Explore the vast range of titles available.

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients.

BackgroundGrey matter (GM) atrophy is associated with cognitive impairment (CI) in multiple sclerosis (MS). We aimed to investigate the predictive role of early regional GM damage for long-term CI.MethodsA post-hoc cluster analysis was conducted on 175 patients with MS followed for 20 years from onset. Participants underwent a 1.5T-MRI scanning at diagnosis and after 2 years, and a comprehensive neuropsychological assessment after 20 years.ResultsThree clusters have been identified: cluster 1 (primarily patients with long-term normal cognition), cluster 2 (primarily patients with long-term mild CI) and cluster 3 (primarily patients with long-term severe CI). Five brain regions have been identified showing a significant difference in early atrophy from cluster 1 and both clusters 2 and 3: precuneus (1 vs 2: p<0.001, relative risk ratio (RRR)=4.9, 95% confidence intervals (95% CIs) =2.4-10.1; 1 vs 3: p<0.001, RRR=5.5, 95% CIs=3.1-9.7), insula (1 vs 2: p<0.001, RRR=4.1, 95% CIs=1.9-8.6; 1 vs 3: p<0.001, RRR=4.3, 95% CIs=2.5-7.5), parahippocampal gyrus (1 vs 2: p<0.001, RRR=3.2, 95% CIs=1.8-5.7; 1 vs 3: p<0.001, RRR=3.1, 95% CIs=2.1-4.6), cingulate gyrus (1 vs 2: p<0.001, RRR=3.0, 95% CIs=1.7-5.3; 1 vs 3: p<0.001, RRR=2.2, 95% CIs=1.6-5.3) and cerebellum (1 vs 2: p=0.027, RRR=2.6, 95% CIs=1.5-4.6; 1 vs 3: p<0.001, RRR=2.1, 95% CIs=1.5-2.9). Four additional brain regions showed a significant difference in terms of early atrophy between cluster 1 and cluster 3: precentral gyrus (p<0.001, RRR=7.3, 95% CIs=3.1-17.3), postcentral gyrus (p<0.001, RRR=4.6, 95% CIs=2.2-9.8), superior frontal gyrus (p<0.001, RRR=4.0, 95% CIs=2.0-8.0) and hippocampus (p<0.001, RRR=2.4, 95% CIs=1.6-3.6).ConclusionsCluster analysis identified the most specific brain regions whose early atrophy best distinguished future patients with CI. Long-term CI accumulation in MS can be predicted by early GM volume loss of specific cortical/deep GM regions.

Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID). Methods: We enrolled patients who underwent a diagnostic spinal tap throughout two years. KFLC levels were determined using a Freelite assay (Binding Site) and the turbidimetric Optilite analyzer. Results: Of 540 included patients, 223 had a CNSID, and 84 had MS. The kappa index was more sensitive (0.89 versus 0.85) and less specific (0.84 versus 0.89), with the same AUC (0.87) as OCB for MS diagnosis (optimal cut-off: 6.2). Adding patients with a single CSF IgG band to the OCB-positive group slightly increased the AUC (0.88). Likewise, the kappa index (cut-off: 3.9) was more sensitive (0.67 versus 0.50) and less specific (0.81 versus 0.97), with the same AUC (0.74) as OCB, for a CNSID diagnosis. Conclusion: The kappa index and CSF OCB have comparable diagnostic accuracies for a MS or CNSID diagnosis and supply the clinician with useful, complementary information.

Background: Multiple sclerosis (MS) pathology is characterized by acute and chronic inflammation, demyelination, axonal injury, and neurodegeneration. After decades of research into MS-related degeneration, recent efforts have shifted toward recovery and the prevention of further damage. A key area of focus is the remyelination process, where researchers are studying the effects of pharmacotherapy on myelin repair mechanisms. Multiple compounds are being tested for their potential to foster remyelination in different clinical settings through the application of less or more complex techniques to assess their efficacy. Objective: To review current methods and biomarkers to track myelin regeneration and recovery over time in people with MS (PwMS), with potential implications for promyelinating drug testing. Methods: Narrative review, based on a selection of PubMed articles discussing techniques to measure in vivo myelin repair and functional recovery in PwMS. Results: Non-invasive tools, such as structural Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET), are being implemented to track myelin repair, while other techniques like evoked potentials, functional MRI, and digital markers allow the assessment of functional recovery. These methods, alone or in combination, have been employed to obtain precise biomarkers of remyelination and recovery in various clinical trials on MS. Conclusions: Combining different techniques to identify myelin restoration in MS could yield novel biomarkers, enhancing the accuracy of clinical trial outcomes for remyelinating therapies in PwMS.

The impact of disease-modifying therapies (DMTs) on the immune response to coronavirus disease-2019 (COVID-19) vaccines in persons with multiple sclerosis (pwMS) needs further elucidation. We investigated BNT162b2 mRNA COVID-19 vaccine effects concerning antibody seroconversion, inflammatory mediators’ level and immunophenotype assessment in pwMS treated with cladribine (c-pwMS, n = 29), fingolimod (f-pwMS, n = 15) and ocrelizumab (o-pwMS, n = 54). Anti-spike immunoglobulin (Ig)-G detection was performed by an enzyme immunoassay; molecular mediators (GrB, IFN-γ and TNF-α) were quantified using the ELLA platform, and immunophenotype was assessed by flow cytometry. ANCOVA, Student’s t-test and Pearson correlation analyses were applied. Only one o-pwMS showed a mild COVID-19 infection despite most o-pwMS lacking seroconversion and showing lower anti-spike IgG titers than c-pwMS and f-pwMS. No significant difference in cytokine production and lymphocyte count was observed in c-pwMS and f-pwMS. In contrast, in o-pwMS, a significant increase in GrB levels was detected after vaccination. Considering non-seroconverted o-pwMS, a significant increase in GrB serum levels and CD4+ T lymphocyte count was found after vaccination, and a negative correlation was observed between anti-spike IgG production and CD4+ T cells count. Differences in inflammatory mediators’ production after BNT162b2 vaccination in o-pwMS, specifically in those lacking anti-spike IgG, suggest a protective cellular immune response.

BackgroundVaccination is a recognised trigger of ADEM and approximately 50% paediatric cases have antibodies to MOG. The SARS-CoV-2 mass vaccination programme could therefore trigger cases of MOGAD. Neuromyelitis optica (NMO) is an autoimmune inflammatory condition of the CNS associ- ated with antibodies to AQP4.MethodTen patients (ages 22 – 65 years) with antibodies to MOG or AQP4 were referred to the NHS England NMO service having developed acute onset CNS inflammation within 8 weeks of vaccination.ResultsEight patients had MOGAD, seven of whom received the AstraZeneca vaccine (AZV) and one the Pfizer vaccine (PV). Only the post-PV MOGAD patient presented with typical adult-onset phenotype of isolated ON. All post-AZV MOGAD patients presented atypically; 85.7% had LETM and 71.4% had intrac- erebral lesions, resembling ADEM more commonly seen in paediatric MOGAD. The atypical presentation supports a causative role of AZV, but the role of PV is less convincing.Two patients had AQP4-NMOSD with typical demographic features. Both received AZV. Less typically, one young adult presented with LETM rather than characteristic young adult ON, the other had a silent short segment myelitis, which is rarely seen in AQP4-NMOSD. Both patients achieved good outcomes.ConclusionWe discuss the potential causation and pathophysiological mechanisms.

In multiple sclerosis, magnetic resonance imaging (MRI) new silent lesions contribute to the diagnostic criteria, have prognostic value, and are used in treatment monitoring; but in aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-NMOSD), they are rare between attacks. Their frequency and their association with relapses in adults with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are still unclear. To examine the frequency and characteristics of MRI new silent lesions in MOGAD and AQP4-NMOSD. This retrospective cohort study analyzed clinical and MRI data of 404 patients with MOGAD or AQP4-NMOSD between February 1, 1994, and April 1, 2021; data were prospectively recorded on the Oxford NMOSD clinical database under follow-up. The study was conducted at the Oxford National Referral Center for NMOSD. Participants included patients with MOGAD and AQP4-NMOSD who were treated within the Oxford National NMO Specialist Service. Seropositive MOGAD and AQP4-NMOSD patients who had MRIs during attacks and the remission phase of their disease. Frequency of new silent lesions detected by either attack MRIs (during the acute clinical event) or remission MRIs (performed outside of a relapse and at least 3 months from last attack). Median time to next relapse in the presence of definite (reference MRI performed at least 4 weeks from last attack onset), probable (reference MRI performed during last attack), and no new silent lesions on remission MRIs was also evaluated. One hundred eighty-two MOGAD patients and 222 AQP4-NMOSD patients were included. Of the MOGAD patients, 113 (62%) were female, median age at onset was 28 years (range, 2-72), and median follow-up was 52 months (range, 11-253). Of the AQP4-NMOSD patients, 189 (85%) were female, median age at onset was 43 years (range, 2-82), and median follow-up was 87.5 months (range, 11-260). MOGAD patients had 296 attack MRI sessions and 167 remission MRI sessions. New attack silent lesions were found in 97 of 296 (33%) attack MRI sessions, whereas new remission silent lesions were found in 5 of 167 (3.0%) remission MRI sessions. Median time from remission scan to the next relapse in the presence of definite or probable new remission lesions was 2 months (IQR, 1-6), whereas in the absence of any new remission lesions it was 73 months (IQR, 20-104; hazard ratio, 23.86; 95% CI, 7.51-75.79; P < .001). AQP4-NMOSD patients had 470 attack MRI sessions and 269 remission MRI sessions. New attack silent lesions were detected in 88 of 470 (18.7%) attack MRI sessions, whereas new remission silent lesions were found in 7 of 269 (2.6%) remission MRI sessions. Median time from remission scan to the next relapse in the presence of definite or probable new remission lesions was 5 months (IQR, 2-6), whereas in the absence of any new remission lesions it was 85 months (IQR, 29-167; hazard ratio, 21.23; 95% CI, 8.05-53.65; P < .001). In contrast to that reported in multiple sclerosis, results of this cohort study suggest that new remission silent lesions are rare on follow-up scans in MOGAD and AQP4-NMOSD and appear to indicate a high risk of imminent relapse.

ObjectiveTo describe onset clinical features predicting time to first relapse and time to long-term visual, motor and cognitive disabilities in paediatric-onset aquaporin-4 antibody (AQP4-IgG) neuromyelitis optica spectrum disorders (NMOSDs).MethodsIn this retrospective UK multicentre cohort study, we recorded clinical data of paediatric-onset AQP4-IgG NMOSD. Univariate and exploratory multivariable Cox proportional hazard models were used to identify long-term predictors of permanent visual disability, Expanded Disability Status Scale (EDSS) score of 4 and cognitive impairment.ResultsWe included 49 paediatric-onset AQP4-IgG patients (38.8% white, 34.7% black, 20.4% Asians and 6.1% mixed), mean onset age of 12±4.1 years, and 87.7% were female. Multifocal onset presentation occurred in 26.5% of patients, and optic nerve (47%), area postrema/brainstem (48.9%) and encephalon (28.6%) were the most involved areas. Overall, 52.3% of children had their first relapse within 1 year from disease onset. Children with onset age <12 years were more likely to have an earlier first relapse (p=0.030), despite showing no difference in time to immunosuppression compared with those aged 12–18 years at onset. At the cohort median disease duration of 79 months, 34.3% had developed permanent visual disability, 20.7% EDSS score 4 and 25.8% cognitive impairment. Visual disability was associated with white race (p=0.032) and optic neuritis presentations (p=0.002). Cognitive impairment was predicted by cerebral syndrome presentations (p=0.048), particularly if resistant to steroids (p=0.034).ConclusionsAge at onset, race, onset symptoms and resistance to acute therapy at onset attack predict first relapse and long-term disabilities. The recognition of these predictors may help to power future paediatric clinical trials and to direct early therapeutic decisions in AQP4-IgG NMOSD.

Background/Objectives: Little is known about the impact of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) on brain atrophy. This multicenter longitudinal study compares brain MRI volumes and T2 lesion volume between MOGAD patients, relapsing-remitting MS (RRMS) patients and a healthy control (HC) group with brain MRI scans available from an online repository. Methods: In total, 16 adult MOGAD patients (9 F) were age- and sex-matched with 44 RRMS patients (17 F) recruited in Verona MS Center and 14 HC subjects. The availability of two brain MRI scans performed 18 ± 6 months apart was mandatory for each patient. Annual percentage brain volume change (PBVC/y), baseline global brain, white matter (WM), gray matter (GM) regional brain volumes and T2 lesion volume were compared between groups. Results: PBVC/y was lower in MOGAD than in RRMS patients (p = 0.014) and lower in HC subjects than in MS patients (p = 0.005). Overall, MOGAD showed higher mean global brain (p = 0.012) and WM volume (p = 0.024) but lower median T2 lesion volume at timepoint 1 (p < 0.001); T2 lesion volume increased over time in the RRMS (p < 0.001) but not in the MOGAD cohort (p = 0.262). Conclusions: The structural brain MRI features of MOGAD show higher global brain and WM volumes and lower brain volume loss over time compared to RRMS, suggesting different underlining pathogenetic mechanisms.