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The article presents a study which aims to conduct retrospective cohort study to estimate the perception and risk awareness of multiple sclerosis (MS) patients which treated motoxantrone in Hamburg, Germany. The study made use of an wilcoxon rank-sum test to compare knowledge and risk awareness before reading the brochure.The results of the study show that the accuracy of LK risk estimation increased by reading the information.

Objectives: Compelling evidence indicates a significant involvement of cortical lesions in the progressive phase of multiple sclerosis (MS), significantly contributing to late-stage disability. Despite the promise of ultra-high-field magnetic resonance imaging (MRI) in detecting cortical lesions, current evidence falls short in providing insights into the existence of such lesions during the early stages of MS or their underlying cause. This study delineated, at the early stage of MS, (1) the prevalence and spatial distribution of cortical lesions identified by 7 T MRI, (2) their relationship with white matter lesions, and (3) their clinical implications., Materials and Methods: Twenty individuals with early-stage relapsing-remitting MS (disease duration <1 year) underwent a 7 T MRI session involving T1-weighted MP2RAGE, T2*-weighted multiGRE, and T2-weighted FLAIR sequences for cortical and white matter segmentation. Disability assessments included the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite, and an extensive evaluation of cognitive function., Results: Cortical lesions were detected in 15 of 20 patients (75%). MP2RAGE revealed a total of 190 intracortical lesions (median, 4 lesions/case [range, 0-44]) and 216 leukocortical lesions (median, 2 lesions/case [range, 0-75]). Although the number of white matter lesions correlated with the total number of leukocortical lesions ( r = 0.91, P < 0.001), no correlation was observed between the number of white matter or leukocortical lesions and the number of intracortical lesions. Furthermore, the number of leukocortical lesions but not intracortical or white-matter lesions was significantly correlated with cognitive impairment ( r = 0.63, P = 0.04, corrected for multiple comparisons)., Conclusions: This study highlights the notable prevalence of cortical lesions at the early stage of MS identified by 7 T MRI. There may be a potential divergence in the underlying pathophysiological mechanisms driving distinct lesion types, notably between intracortical lesions and white matter/leukocortical lesions. Moreover, during the early disease phase, leukocortical lesions more effectively accounted for cognitive deficits., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Progression independent of relapse activity (PIRA) has been described since the early stage of relapsing multiple sclerosis (RMS). However, little is known about the relation between PIRA and inflammatory activity that is particularly important at this stage of the disease., Method: We included 110 patients in a prospective study within 18 months of RMS onset. MRI examinations and clinical visits were scheduled on the same day for months 0, 6, 12, 24, 36, 60, 84, 120, 180 and 240., Results: The mean (SD) age of patients was 30 (6.7) years at inclusion and median (range) follow-up 15 (9-20) years. Analysis of 1118 between-visit intervals revealed 93 confirmed disability accumulation events in 68 (62%) patients: 50 (54%) events related to relapse activity worsening and 43 (46%) PIRA events, including 17 (18%) with MRI activity. The risk of PIRA between two visits (stable event as the reference category) was associated with Expanded Disability Status Scale (EDSS) score (HR: 1.41; 95% CI: 1.18 to 1.69; p<0.001), disease duration (HR: 0.75; 95% CI: 0.62 to 0.90; p<0.005) and new lesions between the visits (HR: 1.09 per lesion; 95% CI: 1.01 to 1.17; p<0.05). As compared with PIRA events with MRI activity, PIRA events without such activity occurred in patients with more disability (mean EDSS score 3, p<0.05), longer disease duration (mean 11 years, p<0.001) and greater number of T2-weighted lesions (p<0.05)., Conclusion: This study evidenced that inflammatory activity increases the risk of PIRA in early RMS, arguing that a significant part of PIRA is accessible to treatment targeting inflammation in these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein IgG-associated disease (MOGAD). This study evaluated the applicability of optical coherence tomography (OCT) for differentiating between both diseases in two independent cohorts., Methods: One hundred sixty two patients from seven sites underwent standard OCT and high-contrast visual acuity (HCVA) testing at least 6 months after first ON. Of these, 100 patients (32 MOGAD, 68 MS) comprised the primary investigational cohort, while 62 patients (31 MOGAD, 31 MS) formed a validation cohort. A composite score distinguishing between MOGAD and MS was developed using multivariate logistic regression., Results: Bilateral simultaneous ON occurred more frequently in MOGAD compared to MS (46.9 vs. 11.8%, p < 0.001). OCT revealed more peripapillary retinal nerve fiber layer (pRNFL) atrophy in all segments in MOGAD compared to predominantly temporal pRNFL atrophy in MS (p < 0.001). HCVA was better preserved in MS (p = 0.007). pRNFL thickness in all except for temporal segments was suitable for differentiating MOGAD and MS. Simultaneous bilateral ON and critical atrophy in nasal (< 58.5 µm) and temporal superior (< 105.5 µm) segments were included into the composite score as three independent predictors for MOGAD. The composite score distinguished MOGAD from MS with 75% sensitivity and 90% specificity in the investigational cohort, and 68% sensitivity and 87% specificity in the validation cohort., Conclusion: Following a single ON-episode, MOGAD exhibits more pronounced global pRNFL atrophy and lower visual acuity after ON compared to MS. The introduced OCT-based composite score enabled differentiation between the two entities across both cohorts., (© 2024. The Author(s).)

Background: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD., Methods: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses., Results: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance., Conclusions: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions., Competing Interests: Competing interests: SP, CStern, SJ, MK-K, VH, J-PS, MG, RS, JRK, AW, FTB, PSS and BK report no disclosures relevant to the manuscript. TK has received speaker honoraria and/or personal fees for advisory boards from Merck, Roche Pharma, Alexion/Astra Zeneca, Horizon, Chugai and Biogen. JH reports grants from the Friedrich-Baur-Stiftung, Merck and Horizon, personal fees and non-financial support from Alexion, Horizon, Roche, Merck, Novartis, Biogen, BMS and Janssen, and non-financial support from the Guthy-Jackson Charitable Foundation and The Sumaira Foundation. DE received speaker honoraria from Alexion and Horizon/Amgen. BW received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck, Novartis and personal fees from Alexion, INSTAND, Roche. MS has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Horizon, Roche and Sanofi Genzyme. CW has received institutional support from Novartis, Alexion, Sanofi Genzyme, Biogen, Merck, Roche and Hexal. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer and Merck all outside the submitted work. LK received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis, Roche and Viatris. She received speaker honoraria and travel support from Argenx, Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. She receives research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis and Merck Serono. OA reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics and Zambon. MR received speaker honoraria from Novartis, Bayer Vital, Roche, Alexion, Horizon and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Horizon and Merck, none related to this study. IA has received research support from Diamed and Chugai, speaking honoraria, travel grants and compensation for serving on a scientific advisory board from Alexion, Horizon, Roche, Merck and Sanofi-Aventis/Genzyme, all unrelated to this study. CSchwake has received speaker honoraria from Alexion and travel support from Novartis and UCB. All not related to the content of this manuscript. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi. RR received speaking honorar from Roche unrelated to this study. PS received travel reimbursement by UCB. JB-S has received research support from NEMOS e.V. and Bayer AG, personal compensation from Alexion, speaking honoraria and travel grants from Bayer Healthcare, Horizon, Novartis and Sanofi-Aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Roche and Merck, all unrelated to the presented work. FP receives honoraria for lecturing, and travel expenses from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, Celgene and support for attending meetings from Alexion. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel and Almirall. FP serves on advisory boards and steering committees for Celgene, Roche, UCB and Merck and is associate editor of Neurology, Neuroimmunology & Neuroinflammation and academic editor for PLoS ONE. CT has received honoraria for consultation and expert testimony from Alexion Pharma Germany. None of this interfered with the current report. MWH received research support from Myelitis e. V., speaker honoraria from selpers og, Horizon, and Alexion, and reimbursement of travel expenses and compensation for serving on an advisory board from Alexion. None of this interfered with the current manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Retinal optical coherence tomography has been identified as biomarker for disease progression in relapsing-remitting multiple sclerosis (RRMS), while the dynamics of retinal atrophy in progressive MS are less clear. We investigated retinal layer thickness changes in RRMS, primary and secondary progressive MS (PPMS, SPMS), and their prognostic value for disease activity. Here, we analyzed 2651 OCT measurements of 195 RRMS, 87 SPMS, 125 PPMS patients, and 98 controls from five German MS centers after quality control. Peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL) thickness predicted future relapses in all MS and RRMS patients while mRNFL and ganglion cell-inner plexiform layer (GCIPL) thickness predicted future MRI activity in RRMS (mRNFL, GCIPL) and PPMS (GCIPL). mRNFL thickness predicted future disability progression in PPMS. However, thickness change rates were subject to considerable amounts of measurement variability. In conclusion, retinal degeneration, most pronounced of pRNFL and GCIPL, occurs in all subtypes. Using the current state of technology, longitudinal assessments of retinal thickness may not be suitable on a single patient level., (© 2024. The Author(s).)

Background and Purpose: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS., Materials and Methods: We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T ( n  = 19) or 7T ( n  = 10) MR imaging, serum ( n  = 23) and CSF ( n  = 15) neurofilament light chains, and clinical ( n  = 29) and electrophysiologic ( n  = 27) assessments. The control group had equivalent 3T ( n  = 25) or 7T ( n  = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies ( n  = 29 patients, n  = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed., Results: We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy ( P  = .003) and FLAIR corticospinal tract hypersignal anomalies ( P  = .033), correlated positively with serum neurofilament light chains., Conclusions: Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels., (© 2024 by American Journal of Neuroradiology.)

Objective: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age., Methods: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS)., Results: We included 483 patients: 298 AQP4-IgG + NMOSD, 52 AQP4-IgG - /MOG-IgG - NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG - /MOG-IgG - NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG + NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time., Interpretation: AQP4-IgG + NMOSD, AQP4-IgG - /MOG-IgG - NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Autologous hematopoietic stem cell transplantation (aHSCT) exhibits promising results for multiple sclerosis (MS) in the short term. We investigated the long-term outcome differences in disease progression and cognitive impairment after aHSCT and alemtuzumab treatment., Methods: 20 patients receiving aHSCT and 21 patients treated with alemtuzumab between 2007 and 2020 were included in this monocentric observational cohort study. The primary objective was to compare the outcome of both groups with regards to achieving No Evidence of Disease Activity (NEDA-3), defined by the absence of relapses, EDSS progression, and MRI activity. Secondary endpoints in the study included the assessment of neurocognitive functioning, quality of life (QoL), Multiple Sclerosis Functional Composite (MSFC), and EDSS improvement., Results: Baseline characteristics between both groups were comparable, except for a longer disease duration in the alemtuzumab group of 11.3 years compared to 5.4 years in aHSCT-treated patients (p = 0.002) and a longer mean follow-up time in the aHSCT cohort of 9.0 (range 2.8-15.7) years compared to 5.9 years (range 0.9-9.2) in alemtuzumab patients. NEDA-3 was more frequently observed in the aHSCT group with 75.0 % and 55.0 % at five and 10 years, respectively, than in the alemtuzumab group with only 40.0 % at five years (p = 0.012). Relapse free survival was higher in the aHSCT group (p < 0.001). None of the aHSCT-treated patients showed new T2-lesions six months after therapy initiation until the end of the observational period in contrast to 35.0 % of the alemtuzumab-treated patients showing new T2-lesions (95 %CI 14.2-98.9, p = 0.002). aHSCT-treated patients showed significantly improved cognitive performance in five out of 12 cognitive tests whereas alemtuzumab treated patients deteriorated in four out of 12 tests. Quality of life remained on a constant level for up to 10 years in patients receiving aHSCT with improved scores for the subscale fatigue (p = 0.013)., Conclusion: aHSCT seems to be superior to alemtuzumab in maintaining long-term NEDA-3 status, improving cognition and stabilizing quality of life for up to 10 years., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

This manuscript presents practical recommendations for managing acute attacks and implementing preventive immunotherapies for neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease that causes severe inflammation in the central nervous system (CNS), primarily affecting the optic nerves, spinal cord, and brainstem. The pillars of NMOSD therapy are attack treatment and attack prevention to minimize the accrual of neurological disability. Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) are a diagnostic marker of the disease and play a significant role in its pathogenicity. Recent advances in understanding NMOSD have led to the development of new therapies and the completion of randomized controlled trials. Four preventive immunotherapies have now been approved for AQP4-IgG-positive NMOSD in many regions of the world: eculizumab, ravulizumab - most recently-, inebilizumab, and satralizumab. These new drugs may potentially substitute rituximab and classical immunosuppressive therapies, which were as yet the mainstay of treatment for both, AQP4-IgG-positive and -negative NMOSD. Here, the Neuromyelitis Optica Study Group (NEMOS) provides an overview of the current state of knowledge on NMOSD treatments and offers statements and practical recommendations on the therapy management and use of all available immunotherapies for this disease. Unmet needs and AQP4-IgG-negative NMOSD are also discussed. The recommendations were developed using a Delphi-based consensus method among the core author group and at expert discussions at NEMOS meetings., (© 2023. The Author(s).)

Background: As exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. However, a clear mechanistic link between exercise and disease-modifying effects in MS has yet to be established., Objective: Establish recommendations for future mechanistic exercise studies in MS., Methods: In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research., Results: We concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. Consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies., Conclusion: The resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Neurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood., Methods: We assessed longitudinal changes in visual function, retinal neurodegeneration using optical coherence tomography, MRI and serum NfL (sNfL) levels in a prospective PPMS cohort and matched healthy controls. We investigated the changes over time, correlations between outcomes and with loss of visual function., Results: We followed 81 patients with PPMS (mean disease duration 5.9 years) over 2.7 years on average. Retinal nerve fibre layer thickness (RNFL) was reduced in comparison with controls (90.1 vs 97.8 µm; p<0.001). Visual function quantified by the area under the log contrast sensitivity function (AULCSF) remained stable over a continuous loss of RNFL (0.46 µm/year, 95% CI 0.10 to 0.82; p=0.015) up until a mean turning point of 91 µm from which the AULCSF deteriorated. Intereye RNFL asymmetry above 6 µm, suggestive of subclinical optic neuritis, occurred in 15 patients and was related to lower AULCSF but occurred also in 5 out of 44 controls. Patients with an AULCSF progression had a faster increase in Expanded Disability Status Scale (beta=0.17/year, p=0.043). sNfL levels were elevated in patients (12.2 pg/mL vs 8.0 pg/mL, p<0.001), but remained stable during follow-up (beta=-0.14 pg/mL/year, p=0.291) and were not associated with other outcomes., Conclusion: Whereas neurodegeneration in the anterior visual system is already present at onset, visual function is not impaired until a certain turning point. sNfL is not correlated with structural or functional impairment in the visual system., Competing Interests: Competing interests: MD has financial and intellectual property interests in and holds employment by Adaptive Sensory Technology. MAF has received honoraria as speaker and for consultation from Biogen, Lundbeck, Merck KGaA, Novartis and Roche. His research is funded by the Bundesministerium für Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Landesforschungsförderung Hamburg, Gemeinnützige Hertie-Stiftung, Else Kröner-Fresenius-Stiftung, Fritz Thyssen-Stiftung, Werner Otto-Stiftung and Deutsche Multiple Sklerose-Gesellschaft. HZ received speaking honoraria from Bayer Healthcare and Novartis and research grants from Novartis., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Gait impairment is a relevant problem in persons with multiple sclerosis (pwMS). The Multiple Sclerosis Walking Scale 12 (MSWS-12) is a valid Patient Reported Outcome Measure (PROM) to evaluate walking ability in pwMS. The aim of this study was to provide a linguistically valid translation of MSWS-12 into German language (MSWS-12/D) and to evaluate its psychometric properties., Methods: The MSWS-12 was translated in a process modified from guidelines for the cross-cultural adaption of PROMs, and a pre-test was applied in a small sample of 20 pwMS to evaluate comprehensibility and acceptance. Psychometric properties (floor and ceiling effects, internal consistency, construct validity) were then assessed in 124 pwMS seen at academic MS centers. Construct validity was evaluated against Expanded Disability Status Scale (EDSS) and maximum gait speed in the Timed 25-Foot Walk (T25FW)., Results: Although the sample covered a wide spectrum of symptom severity, the majority had rather low levels of disability (EDSS median 2.0) and 6.5% scored EDSS of 0. In this sample, MSWS-12/D showed floor effects (36% with score 0) and for internal consistency, a Cronbach's alpha of 0.98 was calculated. MSWS-12/D score showed a relevant correlation to EDSS (ρ = 0.73) and T25FW speed (r=-0.72)., Conclusion: We provide MSWS-12/D as a linguistically valid German version of MSWS-12. Psychometric properties (acceptance, floor and ceiling effects, internal consistency and construct validity) in pwMS were similar to those described for the original version. This indicates that MSWS-12/D can be applied as equivalent to the original version in German speaking pwMS. Results support the relevance of PROMs to capture patient perception of walking ability in addition to performance-based assessments such as maximum walking speed or maximum walking distance., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Neurodegeneration leads to continuous accumulation of disability in progressive Multiple Sclerosis (MS). Exercise is considered to counteract disease progression, but little is known on the interaction between fitness, brain networks and disability in MS., Objective: The aim of this study to explore functional and structural brain connectivity and the interaction between fitness and disability based on motor and cognitive functional outcomes in a secondary analysis of a randomised, 3-month, waiting group controlled arm ergometry intervention in progressive MS., Methods: We modelled individual structural and functional brain networks based on magnetic resonance imaging (MRI). We used linear mixed effect models to compare changes in brain networks between the groups and explore the association between fitness, brain connectivity and functional outcomes in the entire cohort., Results: We recruited 34 persons with advanced progressive MS (pwMS, mean age 53 years, females 71%, mean disease duration 17 years and an average walking restriction of < 100 m without aid). Functional connectivity increased in highly connected brain regions of the exercise group (p = 0.017), but no structural changes (p = 0.817) were observed. Motor and cognitive task performance correlated positively with nodal structural connectivity but not nodal functional connectivity. We also found that the correlation between fitness and functional outcomes was stronger with lower connectivity., Conclusions: Functional reorganisation seems to be an early indicator of exercise effects on brain networks. Fitness moderates the relationship between network disruption and both motor and cognitive outcomes, with growing importance in more disrupted brain networks. These findings underline the need and opportunities associated with exercise in advanced MS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS., Objective: To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project., Methods: An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings., Results: We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM)., Conclusion: Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s), 2023.)

Background and Purpose: The detection of spinal cord lesions in patients with MS is challenging. Recently, the 3D MP2RAGE sequence demonstrated its usefulness at 3T. Benefiting from the high spatial resolution provided by ultra-high-field MR imaging systems, we aimed to evaluate the contribution of the 3D MP2RAGE sequence acquired at 7T for the detection of MS lesions in the cervical spine., Materials and Methods: Seventeen patients with MS participated in this study. They were examined at both 3T and 7T. The MR imaging examination included a Magnetic Imaging in MS (MAGNIMS) protocol with an axial T2*-WI gradient recalled-echo sequence ("optimized MAGNIMS protocol") and a 0.9-mm isotropic 3D MP2RAGE sequence at 3T, as well as a 0.7-mm isotropic and 0.3-mm in-plane-resolution anisotropic 3D MP2RAGE sequences at 7T. Each data set was read by a consensus of radiologists, neurologists, and neuroscientists. The number of lesions and their topography, as well as the visibility of the lesions from one set to another, were carefully analyzed., Results: A total of 55 lesions were detected. The absolute number of visible lesions differed among the 4 sequences (linear mixed effect ANOVA, P = .020). The highest detection was observed for the two 7T sequences with 51 lesions each (92.7% of the total). The optimized 3T MAGNIMS protocol and the 3T MP2RAGE isotropic sequence detected 41 (74.5%) and 35 lesions (63.6%), respectively., Conclusions: The 7T MP2RAGE sequences detected more lesions than the 3T sets. Isotropic and anisotropic acquisitions performed comparably. Ultra-high-resolution sequences obtained at 7T improve the identification and delineation of lesions of the cervical spinal cord in MS., (© 2023 by American Journal of Neuroradiology.)

The term 'neuromyelitis optica spectrum disorders' (NMOSD) is used as an umbrella term that refers to aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica (NMO) and its formes frustes and to a number of closely related clinical syndromes without AQP4-IgG. NMOSD were originally considered subvariants of multiple sclerosis (MS) but are now widely recognized as disorders in their own right that are distinct from MS with regard to immunopathogenesis, clinical presentation, optimum treatment, and prognosis. In part 1 of this two-part article series, which ties in with our 2014 recommendations, the neuromyelitis optica study group (NEMOS) gives updated recommendations on the diagnosis and differential diagnosis of NMOSD. A key focus is on differentiating NMOSD from MS and from myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD), which shares significant similarity with NMOSD with regard to clinical and, partly, radiological presentation, but is a pathogenetically distinct disease. In part 2, we provide updated recommendations on the treatment of NMOSD, covering all newly approved drugs as well as established treatment options., (© 2023. The Author(s).)

Background: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD)., Objective: To assess cognitive performance and changes over time in NMOSD., Methods: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data ( N  = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model., Results: NMOSD patients were impaired in SDMT ( p  = 0.007), MuSIC semantic fluency ( p  < 0.001), and MuSIC congruent speed ( p  < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability ( p Bon  < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD., Conclusions: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Objective: Automated brain volumetric analysis based on high-resolution T1-weighted MRI datasets is a frequently used tool in neuroimaging for early detection, diagnosis, and monitoring of various neurological diseases. However, image distortions can corrupt and bias the analysis. The aim of this study was to explore the variability of brain volumetric analysis due to gradient distortions and to investigate the effect of distortion correction methods implemented on commercial scanners., Material and Methods: 36 healthy volunteers underwent brain imaging using a 3T magnetic resonance imaging (MRI) scanner, including a high-resolution 3D T1-weighted sequence. For all participants, each T1-weighted image was reconstructed directly on the vendor workstation with (DC) and without (nDC) distortion correction. For each participant's set of DC and nDC images, FreeSurfer was used for the determination of regional cortical thickness and volume., Results: Overall, significant differences were found in 12 cortical ROIs comparing the volumes of the DC and nDC data and in 19 cortical ROIs comparing the thickness of the DC and nDC data. The most pronounced differences for cortical thickness were found in the precentral gyrus, the lateral occipital and postcentral ROI (2.69, -2.91% and -2.79%, respectively) while cortical volumes differed most prominently in the paracentral, the pericalcarine and lateral occipital ROI (5.52%, -5.40% and -5.11%, respectively)., Conclusion: Correcting for gradient non-linearities can have significant influence on volumetric analysis of cortical thickness and volume. Since the distortion correction is an automatic feature of the MR scanner, it should be stated by each study that applies volumetric analysis which images were used., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Thaler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Balloon-assisted mechanical angioplasty for cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) has a number of limitations, including transient occlusion of the spastic blood vessel. Comaneci is an FDA-approved device for temporary coil embolization assistance which has recently also been approved for the treatment of distal symptomatic refractory vasospasm. We aimed to report the feasibility, efficacy and safety of our experience with Comaneci angioplasty for refractory distal vasospasm (up to the second segment of the cerebral arteries) following aSAH., Methods: This is a retrospective analysis of a prospective series of 18 patients included between April 2019 and June 2021 with aSAH and symptomatic vasospasm refractory to medical therapy, who were treated using Comaneci-17-asssisted mechanical distal angioplasty. Immediate angiographic results, procedure-related complications, and clinical outcomes were assessed. Inter-rater reliability of the scores was determined using the intraclass correlation coefficient., Results: Comaneci-assisted distal angioplasty was performed in 18 patients, corresponding to 31 target arteries. All distal anterior segments were easily accessible with the Comaneci-17 device. Vasospasm improvement after Comaneci mechanical angioplasty was seen in 22 distal arteries (71%) (weighted Cohen's kappa (κ w ) 0.73, 95% CI 0.69 to 0.93). Vasospasm recurrence occurred in three patients (16.67%) and delayed cerebral infarction in three patients (16.67%), with a mean±SD delay between onset of symptoms and imaging follow-up (MRI/CT) of 32.61±8.93 days (κ w 0.98, 95% CI 0.88 to 1)., Conclusion: This initial experience suggests that distal mechanical angioplasty performed with the Comaneci-17 device for refractory vasospasm following aSAH seems to be safe, with good feasibility and efficacy., Competing Interests: Competing interests: XC and J-FH are consultants for educational work with Rapid Medical., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD)., Methods: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database., Results: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3)., Discussion: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Multiple sclerosis (MS) is an inflammatory and demyelinating disease which leads to impairment in several functional systems including cognition. Alteration of brain networks is linked to disability and its progression. However, results are mostly cross-sectional and yet contradictory as putative adaptive and maladaptive mechanisms were found. Here, we aimed to explore longitudinal reorganization of brain networks over 2-years by combining diffusion tensor imaging (DTI), resting-state functional MRI (fMRI), magnetoencephalography (MEG), and a comprehensive neuropsychological-battery. In 37 relapsing-remitting MS (RRMS) and 39 healthy-controls, cognition remained stable over-time. We reconstructed network models based on the three modalities and analyzed connectivity in relation to the hierarchical topology and functional subnetworks. Network models were compared across modalities and in their association with cognition using linear-mixed-effect-regression models. Loss of hub connectivity and global reduction was observed on a structural level over-years (p < .010), which was similar for functional MEG-networks but not for fMRI-networks. Structural hub connectivity increased in controls (p = .044), suggesting a physiological mechanism of healthy aging. Despite a general loss in structural connectivity in RRMS, hub connectivity was preserved (p = .002) over-time in default-mode-network (DMN). MEG-networks were similar to DTI and weakly correlated with fMRI in MS (p < .050). Lower structural (β between .23-.33) and both lower (β between .40-.59) and higher functional connectivity (β = -.54) in DMN was associated with poorer performance in attention and memory in RRMS (p < .001). MEG-networks involved no association with cognition. Here, cognitive stability despite ongoing neurodegeneration might indicate a resilience mechanism of DMN hubs mimicking a physiological reorganization observed in healthy aging., (© 2022 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Background and Purpose: While conventional MR imaging has limited value in amyotrophic lateral sclerosis, nonconventional MR imaging has shown alterations of microstructure using diffusion MR imaging and recently sodium homeostasis with sodium MR imaging. We aimed to investigate the topography of brain regions showing combined microstructural and sodium homeostasis alterations in amyotrophic lateral sclerosis subgroups according to their disease-progression rates., Materials and Methods: Twenty-nine patients with amyotrophic lateral sclerosis and 24 age-matched healthy controls were recruited. Clinical assessments included disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Patients were clinically differentiated into fast ( n = 13) and slow ( n = 16) progressors according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale progression rate. 3T MR imaging brain protocol included 1 H T1-weighted and diffusion sequences and a 23 Na density-adapted radial sequence. Quantitative maps of diffusion with fractional anisotropy, mean diffusivity, and total sodium concentration were measured. The topography of diffusion and sodium abnormalities was assessed by voxelwise analyses., Results: Patients with amyotrophic lateral sclerosis showed significantly higher sodium concentrations and lower fractional anisotropy, along with higher sodium concentrations and higher mean diffusivity compared with healthy controls, primarily within the corticospinal tracts, corona radiata, and body and genu of the corpus callosum. Fast progressors showed wider-spread abnormalities mainly in the frontal areas. In slow progressors, only fractional anisotropy measures showed abnormalities compared with healthy controls, localized in focal regions of the corticospinal tracts, the body of corpus callosum, corona radiata, and thalamic radiation., Conclusions: The present study evidenced widespread combined microstructural and sodium homeostasis brain alterations in fast amyotrophic lateral sclerosis progressors., (© 2022 by American Journal of Neuroradiology.)

Purpose: AI brain tumour segmentation and brain extraction algorithms promise better diagnostic and follow-up of brain tumours in adults. The development of such tools for paediatric populations is restricted by limited training data but careful adaption of adult algorithms to paediatric population might be a solution. Here, we aim exploring the transferability of algorithms for brain (HD-BET) and tumour segmentation (HD-GLIOMA) in adults to paediatric imaging studies., Method: In a retrospective cohort, we compared automated segmentation with expert masks. We used the dice coefficient for evaluating the similarity and multivariate regressions for the influence of covariates. We explored the feasibility of automatic tumor classification based on diffusion data., Results: In 42 patients (mean age 7 years, 9 below 2 years, 26 males), segmentation was excellent for brain extraction (mean dice 0.99, range 0.85-1), moderate for segmentation of contrast-enhancing tumours (mean dice 0.67, range 0-1), and weak for non-enhancing T2-signal abnormalities (mean dice 0.41). Precision was better for enhancing tumour parts (p < 0.001) and for malignant histology (p = 0.006 and p = 0.012) but independent from myelinisation as indicated by the age (p = 0.472). Automated tumour grading based on mean diffusivity (MD) values from automated masks was good (AUC = 0.86) but tended to be less accurate than MD values from expert masks (AUC = 1, p = 0.208)., Conclusion: HD-BET provides a reliable extraction of the paediatric brain. HD-GLIOMA works moderately for contrast-enhancing tumours parts. Without optimization, brain tumor AI algorithms trained on adults and used on paediatric patients may yield acceptable results depending on the clinical scenario., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Extent and dynamic of neurodegeneration in progressive multiple sclerosis (MS) might be reflected by global and regional brain perfusion, an outcome at the intercept between structure and function. Here, we provide a first insight into the evolution of brain perfusion and its association with disability in primary progressive MS (PPMS) over several years., Methods: Seventy-seven persons with PPMS were followed over up to 5 years. Visits included a 3-T magnetic resonance imaging with pulsed arterial spin labelling perfusion, the Timed 25-Foot Walk, 9-Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and Expanded Disability Status Scale (EDSS). We extracted regional cerebral blood flow surrogates and compared them to 11 controls. Analyses focused on cortical and deep grey matter, the change over time, and associations with disability on the regional and global levels., Results: Baseline brain perfusion of patients and controls was comparable for the cortex (p = 0.716) and deep grey matter (p = 0.095). EDSS disability increased mildly (p = 0.023), whereas brain perfusion decreased during follow-up (p < 0.001) and with disease duration (p = 0.009). Lower global perfusion correlated with higher disability as indicated by EDSS, NHPT, and Timed 25-Foot Walk (p < 0.001). The motor task NHPT showed associations with 20 grey matter regions. In contrast, better SDMT performance correlated with lower perfusion (p < 0.001) in seven predominantly frontal regions, indicating a functional maladaptation., Conclusions: Decreasing perfusion indicates a putative association with MS disease mechanisms such as neurodegeneration, reduced metabolism, and loss of resilience. A low alteration rate limits its use in clinical practice, but regional association patterns might provide a snapshot of adaptive and maladaptive functional reorganization., (© 2022 European Academy of Neurology.)

Background and Objectives: To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database., Results: Two hundred twelve patients (80% women, median age 50 [19-83] years, median disease duration 7 [0-43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0-8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225-68,293 or US dollars [USD] 70,297, 95% CI 60,445-80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65-0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45-0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946-160,336 or USD 153,031, 95% CI 120,296-189,196). The HRQoL revealed a negative correlation to disease severity (ρ = -0.69, 95% CI -0.76 to -0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13-0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL., Discussion: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Cortical and thalamic pathologies have been associated with cognitive impairment in patients with multiple sclerosis (MS). Objective: We aimed to quantify cortical and thalamic damage in patients with MS using a high-resolution T1 mapping technique and to evaluate the association of these changes with clinical and cognitive impairment. Methods: The study group consisted of 49 patients with mainly relapsing-remitting MS and 17 age-matched healthy controls who received 3T MRIs including a T1 mapping sequence (MP2RAGE). Mean T1 relaxation times (T1-RT) in the cortex and thalami were compared between patients with MS and healthy controls. Additionally, correlation analysis was performed to assess the relationship between MRI parameters and clinical and cognitive disability. Results: Patients with MS had significantly decreased normalized brain, gray matter, and white matter volumes, as well as increased T1-RT in the normal-appearing white matter, compared to healthy controls ( p < 0.001). Partial correlation analysis with age, sex, and disease duration as covariates revealed correlations for T1-RT in the cortex ( r = -0.33, p < 0.05), and thalami (right thalamus: r = -0.37, left thalamus: r = -0.50, both p < 0.05) with working memory and information processing speed, as measured by the Symbol-Digit Modalities Test. Conclusion: T1-RT in the cortex and thalamus correlate with information processing speed in patients with MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thaler, Hartramph, Stellmann, Heesen, Bester, Fiehler and Gellißen.)

Background and Objectives: To determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX)., Methods: This prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months., Results: We included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0-36], median Expanded Disability Status Scale 5 [range 0-8], median follow-up 3.5 years [range 1-5.8], and median number of RTX infusions 5 [range 1-9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0-33.1) were free of any infection and 92.0% (95% CI 87.1-97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75-0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05-1.75, p = 0.01)., Discussion: In PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD)., Methods: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab., Results: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD ( p = 0.04; for the brain) and in AQP4-IgG+ NMOSD ( p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy., Discussion: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: As phase III trials have shown interest in innovative but expensive drugs in the treatment of neuromyelitis optica spectrum disorder (NMOSD), data are needed to clarify strategies in the treatment of neuromyelitis optica (NMO). This meta-analysis compares the efficacy of first-line strategies using rituximab (RTX), mycophenolate mofetil (MMF), or azathioprine (AZA), which are still widely used., Methods: Studies identified by the systematic review of Huang et al. (2019) were selected if they considered at least two first-line immunosuppressants among RTX, MMF, and AZA. We updated this review. The Medline, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials databases were queried between November 2018 and April 2020. To be included, the hazard ratio (HR) [95% CI] for the time to first relapse after first-line immunosuppression had to be available, calculable, or provided by the authors., Results: We gathered data from 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). The risk of first relapse after first-line immunosuppression was 1.55 [1.04, 2.31] (p = 0.03) for MMF compared with RTX, 1.42 [0.87, 2.30] (p = 0.16) for AZA compared with RTX, and 0.94 [0.58, 1.54] (p = 0.08) for MMF compared with AZA., Interpretation: The findings suggest that RTX is more efficient than MMF as a first-line therapy. Even if the results of our meta-analysis cannot conclude that RTX has a better efficacy in delaying the first relapse than AZA, the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of RTX., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Although multiple sclerosis (MS) is frequently accompanied by visuo-cognitive impairment, especially functional brain mechanisms underlying this impairment are still not well understood. Consequently, we used a functional MRI (fMRI) backward masking task to study visual information processing stratifying unconscious and conscious in MS. Specifically, 30 persons with MS (pwMS) and 34 healthy controls (HC) were shown target stimuli followed by a mask presented 8-150 ms later and had to compare the target to a reference stimulus. Retinal integrity (via optical coherence tomography), optic tract integrity (visual evoked potential; VEP) and whole brain structural connectivity (probabilistic tractography) were assessed as complementary structural brain integrity markers. On a psychophysical level, pwMS reached conscious access later than HC (50 vs. 16 ms, p < .001). The delay increased with disease duration (p < .001, β = .37) and disability (p < .001, β = .24), but did not correlate with conscious information processing speed (Symbol digit modality test, β = .07, p = .817). No association was found for VEP and retinal integrity markers. Moreover, pwMS were characterized by decreased brain activation during unconscious processing compared with HC. No group differences were found during conscious processing. Finally, a complementary structural brain integrity analysis showed that a reduced fractional anisotropy in corpus callosum and an impaired connection between right insula and primary visual areas was related to delayed conscious access in pwMS. Our study revealed slowed conscious access to visual stimulus material in MS and a complex pattern of functional and structural alterations coupled to unconscious processing of/delayed conscious access to visual stimulus material in MS., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: Dynamic susceptibility contrast (DSC) and arterial spin labeling (ASL) perfusion MRI are applied in pediatric brain tumor grading, but their value for clinical daily practice remains unclear. We explored the ability of ASL and DSC to distinguish low- and high-grade lesions, in an unselected cohort of pediatric cerebral tumors., Methods: We retrospectively compared standard perfusion outcomes including blood volume, blood flow, and time parameters from DSC and ASL at 1.5T or 3T MRI scanners of 46 treatment-naive patients by drawing ROI via consensus by two neuroradiologists on the solid portions of every tumor. The discriminant abilities of perfusion parameters were evaluated by receiver operating characteristic (ROC) over the entire cohort and depending on the tumor location and the magnetic field., Results: ASL and DSC parameters showed overall low to moderate performances to distinguish low- and high-grade tumors (area under the curve: between 0.548 and 0.697). Discriminant abilities were better for tumors located supratentorially (AUC between 0.777 and 0.810) than infratentorially, where none of the metrics reached significance. We observed a better differentiation between low- and high-grade cancers at 3T than at 1.5-T. For infratentorial tumors, time parameters from DSC performed better than the commonly used metrics (AUC ≥ 0.8)., Conclusion: DSC and ASL show moderate abilities to distinguish low- and high-grade brain tumors in an unselected cohort. Absolute value of K2, TMAX, tMIP, and normalized value of TMAX of the DSC appear as an alternative to conventional parameters for infratentorial tumors. Three Tesla evaluation should be favored over 1.5-Tesla., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: Walking disability is one of the most frequent and burdening symptoms of progressive multiple sclerosis (MS). Most of the exercise intervention studies that showed an improvement in mobility performance were conducted in low to moderately disabled relapsing-remitting MS patients with interventions using the legs. However, MS patients with substantial walking disability hardly can perform these tasks. Earlier work has indicated that aerobic arm training might also improve walking performance and could therefore be a therapeutic option in already moderately disabled progressive MS patients. Methods: Patients with progressive MS and EDSS 4-6.5 were randomized using a computer-generated algorithm list to either a waitlist control group (CG) or an intervention group (IG). The IG performed a 12-week home-based, individualized arm ergometry exercise training program. Maximum walking distance as measured by the 6-min walking test (6MWT) was the primary endpoint. Secondary endpoints included aerobic fitness, other mobility tests, cognitive functioning, as well as fatigue and depression. Results: Of n = 86 screened patients, 53 with moderate disability (mean EDSS 5.5, SD 0.9) were included and data of 39 patients were analyzed. Patients in the IG showed strong adherence to the program with a mean of 67 (SD 26.4) training sessions. Maximum work load ( P max ) increased in the training group while other fitness indicators did not. Walking distance in the 6MWT improved in both training and waitlist group but not significantly more in trained patients. Similarly, other mobility measures showed no differential group effect. Cognitive functioning remained unchanged. No serious events attributable to the intervention occurred. Conclusion: Although maximum work load improved, 3 months of high-frequency arm ergometry training of low to moderate intensity could not show improved walking ability or cognitive functioning in progressive MS compared to a waitlist CG. The study was registered at www.clinicaltrials.gov (NCT03147105) and funded by the local MS self-help organization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Heinrich, Rosenthal, Patra, Schulz, Welsch, Vettorazzi, Rosenkranz, Stellmann, Ramien, Pöttgen, Gold and Heesen.)

Objective: Autologous hematopoietic stem cell transplantation (aHSCT) is increasingly recognized as a potential therapy for patients with highly active multiple sclerosis (MS). This study aims to assess outcome differences in disease activity in MS patients treated either with aHSCT or alemtuzumab., Methods: We conducted a monocentric registry-based cohort study by recording the clinical course (EDSS and relapses), MRI parameters (new T2 lesions), and neuropsychological assessment in all 19 MS patients receiving aHSCT, and all 21 patients receiving alemtuzumab between 2007 and 2018. We used survival analyses of no evidence of disease activity (NEDA) as the primary objective which was defined by no EDSS progression, no relapse, and no new T2 lesion on MRI. Secondary objectives were EDSS improvement and neurocognitive performance., Results: Both treatment groups were similar in respect of age, gender, disability, and neurocognitive performance except for significantly longer disease duration in the alemtuzumab group. Mean follow-up was 58.8 [range 29-140] months in the aHSCT group compared to 27.6 [range 11-52] months in the alemtuzumab-treated group. We observed significantly more patients maintaining NEDA in the aHSCT group (p = 0.048) compared to the alemtuzumab-treated patients. Furthermore, 37% of the aHSCT patients showed an improvement of EDSS compared to none in the alemtuzumab-treated group (p = 0.033). It is of note that cognitive function was significantly improved in the aHSCT-treated patients., Interpretation: aHSCT suppresses inflammatory activity more effectively than alemtuzumab and might enable improvement of overall disability and cognition in MS., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: To evaluate prevalence, clinical characteristics, and predictors of pain, depression, and their impact on the quality of life (QoL) in a large neuromyelitis optica spectrum disorder (NMOSD) cohort., Methods: We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers. Patients received questionnaires on demographic and clinical characteristics, PainDetect, short form of Brief Pain Inventory, Beck Depression Inventory-II, and Short Form 36 Health Survey., Results: One hundred twenty-five (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR = 1.27, p = 0.018) and involved upper thoracic segments (OR = 1.31, p = 0.018) were the only predictive factors for chronic pain. The latter was specifically associated with spasticity-associated pain (OR = 1.36, p = 0.002). More than a third (39.8%) suffered from depression, which was moderate to severe in 51.5%. Pain severity (OR = 1.81, p < 0.001) and especially neuropathic character (OR = 3.44, p < 0.001) were associated with depression. Pain severity and walking impairment explained 53.9% of the physical QoL variability, while depression and walking impairment 39.7% of the mental QoL variability. No specific medication was given to 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain. Two-thirds (64.2%) of patients with symptomatic treatment still reported moderate to severe pain., Conclusions: Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine the potential association between infections and rituximab (RTX)-induced hypogammaglobulinemia among patients with CNS inflammatory diseases., Methods: We included in a prospective observational study all consecutive adults with aquaporin 4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) antibody-positive disorders treated with RTX. Dosing schedule was adapted to memory B-cell measurement., Results: We included 48 patients (mean age 47 [SD: 14] years; 77% females; 31 AQP4 positive and 17 MOG positive). The median follow-up was 3.6 years (range: 0.9-8.1 years). The median number of RTX infusions was 8 (range: 2-14). The median dosing interval was 6 months (range: 1.7-13.7 months). Sixty-seven symptomatic infections (SIs) were observed in 26 of 48 (54%) patients, including 13 severe infections in 9 (19%). Urinary and lower respiratory tract infections were the most frequent, representing 42% and 21% of SI. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 3 of 48 (6%) patients. After RTX, 15 (31%), 11 (23%), 3 (6%), and 0 of 48 patients showed sustained IgG level <7, <6, <4, and <2 g/L, respectively. On multivariate Cox proportional hazards analysis, the main variables explaining the risk of SI were the presence of urinary tract dysfunction (hazard ratio [HR] = 34, 95% CI 4-262, p < 0.001), the dosing intervals (HR = 0.98, 95% CI 0.97-0.99, p < 0.001), and the interaction between IgG level and urinary tract dysfunction (HR = 0.67, 95% CI 0.53-0.85, p < 0.005). IgG level <6 g/L during RTX was associated with male sex (HR = 4, 95% CI 1.4-11.4, p < 0.01) and previous immunosuppression (HR = 3.4, 95% CI 1.2-10, p < 0.05)., Conclusions: RTX used as maintenance therapy in CNS inflammatory diseases is frequently associated with reduced IgG level and increases the infection risk of the most vulnerable patients., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)