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We present a case of a 61-year-old woman with an atypical non-arteritic anterior ischemic optic neuropathy (NA-AION) as a unique manifestation of COVID-19. Furthermore, the patient worsened after Pfizer-BioNTech COVID-19 vaccine administration. Our findings suggest that NA-AION could result from microangiopathic/thrombotic events that may occur during SARS-CoV-2 infection and/or vaccination against COVID-19. This report sheds light on possible ophthalmologic complications of COVID-19.

Aims: Lower urinary tract symptoms are common in multiple sclerosis (MS) and have a great impact on quality of life. We evaluated prevalence and characteristics of urological symptoms in a cohort of patients with MS. Methods: This is a cross-sectional study conducted on consecutive patients with MS attending our Center in 2018. We evaluated prevalence, clinical features, and response to symptomatic treatments of lower urinary tract disorders; we investigated the relationship between them and clinical and demographic features. Data of urodynamic studies were also collected. Results: In our cohort of 806 patients, the overall prevalence of urological symptoms was 52.9% and urgency was the most frequent symptom (59.4%). Symptomatic patients had a higher disability, a longer disease duration, a later age at onset, and a greater mean age at the time of evaluation. Urinary disorders were more frequent in patients with progressive disease and in women. About 41.8% of patients were under treatment for the urological disorder and 81.5% of them reported an improvement of symptoms. Conclusion: Urinary disorders in patients with MS have a high prevalence. An early and correct characterization of types of symptoms and an early and targeted therapeutic strategy are essential to improve the patient's quality of life and avoid future complications.

OBJECTIVE: Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease that affect both white and gray matter. The relapsing and the eventually progressive course of MS is heterogeneous; thus, a confident longterm prediction of individual prognosis is not possible yet. Recent studies have demonstrated the role of long non-coding RNA (lncRNAs) as potential biomarkers that could provide information to predict disease activity and progression. PATIENTS AND METHODS: By qRT-PCR, we analysed the lncRNAs expression in the serum of 16 secondary progressive MS (SP-MS), 12 primary progressive (PP-MS) patients and 8 healthy controls. RESULTS: We found that TUG1 was upregulated in SP-MS, while the comparison of PP-MS vs. controls showed a downregulation of non-protein coding RNA 188 (LRRC75A-AS1) and a significant upregulation of two lncRNAs: long intergenic non-protein coding RNA 293 (LINC00293) and RP11-29G8.3. Moreover, we performed an in-silico analysis using DIANA-LncBase v2 and HMDD v3.0 software, in order to predict the possible interaction of these four lncRNAs with miRNAs. We identified 21 miRNAs prediction targets possibly involved in MS. CONCLUSIONS: Our data indicate a regulatory function of these lncRNAs in autoimmune and inflammatory processes related to MS suggesting their potential role in progressive MS pathogenesis.

OBJECTIVE: Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease t hat affect both white and gray matter. The relapsing and the eventually progressive course of MS is heterogeneous; thus, a confident longterm prediction of individual prognosis is not possible yet. Recent studies have demonstrated the role of long non-coding RNA (lncRNAs) as potential biomarkers that could provide information to predict disease activity and progression.PATIENTS AND METHODS: By qRT-PCR, we analysed the lncRNAs expression in the serum of 16 secondary progressive MS (SP-MS), 12 primary progressive (PP-MS) patients and 8 healthy controls.RESULTS: We found that TUG1 was upregulated in SP-MS, while the comparison of PP-MS vs. controls showed a downregulation of non-protein coding RNA 188 (LRRC75A-AS1) and a significant upregulation of two lncRNAs: long intergenic non-protein coding RNA 293 (LINC00293) and RP11-29G8.3. Moreover, we performed an in-silico analysis using DIANA-LncBase v2 and HMDD v3.0 software, in order to predict the possible interaction of these four lncRNAs with miRNAs. We identified 21 miRNAs prediction targets possibly involved in MS.CONCLUSIONS: Our data indicate a regulatory function of these lncRNAs in autoimmune and inflammatory processes related to MS suggesting their potential role in progressive MS pathogenesis.

Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033–0.087) in the SID group and 0.039 (95% CI = 0.017–0.063) in the EID group. The non-inferiority of EID versus SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.

Several biomarkers from multiple sclerosis (MS) patients' biological fluids have been considered to support diagnosis, predict disease course, and evaluate treatment response. In this study, we assessed the CSF concentration of selected molecules implicated in the MS pathological process. To investigate the diagnostic and prognostic significance of CSF concentration of target candidate biomarkers in both relapsing (RMS, n = 107) and progressive (PMS, n = 18) MS patients and in other inflammatory (OIND, n = 10) and non-inflammatory (ONIND, n = 15) neurological disorders. We measured the CSF concentration of APRIL, BAFF, CHI3L1, CCL-2, CXCL-8, CXCL-10, CXCL-12, CXCL-13 through a Luminex Assay. MS patients were prospectively evaluated, and clinical and radiological activity were recorded. CHI3L1 and CXCL13 CSF levels were significantly higher in both MS groups compared to control groups, while CCL2, BAFF, and APRIL concentrations were lower in RMS patients compared to PMS and OIND. Considering RMS patients with a single demyelinating event, higher concentrations of CHI3L1, CXCL10, CXCL12, and CXCL13 were recorded in patients who converted to clinically defined MS(CDMS). RMS patients in the CXCL13 and CHI3L1 high concentration group had a significantly higher risk of relapse (HR 12.61 and 4.57), MRI activity (HR 7.04 and 2.46), and of any evidence of disease activity (HR 12.13 and 2.90) during follow-up. CSF CXCL13 and CHI3L1 levels represent very good prognostic biomarkers in RMS patients, and therefore can be helpful in the treatment choice. Higher CSF concentrations of neuro-inflammatory biomarkers were associated with a higher risk of conversion to CDMS in patients with a first clinical demyelinating event. Differential CSF BAFF and APRIL levels between RMS and PMS suggest a different modulation of B-cells pathways in the different phases of the disease.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system characterized by broad inter-and intraindividual heterogeneity. The relapse rate, disability progression, and lesion load assessed through MRI are used to detect disease activity and response to treatment. Although it is possible to standardize these characteristics in larger patient groups, so far, this has been difficult to achieve in individual patients. Easily detectable molecular biomarkers can be powerful tools, permitting a tailored therapy approach for MS patients. However, only a few molecular biomarkers have been routinely used in clinical practice as the validation process, and their transfer into clinical practice takes a long time. This review describes the characteristics of an ideal MS biomarker, the challenges of establishing new biomarkers, and promising molecular biomarkers from blood or CSF samples used to monitor MS treatment effects in clinical practice.

Background: To minimize the risk of Progressive Multifocal Leukoencephalopathy and rebound in JCV-positive multiple sclerosis (MS) patients after 24 natalizumab doses, it has been proposed to extend the administrations interval. The objective is to evaluate the EID efficacy on MRI activity compared with the standard interval dosing (SID). Methods: Observational, multicentre, retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Three hundred and sixteen patients were enrolled. The median dose interval (MDI) following the 24th infusion was 5 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Patients were grouped into 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Results: One hundred and eighty-seven patients were in the SID group (MDI = 4.5 weeks) and 129 in the EID group (MDI 6.1 weeks). The risk to develop active lesions on MRI is similar in SID and EID groups during the 6 and 12 months after the 24th natalizumab infusion, respectively 4.27% (95% CI:0.84–7.70) vs 4.71% (95% CI:0.16–9.25%) [p = 0.89] and 8.50% (95% CI:4.05–12.95) vs 6.55% (95% CI:2.11–11.00%) [p = 0.56]. The EID regimen does not appear to increase the occurrence of MRI activity during follow-up. Conclusion: There is no evidence of the reduced efficacy of natalizumab in an EID setting regarding the MRI activity. This observation supports the need for a bigger randomized study to assess the need to change the standard of the natalizumab dosing schedule, to better manage JCV-positive patients.

Multiple sclerosis is a chronic, inflammatory and degenerative disease of the central nervous system of unknown aetiology although well-defined evidence supports an autoimmune pathogenesis. So far, the exact mechanisms leading to autoimmune diseases are still only partially understood. We know that genetic, epigenetic, molecular, and cellular factors resulting in pathogenic inflammatory responses are certainly involved. Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides that play an important role in both innate and acquired immunity, so there is great interest in lncRNAs involved in autoimmune diseases. The research on multiple sclerosis has been enriched with many studies on the molecular role of lncRNAs in the pathogenesis of the disease and their potential application as diagnostic and prognostic biomarkers. In particular, many multiple sclerosis fields of research are based on the identification of lncRNAs as possible biomarkers able to predict the onset of the disease, its activity degree, its progression phase and the response to disease-modifying drugs. Last but not least, studies on lncRNAs can provide a new molecular target for new therapies, missing, so far, a cure for multiple sclerosis. While our knowledge on the role of lncRNA in multiple sclerosis has recently improved, further studies are required to better understand the specific role of lncRNAs in this neurological disease. In this review, we present the most recent studies on molecular characterization of lncRNAs in multiple sclerosis disorder discussing their clinical relevance as biomarkers for diagnosis and treatments.

Objective: To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. Methods: An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. Results: From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. Conclusions: Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly.

Background: The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study. Methods: Neurologists members of the RIREMS group (Rising Researchers in MS) enrolled MS patients with a TN diagnosis and filled out a spreadsheet comprising their clinical data. Results: Population consisted of 298 patients. First-choice preventive treatments were carbamazepine and oxcarbazepine. A surgical procedure was performed in 81 (30%) patients, most commonly gamma knife stereotactic radiosurgery (37%), followed by microvascular decompression (22%) and radiofrequency thermocoagulation (21%); one third of patients underwent at least two procedures. Surgery was associated with higher disability, male sex and longer interval between MS and TN onset. Patients (77%) who stayed on at least one preventive medication at most recent follow-up, after a mean period of 8 years, had a higher disability compared to the untreated group. Furthermore, patients with higher disability at TN onset were less likely to discontinue their first preventive medication due to pain remission, had bilateral TN more frequently and underwent surgical interventions earlier. Conclusion: MS patients with a higher disability at TN onset and with a longer interval between MS and TN onset had differing clinical features and outcomes: pain was more frequently bilateral, surgery was more frequent and anticipated, and preventive medication discontinuation due to pain remission was less common.

The emergency represented by the COVID-19 pandemic represents a new challenge for clinicians who deal with autoimmune diseases because of patients undergoing immunosuppressive therapy. Few cases of Multiple Sclerosis (MS) patients receiving ocrelizumab who contracted COVID-19 with a benign course have recently been published. We present the case of a MS patient with mild COVID-19 who developed SARS-CoV-2 specific IgA without IgG ten weeks after infection. Patients on B-cell depleting drugs have a reduced antibody immune response to viral neoantigens. A relative sparing of mucosal-associated lymphoid tissues (MALT) could be responsible for IgA response in our patient.

In this independent, multicenter, post-marketing study, we directly compare induction immunosuppression versus escalation strategies on the risk of reaching the disability milestone of Expanded Disability Status Scale (EDSS) ≥ 6.0 over 10 years in previously untreated patients with relapsing-remitting multiple sclerosis. We collected data of patients who started interferon beta (escalation) versus mitoxantrone or cyclophosphamide (induction) as initial treatment. Main eligibility criteria included an EDSS score ≤ 4.0 at treatment start and either ≥ 2 relapses or 1 disabling relapse with evidence of ≥ 1 gadolinium-enhancing lesion at magnetic resonance imaging scan in the pre-treatment year. Since patients were not randomized to treatment group, we performed a propensity score (PS)–based matching procedure to select individuals with homogeneous baseline characteristics. Comparisons were then conducted using Cox models stratified by matched pairs. Overall, 75 and 738 patients started with induction and escalation, respectively. Patients in the induction group were older and more disabled than those in the escalation group (p < 0.05). The PS-matching procedure retained 75 patients per group. In the re-sampled population, a lower proportion of patients reached the outcome after induction (21/75, 28.0%) than escalation (29/75, 38.7%) (hazard ratio = 0.48; p = 0.024). Considering the whole sample, serious adverse events occurred more frequently after induction (8/75, 10.7%) than escalation (18/738, 2.4%) (odds ratio = 3.36, p = 0.015). These findings suggest that, in patients with poor prognostic factors, induction was more effective than escalation in reducing the risk of reaching the disability milestone, albeit with a worse safety profile. Future studies are warranted to explore if newer induction agents may provide a more advantageous long-lasting risk:benefit profile.

Background: Respiratory alemtuzumab-related adverse events are clinically heterogeneous and include respiratory infections, infusion-related dyspnea, hypoxia and secondary autoimmune disorders. Case report: Here we report three cases of drug-induced lung disease following treatment with alemtuzumab in multiple sclerosis patients. First case was diagnosed as a non-specified intestitial pneumonitis associated with organizing pneumonia with subacute onset, second case was an acute respiratory distress syndrome with onset during second cycle, third case was a diffuse acute alveolar hemorrhage during first cycle infusion. All patients developed acute respiratory failure, reversible after steroid therapy. Conclusions: Clinicians should be aware to early recognize acute and subacute respiratory adverse events for a promptly management. In these patients re-treatment is challenging.

Background: Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory, neurodegenerative disorder. Many studies are investigating the potential role of body fluid biomarkers as prognostic factors for early identification of patients presenting with clinical isolated syndrome (CIS) at high risk for conversion to MS or to recognize RRMS patients at high risk for progression.Objectives: To evaluate the correlation between levels of BAFF, chitinase 3-like 1 (CHI3L1), sCD163, Osteopontin (OPN), both on serum and cerebral spinal fluid (CSF), and the disease activity and progression. We also want to explore a possible relationship between serological and CSF biomarker's levels.Patients and methods: We enrolled 82 patients between June 2014 and June 2016. Seventy-one received a diagnosis of demyelinating disease of CNS (46 RRMS and 25 CIS), while 11 were affected by other neurological diseases. All patients underwent a neural axis MRI, lumbar puncture and blood samples. Levels of BAFF, CHI3L1, sCD163, OPN on serum and CSF were analyzed by Luminex xMAP system, with a kit 11-plex ad hoc.Results: The CSF CHI3L1, sCD163 and OPN levels were significantly higher in MS patients than in controls. We did not find significant differences in serum CHI3L1, sCD163 and OPN levels, nor CSF or serum BAFF levels between patient and control groups.We found significantly higher CSF level of sCD163 and CHI3L1 in all patients' subgroups compared with controls, while OPN was higher in CIS and RR subgroups. We did not find significant differences for serum and CSF levels of all the markers between patients with or without clinical or radiological disease activity.CSF sCD163 and CHI3L1 levels was significant higher in CIS patients who converted to MS (p < 0.05).Using ROC curve analysis, CSF sCD163 resulted the best predictive factor. CSF CHI3L1 and OPN levels resulted useful independent predictors too. Combined ROCS of those three analytes demonstrated a better predictive value, with

Patients with multiple sclerosis on long-term injectable therapies may suffer from the so-called “needle fatigue”, i.e., a waning commitment to continue with the prescribed injectable treatment. Therefore, alternative treatment strategies to enhance patients’ adherence are warranted. In this independent, multicentre post-marketing study, we sought to directly compare switching to either teriflunomide (TFN), dimethyl fumarate (DMF), or pegylated interferon (PEG) on treatment persistence and time to first relapse over a 12-month follow-up. We analyzed a total of 621 patients who were free of relapses and gadolinium-enhancing lesions in the year prior to switching to DMF (n = 265), TFN (n = 160), or PEG (n = 196). Time to discontinuation and time to first relapse were explored in the whole population by Cox regression models adjusted for baseline variables and after a 1:1:1 ratio propensity score (PS)-based matching procedure. Treatment discontinuation was more frequent after switching to PEG (28.6%) than DMF (14.7%; hazard ratio [HR] = 0.25, p < 0.001) and TFN (16.9%; HR = 0.27, p < 0.001). We found similar results even in the re-sampled cohort of 222 patients (74 per group) derived by the PS-based matching procedure. The highest discontinuation rate observed in PEG recipient was mainly due to poor tolerability (p = 0.005) and pregnancy planning (p = 0.04). The low number of patients who relapsed over the 12-month follow-up (25 out of 621, approximately 4%) prevented any analysis on the short-term risk of relapse. This real-world study suggests that oral drugs are a better switching option than low-frequency interferon for promoting the short-term treatment persistence in stable patients who do not tolerate injectable drugs.

Introduction: To compare a schedule with cyclic withdrawal (CW) of interferon beta (IFN-b) 1b, respect to the full regimen (FR), in relapsing-remitting MS (RR-MS). Methods: Participants were randomly assigned to CW or FR schedule and monthly monitored with brain MRI scans for 12 months (three of run-in and 9 of treatment). CW schedule included drug withdrawal for 1 month after two of treatment for a total of three quarters over the 9-month treatment period. The assessing neurologist and the expert neuroradiologists were blind. After the blind phase of the study all participants took their indicated disease modifying therapies in a prospectively planned, open-label extension phase (up to 120 months). Results: Of 60 randomized subjects 56 (29 in FR and 27 in CW group) completed the single-blind phase: the two groups were comparable, except for a non-significant difference in the number of contrast-enhanced lesions (CEL) at the end of run-in. The two-sided 90% CI for the ratio between median number of cumulative CEL was 0.29-1.07, allowing to significantly reject the null hypothesis of a ratio ≥1.2 and to meet the primary end-point of non-inferiority (the threshold and the ratio between median were chosen according to the non-normal distribution of the data). The differences (CW vs. FR) were also non-significant for secondary end points: mean cumulative number of T2-weighted new and enlarging lesions (3.48 ± 5.34 vs. 3.86 ± 6.76); mean number and volume (cm3) of black holes (1.24 ± 1.61 vs. 2.71 ± 4.56; 489.11 ± 1488.12 vs. 204.48 ± 396.98); number of patients with at least an active scan (21 vs. 22); mean relapse rate (0.52 ± 0.89 vs. 0.34 ± 0.66), relapse risk ratio adjusted for baseline variables (2.15 [0.64-7.18]), EDSS score (1.0 [1-1.56] vs. 1.5 [1-1.78]), proportion of patients with antibodies anti-IFN (5 [21%] vs. 8 [36%]). Fifty-four patients (27 for each study arm) completed the open-label phase. The annualized RR, EDSS, proportion of patients shifting to pro

Background: Acute disseminated encephalomyelitis (ADEM) is a monophasic post-infectious demyelinating disease, clinically defined by the acute onset of polyfocal neurological deficits including encephalopathy. A subset of ADEM patients will subsequently be diagnosed with relapsing disorders, including recurrent DEM (RDEM), multiphasic DEM (MDEM), neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS). Here we describe the case of an adult patient, who presented two ADEM-like episodes after a very long (8 years) symptoms-free period. Clinical case: A 48 years old man presented a first case of sub-acute onset of encephalopathy and dysarthria with MRI findings suggestive for ADEM for which he underwent an intravenous and oral steroid treatment followed by a complete clinical remission. After 8 years he presented a new sub-acute onset of encephalopathy and balance disorders with the onset of new lesions at the MRI. The search for oligoclonal band (OCB) showed a single CSF-restricted IgG band. Suspecting a new ADEM episode he was treated with intravenous steroids without benefit and 3 apheresis sessions with clinical improvement followed by an oral steroid treatment. After 2 months he experienced a paroxysmal episode of dysarthria, upper and lower left limbs impairment and urge incontinence with a stable new brain and spinal cord MRI. The search for anti-aquaporin-4 and anti-MOG (cell-based assay) antibodies was repeated twice within a 6 months span and resulted in both cases negative. The patient was treated with Rituximab (1g followed by 1g after 15 days, followed by 1g after 6 months) with stability of the neurological and radiological examinations at the last follow-up. Conclusions: To the best of our knowledge, this is the first case of MDEM in which the two episodes of ADEM occurred 8 years apart. Although this case fulfills the diagnostic criteria for MDEM, the time elapsed between the two episodes is very long. Therefore, we cannot exclude th