Clinical variables influencing the perception of fatigue in people with multiple sclerosis: a cross-sectional study using FSIQ-RMS.

BACKGROUND: Physical fatigue is one of the most disabling symptoms in people with Multiple Sclerosis (PwMS). Several factors might influence the development of fatigue, such as gender, education, body mass index (BMI), Expanded Disability Status Scale (EDSS), disease duration, working status (Ws), physiotherapy (Ph), and disease-modifying therapies (DMTs). Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a patient-reported outcome (PRO) that allows one to define the impact of fatigue in PwMS clearly. This study aimed to assess fatigue impact on PwMS by using FSIQ-RMS. METHODS: The participants were enrolled from May to July 2021 in MS Centers of Sant'Andrea Hospital and Policlinico Umberto I Hospital in Rome. Fatigue was evaluated using the FSIQ-RMS, validated, and culturally adapted in Italian. Clinical and demographic data were collected at the same time. RESULTS: We enrolled 178 PwMS [Female 74.16%; RMS 82.58%, SPMS 17.52%]. FSIQ-RMS scores were significantly correlated with EDSS (p-value < 0.01). Analysis of variance between means showed a statistically significant difference between the BMI groups at the 24hours_FSIQ-RMS score and the 7days_FSIQ-RMS score (p < 0.01), with the lower BMI group having the highest scores. Furthermore, perceived fatigue significantly improved both in subjects performing Ph (p < 0.05) and in those who actively work (p < 0.01). CONCLUSIONS: The use of FSIQ-RMS in a real-world setting confirmed that underweight and high levels of disability are closely related to fatigue. In addition, Ph and active Ws are strongly correlated with fatigue in PwMS.

Neural bases of motor fatigue in multiple sclerosis: A multimodal approach using neuromuscular assessment and TMS-EEG.

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear. This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network. Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task. Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values. To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS.

Italian translation and validation of fatigue symptoms and impacts questionnaire in relapsing multiple sclerosis (FSIQ-RMS).

BACKGROUND: Fatigue is a disabling symptom of multiple sclerosis (MS) and impacts on daily life. The Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new 20-item tool that investigates the aspects of fatigue in MS. It concerns motor, cognitive, social, and emotional aspects of fatigue. We aim at validating the Italian version of FSIQ-RMS in an Italian population of MS patients and demonstrate its reliability and construct validity. METHODS: We included patients with diagnosis of MS, age between 18 and 70 years with ability to participate in a 90-min interview. Each patient completed the Italian version of FSIQ-RMS and Fatigue Severity Scale (FSS) at the same time. Construct validity was explored by the exploratory factor analysis; reliability was assessed with Cronbach's alpha; and test-retest stability was examined through intraclass correlation coefficient (ICC). Concurrent validity was calculated using Pearson's correlation. RESULTS: We enrolled 171 patients (126 female and 45 male), 83% with relapsing MS (RMS), and 17% with secondary progressive MS (SPMS). Italian FSIQ-RMS showed a Cronbach's alpha of 0.92; ICC was 0.96. Pearson's correlation coefficient between FSIQ-RMS and FSS total score was statistically significant (p < 0.01); FSIQ-RMS inversely correlated also with BMI and positively with EDSS. CONCLUSION: The Italian version of FSIQ-RMS has excellent psychometric properties and can be used in research and clinical setting to evaluate physical, cognitive, and social fatigue in both RMS and SPMS.

Long-term follow-up (up to 11 years) of an Italian pediatric MS cohort treated with Natalizumab: a multicenter, observational study.

BACKGROUND: Natalizumab (NAT) has a strong impact on disease activity of aggressive pediatric multiple sclerosis (MS), with no difference in safety profile compared to adult MS. However, available data are limited by short follow-up. Our aim was to report long-term follow-up data (up to 11 years) of a large Italian pediatric MS cohort treated with NAT. MATERIALS AND METHODS: We retrospectively collected data of pediatric MS patients treated with NAT included in a previous study and prospectively followed in Italian MS centers. We compared disease activity pre, during, and post-NAT and we performed survival analyses of time to evidence of disease activity (EDA) during NAT, time to reach EDA post-NAT, and time to NAT discontinuation. RESULTS: Ninety-two patients were included from 19 MS centers in Italy. At NAT initiation, cohort's characteristics were as follows: 55 females; 14.7 ± 2.4 (mean ± SD) years of age; 34 naïve to disease modifying therapies; 1-year pre-NAT annualized relapse rate (ARR): 2.2 ± 1.2; EDSS (median [IQR]): 2.5 [2.0-3.0]; gadolinium-enhancing lesions: 2 [1-5]; 41 JCV positives. During NAT treatment (61.9 ± 35.2 mean infusions), ARR lowered to 0.08 ± 0.23 (p < 0.001), EDSS score to 1.5 [1.0-2.5] at last infusion (p < 0.001), and 51% patients had EDA (21% after 6 months of rebaseline). No serious adverse events were reported. Forty-nine patients discontinued NAT, mainly due to PML concern; the majority (29/49) had disease reactivation in the subsequent 12 months, of which three with a clinical rebound. CONCLUSION: NAT treatment maintains its high efficacy for a long time in pediatric MS patients, with no new safety issues.

COVID-19 pandemic and mental distress in multiple sclerosis: Implications for clinical management.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), disease-related factors and dysfunctional coping might favor the development of mental distress induced by COVID-19 containment measures. Aim of this study was exploring the relationship between disability, coping strategies, daily life reorganization and neuropsychiatric symptoms in an Italian MS population during the COVID-19 lockdown, in order to identify potentially modifiable factors that could inform clinical management of mental distress in people with MS. METHODS: We explored the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown. Structural equation modeling was applied to information collected via web survey to identify modifiable factors that could account for mental distress. RESULTS: A total of 845 participants (497 with MS and 348 controls) were included in the study. The MS group had higher scores than the control group for depression (p = 0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The structural equation modeling explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (ß = 0.509 and ß = 0.836; p < 0.001); positive attitude and exercise contributed to active attitude (ß = 0.386 and ß = 0.297; p < 0.001); and avoidance, social support and watching television contributed to passive attitude (ß = 0.301, ß = 0.243 and ß = 0.212; p < 0.001). With regard to the relationship between latent factors and their influence on depression, disability contributed to passive attitude (ß = 0.855; p < 0.001), while both passive and active attitude significantly influenced depression (ß = 0.729 and ß = -0.456; p < 0.001). CONCLUSION: As a practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool in facing COVID-19-related mental distress.

Validation of the Italian version of the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19.

BACKGROUND: People with multiple sclerosis (MS) may experience sexual dysfunction throughout the disease course. Validated scales to assess sexual dysfunction in MS for Italian patients are lacking. Hence, we aimed at validating Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-19) for Italian MS patients. METHODS: We included both male and female MS patients. Each patient completed the Italian translation of the MSISQ-19. Construct validity was explored by the exploratory factor analysis and the Cronbach's alpha coefficient. Test-retest stability and concurrent internal and external validity were examined by Pearson' correlation coefficients. RESULTS: We enrolled 369 MS patients (323 female and 46 male). Italian MSISQ-19 showed a Cronbach's alpha of 0.92. MSISQ-19 test and retest total scores correlated between each other (r = 0.48, p = 0.01). MSISQ-19 total score also correlated with primary, secondary and tertiary subscales (p < 0.001). CONCLUSION: The Italian Version of the MSISQ-19 showed satisfactory internal consistency and reliability with moderately adequate test-retest reproducibility, suggesting that it may be used as a valuable measure of sexual dysfunction in the Italian population.

Advanced MRI Techniques: Diagnosis and Follow-Up of Multiple Sclerosis.

Brain and spinal cord imaging plays a pivotal role in aiding clinicians with the diagnosis and monitoring of multiple sclerosis. Nevertheless, the significance of magnetic resonance imaging in MS extends beyond its clinical utility. Advanced imaging modalities have facilitated the in vivo detection of various components of MS pathogenesis, and, in recent years, MRI biomarkers have been utilized to assess the response of patients with relapsing-remitting MS to the available treatments. Similarly, MRI indicators of neurodegeneration demonstrate potential as primary and secondary endpoints in clinical trials targeting progressive phenotypes. This review aims to provide an overview of the latest advancements in brain and spinal cord neuroimaging in MS.

Insight into motor fatigue mechanisms in natalizumab treated multiple sclerosis patients with wearing off.

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Treatment modifiers across different regimens of natalizumab treatment in MS: An Italian real-world experience.

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 â€‹± â€‹1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.

ChatGPT vs. neurologists: a cross-sectional study investigating preference, satisfaction ratings and perceived empathy in responses among people living with multiple sclerosis.

BACKGROUND: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT. METHODS: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy. RESULTS: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01). CONCLUSIONS: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative.

Should we treat pediatric radiologically isolated syndrome? An 18-year follow-up case report.

Background: Radiologically isolated syndrome (RIS) describes asymptomatic individuals with incidental radiologic abnormalities suggestive of multiple sclerosis (MS). Much of RIS literature is about adult-onset cases. Treatment of RIS is controversial, especially in pediatric age, but early treatment in selected patients might improve long-term outcomes. Case presentation: We report a single RIS patient who followed up for 18 years in our MS center. At first, she was only monitored with follow-up MRIs. Then, as the lesion load increased, she was treated with a first-line disease-modifying treatment (DMT) reaching MRI stability. Conclusion: This report highlights how treatment can be an appropriate choice in pediatric forms of RIS.

Sexual Dysfunction in People with Multiple Sclerosis: The Role of Disease Severity, Illness Perception, and Depression.

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.

No Changes in Functional Connectivity After Dimethyl Fumarate Treatment in Multiple Sclerosis.

INTRODUCTION: Despite the increased availability of disease-modifying therapies (DMTs) for treating relapsing-remitting multiple sclerosis (RR-MS), only a few studies have evaluated DMT-associated brain functional changes. METHODS: We investigated whether significant resting-state functional connectivity (FC) changes occurred in RR-MS patients after 6 and 12 months of dimethyl fumarate (DMF) treatment using both a seed-based and data-driven approach. RESULTS: Thirty patients were followed up after 6 months of therapy, and 27 of them reached a 12-month follow-up. Three patients at baseline and only one after 12 months showed gadolinium-enhancing lesions. We did not find any significant FC changes after therapy at either time point. After 12 months of DMF, we observed relatively modest brain volume loss and a significant improvement in Paced Auditory Serial Addition Test 3 s and 25-Foot Walk Test scores. CONCLUSION: The absence of FC changes could be due to the low degree of baseline inflammation in our patients, though we cannot exclude that more time may be required to observe such changes. No FC changes may reflect a beneficial effect of DMF therapy, as supported by conventional MRI findings and clinical improvement.

Eating Hubs in Multiple Sclerosis: Exploring the Relationship Between Mediterranean Diet and Disability Status in Italy.

Background: Multiple Sclerosis (MS) is a complex disease in which multiple factors contribute to disability accrual. Mediterranean Diet (MeDi) has shown beneficial effects across neurodegenerative diseases. We hypothesize that specific food habits, rather than global adherence to MeDi, might impact on MS. We aimed to (i) evaluate differences in adherence to MeDi between people living with MS (PwMS) and healthy controls (HC); (ii) characterize eating patterns in PwMS and HC, identifying the most influential MeDi items for each group by the use of network analysis; (iii) explore the relationship between patients' eating habits and disability. Materials and Methods: In this cross-sectional study, we consecutively recruited 424 PwMS and 165 matched HC. Data were obtained through the administration of self-reported questionnaires. Expanded Disability Status Scale (EDSS) and Fatigue Severity Scale (FSS) were evaluated in the MS population. We performed between-groups comparisons via unpaired two-sample t-test and X2 test as appropriate. We calculated food networks in both MS cases and HC using and tested the association between hub nodes and disability. Finally, we conducted a post-hoc analysis, investigating the relationship between food items, lifestyle factors (smoking, exercise) and clinical outcomes. Results: Most participants adhered sufficiently to MeDi. Exploring each group separately, fruit, vegetables, cereal, and fish were identified as hubs in PwMS, while meat and alcohol were identified as hubs in HC. Hubs were all inter-correlated, indicating that eating habits of PwMS include a large intake of all the foods identified as hubs. EDSS was predicted by the intake of vegetables (beta = -0.36, p < 0.03) and fish (beta = -0.34, p < 0.02). The model including smoking pack/year, International Physical Activity Questionnaire (IPAQ) score and intake of "negative foods" predicted 6% of the variance in EDSS (p < 0.001), while the model including smoking pack/year and IPAQ score predicted 4% of the variance in FSS (p < 0.001). Conclusions: We identified a sufficient adherence to MeDi in our population. PwMS showed overall a healthier dietary pattern than HC. Vegetables and fish intake were associated with disability outcomes. Future longitudinal studies applying integrated approaches are needed to understand lifestyle added value to the use of standard pharmacological therapies.

Are Neurophysiological Biomarkers Able to Discriminate Multiple Sclerosis Clinical Subtypes?

Secondary progressive multiple sclerosis (SPMS) subtype is retrospectively diagnosed, and biomarkers of the SPMS are not available. We aimed to identify possible neurophysiological markers exploring grey matter structures that could be used in clinical practice to better identify SPMS. Fifty-five people with MS and 31 healthy controls underwent a transcranial magnetic stimulation protocol to test intracortical interneuron excitability in the primary motor cortex and somatosensory temporal discrimination threshold (STDT) to test sensory function encoded in cortical and deep grey matter nuclei. A logistic regression model was used to identify a combined neurophysiological index associated with the SP subtype. We observed that short intracortical inhibition (SICI) and STDT were the only variables that differentiated the RR from the SP subtype. The logistic regression model provided a formula to compute the probability of a subject being assigned to an SP subtype based on age and combined SICI and STDT values. While only STDT correlated with disability level at baseline evaluation, both SICI and STDT were associated with disability at follow-up. SICI and STDT abnormalities reflect age-dependent grey matter neurodegenerative processes that likely play a role in SPMS pathophysiology and may represent easily accessible neurophysiological biomarkers for the SPMS subtype.

Predictors of Cladribine Effectiveness and Safety in Multiple Sclerosis: A Real-World, Multicenter, 2-Year Follow-Up Study.

INTRODUCTION: Cladribine administration has been approved for the treatment of relapsing-remitting multiple sclerosis (MS) in 2017; thus, data on cladribine in a real-world setting are still emerging. METHODS: We report on cladribine effectiveness, safety profile, and treatment response predictors in 243 patients with MS followed at eight tertiary MS centers. Study outcomes were: (1) No Evidence of Disease Activity-3 (NEDA-3) status and its components (absence of clinical relapses, MRI activity, and sustained disability worsening); (2) development of grade III/IV lymphopenia. The relationship between baseline features and the selected outcomes was tested via multivariate logistic models. RESULTS: Of the 243 subjects included in the study (66.5% female, age 34.2 ± 10 years, disease duration 6.6 ± 9.6 years), 64% showed NEDA-3 at median follow-up (22 months). Patients with higher number of previous treatments had lower probability to retain NEDA-3 [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.41-0.98, p = 0.04] and were more prone to experience clinical relapses (OR 1.6, 95% CI 1-2.6, p = 0.04). The presence of active lesions at baseline was associated with follow-up magnetic resonance imaging (MRI) activity (OR 1.92, 95% CI 1.04-3.55, p = 0.04). Patients with higher rate of relapses in the year prior to cladribine start were at higher risk of developing sustained disability worsening (OR 2.95% CI 1-4.2, p = 0.04). Lymphopenia grade III/IV over the follow-up was associated with baseline lymphocyte count (OR 0.998, 95% CI 0.997-0.999, p = 0.01). CONCLUSION: In this large cohort, we confirm previous data about cladribine effectiveness on disease activity and disability worsening and provide information on response predictors that might inform therapeutic choices.

Alopecia Universalis Occurring after Alemtuzumab Treatment for Multiple Sclerosis. A Two-Year Follow-Up of Two Patients.

Alopecia Universalis (AU) is the most severe form of Alopecia Areata and is caused by cytotoxic T-cells reacting with follicular autoantigens, producing complete loss of scalp and body hair. Alemtuzumab is a highly efficacious monoclonal antibody used in the treatment of Multiple Sclerosis (MS), but it causes secondary autoimmunity in up to 40% of patients. Many factors are believed to contribute to this process, but pathogenic mechanisms are not well clear. To date, three cases of AU after treatment with Alemtuzumab have been reported. In this paper we report the cases of two patients who developed AU 12 months after the second cycle of Alemtuzumab, with a review of the literature. One year after the end of the second cycle, two female patients in their thirties experienced complete hair loss. The first case was temporally associated with a significant drop in vitamin D (VD) levels. The second case was accompanied by joint swelling. Both patients had thyroid alterations and showed no hair regrowth after a 2-year follow-up. AU must be considered among the secondary autoimmune manifestations of Alemtuzumab treatment. We emphasize the need for appropriate patient screening and thorough clinical surveillance for factors predisposing patients to secondary autoimmunity.

Case Report: Multiple Sclerosis Relapses After Vaccination Against SARS-CoV2: A Series of Clinical Cases.

Objective: To describe a temporal association between COVID-19 vaccine administration and multiple sclerosis (MS) relapses. Methods: This case series study was collected in four MS Centres in Central Italy, using data from 16 MS patients who received COVID-19 vaccination and presented both clinically and radiologically confirmed relapses between March and June 2021. We collected patients' relevant medical history, including demographics, MS clinical course, disease-modifying treatment (DMT) received (if applicable), and data from MRI scans obtained after the COVID-19 vaccination. Results: Three out of 16 patients received a diagnosis of MS with a first episode occurring after COVID-19 vaccination; 13 had already a diagnosis of MS and, among them, 9 were on treatment with DMTs. Ten patients received BNT162b2/Pfizer-BioNTech, 2 patients mRNA-1273/Moderna, and 4 patients ChAdOx1 nCoV-19/AstraZeneca. All MS relapses occurred from 3 days to 3 weeks after receiving the first dose of the COVID-19 vaccination or the booster. All patients had evidence of radiological activity on MRI. Discussion: Clinical and radiological findings in these cohort of MS patients confirmed disease re/activation and suggested a temporal association between disease activity and COVID-19 vaccination. The nature of this temporal association, whether causative or incidental, remains to be established.

Predictors of lymphocyte count recovery after dimethyl fumarate-induced lymphopenia in people with multiple sclerosis.

BACKGROUND: Dimethyl fumarate (DMF) is an oral drug approved for Relapsing Multiple Sclerosis (RMS) patients. Grade III lymphopenia is reported in 5-10% DMF-treated patients. Data on lymphocyte count (ALC) recovery after DMF withdrawal following prolonged lymphopenia are still scarce. OBJECTIVES: To characterize ALC recovery and to identify predictors of slower recovery after DMF interruption. METHODS: Multicenter data from RMS patients who started DMF and developed lymphopenia during treatment were collected. In patients with grade II-III lymphopenia, ALCs were evaluated from DMF withdrawal until reaching lymphocyte counts > 800/mm3. RESULTS: Among 1034 patients who started DMF, we found 198 (19.1%) patients with lymphopenia and 65 patients (6.3%) who discontinued DMF due to persistent grade II-III lymphopenia. Complete data were available for 51 patients. All patients recovered to ALC > 800 cells/mm3 with a median time of 3.4 months. Lower ALCs at DMF suspension (HR 0.98; p = 0.005), longer disease duration (HR 1.29; p = 0.014) and prior exposure to MS treatments (HR 0.03; p = 0.025) were found predictive of delayed ALC recovery. CONCLUSION: ALC recovery after DMF withdrawal is usually rapid, nevertheless it may require longer time in patients with lower ALC count at DMF interruption, longer disease duration and previous exposure to MS treatments, potentially leading to delayed initiation of a new therapy.

Physical Exercise Moderates the Effects of Disability on Depression in People with Multiple Sclerosis during the COVID-19 Outbreak.

Physical disability impacts psychosocial wellbeing in people with multiple sclerosis. However, the role of physical activity in this context is still debated. By taking advantage of a previous survey, conducted online from 22 April to 7 May 2020, we performed a post-hoc analysis with the aim to assess the associations between disability, physical exercise, and mental health in multiple sclerosis. We retrieved the following data: (i) sociodemographic information, (ii) changes in lifestyle (including exercise), (iii) physical disability, as measured with the Patient-Determined Disease Steps scale, and (iv) anxiety feelings and depressive symptoms assessed via the items included in the Quality of Life in Neurological Disorders measurement system. Examination of the interaction plot showed that the effect of disability on depression, but not on anxious symptoms, was significant for all levels of physical exercise (low: b = 1.22, 95% C.I. 0.85, 1.58, p < 0.001; moderate: b = 0.95, 95% C.I. 0.66, 1.24, p < 0.001; and high: b = 0.68, 95% C.I. 0.24, 1.13, p = 0.003). Based on these data, we can conclude that disability significantly impacted depression during the COVID-19 pandemic, with physical activity playing a moderating role. Our results suggest that favoring exercise in multiple sclerosis (MS) would ameliorate psychological wellbeing regardless of the level of physical disability.