Lesion topographies in multiple sclerosis diagnosis

To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases

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

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). 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. 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. 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

Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis

This cohort study investigates the long-term outcomes of patients who develop progression independent of relapse activity after a first demyelinating event in multiple sclerosis. What are the long-term outcomes of patients developing progression independent of relapse activity (PIRA) after a first demyelinating event in multiple sclerosis? In this longitudinal cohort study including 1128 patients with a first demyelinating event in multiple sclerosis, presenting with PIRA was associated with significantly shorter times to developing severe disability compared with not presenting with PIRA. Patients presenting with PIRA within the first 5 years of multiple sclerosis had a significantly 26-fold greater risk of developing severe disability than patients whose first PIRA appeared late in the disease. Results suggest that presenting with PIRA after a first demyelinating event in multiple sclerosis is an ominous prognosis, especially if it occurs early in the disease course. Progression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS). To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA. This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments. Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA). Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0. Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P <.001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009). Results of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course

Global and Regional Deep Learning Models for Multiple Sclerosis Stratification From MRI

Altres ajuts: acords transformatius de la UABBackground: The combination of anatomical MRI and deep learning-based methods such as convolutional neural networks (CNNs) is a promising strategy to build predictive models of multiple sclerosis (MS) prognosis. However, studies assessing the effect of different input strategies on model's performance are lacking. Purpose: To compare whole-brain input sampling strategies and regional/specific-tissue strategies, which focus on a priori known relevant areas for disability accrual, to stratify MS patients based on their disability level. Study Type: Retrospective. Subjects: Three hundred nineteen MS patients (382 brain MRI scans) with clinical assessment of disability level performed within the following 6 months (~70% training/~15% validation/~15% inference in-house dataset) and 440 MS patients from multiple centers (independent external validation cohort). Field Strength/Sequence: Single vendor 1.5 T or 3.0 T. Magnetization-Prepared Rapid Gradient-Echo and Fluid-Attenuated Inversion Recovery sequences. Assessment: A 7-fold patient cross validation strategy was used to train a 3D-CNN to classify patients into two groups, Expanded Disability Status Scale score (EDSS) ≥ 3.0 or EDSS < 3.0. Two strategies were investigated: 1) a global approach, taking the whole brain volume as input and 2) regional approaches using five different regions-of-interest: white matter, gray matter, subcortical gray matter, ventricles, and brainstem structures. The performance of the models was assessed in the in-house and the independent external cohorts. Statistical Tests: Balanced accuracy, sensitivity, specificity, area under receiver operating characteristic (ROC) curve (AUC). Results: With the in-house dataset, the gray matter regional model showed the highest stratification accuracy (81%), followed by the global approach (79%). In the external dataset, without any further retraining, an accuracy of 72% was achieved for the white matter model and 71% for the global approach. Data Conclusion: The global approach offered the best trade-off between internal performance and external validation to stratify MS patients based on accumulated disability. Evidence Level: 4. Technical Efficacy: Stage 2

Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis

ObjectiveTo investigate the effect of menarche, pregnancies, and breastfeeding on the risk of developing multiple sclerosis (MS) and disability accrual using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndrome (CIS).MethodsA cross-sectional survey of the reproductive information of female participants in a CIS cohort was performed. We examined the relationship of age at menarche with the risk of clinically definite MS (CDMS), McDonald 2010 MS, and Expanded Disability Status Scale (EDSS) 3.0 and 6.0. The effect of pregnancy (before and after CIS) and breastfeeding in the risk of CDMS, McDonald 2010 MS, and EDSS 3.0 was also examined. Univariate and multivariate analyses were performed and findings were confirmed using sensitivity analyses and a propensity score model.ResultsThe data of 501 female participants were collected. Age at menarche did not correlate with age at CIS and was not associated with the risk of CDMS or EDSS 3.0 or 6.0. Pregnancy before CIS was protective for CDMS in the univariate analysis, but the effect was lost in the multivariate model and did not modify the risk of EDSS 3.0. Pregnancy after CIS was protective for both outcomes in univariate and multivariate analyses when pregnancy was considered a baseline variable, but the protective effect disappeared when analyzed as a time-dependent event. Breastfeeding did not modify the risk for the 3 outcomes.ConclusionsThese results demonstrate that menarche, pregnancies, and breastfeeding did not substantially modify the risk of CDMS or disability accrual using a multivariable and time-dependent approach

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

The 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

Lesion topographies in multiple sclerosis diagnosis

To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n = 326), by age, and by CIS topography. Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current ≥1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases

Humoral and Cellular Responses to SARS-CoV-2 in Convalescent COVID-19 Patients With Multiple Sclerosis

Information about humoral and cellular responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and antibody persistence in convalescent (COVID-19) patients with multiple sclerosis (PwMS) is scarce. The objectives of this study were to investigate factors influencing humoral and cellular responses to SARS-CoV-2 and its persistence in convalescent COVID-19 PwMS. This is a retrospective study of confirmed COVID-19 convalescent PwMS identified between February 2020 and May 2021 by SARS-CoV-2 antibody testing. We examined relationships between demographics, MS characteristics, disease-modifying therapy (DMT), and humoral (immunoglobulin G against spike and nucleocapsid proteins) and cellular (interferon-gamma [IFN-γ]) responses to SARS-CoV-2. A total of 121 (83.45%) of 145 PwMS were seropositive, and 25/42 (59.5%) presented a cellular response up to 13.1 months after COVID-19. Anti-CD20-treated patients had lower antibody titers than those under other DMTs (p < 0.001), but severe COVID-19 and a longer time from last infusion increased the likelihood of producing a humoral response. IFN-γ levels did not differ among DMT. Five of 7 (71.4%) anti--CD20-treated seronegative patients had a cellular response. The humoral response persisted for more than 6 months in 41/56(81.13%) PwMS. In multivariate analysis, seropositivity decreased due to anti-CD20 therapy (OR 0.08 [95% CI 0.01-0.55]) and increased in males (OR 3.59 [1.02-12.68]), whereas the cellular response decreased in those with progressive disease (OR 0.04 [0.001-0.88]). No factors were associated with antibody persistence. Humoral and cellular responses to SARS-CoV-2 are present in COVID-19 convalescent PwMS up to 13.10 months after COVID-19. The humoral response decreases under anti-CD20 treatment, although the cellular response can be detected in anti-CD20-treated patients, even in the absence of antibodie