A multiple sclerosis training using the kinect-based MSFIT exergame. An Italian multicenter feasibility study

Introduction: Balance impairments are common in multiple sclerosis (MS). Pilates is a popular alternative method for balance performance maintenance and improvement that may reduce the rapid symptoms worsening frequently associated with physical inactivity. An Italian network of fifteen experts in MS rehabilitation developed through a User-Centered Design approach the MS-FIT exergame, a Kinect-based tool, to autonomously train balance through Pilates exercises. The MS-FIT user executes the exercises shown by a teacher's avatar and improves the performances through the feedbacks on the execution correctness. Aim(s): This study (Clinical.Trials.gov, NCT04011579) aims at evaluating the feasibility of an at-home intervention with MS-FIT. Method(s): Feasibility was investigated in terms of adherence (sessions number), usability (usability items of Tele-healthcare Satisfaction Questionnaire, u-TSQ, satisfaction (Client Satisfaction Questionnaire, CSQ-8), safety (adverse events), and physical effectiveness (Timed UP-&-GO, TUG;Timed 25-Foot Walk, T25FW;2-Minutes Walking Test, 2MWT). Result(s): Forty-five people with MS (PwMS) were enrolled and randomized into the experimental (EXP, n=23) and control (CTRL, n=22) groups. During the 6 weeks of the study, only the usual physical activities were admitted (rehabilitation excluded) and, in addition, EXP had to practice MS-FIT at least three times a week. Due to organizational consequences of COVID pandemic, 8 subjects dropped-out (EXP, n=17;CTRL, n=20). The sample analysed showed the following characteristics: gender (EXP: 6M;CTRL: 7M), age (EXP: 41.9+/-9.6y;CTRL: 43.3+/-10.5y), course (EXP: 94.4% and CTRL: 95.0% relapsing-remitting), disease duration (EXP: 9.9+/-7.2y;CTRL: 12.5+/-9.8y) and EDSS (EXP: 2.6+/-0.8;CTRL: 2.6+/-0.8). EXP highly adhered to the MS-FIT training (23.6+/-6.1 sessions);the tool was usable (u-TSQ: 3.01/4);satisfaction was medium-tohigh (CSQ-8: 25.1/32);the training with MS-FIT was safe (no adverse events). The groups did not differ in TUG, T25FW and 2MWT. An analysis separate for each group showed a significant improvement only in EXP (TUG: pre 7.5+/-1.2s, post 7.0+/-1.2s, p<0.05;T25FW: pre 6.1+/-1.5s, post 5.0+/-1.2s, p<0.01;2MWT: pre 175.4+/-51.0m, post 194.1+/-56.9m, p<0.01). Conclusion(s): MS-FIT is well-accepted and effective and could be a complement of traditional MS interventions. Based on the results and participants' feedbacks MS-FIT has been refined and is used in an ongoing randomized controlled trial.

Effect of SARS-CoV-2 mRNA vaccination in multiple sclerosis patients treated with disease modifying therapies

Introduction: In patients with Multiple Sclerosis (pwMS) disease- modifying therapies (DMTs) are known to affect immune response to antigens and possibly to SARS-CoV2 vaccine. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Objectives and aims: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARSCov- 2 vaccination with mRNA vaccines (BNT162b2, Pfizer/ BioNTech, Inc or mRNA-1273, Moderna Tx, Inc) to evaluate their effect on SARS-CoV-2 antibody response. Methods: A blood collection for the measure of SARS-CoV-2 antibody before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized and blinded serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche Diagnostics). Results: Preliminary data were collected on 780 pwMS (76% BNT162b2 and 24% mRNA-1273) who had pre- and 4-week post-vaccination blood assessments. 87 (11.2%) were untreated, 154 (19.7%) on ocrelizumab, 25 (3.2%) on rituximab, 85 (10.9%) on fingolimod, 25 (3.2%) on cladribine and 404 (51.7%) on other DMTs. 677 patients (86.8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariate analysis, the antibody levels of patients on ocrelizumab (178-fold decrease, p<0.001), fingolimod (26-fold decrease, p<0.001) and rituximab (17-fold decrease, p<0.001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3.5-fold higher antibody level than with the BNT162b2 vaccine (p<0.001). Interpretation: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3.5-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those that will be produced by studying the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. At the time of the ECTRIMS presentation data on the full sample (about 2000 subjects) will be presented.

An analysis of main symptoms of COVID-19 in MS patients and related risk factors

Introduction: MS patients affected by SARS-CoV-2 disease may present with a wide pattern of symptoms, not always suggestive of the severity of infection. A recent study has shown that main symptoms of Covid-19 can be grouped in seven different clusters. Risk and protective factors for their occurrence in MS patients has never been investigated. Objectives: To identify the most common symptoms of Covid-19 that are part of specific clusters in MS patients and evaluate all factors associated with their manifestation. Methods: As part of the MuSC-19 Italian project, all data were extracted from a dedicated web-based platform that allows researchers to evaluate the impact of Covid-19 on people affected by MS. After having tested the degree of agreement between different types of symptoms (Cohen's k), univariate and multivariate logistic regression models were applied to identify predicting factors for each group. Results: 1554 MS patients with confirmed Covid-19 and presenting at least one symptom referred to a specific cluster were analyzed. Patients presented nearly three groups of symptoms (mean: 2.8). The most common include fever/chills/rigor/fatigue/ cough (87%), followed by ageusia/anosmia (46%). Smoking habit was the most confirmed risk factor for developing a wide range of symptoms: common cold-like symptoms (OR:1.6, 95%CI:1.3- 2.1;p<0.001), joint and muscle pain (OR:1.3, 95%CI:1.1-1.7;p=0.037), gastrointestinal problems (OR:1.3, 95%CI: 1.1-1.7;p = 0.029), and loss of smell/taste (OR:1.4, 95%CI: 1.07-1.72;p=0.013). Smoking was confirmed also as risk factor for increasing the number of symptoms (OR:1.5, 95%CI:1.2-1.8;p<0.001), together with alcohol use (OR:1.25, 95%CI:1.1-1.5;p=0.021) and with assumption of anti-CD20 therapies (OR:1.7, 95%CI:1.2-2.5;p=0.004). Males have a lower risk for developing a major number of symptoms (OR:0.8, 95%CI:0.6 - 0.9;p=0.006). Finally, a lower EDSS was associated to a slight increment of symptoms, probably due to an already underlying presence of some common symptoms in most critical MS patients, which consequently were not reported (OR:0.9, 95%CI:0.8-0.9;p=0.005). Conclusions: Knowing possible risk factors and modifying some lifestyle behaviors might minimize the occurrence of Covid-19 symptoms. Anyway, further studies are needed for confirming these findings, and an additional follow up study on the presence of persistent symptoms after apparent Covid-19 resolution may help to better understand all possible risk factors.

Is the multiple sclerosis population of the rehabilitation centers vulnerable during the COVID-19 pandemic?

Introduction: During the COVID-19 pandemic, the multidisciplinary team involved in the care of people with Multiple Sclerosis (pwMS) had to deal with many due to the vulnerability of these patients. A possible way to guarantee their management has been to use digital tools for surveillance and monitoring through remote contacts (telephone calls and e mails) to assess symptoms and needs. Aim: The aim of the study was to describe the vulnerability degree of a sample of pwMS that attend the rehabilitation centers at the beginning of the Covid-19 Pandemic. Methods: During April 1, 2020, to April 30, 2020 a multicenter observational retrospective study was conduct. The enrolment took place in five rehabilitation centers of North Italy (part of the country heavily affected by SARS-CoV-2 diffusion at the beginning of the Pandemic that followed mainly MS patients. Results: 2106 patients have been contacted, 2072 responded to the telephone interview about presence of symptoms and signs of Covid-19 infection (response rate: 98%). 99 (4.8%) subjects have been identified as Covid-19: 10 confirmed cases (tested positive for Covid-19) and 89 suspected Covid-19 symptoms. Two subjects (2.0%) were dead. There were no significant differences in gender, levels of disability (EDSS score) and use of disease modifying treatment between subjects with and those without Covid- 19. The Covid-19 patients had a younger age (53.1±10.4 vs. 56.5±12.7, p=0.06), a different distribution of MS course (16.2% vs 12.9% PP form;29.3% vs. 44.0% SP form and 54.5% vs 43.15 RR form, respectively, p=0.016) and a shorter duration of illness (12.6±10.6 vs. 17.2±11.1, p<0.001) than Covid-19 free ones. Conclusions: The MS Covid cases analyzed were younger, with lower percentages of SP form and with shorter disease duration than MS subjects Covid free. This could be explained by the higher probability to be in contact with other people and so higher probability of infection. In fact, subjects younger and with less severe form of disease have higher probability to move, work and to have social contacts. In conclusion, during the pandemic period the restriction to move are resulted the most effective indications, so it is urgent to implement use digital tools for surveillance and monitoring through remote contacts.

The impact of PM2.5 on COVID-19 severity among Italian MS patients

Introduction: Studies have pointed out that air pollution longterm exposure may play a role in the severity and prognosis of SARS-CoV-2 infections. Additionally, air pollution has been associated to MS prevalence and course. However, the role of air pollution in COVID-19 severity has never been explored specifically among MS patients. Aims: To explore the association between air pollution assessed by PM2.5 levels and COVID-19 severity among MS patients. Methods: Demographic and clinical characteristics as well as data about Covid-19 severity were extracted from an Italian webbased platform (Musc-19 project) containing clinician-reported data from 118 Italian MS centers. PM2.5 ground-level concentrations were derived from air quality model results, as provided by the 'Copernicus Atmospheric Monitoring Service' (CAMS). Ordered logistic regression models were used to assess the association between PM2.5 (continuous and in tertiles) and Covid-19 prognosis (defined on three levels as mild course, hospitalization, and intensive care unit (ICU) admission or death) while controlling for possible confounders. Results: PM2.5 concentrations were available for 1517 MS patients, of whom 1321(87%) were classified as mild Covid-19 cases, 172(11%) were hospitalized and 24(2%) were admitted to ICU or died. Higher concentrations of PM2.5 were associated with increased odds of developing a worst Covid-19 prognosis (10-unit increase in PM2.5: OR(95% CI)=1.76(1.16-2.67) p-value=0.008;3rd vs 1st tertile: OR(95% CI)=1.74(1.17-2.59) p-value=0.006). Results remained consistent when we included only the Covid-19 cases confirmed by a nasopharyngeal swab (N=1087). Conclusions: Higher concentrations of PM2.5 are associated with Covid-19 severity among MS patients. Further studies are needed to evaluate the impact of other air pollutants, but urgent measures to reduce air pollution must be surely adopted.

Pandemia in the life of persons with MS in Italy

Inroduction: Persons with MS (PwMS) need regular access to healthcare and social inclusion services to maintain their wellbeing and quality of life. The Covid-19 pandemic caused discontinuities to a broad range of services, because much of the health system's efforts were diverted towards the response to Covid patients, and because social distancing reduced the capacity of care providers overall. Some providers implemented various forms of telemedicine and remote monitoring to minimize discontinuities. Aim: To investigate on the reported impact of the pandemic on availability of services, on the perceived health status and psychological wellbeing of PwMS. Methods: 1,797 PwMS living in Italy participated to an online survey carried out by the Italian MS Society (AISM) between March 18, 2020 and April 8, 2021. Participants were recruited through AISM's website and social network pages, and via email to PwMS who had provided their address and agreed to be invited to regular surveys. Results: The sample is consistent with the known characteristics of the Italian population with MS, based on age, gender and area of residence (albeit with a slight underrepresentation of those living in the southern and insular regions). 64% of PwMS needed health care during the year of the pandemic, but 42% of them could not receive all the care they needed, 27% needed psychological support and 50% could not receive all of it. 32% needed rehabilitation, and 65% of them could not receive all of it. 26% needed personal care and support, and 68% of them could not receive all of it. 22% felt that their MS got worse because of the pandemic, especially those with self-reported EDSS >=6 (37%). 62% reported feeling isolated, 51% felt anxious, 40% felt depressed and 28% felt abandoned because of the pandemic. 45% reported that they could receive some form of remote monitoring, while 10% could receive some remote therapy. Conclusions: Despite the availability of some remote services, the pandemic had a negative impact on the accessibility of a broad range of services needed by PwMS in Italy. Many Italian PwMS attribute to the pandemic the negative evolution of their MS and their current psychological discomfort.

The risk of COVID-19 in people with multiple sclerosis: A case-control study from the Italian MS Register

Background: Data collected from several international platforms provided important information about risk factors, including treatment exposure, impacting COVID-19 severity in people with multiple sclerosis (PwMS). However, up to now, factors increasing the risk of getting SARS-CoV2 infection in PwMS are not known. MS registers represent a suitable tool to provide denominators for risks assessment. Objectives: To assess risk factors for SARS-CoV2 infection in PwMS by using data collected in the Italian MS Register (IMSR). Methods: A case-control (1-2) study was set-up. PwMS with (cases) and without (controls) COVID-19 were identified within the IMRS and propensity-score matched by the date of COVID-19 diagnosis (cases) and the date of last visit (controls) and for the region of residence. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The role of DMTs exposure was assessed in 3 different models including: last recorded DMT or DMT sequences (induction strategy/escalation strategy/only first line DMT exposure/ never treated) or last DMTs grouped according to the place of administration (at hospital or self-administered at home). A minimal treatment exposure for each DMT was defined on the basis of the recognized minimal time required to be potentially effective. Results: A total of 779 [median (IQR) age: 42.40 years (33.00- 50.80);30.17% male] confirmed COVID-19 cases were matched to 1558 controls [46.90 years (37.50-55.70);35.82% male]. In all models, comorbidities, female sex and age were significantly associated (p<0.02) to a higher risk of getting COVID-19. Patients receiving Natalizumab as last DMT (OR (95% CI): 2.38(1.66-3.42), p<0.0001) and those who underwent an escalation treatment strategy (1.57 (1.16-2.13), p=0.003) were at significant higher COVID-19 risk. Moreover, the group of PwMS receiving last DMTs requiring hospital access (1.65(1.34-2.04), p<0.0001) showed a significant higher risk than those taking selfadministered DMTs at home. Conclusions: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to increase significantly the risk SARS-CoV2 infection in PwMS.

Different disease modifying therapies can increase or decrease Covid-19 severity in Multiple Sclerosis

Objective: To describe the effect of disease modifying therapies (DMT) on Covid-19 severity in a large cohort of Italian patients with Covid-19 and multiple sclerosis (MS). Background: We previously presented data from a nationwide study of persons with MS with suspected or confirmed Covid-19, collected from March 2020. In June we started collecting also asymptomatic patients, when serological tests started to be routinely done. Design/Methods: This was a retrospective multi-center observational study. We defined Covid-19 severity as a 4-level variable: Level 1=asymptomatic, level 2=symptomatic without signs of pneumonia, level 3=radiologically defined pneumonia or hospitalization, level 4=intensive care unit (ICU) or death. We analysed the impact of baseline variables on this outcome by a multivariable ordinal logistic model quantifying the association by Odds Ratio (OR). Results: On October 12, we enrolled 902 MS patients, 298 (33%) with confirmed and 604 (67%) with suspected Covid-19;37 (4%) were asymptomatic. The number of ICU/deaths were 8/95 (8%) among those treated with anti-CD20 therapies (mean age=41 years), 0/84 (0%) among those treated with Interferon (mean age=47 years) and 37/723 (5%) among those treated with other drugs (mean age=43 years). Among the 37 asymptomatic patients, 7/84 (8.3%) were in Interferon, 1/95 (1.1%) was on anti-CD20 and 29/723 (4%) were on other drugs. At multivariable analysis, independent risk factors for a severe Covid-19 were age (OR=1.05, p<0.001), EDSS(OR=1.13, p=0.02), Male sex(OR=1.44, p=0.057) and DMT used: Treatment with anti-CD20 (Ocrelizumab or Rituximab) increased the risk (OR=1.99, p=0.035) and treatment with Interferon reduced the risk (OR=0.48, p=0.05) of severe Covid-19 as compared to treatment with DMF, used as the reference DMT. Conclusions: This analysis confirms on a larger population the increase of risk of severe Covid-19 of anti-CD20 therapies and highlights the protective role of Interferon. Data on asymptomatic patients are rapidly accumulating and will provide useful information about this.