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Julia Sabin,1 Elisa Salas,2 Jesús Martín-Martínez,3 Antonio Candeliere-Merlicco,4 Francisco Javier Barrero Hernández,5 Ana María Alonso Torres,6 José Luis Sánchez-Menoyo,7 Laura Borrega,8 María Rodríguez-Rodríguez,9 Montserrat Gómez-Gutiérrez,10 Sara Eichau,11 Miguel Ángel Hernández-Pérez,12 Carmen Calles,13 Eva Fernandez-Diaz,14 Olga Carmona,15 Aida Orviz,16 Ana López-Real,17 Pablo López-Muñoz,18 Amelia Mendoza Rodríguez,19 Eduardo Aguera-Morales,20 Jorge Maurino2 1Department of Neurology, Hospital Universitario Puerta de Hierro, Madrid, Spain; 2Medical Department, Roche Farma, Madrid, Spain; 3Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 4Department of Neurology, Hospital Rafael Méndez, Lorca, Spain; 5Department of Neurology, Hospital Clínico Universitario San Cecilio, Granada, Spain; 6Department of Neurology, Hospital Regional Universitario de Málaga, Málaga, Spain; 7Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao, Spain; 8Department of Neurology, Hospital Universitario Fundación Alcorcón, Alcorcón, Spain; 9Department of Neurology, Hospital Universitario Lucus Augusti, Lugo, Spain; 10Department of Neurology, Hospital San Pedro de Alcántara, Cáceres, Spain; 11Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain; 12Department of Neurology, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain; 13Department of Neurology, Hospital Universitario Son Espases, Palma de Mallorca, Spain; 14Department of Neurology, Hospital Universitario de Albacete, Albacete, Spain; 15Department of Neurology, Fundació Salut Empordà, Figueres, Spain; 16Department of Neurology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 17Department of Neurology, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; 18Department of Neurology, Hospital Arnau de Vilanova, Llíria, Spain; 19Department of Neurology, Complejo Asistencial de Segovia, Segovia, Spain; 20Department of Neurology, Hospital Universitario Reina Sofía, Córdoba, SpainCorrespondence: Jorge Maurino, Ribera del Loira 50, Madrid, 28042, Spain, Tel + 34 913 24 81 00, Email jorge.maurino@roche.comPurpose: Shared decision-making is critical in multiple sclerosis (MS) due to the uncertainty of the disease trajectory over time and the large number of treatment options with differing efficacy, safety and administration characteristics. The aim of this study was to assess patients’ decisional conflict regarding the choice of a disease-modifying therapy and its associated factors in patients with mid-stage relapsing-remitting multiple sclerosis (RRMS).Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS (2017 revised McDonald criteria) and disease duration of 3 to 8 years were included. The level of uncertainty experienced by a patient when faced with making a treatment choice was assessed using the 4-item Decisional Conflict Scale. A battery of patient-reported and clinician-rated measures was administered to obtain information on symptom severity, illness perception, illness-related uncertainty, regret, MS knowledge, risk taking behavior, preferred role in the decision-making process, cognition, and self-management. Patients were recruited during routine follow-up visits and completed all questionnaires online using electronic tablets at the hospital. A multivariate logistic regression analysis was conducted.Results: A total of 201 patients were studied. Mean age (Standard deviation) was 38.7 (8.4) years and 74.1% were female. Median disease duration (Interquartile range) was 6.0 (4.0– 7.0) years. Median EDSS score was 1.0 (0– 2.0). Sixty-seven (33.3%) patients reported a decisional conflict. These patients had lower MS knowledge and more illness uncertainty, anxiety, depressive symptoms, fatigue, subjective symptom severity, a threatening illness perception, and poorer quality of life than their counterparts. Lack of decisional conflict was associated with MS knowledge (Odds ratio [OR]=1.195, 95% CI 1.045, 1.383, p=0.013), self-management (OR=1.049, 95% CI 1.013, 1.093, p=0.018), and regret after a healthcare decision (OR=0.860, 95% CI 0.756, 0.973, p=0.018) in the multivariate analysis.Conclusion: Decisional conflict regarding the selection of a disease-modifying therapy was a common phenomenon in patients with mid-stage RRMS. Identifying factors associated with decisional conflict may be useful to implement preventive strategies that help patients better understand their condition and strengthen their self-management resources.Keywords: multiple sclerosis, disease-modifying therapies, decision-making, decisional conflict, disease-related knowledge, self-management

Background: Patients with multiple sclerosis (MS) have to deal with a variable disease trajectory often associated with disability and productivity loss., Objective: This study aimed to assess illness-related uncertainty and associated correlates in patients with relapsing-remitting multiple sclerosis (RRMS) beyond the near diagnosis phase., Methods: We conducted a multicenter, non-interventional study including patients diagnosed with RRMS (2017 revised McDonald criteria) and a disease duration of 3 to 8 years. Perceived uncertainty was measured using the Mishel Uncertainty of Illness Scale (MUIS). Associations between the MUIS and different patient-based outcome measures were analyzed using Spearman's rank correlation., Results: A total of 201 patients were studied (mean age (standard deviation): 38.7 (8.4) years, 71.4 % female). The median disease duration (interquartile range) was 6.0 (4.0-7.0) years and the median EDSS score was 1.0 (0.0-2.0). The mean MUIS score was 38.2 (10.8). Perceived uncertainty was positively correlated with fatigue (p < 0.001), symptom severity (p < 0.001), anxiety (p < 0.001), depressive symptoms (p < 0.001), and a threatening illness perception (p < 0.001), and negatively correlated with self-management (p < 0.001), self-efficacy (p < 0.001), processing speed (p < 0.001), knowledge of MS (p = 0.006), and quality of life (p < 0.001)., Conclusion: Illness-related uncertainty was common in a population of mid-stage RRMS. Identifying uncertainty and its associated factors may be useful for implementing preventive strategies to help patients cope with the disease throughout life., Competing Interests: Declaration of competing interest J.S. received honoraria for lecturing, consulting or travel expenses from Biogen, Merck, Teva, Novartis, BMS, Janssen, Almirall, Roche and Sanofi. J.M-M. served on scientific advisory boards and/or received speaking honoraria, research funding and support to attend scientific meetings from Biogen, Merck, Novartis, Roche and Teva. F.B. received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi and Teva. A.A. received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall and Novartis. J.S-M. received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva; and participated in clinical trials of Biogen, Merck and Roche. L.B. received compensation for consulting services, speaking honoraria and support to attend scientific meetings from Bayer, Celgene, Biogen, Sanofi, Merck, Novartis, Roche, Almirall and Teva. M. G-G. received honoraria as speaker from Biogen, BMS, Janssen, Merck, Mylan, Novartis, Roche, Sanofi and Bial. S.E. received consulting fees and lecture honoraria from Biogen, Novartis, Sanofi, Merck, Roche and Almirall. C.C. received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi, Novartis, Biogen, Roche, and BMS. E.F-D. received honoraria and travel expenses for participation in scientific meetings and advisory boards from Almirall, Biogen, Merck, Roche and Sanofi. O.C. received honoraria for speaker services and advisory boards from Sanofi, Roche, Janssen and Merck. A.O. received research grants, travel support, advisory activities or honoraria for speaking engagements from Almirall, Biogen, BMS, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. A.L-R. received speaker and consultation fees, and congress travel support from Biogen, Janssen, Merck, Novartis, Roche and Sanofi. A. M. received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. E.A. received speaking honoraria from Roche, Novartis, Merck, Sanofi and Biogen. E.S. and J.M. are employees of Roche Farma Spain. The rest of the authors declared no potential conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Recent advances in multiple sclerosis (MS) management have shifted perspectives on treatment strategies, advocating for the early initiation of high-efficacy disease-modifying therapies (heDMTs). This perspective review discusses the rationale, benefits, and challenges associated with early heDMT initiation, reflecting on the obsolescence of the traditional "first-line" and "second-line" treatment classifications. The article emerges from the last update of the consensus document of the Spanish Society of Neurology on the treatment of MS. During its development, there was a recognized need to further discuss the concept of treatment lines and the early use of heDMTs. Evidence from randomized controlled trials and real-world studies suggests that early heDMT initiation leads to improved clinical outcomes, including reduced relapse rates, slowed disease progression, and decreased radiological activity, especially in younger patients or those in early disease stages. Despite the historical belief that heDMTs involve more risks and adverse events compared to moderate-efficacy DMTs (meDMTs), some studies have reported comparable safety profiles between early heDMTs and meDMTs, though long-term safety data are still lacking. The review also addresses the need for a personalized approach based on patient characteristics, prognostic factors, and preferences, explores the importance of therapeutic inertia, and highlights the evolving landscape of international and national guidelines that increasingly advocate for early intensive treatment approaches. The article also addresses the challenges of ensuring access to these therapies and the importance of further research to establish long-term safety and effectiveness of DMTs in MS., (© The Author(s), 2024.)

Background: People with secondary progressive multiple sclerosis (pwSPMS) experience increasing disability, which impacts negatively on their health-related quality of life (HRQoL). Our aims were to assess the impact of secondary progressive multiple sclerosis (SPMS) on functional status and HRQoL and describe the clinical profile in this population., Methods: DISCOVER is an observational, cross-sectional, multicenter study with retrospective data collection in real-world clinical practice in Spain. Sociodemographic and clinical variables, functional and cognitive scales, patient-reported outcomes (PROs), and direct healthcare, and non-healthcare and indirect costs were collected., Results: A total of 297 evaluable pwSPMS with a EDSS score between 3-6.5 participated: 62.3 % were female and 18.9 % had active SPMS. At the study visit, 77 % of them presented an Expanded Disability Scale Score (EDSS) of 6-6.5. Nearly 40 % did not receive any disease-modifying treatment. Regarding the working situation, 61.6 % were inactive due to disability. PROs: 99.3 % showed mobility impairment in EuroQoL-5 Dimensions-5 Levels, and about 60 % reported physical impact on the Multiple Sclerosis Impact Scale-29. Fatigue was present in 76.1 %, and almost 40 % reported anxiety or depression. The Symbol Digit Modalities Test was used to assess cognitive impairment; 80 % of the patients were below the mean score. Participants who presented relapses two years before and had high EDSS scores had a more negative impact on HRQoL. PwSPMS with a negative impact on HRQoL presented a higher cost burden, primarily due to indirect costs., Conclusions: PwSPMS experience a negative impact on their HRQoL, with a high physical impact, fatigue, cognitive impairment, and a high burden of indirect costs., Competing Interests: Declaration of competing interest None, (Copyright © 2024. Published by Elsevier B.V.)

A multicenter study involving 204 adults with relapsing-remitting multiple sclerosis (RRMS) assessed the dimensionality and item characteristics of the Mishel-Uncertainty of Illness Scale (MUIS), a generic self-assessment tool. Mokken analysis identified two dimensions in the MUIS with an appropriate item and overall scale scalability after excluding nonclassifiable items. A refined 12-item MUIS, employing a grade response model, effectively discriminated uncertainty levels among RRMS patients (likelihood ratio test p -value = .03). These findings suggest the potential value of the 12-item MUIS as a reliable measure for assessing uncertainty associated with the course of illness in RRMS., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: ES and JM are employees of Roche Farma Spain. JS received honoraria for lecturing, consulting, or travel expenses from Biogen, Merck, Teva, Novartis, BMS, Janssen, Almirall, Roche, and Sanofi. JMM served on scientific advisory boards and/or received speaking honoraria, research funding and support to attend scientific meetings from Biogen, Merck, Novartis, Roche, and Teva. FJB received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. AA received compensation for consulting services from Biogen, BMS, Sanofi, Roche, Janssen, and Novartis; and speaking honoraria from Biogen, BMS, Sanofi, Roche, Janssen, Merck, Almirall, and Novartis. JLSM received support to attend scientific meetings from Novartis, Merck, and Biogen; speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer, and Teva; and participated in clinical trials from Biogen, Merck, and Roche. LB received compensation for consulting services, speaking honoraria, and support to attend scientific meetings from Bayer, Celgene, Biogen, Sanofi, Merck, Novartis, Roche, Almirall, and Teva. MGG received speaking honoraria from Biogen, BMS, Janssen, Merck, Mylan, Novartis, Roche, Sanofi, and Bial. SE received consulting fees and lecture honoraria from Biogen, Novartis, Sanofi, Merck, Roche, and Almirall. CC received compensation for consulting services, speaking honoraria and support to attend scientific meetings and courses from Merck, Teva, Sanofi, Novartis, Biogen, Roche, and BMS. EFD received honoraria and travel expenses for participation in scientific meetings and advisory boards from Almirall, Biogen, Merck, Roche, and Sanofi. OC received honoraria for speaker services and advisory boards from Sanofi, Roche, Janssen, and Merck. AO received research grants, travel support, advisory activities, and honoraria for speaking from Almirall, Biogen, BMS, Merck, Mylan, Novartis, Roche, Sanofi, and Teva. ALR received speaker and consultation fees, and congress travel support from Biogen, Janssen, Merck, Novartis, Roche, and Sanofi. AM received research grants, travel support or honoraria for speaking engagements from Biogen, Merck, Novartis, Roche, Sanofi, and Teva. EA received speaking honoraria from Roche, Novartis, Merck, Sanofi, and Biogen. The rest of the authors declared no potential conflicts of interest. The abstract of this article was presented at the European Congress of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) as a poster presentation with interim findings (PCR178; Copenhagen, Denmark; November 14, 2023)., (© The Author(s), 2024.)

The last consensus statement of the Spanish Society of Neurology's Demyelinating Diseases Study Group on the treatment of multiple sclerosis (MS) was issued in 2016. Although many of the positions taken remain valid, there have been significant changes in the management and treatment of MS, both due to the approval of new drugs with different action mechanisms and due to the evolution of previously fixed concepts. This has enabled new approaches to specific situations such as pregnancy and vaccination, and the inclusion of new variables in clinical decision-making, such as the early use of high-efficacy disease-modifying therapies (DMT), consideration of the patient's perspective, and the use of such novel technologies as remote monitoring. In the light of these changes, this updated consensus statement, developed according to the Delphi method, seeks to reflect the new paradigm in the management of patients with MS, based on the available scientific evidence and the clinical expertise of the participants. The most significant recommendations are that immunomodulatory DMT be started in patients with radiologically isolated syndrome with persistent radiological activity, that patient perspectives be considered, and that the term "lines of therapy" no longer be used in the classification of DMTs (> 90% consensus). Following diagnosis of MS, the first DMT should be selected according to the presence/absence of factors of poor prognosis (whether epidemiological, clinical, radiological, or biomarkers) for the occurrence of new relapses or progression of disability; high-efficacy DMTs may be considered from disease onset., (Copyright © 2023 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis., Objective: A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain., Development: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group., Conclusion: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice., (Copyright © 2019 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Previous studies have shown that cerebrospinal fluid (CSF) kappa free light chains (K-FLCs) may have a role in MS diagnosis. In this regard, the kappa index (K-Index) has demonstrated higher sensitivity, and slightly lower specificity than oligoclonal bands (OCBs), the gold standard for the detection of intrathecal immunoglobulin synthesis, a feature of MS. Here, we evaluated the performance of the K-Index (K-Index = CSF/serum K-FLC divided by CSF/serum albumin) for the differential diagnosis of MS in a cohort of patients with suspected MS. K-FLCs were quantitatively measured in parallel serum and CSF samples by turbidimetry (Freelite Mx reagent on an Optilite system, The Binding Site Group Ltd). From 160 (63.4%) of a total of 252 patients who had K-FLC in CSF <0.03 mg/dl, below the sensitivity limit of the technique, only one had a diagnosis of MS. However, the absence of OCB in this same patient suggested no synthesis of intrathecal immunoglobulin. Globally, MS patients presented significantly higher K-Index levels than patients without an MS diagnosis (66.96 vs. 0.025, respectively; p < 0.0001). In agreement, patients with positive OCB testing also exhibited higher K-Index levels than patients negative for OCB (65.02 vs. 0.024, respectively; p < 0.0001). An optimal K-Index cutoff of 3.045 was defined by receiver operating characteristic (ROC) analysis for screening suspected MS, achieving a higher diagnostic sensitivity and slightly lower specificity than OCB (Sens. 0.9778 and Spec. 0.8629 vs. Sens. 0.8889 and Spec. 0.9086, respectively). A previously reported K-Index cutoff of 6.6 also showed good diagnostic performance (Sens. 0.9333; Spec. 0.8731), validating its power as a diagnostic biomarker for MS. Finally, a time- and cost-effective algorithm for MS screening is proposed that would offer an initial rapid evaluation of the intrathecal immunoglobulin synthesis through the K-FLC in CSF and K-Index analysis, followed by reflexing OCB testing that may be ordered more selectively., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sanz Diaz, de las Heras Flórez, Carretero Perez, Hernández Pérez and Martín García.)

Crucial elements for achieving optimal long-term outcomes in multiple sclerosis (MS) are patient confidence and effective physician-patient communication. Patient-reported instruments may provide the means to fill the gap in currently available clinician-rated measures. The SymptoMScreen (SMSS) is a brief self-assessment tool for measuring symptom severity in 12 neurologic domains commonly affected by MS. We conducted a non-interventional study to assess the dimensional structure and item characteristics of the SMSS. A total of 218 patients with relapsing-remitting MS and mild disability (median Expanded Disability Status Scale score 2.0) were studied. Symptom severity was low (SMSS score 13.5, interquartile range 4.2-27), fatigue being the domain with the highest impact. A non-parametric item response theory, i.e., Mokken analysis, found that the SMSS is a robust one-dimensional scale (overall scalability index H  0.60) with high reliability (Cronbach's alpha  0.94). The confirmatory factor analysis model confirmed the unidimensional structure (comparative fit index 1.0, root-mean-square error of approximation  0.001). Samejima's model fitted well an unconstrained model with different item difficulties. The SMSS shows appropriate psychometric characteristics and may constitute a valuable and easy-to-implement addition to measure the symptom severity in clinical practice.

Introduction: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis., Objective: A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain., Development: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group., Conclusion: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice., (Copyright © 2019 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Cognitive impairment has been reported at all phases and all subtypes of multiple sclerosis. It remains a major cause of neurological disability in young and middle-aged adults suffering from the disease. The severity and type of cognitive impairment varies considerably among individuals and can be observed both in early and in later stages. The areas which have commonly shown more deficits are: information processing speed, complex attention, memory, and executive function. Even though an alteration in both the white matter and in the gray matter has been found in patients with multiple sclerosis and cognitive impairment, the underlying process still remains unknown. Standardized neurological examinations fail to detect emerging cognitive deficits and self-reported cognitive complaints by the patients can be confounded by other subjective symptoms. This review is a comprehensive and short update of the literature on cognitive dysfunctions, the possible confounders and the impact of quality of life in patients with multiple sclerosis.