A R-Script for Generating Multiple Sclerosis Lesion Pattern Discrimination Plots

Càlcul estadístic R; Geoestadística; Esclerosi múltipleCálculo estadístico R; Geoestadística; Esclerosis múltipleR statistical computing; Geostatistics; Multiple sclerosisOne significant characteristic of Multiple Sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system, is the evolution of highly variable patterns of white matter lesions. Based on geostatistical metrics, the MS-Lesion Pattern Discrimination Plot reduces complex three- and four-dimensional configurations of MS-White Matter Lesions to a well-arranged and standardized two-dimensional plot that facilitates follow-up, cross-sectional and medication impact analysis. Here, we present a script that generates the MS-Lesion Pattern Discrimination Plot, using the widespread statistical computing environment R. Input data to the script are Nifti-1 or Analyze-7.5 files with individual MS-White Matter Lesion masks in Montreal Normal Brain geometry. The MS-Lesion Pattern Discrimination Plot, variogram plots and associated fitting statistics are output to the R console and exported to standard graphics and text files. Besides reviewing relevant geostatistical basics and commenting on implementation details for smooth customization and extension, the paper guides through generating MS-Lesion Pattern Discrimination Plots using publicly available synthetic MS-Lesion patterns. The paper is accompanied by the R script LDPgenerator.r, a small sample data set and associated graphics for comparison

Slowly expanding lesions relate to persisting black-holes and clinical outcomes in relapse-onset multiple sclerosis

Black holes; Chronic active lesions; Volumetric MRIAgujeros negros; Lesiones activas crónicas; Resonancia magnética volumétricaForats negres; Lesions actives cròniques; Ressonància magnètica volumètricaBackground 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

Serum neurofilament light and MRI predictors of cognitive decline in patients with secondary progressive multiple sclerosis: Analysis from the MS-STAT randomised controlled trial

Magnetic resonance imaging; Neurofilament light; Secondary progressive multiple sclerosisImatge per ressonància magnètica; Llum del neurofilament; Esclerosi múltiple secundària progressivaImagen por resonancia magnética; Luz de neurofilamento; Esclerosis múltiple secundaria progresivaBackground: Cognitive impairment affects 50%–75% of people with secondary progressive multiple sclerosis (PwSPMS). Improving our ability to predict cognitive decline may facilitate earlier intervention. Objective: The main aim of this study was to assess the relationship between longitudinal changes in cognition and baseline serum neurofilament light chain (sNfL) in PwSPMS. In a multi-modal analysis, MRI variables were additionally included to determine if sNfL has predictive utility beyond that already established through MRI. Methods: Participants from the MS-STAT trial underwent a detailed neuropsychological test battery at baseline, 12 and 24 months. Linear mixed models were used to assess the relationships between cognition, sNfL, T2 lesion volume (T2LV) and normalised regional brain volumes. Results: Median age and Expanded Disability Status Score (EDSS) were 51 and 6.0. Each doubling of baseline sNfL was associated with a 0.010 [0.003–0.017] point per month faster decline in WASI Full Scale IQ Z-score (p = 0.008), independent of T2LV and normalised regional volumes. In contrast, lower baseline volume of the transverse temporal gyrus was associated with poorer current cognitive performance (0.362 [0.026–0.698] point reduction per mL, p = 0.035), but not change in cognition. The results were supported by secondary analyses on individual cognitive components. Conclusion: Elevated sNfL is associated with faster cognitive decline, independent of T2LV and regional normalised volumes.The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: No specific funding was received for this research. T.W. is currently funded by the MS-STAT2 trial grant (NCT03387670). This is funded by the NIHR Health Technology Assessment (HTA) Programme, Multiple Sclerosis Society (UK) and the National Multiple Sclerosis Society (US)

Assessing Lumbar Plexus and Sciatic Nerve Damage in Relapsing-Remitting Multiple Sclerosis Using Magnetisation Transfer Ratio

Neurografia de ressonància magnètica (MRN); Relació de transferència de magnetització (MTR); Esclerosi múltiple del sistema nerviós perifèric (SNP)Neurografía de resonancia magnética (MRN); Relación de transferencia de magnetización (MTR); Esclerosis múltiple del sistema nervioso periférico (SNP)Magnetic resonance neurography (MRN); Magnetisation transfer ratio (MTR); Multiple sclerosis peripheral nervous system (PNS)Background: Multiple sclerosis (MS) has traditionally been regarded as a disease confined to the central nervous system (CNS). However, neuropathological, electrophysiological, and imaging studies have demonstrated that the peripheral nervous system (PNS) is also involved, with demyelination and, to a lesser extent, axonal degeneration representing the main pathophysiological mechanisms. Aim: The purpose of this study was to assess PNS damage at the lumbar plexus and sciatic nerve anatomical locations in people with relapsing-remitting MS (RRMS) and healthy controls (HCs) in vivo using magnetisation transfer ratio (MTR), which is a known imaging biomarker sensitive to alterations in myelin content in neural tissue, and not previously explored in the context of PNS damage in MS. Method: Eleven HCs (7 female, mean age 33.6 years, range 24-50) and 15 people with RRMS (12 female, mean age 38.5 years, range 30-56) were recruited for this study and underwent magnetic resonance imaging (MRI) investigations together with clinical assessments using the expanded disability status scale (EDSS). Magnetic resonance neurography (MRN) was first used for visualisation and identification of the lumbar plexus and the sciatic nerve and MTR imaging was subsequently performed using identical scan geometry to MRN, enabling straightforward co-registration of all data to obtain global and regional mean MTR measurements. Linear regression models were used to identify differences in MTR values between HCs and people with RRMS and to identify an association between MTR measures and EDSS. Results: MTR values in the sciatic nerve of people with RRMS were found to be significantly lower compared to HCs, but no significant MTR changes were identified in the lumbar plexus of people with RRMS. The median EDSS in people with RRMS was 2.0 (range, 0-3). No relationship between the MTR measures in the PNS and EDSS were identified at any of the anatomical locations studied in this cohort of people with RRMS. Conclusion: The results from this study demonstrate the presence of PNS damage in people with RRMS and support the notion that these changes, suggestive of demyelination, maybe occurring independently at different anatomical locations within the PNS. Further investigations to confirm these findings and to clarify the pathophysiological basis of these alterations are warranted.The UK MS Society and the UCL-UCLH Biomedical Research Centre for ongoing support. CGW-K receives funding from the MS Society (#77), Wings for Life (#169111), BRC (#BRC704/CAP/CGW), UCL Global Challenges Research Fund (GCRF), MRC (#MR/S026088/1), Ataxia UK. FP had a non-clinical Postdoctoral Guarantors of Brain fellowship (2017-2020). FP was supported by the National Institute for Health Research, UCL Hospitals Biomedical Research Centre. CT is being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by la Caixa Foundation (ID 100010434). She has also received the 2021 Merck's Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain). In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She has also received honoraria from Roche and Novartis, and is a steering committee member of the O'HAND trial and of the Consensus group on Follow-on DMTs. This project has received funding under the European Union's Horizon 2020 research and innovation programme under grant agreement No. 634541 and from the Engineering and Physical Sciences Research Council (EPSRC EP/R006032/1), funding FG. FG was currently supported by PREdICT, a study at the Vall d'Hebron Institute of Oncology in Barcelona funded by AstraZeneca

Use of Disease-Modifying Therapies in Pediatric Relapsing-Remitting Multiple Sclerosis in the United Kingdom

Esclerosi múltiple; Ressonància magnèticaEsclerosis múltiple; Resonancia magnéticaMultiple sclerosis; Magnetic resonance imagingObjectives To compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS). Methods In this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records. Annualized relapse rates (ARRs) before and on treatment, time to relapse, time to new MRI lesions, and change in Expanded Disability Status Scale (EDSS) score were calculated. Results Of 103 children treated with DMTs, followed up for 3.8 years, relapses on treatment were recorded in 53/89 (59.5%) on injectables vs 8/54 (15%) on newer DMTs. The ARR was reduced from 1.9 to 1.1 on injectables (p < 0.001) vs 1.6 to 0.3 on newer DMTs (p = 0.002). New MRI lesions occurred in 77/89 (86.5%) of patients on injectables vs 26/54 (47%) on newer DMTs (p = 0.0001). Children on newer DMTs showed longer time to relapse, time to switch treatment, and time to new radiologic activity than patients on injectables (log-rank p < 0.01). After adjustment for potential confounders, multivariable analysis showed that injectables were associated with 12-fold increased risk of clinical relapse (adjusted hazard ratio [HR] = 12.12, 95% CI = 1.64–89.87, p = 0.015) and a 2-fold increased risk of new radiologic activity (adjusted HR = 2.78, 95% CI = 1.08–7.13, p = 0.034) compared with newer DMTs. At 2 years from treatment initiation, 38/103 (37%) patients had MRI activity in the absence of clinical relapses. The EDSS score did not change during the follow-up, and only 2 patients had cognitive impairment. Conclusion Newer DMTs were associated with a lower risk of clinical and radiologic relapses in patients compared with injectables. Our study adds weight to the argument for an imminent shift in practice toward the use of newer, more efficacious DMTs in the first instance. Classification of Evidence This study provides Class IV evidence that newer DMTs (oral or infusions) are superior to injectables (interferon beta/glatiramer acetate) in reducing both clinical relapses and radiologic activity in children with RRMS.O.A. Abdel-Mannan is funded by a Guarantors of Brain Clinical Entry Fellowship. C. Hemingway is funded by an MRC Clinical Academic Research Partnership grant (MR/T024437/1). Y. Hacohen is funded by the UK MS society. O. Ciccarelli is NIHR Research Professor (Round 8)

Genetic influences on disease course and severity, 30 years after a clinically isolated syndrome

Genetics; Multiple sclerosis; PhenotypeGenética; Esclerosis múltiple; FenotipoGenètica; Esclerosi múltiple; FenotipMultiple 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.This study was funded by the Multiple Sclerosis Society of Great Britain and Northern Ireland (20; 984) and supported by the National Institute for Health and Care Research University College London Hospitals (UCLH) Biomedical Research Centre. Funding for extended SNP analysis was supported by a Small Acorns Fund from The National Brain Appeal (NBA/QSQ/SAF/R17)

Differentiating Multiple Sclerosis From AQP4-Neuromyelitis Optica Spectrum Disorder and MOG-Antibody Disease With Imaging

Multiple sclerosis; Neuromyelitis optica; ImagingEsclerosis múltiple; Neuromielitis óptica; ImágenesEsclerosi múltiple; Neuromielitis òptica; ImatgesBackground and Objectives Relapsing-remitting multiple sclerosis (RRMS), aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) may have overlapping clinical features. There is an unmet need for imaging markers that differentiate between them when serologic testing is unavailable or ambiguous. We assessed whether imaging characteristics typical of MS discriminate RRMS from AQP4-NMOSD and MOGAD, alone and in combination. Methods Adult, nonacute patients with RRMS, APQ4-NMOSD, and MOGAD and healthy controls were prospectively recruited at the National Hospital for Neurology and Neurosurgery (London, United Kingdom) and the Walton Centre (Liverpool, United Kingdom) between 2014 and 2019. They underwent conventional and advanced brain, cord, and optic nerve MRI and optical coherence tomography (OCT). Results A total of 91 consecutive patients (31 RRMS, 30 APQ4-NMOSD, and 30 MOGAD) and 34 healthy controls were recruited. The most accurate measures differentiating RRMS from AQP4-NMOSD were the proportion of lesions with the central vein sign (CVS) (84% vs 33%, accuracy/specificity/sensitivity: 91/88/93%, p < 0.001), followed by cortical lesions (median: 2 [range: 1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/90/77%, p = 0.002) and white matter lesions (mean: 39.07 [±25.8] vs 9.5 [±14], accuracy/specificity/sensitivity: 78/84/73%, p = 0.001). The combination of higher proportion of CVS, cortical lesions, and optic nerve magnetization transfer ratio reached the highest accuracy in distinguishing RRMS from AQP4-NMOSD (accuracy/specificity/sensitivity: 95/92/97%, p < 0.001). The most accurate measures favoring RRMS over MOGAD were white matter lesions (39.07 [±25.8] vs 1 [±2.3], accuracy/specificity/sensitivity: 94/94/93%, p = 0.006), followed by cortical lesions (2 [1–14] vs 1 [0–1], accuracy/specificity/sensitivity: 84/97/71%, p = 0.004), and retinal nerve fiber layer thickness (RNFL) (mean: 87.54 [±13.83] vs 75.54 [±20.33], accuracy/specificity/sensitivity: 80/79/81%, p = 0.009). Higher cortical lesion number combined with higher RNFL thickness best differentiated RRMS from MOGAD (accuracy/specificity/sensitivity: 84/92/77%, p < 0.001). Discussion Cortical lesions, CVS, and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4-NMOSD and MOGAD. This information may be useful in clinical practice, especially outside the acute phase and when serologic testing is ambiguous or not promptly available. Classification of Evidence This study provides Class II evidence that selected conventional and advanced brain, cord, and optic nerve MRI and OCT markers distinguish adult patients with RRMS from AQP4-NMOSD and MOGAD.The study was funded by the UK MS Society (Grant No.: 917-09) and the National Institute for Health and Care Re- search (RP-2017-08-ST2-004)

Spatial patterns of brain lesions assessed through covariance estimations of lesional voxels in multiple Sclerosis: The SPACE-MS technique

Anisotropy; Lesion spatial distribution; Multiple sclerosisAnisotropia; Distribució espacial de la lesió; Esclerosi múltipleAnisotropía; Distribución espacial de la lesión; Esclerosis múltiplePredicting disability in progressive multiple sclerosis (MS) is extremely challenging. Although there is some evidence that the spatial distribution of white matter (WM) lesions may play a role in disability accumulation, the lack of well-established quantitative metrics that characterise these aspects of MS pathology makes it difficult to assess their relevance for clinical progression. This study introduces a novel approach, called SPACE-MS, to quantitatively characterise spatial distributional features of brain MS lesions, so that these can be assessed as predictors of disability accumulation. In SPACE-MS, the covariance matrix of the spatial positions of each patient’s lesional voxels is computed and its eigenvalues extracted. These are combined to derive rotationally-invariant metrics known to be common and robust descriptors of ellipsoid shape such as anisotropy, planarity and sphericity. Additionally, SPACE-MS metrics include a neuraxis caudality index, which we defined for the whole-brain lesion mask as well as for the most caudal brain lesion. These indicate how distant from the supplementary motor cortex (along the neuraxis) the whole-brain mask or the most caudal brain lesions are. We applied SPACE-MS to data from 515 patients involved in three studies: the MS-SMART (NCT01910259) and MS-STAT1 (NCT00647348) secondary progressive MS trials, and an observational study of primary and secondary progressive MS. Patients were assessed on motor and cognitive disability scales and underwent structural brain MRI (1.5/3.0 T), at baseline and after 2 years. The MRI protocol included 3DT1-weighted (1x1x1mm3) and 2DT2-weighted (1x1x3mm3) anatomical imaging. WM lesions were semiautomatically segmented on the T2-weighted scans, deriving whole-brain lesion masks. After co-registering the masks to the T1 images, SPACE-MS metrics were calculated and analysed through a series of multiple linear regression models, which were built to assess the ability of spatial distributional metrics to explain concurrent and future disability after adjusting for confounders. Patients whose WM lesions laid more caudally along the neuraxis or were more isotropically distributed in the brain (i.e. with whole-brain lesion masks displaying a high sphericity index) at baseline had greater motor and/or cognitive disability at baseline and over time, independently of brain lesion load and atrophy measures. In conclusion, here we introduced the SPACE-MS approach, which we showed is able to capture clinically relevant spatial distributional features of MS lesions independently of the sheer amount of lesions and brain tissue loss. Location of lesions in lower parts of the brain, where neurite density is particularly high, such as in the cerebellum and brainstem, and greater spatial spreading of lesions (i.e. more isotropic whole-brain lesion masks), possibly reflecting a higher number of WM tracts involved, are associated with clinical deterioration in progressive MS. The usefulness of the SPACE-MS approach, here demonstrated in MS, may be explored in other conditions also characterised by the presence of brain WM lesions.Carmen Tur 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). The fellowship code is LCF/BQ/PI20/11760008. She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by the Merck Foundation. In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She has also received honoraria from Roche and Novartis. Francesco Grussu has received funding under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 634541, from the Engineering and Physical Sciences Research Council (EPSRC EP/R006032/1, M020533/1) and Rosetrees Trust (UK), and is now supported by PREdICT (a study funded by AstraZeneca in Spain). Ferran Prados was supported by the Guarantors of Brain and the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. Rosa Cortese is supported by the ECTRIMS-MAGNIMS fellowships programme. Alberto Calvi is supported by ECTRIMS-MAGNIMS fellowship (2018), Guarantors of Brain “Entry” clinical fellowship (2019) and the UK MS Society PhD studentship (2020). Declan Chard is a consultant for Biogen and Hoffmann-La Roche. In the last 3 years, he has received research funding from the International Progressive MS Alliance, the UK MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre. Jeremy Chataway, in the last three years, has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Biogen, Novartis and Roche; has received an investigator grant from Novartis; and has taken part in advisory boards/consultancy for Azadyne, Biogen, Celgene, Janssen, MedDay, Merck, Novartis and Roche. Alan J Thompson acknowledges grant support from the National Institute for Health Research HTA and BRC, and has received honoraria for consultancy from Eisai and Abbvie (paid to Institution), support for travel for consultancy from the International Progressive MS Alliance and National MS Society (USA), and receives an honorarium from SAGE Publishers as Editor-in-Chief of Multiple Sclerosis Journal. Olga Ciccarelli is supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. OC also receives research grant support from the MS Society of Great Britain and Northern Ireland, and the NIHR UCLH Biomedical Research Centre. She is an Associate Editor for Neurology, for which he receives an honorarium. Claudia A.M. Gandini Wheeler-Kingshott has received research grants (principal investigator and co-applicant) from the UK MS Society (#77), Wings for Life (#169111), BRC (#BRC704/CAP/CGW), UCL Global Challenges Research Fund (GCRF), MRC (#MR/S026088/1), Ataxia UK. CGWK is a shareholder in Queen Square Analytics Ltd

Oral contraceptives do not modify the risk of a second attack and disability accrual in a prospective cohort of women with a clinically isolated syndrome and early multiple sclerosis

Cohort study; Oral contraceptives; Second relapseEstudio de cohorte; Anticonceptivos orales; Segunda recaídaEstudi de cohorts; Anticonceptius orals; Segona recaigudaObjective: To evaluate whether oral contraceptive (OC) use is associated with the risk of a second attack and disability accrual in women with a clinically isolated syndrome (CIS) and early multiple sclerosis (MS). Methods: Reproductive information from women included in the Barcelona CIS prospective cohort was collected through a self-reported cross-sectional survey. We examined the relationship of OC exposure with the risk of a second attack and confirmed Expanded Disability Status Scale of 3.0 using multivariate Cox regression models, adjusted by age, topography of CIS, oligoclonal bands, baseline brain T2 lesions, body size at menarche, smoking, and disease-modifying treatment (DMT). OC and DMT exposures were considered as time-varying variables. Findings were confirmed with sensitivity analyses using propensity score models. Results: A total of 495 women were included, 389 (78.6%) referred to ever use OC and 341 (68.9%) started OC before the CIS. Exposure to OC was not associated with a second attack (adjusted hazard ratio (aHR) = 0.73, 95% confidence interval (CI) = 0.33–1.61) or disability accrual (aHR = 0.81, 95% CI = 0.17–3.76). Sensitivity analyses confirmed these results. Conclusion: OC use does not modify the risk of second attack or disability accrual in patients with CIS and early MS, once considered as a time-dependent exposure and adjusted by other potential confounders.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was supported by FIS PI15/0070 from Ministry of Economy and Competitiveness of Spain

Deciphering multiple sclerosis disability with deep learning attention maps on clinical MRI

Deep learning; Disability; Structural MRIAprendizaje profundo; Discapacidad; Resonancia magnética estructuralAprenentatge profund; Discapacitat; Ressonància magnètica estructuralThe application of convolutional neural networks (CNNs) to MRI data has emerged as a promising approach to achieving unprecedented levels of accuracy when predicting the course of neurological conditions, including multiple sclerosis, by means of extracting image features not detectable through conventional methods. Additionally, the study of CNN-derived attention maps, which indicate the most relevant anatomical features for CNN-based decisions, has the potential to uncover key disease mechanisms leading to disability accumulation. From a cohort of patients prospectively followed up after a first demyelinating attack, we selected those with T1-weighted and T2-FLAIR brain MRI sequences available for image analysis and a clinical assessment performed within the following six months (N = 319). Patients were divided into two groups according to expanded disability status scale (EDSS) score: ≥3.0 and < 3.0. A 3D-CNN model predicted the class using whole-brain MRI scans as input. A comparison with a logistic regression (LR) model using volumetric measurements as explanatory variables and a validation of the CNN model on an independent dataset with similar characteristics (N = 440) were also performed. The layer-wise relevance propagation method was used to obtain individual attention maps. The CNN model achieved a mean accuracy of 79% and proved to be superior to the equivalent LR-model (77%). Additionally, the model was successfully validated in the independent external cohort without any re-training (accuracy = 71%). Attention-map analyses revealed the predominant role of frontotemporal cortex and cerebellum for CNN decisions, suggesting that the mechanisms leading to disability accrual exceed the mere presence of brain lesions or atrophy and probably involve how damage is distributed in the central nervous system.MS PATHS is funded by Biogen. This study has been possible thanks to a Junior Leader La Caixa Fellowship awarded to C. Tur (fellowship code is LCF/BQ/PI20/11760008) by “la Caixa” Foundation (ID 100010434). The salaries of C. Tur and Ll. Coll are covered by this award