Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Cardiac autonomic dysfunction (CAD) has been reported in patients with multiple sclerosis (MS). This systematic review summarizes the evidence for the types and prevalence of CAD in MS patients, as well as its association with MS type, disease characteristics, fatigue and immunotherapies used to treat MS. The analysis revealed that CAD is correlated with pathophysiological processes of MS, can trigger serious cardiovascular complications that may reduce life expectancy, and may have implications for treatment with immunotherapies, especially fingolimod. Numerous mainly small case–control or cohort studies have reported various measures of CAD (particularly heart rate variation) in MS patients, showing higher rates of abnormality versus controls. A smaller number of studies have reported on cardiac autonomic symptoms in MS, including orthostatic intolerance/dizziness in around 50% of patients. CAD also appears to be associated with disease duration and to be more common in progressive than relapsing–remitting MS. However, although a substantial evidence base suggests that assessing CAD in people with MS may be important, standardised methods to evaluate CAD in these patients have not yet been established. In addition, no studies have yet looked at whether treating CAD can reduce the burden of MS symptoms, disease activity or the rate of progression.

CD20 depletion is a risk factor for unfavorable outcomes of COVID-19 in people with MS (pwMS). Evidence suggests that protective IgG response to mRNA-based vaccines in B cell-depleted individuals is limited. We studied the seroconversion after the third mRNA SARS-CoV-2 vaccine in B cell-depleted pwMS with limited or no IgG response after the standard immunization. Sixteen pwMS treated with ocrelizumab or rituximab received a third homologous SARS-CoV-2 mRNA vaccine, either the Moderna mRNA-1273 or Pfizer-BioNTech’s BNT162b2 vaccine. We quantified the response of IgG antibodies against the spike receptor-binding domain of SARS-CoV-2 four weeks later. An antibody titer of 100 AU/mL or more was considered clinically relevant. The median time between the last infusion of the anti-CD20 treatment and the third vaccination was 22.9 weeks (range 15.1–31.3). After the third vaccination, one out of 16 patients showed an IgG titer deemed clinically relevant. Only the seroconverted patient had measurable B-cell counts at the time of the third vaccination. The development of a humoral immune response remains rare in pwMS on anti-CD20 therapy, even after third dose of the homologous SARS-CoV-2 mRNA vaccine. It remains to be determined whether T-cell responses can compensate for the lack of seroconversion and provide sufficient protection against CoV-2 infections.

We compared changes in balance control due to chronic inflammatory demyelinating polyneuropathy (CIDP) and non-inflammatory (non-inf) polyneuropathy (PNP) to each other and with respect to healthy controls (HCs). Differences in patients’ subjective impressions of balance capabilities were also compared. Balance control of 11 CIDP patients (mean age 61.1±(sd) 11, 8 male) and 10 non-inf PNP patients (mean age 68.5±11.7, all male) was examined and compared to that of 18 age- and gender-matched healthy controls. Balance control during stance and gait tasks was measured as trunk sway angles and angular velocities with body-worn gyroscopes. Patients’ subjective impressions of balance were obtained using the Dizziness Handicap Inventory (DHI). The Neuropathy Impairment Score in the Lower Limbs (NIS-LL) was used to measure clinical disease status. Non-inf PNP patients had slightly lower NIS-LL (13.5±7.2 vs. 17.9±15.1) and DHI scores (22.6±17.1 vs 27.6±16.3). Gait tasks showed a significant decrease in gait speed with respect to HCs for both patient groups but reduced trunk sway for non-inf PNP patients. Trunk sway during tandem walking and walking on the heels was greater for both groups than that of HCs. Sway during 2-legged stance tasks with eyes closed on a firm or foam surface was also greater than for HCs. Compared to HCs both groups of patients have significantly greater sway for most stance and gait tasks accompanied by reduced gait speed. As for HCs, non-inf PNP patients reduced trunk sway with slower gait speed. In CIDP patients this compensatory strategy was absent, possibly due to a greater deficit of efferent and motor nerve fibers. An interpretation of these findings is that CIDP patients have reduced ability to decrease trunk sway with slower gait speed and is possibly associated with an increased risk of falls.

Background: Natalizumab significantly reduces the disease activity in patients with relapsing-remitting multiple sclerosis but due to the risk of progressive multifocal leukoencephalopathy it is often discontinued. Fingolimod is seen as an alternative, but there are no long-term analyses of the efficacy of fingolimod in this setting using the no evidence of disease activity (NEDA)-3 criteria. We provide an assessment of patients who discontinued natalizumab and switched to fingolimod or other treatments by evaluating the proportion of patients who fulfil NEDA-3 criteria after prolonged follow-up periods. Methods: We conducted a retrospective observational study of multiple sclerosis patients, who were treated with continuous natalizumab or who had switched to fingolimod or other treatments after natalizumab discontinuation. We assessed NEDA-3 status, annual relapse rate and determined the odds ratio between disease course after treatment switch and other patient and treatment characteristics. Results: A total of 61 patients on continuous natalizumab treatment and 53 patients who switched from natalizumab to fingolimod or other treatments were accompanied for up to 5 years. While the proportion of natalizumab patients fulfilling NEDA-3 criteria remained stable at 90% during the entire follow-up period, the proportion of patients switching to fingolimod or other therapies dropped to 76.7% in the first year after discontinuation, and to 50% in the years thereafter. While the median Expanded Disability Status Scale remained stable and the percentage of relapsing patients did not change significantly, recurring magnetic resonance imaging activity was found in up to 42% of the patients after switching from natalizumab to other treatments. New disease activity was significantly correlated with extended treatment gap between natalizumab discontinuation and the start of a new therapy. Discussion: Patients remain clinically stable after discontinuing natalizumab and switching to other therapies. However, when considering NEDA-3 criteria, a considerable proportion of patients show disease reactivation. Careful monitoring and early evaluation of alternatives is necessary after switching from natalizumab to other treatments.