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Yolanda Higueras,1 Elisa Salas,2 Virginia Meca-Lallana,3 Pedro Carrascal Rueda,4 Ofir Rodríguez De la Fuente,5 Rosana Cabello-Moruno,2 Jorge Maurino,2 Miguel Ángel Ruiz Díaz6 1Department of Neurology, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; 2Medical Department, Roche Pharma, Madrid, Spain; 3Department of Neurology, Hospital Universitario La Princesa, Madrid, Spain; 4Esclerosis Múltiple España, Madrid, Spain; 5Department of Neurology, Hospital Universitario Puerta de Hierro, Madrid, Spain; 6Universidad Autónoma de Madrid, Madrid, SpainCorrespondence: Elisa SalasMedical Department, Roche Pharma, Calle Ribera del Loira, 50, Madrid, 28042, SpainTel +34 913248173Email elisa.salas@roche.comPurpose: Patients with multiple sclerosis (MS) are increasingly demanding access to reliable information regarding their disease. The objective of the INFOSEEK-MS study was to assess what are the strategies people with MS use when searching for information on their disease, including sources, frequency, reliability, and preferred content.Patients and Methods: A non-interventional, cross-sectional study was conducted. Patients with a diagnosis of MS according to the 2010 McDonald criteria were included. The InfoSeek questionnaire was used to assess patients’ strategies when seeking information about the disease. Clinical characteristics and other variables, including disability, quality of life, fatigue, cognition, anxiety and depression, were analysed using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), 5-item Modified Fatigue Scale (MFIS-5), Symbol Digit Modalities Test (SDMT), and Hospital Anxiety and Depression Scale (HADS), respectively.Results: Three hundred and two patients were studied (mean age: 42.3 ± 10 years, 64% female, mean disease duration: 9.6 ± 7.0 years, 90% with relapsing-remitting MS, and mean EDSS score: 2.6 ± 1.9). The internet (either via mobile or computer) is a frequently reported source of information. Lifestyle-related information (67.2%), research and emerging treatments (63.6%), symptom control (49.7%), sharing experiences with other patients (46.4%), and disease prognosis (46.4%) were the most searched topics. Neurologists and nurses were the most trusted source of information. Younger patients and higher SDMT scores were associated with all search resources (M = 37.7 and M = 49.97, respectively). The frequency of searches was related to the number of relapses (R2 = 0.07), EDSS (R2 = 0.14), MSIS-29 physical and psychological components (R2 = 0.132) and inversely with depression (R2 = 0.132).Conclusion: Although healthcare professionals are considered the most reliable source of information for people with MS, searching for information on the Internet is very frequent. An individualized information strategy considering the different factors involved is needed.Keywords: multiple sclerosis, information sources, internet, quality of life, healthcare professionals

Background and purpose: Neurofilament light chain is a cytoskeletal protein of neurons. Its levels are increasingly recognized as measures of neuroaxonal damage. The aim of this study was to explore serum neurofilament light chain (sNfL) levels in multiple sclerosis (MS) patients and healthy controls during pregnancy and puerperium. Methods: This was a prospective, longitudinal, single‐center study. sNfL concentration was assessed using a highly sensitive single‐molecule array during pregnancy and in puerperium, in a cohort of 39 pregnant patients with relapsing multiple sclerosis (P‐MS). Twenty‐one healthy pregnant women (HPW) served as a control group. Eight P‐MS suffered relapses during pregnancy (P‐MS‐R) in the first or second trimesters. Results: No differences in pregnancy and delivery data were observed between P‐MS and HPW. P‐MS showed higher sNfL values than HPW in the first trimester, independently of the presence (P = 0.002) or not (P = 0.02) of relapses during pregnancy. However, in the third trimester, only P‐MS‐R showed higher sNfL values than HPW (P = 0.001). These differences extended to the puerperium, where P‐MS‐R showed higher sNfL values than those with no relapses during gestation (P = 0.02). Conclusion: These data strongly suggest that sNfL levels reflect MS activity during pregnancy. Additionally, the absence of relapses during pregnancy may have a beneficial effect on neurodegeneration during puerperium. [ABSTRACT FROM AUTHOR]

Introduction: Spasticity is a common symptom in multiple sclerosis (MS) and it is often associated with other symptoms such as spasms/cramps and pain. The concept of Spasticity-Plus syndrome takes into account that spasticity is accompanied by one or more symptoms (spasms/cramps, pain, bladder dysfunction, sleep disorders, fatigue and/or tremor). As these symptoms share a common cannabinoid control, therapy acting on cannabinoid receptors may be useful. The main study objectives were to determine the number of MS patients who met Spasticity-Plus syndrome criteria and to identify the most common symptoms., Methods: Clinical records of MS patients treated with nabiximols in a tertiary hospital from 2002 to 2022 were reviewed retrospectively., Results: Of the 73 patients included in the study, 53.4% were women, and most had secondary progressive MS (64.4%). All patients met the criteria for Spasticity-Plus syndrome: 100% had spasticity and at least another symptom. Pain was the second most common symptom (91.8%), followed by spasms/cramps (79.4%), and fatigue (76.7%). Sleep disturbances ( p  < 0.0001) and tremor ( p  < 0.027) were more frequent in patients with relapsing-remitting MS than in patients with progressive MS. No statistically significant differences were found for spasticity, pain, spasms/cramps, and fatigue between MS phenotypes. Regarding symptoms clusters, 94.4% of the patients had three or more symptoms. Spasticity was more frequently associated with pain (91.8%) and spasms/cramps (79.4%)., Conclusion: Spasticity-Plus syndrome was present in all the study population of patients with different MS phenotypes, and treated with nabiximols., 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 © 2024 Goicochea Briceño, Higueras, Ruiz Pérez, García Domínguez, Cuello, Meldaña Rivera and Martínez Ginés.)

Background: Patient disability, relapse rate, and age are used for family planning in multiple sclerosis (MS). However, the need for more accurate biomarkers is widely recognized. We aimed to explore the influence of age on neurofilament light chain (sNfL), which reflects acute inflammation; glial fibrillary acidic protein (GFAP), associated with disability progression independent of relapses; and anti-Müllerian hormone (AMH), reflecting ovarian reserve, to provide a tailored family planning strategy., Methods: This case-control study included 95 MS patients and 61 healthy control women (HCW). sNfL and GFAP levels were measured using a sensitive single-molecule array assay. AMH levels were measured by the automated Elecsys ® Anti-Müllerian Hormone Assay., Results: We observed no significant differences in AMH values between MS patients and the control group within any of the age-matched categories. Age exhibited a negative correlation with AMH values in both groups, as expected. Nevertheless, our findings suggest a slight tendency toward reduced ovarian reserve in MS patients (rho MS patients = -0.67, p < 0.0001; rho HCW = -0.43, p = 0.0006). Interestingly, among the 76 MS participants under 40 years old, we identified ten individuals (13.1%) with AMH levels below 0.7 ng/ml, indicative of a low ovarian reserve, and an additional six individuals (7.8%) with AMH levels between 0.7 ng/ml and 0.9 ng/ml, suggesting a potential risk of premature ovarian failure. Conversely, sNfL and GFAP levels in the MS group exhibited high variability but showed no significant association with age intervals., Conclusion: We found no significant differences in AMH, sNfL or GFAP values between MS patients and the control group within any of the age-matched categories. The assessment of AMH, sNFL and GFAP levels at MS onset facilitates personalized therapeutic and family planning strategies for childbearing-age women., 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 © 2024 Cuello, Meldaña Rivera, Monreal, Gómez Lozano, García Cano, García Domínguez, Fernández Velasco, Costa-Frossard França, Goicochea, Higueras, De León-Luis, Sainz De La Maza, Villarrubia, Arribas Gómez, Ruiz Perez, Martinez Ginés and Villar.)

Background: Radiologically isolated syndrome (RIS) patients might have psychiatric and cognitive deficits, which suggests an involvement of major resting-state functional networks. Notwithstanding, very little is known about the neural networks involved in RIS., Objective: To examine functional connectivity differences between RIS and healthy controls using resting-state functional magnetic resonance imaging (fMRI)., Methods: Resting-state fMRI data in 25 RIS patients and 28 healthy controls were analyzed using an independent component analysis; in addition, seed-based correlation analysis was used to obtain more information about specific differences in the functional connectivity of resting-state networks. Participants also underwent neuropsychological testing., Results: RIS patients did not differ from the healthy controls regarding age, sex, and years of education. However, in memory (verbal and visuospatial) and executive functions, RIS patients' cognitive performance was significantly worse than the healthy controls. In addition, fluid intelligence was also affected. Twelve out of 25 (48%) RIS patients failed at least one cognitive test, and six (24.0%) had cognitive impairment. Compared to healthy controls, RIS patients showed higher functional connectivity between the default mode network and the right middle and superior frontal gyri and between the central executive network and the right thalamus ( p FDR < 0.05; corrected). In addition, the seed-based correlation analysis revealed that RIS patients presented higher functional connectivity between the posterior cingulate cortex, an important hub in neural networks, and the right precuneus., Conclusion: RIS patients had abnormal brain connectivity in major resting-state neural networks and worse performance in neurocognitive tests. This entity should be considered not an "incidental finding" but an exclusively non-motor (neurocognitive) variant of multiple sclerosis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.

Background and Purpose: Short-chain fatty acids (SCFAs) can have pro- or anti-inflammatory properties, but their relationship with multiple sclerosis (MS) relapses during pregnancy remains unknown. This study aimed to explore SCFA profiles in MS patients during pregnancy and to assess their association with the appearance of relapses during pregnancy and postpartum., Methods: We prospectively included 53 pregnant MS patients and 21 healthy control women. Patients were evaluated during pregnancy and puerperium. SCFAs were measured by liquid chromatography-mass spectrometry., Results: Sixteen patients (32%) had relapses during pregnancy or puerperium, and 37 (68%) did not. All MS patients showed significant increases in acetate levels during pregnancy and the postpartum period compared to non-MS women. However, propionate and butyrate values were associated with disease activity. Their values were higher in nonrelapsing patients and remained similar to the control group in relapsing patients. The variable that best identified active patients was the propionate/acetate ratio. Ratios of <0.36 during the first trimester were associated with higher inflammatory activity (odds ratio = 165, 95% confidence interval = 10.2-239.4, p < 0.01). Most nonrelapsing patients showed values of >0.36, which were similar to those in healthy pregnant women., Conclusions: Low propionate/acetate ratio values during the first trimester of gestation identified MS patients at risk of relapses during pregnancy and the postpartum period., (© 2021 European Academy of Neurology.)

Introduction: Cognitive impairment (CI) has a prevalence of 45-70% in people with multiple sclerosis (MS), producing a negative impact on their quality of life, personal life, and work. Early detection of CI has become an important aspect to be considered for an adequate follow-up, to optimize social adaptation and to implement specific cognitive rehabilitation strategies. The aim of this work is to propose a suitable cognitive evaluation of patients with MS based on available and efficient tools for diagnosis and monitoring purposes well supported by literature review and clinical experience., Methods: A multidisciplinary panel of professionals from the field of neurology, neuropsychology, and neuroimaging performed a literature review of the topic of cognitive impairment assessment. This was combined and completed with their clinical experience to produce a set of recommendations., Results: Some limitations to cognitive evaluation are described: shortage of time and resources during the neurology consultation, scarceness or absence of specialized professionals' availability, importance of tests adaptation, and doubts about its use to define therapeutic efficiency. We recommend a baseline and annual screening evaluation, and we suggest a baseline and periodic neuropsychological assessment. The latter ought to change to a recommendation with the presence of either positive screening test, or subjective to cognitive complaints, screening-test results and patient or family report mismatch, or in specific social/work situations., Conclusions: Cognitive evaluation should be performed on all patients diagnosed with MS and throughout follow-up. It is necessary to support the creation of multidisciplinary MS teams to optimize the evaluation and follow-up of MS patients., (© 2021. The Author(s).)

Epstein-Barr virus (EBV), human herpesvirus 6A/B (HHV-6A/B) and multiple sclerosis (MS)-associated retrovirus (MSRV) have been described as possible MS triggers. We analysed antibody titres against EBV and HHV-6, and MSRV envelope (env) mRNA expression, in the serum of pregnant multiple sclerosis patients (P-MS) to study their possible link to the clinical activity of MS during pregnancy and postpartum and their possible role as relapse predictors. For that purpose, serum samples were collected from 71 pregnant women (50 pregnant MS and 21 pregnant healthy controls-P-HC) during pregnancy and postpartum. Relating to antibody titres, IgM antibody titres against HHV-6A/B were significantly higher in P-MS than in P-HC both in each pregnancy trimester and in the postpartum period. Moreover, IgM antibody titres against HHV-6A/B were higher in P-MS who suffered a relapse during the postpartum. Regarding MSRV env mRNA expression, the prevalence in the first trimester of pregnancy was significantly higher in P-MS who suffered relapses during pregnancy. Summing it up, high IgM antibody titres against HHV-6A/B and MSRV env mRNA expression during the first trimester of pregnancy could act as relapse predictors for the gestation/postpartum periods.

Multiple sclerosis (MS) is primarily an inflammatory and degenerative disease of the central nervous system, triggered by unknown environmental factors in patients with predisposing genetic risk profiles. The prevention of neurological disability is one of the essential goals to be achieved in a patient with MS. However, the pathogenic mechanisms driving the progressive phase of the disease remain unknown. It was described that the pathophysiological mechanisms associated with disease progression are present from disease onset. In daily practice, there is a lack of clinical, radiological, or biological markers that favor an early detection of the disease's progression. Different definitions of disability progression were used in clinical trials. According to the most descriptive, progression was defined as a minimum increase in the Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 from a baseline level of 0, 1.0-5.0, and 5.5, respectively. Nevertheless, the EDSS is not the most sensitive scale to assess progression, and there is no consensus regarding any specific diagnostic criteria for disability progression. This review document discusses the current pathophysiological concepts associated with MS progression, the different measurement strategies, the biomarkers associated with disability progression, and the available pharmacologic therapeutic approaches., Competing Interests: VM-L has received compensation for consulting services and speaking honoraria from Almirall, Biogen, Genzyme, Merck Serono, Novartis, Roche, Terumo, Sanofi and Teva. LB-R has received compensation for consulting services and speaking honoraria from Biogen, Sanofy-Genzyme, Merck Serono, Novartis, Roche, and Teva. JC-P has received compensation for consulting services from Roche. SE-M has received compensation for consulting services and speaking honoraria from Biogen Idec, Novartis, Merck, Bayer, Sanofi-Genzyme, Roche, and Teva. JF-L has received compensation for consulting services from Roche. LF has received compensation for consulting services from Roche, Merck, Novartis and Genzyme, for speaking honoraria from Roche, Merck and Novartis, and for traveling grants from Genzyme, Roche and Novartis. YH has received compensation for consulting services from Roche and Merck, Novartis, Teva and Genzyme, for speaking, honoraria from Roche, Merck and Novartis, and for traveling grants from Merck, Genzyme, Roche and Novartis. NT has received compensation for consulting services, traveling grants and speaking honoraria from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, Teva, and Roche. AV-J has received investigation grants Juan Rodes (JR16/00024) from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, and has received compensation for consulting services, participation in advisory boards, and speaking honoraria from Novartis, Stendhal, Roche, Teva, Biogen, and Genzyme-Sanofi. FP-M has received compensation for consulting services and speaking honoraria from Roche, Sanofi-Genzyme y Biogen, and speaking honoraria from Novartis, Almirall and Teva., (Copyright © 2021 Meca-Lallana, Berenguer-Ruiz, Carreres-Polo, Eichau-Madueño, Ferrer-Lozano, Forero, Higueras, Téllez Lara, Vidal-Jordana and Pérez-Miralles.)

Objective: To explore the serum cytokine profile associated with disease activity during pregnancy and postpartum in MS, and to assess any potential biomarkers predicting the occurrence of relapses during this period., Methods: We included 53 MS pregnant women recruited between 2007 and 2018. Interferon-gamma, Tumor necrosis factor-alpha, interleukin-17, granulocyte/macrophage-colony stimulating factor, Activin-A, interleukin-10, and programmed-death-ligand-1 (PD-L1) were measured quarterly in serum by ELISA., Results: Seventeen patients (32%) experienced relapses during pregnancy or puerperium and 37(68%) did not. We did not found differences in clinical characteristics or treatment status between the two groups. However, relapsing patients showed at the first trimester of pregnancy considerably lower levels of serum Activin-A (336.4 pg/dl [289.6-491.7], median [IQR] vs. 760.0 pg/dl [493.2-1108.0],p = .003), which correlated positively with serum PD-L1 (r = 0.53,p = .0005) and IL-10 (r = 0.43,p = .004) values. Activin-A levels lower than 515 pg/ml at the first trimester identified patients with high probability of relapsing during pregnancy and postpartum (OR = 13.75, CI: 2.5-76.8, p = .001)., Conclusions: MS patients with no relapses during pregnancy and puerperium showed an early triggering of a tolerogenic innate immune response evidenced by high serum Activin-A concentrations during the first trimester of pregnancy. Thus, serum Activin-A can be a useful biomarker to predict clinical activity during this period., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Fatigue in multiple sclerosis is a key symptom associated with work-related problems and poor quality of life outcomes. The five-item Modified Fatigue Impact Scale is a brief self-assessment tool for measuring the impact of fatigue on cognitive, physical and psychosocial function. A non-interventional, cross-sectional study was conducted to assess dimensionality and item characteristics of the five-item Modified Fatigue Impact Scale in multiple sclerosis. A total of 302 subjects were studied. Mokken analysis found the five-item Modified Fatigue Impact Scale is a strong one-dimensional scale (overall scalability index H  = 0.67) with high reliability (Cronbach's alpha = 0.90). The confirmatory factor analysis model confirmed the one-dimensional structure (comparative fit index = 1.0, root-mean-square error of approximation = 0.035). Samejima's model fitted well as an unconstrained model with different item difficulties. The five-item Modified Fatigue Impact Scale shows appropriate psychometric characteristics and may constitute a valuable and easy-to-implement addition to measure the impact of fatigue in clinical practice., (© The Author(s) 2019.)

Unlabelled: Up until now, no information has existed regarding a comparison of the pattern and frequency of cognitive deficits between radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS) patients. Within this objective, Rao's Brief Repeatable Battery and Stroop test were administered to 28 RIS patients, 25 CIS patients, and 22 healthy controls., Conclusions: The prevalence of cognitive deficits in RIS was similar to that of CIS. Cognitive deficits seem to be present in RIS patients regardless of the presence of risk factors for a future symptomatic demyelinating event., (© The Author(s), 2015.)

Background: Radiologically isolated syndrome (RIS) is characterized by incidental lesions suggestive of multiple sclerosis (MS) on MRI without typical symptoms of MS. Clinically isolated syndrome (CIS) is characterized by a first episode of neurologic symptoms caused by demyelination in the central nervous system. To date, psychiatric disorders have not been systematically addressed in RIS subjects. We assessed emotional disturbances, personality features and health-related quality of life (HRQoL) in a cohort of RIS patients as compared with clinically isolated syndrome (CIS)., Methods: Twenty-eight RIS patients, 25 clinically isolated syndrome (CIS) patients, and 22 healthy subjects were enrolled in the study. Participants were administered a mood scale (Hamilton Depression Rating Scale), behavioural measures (Personality Assessment Inventory), and fatigue measures (Fatigue Impact Scale for Daily Use). HRQoL was quantified using the EuroQol-5., Results: 14 (50%) of RIS patients had clinically significant depression, with over one-third of these having moderate depression, scores virtually identical to those observed in CIS patients. 11 of 28 (39.3%) subjects with RIS had anxious depression, a figure three times higher than that found in CIS patients. RIS patients' HAMD-17 total score showed a very strong correlation with severity of fatigue. In addition, RIS patients reported lower HRQoL (p = 0.036) and a significantly higher symptoms load for somatisation compared to both CIS and control groups (p < 0.002)., Conclusion: RIS patients had high rates of depression, particularly anxious depression and somatization. Future studies are warranted to clarify whether these psychiatric disturbances are causally associated with a distinct white matter psychopathologic process., (Copyright © 2015 Elsevier Ltd. All rights reserved.)