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While the spectrum of neurological immune checkpoint inhibitor-related adverse events is expanding, patients’ outcomes are not well documented. This study aimed to assess outcomes of neurological immune-related adverse events and to identify prognostic factors. All patients experiencing grade ≥2 neurological immune-related adverse events identified at two clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; and OncoNeuroTox, Paris) over five years were included. Modified Rankin scores were assessed at onset, 6, 12, 18 months, and last visit. A multi-state Markov model was used to estimate the transition rates between minor disability (mRS A total of 147 patients were included out of 205 patients with a suspicion of neurological immune-related adverse events. Median age was 65 years (range 20-87), and 87/147 patients (59.2%) were male. Neurological immune-related adverse events involved the peripheral nervous system in 87/147 patients (59.2%), the central nervous system in 51/147 (34.7%), and both systems in 9/147 (6.1%). Paraneoplastic-like syndromes were observed in 30/147 patients (20.4%). Cancers included lung cancers (36.1%), melanoma (30.6%), urological cancers (15.6%), and others (17.8%). Patients were treated with PD(L)1 inhibitors (70.1%), CTLA4 inhibitors (3.4%), or both (25.9%). Severe disability was reported in 108/144 patients (75.0%) at onset, and in 33/146 patients (22.6%) at last visit (median follow-up duration: 12 months, range 0.5-50); 48/147 (32.7%) patients died, from cancer progression (17/48, 35.4%), neurological toxicity (15/48, 31.2%), other causes (10/48, 20.8%), or unknown causes (6/48, 12.5%). The rate of transition from severe to minor disability independently increased with melanoma (compared to lung cancer, HR = 3.26, 95%CI [1.27; 8.41]) and myositis/neuromuscular junction disorders (HR = 8.26, 95%CI [2.90; 23.58]), and decreased with older age (HR = 0.68, 95%CI [0.47; 0.99]) and paraneoplastic-like syndromes (HR = 0.29, 95%CI [0.09; 0.98]). In patients with neurological immune-related adverse events, myositis/neuromuscular junction disorders and melanoma increase the transition rate from severe to minor disability, while older age and paraneoplastic-like syndromes result in poorer neurological outcomes; future studies are needed to optimize the management of such patients.

During the COVID-19 pandemic, myasthenia gravis (MG) patients have been identified as subjects at high risk of developing severe COVID-19, and thus were offered vaccination with priority. The lack of direct data on the safety and tolerability of SARS-CoV-2 vaccines in MG have contributed to vaccine hesitancy. To address this issue, the safety and tolerability of SARS-CoV-2 vaccines were assessed in a large cohort of MG patients from two referral centers.Patients with confirmed MG diagnosis, consecutively seen between October and December 2021 at two MG centers, were enrolled. Demographics, clinical characteristics, and information regarding SARS-CoV-2 infection/vaccination were extracted from medical reports and/or collected throughout telephonic or in-person interviews.Ninety-eight (94.2%) of 104 patients included were administered at least two vaccine doses 4 weeks before the interview or earlier, and among them, 63 of 98 (64.2%) have already received the "booster" dose. The most frequently used vaccines were BNT162b2-Pfizer-BioNTech and mRNA-1273-Moderna. Overall, only minor side effects were reported, most commonly local pain and fever. MG worsening after vaccination was observed in eight of 104 (7.7%) cases. The frequency of worsening among muscle-specific tyrosine kinase MG cases (3/9, 33.3%) was significantly higher compared to other serological subgroups. Spontaneous symptom regression was observed in six of eight cases. Twelve of 104 (11.5%) patients had SARS-CoV-2 infection, and none of the SARS-CoV-2-infected MG patients worsened after vaccination.Our data support the safety and tolerability of mRNA COVID-19 vaccines, which should be strongly recommended in MG patients, who could be at higher risk of complications if exposed to SARS-CoV-2 infection.

Objective Discontinuation of antiepileptic drugs (AEDs) in seizure‐free patients is an important goal because of possible long‐term side effects and the social stigma burden of epilepsy. The purpose of this work was to assess seizure recurrence risk after suspension of AEDs, to evaluate predictors for recurrence, and to investigate the recovery of seizure control after relapse. In addition, the accuracy of a previously published prediction model of seizure recurrence risk was estimated. Methods Seizure‐free patients with epilepsy who had discontinued AEDs were retrospectively enrolled. The frequency of seizure relapses after AED withdrawal as well as prognosis after recurrence were assessed and the predictive role of baseline clinical‐demographic variables was evaluated. The aforementioned prediction model was also validated and its accuracy assessed at different seizure‐relapse probability levels. Results The enrolled patients (n = 133) had been followed for a median of 3 years (range 0.8–33 years) after AED discontinuation; 60 (45%) of them relapsed. Previous febrile seizures in childhood (hazard ratio [HR] 3.927; 95% confidence interval [CI] 1.403–10.988), a seizure‐free period on therapy of less than 2 years (HR 2.313; 95% CI 1.193–4.486), and persistent motor deficits (HR 4.568; 95% CI 1.412–14.772) were the clinical features associated with relapse risk in univariate analysis. Among these variables, only a seizure‐free period on therapy of less than 2 years was associated with seizure recurrence in multivariate analysis (HR 2.365; 95% CI 1.178–4.7444). Pharmacological control of epilepsy was restored in 82.4% of the patients who relapsed. In this population, the aforementioned prediction model showed an unsatisfactory accuracy. Significance A period of freedom from seizure on therapy of less than 2 years was the main predictor of seizure recurrence. The accuracy of the previously described prediction tool was low in this cohort, thus suggesting its cautious use in real‐world clinical practice.

ObjectiveTo determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS.MethodsTo be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required.ResultsTwo hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1–9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening–free survival (95% confidence interval [CI]) was 85.5% (76.9%–94.1%) at 5 years and 71.3% (57.8%–84.8%) at 10 years. In patients with progressive MS, disability worsening–free survival was 71.0% (59.4%–82.6%) and 57.2% (41.8%–72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT (p = 0.001; mean EDSS change per year −0.09 [95% CI −0.15% to −0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14–0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007.ConclusionsaHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity.Classification of EvidenceThis study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.

Evidence of the effectiveness of B-cell-depleting monoclonal antibodies (mAbs) in multiple sclerosis (MS) prompted a partial revisitation of the pathogenetic paradigm of the disease, which was, so far, considered a T-cell-mediated autoimmune disorder. Mechanisms underlying the efficacy of B-cell-depleting mAbs in MS are still unknown. However, they likely involve the impairment of pleiotropic B-cell functions different from antibody secretion, such as their role as antigen-presenting cells during both the primary immune response in the periphery and the secondary response within the central nervous system (CNS). A potential impact of B-cell-depleting mAbs on inflammation compartmentalised within the CNS was also suggested, but little is known about the mechanism underlying this latter phenomenon as no definite evidence was provided so far on the ability of mAbs to cross the blood–brain barrier and reliable biomarkers of compartmentalised inflammation are lacking. The present paper briefly summarises the immunopathogenesis of MS with a focus on onset of autoimmunity and compartmentalisation of the immune response; mechanisms mediating B-cell depletion and underlying the effectiveness of B-cell-depleting mAbs are also discussed.

Background: The concept of improvement of disability recently emerged as a new target in multiple sclerosis (MS) studies since the approval of new potent drugs and for testing drugs for neuroprotection and repair. Objective: To propose a simple estimator for assessing and comparing the prevalence of improvement over time between groups. Methods: The prevalence of a transient condition takes into account the incidence and the duration of such condition. We propose here the application of a modified Kaplan–Meier estimator to evaluate and compare between groups the prevalence of improvement over time in a cohort of 121 patients treated with autologous hematopoietic stem cell transplantation. Results: The prevalence of improvement after 5 years from transplant was 50.3% (95%CI: [38.0–63.0]) in relapsing–remitting patients and 6.5% (95%CI: [0–17.8]) in secondary-progressive patients ( p Conclusion: This study shows the relevance of a new estimator of prevalence of improvement in MS. This estimator gives simple information on whether a drug can induce a durable improvement in disability and can be considered a potential outcome for trials assessing drugs for neuroprotection or repair.

Background: Autologous haematopoietic stem cell transplantation (aHSCT) is a valuable option in aggressive relapsing–remitting multiple sclerosis (MS), but its efficacy in secondary progressive (SP)-MS is still controversial. Objective: Assessing efficacy of aHSCT in SP-MS by clinical-radiological outcomes. Methods: Open-label monocentric retrospective study enrolling consecutive SP-MS patients treated with BEAM-aHSCT in the period 1999–2016. Results: In total, 26 SP-MS patients with moderate–severe disability were included. Progression-free survival (PFS) at years 5 and 10 after aHSCT were, respectively, 42% and 30%. Out of 16 patients who worsened, only 6 patients (23% overall) maintained continuous disability accrual (CDA), whereas 10 patients stabilized following one single-step Expanded Disability Status Scale (EDSS) worsening. CDA-free survival was 74% at 5–10 years. No relapses or magnetic resonance imaging (MRI) activity were reported, thus no evidence of disease activity (NEDA)-3 corresponded to PFS. Annualized rate of brain atrophy (AR-BVL) normalized after 1 year in 55% of the cases analysed (12/22). Conclusion: BEAM-aHSCT halted CDA and normalized AR-BVL in most of the treated patients, inducing long-term remission of inflammatory activity at a median follow-up of 99 months (range 27–222). These data suggest that CDA might still be mainly driven by inflammation in a subgroup of SP-MS and could therefore be reversed by treatments. CDA should be analysed independently from any isolated disability worsening.

Few data are available so far on the antibody-mediated immune response to anti-SARS-Cov2 vaccination in people with multiple sclerosis (pwMS) treated with disease-modifying treatments (DMTs), therefore this issue was explored in a real-life cohort of pwMS.Retrospective monocentric study on anti-spike protein antibody response in pwMS who had received vaccination for Sars-Cov2. Adverse events following vaccination were also recorded.One hundred and twenty pwMS were included: 83 females (69%); median age at vaccination 42 years (range 21-73); 112/120 patients (93%) were receiving DMTs at vaccination. Anti-spike protein IgG antibodies were detectable in 102/120 (85%) cases overall, being the proportion lower in pwMS receiving anti-CD20 antibodies (14/31, 45%) compared to non-depletive treatments (77/78, 99%), p 0.0001. Median anti-spike titre was lower in anti-CD20 antibodies and fingolimod-treated pwMS compared to those receiving other DMTs, and it correlated with anti-CD20 treatment duration (R - 0.93, p 0.0001) and with age at vaccination in pwMS not receiving depletive treatments (R - 0.25, p = 0.028). Baseline CD19+ cell count (where available) was higher in the responder group than in non-responders, p 0.0001. Two symptomatic COVID-19 infections were diagnosed over a median follow-up of 5 months (range 2-7); adverse events were aligned with the published literature.Antibody response to anti-COVID-19 vaccines was detected in most of the pwMS analysed, but frequency of responders was reduced in those receiving CD20 depleting therapies compared to other DMTs-treated pwMS. Investigations on cell-mediated immune response are needed to assess whether a protective immune response is elicited also in non-antibody responders.

Effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) in relapsing-remitting multiple sclerosis (MS) is well known, but in secondary-progressive (SP)-MS it is still controversial. Therefore, AHSCT activity was evaluated in SP-MS using low-dose immunosuppression with cyclophosphamide (Cy) as a comparative treatment.In this retrospective monocentric 1:2 matched study, SP-MS patients were treated with intermediate-intensity AHSCT (cases) or intravenous pulses of Cy (controls) at a single academic centre in Florence. Controls were selected according to baseline characteristics adopting cardinality matching after trimming on the estimated propensity score. Kaplan-Meier and Cox analyses were used to estimate survival free from relapses (R-FS), survival free from disability progression (P-FS), and no evidence of disease activity 2 (NEDA-2).A total of 93 SP-MS patients were included: 31 AHSCT, 62 Cy. Mean follow-up was 99 months in the AHSCT group and 91 months in the Cy group. R-FS was higher in AHSCT compared to Cy patients: at Year 5, 100% versus 52%, respectively (p 0.0001). P-FS did not differ between the groups (at Year 5: 70% in AHSCT and 81% in Cy, p = 0.572), nor did NEDA-2 (p = 0.379). A sensitivity analysis including only the 31 "best-matched" controls confirmed these results. Three neoplasms (2 Cy, 1 AHSCT) and two fatalities (2 Cy) occurred.This study provides Class III evidence, in SP-MS, on the superior effectiveness of AHSCT compared to Cy on relapse activity, without differences on disability accrual. Although the suppression of relapses was observed in the AHSCT group only, AHSCT did not show advantages over Cy on disability, suggesting that in SP-MS disability progression becomes based more on noninflammatory neurodegeneration than on inflammation.

Background The coronavirus disease 2019 (COVID-19) pandemic has severely impacted the Italian healthcare system, underscoring a dramatic shortage of specialized doctors in many disciplines. The situation affected the activity of the residents in neurology, who were also offered the possibility of being formally hired before their training completion. Aims (1) To showcase examples of clinical and research activity of residents in neurology during the COVID-19 pandemic in Italy and (2) to illustrate the point of view of Italian residents in neurology about the possibility of being hired before the completion of their residency program. Results Real-life reports from several areas in Lombardia—one of the Italian regions more affected by COVID-19—show that residents in neurology gave an outstanding demonstration of generosity, collaboration, reliability, and adaptation to the changing environment, while continuing their clinical training and research activities. A very small minority of the residents participated in the dedicated selections for being hired before completion of their training program. The large majority of them prioritized their training over the option of earlier employment. Conclusions Italian residents in neurology generously contributed to the healthcare management of the COVID-19 pandemic in many ways, while remaining determined to pursue their training. Neurology is a rapidly evolving clinical field due to continuous diagnostic and therapeutic progress. Stakeholders need to listen to the strong message conveyed by our residents in neurology and endeavor to provide them with the most adequate training, to ensure high quality of care and excellence in research in the future.

Background The natural history of multiple sclerosis (MS) following discontinuation of a first-line disease-modifying treatment (DMT) in relapsing-remitting (RR-) MS patients is controversial, as few data are available on the risk of disease reactivation. This study aims to investigate the disease course after DMT discontinuation in selected RR-MS patients, exploring potential predictive factors of disease reactivation. Methods RR-MS patients, aged 18-65, who had discontinued a first-line DMT were selected from 1107 clinical records. Relapses, disability worsening and new brain lesions, before and after DMT interruption, were retrospectively evaluated. Potentially predictive baseline characteristics of disease reactivation were also analysed. Results N= 60 patients were included, median age and treatment duration were 47.8 (22.1-64.3) and 7.2 (0.5-17.8) years respectively. Median clinical follow-up after discontinuation was 4.6 (0.5-16.6) years. No disease rebound occurred. Mean annualized disease activity and relapse rate after discontinuation were both lower than during treatment(0.10±0.05 vs 0.15 ±0.05; p=0.017). A NEDA-3 period on treatment ≥5.5 years was associated with a low rate (7.7%) and a low risk of new disease activity (aHR 0.16, CI 0.03-0.78, p=0.024; Cox regression model multivariate analysis). The patients with NEDA-3 period threshold above 5.5 years showed a higher probability of surviving to disease reactivation than others (p=0.014). Conclusion In most of the MS patients who showed a long NEDA-3 period while on treatment remission of disease activity persists following first-line DMT discontinuation, suggesting that prolonged suppression of disease activity on treatment can determine long term sustained remission of the disease also in absence of treatment.

Background: The central vein sign (CVS) has been shown to help in the differential diagnosis of multiple sclerosis (MS), but most prior studies are retrospective. Objectives: To prospectively assess the diagnostic predictive value of the CVS in diagnostically difficult cases. Methods: In this prospective multicenter study, 51 patients with suspected MS who had clinical, imaging, or laboratory “red flags” (i.e. features atypical for MS) underwent 3T fluid-attenuated inversion recovery (FLAIR*) magnetic resonance imaging (MRI) for CVS assessment. After the diagnostic work-up, expert clinicians blinded to the results of the CVS assessment came to a clinical diagnosis. The value of the CVS to prospectively predict an MS diagnosis was assessed. Results: Of the 39 patients who received a clinical diagnosis by the end of the study, 27 had MS and 12 received a non-MS diagnosis that included systemic lupus erythematosus, sarcoidosis, migraine, Sjögren disease, SPG4-spastic-paraparesis, neuromyelitis optica, and Susac syndrome. The percentage of perivenular lesions was higher in MS (median = 86%) compared to non-MS (median = 21%; p < 0.0001) patients. A 40% perivenular lesion cutoff was associated with 97% accuracy and a 96% positive/100% negative predictive value. Conclusion: The CVS detected on 3T FLAIR* images can accurately predict an MS diagnosis in patients suspected to have MS, but with atypical clinical, laboratory, and imaging features., SCOPUS: ar.j, info:eu-repo/semantics/published

Background and purpose : Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients’ management was studied, focusing on the subgroupofAb-negative-AE. Methods: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). Results: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P=0.045), responded more frequently to treatments (92.3% vs. 65.6%, P&nbsp

Objectives In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the "central vein sign") improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). Methods In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3-dimensional T2*-weighted and T2-fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. Results MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behcet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjogren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. Interpretation The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283-294.

Magnetic resonance imaging (MRI) is an invaluable tool for the diagnosis and monitoring of patients with multiple sclerosis (MS) as well as for the study of the disease pathophysiology. Because of its strong clinical, radiological and histopathological similarities with the human disease, experimental autoimmune encephalomyelitis (EAE) in the common marmoset has been studied more intensively over the past several years. Here, we review the current knowledge on MRI in the marmoset EAE, and we outline the physiopathological significance and translational values of these studies with respect to MS. Accumulating evidences suggest that the application of conventional, as well as non-conventional, MRI techniques in the marmoset EAE is a promising approach to elucidate the pathological processes underlying the development of inflammatory demyelinated lesions in the central nervous system, potentially improving the identification and development of new therapeutics.

We reported the case of a John Cunningham virus (JCV) and human herpesvirus 6 (HHV-6) mediated progressive multifocal leukoencephalopathy (PML) after human stem cell transplant, reactivated 6 months later in absence of immunosuppressive therapy, successfully treated with anti-5HT2A receptors agents and antiviral therapy. Few cases of JCV and HHV-6 coinfection associated PML are described in literature and the role of HHV-6 in the pathogenesis and prognosis of PML is not completely clear. Our case suggests that, in a possible PML, the research of HHV-6 and JCV should be always performed on cerebrospinal fluid (CSF) and on blood samples and in case of detection of HHV-6 DNA a chromosomally integrated human herpesvirus 6(ciHHV-6) should be excluded. Furthermore we recommend to start an appropriate therapy with antiviral and anti-5HT2A receptors agents in case of possible PML due to JCV and HHV-6 coinfection.

Natalizumab (NTZ) and autologous hematopoietic stem cell transplantation (AHSCT) are two successful treatments for relapsing-remitting multiple sclerosis (RRMS), an autoimmune T-cell-driven disorder affecting the central nervous system that is characterized by relapses interspersed with periods of complete or partial recovery. Both RRMS treatments have been documented to impact T-cell subpopulations and the T-cell receptor (TCR) repertoire in terms of clone frequency, but, so far, the link between T-cell naive and memory populations, autoimmunity, and treatment outcome has not yet been established hindering insight into the post-treatment TCR landscape of MS patients. To address this important knowledge gap, we tracked peripheral T-cell subpopulations (naïve and memory CD4+ and CD8+) across 15 RRMS patients before and after two years of continuous treatment (NTZ) and a single treatment course (AHSCT) by high-throughput TCRß sequencing. We found that the two MS treatments left treatment-specific multidimensional traces in patient TCRß repertoire dynamics with respect to clonal expansion, clonal diversity and repertoire architecture. Comparing MS TCR sequences with published datasets suggested that the majority of public TCRs belonged to virus-associated sequences. In summary, applying multi-dimensional computational immunology to a TCRß dataset of treated MS patients, we show that qualitative changes of TCRß repertoires encode treatment-specific information that may be relevant for future clinical trials monitoring and personalized MS follow-up, diagnosis and treatment regimes. Natalizumab (NTZ) and autologous hematopoietic stem cell transplantation (AHSCT) are two successful treatments for relapsing–remitting multiple sclerosis (RRMS), an autoimmune T-cell–driven disorder affecting the central nervous system that is characterized by relapses interspersed with periods of complete or partial recovery. Both RRMS treatments have been documented to impact T-cell subpopulations and the T-cell receptor (TCR) repertoire in terms of clone frequency, but, so far, the link between T-cell naive and memory populations, autoimmunity, and treatment outcome has not yet been established hindering insight into the posttreatment TCR landscape of MS patients. To address this important knowledge gap, we tracked peripheral T-cell subpopulations (naive and memory CD4+ and CD8+) across 15 RRMS patients before and after 2 years of continuous treatment (NTZ) and a single treatment course (AHSCT) by high-throughput TCRβ sequencing. We found that the two MS treatments left treatment-specific multidimensional traces in patient TCRβ repertoire dynamics with respect to clonal expansion, clonal diversity, and repertoire architecture. Comparing MS TCR sequences with published datasets suggested that the majority of public TCRs belonged to virus-associated sequences. In summary, applying multidimensional computational immunology to a TCRβ dataset of treated MS patients, we show that qualitative changes of TCRβ repertoires encode treatment-specific information that may be relevant for future clinical trials monitoring and personalized MS follow-up, diagnosis, and treatment regimens.

Background Severe multiple sclerosis reactivation following second line treatment withdrawal, defined “rebound syndrome”, is becoming a prominent issue to consider when deciding to discontinue a treatment. In particular disease recurrence after cessation of fingolimod is actually poorly characterized as to date, only case reports and small case series have been described. Case presentation We herewith describe 2 cases of severe disease reactivation associated to a high number of brain gadolinium enhancing lesions at magnetic resonance imaging (MRI) despite high dose steroid treatment, observed a few weeks after cessation of fingolimod administration, causing a substantial and persistent worsening of patient disability that required long term hospitalization. The severity of the neurological symptom worsening and of the brain lesion largely exceeded the disease activity observed during treatment. Conclusions Our patients developed a rebound syndrome after ceasing fingolimod treatment, defined as the development of severe neurological symptoms and multiple new or enhancing lesions exceeding previous activity. Further analysis are needed to identify patients at greatest risk of a rebound syndrome.

Background and purpose Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (MS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, the safety and efficacy of autologous hematopoietic stem-cell transplantation (aHSCT) performed following NTZ discontinuation were retrospectively compared with conventional DMTs. Methods Patients with relapsing-remitting MS treated with NTZ who discontinued the drug after at least six administrations and with at least 6 months of follow-up were included. Patients underwent aHSCT after a minimum of 6 months following NTZ withdrawal, receiving meanwhile cyclophosphamide or corticosteroids, or other DMTs approved for MS (control group) after an adequate wash-out period. Both hematological and neurological follow-up were assessed according to standard policies. Results A total of 52 patients were included, 11 who received aHSCT and 41 who received DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including progressive multifocal leukoencephalopathy, were observed. At 3 years following NTZ discontinuation, no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared with 11.5% of those in the DMT group (P = 0.0212). Disease reactivation in the patients with aHSCT was observed only during wash-out/bridging therapy and 100% of the cases were free from disease activity after aHSCT. Conclusions These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. aHSCT after 6 months from NTZ withdrawal appears to be safe.

BACKGROUND: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses.METHODS: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18-58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0-6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0-5·5 vs 6·0-6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181.FINDINGS: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66-1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74-1·53; nominal p=0·753) or the T25FW (0·98, 0·74-1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40-0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108-221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred.INTERPRETATION: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components.FUNDING: Biogen.

Objective The objective of this study was to evaluate prespecified and post hoc analyses in RENEW subgroups to identify participants more likely to benefit from opicinumab. Methods RENEW assessed the efficacy/safety of opicinumab versus placebo in participants with a first unilateral acute optic neuritis (AON) episode. Difference in visual evoked potential (VEP) latency of the affected eye at 24 weeks versus the fellow eye at baseline was the primary endpoint. Interactions between the primary endpoint and prespecified baseline variables (including age, timing of treatment initiation, and visual impairment) using the median as cut‐off were evaluated in the per protocol population using analysis of covariance (ANCOVA); subgroups based on preexisting brain T2 lesion volume were also analyzed. Interactions between the primary endpoint and retinal ganglion cell layer/inner plexiform layer (RGCL/IPL) and retinal nerve fiber layer (RNFL) thickness were assessed post hoc as was weight gain by treatment. Results Treatment benefit of opicinumab (n = 33) over placebo (n = 36) on the primary endpoint was greatest in participants older than the median age at baseline (≥33 years); the difference versus placebo for baseline age ≥33 years was −14.17 msec [P = 0.01] versus −0.89 msec for baseline age

Objectives: In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the “central vein sign”) improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). Methods: In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing–remitting MS, 3-dimensional T2*-weighted and T2–fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. Results: MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. Interpretation: The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283–294., SCOPUS: ar.j, info:eu-repo/semantics/published

Polyomavirus JC (JCPyV) reactivation and development of progressive multifocal leukoencephalopathy is a health concern in multiple sclerosis patients under natalizumab therapy. Here, the JCPyV microRNA-J1-3p and microRNA-J1-5p expressions and genomic variability were investigated in blood and urine samples of multiple sclerosis patients before and under natalizumab therapy and in healthy controls. The two JCPyV microRNAs were detected in the JCPyV-DNA-positive peripheral blood mononuclear cell samples and in the exosomes derived from plasma and urine obtained from JCPyV-DNA-positive and JCPyV-DNA-negative patients. In particular, the increased JCPyV microRNA expression in samples of multiple sclerosis patients under natalizumab therapy was consistent with the high JCPyV-DNA positivity observed in these samples. Moreover, JCPyV microRNA genomic region showed few nucleotide differences in samples obtained from blood and urine of multiple sclerosis patients and healthy controls. Overall, these data suggest a potential role of the JCPyV microRNA expression in counteracting the viral reactivation to maintain JCPyV asymptomatic persistence in the host.

Importance Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies. Objective To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort. Design, Setting, and Participants Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015. Exposures Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen. Main Outcomes and Measures The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models. Results Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95). Conclusions and Relevance In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

This document presents the guidelines for anti-aquaporin-4 (AQP4) antibody testing that has been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on neuromyelitis optica spectrum disorders, indications and limits of anti-AQP4 antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Objective Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. Methods By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood–brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. Results On average, BBB permeability increased 3.5-fold (p

Objective To confirm CXCL10 over production in bone marrow mesenchymal stem cells (MSCs) and circulating monocytes isolated from multiple sclerosis patients (MS) and identify predate cell molecular signature; to extend this analysis after autologous hematopoietic stem cell transplantation (AHSCT) to test if therapy has modifying effects on MSCs and circulating monocytes. Methods MSCs and monocytes were isolated from 19 MS patients who undergone AHSCT before and seven of them at least 3 years after transplant. CXCL10 production was detected after LPS/IFN-γ stimulation. TLR4 signaling pathways were investigated by means of transcription factors phosphorylation/activation level. RT-PCR of activated transcription factors was performed to quantify their expression. All experiments were conducted in parallel with 24 matched healthy donors (HD). Results CXCL10 expression was significantly increased in both peripheral circulating monocytes and BM MSCs compared to HD. We showed that CXCL10 production is determined by an altered signaling pathway downstream TLR4, with the involvement of STAT-1, NF-κB, p38, JNK, and CREB. All upregulated transcription factors are more phosphorylated in MS patient sample. These features are not modified after AHSCT. Interpretation We demonstrated that in MS two different cell lineages are characterized by significantly increased production of CXCL10, due to altered signaling pathways of innate immune reaction mediated by TLR4, probably associated with disease phenotype. This characteristic is not modified by AHSCT, suggesting that when T and B lymphocytes are reset, other possible components of MS pathology, such as CXCL10 over production, do not determine therapy outcome.

Objective Recently autologous haematopoietic stem cell transplantation (AHSCT) has been introduced for the treatment of severe forms of multiple sclerosis (MS). As little data are available on bone marrow (BM) of MS patients undergoing AHSCT, we investigated the morphological and phenotypic characteristics of MS BM. Methods BM biopsies of 14 MS patients screened for AHSCT and 10 control patients were evaluated to assess cellularity, morphology, immunological profile and bone marrow microenvironment. Immunohistochemistry analysis was performed to evaluate the expression of CD3, CD4, CD8, CD20, CD68, CD45, MMP-9. Results 8 out of 14 MS (57%) patients showed a reduction of age-related bone marrow cellularity, possibly due to previous immunosuppressive therapies. There were no differences in the T CD3+ lymphocyte expression rate amongst MS and the control patients, the CD4/CD8 ratio (2:1) was maintained as was the rate of B lymphocytes. We found an increased, although not significant, MMP-9 expression (9.2%) in the bone marrow of MS patients, when compared to the control patients (6.3%). Conclusion The BM of MS patients showed a reduced cellularity and CD45+ cells content in comparison to the controls. A slightly increased expression of MMP-9 was also shown, possibly confirming an involvement of this compartment in the pathogenesis of the disease.