Multiple sclerosis (MS) is a complex chronic disease with an unknown etiology. It is considered an inflammatory demyelinating and neurodegenerative disorder of the central nervous system (CNS) ...characterized, in most cases, by an unpredictable onset of relapse and remission phases. The disease generally starts in subjects under 40; it has a higher incidence in women and is described as a multifactorial disorder due to the interaction between genetic and environmental risk factors. Unfortunately, there is currently no definitive cure for MS. Still, therapies can modify the disease’s natural history, reducing the relapse rate and slowing the progression of the disease or managing symptoms.
The limited access to human CNS tissue slows down. It limits the progression of research on MS. This limit has been partially overcome over the years by developing various experimental models to study this disease. Animal models of autoimmune demyelination, such as experimental autoimmune encephalomyelitis (EAE) and viral and toxin or transgenic MS models, represent the most significant part of MS research approaches. These models have now been complemented by ex vivo studies, using organotypic brain slice cultures and in vitro, through induced Pluripotent Stem cells (iPSCs). We will discuss which clinical features of the disorders might be reproduced and investigated in vivo, ex vivo, and in vitro in models commonly used in MS research to understand the processes behind the neuropathological events occurring in the CNS of MS patients. The primary purpose of this review is to give the reader a global view of the main paradigms used in MS research, spacing from the classical animal models to transgenic mice and 2D and 3D cultures.
•Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system (CNS).•Several preclinical models that reproduce different aspects of the disease are used in MS research.•Transgenic and humanized mice models contribute to the understanding of key pathophysiological mechanisms underlying MS.•The use of in vitro models gives new opportunities and perspectives for the study of MS.
Background and purpose
There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of ...highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS.
Methods
Patients with relapsing–remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis.
Results
A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound.
Conclusions
The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described.
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Emerging evidence suggests the prognostic value of spinal cord (SC) pathology in multiple sclerosis (MS). However, the 2021 MAGNIMS-CMSC-NAIMS guidelines don't recommend routine SC MRI for disease ...monitoring. This study investigates the frequency of new asymptomatic and isolated SC lesions, exploring their potential to predict clinical activity and guide treatment decisions.
We enrolled relapsing-remitting MS (RRMS) patients who underwent brain and SC MRI at baseline and after 12 months. New, enlarged, or gadolinium-enhanced (Gd+) lesions on MRI were considered disease activity markers. Clinical relapses and treatment changes observed 3 months after the 12-month MRI were analyzed using regression analysis, evaluating their association with worsening SC findings.
A total of 201 RRMS patients (56 males, 27.9%, mean age 42.5 ± 12.1 years, mean EDSS 2.7 ± 1.9) were included. Isolated worsening of T2 lesion burden in the SC occurred in 16 patients (8%), and 12 (6%) had Gd + lesions. Among patients without brain MRI activity (n = 138), regression analysis revealed a significant association between new Gd + SC lesions and clinical relapses within 3 months of the 12-month MRI (p = 0.024). Worsening SC findings (p = 0.021) and SC lesion enhancement (p = 0.046) emerged as key factors influencing disease-modifying therapy changes within 3 months in these patients. Notably, even without clinical symptoms, worsening SC findings significantly predicted treatment changes (p = 0.003).
Our findings highlight the independent value of SC MRI findings in MS monitoring. Importantly, isolated and asymptomatic SC worsening significantly impacted treatment decisions.
•This study investigated the frequency of new, asymptomatic, and isolated spinal cord (SC) lesions in relapsing-remitting MS (RRMS) patients.•The study aimed to assess the potential of SC lesions for predicting clinical activity and guiding treatment decisions.•This study suggests that SC MRI may aid MS monitoring & treatment decisions beyond brain MRI.
•In the current therapeutic scenario, new drugs are available for patients with progressively active MS.•The review critically analyzes the current measures to assess treatment response in ...progressive MS.•The impact of age and comorbidities on the assessment of MS outcomes is also examined.•A more comprehensive and patient-centered approach to evaluating DMT efficacy is discussed.
New treatment options are available for active progressive multiple sclerosis (MS), including primary and secondary progressive forms. Several pieces of evidence have recently suggested a “window of beneficial treatment opportunities,” principally in the early stages of progression. However, for progressive MS, which is characterised by an inevitable tendency to get worse, it is crucial to redefine the “response to treatment” beyond the concept of “no evidence of disease activity” (NEDA-3), which was initially conceived to evaluate disease outcomes in relapsing-remitting form, albeit it is currently applied to all MS cases in clinical practice. This review examines the current perspectives and limitations in assessing the effectiveness of DMTs and disease outcomes in progressive MS, the current criteria applied in defining the response to DMTs, and the strengths and limitations of clinical scales and tools for evaluating MS evolution and patient perception. Additionally, the impact of age and comorbidities on the assessment of MS outcomes was examined.
The present study aims to describe the evolution of teriflunomide use for multiple sclerosis (MS) in the clinical setting, in particular for naïve patients and young women. Predictors of treatment ...response were also investigated.
This was an independent, retrospective, real-world monocentric study. We analysed the use of teriflunomide from 2016 to 2020 in patients categorized as naïve or switchers, and assessed the variations in its use in men and women by age group. Clinical and MRI data of treated patients were evaluated, and NEDA-3 status at 24 and 36 months was defined. Determinants of therapeutic response were examined using regression analysis.
The study included 319 MS patients exposed to teriflunomide 209 women (65.5%). Of these, 67 (21%) were naïve and 252 (79%) were switchers. A 20% increase of teriflunomide use in the naïve group in the past two years, particularly in 2020, the first year of global Sars-Cov-2 spread, was observed. An increase of teriflunomide use of more than 10% in young women under age 45 was also reported. NEDA-3 status was calculated for 204 patients after 24 months and was achieved in 120 (58.8%) of these ones. NEDA-3 was also achieved in 92/160 (56.8%) patients at 36 months. A lower ARR in the two years prior to teriflunomide treatment (p = 0.026), lower baseline age (p = 0.05), and lower EDSS score (p = 0.009) were associated with achievement of the NEDA-3.
Our study confirms a major evolution in teriflunomide use in clinical settings, particularly for naïve patients and young women.
•Teriflunomide use has progressively increased for treatment of Multiple Sclerosis (MS).•In the last two years, we described a 20% and 10% increase of its use in naïve patients and young women.•The efficacy goal of NEDA-3 at 24 and 36 months was achieved in more than 55% patients.•An adequate shared decision-making process is necessary to identify the best candidate patient.
The relationship between cognitive assessment results in multiple sclerosis (MS) and performance in daily activities (DAs) remains unclear. Our study aimed to evaluate the relationship between ...cognitive functions (CF) measured by tests, performance in DAs, and the perception of CF in patients and their caregivers (CG) in MS.
The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery was used to evaluate cognitive status. We created an ad hoc questionnaire (DaQ) to assess performance in DAs not requiring specific motor skills. We used the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) to measure each patient self-judgment and caregiver's perception of CF.
Forty-nine patients and their caregivers were included in the study. Significant correlations were found between the BICAMS and the DaQ (Symbol Digit Modalities Test (SDMT): r = - 0.48, p < 0.001; California Verbal Learning Test (CVLT): r = - 0.33, p = 0.01; Brief Visual Memory Test (BVMT-R): r = - 0.42; p = 0.002); patients self-judgment (SDMT: r = - 0.38, p = 0.004; CVLT: r = - 0.26, p = 0.03); caregiver perception of patient's CF (SDMT: r = - 0.52, p < 0.001; CVLT: r = - 0.3, p = 0.01; BVMT-R: r = - 0.42, p = 0.002). The difference in perception between the patients and their caregivers was related to patient age (p = 0.001) and severity of cognitive impairment (p = 0.03).
Cognitive assessment results show a significant correlation with performance in daily activities and with patients and, especially, caregiver perception of cognitive impairment. These data support the importance of a routine evaluation of cognitive function in MS that includes an anamnestic evaluation of patients, and, when possible, consideration of the caregiver's point of view.
Agri-environmental measures improve the environment in the Veneto Region, Italy.Agroecosystems benefit from the adoption of continuous soil cover and minimal soil disturbance.DAYCENT model ...simulates correctly nutrients and C dynamics.Agri-environmental policies can be improved with a result-oriented approach.
Many efforts have been made in Europe to improve the environmental quality of agro-ecosystems. Since the 2000s, agri-environmental measures (AEMs) have been financed and implemented in EU countries, although their beneficial effects are still questioned due to poorly targeted environmental issues and a lack of site-specific payments. Indeed, estimates of AEM outcomes at the territorial level require considerable efforts to consider simultaneously multiple environmental objectives with multiple targets. As a result, a DAYCENT model-GIS platform was developed that integrates multiple types of pedo-climatic and land management information. The aim was to provide a decision support system for spatially evaluating and selecting the best AEMs in terms of soil, water and air quality, when compared with a standard scenario without any adopted measure. Our modelled results showed that in the Veneto Region, north-eastern Italy, the AEMs applied from 2007 to 2013 improved the environmental value of the agro-ecosystems, especially in terms of soil and water quality. Continuous soil cover, reduction of soil disturbance through grasslands, conservation agriculture and cover crops were the best simulated strategies to increase soil organic matter content (+25%) and reduce nitrogen leaching (⿿90%). These strategies were also able to sharply reduce soil water erosion (⿿86%) and as a consequence P loss, in particular in the steep hilly and mountain areas, although their application to arable lands in those landscapes is still rare. In contrast, care should be taken in the long-term regarding an increase in P leaching, since predictions up to +0.15kgha⿿1y⿿1 are reached compared to the standard scenario. Finally, greenhouse gas (GHG) emissions (N2O and CH4) were reduced mainly due to increased fertilisation efficiency. The proposed method can be a flexible decision support tool for a result-oriented and scientifically-based evaluation of AEMs that may help policy makers to evaluate the most effective measures for increasing the environmental value of agro-ecosystems.
Several studies indicated leukocyte telomere length (LTL) as a biomarker of multiple sclerosis (MS) evolution. This study aimed to investigate LTL in women with multiple sclerosis (MS) compared to ...that in healthy women (HW) across different reproductive phases, and to evaluate its relationship with MS activity.
Blood samples were collected from women with MS and HW during the fertile phase, pregnancy, and puerperium. LTL was determined using quantitative fluorescence in situ hybridization (Q-FISH).
Blood samples from 68 women with MS (22 during fertile life, 23 during pregnancy, and 23 post-partum) and 52 HW (23 during fertile life, 20 during pregnancy, and 9 post-partum) were analyzed. During pregnancy, LTL in MS women and HW was 84.7 ± 10.5 and 77.6 ± 11.5, respectively (p < 0.005). Regression analysis showed that shorter LTL was associated with pregnancy in HW (p = 0.021); this relationship was not observed in MS women, for whom shorter LTL was related to a higher EDSS (p = 0.036). A longitudinal analysis was performed in eight MS women, showing LTL shortening from pregnancy to puerperium (p = 0.003), which was related to MS reactivation (p = 0.042).
Our results highlight the possible associations between LTL, reproductive biological phases, and MS activity after delivery.
•Telomere length (TL) is hypothesized to be an indicator of Multiple Sclerosis (MS) evolution.•Beneficial effects of pregnancy on MS activity have been reported.•Conversely, MS reactivation is frequently reported in the post-partum period.•This study evaluated associations between TL, reproductive biological phases, and MS activity.•From pregnancy to puerperium, an LTL shortening was reported, also related to MS reactivation.
Introduction
C
ladribine is an oral immune reconstitution therapy for relapsing multiple sclerosis (RMS). Hormonal and immune changes are responsible for the decline of disease activity in the third ...trimester of pregnancy and disease reactivation in the early post-partum period.We investigate the impact of pregnancy on disease activity in women with MS who conceived after cladribine treatment.
Methods
We recruited women of childbearing age with relapsing–remitting MS (RRMS) who became pregnant or not after being treated with cladribine. For both groups, demographic, clinical and radiological data were collected 1 year before and after treatment during a mean follow-up of 3.53 years. We compared disease activity over time between groups using variance analysis for repeated measures.
Results
48 childbearing women were included. 25 women had a pregnancy after a mean of 1.75 years from the first treatment cycle. Women with or without pregnancy did not differ in demographics or pre-cladribine disease activity. No significant differences in disease activity or EDSS worsening were found between women with or without pregnancy.
Discussion
Our findings suggest that pregnancy does not appear to influence disease activity and disability in women previously treated with cladribine; further studies with larger numbers and longer follow-up are needed to confirm this finding.
Given the aging population, with a peak age-specific prevalence that is shifting beyond the age of 50, several women currently living with MS are very close to menopause. Menopause is usually ...characterized by several specific symptoms with adverse impacts on different aspects of a woman's quality of life, such as fatigue, and cognitive, mood and bladder disorders, which overlap with symptoms of MS. Generally, after this biological transition, women with MS appear to be subject to less inflammatory activity. However, several studies have reported an increase of disability accumulation after menopause, suggesting that it is a turning point to a more progressive phase of the disease. This may be attributable to the hormonal and immunological changes associated with menopause, with several effects on neuroinflammation and neurodegeneration increasing due to the immunosenescence of aging. This review summarizes the hormonal and immunological changes associated with menopause, detailing the effects on MS symptoms, outcomes, and the aging process. Furthermore, possible interventions to improve patients' quality of life are evaluated. In fact, it is increasingly necessary to improve the global management of MS women, as well as their lives, at this multifaceted turning point.
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