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Aims: To evaluate how improved treatment adherence with a lower-frequency regimen/treatment of intramuscular (IM) IFN beta-1a impacts therapeutic effectiveness in relapsing-remitting multiple sclerosis (MS) patients switching from a higher-frequency injectable regimen/treatment. Patients & methods: Italian patients with relapsing-remitting MS and prior poor adherence to high-frequency injectable treatments (n = 181) were followed for 24 months after starting IM IFN beta-1a. Results: During the study, 97.4% of patients were treatment adherent; 22.1% of patients reported a relapse. The estimated probability of remaining relapse-free after 2 years was 78%. A high dropout rate (52.5%) led to small sample size and reduced statistical power. Conclusion: Intramuscular IFN beta-1a treatment was associated with high adherence and a low relapse rate. Unfortunately, low patient retention limited the generalizability of these findings.Plain language summary: Prior research suggests that taking the drug IFN beta-1a through less frequent muscle injections enables more patients to adhere to their prescription than taking other medications. This study included 181 Italian patients with relapsing-remitting multiple sclerosis (MS) who historically did not take medication as often as prescribed. Relapses of MS were counted among patients treated with muscle injections of IFN beta-1a for 2 years; 97.4% of patients followed their prescription and 22.1% experienced a relapse. From these data, 78% of patients were estimated not to experience a relapse during 2 years of IFN beta-1a muscle injections. However, an unusually high number of patients (52.5%) left the study within 2 years, which makes it difficult to draw firm conclusions.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p

Background Blood is a common source of RNA for gene expression studies. However, it is known to be vulnerable to pre-analytical variables. Although RNA stabilization systems have been shown to reduce such influence, traditional EDTA tubes are still widely used since they are less expensive and enable to study specific leukocyte populations. This study aimed to assess the influence of storage time and temperature between blood sampling and handling on RNA from peripheral blood mononuclear cells (PBMCs). Methods and results Nine blood samples were collected in EDTA tubes from 10 healthy donors. One tube from each donor was immediately processed for PBMC isolation, while the others were first incubated at either 4 degrees Celsius (°C) or room temperature for 2, 4, 6 and 24 h. RNA yield and quality and the expression level of fourt housekeeping (B2M, CASC3, GAPDH, HPRT1) and 8 target genes (CD14, CD19, CD20, IL10, MxA, TNF, TNFAIP3, NR4A2) were compared between samples. RNA yield, quality and integrity did not vary significantly with time and temperature. B2M was the most stable housekeeping gene, while the others were increasingly influenced by storing time, especially at 4 °C. Even when normalized to B2M, the expression level of some target genes, particularly TNFAIP3 and NR4A2, was highly affected by delays in blood processing at either temperature, already from 2 h. Conclusion Pre-analytical processing has a great impact on transcript expression from blood collected in EDTA tubes, especially on genes related to inflammation. Standardized procedure of blood handling are needed to obtain reliable results.

Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot-Marie-Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated.The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group. An MFIS score38 indicated abnormal fatigue. The correlation with disease severity and clinical characteristics, the Hospital Anxiety and Depression Scale and Epworth Sleepiness Scale scores, and drug use was analysed.Data were collected from 251 CMT patients (136 women) and 57 controls. MFIS total (mean ± standard deviation 32 ± 18.3, median 33), physical (18.9 ± 9.7, 20) and psychosocial (2.9 ± 2.4, 3) scores in CMT patients were significantly higher than controls. Abnormal fatigue occurred in 36% of the patients who, compared to patients with normal scores, had more severe disease (median CMT Examination Score 9 vs. 7), more frequent use of foot orthotics (22% vs. 11%), need of support for walking (21% vs. 8%), hand disability (70% vs. 52%) and positive sensory symptoms (56% vs. 36%). Patients with abnormal fatigue had significantly increased frequency of anxiety/depression/general distress (Hospital Anxiety and Depression Scale), somnolence (Epworth Sleepiness Scale), obesity (body mass index ≥ 30) and use of anxiolytic/antidepressant or anti-inflammatory/analgesic drugs.Fatigue is a relevant symptom in CMT as 36% of our series had scores indicating abnormal fatigue. It correlated with disease severity but also with anxiety, depression, sleepiness and obesity, indicating different components in the generation of fatigue. CMT patients' management must include treatment of fatigue and of its different generators, including general distress, sleepiness and obesity.

Extended interval dosing (EID) of Natalizumab (NAT) has been proposed to reduce progressive multifocal leukoencephalopathy (PML) risk associated with standard interval dosing (SID) in people with multiple sclerosis (MS). Previous studies have suggested that NAT effectiveness is maintained in the great majority of patients who switch from SID to EID; monitoring of disease activity is currently based exclusively on clinical and MRI parameters. Frequent MRI are expensive and not always applicable, underlining the need for biological markers able to detect central nervous system lesions. Serum Neurofilament-light chain (sNFL) currently represents the most promising biomarker of disease activity, prognosis and treatment response in MS, and their clinical suitability is increasingly evident. The objective of the present study is to assess the applicability of sNFL as additional/alternative measure of treatment efficacy during EID regimen.We measured sNFL by Simoa technology in longitudinal samples from 63 Relapsing Remitting (RR) MS patients switched from SID to EID.diagnosis of RRMS, age 18-60 years; NAT SID for at least 12 months; NEDA-3 (no evidence of disease activity) for at least 12 months; availability of at least 2 serum samples collected 6 months apart. Patients' follow-up time during EID was at least 12 months and 2 blood samples were collected after at least 6 and 12 months. Clinical examination was performed before each infusion, while MRI 6 and 12 months after NAT initiation and according to PML risk during the whole study.No patients showed clinical or MRI activity during the whole follow-up. sNFL levels measured during SID and EID were comparable, without significant difference between groups. The effect of EID on NFL levels did not show significant effects (LMM, p0.05) and sNFL levels did not vary with time during SID or EID protocols (LMM, p0.05). Intra-individual sNFL levels demonstrated overall stability during SID and EID (median CV=11% between SID and EID samples). According to our previously published reference values, sNFL levels were in the normal range in all samples, both during SID and EID.Our results suggest that sNFL quantification can be used as an alternative/additional approach to MRI in managing individual patients. The present work provides a new clinical application of sNFL to monitor NAT efficacy.

Portaccio et al. report that in early relapsing-onset multiple sclerosis, progression independent of relapse activity is an important contributor to disability accumulation. Insidious progression occurs even in the earliest disease phases, suggesting that inflammation and degeneration may represent a single disease continuum.Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up >= 5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 +/- 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.

Background There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. Methods We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. Results We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. Conclusions An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.

Objective Aim of the research was to define the quality of life of Italian neurologists and nurses’ professional caring for multiple sclerosis, to understand their living the clinical practice and identify possible signals of compassion fatigue. Material and methods One hundred five neurologists and nurses from 30 Italian multiple sclerosis centres were involved in an online quali-quantitative survey on the organization of care, combined with the Satisfaction and Compassion Fatigue Test and a collection of narratives. Descriptive statistics of the quantitative data were integrated with the results obtained by the narrative medicine methods of analysis. Results Most of the practitioners were neurologists, 46 average years old, 69% women, 43% part time dedicated to multiple sclerosis. An increased number of patients in the last 3 years were referred in 29 centres. Differences were found between neurologists and nurses. Physicians showed higher risks of burnout, reporting intensive working paces, lack of medical personnel, and anxiety caused by the precarious employment conditions. Nurses appeared more satisfied, although the reference to the lack of spaces, and the cross professional roles risk of compassion fatigue. Both positive and negative relationships of care were depicted as influencing the professional quality of life. Conclusion The interviewed neurological teams need to limit the risk of compassion fatigue, which appeared from the first years of the career. The prevalence of the risk among neurologists suggests more awareness among scientific societies and health care managers on the risk for this category, as first step to prevent it. Electronic supplementary material The online version of this article (10.1007/s10072-020-04301-z) contains supplementary material, which is available to authorized users.

Background: In the phase III, OPERA I and OPERA II, clinical trial lymphopenia was reported in 20.7% of relapsing–remitting multiple sclerosis (RRMS) patients taking Ocrelizumab (OCR). Objective: The objective of this study was to investigate the effect of OCR on lymphocyte subtypes in MS patients with and without lymphopenia. Methods: Retrospective study comparing lymphocyte subtypes in OCR-treated MS patients with low (G1) and normal (G2) absolute lymphocyte count (ALC) at the six-month follow-up (cut-off: 1000 × 106/L). Mann Whitney U test was used to compare ALC, CD19, CD4 T, CD8 T and NK cell counts at baseline and at the six-month follow up between the two groups. A linear mixed model was applied to compare changes in ALC, and subset counts and proportions between patients with and without lymphopenia. We performed the same analyses in a subpopulation of naïve to treatment patients to exclude the possible influence of the previous disease modifying therapy (DMT) in the different kinetics observed between the two groups. Results:: One hundred sixty-seven patients were included (G1, n = 34; G2, n = 133). At the six-month follow-up, compared with baseline, in the whole population we observed a significant reduction in ALC (p

Objective: This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset pediatric multiple sclerosis. Methods: Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease-modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated. Results: A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all disability milestones. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease, and disease-modifying treatment exposure were independent predictors for long-term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms, and progressive course at disease onset were additional predictors for long-term disability. Interpretation: These findings point toward the existence of a different natural history in early versus late onset pediatric multiple sclerosis patients. ANN NEUROL 2022.

Clinicians are increasingly recognizing the importance of shared decision-making in complex treatment choices, highlighting the importance of the patient's rationale and motivation for switching therapies. This study aimed to evaluate the association between different modalities of changing multiple sclerosis (MS) treatments, cognitive profile and attitude and preferences of patients concerning treatment choice.This multicenter cross-sectional study was conducted at 28 Italian MS centers in the period between June 2016 and June 2017. We screened all MS patients treated with any DMT, with a treatment compliance of at least 80% of therapy administered during the 3 last months who needed to modify MS therapy because of efficacy, safety or other reasons during a follow-up visit. At the time of switching the symbol digit modalities test (SDMT) and the Control Preference Scale (CPS) were evaluated. According to the CPS, patients were classified as "active" (i.e. who prefer making the medical decision themselves), "collaborative" (i.e. who prefer decisions be made jointly with the physician), or "passive" (i.e. who prefer the physician make the decision).Out of 13,657 patients recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%) patients, 69.6% were female and with mean age 40.6 ± 10.5 years, were enrolled. According to the CPS score evaluation, a significant high percentage of patients (51.1%) were considered collaborative, 74 patients (22.5%) were passive, and 60 (18.2%) patients were active. Stratifying according to CPS results, we found a higher SDMT score among collaborative patients compared to active and passive ones (45.8 ± 12.3 versus 41.0 ± 13.2 versus 41.7 ± 12.8, p 0.05).In this study, the CPS evaluation showed that more than 50% of patients who needed to change therapy chose a "collaborative" role in making treatment decision. Cognitive profile with SDMT seems to correlate with patients' preference on treatment decision, showing better scores in collaborative patients.

Background: Several observational studies have shown an association between low circulating levels of 25-hydroxy- vitamin D (25(OH)D) and an increase in inflammatory activity in Multiple Sclerosis (MS). Among its immunomodulatory functions, 25(OH)D suppresses proliferation and immunoglobulin production of B cells. 25(OH)D supplementation has been associated with better radiological outcomes in MS patients treated with interferon (IFN)-B, glatiramer acetate, fingolimod, natalizumab and rituximab. Our study is aimed at analyzing the association of 25(OH)D serum levels and supplementation with B cell kinetics and clinical-radiological outcomes of people with MS treated with ocrelizumab. Methods: We have retrospectively collected clinical and radiological data from 136 MS patients who have been treated with ocrelizumab, have undergone at least two treatment cycles and for whom data on serum 25(OH)D levels and intake were available. The patients were divided into three groups according to baseline 25(OH)D serum levels: deficient (≤19,9 ng/ml), insufficient (20-29,9 ng/ml), and normal range 25(OH)D (>30 ng/ml). According to 25(OH)D intake, we divided our population into users and non-users. To explore B cell kinetics at six- and twelve-month follow-ups, the patients were divided into two groups: with fast repopulation (FR) and slow repopulation rate (SR), based on the reappearance or non- appearance of CD19 at each time point. Results: When considering the entire population, the mean 25(OH)D serum level (sd) was 26.27 ng/ml (14.15). 43 (31,62%) patients were classified as deficient, 52 (38,24%) were classified as insufficient, and 41 (30,14%) showed 25(OH)D serum levels within the normal range. 60.29% (82/136) of the patients were classified as users, and 39.70% (54/136) as non-users. Over the eighteen-month treatment period, we observed a significant difference between the 25(OH)D users and the non-users as concerns the number of scans with at least one new/enlarging T2 lesion (2% vs 15.38%, respectively; p= 0.025). In the multinomial regression model, 25(OH)D deficiency (serum levels ≤19,9 ng/ml) was significantly associated with a higher likelihood of disease activity during a follow-up of eighteen months (p=0.029, RRR=4.84, Confidence Interval (CI) 1.17 - 20.01). After six months, there were 30/136 FR patients (22,05%), whereas only 22/136 (16,17%) showed early B cell reappearance at twelve month follow up. 86.66% of the patients in the FR group showed 25(OH)D levels lower than 30 ng/ml (25(OH)D deficiency or insufficiency), whereas only 65.09% of the SR patients presented vitamin D levels lower than 30 ng/ml (p= 0.024). In the logistic regression model, 25(OH)D serum levels below 30 ng/ml were associated with a higher likelihood of early B cell reappearance at six month follow up (p= 0.042). Conclusions: 25(OH)D supplementation and serum levels might be associated with B cell kinetics and radiological activity of patients with MS treated with ocrelizumab.

Background: The kinetics of B cell repopulation in MS patients treated with Ocrelizumab is highly variable, suggesting that a fixed dosage and time scheduling might be not optimal. We aimed to investigate whether B cell repopulation kinetics influences clinical and radiological outcomes and whether circulating immune asset at baseline affects B cell repopulation kinetics. Methods: 218 MS patients treated with Ocrelizumab were included. Every six months we collected data on clinical and magnetic resonance imaging (MRI) activity and lymphocyte subsets at baseline. According to B cell counts at six and twelve months, we identified two groups of patients, those with fast repopulation rate (FR) and those with slow repopulation rate (SR). Results: A significant reduction in clinical and radiological activity was found. One hundred fifty-five patients had complete data and received at least three treatment cycles (twelve-month follow-up). After six months, the FR patients were 41/155 (26.45%) and 10/41 (29.27%) remained non-depleted after twelve months. FR patients showed a significantly higher percentage of active MRI scan at twelve months (17.39% vs. 2.53%, p = 0,008). Furthermore, FR patients had a higher baseline B cell count compared to patients with an SR (p = 0.02 and p = 0.002, at the six- and twelve-month follow-ups, respectively). Conclusion: A considerable proportion of MS patients did not achieve a complete CD19 cell depletion and these patients had a higher baseline CD19 cell count. These findings, together with the higher MRI activity found in FR patients, suggest that the Ocrelizumab dosage could be tailored depending on CD19 cell counts at baseline in order to achieve complete disease control in all patients.

The introduction of oral disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) changed the therapeutic landscape and algorithms of RRMS treatment (1). In Europe, dimethyl fumarate (DMF) and teriflunomide (TRF) are approved as first-line agents and are often used as the initial therapeutic choice (2, 3). Pivotal trials showed the efficacy of both DMTs on controlling clinical relapses, disability accrual and magnetic resonance imaging (MRI) activity (4-8). Both DMTs had overall good tolerability. There have been no head-to-head randomized trials to compare these two DMTs; however, several real-world evidence (RWE) studies have compared DMF and TRF and provided useful information to guide the selection of either drug for MS patients (9, 10). Although different statistical methods were used, both drugs demonstrated an ability to control disease activity (11-13). In some RWE studies, patients on DMF had a lower relapse rate and a higher relapse-free survival time (11, 12). In this registry-based nationwide cohort Cox-model study, we compared the clinical and radiological activity between patients treated with DMF or TRF.

The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR0.485, CI 95% 0.264–0.893,p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR0.248 CI 95% 0.065–0.948,p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.

Objective: To explore, through a digital triage monitoring, the frequency of demographic and clinical characteristics suggestive for COVID-19 among two large samples of people with Multiple Sclerosis (pwMS) and to evaluate the association between demographic and clinical characteristics of pwMS and the likelihood of being identified as COVID-19 suspect. Methods: A Google Forms triage was e-mailed to 3500 pwMS. pwMS suspects for having COVID-19 were: A) patients who reported recent contact with a patient with suspicion or diagnosis of COVID-19 and the presence of at least one symptom suggestive of COVID-19; B) pwMS with at least two symptoms suggestive of COVID-19. Demographics, clinical characteristics, and DMT categories of COVID-19-suspect vs non-suspect pwMS were compared.Results: 1035/1500 questionnaires were fulfilled by Italian pwMS and 1346/2000 by Iranian patients. 4.9% of Iranian and 1,5% of Italian pwMS met our criteria for the COVID-19-suspect case. Only diabetes and heart disease (OR: 5,374, 95%CI: 2,470 – 11,985, p-valueConclusion: The results of a digital triage system applied to a large Italian-Iranian population of pwMS to identify suspect cases of COVID-19 were discussed. Demographic and clinical characteristics of pwMS suspect for COVID-19 and the factors influencing the likelihood of being COVID-19 suspect are comparable to those of previous studies. Therefore, we encourage the use of the digital triage in patients with this chronic and severely disabling disease to pinpoint suspect case of COVID-19 in order to promptly activate the second phase of the intervention.

Few cases of complicated infections with Listeria monocytogenes (LM) have been reported to date in patients with multiple sclerosis (MS) treated with alemtuzumab. Primary prevention strategies may be suggested in such patients to avoid infections. However, these may be ineffective because patients may already be carriers of LM. We report herein a case of bloodstream infection due to LM in a 25-year-old woman with MS treated with alemtuzumab. We searched the UMC/WHO Vigibase system for all reported cases of LM in patients treated with alemtuzumab and found 29 cases overall up to 21 July 2019. We also performed a literature review of MS cases with LM on alemtuzumab, in order to evaluate epidemiology, clinical characteristics, and outcome of this complication. Since the published cases (N=8) were mainly reported in recent years but more cases were found in the UMC/WHO Vigibase system (although not necessarily in patients with MS), we hypothesize that this complication is more frequent than currently believed and may become even more important in the future. Therefore, it is worth reaching a consensus on appropriate algorithms to stratify individuals by risk so as to implement targeted prevention strategies (whether primary or secondary).

Aim: The aim of this study was to evaluate the corticospinal tract (CST) diffusion profile in pure lower motor neuron disease (pLMND) patients who at baseline did not show any clinical or electrophysiological involvement of upper motor neurons (UMN), and in amyotrophic lateral sclerosis (ALS) patients. Materials and Methods: Fifteen ALS patients with delayed central motor conduction time (CMCT) and 14 pLMND patients with normal CMCT were enrolled together with 15 healthy controls. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) maps were obtained. The tract profile of CST was reconstructed with the automated fiber quantification tool and its diffusion properties were quantified voxel-by-voxel and then compared pairwise between groups. Moreover, a random forest (RF) classifier was trained to evaluate the ability of CST diffusion metrics in distinguishing pairwise the groups from the controls. Results: ALS patients presented wide microstructural abnormalities in the entire CST as assessed by FA decrease and RD increase while pLMND patients showed focal FA decrease and a larger AD increase in the cerebral peduncle and posterior limb of the internal capsule in comparison with controls. RF revealed that diffusion tensor imaging (DTI) metrics accurately distinguished ALS patients and pLMND patients from controls (96.67 and 95.71% accuracy, respectively). Conclusions: Our study demonstrates that the CST was impaired in both ALS and pLMND patients, thus suggesting that DTI metrics are a reliable tool in detecting subtle changes of UMN in pLMND patients, also in the absence of clinical and CMCT abnormalities.

Machine Learning application on clinical data in order to support diagnosis and prognostic evaluation arouses growing interest in scientific community. However, choice of right algorithm to use was fundamental to perform reliable and robust classification. Our study aimed to explore if different kinds of Machine Learning technique could be effective to support early diagnosis of Multiple Sclerosis and which of them presented best performance in distinguishing Multiple Sclerosis patients from control subjects. We selected following algorithms: Random Forest, Support Vector Machine, Naïve-Bayes, K-nearest-neighbor and Artificial Neural Network. We applied the Independent Component Analysis to resting-state functional-MRI sequence to identify brain networks. We found 15 networks, from which we extracted the mean signals used into classification. We performed feature selection tasks in all algorithms to obtain the most important variables. We showed that best discriminant network between controls and early Multiple Sclerosis, was the sensori-motor I, according to early manifestation of motor/sensorial deficits in Multiple Sclerosis. Moreover, in classification performance, Random Forest and Support Vector Machine showed same 5-fold cross-validation accuracies (85.7%) using only this network, resulting to be best approaches. We believe that these findings could represent encouraging step toward the translation to clinical diagnosis and prognosis.

Background and aims: Neurological manifestations of COVID-19 have been described. We report a case of seropositive NMOSD and acute myositis following SARS-CoV-2 infection. Methods: A previous healthy 35-years old man was admitted for NORB, a month after paucisymptomatic SARS-CoV-2 infection. Nasopharyngeal tests for SARS-CoV-2 was negative and serological IgG and IgM were positive. The neurological examination showed left eye blindness and myalgia. Blood examination showed elevated CK (>1000 UI/l), positive ANA (1:640) and anti-TPO (>1300 U/ml). Brain MRI showed T2/FLAIR left optic nerve hyperintensity with contrast enhancement. The EMG revealed signs of acute myogenic damage. He received intravenous methylprednisolone with poor recovery on vison but full recovery on muscle symptoms. Four months later he present NORB in contralateral eye;MRI showed optic chiasm hyperintensity, serum anti-AQP-4-antibodies were positive, EMG and CK were normalized. The patient received intravenous steroids and Immunoglobulins and started rituximab. Nevertheless, three months later he developed the area postrema syndrome, he was retreated with intravenous steroids and immunoglobulins and achieved a complete recovery. In March 2021, he underwent the second course of rituximab with clinical and radiological stability. Results: The patient was diagnosed with seropositive NMOSD, presented with recurrent NORB and area postrema syndrome, associated to acute myositis and autoimmune tiroiditis after SARS-CoV-2 infection. Conclusions: We supposed that SARS-CoV-2 may cause a post-infectious autoimmune response directed against AQP4 and other target (the muscle, the tiroid gland). Post-infectious autoimmunity is a potential mechanism in a subset of patients with COVID-19-related neurologic disease. Further research is needed to clarify this association.

Background and aims: Many patients treated with Natalizumab experience End of Dose Interval (EDI) symptoms towards the end of the administration cycle. During the pandemic, due to the unknown effects of SARS-CoV-2 infection on patients undergoing treatment with Natalizumab (NTZ), we decided to shift patients on NTZ from a Standard Interval Dosing (SID of 4 weeks) to an Extended Interval Dosing (EID of 5–6 weeks). Our main objective was to study the prevalence and incidence of EDI symptoms in our MS center, along with its efficacy and safety. Methods We reviewed 102 patients in our MS center treated with natalizumab for at least 12 months using EID. When tolerated/possible, patients were shifted from a SID of 4 weeks to an EID of 5–6 weeks. Patients were asked to report any worsening of their symptoms during the administration cycle, fatigue was assessed right before the administration of NTZ, with surveys and Fatigue Severity Scale (FSS). Results: Among the 102 patients, 41 (40.19%) reported end of dose interval (EDI) symptoms, and the most common one was fatigue. Among those 41 patients: 26 (63%) had a Relapsing Remitting (RR) course while 15 (37%) had a Secondary Progressive (SP) course. Of note, 15 (36.58%) patients reported a new onset of fatigue where none was present before the EID. Our data suggest that with EID efficacy is still preserved since only 6 patients showed new lesions on follow-up-MRI and with little clinical significance. Conclusions: Our study shows that when EID was adopted, fatigue was higher in the RR course group, with efficacy still preserved.

Background Serum Neurofilament Light (sNFL) is the most promising marker for patient's monitoring in Multiple Sclerosis (MS). However, operating reference values for use in clinical practice are still lacking. Here, we defined sNFL reference cut-off values in a cohort of healthy controls (HC) and assessed their performance in Multiple Sclerosis (MS) patients, as well as the intra-individual sNFL variability. Methods We measured sNFL by single molecule array (Simoa) assay in 79 HC assessing their correlation with age. Changes of sNFL levels were evaluated during a short-term follow-up (median 67 days between consecutive samples) in a subgroup of 27 participants. sNFL were tested in 23 untreated MS patients, at both diagnostic time and start of therapy (median 80 days after), considering disease activity. Results Findings confirmed a correlation between sNFL levels and age in HC, thus cut-off values specific for age decades were calculated. sNFL did not vary significantly with time during short-term follow-up (median CV 13%). sNFL levels in MS patients were higher and demonstrated a higher variability between diagnostic time and treatment start (median CV 39%). According to cut-off values, “pathologic” sNFL levels were found in 57% of MS patients at diagnostic time, and in 30% of samples at treatment start. In particular, “pathologic” sNFL levels were found in 80% of samples (16/20) obtained during a phase of disease activity, while a total of 85% of samples (22/26) associated with inactive disease showed sNFL in the normal range. Conclusion This study demonstrates an overall intra-individual stability of sNFL values in the short-term in HC and suggests age-dependent reference cut-off values that could be beneficial for sNFL implementation in clinical practice.

The presence of KIR4.1 antibodies has been proposed to be a characteristic of Multiple Sclerosis (MS). This could have a significant impact on disease management. However, the validation of the initial findings has failed till date. Conflicting results have been attributed to difficulties in isolating the lower-glycosylated (LG) KIR4.1 expressed in oligodendrocytes, the putative target antigen of autoantibodies. The aim of this study is to verify the presence of KIR4.1 antibodies in MS patients, by independently replicating the originally-described procedure. Assay procedure consisted of KIR4.1 expression in HEK293 cells, 3-step elution to isolate LG-KIR4.1 in elution fraction 3, and ELISA. Sera of 48 MS patients and 46 HCs were studied in 21 working sessions. In a preliminary analysis, we observed different KIR4.1 antibody levels between MS patients and Healthy Controls (HCs). However, a high variability across working sessions was observed and the sensitivity of the assay was very low. Thus, stringent criteria were established in order to identify working sessions in which the pure LG-KIR4.1 was isolated. As per these criteria, we detected LG-KIR4.1 antibodies in 28% of MS patients and 5% of HCs. Unlike previous findings, this study is in agreement with the original report. We propose further efforts be made towards the development of a uniform method to establish the detection of KIR4.1 antibodies in MS patients.

ObjectiveTo collect information on frequency of pregnancy and delivery complications in Charcot-Marie-Tooth (CMT) disease and on CMT course during pregnancy.MethodsThrough an ad hoc online questionnaire, we investigated pregnancy and neuropathy course in women with CMT adhering to the Italian CMT Registry. Data were compared to those of controls (recruited among friends and unaffected relatives) and the Italian (or other reference) population.ResultsWe collected data on 193 pregnancies from 86 women with CMT (age 20–73 years) with 157 deliveries (81.4%) after a mean of 38.6 gestational weeks. In women with CMT, there were no differences compared to controls (59 pregnancies and 46 deliveries from 24 controls) and the reference population for miscarriages (11.4%) and planned (21.0%) and emergency (14.0%) cesarean sections. We found a significantly higher frequency of placenta previa (1.6% vs 0.4%), abnormal fetal presentations (8.4% vs 4.5%), and preterm deliveries (20.3% vs 6.9%; most in week 34–36 of gestation) compared to reference populations. Excluding twins, newborn weight did not differ from the reference population. Postpartum bleeding rate in patients with CMT (2.1%) was similar to that of the general population (2.4%). CMT status worsened during 18 of 193 pregnancies (9.3%) with no recovery in 16 of them and with similar figures in the CMT1A and non-CMT1A subtypes.ConclusionsWe observed higher rates of placenta previa, abnormal presentations, and preterm deliveries in CMT, but pregnancy outcome and newborn weight and health were similar to those of the reference populations. Worsening of CMT is not infrequent and occurs not only in CMT1A. Pregnant women with CMT should be monitored with particular care.

IntroductionDelta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation.Materials and methodsThis prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline.ResultsA total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, pDiscussionTHC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.