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Despite being a common issue in people with multiple sclerosis (pwMS), sexual dysfunction is still underinvestigated. This work aims to assess the potential determinants of sexual dysfunction in pwMS by considering its relationship with disease severity (in terms of global disability), illness perception, and depressive symptoms. In this multicenter study, 1010 pwMS responded to an online survey. A serial mediation model considering negative illness perception and depressive symptoms as mediators of the relationship between disease severity and sexual dysfunction was conducted using the SPSS PROCESS Macro with bias-corrected bootstrapping (5000 samples). Disease severity exerts an indirect effect on sexual dysfunction via illness perception, both independently and through depressive symptoms. However, the results indicated that illness perception plays a more crucial role in sexual dysfunction in pwMS with mild disability than in pwMS with moderate-severe disability. This study suggests that higher disability increases its magnitude by enhancing negative illness perception, that, in turn, affects sexual dysfunction both directly and through depressive symptoms, especially in pwMS with mild disability. Modulating the effect of illness perception by favoring adaptive coping strategies might represent a valid approach to mitigate sexual dysfunction symptoms in MS.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, the neurobiological mechanisms underlying the rTMS therapeutic effects are still only partially investigated. Maladaptive plasticity, glial activation, and neuroinflammation, including metalloproteases (MMPs) activation, might represent new potential targets of the neurodegenerative process and progression from MCI to AD. In this study, we aimed to evaluate the effects of bilateral rTMS over the dorsolateral prefrontal cortex (DLPFC) on plasmatic levels of MMP1, -2, -9, and -10; MMPs-related tissue inhibitors TIMP1 and TIMP2; and cognitive performances in MCI patients. Patients received high-frequency (10 Hz) rTMS (MCI-TMS, n = 9) or sham stimulation (MCI-C, n = 9) daily for four weeks, and they were monitored for six months after TMS. The plasmatic levels of MMPs and TIMPs and the cognitive and behavioral scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Beck Depression Inventory II, Beck Anxiety Inventory, and Apathy Evaluation Scale, were assessed at baseline (T0) and after 1 month (T1) and 6 months (T2) since rTMS. In the MCI-TMS group, at T2, plasmatic levels of MMP1, -9, and -10 were reduced and paralleled by increased plasmatic levels of TIMP1 and TIMP2 and improvement of visuospatial performances. In conclusion, our findings suggest that targeting DLPFC by rTMS might result in the long-term modulation of the MMPs/TIMPs system in MCI patients and the neurobiological mechanisms associated with MCI progression to dementia.

Background: Many factors are believed to be positively associated with the incidence of relapses in people with multiple sclerosis (MS), including infections. However, their role is still controversial. We aimed to investigate whether symptomatic infections in people with MS increase the risk of relapse in the short, medium, or long term. Materials and Methods: We enrolled consecutive patients with relapsing MS (RMS) from October to December 2018. From enrolment up to September 2020, an online questionnaire investigating the occurrence of infections was sent via WhatsApp® monthly to the enrolled patients, while in-person visits were performed every six months. When patients complained of symptoms compatible with relapses, they attended an extra in-person visit. Results: We enrolled 155 patients with RMS, and 88.38% of patients were treated with disease-modifying therapies. In the dataset, 126,381 total patient days, 78 relapses, and 1202 infections were recorded over a period of about 2 years. No increased risk of relapse after clinically manifest infections was found in the short-, medium-, or long-term period. No correlation was found between all infections and the number of relapses (p = 0.212). The main analyses were repeated considering only those infections that had at least two of the following characteristics: duration of infection ≥ 4 days, body temperature > 37° Celsius, and the use of drugs (antibiotics and/or antivirals), and no significant associations were observed. Conclusions: No associations between infections and relapses were observed, likely suggesting that disease-modifying therapies may protect against the risk of relapse potentially triggered by infections.

Siponimod, a selective modulator of sphingosine 1-phosphate receptors 1 (S1P1) and 5 (S1P5), has recently been marketed for patients with Secondary Progressive Multiple Sclerosis (SPMS). Herein, we report three SPMS patients presenting disease reactivation in the first three months after switching from fingolimod to siponimod. Fingolimod binds to S1P1, S1P3, S1P4 and S1P5 receptors. S1P3 holds a central role in eliciting central proinflammatory responses, thus it has been hypothesized that upregulation of S1P3 may be the mechanism behind relapses after switching from fingolimod to siponimod. Further studies are needed to investigate the safety and efficacy of this treatment sequencing.

Cognitive impairment (CI) occurs in about 40–65% of people with multiple sclerosis (MS) during the disease course. Cognitive rehabilitation has produced non-univocal results in MS patients. Objective: The present study aimed to evaluate whether an Integrated Cognitive Rehabilitation Program (ICRP) in MS patients might significantly improve CI. Methods: Forty patients with three phenotypes of MS were randomly assigned into two groups: the experimental group (EG, n = 20), which participated in the ICRP for 10 weeks of training; and the control group (CG, n = 20). All participants’ cognitive functions were assessed at three timepoints (baseline, post-treatment, and 3-month follow-up) with the California Verbal Learning (CVLT), Brief Visuospatial Memory (BVMTR), Numerical Stroop, and Wisconsin tests. Results: When compared to CG patients, EG patients showed significant improvements in several measures of cognitive performance after ICRP, including verbal learning, visuospatial memory, attention, and executive functions. Conclusions: Home-based ICRP can improve cognitive functions and prevent the deterioration of patients’ cognitive deficits. As an integrated cognitive rehabilitation program aimed at potentiation of restorative and compensatory mechanisms, this approach might suggest an effective role in preserving neuronal flexibility as well as limiting the progression of cognitive dysfunction in MS.