent. Functional connectivity, on the other hand, showed a more diffuse pattern of damage. Correlations were found between the integrity of the affected fibers and patients' visual abilities suggesting that fiber integrity plays a role in determining behavioral manifestation.

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