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Background and ObjectivesTo explore whether time to diagnosis, time to treatment initiation, and age to reach disability milestones have changed in patients with clinically isolated syndrome (CIS) according to different multiple sclerosis (MS) diagnostic criteria periods.MethodsThis retrospective study was based on data collected prospectively from the Barcelona-CIS cohort between 1994 and 2020. Patients were classified into 5 periods according to different MS criteria, and the times to MS diagnosis and treatment initiation were evaluated. The age at which patients with MS reached an Expanded Disability Status Scale (EDSS) score ≥3.0 was assessed by Cox regression analysis according to diagnostic criteria periods. Last, to remove the classic Will Rogers phenomenon by which the use of different MS criteria over time might result in a changes of prognosis, the 2017 McDonald criteria were applied, and age at EDSS score ≥3.0 was assessed by Cox regression.ResultsIn total, 1,174 patients were included. The median time from CIS to MS diagnosis and from CIS to treatment initiation showed a 77% and 82% reduction from the Poser to the McDonald 2017 diagnostic criteria periods, respectively. Patients of a given age diagnosed in more recent diagnostic criteria periods had a lower risk of reaching an EDSS score ≥3.0 than patients of the same age diagnosed in earlier diagnostic periods (reference category Poser period): adjusted hazard ratio (aHR) 0.47 (95% confidence interval 0.24–0.90) for McDonald 2001, aHR 0.25 (0.12–0.54) for McDonald 2005, aHR 0.30 (0.12–0.75) for McDonald 2010, and aHR 0.07 (0.01–0.45) for McDonald 2017. Patients in the early-treatment group displayed an aHR of 0.53 (0.33–0.85) of reaching age at EDSS score ≥3.0 compared to those in the late-treatment group. Changes in prognosis together with early-treatment effect were maintained after the exclusion of possible bias derived from the use of different diagnostic criteria over time (Will Rogers phenomenon).DiscussionA continuous decrease in the time to MS diagnosis and treatment initiation was observed across diagnostic criteria periods. Overall, patients diagnosed in more recent diagnostic criteria periods displayed a lower risk of reaching disability. The prognostic improvement is maintained after the Will Rogers phenomenon is discarded, and early treatment appears to be the most likely contributing factor.

Intrathecal production of kappa free light chains occurs in multiple sclerosis and can be measured using the kappa free light chain index. Kappa free light chain index values can be determined more easily than oligoclonal bands detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of oligoclonal bands, kappa free light chain index cut-offs 5.9, 6.6 and 10.61, and IgG index to diagnose multiple sclerosis with prospectively acquired data from a clinically isolated syndrome inception cohort. We selected patients with sufficient data to determine oligoclonal bands positivity, MRI dissemination in space and time, IgG index and sufficient quantities of paired CSF and blood samples to determine kappa free light chain indexes (n = 214). We used Kendall’s Tau coefficient to estimate concordance, calculated the number of additional diagnoses when adding each positive index to dissemination in space and positive oligoclonal bands, performed survival analyses for oligoclonal bands and each index with the outcomes second attack and 2017 MRI dissemination in space and time and estimated the diagnostic properties of oligoclonal bands and the different indexes for the previously mentioned outcomes at 5 years. Oligoclonal bands were positive in 138 patients (64.5%), kappa free light chain-5.9 in 136 (63.6%), kappa free light chain-6.6 in 135 (63.1%), kappa free light chain-10.61 in 126 (58.9%) and IgG index in 101 (47.2%). The highest concordance was between oligoclonal bands and kappa free light chain-6.6 (τ = 0.727) followed by oligoclonal bands and kappa free light chain-5.9 (τ = 0.716). Combining dissemination in space plus oligoclonal bands or kappa free light chain-5.9 increased the number of diagnosed patients by 11 (5.1%), with kappa free light chain-6.6 by 10 (4.7%), with kappa free light chain-10.61 by 9 (4.2%) and with IgG index by 3 (1.4%). Patients with positive oligoclonal bands or indexes reached second attack and MRI dissemination in space and time faster than patients with negative results (P < 0.0001 except IgG index in second attack: P = 0.016). In multivariable Cox models [adjusted hazard ratio (95% confidence interval)], the risk for second attack was very similar between kappa free light chain-5.9 [2.0 (0.9–4.3), P = 0.068] and kappa free light chain-6.6 [2.1 (1.1–4.2), P = 0.035]. The highest risk for MRI dissemination in space and time was demonstrated with kappa free light chain-5.9 [4.9 (2.5–9.6), P < 0.0001], followed by kappa free light chain-6.6 [3.4 (1.9–6.3), P < 0.0001]. Kappa free light chains-5.9 and -6.6 had a slightly higher diagnostic accuracy than oligoclonal bands for second attack (70.5, 71.1 and 67.8) and MRI dissemination in space and time (85.7, 85.1 and 81.0). Kappa free light chain indexes 5.9 and 6.6 performed slightly better than oligoclonal bands to assess multiple sclerosis risk and in terms of diagnostic accuracy. Given the concordance between oligoclonal bands and these indexes, we suggest using dissemination in space plus positive oligoclonal bands or positive kappa free light chain index as a modified criterion to diagnose multiple sclerosis.

Background and purpose Information regarding multiple sclerosis (MS) patients with the 2019 novel coronavirus disease (COVID-19) is scarce. The study objective was to describe the incidence and characteristics of MS patients with COVID-19, to identify susceptibility and severity risk factors and to assess the proportion of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serologies according to disease-modifying treatments. Methods This was a retrospective study of an MS cohort analysing data collected between February and May 2020. Cases were identified through an email survey and clinical visits. The relationship of demographic and MS characteristics with COVID-19 and of the disease-modifying treatments with SARS-CoV-2 serostatus were examined. Results Data from 48 suspected cases out of 758 valid respondents and from 45 COVID-19 cases identified through clinical visits were collected. Incidence was 6.3%. Nineteen (20.3%) patients were hospitalized and two (2.2%) died. Multivariable models determined that age (odds ratio [OR] per 10 years 0.53, 95% confidence interval [CI] 0.34-0.85), contact with a confirmed case (OR 197.02, 95% CI 56.36-688.79), residence in Barcelona (OR 2.23, 95% CI 1.03-4.80), MS duration (OR per 5 years 1.41, 95% CI 1.09-1.83) and time on anti-CD20 treatment (OR per 2 years 3.48, 95% CI 1.44-8.45) were independent factors for presenting COVID-19 and age (OR per 10 years 2.71, 95% CI 1.13-6.53) for a severe COVID-19. Out of the 79 (84.9%) with serological test, 45.6% generated antibodies, but only 17.6% of those on anti-CD20 therapies. Lymphopaenia or immunoglobulin levels did not relate to COVID-19. Conclusions Multiple sclerosis patients present similar incidence, risk factors and outcomes for COVID-19 as the general population. Patients treated with an anti-CD20 therapy for a longer period of time might be at a higher risk of COVID-19 and less than 20% generate an antibody response. Only age was related to severity.

Cultural adaptation; Linguistic validation; Psychological flexibility Adaptación cultural; Validación lingüística; Flexibilidad psicológica Adaptació cultural; Validació lingüística; Flexibilitat psicològica Purpose: The Comprehensive assessment of Acceptance and Commitment Therapy (ACT) processes (CompACT) is a 23-item self-report questionnaire assessing psychological flexibility, which is the overarching construct underpinning the ACT framework. We conducted a two-phase project to develop validated versions of the CompACT in three languages: phase 1—cross-cultural adaptation; and phase 2—psychometric validation of the questionnaire for use in Italy, Germany and Spain. This article focuses on the first phase. Methods: We translated and culturally adapted the CompACT in the three target languages, following the ISPOR TCA Task Force guidelines. The process was overseen by a translation panel (three translators, at least two multiple sclerosis (MS) researchers and a lay person), ACT experts and clinicians from the research team of each country and the original CompACT developers. We debriefed the new questionnaire versions via face-to-face interviews with a minimum of four adults from the general population (GP) and four adults with MS in each country. Results: The translation-adaptation process went smoothly in the three countries, with some items (7 in Italy, 4 in Germany, 6 in Spain) revised after feedback from ACT experts. Cognitive debriefing showed that the CompACT was deemed easy to understand and score in each target country by both GP and MS adults. Conclusions: The Italian, German and Spanish versions of the CompACT have semantic, conceptual and normative equivalence to the original scale and good content validity. Our findings are informative for researchers adapting the CompACT and other self-reported outcome measures into multiple languages and cultures. This study is supported by the “REHABILITATION IN MULTIPLE SCLEROSIS-RIMS European network for best practice and resource” (RIMS GRANT PROGRAM 2018 to AMG). The funding source had no role in study design, data collection, data analysis, data interpretation or report writing.

The presence of oligoclonal bands in clinically isolated syndromes is an independent risk factor for developing multiple sclerosis and has been largely excluded from the more recent multiple sclerosis diagnostic criteria. Therefore, our objective was to explore the value of oligoclonal bands in the context of the 2010 McDonald criteria, especially in patients fulfilling exclusively dissemination in space at baseline. For this purpose, we selected 566 patients from a clinically isolated syndrome inception cohort who had IgG oligoclonal bands determination and sufficient data on baseline brain MRI to assess dissemination in space and time. We excluded the cases already fulfilling both dissemination in space and time and divided the remaining 398 into 'no dissemination in space and time' (n = 218), 'dissemination in space' (n = 164) and 'dissemination in time' (n = 16). We assessed Cox proportional hazards regression models with 2010 McDonald as the outcome, using 'no dissemination in space and time' with 0 lesions and negative oligoclonal bands as the reference for different subgroups according to oligoclonal bands status (positive/negative). To assess the diagnostic properties, we selected cases with a follow-up ≥3 years or fulfilling 2010 McDonald within 3 years of the clinically isolated syndrome (n = 314), and compared the performance of all 'dissemination in space' cases (n = 137) versus patients with 'dissemination in space' and positive oligoclonal bands (n = 101). The remaining patients classified as fulfilling 'dissemination in time' or 'no dissemination in space and time' were taken into account to calculate the diagnostic properties. The respective adjusted hazard ratios (95% confidence interval) were 1.5 (0.4-5.7) for 'no dissemination in space and time' with 0 lesions and positive oligoclonal bands, 3.1 (1.4-7.2) for 'no dissemination in space and time' with ≥1 lesions and negative oligoclonal bands, 7.4 (3.5-15.7) for 'no dissemination in space and time' with ≥1 lesions and positive oligoclonal bands, 10.4 (4.8-22.6) for 'dissemination in space' with negative oligoclonal bands, 15.3 (7.5-31.3) for 'dissemination in space' with positive oligoclonal bands, and 9.1 (3.5-23.4) for 'dissemination in time' (not subdivided due to the sample size). The specificity for all cases with 'dissemination in space' was 80.6 and increased to 88.1 after selecting those with positive oligoclonal bands. According to these results, we propose radiological dissemination in space at any time plus positive oligoclonal bands as an additional criterion for diagnosing multiple sclerosis.

Background: The usefulness of performing a spinal cord (SC) magnetic resonance imaging (MRI) in all clinically isolated syndromes (CIS) is controversial. Objective: To assess the value of SC lesions for predicting multiple sclerosis (MS) diagnosis and disability accrual in CIS. Methods: Concerning SC lesions and MS diagnosis (2010 McDonald), adjusted Cox regression analyses were performed in increasingly specific CIS groups: all cases ( n = 207), non-SC CIS ( n = 143), non-SC CIS with abnormal brain MRI ( n = 90) and non-SC CIS with abnormal brain MRI not fulfilling 2010 MS ( n = 67). For the outcome Expanded Disability Status Scale (EDSS) ≥3.0, similar analyses were performed in all cases ( n = 207), non-SC CIS ( n = 143) and SC CIS ( n = 64). Performance at 2 years was assessed for all outcomes. Results: The presence of SC lesions increased MS risk 2.0–2.6 times independently of factors like brain lesions. If considering lesion number, the risk ranged from 1.6 to 2.1 for one lesion to 2.4–3.3 for ≥2. SC lesions increased the short-term disability risk around fivefold, better demonstrated in non-SC CIS. SC lesions were very specific for evolution to MS and showed very high sensitivity for EDSS ≥3.0. Conclusion: SC lesions are independent predictors of MS in all CIS and contribute to short-term disability accrual. SC MRIs in CIS could be useful to estimate their prognosis.

ObjectiveTo assess the added value of the optic nerve region (by using visual evoked potentials [VEPs]) to the current diagnostic criteria.MethodsFrom the Barcelona clinically isolated syndrome (CIS) cohort, patients with complete information to assess dissemination in space (DIS), the optic nerve region, and dissemination in time at baseline (n = 388) were selected. Modified DIS (modDIS) criteria were constructed by adding the optic nerve to the current DIS regions. The DIS and modDIS criteria were evaluated with univariable Cox proportional hazard regression analyses with the time to the second attack as the outcome. A subset of these patients who had at least 10 years of follow-up or a second attack occurring within 10 years (n = 151) were selected to assess the diagnostic performance. The analyses were also performed according to CIS topography (optic neuritis vs non–optic neuritis).ResultsThe addition of the optic nerve as a fifth region improved the diagnostic performance by slightly increasing the accuracy (2017 DIS 75.5%, modDIS 78.1%) and the sensitivity (2017 DIS 79.2%, modDIS 82.3%) without lowering the specificity (2017 DIS 52.4%, modDIS 52.4%). When the analysis was conducted according to CIS topography, the modDIS criteria performed similarly in both optic neuritis and non–optic neuritis CIS.ConclusionThe addition of the optic nerve, assessed by VEP, as a fifth region in the current DIS criteria slightly improves the diagnostic performance because it increases sensitivity without losing specificity.

Alemtuzumab, a humanized monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis, produce the rapid depletion of all mature lymphocytes. For this reason, patients are at an increased risk of developing infections due to the reactivation of latent agents or acquired microorganisms. Most infections reported during the phase III trials were mild or moderate in severity, while serious infections were surprisingly uncommon.1 However, during the postmarketing use of alemtuzumab, several opportunistic infections have been reported.2–5 We describe a patient who presented simultaneous cytomegalovirus (CMV) reactivation and Listeria meningitis promptly following the first course of alemtuzumab.

Natural history studies have identified factors that predict evolution to multiple sclerosis or risk of disability accumulation over time. Although these studies are based on large multicentre cohorts with long follow-ups, they have limitations such as lack of standardized protocols, a retrospective data collection or lack of a systematic magnetic resonance imaging acquisition and analysis protocol, often resulting in failure to take magnetic resonance and oligoclonal bands into account as joint covariates in the prediction models. To overcome some of these limitations, the aim of our study was to identify and stratify baseline demographic, clinical, radiological and biological characteristics that might predict multiple sclerosis development and disability accumulation using a multivariate approach based on a large prospective cohort of patients with clinically isolated syndromes. From 1995 to 2013, 1058 patients with clinically isolated syndromes were included. We evaluated the influence of baseline prognostic factors on the risk for developing clinically definite multiple sclerosis, McDonald multiple sclerosis, and disability accumulation (Expanded Disability Status Scale score of 3.0) based on univariate (hazard ratio with 95% confidence intervals) and multivariate (adjusted hazard ratio with 95% confidence intervals) Cox regression models. We ultimately included 1015 patients followed for a mean of 81 (standard deviation = 57) months. Female/male ratio was 2.1. Females exhibited a similar risk of conversion to multiple sclerosis and of disability accumulation compared to males. Each younger decade at onset was associated with a greater risk of conversion to multiple sclerosis and with a protective effect on disability. Patients with optic neuritis had a lower risk of clinically definite multiple sclerosis [hazard ratio 0.6 (0.5-0.8)] and disability progression [hazard ratio 0.5 (0.3-0.8)]; however, this protective effect remained marginal only for disability [adjusted hazard ratio 0.6 (0.4-1.0)] in adjusted models. The presence of oligoclonal bands increased the risk of clinically definite multiple sclerosis [adjusted hazard ratio 1.3 (1.0-1.8)] and of disability [adjusted hazard ratio 2.0 (1.2-3.6)] independently of other factors. The presence of 10 or more brain lesions on magnetic resonance increased the risk of clinically definite multiple sclerosis [adjusted hazard ratio 11.3 (6.7-19.3)] and disability [adjusted hazard ratio 2.9 (1.4-6.0)]. Disease-modifying treatment before the second attack reduced the risk of McDonald multiple sclerosis [adjusted hazard ratio 0.6 (0.4-0.9)] and disability accumulation [adjusted hazard ratio 0.5 (0.3-0.9)]. We conclude that the demographic and topographic characteristics are low-impact prognostic factors, the presence of oligoclonal bands is a medium-impact prognostic factor, and the number of lesions on brain magnetic resonance is a high-impact prognostic factor.

Objectives: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).Methods: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.Results: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.Conclusions: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.

Bayer Health Care Merck Serono TEVA Objective: We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance.Methods: From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls.Results: No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p

Background/Aims: Neurodegenerative disorders (ND) have a major impact on quality of life (QoL) and place a substantial burden on patients, their families and carers; they are the second leading cause of disability. The objective of this study was to examine QoL in persons with ND. Methods: A battery of subjective assessments was used, including the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) and the World Health Organization Quality of Life – Disability (WHOQOL-DIS). Psychometric properties of the WHOQOL-BREF and WHOQOL-DIS were investigated using classical psychometric methods. Results: Participants (n = 149) were recruited and interviewed at two specialized centers to obtain information on health and disability perceptions, depressive symptoms (Hospital Anxiety and Depression Scale – Depression, HADS-D), Fatigue Assessment Scale (FAS), Satisfaction with Life (SWL), generic QoL (WHOQOL-BREF, WHOQOL-DIS), specific QoL (Multiple Sclerosis Impact Scale, MSIS-29; Parkinson’s Disease Questionnaire, PDQ-39) and sociodemographics. Internal consistency was acceptable, except for the WHOQOL-BREF social (0.67). Associations, using Pearson’s and Spearman’s rho correlations, were confirmed between WHOQOL-BREF and WHOQOL-DIS with MSIS-29, PDQ-39, HADS-D, FAS and SWL. Regarding ‘known group’ differences, Student’s t tests showed that WHOQOL-BREF and WHOQOL-DIS scores significantly discriminated between depressed and nondepressed and those perceiving a more severe impact of the disability on their lives. Conclusion: This study is the first to report on use of the WHOQOL-BREF and WHOQOL-DIS in Spanish persons with ND; they are promising useful tools in assessing persons with ND through the continuum of care, as they include important dimensions commonly omitted from other QoL measures.

To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and magnetic resonance imaging results between trial arms and to investigate correlations between in-trial changes in Multiple Sclerosis Functional Composite (MSFC) score and magnetic resonance imaging variables and Expanded Disability Status Scale (EDSS) score evolution.Five-year clinical trial follow-up.Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Autonomous University of Barcelona, Spain. Patients Seventy-three patients received interferon beta-1b or placebo during the trial.After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 patients, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 patients, respectively.After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (P = .02) and Word List Generation Test (P .001) scores, and their magnetization transfer ratio measures in the normal-appearing white matter were significantly higher (P = .02, P = .009, and P = .03 for the mean, peak location, and peak height magnetic transfer ratios, respectively). During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain parenchymal fraction (P = .004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (P = .004).Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.