Cortical lesions at diagnosis predict long-term cognitive impairment in multiple sclerosis: A 20-year study.

BACKGROUND AND PURPOSE: Although cognitive impairment (CI) is frequent in multiple sclerosis (MS) patients, few studies (and with conflicting results) have evaluated early predictors of CI in the long term. We aimed at determining associations between early clinical/neuroradiological variables with reference to CI after 20 years of MS. METHODS: We investigated in 170 MS patients the relationship between clinical/magnetic resonance imaging (MRI) data at diagnosis and cognitive status almost 20 years after MS onset. Among others, number and volume of both white matter lesions (WMLs) and cortical lesions (CLs) were evaluated at diagnosis and after 2 years. All MS patients were followed over time and underwent a comprehensive neuropsychological assessment at the end of study. Advanced statistical methods (unsupervised cluster analysis and random forest model) were conducted. RESULTS: CI patients showed higher focal cortical pathology at diagnosis compared to cognitively normal subjects (p < 0.001). Volumes of both WMLs and CLs emerged as the MRI metrics most associated with long-term CI. Moreover, number of CLs (especially ≥3) was also strongly associated with long-term CI (≥3 CLs: odds ratio [OR] = 3.7, 95% confidence interval = 1.8-7.5, p < 0.001), more than number of WMLs; the optimal cutoff of three CLs (area under the curve = 0.67, specificity = 75%, sensitivity = 55%) was estimated according to the risk of developing CI. CONCLUSIONS: These results highlight the impact of considering both white and gray matter focal damage from early MS stages. Given the low predictive value of WML number and the poor clinical applicability of lesion volume estimation in the daily clinical context, the evaluation of number of CLs could represent a reliable prognostic marker of CI.

Volume changes of thalamus, hippocampus and cerebellum are associated with specific CSF profile in MS.

BACKGROUND: The underlying pathogenesis of surface-in grey matter abnormalities in MS, demonstrated by both neuropathology and advanced MRI analyses, is under investigation and it might be related to CSF-mediated mechanism of inflammation and/or damage. OBJECTIVE: To examine the link of CSF inflammatory profile with the damage of three regions early-involved in MS and bordering with CSF: thalamus, hippocampus and cerebellum. METHODS: In this longitudinal, prospective study, we evaluated, in 109 relapsing-remitting MS patients, at diagnosis and after 2-year follow-up, the association between the baseline CSF level of 19 inflammatory mediators and the volume changes of thalamus, hippocampus, cerebellar cortex and control regions (globus pallidus, putamen). RESULTS: The multivariable analysis showed that the CXCL13 and sCD163 CSF levels at baseline were independent predictors of thalamus (Rmodel2=0.80; p < 0.001) and hippocampus (Rmodel2=0.47; p < 0.001) volume change after 2-year follow-up. These molecules, plus CCL25, IFN-γ and fibrinogen, were independent predictors of the cerebellar cortex volume loss (Rmodel2=0.60; p < 0.001). No independent predictors of volume changes of the control regions were found. CONCLUSION: Our results indicate an association between the CSF inflammatory profile and grey matter volume loss of regions anatomically close to CSF boundaries, thus supporting the hypothesis of a surface-in GM damage in MS.

Two years' effect of dimethyl fumarate on focal and diffuse gray matter pathology in multiple sclerosis.

BACKGROUND: Data on the effect of dimethyl fumarate (DMF) on focal and diffuse gray matter (GM) damage, a relevant pathological substrate of multiple sclerosis (MS)-related disability are lacking. OBJECTIVE: To evaluate the DMF effect on cortical lesions (CLs) accumulation and global and regional GM atrophy in subjects with relapsing-remitting MS. METHODS: A total of 148 patients (mean age 38.1 ± 9.7 years) treated with DMF ended a 2-year longitudinal study. All underwent regular Expanded Disability Status Scale (EDSS assessment), and at least two 3T-magnetic resonance imaging (MRI) at 3 and 24 months after DMF initiation. CLs and changes in global and regional atrophy of several brain regions were compared with 47 untreated age and sex-matched patients. RESULTS: DMF-treated patients showed lower CLs accumulation (median 0[0-3] vs 2[0-7], p < 0.001) with respect to controls. Global cortical thickness (p < 0.001) and regional thickness and volume were lower in treated group (cerebellum, hippocampus, caudate, and putamen: p < 0.001; thalamus p = 0.03). Lower relapse rate (14% vs 40%, p < 0.001), EDSS change (0.2 ± 0.4 vs 0.4 ± 0.9, p < 0.001), and new WM lesions (median 0[0-5] vs 2[0-6], p < 0.001) were reported. No severe adverse drug reactions occurred. CONCLUSIONS: Beyond the well-known effect on disease activity, these results provide evidence of the effect of DMF through reduced progression of focal and diffuse GM damage.

Benign food-borne type B botulism presenting as unilateral internal ophthalmoplegia: a case report.

BACKGROUND: Food-borne botulism is a rare neuromuscular junction disorder due to the effect of toxins released from Clostridium botulinum ingested by eating improperly stored food. Its classic manifestation is a rapidly evolving descending symmetrical flaccid paralysis with dysautonomia. CASE PRESENTATION: We have described a case of type B food-borne botulism with a benign clinical course characterized by an initially unilateral tonic mydriatic pupil. An extensive neurophysiological evaluation inclusive of pilocarpine eye drop(s) test, facial and limbs nerve stimulation and sudomotor tests, was decisively leading the diagnostic process. CONCLUSIONS: The importance of what has been described here lies in underlining that it is always advisable to consider food-borne botulinum intoxication, even in the case of unilateral/asymmetrical internal ophthalmoplegia without generalized progressive involvement of the voluntary muscles.

Early multiple sclerosis: diagnostic challenges in clinically and radiologically isolated syndrome patients.

PURPOSE OF REVIEW: With the introduction of new diagnostic criteria, the sensibility for multiple sclerosis (MS) diagnosis increased and the number of cases with the clinically isolated syndrome (CIS) decreased. Nevertheless, a misdiagnosis might always be around the corner, and the exclusion of a 'better explanation' is mandatory.There is a pressing need to provide an update on the main prognostic factors that increase the risk of conversion from CIS or from radiologically isolated syndrome (RIS) to MS, and on the potential 'red flags' to consider during the diagnostic workup. RECENT FINDINGS: We discuss diagnostic challenges when facing patients presenting with a first demyelinating attack or with a RIS, with a focus on recently revised diagnostic criteria, on other neuroinflammatory conditions to be considered in the differential diagnosis and on factors distinguishing patients at risk of developing MS.A correct definition of a 'typical' demyelinating attack, as well as a correct interpretation of MRI findings, remains crucial in the diagnostic process. The cerebrospinal fluid examination is warmly recommended to confirm the dissemination in time of the demyelinating process and to increase the diagnostic accuracy. SUMMARY: An early and accurate diagnosis of MS requires careful consideration of all clinical, paraclinical and radiological data, as well the reliable exclusion of other mimicking pathological conditions. This is advocated to promptly initiate an appropriate disease-modifying therapy, which can impact positively on the long-term outcome of the disease.

A novel prognostic score to assess the risk of progression in relapsing-remitting multiple sclerosis patients.

BACKGROUND: At the patient level, the prognostic value of several features that are known to be associated with an increased risk of converting from relapsing-remitting (RR) to secondary phase (SP) multiple sclerosis (MS) remains limited. METHODS: Among 262 RRMS patients followed up for 10 years, we assessed the probability of developing the SP course based on clinical and conventional and non-conventional magnetic resonance imaging (MRI) parameters at diagnosis and after 2 years. We used a machine learning method, the random survival forests, to identify, according to their minimal depth (MD), the most predictive factors associated with the risk of SP conversion, which were then combined to compute the secondary progressive risk score (SP-RiSc). RESULTS: During the observation period, 69 (26%) patients converted to SPMS. The number of cortical lesions (MD = 2.47) and age (MD = 3.30) at diagnosis, the global cortical thinning (MD = 1.65), the cerebellar cortical volume loss (MD = 2.15) and the cortical lesion load increase (MD = 3.15) over the first 2 years exerted the greatest predictive effect. Three patients' risk groups were identified; in the high-risk group, 85% (46/55) of patients entered the SP phase in 7 median years. The SP-RiSc optimal cut-off estimated was 17.7 showing specificity and sensitivity of 87% and 92%, respectively, and overall accuracy of 88%. CONCLUSIONS: The SP-RiSc yielded a high performance in identifying MS patients with high probability to develop SPMS, which can help improve management strategies. These findings are the premise of further larger prospective studies to assess its use in clinical settings.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Background: 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. Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Methods: 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. Results: 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). Conclusions: 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.

Immune Response after COVID-19 mRNA Vaccination in Multiple Sclerosis Patients Treated with DMTs.

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.

CSF TNF and osteopontin levels correlate with the response to dimethyl fumarate in early multiple sclerosis.

Background: Disease activity in the first years after a diagnosis of relapsing-remitting multiple sclerosis (RRMS) is a negative prognostic factor for long-term disability. Markers of both clinical and radiological responses to disease-modifying therapies (DMTs) are advocated. Objective: The objective of this study is to estimate the value of cerebrospinal fluid (CSF) inflammatory markers at the time of diagnosis in predicting the disease activity in treatment-naïve multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF). Methods: In total, 48 RRMS patients (31 females/17 males) treated with DMF after the diagnosis were included in this 2-year longitudinal study. All patients underwent a CSF examination, regular clinical and 3T magnetic resonance imaging (MRI) scans that included the assessment of white matter (WM) lesions, cortical lesions (CLs) and global cortical thickness. CSF levels of 10 pro-inflammatory markers - CXCL13 [chemokine (C-X-C motif) ligand 13 or B lymphocyte chemoattractant], CXCL12 (stromal cell-derived factor or C-X-C motif chemokine 12), tumour necrosis factor (TNF), APRIL (a proliferation-inducing ligand, or tumour necrosis factor ligand superfamily member 13), LIGHT (tumour necrosis factor ligand superfamily member 14 or tumour necrosis factor superfamily member 14), interferon (IFN) gamma, interleukin 12 (IL-12), osteopontin, sCD163 [soluble-CD163 (cluster of differentiation 163)] and Chitinase3-like1 - were assessed using immune-assay multiplex techniques. The combined three-domain status of 'no evidence of disease activity' (NEDA-3) was defined by no relapses, no disability worsening and no MRI activity, including CLs. Results: Twenty patients (42%) reached the NEDA-3 status; patients with disease activity showed higher CSF TNF (p = 0.009), osteopontin (p = 0.005), CXCL12 (p = 0.037), CXCL13 (p = 0.040) and IFN gamma levels (p = 0.019) compared with NEDA-3 patients. After applying a random forest approach, TNF and osteopontin revealed the most important variables associated with the NEDA-3 status. Six molecules that emerged at the random forest approach were added in a multivariate regression model with demographic, clinical and MRI measures of WM and grey matter damage as independent variables. TNF levels confirmed to be associated with the absence of disease activity: odds ratio (OR) = 0.25, CI% = 0.04-0.77. Conclusion: CSF inflammatory markers may provide prognostic information in predicting disease activity in the first years after DMF initiation. CSF TNF levels are a possible candidate in predicting treatment response, in addition to clinical, demographic and MRI variables.

"What Is Hidden behind the Mask?" Facial Emotion Recognition at the Time of COVID-19 Pandemic in Cognitively Normal Multiple Sclerosis Patients.

Social cognition deficits have been described in people with multiple sclerosis (PwMS), even in absence of a global cognitive impairment, affecting predominantly the ability to adequately process emotions from human faces. The COVID-19 pandemic has forced people to wear face masks that might interfere with facial emotion recognition. Therefore, in the present study, we aimed at investigating the ability of emotion recognition in PwMS from faces wearing masks. We enrolled a total of 42 cognitively normal relapsing-remitting PwMS and a matched group of 20 healthy controls (HCs). Participants underwent a facial emotion recognition task in which they had to recognize from faces wearing or not surgical masks which of the six basic emotions (happiness, anger, fear, sadness, surprise, disgust) was presented. Results showed that face masks negatively affected emotion recognition in all participants (p < 0.001); in particular, PwMS showed a global worse accuracy than HCs (p = 0.005), mainly driven by the "no masked" (p = 0.021) than the "masked" (p = 0.064) condition. Considering individual emotions, PwMS showed a selective impairment in the recognition of fear, compared with HCs, in both the conditions investigated ("masked": p = 0.023; "no masked": p = 0.016). Face masks affected negatively also response times (p < 0.001); in particular, PwMS were globally hastier than HCs (p = 0.024), especially in the "masked" condition (p = 0.013). Furthermore, a detailed characterization of the performance of PwMS and HCs in terms of accuracy and response speed was proposed. Results from the present study showed the effect of face masks on the ability to process facial emotions in PwMS, compared with HCs. Healthcare professionals working with PwMS at the time of the COVID-19 outbreak should take into consideration this effect in their clinical practice. Implications in the everyday life of PwMS are also discussed.

Coping Strategies and Their Impact on Quality of Life and Physical Disability of People with Multiple Sclerosis.

The aim of the study is to investigate the impact of coping strategies on Health-Related Quality of Life (HRQoL) and physical disability assessed with the Expanded Disability Status Scale (EDSS) of people with multiple sclerosis (pwMS). PwMS were asked to focus on "MS diagnosis" as the core stressor. One hundred eight pwMS completed the Coping Responses Inventory-Adult form (CRI-Adult), the Multiple Sclerosis Quality of Life-29 (MSQoL-29), and the Depression Anxiety Stress Scale-21 (DASS-21). Multiple regression analyses (first block: EDSS, disease duration, and DASS-21) revealed that physical MSQoL-29 was positively associated with Alternative Rewards and negatively with Resigned Acceptance of the CRI-Adult. The mental MSQoL-29 was positively associated with Problem-Solving and negatively with Emotional Discharge. The Expanded Disability Status Scale (EDSS; first block: disease duration and general distress) was negatively associated with Positive Reappraisal. The Analysis of covariance (ANCOVA) revealed that pwMS with lower physical disability showed higher scores in Positive Reappraisal and lower scores in Emotional Discharge than pwMS with a higher physical disability. Coping strategies can play a role on HRQoL and physical disability in pwMS above and beyond EDSS, disease duration, and general distress. Psychological interventions should be considered in pwMS since the time of diagnosis to promote engagement in adaptive coping strategies and contrast the maladaptive ones.

CSF Levels of CXCL12 and Osteopontin as Early Markers of Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate the extent of intrathecal inflammation in patients with primary progressive MS (PPMS) at the time of diagnosis and to define markers and a specific inflammatory profile capable of distinguishing progressive from relapsing-remitting multiple sclerosis (RRMS). METHODS: Levels of 34 pro- and anti-inflammatory cytokines and chemokines in the CSF were evaluated at the diagnosis in 16 patients with PPMS and 80 with RRMS. All patients underwent clinical evaluation, including Expanded Disability Status Scale assessment and a 3T brain MRI to detect white matter and cortical lesion number and volume and global and regional cortical thickness. RESULTS: Higher levels of CXCL12 (odds ratio [OR] = 3.97, 95% CI [1.34-11.7]) and the monocyte-related osteopontin (OR = 2.24, 95% CI [1.01-4.99]) were detected in patients with PPMS, whereas levels of interleukin-10 (IL10) (OR = 0.28, 95% CI [0.09-0.96]) were significantly increased in those with RRMS. High CXCL12 levels were detected in patients with increased gray matter lesion number and volume (p = 0.001, r = 0.832 and r = 0.821, respectively). Pathway analysis confirmed the chronic inflammatory processes occurring in PPMS. CONCLUSIONS: At the time of diagnosis, a specific CSF protein profile can recognize the presence of early intrathecal inflammatory processes, possibly stratifying PPMS with respect to RRMS. Elevated CSF levels of CXCL12 and osteopontin suggested a key role of brain innate immunity and glia activity in MS. These molecules could represent useful candidate markers of MS progression, with implications for the pathogenesis and treatment of progressive MS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CXCL12 and monocyte-related osteopontin may be correlated with PPMS, and IL-10 may be related to RRMS. It is may be correlated due to Bonferroni correction negating the statistical correlations found in the study.

The Prognostic Value of White-Matter Selective Double Inversion Recovery MRI Sequence in Multiple Sclerosis: An Exploratory Study.

Using a white-matter selective double inversion recovery sequence (WM-DIR) that suppresses both grey matter (GM) and cerebrospinal fluid (CSF) signals, some white matter (WM) lesions appear surrounded by a dark rim. These dark rim lesions (DRLs) seem to be specific for multiple sclerosis (MS). They could be of great usefulness in clinical practice, proving to increase the MRI diagnostic criteria specificity. The aims of this study are the identification of DRLs on 1.5 T MRI, the exploration of the relationship between DRLs and disease course, the characterization of DRLs with respect to perilesional normal-appearing WM using magnetization transfer imaging, and the investigation of possible differences in the underlying tissue properties by assessing WM-DIR images obtained at 3.0 T MRI. DRLs are frequent in primary progressive MS (PPMS) patients. Amongst relapsing-remitting MS (RRMS) patients, DRLs are associated with a high risk of the disease worsening and secondary progressive MS (SPMS) conversion after 15 years. The mean magnetization transfer ratio (MTR) of DRLs is significantly different from the lesion without the dark rim, suggesting that DRLs correspond to more destructive lesions.

Frequency and severity of COVID-19 in multiple sclerosis: A short single-site report from northern Italy.

Neurologists are interested in understanding whether patients with multiple sclerosis (pwMS) undergoing immunomodulatory/immunosuppressive therapy are more susceptible to developing COVID-19 or have worse outcomes. Currently, there are no conclusive data in this regard. We report the prevalence and severity of COVID-19 (confirmed and possible) in pwMS followed at the Veneto Regional MS Center in Verona (Italy), an area most stricken by COVID-19. In our sample size, the prevalence of COVID-19 seems to be much higher than that officially reported at the regional level on the general population, but it also characterized by a favourable course.

The Use of the Central Vein Sign in the Diagnosis of Multiple Sclerosis: A Systematic Review and Meta-analysis.

Background: The central vein sign (CVS) is a radiological feature proposed as a multiple sclerosis (MS) imaging biomarker able to accurately differentiate MS from other white matter diseases of the central nervous system. In this work, we evaluated the pooled proportion of the CVS in brain MS lesions and to estimate the diagnostic performance of CVS to perform a diagnosis of MS and propose an optimal cut-off value. Methods: A systematic search was performed on publicly available databases (PUBMED/MEDLINE and Web of Science) up to 24 August 2020. Analysis of the proportion of white matter MS lesions with a central vein was performed using bivariate random-effect models. A meta-regression analysis was performed and the impact of using particular sequences (such as 3D echo-planar imaging) and post-processing techniques (such as FLAIR*) was investigated. Pooled sensibility and specificity were estimated using bivariate models and meta-regression was performed to address heterogeneity. Inclusion and publication bias were assessed using asymmetry tests and a funnel plot. A hierarchical summary receiver operating curve (HSROC) was used to estimate the summary accuracy in diagnostic performance. The Youden index was employed to estimate the optimal cut-off value using individual patient data. Results: The pooled proportion of lesions showing a CVS in the MS population was 73%. The use of the CVS showed a remarkable diagnostic performance in MS cases, providing a pooled specificity of 92% and a sensitivity of 95%. The optimal cut-off value obtained from the individual patient data pooled together was 40% with excellent accuracy calculated by the area under the ROC (0.946). The 3D-EPI sequences showed both a higher pooled proportion compared to other sequences and explained heterogeneity in the meta-regression analysis of diagnostic performances. The 1.5 Tesla (T) scanners showed a lower (58%) proportion of MS lesions with a CVS compared to both 3T (74%) and 7T (82%). Conclusions: The meta-analysis we have performed shows that the use of the CVS in differentiating MS from other mimicking diseases is encouraged; moreover, the use of dedicated sequences such as 3D-EPI and the high MRI field is beneficial.

Cerebrospinal Fluid IgM Levels in Association With Inflammatory Pathways in Multiple Sclerosis Patients.

BACKGROUND: Intrathecal immunoglobulin M (IgM) synthesis has been demonstrated in the early disease stages of multiple sclerosis (MS) as a predictor factor of a worsening disease course. Similarly, increased cerebrospinal fluid (CSF) molecules related to B-cell intrathecal activity have been associated with a more severe MS progression. However, whether CSF levels of IgM are linked to specific inflammatory and clinical profile in MS patients at the time of diagnosis remains to be elucidated. METHODS: Using customized Bio-Plex assay, the protein levels of IgG, IgA, IgM, and of 34 other inflammatory molecules, related to B-cell, T-cell, and monocyte/macrophage activity, were analyzed in the CSF of 103 newly diagnosed relapsing-remitting MS patients and 36 patients with other neurological disorders. CSF IgM levels were also correlated with clinical and neuroradiological measures [advanced 3-T magnetic resonance imaging (MRI) parameters], at diagnosis and after 2 years of follow-up. RESULTS: A 45.6% increase in CSF IgM levels was found in MS patients compared to controls (p = 0.013). CSF IgM levels correlated with higher CSF levels of CXCL13 (p = 0.039), CCL21 (p = 0.023), interleukin 10 (IL-10) (p = 0.025), IL-12p70 (p = 0.020), CX3CL1 (p = 0.036), and CHI3L1 (p = 0.048) and were associated with earlier age of patients at diagnosis (p = 0.008), white matter lesion (WML) number (p = 0.039) and disease activity (p = 0.033) after 2 years of follow-up. CONCLUSION: IgMs are the immunoglobulins mostly expressed in the CSF of naive MS patients compared to other neurological conditions at the time of diagnosis. The association between increased CSF IgM levels and molecules related to both B-cell immunity (IL-10) and recruitment (CXCL13 and CCL21) and to macrophage/microglia activity (IL-12p70, CX3CL1, and CHI3L1) suggests possible correlation between humoral and innate intrathecal immunity in early disease stage. Furthermore, the association of IgM levels with WMLs and MS clinical and MRI activity after 2 years supports the idea of key role of IgM in the disease course.

Increased NK Cell Count in Multiple Sclerosis Patients Treated With Dimethyl Fumarate: A 2-Year Longitudinal Study.

Background: Dimethyl fumarate (DMF) is a disease-modifying drug for relapsing-remitting multiple sclerosis. Among others, DMF impedes immune activation by shifting the balance between inflammatory and regulatory cell types and by inducing apoptosis-triggered lymphopenia. Although the decrease in lymphocyte count is an early effect of the drug in several patients, the long-term impact on lymphocyte subsets is largely unknown. Methods: We performed a 2-years observational study on total lymphocyte count and subsets thereof by flow cytometry of peripheral blood of 38 multiple sclerosis patients in treatment with DMF. Data were collected at the beginning and after 3, 6, 12, and 24 months of therapy. Results: Total lymphocyte count decreased in relation to time of exposure to DMF. Mean absolute B cell count decreased by 34.1% (p < 0.001) within the first 3 months of therapy and then remained stable over time. Mean absolute CD3+ T cells count decrement reached 47.5% after 12 months of treatment (p < 0.001). NK cells count showed a heterogeneous trend, increasing by 85.9% (p < 0.001) after 2 years of treatment. CD4+ T cells and CD8+ T cells substantially decreased, with a significant increase of CD4+/CD8+ ratio during the first year of therapy. Conclusions: NK cells showed a heterogeneous behavior during DMF treatment with a significant increase over time. Since NK cells may also have a regulatory effect on immune system modulation, their increase during DMF treatment might play a role in the efficacy and safety of the drug.

Clinical correlates of endothelial function in chronic heart failure.

OBJECTIVE: There is a close link between heart failure and endothelial dysfunction. Brachial flow-mediated dilation (FMD) is a validated non-invasive measure of endothelial function. The aim of this study was to investigate the clinical correlates of FMD in patients with chronic heart failure (CHF). DESIGN, SETTING, PATIENTS: We evaluated 60 CHF outpatients (age 62 ± 14 years; 49 males, NYHA class 2.2 ± 0.7, left ventricular ejection fraction, LVEF, 33 ± 8%) taking conventional medical therapy (ACE-inhibitors and/or ARBs 93%, beta-blockers 95%) and in stable clinical conditions. MAIN OUTCOME MEASURES: The maximum recovery value of FMD was calculated as the ratio of the change in diameter (maximum-baseline) over the baseline value. RESULTS: As compared with patients with a higher FMD, those with FMD below the median value (4.3%) were more frequently affected by ischemic cardiopathy (50 vs. 23%; p = 0.032) and diabetes mellitus (20 vs. 3%; p = 0.044), had a higher NYHA class (2.5 ± 0.5 vs. 1.9 ± 0.7; p < 0.001) and NT-proBNP (2,690 ± 3,690 vs. 822 ± 1,060; p = 0.001), lower glomerular filtration rate estimated by Cockcroft-Gault (GFRCG: 63 ± 28 vs. 78 ± 25; p = 0.001) and LVEF (29 ± 8 vs. 37 ± 9; p = 0.001), as well as more frequently showing a restrictive pattern (40 vs. 7%; p = 0.002). In a multivariate regression model (R (2) = 0.48; p < 0.001), FMD remained associated only with the NYHA class (p = 0.039) and diabetes mellitus (p = 0.024). CONCLUSIONS: This study demonstrates that a better functional status and absence of diabetes mellitus are associated to higher FMD regardless of the etiology of the cardiac disease.