Search

Science has been an important partner of the field of learning disabilities since its inception. Special educators have used science to confirm or reject approaches to identifying and teaching students with disabilities. Current research and practice is using science to find better approaches to preventing learning difficulties and reducing the number of students referred for special education. However, I caution that if we want science to have the desired impact on the educational and social outcomes of students with learning disabilities, we must take care not to misuse it.

Background In multiple sclerosis, grey matter (GM) damage appears more clinically relevant than either white matter damage or lesion load. Objective We investigated if normal-appearing white matter (NAWM) and grey matter tissue changes assessed by magnetization transfer ratio were associated with long-term disability. Methods Sixty-nine people were assessed 20 years after presentation with a clinically isolated syndrome (CIS) [28 still CIS, 31 relapsing-remitting multiple sclerosis, 10 secondary progressive multiple sclerosis], along with 19 healthy subjects. Mean magnetization transfer ratio, peak height (PH) and peak location of the normalized magnetization transfer ratio histograms were determined in NAWM and grey matter, as well as, white matter and GM Fraction (GMF) and T2-weighted lesion load. Results Median expanded disability status scale for multiple sclerosis patients was 2.5 (range 1-8). GM-PH, and less so, NAWM mean and peak location, were lower in multiple sclerosis patients (P = 0.009) versus controls, relapsing-remitting multiple sclerosis versus CIS (P = 0.008) and secondary progressive multiple sclerosis versus relapsing-remitting multiple sclerosis (P = 0.002). GM-PH (as well as GMF) correlated with expanded disability status scale (rs = -0.49; P = 0.001) and multiple sclerosis functional score (rs = 0.51; P = 0.001). GM-PH independently predicted disability with similar strength to the associations of GMF with clinical measures. Conclusion Grey matter damage was related to long-term disability in multiple sclerosis cohort with a relatively low median expanded disability status scale. Markers of intrinsic grey matter damage (magnetization transfer ratio) and tissue loss offer clinically relevant information in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Gadolinium (Gd) enhancement of lesions indicates inflammatory lesion activity in multiple sclerosis (MS). The question arises whether early inflammatory lesion activity — measured sensitively using triple dose Gd — is related to the future clinical course, or to the development of brain atrophy that is thought to reflect the underlying pathological progression of the disease. In this study, 26 patients with early relapsing-remitting (RR) MS (median disease duration: 1.7 years) were followed up over two years. Associations were explored between their levels of Gd-lesion enhancement in the first six months and later clinical (Expanded Disability Status Scale (EDSS) and MS Functional Composite Score (MSFC)) and magnetic resonance imaging (MRI) (brain volume, T2 and T1 lesion volumes) measures. The extent of Gd-enhancement in the first six months correlated weakly with concurrent relapses (P=0.041), but there was no consistent correlation with clinical and MRI outcomes at two years. More prolonged follow-up is warranted to clarify the relationship between early inflammatory lesions and long-term clinical course. [ABSTRACT FROM AUTHOR]

Objective To investigate the presence and evolution of T1 relaxation time abnormalities in normal-appearing white matter (NAWM) and grey matter (GM), early in the course of relapsing-remitting multiple sclerosis (MS). Methods Twenty-three patients with early relapsing-remitting MS and 14 healthy controls were imaged six monthly for up to three years. Mean follow-up was 26 months for MS patients and 24 months for controls. Dual-echo fast-spin echo and gradient-echo proton-density and T1-weighted data sets (permitting the calculation of a T1 map) were acquired in all subjects. GM and NAWM T1 histograms were produced and a hierarchical regression model was used to investigate changes in T1 over time. Results At baseline, significant patient-control differences were seen, both in NAWM (P<0.001) and in GM (P=0.01). At follow-up, there was no evidence for a serial change in either mean T1 or peak-location for either NAWM or GM. There was weak evidence for a decline in patient NAWM peak-height and also evidence for a decline in control GM peak-height. Conclusion There are significant and persistent abnormalities of NAWM and GM T1 in early relapsing-remitting MS. Further studies should address whether such T1 measures have a role in prognosis or therapeutic monitoring. [ABSTRACT FROM AUTHOR]

Presents the studies included in the tournament for young neurologists. Raise serum nitric oxide metabolites and disease activity in multiple sclerosis; Re-stenosis after carotid stent implantation; Deep brain stimulation for refractory temporal lobe epilepsy; Decreased levels of amyloid beta peptide in the brains of smokers; Nuclear clumps as a myopathological hallmark lesion of myotonic dystrophy.

While there is now evidence for thalamic abnormality in established secondary progressive and relapsing–remitting multiple sclerosis (MS), it remains unclear when such abnormality begins. This study investigated the emergence of thalamic abnormality in relapsing–remitting MS by assessing the thalamic magnetization transfer ratio (MTR) in a cohort with clinically early disease. Twenty-three patients with early relapsing–remitting MS (mean age 37; mean disease duration 1.9 years; Expanded Disability Status Scale (EDSS) range 0–3) and 19 healthy controls (mean age 34) were imaged yearly with a magnetization transfer imaging sequence. Twenty-two MS patients and 14 controls completed two-year follow-up. Regions of interest were placed in both thalami and mean thalamic MTR calculated. At baseline, significant differences between patient and control thalamic MTR were not observed. However, at years one and two, the thalamic MTR in patients was significantly lower than control MTR. Although baseline lesion volume did not correlate with baseline thalamic MTR, at year one, an association between baseline lesion volume and year one thalamic MTR emerged. There was also a significant inverse correlation between EDSS and thalamic MTR (r = -0.47, P = 0.02). The study suggests that thalamic involvement occurs within the first five years of MS onset, when most patients are still minimally disabled. [ABSTRACT FROM AUTHOR]

Brain atrophy appears to occur in patients with multiple sclerosis (MS) in excess of that associated with normal ageing, and may be observed early in the clinical course of the disease. The dynamics and tissue specificity of this process remain unclear. This preliminary study explored the evolution of brain grey matter (GM) and white matter (WM) volume loss (as fractions of total intracranial volumes) in 13 subjects with relapsing-remitting MS (mean disease duration 1.9 years at first scan), compared with nine normal control (NC) subjects. Subjects were scanned every six months for 18 months. In MS compared with NC subjects, significant differences in WM fractional volumes were observed at baseline (mean -5.8%, P = 0.008) but no apparent progressive WM tissue loss was detected. In contrast, while no significant differences in GM fractional volumes were observed at baseline, there was significantly greater time-related volume loss in MS compared with NC subjects over the follow-up period (circa -0.0086 per year in MS subjects, -0.0021 per year in the NC subjects, difference P = 0.010). These results suggest that while both GM and WM atrophy are seen early in the clinical course of MS, they may not occur concurrently and may evolve at different rates. [ABSTRACT FROM AUTHOR]

Diffusion tensor magnetic resonance imaging (DTI) reveals measurable abnormalities in normal-appearing brain tissue (NABT) in established multiple sclerosis (MS). However, it is unclear how early this occurs. Recent studies have employed whole brain histogram analysis to improve sensitivity, but concern exists regarding reliability of tissue/cerebrospinal fluid segmentation and possible intersubject brain volume differences, which can introduce partial volume error. To address this, 28 early relapsing-remitting MS subjects [median disease duration 1.6 years; median Expanded Disability Status Scale (EDSS) score 1.5] and 20 controls were compared with whole brain histogram analysis using an automated segmentation algorithm to improve reproducibility. Brain parenchymal volumes (BPV) were estimated for each subject in the analysis. The mean, peak height and peak location were calculated for DTI parameters [fractional anisotropy (FA), mean diffusivity and volume ratio]. An increased FA peak height in MS subject NABTwas observed (P=0.02) accounting for age, gender and BPV. Removing BPV revealed additional abnormalities in NABT. The main conclusions are i) FA peak height is increased in NABT in early MS, ii) partial volume edge effects may contribute to apparent NABT histogram abnormalities, and iii) correction for brain volume differences should reduce potential partial volume edge effects. [ABSTRACT FROM AUTHOR]

Focuses on a study which assessed the disability resulting from multiple sclerosis (MS) 14 years after the presentation of clinically isolated syndromes. Patients and methods; Physiological manifestations of MS; Measurement of metabolites; Level of myo-inositol in MS patients.

Objective: To assess the pathological mechanisms contributing to white matter (WM) lesion expansion or contraction and remyelination in multiple sclerosis (MS)., Methods: We assessed 1,613 lesions in 49 people with relapsing-remitting MS in the CCMR-One bexarotene trial (EudraCT 2014-003145-99). We measured lesion orientation relative to WM tracts, surface-in gradients and veins. Jacobian deformation was used to assess lesion expansion over 6 months, while magnetization transfer ratio (MTR) imaging was used to assess remyelination., Results: At baseline, 33% of lesions were aligned with veins, 2% along WM tracts, 0% with surface-in gradients, and 4% orthogonal to veins. No significant differences were observed in lesion shape, while lesions aligned with surface-in gradients and with veins had lower volume compared to all remaining orientations. At follow-up, 13% of lesions expanded and 7% contracted. The directions for both expansion and contraction were 18% and 8%, respectively, along WM tracts, 20% and 15% parallel to veins, 22% and 23% orthogonal to veins and 0% and 1% along surface-in gradients. Bexarotene had no effect on lesion expansion or contraction, but MTR significantly increased in lesions aligned with surface-in gradients and veins., Interpretation: Lesion expansion and shrinkage are affected by venous and WM tract factors, but these do not influence bexarotene's capacity to promote remyelination. This, instead, appears to be affected by surface-in factors. To limit lesion expansion and maximize tissue repair, multiple processes may need to be targeted., (© 2025 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The first genome-wide significant multiple sclerosis severity locus, rs10191329, has been pathologically linked to cortical lesion load and brain atrophy. However, observational cohorts such as MSBase have not replicated associations with disability outcomes, instead finding other loci. We evaluated rs10191329 and MSBase loci in a unique cohort of 53 people followed for 30 years after a clinically isolated syndrome, with deep clinical phenotyping and MRI measures of inflammation and neurodegeneration. After 30 years, 26 had developed relapsing-remitting multiple sclerosis, 15 secondary progressive multiple sclerosis and 12 remained diagnosed with a clinically isolated syndrome. Genetic associations with disease severity (age-related multiple sclerosis severity score and Expanded Disability Status Scale), disease course and brain MRI features (white matter lesions, cortical lesions and grey matter fraction) were investigated using regression models and survival analyses. rs10191329 was not associated with multiple sclerosis severity, secondary progressive multiple sclerosis diagnosis or brain MRI features at 30 years. Similarly, MSBase loci were not associated with 30-year disease severity, although rs73091975 was significantly associated with lower 14-year age-related multiple sclerosis severity score in those developing multiple sclerosis. Given that effect sizes for both rs10191329 and rs73091975 were greatest between 14 and 20 years, these findings suggest genetic effects on multiple sclerosis severity may interact non-linearly with disease duration., Competing Interests: N.S. has been a clinical research fellow in a post supported by Merck (supervised by S.A.T. and D.C.) and subsequently by MRC (MR/W019906/1); he has received speaker honoraria from Merck. K.C. has received honoraria for participation and attendance of educational events from Novartis, Roche, Biogen and Merck; she has received honoraria for consultancy work from Novartis, Roche, Biogen, Merck and Viatris. F.P. received a Guarantors of Brain fellowship 2017–20. F.P. and B.K. are supported by the National Institute for Health Research (NIHR), Biomedical Research Centre initiative at University College London Hospitals (UCLH). A.J.T. reports personal fees paid to his institution from Eisai Ltd; is an editorial board member for The Lancet Neurology receiving a free subscription; is Editor-in-Chief for Multiple Sclerosis Journal receiving an honorarium from SAGE Publications; receives support for travel as member, from Clinical Trials Committee, from International Progressive MS Alliance and from the National MS Society (USA) as member, NMSS Research Programs Advisory Committee. S.A.T. has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years and co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, UK, which is supported by Merck. W.B. has received speaker honoraria and/or acted as a consultant for Biogen, Janssen, Merck, Neuroxpharm, Novartis, Roche, Sandoz, Sanofi and Viatris. He is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. O.C. is a member of an independent DSMB for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium. C.T. is currently being funded by a Junior Leader La Caixa Fellowship [The project that gave rise to these results received the support of a fellowship from ‘la Caixa’ Foundation (ID 100010434), fellowship code is LCF/BQ/PI20/117600080]. She has also received the 2021 Merck’s Award for the Investigation in Multiple Sclerosis (Spain) and a grant from Instituto de Salud Carlos III (ISCIII), Spain (grant ID: PI21/01860). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK Multiple Sclerosis Society (grant number 77). She has also received speaker honoraria from Roche and Novartis. She serves on the Editorial Board of Neurology and Multiple Sclerosis Journal. F.B. is supported by the UCLH Biomedical Research Centre. He is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. He is a consultant for Roche, Biogen, Merck, IXICO, Jansen and Combinostics. He has research agreements with Merck, Biogen, GE Healthcare and Roche. He is co-founder and shareholder of Queen Square Analytics Ltd. D.C. is a consultant for Hoffmann-La Roche. In the last 3 years, he has been a consultant for Biogen; received research funding from Hoffmann-La Roche, the International Progressive Multiple Sclerosis Alliance, the Multiple Sclerosis Society and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre; and received speaker’s honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, UK, which is supported by Merck. The remaining authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: This meta-analysis aimed to assess the treatment effects of immunotherapies in subgroups of adults with clinically isolated syndrome or relapsing forms of multiple sclerosis (MS) and the effect of potential treatment effect modifiers (TEMs)., Methods: Phase 2 and 3 RCTs with a placebo comparator were analyzed. Risk of bias was assessed. Random-effects meta-analyses were conducted to summarize treatment effects within subgroups and differences in treatment effects between subgroups., Results: Thirty-one studies were included. Age < 40 years was the strongest TEM for relapse rate across DMTs with a ratio of rate ratios (RRR) of 1.44 (95% CI 1.09-1.90; 7 studies). Disability progression was influenced by age (ratio of hazard ratios, RHR 1.59, 95% CI 1.11-2.29; 4 studies). Dichotomizing patients based on EDSS cut-offs (EDSS 2.0 and 3.0) also showed a significantly higher benefit for those less disabled for relapse rate (RRR 1.35, CI 1.03-1.76; 8 studies). Sex, baseline MRI parameters, previous immunotherapy, and clinical presentation showed no effect in this meta-analysis., Conclusion: Age < 40 is a robust TEM for a lower relapse rate as well as less disability progression across six MS immunotherapies. Additionally, a lower baseline EDSS was predictive of the relapse rate., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JR: has received honoraria for consultancy from Mylan, Novartis and Sanofi-Aventis and compensation for lectures and educational presentations from, Merck- Serono, Novartis, Teva, and Sanofi-Aventis DC: is a consultant for Biogen and Hoffmann-La Roche. In the last three years he has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and speaker's honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. MPS: has received Grants (Roche, Novartis, Biogen), Fees for educational events and lectures (Roche, Novartis, Biogen, Merck, Sanofi, Celgene), Support for travelling and participation to meetings (Roche, Novartis, Biogen, Merck, Sanofi, Celgene), Payment for participation on a Data Safety Monitoring Board, Advisory Board, or Guideline Panel (Roche, Novartis, Biogen, Merck, Sanofi, Celgene, GeNeuro, Medday), and that they have been involved in conducting a study funded by Merck that is eligible for inclusion in the review. TF: has received within the past three years personal fees for participation in the Scientific Board and lectures of the JUMPstart programme from Fresenius Kabi, for participation in data monitoring committees from Novartis, Bayer, Janssen, Roche, Daiichi-Sankyo, Boehringer Ingelheim, Coherex Medical and BiosenseWebster, and for statistical consultancies from Novartis, Bayer, CSL Behring, Galapagos, Vifor, Mediconomics, Penumbra, but all outside the submitted work. CH: has received research grants from Roche, Merck, Bristol Myers Squibbs, Sanofi, honoraries for talks from Merck and a travel grant from Celgene. Remaining authors have none declared., (© The Author(s), 2024.)

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated demyelinating disease that is challenging to differentiate from multiple sclerosis (MS), as the clinical phenotypes overlap, and people with MOGAD can fulfil the current MRI-based diagnostic criteria for MS. In addition, the MOG antibody assays that are an essential component of MOGAD diagnosis are not standardized. Accurate diagnosis of MOGAD is crucial because the treatments and long-term prognosis differ from those for MS. This Expert Recommendation summarizes the outcomes from a Magnetic Resonance Imaging in MS workshop held in Oxford, UK in May 2022, in which MS and MOGAD experts reflected on the pathology and clinical features of these disorders, the contributions of MRI to their diagnosis and the clinical use of the MOG antibody assay. We also critically reviewed the literature to assess the validity of distinctive imaging features in the current MS and MOGAD criteria. We conclude that dedicated orbital and spinal cord imaging (with axial slices) can inform MOGAD diagnosis and also illuminate differential diagnoses. We provide practical guidance to neurologists and neuroradiologists on how to navigate the current MOGAD and MS criteria. We suggest a strategy that includes useful imaging discriminators on standard clinical MRI and discuss imaging features detected by non-conventional MRI sequences that demonstrate promise in differentiating these two disorders., (© 2024. Springer Nature Limited.)

Background: Decision-making about treatment when planning a pregnancy (family planning) is complex for women living with multiple sclerosis (MS). Decision tools can help this process, in 2016 MS Trust launched their online digital treatment decision tool to support people with MS., Objectives: To evaluate user-experience of this tool by exploring women's opinions about its content, interface, and usefulness in the context of family planning; and to synthesize recommendations to improve the tool., Methods: Thirty participants qualitatively evaluated the tool using Think Aloud methodology. Sessions were conducted online using Microsoft Teams and were video recorded. Transcription was automated and data were thematically analyzed., Results: Women's first impression was that the tool presented a lot of information at once, which was difficult to take in, and they found it difficult to navigate. Although the tool was helpful in allowing them to compare treatment options, the filters were confusing, and the information related to pregnancy sometimes contradicted advice from their healthcare practitioners. They suggested rewording the pregnancy recommendations and filters, updating some content, and making some changes to the interface to meet users' cognitive needs., Conclusion: The MS Trust treatment decision tool is excellent in helping women with treatment choices at initial diagnosis. However, it is not currently as useful when considering family plans. Recommendations were conveyed to MS Trust where some are now applied to the new live version and the rest are to be considered for future updating projects., Competing Interests: Declan Chard is a consultant for Hoffmann-La Roche. In the last three years he has been a consultant for Biogen, has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, the Medical Research Council, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and a speaker’s honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. He is a trustee of the MS Trust. The rest of authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2024.)

Background and Purpose: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment., Methods: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation-based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test, Timed 25-Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed-effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status., Results: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (β = -0.04, 95% confidence interval [CI] = -0.07 to -0.01, p = 0.015; β = -0.36, 95% CI = -0.67 to -0.06, p = 0.019, respectively)., Conclusions: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501 -positive ( n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), P = 3.8 × 10 -3 ], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), P = 1.27 × 10 -3 ] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), P = 0.031] compared with HLA-DRB1*1501 -negative patients ( n = 35). PVRL2 -positive patients ( n = 41) had more cortical lesions (+0.83 [0.08-1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), P = 2.02 × 10 -3 ], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), P = 0.031] than PVRL2 -negative patients ( n = 18). In contrast, IRX1 -positive ( n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), P = 8.4 × 10 -3 ], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), P = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), P = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), P = 5.02 × 10 -3 ] than IRX1 -negative patients ( n = 30). In multiple sclerosis cases, IRX1 -positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis., Competing Interests: N.S. has been a clinical research fellow in a post supported by Merck (supervised by S.A.T. and D.C.) and subsequently by MRC (MR/W019906/1). K.C has received honoraria for participation and attendance of educational events from Novartis, Roche, Biogen and Merck; she has received honoraria for consultancy work from Novartis, Roche, Biogen, Merck and Viatris. F.P.C. received a Guarantors of Brain fellowship 2017–2020. F.P.C. and B.K. are supported by the National Institute for Health Research (NIHR), Biomedical Research Centre initiative at University College London Hospitals (UCLH). A.J.T. reports personal fees paid to his institution from Eisai Ltd; is an editorial board member for The Lancet Neurology receiving a free subscription; is Editor-in-Chief for MS Journal receiving an honorarium from SAGE Publications; receives support for travel as member, Clinical Trials Committee, International PPMS Alliance, and from the National MS Society (NMSS) (USA) as member, NMSS Research Programs Advisory Committee. S.A.T. receives support from the UCLH Biomedical Research Centre; has received honoraria from Roche, Merck, Novartis, Sanofi-Genzyme and Biogen in the last 3 years and co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. W.B. has received speaker honoraria for educational activities and/or acted as a consultant for Biogen, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Viatris. O.C. is a member of independent data and safety monitoring board for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium. C.T. is currently being funded by a Junior Leader La Caixa Fellowship (The project that gave rise to these results received the support of a fellowship from ‘la Caixa’ Foundation (ID 100010434); fellowship code is LCF/BQ/PI20/117600080; She has also received the 2021 Merck’s Award for the Investigation in MS (Spain) and a grant from Instituto de Salud Carlos III (ISCIII), Spain (grant ID: PI21/01860); In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK Multiple Sclerosis Society (grant number 77); She has also received speaker honoraria from Roche and Novartis; She serves on the Editorial Board of Neurology and Multiple Sclerosis Journal. F.B. is supported by the UCLH biomedical research centre; He is a steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena; He is a consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics; He has research agreements with Merck, Biogen, GE Healthcare, Roche; He is co-founder and shareholder of Queen Square Analytics LTD. D.C. is a consultant for Hoffmann-La Roche; In the last three years he has been a consultant for Biogen, received research funding from Hoffmann-La Roche, the International Progressive Multiple Sclerosis Alliance, the Multiple Sclerosis Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre, and speaker’s honorarium from Novartis; He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. The remaining authors, L.H., R.S., C.A.M.G.W.K. and H.H.: nothing to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Competing Interests: Declaration of Competing Interest J.S, SY.X, DC.T, YY.D, XL.X, S.L, GM.C, FD.S, ZZ.Z, XH.Z and Y.L declared there is no conflict of interest. D.C. is a consultant for Biogen and Hoffmann-La Roche. In the last three years he has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research center, and a speaker's honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. F.B acts as a consultant for Bayer-Schering, Biogen-Idec, GeNeuro, Ixico, Merck-Serono, Novartis and Roche. He has received grants, or grants are pending, from the Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) initiative, the Biomedical Research center at University College London Hospitals, the Dutch MS Society, ECTRIMS–MAGNIMS, EU-H2020, the Dutch Research Council (NWO), the UK MS Society, and the National Institute for Health Research, University College London. He has received payments for the development of educational presentations from Ixico and his institution from Biogen-Idec and Merck. He is on the editorial board of Radiology, Neuroradiology, Multiple Sclerosis Journal and Neurology.

Background: Magnetic resonance imaging (MRI) markers for chronic active lesions in MS include slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs)., Objectives: To identify the relationship between SELs and PRLs in MS, and their association with disability., Methods: 61 people with MS (pwMS) followed retrospectively with MRI including baseline susceptibility-weighted imaging, and longitudinal T1 and T2-weighted scans. SELs were computed using deformation field maps; PRLs were visually identified. Mixed-effects models assessed differences in Expanded Disability Status Scale (EDSS) score changes between the group defined by the presence of SELs and or PRLs., Results: The median follow-up time was 3.2 years. At baseline, out of 1492 lesions, 616 were classified as SELs, and 80 as PRLs. 92% of patients had ⩾ 1 SEL, 56% had ⩾ 1 PRL, while both were found in 51%. SELs compared to non-SELs were more likely to also be PRLs (7% vs. 4%, p = 0.027). PRL counts positively correlated with SEL counts (ρ= 0.28, p = 0.03). SEL + PRL + patients had greater increases in EDSS over time (beta = 0.15/year, 95% confidence interval (0.04, 0.27), p = 0.009) than SEL+PRL-patients., Conclusion: SELs are more numerous than PRLs in pwMS. Compared with either SELs or PRLs found in isolation, their joint occurrence was associated with greater clinical progression.

Objective: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response - measured by change in magnetisation transfer ratio - is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values)., Methods: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level., Results: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel-level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores., Interpretation: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post-processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system with an increasing worldwide prevalence. Since 1993, more than 15 disease-modifying immunotherapies (DMTs) have been licenced and have shown moderate efficacy in clinical trials. Based on the heterogeneity of the disease and the partial effectiveness of therapies, a personalised medicine approach would be valuable taking individual prognosis and suitability of a chosen therapy into account to gain the best possible treatment effect. The primary objective of this review is to assess the differential treatment effects of all approved DMTs in subgroups of adults with clinically isolated syndrome or relapsing forms of MS. We will analyse possible treatment effect modifiers (TEM) defined by baseline demographic characteristics (gender, age), and diagnostic (i.e. MRI measures) and clinical (i.e. relapses, disability level) measures of MS disease activity., Methods: We will include all published and accessible unpublished primary and secondary analyses of randomised controlled trials (RCTs) with a follow-up of at least 12 months investigating the efficacy of at least one approved DMT, with placebo or other approved DMTs as control intervention(s) in subgroups of trial participants. As the primary outcome, we will address disability as defined by the Expanded Disability Status Scale or multiple sclerosis functional composite scores followed by relapse frequency, quality of life measures, and side effects. MRI data will be analysed as secondary outcomes. MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL and major trial registers will be searched for suitable studies. Titles and abstracts and full texts will be screened by two persons independently using Covidence. The risk of bias will be analysed based on the Cochrane "Risk of Bias 2" tool, and the certainty of evidence will be assessed using GRADE. Treatment effects will be reported as rate ratio or odds ratio. Primary analyses will follow the intention-to-treat principle. Meta-analyses will be carried out using random-effects models., Discussion: Given that individual patient data from clinical studies are often not available, the review will allow to analyse the evidence on TEM in MS immunotherapy and thus support clinical decision making in individual cases., Systematic Review Registration: PROSPERO CRD42021279665 ., (© 2022. The Author(s).)

New clinical activity in multiple sclerosis (MS) is often accompanied by acute inflammation which subsides. However, there is growing evidence that a substantial proportion of lesions remain active well beyond the acute phase. Chronic active lesions are most frequently found in progressive MS and are characterised by a border of inflammation associated with iron-enriched cells, leading to ongoing tissue injury. Identifying imaging markers for chronic active lesions in vivo are thus a major research goal. We reviewed the literature on imaging of chronic active lesion in MS, focussing on 'slowly expanding lesions' (SELs), detected by volumetric longitudinal magnetic resonance imaging (MRI) and 'rim-positive' lesions, identified by susceptibility iron-sensitive MRI. Both SELs and rim-positive lesions have been found to be prognostically relevant to future disability. Little is known about the co-occurrence of rims around SELs and their inter-relationship with other emerging techniques such as dynamic contrast enhancement (DCE) and positron emission tomography (PET).

Background: People with multiple sclerosis (pwMS) lack sufficient magnetic resonance imaging (MRI) knowledge to truly participate in frequently occurring MRI-related therapy decisions. An evidence-based patient information (EBPI) about MRI is currently lacking., Objective: The aim of this study was to develop an evidence-based online education program about limitations and benefits of MRI for pwMS. Ultimately, our goal was to improve MRI risk-knowledge, empower pwMS, and promote shared decision-making., Methods: The program's contents were based on literature research and a previous pilot study. It was revised following 2 evaluation rounds with pwMS, MRI experts and expert patients. In a pilot study, n = 92 pwMS received access to the program for 4 weeks. User experiences and acceptance, MRI knowledge (MRI-RIKNO 2.0 questionnaire) and emotions and attitudes toward MRI (MRI-EMA questionnaire) were assessed. Results were compared to a previous survey population of n = 508 pwMS without access to the program., Results: Participants rated the program as easy to understand, interesting, relevant, recommendable, and encouraging. In comparison to pwMS without access to the program, MRI risk-knowledge and perceived MRI competence were higher., Conclusion: Satisfaction with the program and good MRI-risk knowledge after usage demonstrates the need and applicability of EBPI about MRI in MS., Competing Interests: IS has received funding for academic conferences by Sanofi Genzyme. AS has received funding from Roche Pharma. CL received a research grant by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no. 01GI1601I, has received consulting and speaker's honoraria from Biogen Idec, Bayer Schering, Daiichi Sanykyo, Merck Serono, Novartis, Sanofi, Genzyme, and TEVA. DC is a consultant for Biogen and Hoffmann-La Roche. He has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. CH received research grants and speaker's honoraria from Biogen, Bristol Myers Squibbs, Merck, Novartis, Roche. The remaining 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 © 2022 Freund, Schiffmann, Rahn, Chard, Lukas, Scheiderbauer, Sippel and Heesen.)

Background: Slowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion's metrics and clinical outcomes in relapse-onset MS has not been widely investigated., Objectives: To explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients., Methods: 135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP)., Results: Mean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI -0.005 to -0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed-effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95%CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006)., Conclusions: SELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity and MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS., (Copyright © 2022. Published by Elsevier Inc.)

Background: Differentiating multiple sclerosis (MS) from vascular risk factor (VRF)-small vessel disease (SVD) can be challenging., Objective and Methods: In order to determine whether or not pontine lesion location is a useful discriminator of MS and VRF-SVD, we classified pontine lesions on brain magnetic resonance imaging (MRI) as central or peripheral in 93 MS cases without VRF, 108 MS patients with VRF and 43 non-MS cases with VRF., Results: MS without VRF were more likely to have peripheral pons lesions (31.2%, 29/93) than non-MS with VRF (0%, 0/43) (Exp( B ) = 29.8; 95% confidence interval (CI) = (1.98, 448.3); p  = 0.014) but there were no significant differences regarding central pons lesions between MS without VRF (5.4%, 5/93) and non-MS with VRF patients (16.3%, 7/43) (Exp( B ) = 0.89; 95% CI = (0.2, 3.94); p  = 0.87). The presence of peripheral pons lesions discriminated between MS and VRF-SVD with 100% (95% CI = (91.8, 100)) specificity. The proportion of peripheral pons lesions in MS with VRF (30.5%, 33/108) was similar to that seen in MS without VRF (31.2%, 29/93, p  = 0.99). Central lesions occurred in similar frequency in MS with VRF (8.3%, 9/108) and non-MS with VRF (16.3%, 7/43, p  = 0.15)., Conclusion: Peripheral pons lesion location is a good discriminator of MS from vascular lesions.