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Reliable immunologic biomarkers able to monitor disease course during multiple sclerosis (MS) are still missing. We aimed at identifying possible immunometabolic biomarkers able to predict the clinical outcome in MS patients during treatment with interferon (IFN)-beta-1a. We measured in 45 relapsing-remitting (RR) MS patients, blood circulating levels of several immunometabolic markers, at enrolment, and correlated their levels to disease activity and progression over time. Higher levels of interleukin (IL)-6, soluble-CD40-ligand (sCD40L) and leptin at baseline associated with a higher relapse rate and a greater risk of experiencing at least one relapse in the following year. Higher values of soluble tumor necrosis factor receptor (sTNF-R) and leptin at baseline were predictive of a higher number of lesions in the following one-year of follow up. In conclusion, our data suggest that an immunometabolic profiling measuring IL-6, sCD40L, leptin and sTNF-R at baseline, could represent a useful tool to predict disease course in RRMS patients during treatment with IFN-beta-1a., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Over the last few decades, patients have increasingly been searching for health information on the Internet. This aspect of information seeking is really important, especially for people affected by chronic pathologies and require lifelong treatment and management. These people are usually very well informed about the disease, but are nonetheless vulnerable to hopes of being cured or saved, often amplified by misinformation, myths, legends, and therapies that are not always scientifically proven. Many studies suggest that some individuals prefer to rely on the Internet as their main source of information, often hindering the patient-doctor relationship. This is why a professional approach is imperative in this posttruth age, in order to maintain confidentiality, honesty, and trust in the medical profession., (©Luigi Lavorgna, Roberta Lanzillo, Vincenzo Brescia Morra, Gianmarco Abbadessa, Gioacchino Tedeschi, Simona Bonavita. Originally published in the Interactive Journal of Medical Research (http://www.i-jmr.org/), 27.09.2017.)

Background: Different retrospective studies compared natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS), with conflicting results. We aimed to explore the prescriptive attitude and the clinical outcome of the two therapies., Methods: We retrospectively included all RRMS patients treated with natalizumab (n=101) or fingolimod (n=78) as their first second-line therapy with at least 24-month follow-up. Demographic and clinical features were recorded to calculate the propensity score (PS). Outcomes of interest were annualized relapse rate (ARR), risk of relapse, and change in the EDSS RESULTS: At baseline, natalizumab patients were younger and had a shorter disease duration, a higher number of relapse in 1 year (1yR) and 2 years (2yR) and overall (ARR-PT) pretherapy, compared to fingolimod patients. On therapy, the proportion of relapsing patients and the mean RR were similar in the two groups. However, the change in the ARR was higher in natalizumab than in fingolimod group (P<.002), but, using PS as a covariate, it was comparable (P=.960). Similarly, the change in EDSS was significantly different for the two groups (P<.004), but not after adjusting for the PS (P=.321)., Conclusion: We observed a comparable efficacy on ARR reduction and on EDSS progression with natalizumab and fingolimod correcting through PS, suggesting that the efficacy difference observed before correction might derive from the clinical attitude in prescribing natalizumab in more active MS patients in real life., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Although improved, the risk of progressive multifocal leukoencephalopathy is a constant threat for patient affected by multiple sclerosis treated with natalizumab. We performed a 24months longitudinal study aimed to evaluate the total WBC and lymphocytes subsets modifications and their correlations with anti-JCV antibody index after 1 and 2years of natalizumab treatment. Natalizumab induced an increase of WBC, total and C19+ lymphocytes together with a decrease of CD3+, CD4+ T lymphocytes and CD4/CD8 ratio, which was positively related to anti-JCV antibodies index at month 0, 12 and 24. Our study confirms that lymphocytes subsets are modified under NAT therapy. Implications of lymphocyte subsets alterations in the pathogenesis of PML are under analyses., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Despite cognitive tests have been validated in multiple sclerosis (MS), a neuropsychological evaluation is not implemented in the Expanded Disability Status Scale (EDSS) scoring., Methods: We used the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and orientation tests (OTs) to measure the cerebral functional system (CFS) score and to evaluate its impact on the EDSS. We compared EDSS calculated as usual (Native-EDSS) and after the use of the BICAMS and OT (NPS-EDSS)., Results: We tested 604 MS patients with BICAMS, OTs, and EDSS. In all, 384 patients (63.6%) had at least one altered test at the BICAMS. Older age, lower education, higher Native-EDSS, and male gender were independently associated with at least one impaired BICAMS test. Native-EDSS was different from NPS-EDSS (-0.112; p < 0.001) in 99 patients (16%). When considering patients with a Native-EDSS ⩽ 4.0, the proportion of miscalculated EDSS was 25%., Conclusion: The use of brief neuropsychological tests leads to a more accurate CFS assessment in two-thirds of MS patients, and a more accurate EDSS calculation in 25% of patients with a score ⩽4.0. This may help clinicians to better recognize cognitive impairment in everyday clinical practice, especially in the case of isolated cognitive worsening.

The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMF's target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Social media are a vital link for people with health concerns who find in Web communities a valid and comforting source for information exchange, debate, and knowledge enrichment. This aspect is important for people affected by chronic diseases like multiple sclerosis (MS), who are very well informed about the disease but are vulnerable to hopes of being cured or saved by therapies whose efficacy is not always scientifically proven. To improve health-related coping and social interaction for people with MS, we created an MS social network (SMsocialnetwork.com) with a medical team constantly online to intervene promptly when false or inappropriate medical information are shared., Objective: The goal of this study was to assess the impact of SMsocialnetwork.com on the health-related coping and social interaction of people with MS by analyzing areas of interest through a Web-based survey., Methods: Referring to previous marketing studies analyzing the online platform's role in targeted health care, we conducted a 39-item Web-based survey. We then performed a construct validation procedure using a factorial analysis, gathering together like items of the survey related to different areas of interest such as utility, proximity, sharing, interaction, solving uncertainty, suggestion attitude, and exploration., Results: We collected 130 Web-based surveys. The areas of interest analysis demonstrated that the users positively evaluated SMsocialnetwork.com to obtain information, approach and solve problems, and to make decisions (utility: median 4.2); improve feeling of closeness (proximity: median 5); catalyze relationships and text general personal opinions (sharing: median 5.6); get in touch with other users to receive innovative, effective, and practical solutions (interaction, solving uncertainty, and suggestion attitude medians were respectively: 4.1, 3, and 3); and share information about innovative therapeutic approaches and treatment options (suggestion attitude: median: 3.3)., Conclusions: SMsocialnetwork.com was perceived by users to be a useful tool to support health-related coping and social interaction, and may suggest a new kind of therapeutic alliance between physicians and people with MS., (©Luigi Lavorgna, Antonio Russo, Manuela De Stefano, Roberta Lanzillo, Sabrina Esposito, Fatemeh Moshtari, Francesco Rullani, Kyrie Piscopo, Daniela Buonanno, Vincenzo Brescia Morra, Antonio Gallo, Gioacchino Tedeschi, Simona Bonavita. Originally published in the Interactive Journal of Medical Research (http://www.i-jmr.org/), 14.07.2017.)

Purpose: Multiple sclerosis (MS) has been proposed as a possible differential diagnosis for Fabry disease (FD). The aim of this work was to evaluate the involvement of corpus callosum (CC) on MR images and its possible role as a radiological sign to differentiate between FD and MS., Methods: In this multicentric study, we retrospectively evaluated the presence of white matter lesions (WMLs) on the FLAIR images of 104 patients with FD and 117 patients with MS. The incidence of CC-WML was assessed in the two groups and also in a subgroup of 37 FD patients showing neurological symptoms., Results: WMLs were detected in 50 of 104 FD patients (48.1%) and in all MS patients. However, a lesion in the CC was detected in only 3 FD patients (2.9%) and in 106 MS patients (90.6%). In the FD subgroup with neurological symptoms, WMLs were present in 26 of 37 patients (70.3%), with two subjects (5.4%) showing a definite callosal lesion., Conclusion: FD patients have a very low incidence of CC involvement on conventional MR images compared to MS, independently from the clinical presentation and the overall degree of WM involvement. Evaluating the presence of CC lesions on brain MR scans can be used as a radiological sign for a differential diagnosis between MS and FD, rapidly addressing the physician toward a correct diagnosis and subsequent treatment options.

Objectives: Disease-modifying treatments (DMTs) constitute the largest direct medical cost for multiple sclerosis (MS). This study aims at investigating predictors of the 10-year economic burden for DMT administration and management., Materials and Methods: This study included 537 newly diagnosed, drug naïve relapsing-remitting MS (RRMS) patients, followed up for 10.1±3.3 years. Costs for DMT administration and management were calculated, and referred to each year of observation (annual costs). Possible predictors of disease evolution were categorized into early predictors (age, gender, disease duration, baseline expanded disability status scale (EDSS), 1-point EDSS progression within 2 years, and annualized relapse rate -ARR- within 2 years), and long-term predictors (reaching of EDSS 4.0, conversion to secondary progressive -SP-, ARR, number of DMTs, follow-up duration). Association between predictors and study outcome was explored using mixed-effects log-linear regression models., Results: A 1-point higher EDSS at diagnosis was associated with 13.21% increase in the annual costs (95%CI=4.16-23.04%). Each additional year of age at diagnosis was associated with a 0.74% decrease in the annual costs (95%CI=-1.43 to-0.04%). Female gender was associated with a 12.43% decrease in the annual costs (95%CI=-22.61 to-0.93%). Converting to SP was associated with a 14.26% decrease in the annual costs (95%CI=-14.26 to-2.94%). Each additional year of follow-up was associated with a 3.05% decrease in the annual costs (95%CI=-4.51 to-1.57%)., Conclusions: An estimate of the 10-year costs associated with DMT administration and management can be calculated by analyzing different factors, and might be of particular interest for planning resources needed for treating people with MS., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Lesbian, gay, bisexual and transgender (LGBT) patients might experience unique difficulties and barriers to treatment of chronic diseases related to their sexual orientation. Thus, we investigated concerns experienced by LGBT patients with multiple sclerosis (MS). We conducted a web-based survey using a multi-choice questionnaire published in an Italian social-network (www.smsocialnetwork.com) for MS patients. The survey investigated: socio-demographic factors, lifestyle habits, MS-related health status and LGBT specific issues (e.g. friendliness to their sexual orientation and eventual homophobic behaviors in the MS Center). Among MS patients willing to use psychological services, LGBT patients were associated with a smaller number of psychological consultations, compared to heterosexuals (Coeff.=-0.449; p<0.001; 95%CI=-0.682 to -0.217). LGBT patients were more likely to change MS Center, compared to heterosexuals (OR=2.064; p=0.046; 95%CI=1.011-4.212). The number of MS Center changes was associated with MS Center friendliness (p=0.037; rho=-0.229) and with the occurrence of homophobic behaviors (p=0.036; rho=0.234). LGBT MS patients more frequently changed MS Center and had a reduced use of psychological services, compared to heterosexuals. The attitude towards LGBT MS patients might affect resource utilizations and LGBTs health status., (Copyright © 2017. Published by Elsevier B.V.)

Purpose: To investigate the moderating role of resilience in the relationship between affective disorders and Health-Related Quality of Life (HRQoL) for adolescents and young adults with multiple sclerosis (MS)., Methods: A quantitative methodology was adopted. Fifty-three adolescents and young adults were interviewed to assess resilience as a personality trait (Ego-Resiliency Scale) and resilience as an interactive competence (CYRM-28), Health-Related Quality of Life (PedsQL 4.0), depression and anxiety (BDI-II and STAI-Y)., Results: Affective disorders, both depression (β = -.38, p < .001) and anxiety (State β = -.35, p < .001; Trait β = -.41, p < .001), were negatively associated with HRQoL. Data also showed that the resilience competencies using Individual (β = .22, p < .001) and relational resources (β = .12, p < .05) are significantly associated HRQoL. According to the regression analyses, we tested the moderating role of resilience competence using individual resources on the relationship between the Depression Cognitive Factor and Emotional Functioning. Data show that in step 2 of the regression analysis, we obtained a variation of β = -.45 (p < .001) to β = -.30 (p < .001) in the dimension for the Depression Cognitive Factor. The Sobel test showed that the moderating effect of resilience was significant regarding the increase in R 2 (p < .01)., Conclusions: Resilience competence using individual resources moderates the relationship between the Depression Cognitive Factor and Emotional Functioning in adolescents with MS. Our study suggests that to improve well-being for adolescents with MS resilience could play a key role.

Background and Purpose: Growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis abnormalities in multiple sclerosis (MS) suggest their role in its pathogenesis. Interferon β (IFN-β) efficacy could be mediated also by an increase of IGF-1 levels. A 2-year longitudinal study was performed to estimate the prevalence of GH and/or IGF-1 deficiency in clinically isolated syndrome (CIS) patients and their correlation with conversion to MS in IFN treated patients., Methods: Clinical and demographic features of CIS patients were collected before the start of IFN-β-1b. IGF-1 levels and GH response after arginine and GH releasing hormone + arginine stimulation tests were assessed. Clinical and magnetic resonance imaging evaluations were performed at baseline, 1 year and 2 years., Results: Thirty CIS patients (24 female) were enrolled. At baseline, four patients (13%) showed a hypothalamic GH deficiency (GHD), whilst no one had a pituitary GHD. Baseline demographic, clinical and radiological data were not related to GHD, whilst IGF-1 levels were inversely related to age (P < 0.001) and GH levels (P = 0.03). GH and IGF-1 serum mean levels were not significantly modified after 1 and 2 years of treatment in the whole group, although 3/4 GHD patients experienced a normalization of GH levels, whilst one dropped out. After 2 years of treatment 13/28 (46%) patients converted to MS. The presence of GHD and GH and IGF-1 levels were not predictive of relapses, new T2 lesions or conversion occurrence., Conclusions: Growth hormone/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to MS conversion. Patients experienced an improvement of GHD during IFN therapy. Longer follow-up is necessary to assess its impact on disease progression., (© 2016 EAN.)

Background: Disease modifying treatments (DMTs) are the main responsible for direct medical costs in multiple sclerosis (MS). The current investigation aims at evaluating possible associations between healthcare costs for treating relapsing remitting MS (RRMS) and disease evolution., Methods: The present cohort study retrospectively included 544 newly diagnosed RRMS patients, prospectively followed up for 10.1±3.3 years. Costs for DMT administration and management were calculated for each year of observation. Following clinical endpoints were recorded: time to first relapse, 1-point EDSS progression, reaching of EDSS 4.0, reaching of EDSS 6.0, and conversion to secondary progressive MS (SP). Covariates for statistical analyses were age, gender, disease duration and EDSS at diagnosis., Results: At time varying Cox regression models, 10% increase in annual healthcare costs was associated with 1.1% reduction in 1-point EDSS progression (HR = 0.897; p = 0.018), with 0.7% reduction in reaching EDSS 6.0 (HR = 0.925; p = 0.030), and with 1.0% reduction in SP conversion (HR = 0.902; p = 0.006)., Conclusion: Higher healthcare costs for treating MS have been associated with a milder disease evolution after 10 years, with possible reduction of long-term non-medical direct and indirect costs., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Grey matter (GM) and white matter (WM) are both affected in multiple sclerosis (MS). WM is predominantly involved in inflammatory demyelination of relapsing-remitting MS (RRMS), whereas GM is predominantly involved in neurodegenerative processes of secondary progressive MS. Thus, we investigated the ratio between GM and WM volumes in predicting MS evolution., Methods: The present 10-year retrospective cohort study included 149 patients with newly-diagnosed RRMS, undergoing magnetic resonance imaging for segmentation and brain volumetry. The ratio between GM and normal-appearing WM (NAWM) volumes was calculated for each subject. Outcome measures of interest were Expanded Disability Status Scale (EDSS) progression, reaching EDSS 4.0 and conversion to secondary progressive (SP) MS., Results: During a period of 10.6 ± 2.4 years, a median 1.5 EDSS progression was observed (range 0-5.5), 54 subjects (36.2%) reached EDSS 4.0 and 30 subjects (20.1%) converted to SP. With ordinal logistic regression models, EDSS progression was associated with GM:NAWM ratio (coefficient, -2.918; 95% CI, -4.739-1.097). With Cox regression models, subjects with higher GM:NAWM ratio at diagnosis had a 90% lower rate of reaching EDSS 4.0 (hazard ratio, 0.111; 95% CI, 0.020-0.609) and of converting to secondary progressive MS (hazard ratio, 0.017; 95% CI, 0.001-0.203) compared with subjects with lower GM:NAWM ratio., Conclusions: The GM:NAWM ratio is a predictor of disability progression and of SP conversion in subjects with newly diagnosed RRMS, suggesting that GM and NAWM are variably affected in relation to disease evolution from the early phases of MS., (© 2016 EAN.)

In autoimmune diseases, there have been proposals that exogenous “molecular triggers”, i.e., specific ‘non-self antigens’ accompanying infectious agents, might disrupt control of the adaptive immune system resulting in serious pathologies. The etiology of multiple sclerosis (MS) remains unclear. However, epidemiologic data suggest that exposure to infectious agents may be associated with increased MS risk and progression may be linked to exogenous, bacterially-derived, antigenic molecules, mimicking mammalian cell surface glycoconjugates triggering autoimmune responses. Previously, antibodies specific to a gluco-asparagine (N-Glc) glycopeptide, CSF114(N-Glc), were identified in sera of an MS patient subpopulation. Since the human glycoproteome repertoire lacks this uniquely modified amino acid, we turned our attention to bacteria, i.e., Haemophilus influenzae, expressing cell-surface adhesins including N-Glc, to establish a connection between H. influenzae infection and MS. We exploited the biosynthetic machinery from the opportunistic pathogen H. influenzae (and the homologous enzymes from A. pleuropneumoniae) to produce a unique set of defined glucosylated adhesin proteins. Interestingly we revealed that a hyperglucosylated protein domain, based on the cell-surface adhesin HMW1A, is preferentially recognized by antibodies from sera of an MS patient subpopulation. In conclusion the hyperglucosylated adhesin is the first example of an N-glucosylated native antigen that can be considered a relevant candidate for triggering pathogenic antibodies in MS.

Objectives: To evaluate changes in T1 and T2* relaxometry of dentate nuclei (DN) with respect to the number of previous administrations of Gadolinium-based contrast agents (GBCA)., Methods: In 74 relapsing-remitting multiple sclerosis (RR-MS) patients with variable disease duration (9.8±6.8 years) and severity (Expanded Disability Status Scale scores:3.1±0.9), the DN R1 (1/T1) and R2* (1/T2*) relaxation rates were measured using two unenhanced 3D Dual-Echo spoiled Gradient-Echo sequences with different flip angles. Correlations of the number of previous GBCA administrations with DN R1 and R2* relaxation rates were tested, including gender and age effect, in a multivariate regression analysis., Results: The DN R1 (normalized by brainstem) significantly correlated with the number of GBCA administrations (p<0.001), maintaining the same significance even when including MS-related factors. Instead, the DN R2* values correlated only with age (p=0.003), and not with GBCA administrations (p=0.67). In a subgroup of 35 patients for whom the administered GBCA subtype was known, the effect of GBCA on DN R1 appeared mainly related to linear GBCA., Conclusions: In RR-MS patients, the number of previous GBCA administrations correlates with R1 relaxation rates of DN, while R2* values remain unaffected, suggesting that T1-shortening in these patients is related to the amount of Gadolinium given., Key Points: • In multiple sclerosis, previous Gadolinium administrations correlate with dentate nuclei T1 relaxometry. • Such correlation is linked to linear Gadolinium chelates and unrelated to disease duration or severity. • Dentate nuclei T2* relaxometry is age-related and independent of previous Gadolinium administrations. • Changes in dentate nuclei T1 relaxometry are not determined by iron accumulation. • MR relaxometry can quantitatively assess Gadolinium accumulation in dentate nuclei.

Background: Interferon-β has long-term safety and efficacy profiles for Relapsing Remitting Multiple Sclerosis (RRMS). However, the increasing number of available treatments requires to improve patient profiling and to perform individualized clinical decisions. Therefore, the present study investigated predictors of Interferon-β discontinuation., Methods: The present retrospective observational cohort study included 499 newly diagnosed, drug naïve RRMS subjects receiving Interferon-β as first disease modifying treatment (DMT), during a 7.9±3.8 year period, up to treatment discontinuation. Possible markers of interest were recorded at the time of diagnosis (age, gender, disease duration, baseline EDSS) or during follow-up as variables of disease evolution (relapse occurrence, annualized relapse rate -ARR-, 1-point EDSS progression, reaching of EDSS 4.0) or of treatment (high-dose Interferon-β1a, low-dose Interferon-β1a, or Interferon-β1b)., Results: 217 patients (43.5%) discontinued the treatment during the follow-up period, with an incidence of 5% person-years (95%CI=4.6-5.9%). A multivariate Cox regression model showed an increased rate of Interferon-β discontinuation for female gender (p=0.019; HR=1.428), higher baseline EDSS (p=0.026; HR=1.346), relapse occurrence (p=0.009; HR=1.618), higher ARR (p<0.001; HR=5.269), and Interferon-β1b treatment (p=0.019; HR=1.506); and a reduced rate for occurrence of EDSS progression (p<0.001; HR=0.299)., Conclusions: Most of the factors associated with Interferon-β discontinuation are not modifiable, and are part of demographic features (i.e. gender), or of disease characteristics (i.e. disability at diagnosis), but should be taken into account when prescribing the first DMT for MS. Noteworthy, the use of Interferon-β1b is associated with 50% increased risk of discontinuation, compared with high-dose Interferon-β1a, highlighting the importance of drug formulations in treatment persistence., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We investigated patients who showed a second-degree atrioventricular block (S-AVB) after the first fingolimod administration. We observed six patients with S-AVB, three Mobitz type I, and three type II. Monitoring continued on the second day for all patients. Three patients showed persistence of the S-AVB, with resolution on the second or third day. One patient had a persistent S-AVB up to the fourth day when fingolimod was discontinued. We conclude that Mobitz type II S-AVB is possible during fingolimod therapy. Patients with S-AVB could be monitored until resolution of the S-AVBs, as these may persist several days after the first fingolimod administration.

Background: A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis., Objectives: The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis., Methods: This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months., Results: A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months., Conclusions: Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis., (© The Author(s), 2015.)

Objective:: We aimed to evaluate the presence of venous stenosis and blood flow abnormalities in the neck vessels of patients with multiple sclerosis (MS), in respect to a group of age- and sex-matched healthy controls (HC), and their possible relations with clinical variables using a semi-automated quantitative MRI method., Methods:: 45 patients with relapsing remitting MS and 40 HC were enrolled in this study. Flow rates and cross-sectional areas of arterial and venous neck vessels were assessed by phase-contrast MRI at two different neck levels (C2-C3 and C6-C7), and differences between groups were evaluated with an unpaired t-test. Correlation between blood flow variables and clinical parameters was analyzed with Spearman's test., Results:: A significant internal jugular vein (IJV) stenosis was found in 23/45 (51.1%) patients with MS and 18/40 (45.0%) HC. No differences were observed between patients with MS and HC for any of the flow measures obtained. No correlations were found between MRI measures and any of the tested clinical variables., Conclusion:: No differences in the IJV area emerged at quantitative MRI evaluation, suggesting that stenosis of the extracranial veins is unrelated to MS. Furthermore, no flow differences in the neck vessels were found between patients with MS and HC in any of the tested flow measures, with no correlation with clinical variables. Our results confirm that the hypothesis of the presence of extracranial venous abnormalities in MS, both in terms of stenosis or flow measures, is not suitable., Advances in Knowledge:: Neck venous drainage abnormalities have been claimed to be associated with MS. Conversely, our quantitative MRI analysis seems to exclude that extracranial venous alterations are related to the disease.

Background: Natalizumab is an effective therapy in relapsing-remitting multiple sclerosis (RRMS), as it reduces lymphocyte transmigration through the blood-brain barrier (BBB) and induces lymphocytosis., Objectives: To analyse natalizumab-induced lymphocytosis (NIL) as a biomarker of drug efficacy., Materials and Methods: We enrolled 50 relapsing-remitting (RR) and progressive-relapsing (PR) natalizumab-treated patients who had received at least 16 infusions and had been tested for lymphocyte count 24 hours before each administration. Clinical, MRI and hematological data were collected. Patients were divided into responders and sub-optimal responders according to the experience of at least one clinical and/or instrumental relapse during the treatment., Results: In 15 (30%) patients, an instrumental/clinical (14) or only instrumental (one) relapse occurred. We found a statistically significant difference in the mean percentage of the lymphocytes between the two groups over the first ten administrations (p=0.04). The comparison between the time-to-relapse in the groups with high and low levels of lymphocytes showed that the group with a low NIL had a greater risk of relapse (p=0.03)., Conclusions: We suggest that NIL could be a biomarker of therapeutic efficacy in patients with RRMS treated with natalizumab, and that the risk of relapse may be higher in patients with a lower-than-expected NIL., (© The Author(s), 2015.)

Background: Autosomal recessive (AR) spastic paraplegia type 5 (SPG5) is due to mutations in the CYP7B1 gene, encoding for the cytochrome P450-7B1, responsible for oxysterols 7α-hydroxylation. Oxysterol/cholestenoic acids pool plays a role in motor neuron survival and immune response. SPG5 is characterized by white matter abnormalities at brain resonance imaging (MRI). In view of clinical presentation and MRI findings, multiple sclerosis (MS) is a possible differential diagnosis of SPG5. This study aimed to evaluate the frequency of CYP7B1 mutations in patients with MS., Methods: One hundred and seventeen MS patients with clinical spastic paraplegia or possible AR transmission were selected for the mutational screening., Results: Forty-three patients had primary progressive, 26 relapsing remitting, 26 secondary progressive, and 22 relapsing progressive MS clinical course. No CYP7B1 homozygous mutations were identified. Two novel variants and one pathogenic mutation were found at heterozygous state., Conclusions: The two novel variants cosegregated with pyramidal signs and autoimmune diseases suggesting that they might be susceptibility factors. Reduced cytochrome P450-7B1 enzymatic activity could alter the balance among neurotoxic and neuroprotective oxysterols promoting motor neuron degeneration and/or immune response., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The TRACER multicenter retrospective study aimed to collect data on treatment adherence in a real-life setting, in order to identify predictors of adherence at baseline., Methods: We recruited 384 relapsing-remitting (RR) multiple sclerosis patients with at least 12 months of use of RebiSmart®. This electronic device records the performed injections and assesses adherence as the percentage of 'not missing doses', through the connection to the iMed database. Subjects with at least 80% of completed doses at the 12 month of therapy were defined 'treatment adherents'., Results: After 12 months, 89.3% of patients were adherent; 93.2% of patients aged 26-40 years at baseline were adherent (vs 79% of the ≤25 and 87.5% of the ≥41 year olds; p = 0.006). Furthermore, 90.5% of patients with a baseline Expanded Disability Status Scale (EDSS) score <4 showed ≥80% adherence (vs 71.4% in those with EDSS score ≥4; p = 0.016). Fifty-four percent of the patients who were not adherent after 3 months were also not adherent after 12 months (OR 16.8; CI 95%:7.1-39.8)., Conclusions: Patients aged 26-40 years and with an EDSS score <4 at baseline were the most adherent. The status of 'treatment adherent' in the first 3 months was predictive of higher adherence in the long term.

Background: The Dress picture recently has become a hot topic on the Internet, prompting a debate whether it was black and blue, or white and gold., Objective: To investigate The Dress color perception in both multiple sclerosis (MS) patients, characterized by frequent visual system impairment with ensuing color vision effects, and general population., Methods: We developed a questionnaire to record demographics, clinical features, and The Dress color perception, posted on general and MS-specific social networks., Results: No statistically significant differences were observed in The Dress color perception between MS patients (n=103) and general population (n=441). Furthermore, white and gold color perception was positively associated with aging in the general population (p=0.04), whereas negatively associated with progressive course (p=0.03) and longer disease duration (p<0.001) in MS patients, independently from patients' age., Conclusion: The Dress black and blue or white and gold perception might be due to aging in the general population, whereas black and blue perception, despite of aging, might suggest a specific effect of the MS burden (i.e. disease duration and progression) on the visual structures specifically involved in the white and gold perception., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Cognitive impairment occurs from the early phases of multiple sclerosis (MS), and more frequently affects secondary progressive (SP) subjects than relapsing-remitting (RR)., Objective: To investigate relationships between cognitive dysfunctions in newly diagnosed RRMS, and long-term MS-related outcomes., Methods: The present 10-year retrospective longitudinal study included 155 RRMS subjects, tested with the Rao Brief Repeatable Battery at MS diagnosis. The reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded., Results: 67 subjects (43.2%) reached EDSS 4.0, and 34 subjects (21.9%) converted to SP during a follow-up period of 10.0±1.8 years. Subjects with cognitive impairment at diagnosis had a rate of reaching EDSS 4.0 more than three times greater (p<0.001; HR=3.183), and a rate of SP conversion more than two times greater, as compared to cognitively preserved subjects (p=0.008; HR=2.535). In particular, better scores in the Selective Reminding Test-Delayed Recall and in the Symbol Digit Modalities Test at baseline were associated with lower SP conversion rates during the follow-up period (p=0.018; HR=0.835; and p=0.001; HR=0.941, respectively)., Conclusion: Cognitive impairment, with particular involvement of processing speed and memory, predicts disability progression and SP conversion in newly diagnosed RRMS, highlighting the importance of cognitive assessment from the beginning of MS., (© The Author(s), 2015.)

People with multiple sclerosis (MS) frequently report difficulties in finding personally relevant information on the Internet. With this in mind, the Google top-ten patient-oriented results were analysed for their overall level of readability. The most commonly visited websites required an average grade level of 11.74 ± 1.54, and an average number of years of formal education of 12.78 ± 1.82, to be easily understood. The average Flesch Reading Ease readability index is 45.26 ± 7.35, a difficult-to-read score. The high educational level required to easily understand most websites worsens health inequalities, not allowing a full participation in health information and decision making., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

This cross-sectional study has investigated the diagnostic and therapeutic management of patients suffering from multiple sclerosis (MS) in the Campania Region (Italy). A survey involving all the reference centers for MS in Campania Region was conducted from March to August 2011. Centers responded to a web-administered questionnaire on management and clinical characteristics of MS patients. In the study period, 3263 patients (mean age 37 years, 66 % females) accessed the centers. Patients received a first diagnosis of MS in 161 cases (4.9 %). About 37 % of the subjects without a previous diagnosis came to the centers on their own initiative. All patients underwent a complete neurological examination and expanded disability status scale. The other most common investigations were magnetic resonance imaging (44.0 %) and evoked potentials (22.1 %). The number of treated patients was 2797 (87.1 %). The most used drugs were interferon β and glatiramer acetate. The time between diagnosis and initiation of therapy exceeded 6 months in 32 % of cases. Second-line drugs were under-used: 16 % of patients who might benefit from them show high clinical and radiological disease activity despite treatment with immunomodulant drugs. The MS care management of the surveyed centers showed consistent margins for improvement in 2011. Even though these data do not represent the current situation, they can be used to monitor improvements in MS care.

Background: Multiple sclerosis (MS) is a demyelinating disease of the CNS occurring in young adults and even in children in 5% of cases. Lower quality of life (QoL) and cognitive impairment (CI) (40-54%) have been reported in early-onset MS (EO-MS) patients., Objective: To assess QoL and cognitive function in EO-MS and their relationship, also considering demographic and clinical variables., Methods: Paediatric Quality of life inventory Version 4.0 for patients aged 13-18 and 19-25 years, Beck Depression Inventory II (BDI II) and the Rao Brief Repeatable Battery were performed in EO-MS patients (onset age ≤25years). EDSS and MSSS were performed at same time. After testing for normal distribution, group comparisons were performed through the two-tailed Student's t test, one-way analysis of variance (ANOVA) and linear or logistic regression when appropriate. The Bonferroni correction for multiple testing was used when appropriate., Results: 59 patients were included (mean age: 20 ± 3.6; Female sex 52.54%). 34 patients had a paediatric onset (<18 years) while 20 patients had a juvenile onset (18 < age < 25 years) of disease. 5 patients were excluded for missing data. HR-QoL was higher in paediatric than juvenile MS patients (p = 0.02), and it was inversely related to EDSS (p = 0.0005) and Multiple Sclerosis Severity score (MSSS) (p = 0.0001). Sixtyone % of patients showed a CI at BRB. No association was found between CI and any socio-demographic and clinical data. HR-QoL total score was not related to CI status nor to any domain-specific cognitive function score, even considering BDI as possible bias. CI was related to social, physical functioning score and EDSS (p = 0.01) at a logistic regression backward stepwise estimation., Conclusion: HR-QoL resulted to be better in paediatric than juvenile MS onset patients and was inversely related to rapidity of disability accumulation, while cognitive impairment was influenced by physical disability and poor social involvement (school, education …). Social participation, affective relations and psychological flexibility could have a protective function on CI., (Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Cardiovascular risk factors can increase the risk of multiple sclerosis (MS) and modify its course. However, such factors possibly interact, determining a global cardiovascular risk. Our aim was to compare the global cardiovascular risk of subjects with and without MS with the simplified 10-year Framingham General Cardiovascular Disease Risk Score (FR) and to evaluate its importance on MS-related outcomes., Methods: Age, gender, smoking status, body mass index, systolic blood pressure, type II diabetes and use of antihypertensive medications were recorded in subjects with and without MS to estimate the FR, an individualized percentage risk score estimating the 10-year likelihood of cardiovascular events., Results: In total, 265 MS subjects were identified with 530 matched controls. A t test showed similar FR in cases and controls (P = 0.212). Secondary progressive MS presented significantly higher FR compared to relapsing-remitting MS (P < 0.001). Linear regression analysis showed a direct relationship between FR and Expanded Disability Status Scale (P < 0.001) and MS Severity Scale (P < 0.001)., Conclusion: The FR, evaluating the global cardiovascular health by the interaction amongst different risk factors, relates to MS disability, severity and course., (© 2015 EAN.)

Background: Uric acid (UA) is a strong natural scavenger of reactive oxygen and nitrogen species, with evidence of possible use in the treatment of animal models of multiple sclerosis (MS). Consequently, serum UA has gained much attention as a possible biomarker of MS. We aim to investigate differences in serum UA levels between MS subjects and controls and evaluate possible relationships of UA with MS clinical features., Methods: We recruited relapsing-remitting and secondary progressive MS subjects and healthy controls and measured their serum UA levels. We excluded subjects presenting concomitant conditions affecting UA levels., Results: MS subjects (n=362) and controls (n=181) were recruited by propensity score matching (PSM). Statistical analyses were corrected for age, gender, and renal function. MS subjects presented significantly lower serum UA levels than controls (analysis of variance, p=0.014, adjusted r2=0.3036). Linear regression analysis showed a relationship between UA levels and disease duration (p<0.001, adjusted r2=0.3158, coefficient -0.00039), time from diagnosis (p<0.001, adjusted r2=0.3100, coefficient -0.0012), and Expanded Disability Status Scale (EDSS) (p<0.001, adjusted r2=0.3230, coefficient -0.1)., Conclusions: Our findings support the importance of serum UA as a biomarker of MS disability and progression. Further studies with longitudinal design should be specifically designed to evaluate the importance of UA in the different stages of MS and in relation to distinct therapeutic strategies.

Background: Magnetic Resonance Imaging (MRI) techniques provided evidences into the understanding of cognitive impairment (CIm) in Multiple Sclerosis (MS)., Objectives: To investigate the role of white matter (WM) and gray matter (GM) in predicting long-term CIm in a cohort of MS patients., Methods: 303 out of 597 patients participating in a previous multicenter clinical-MRI study were enrolled (49.4% were lost at follow-up). The following MRI parameters, expressed as fraction (f) of intracranial volume, were evaluated: cerebrospinal fluid (CSF-f), WM-f, GM-f and abnormal WM (AWM-f), a measure of lesion load. Nine years later, cognitive status was assessed in 241 patients using the Symbol Digit Modalities Test (SDMT), the Semantically Related Word List Test (SRWL), the Modified Card Sorting Test (MCST), and the Paced Auditory Serial Addition Test (PASAT). In particular, being SRWL a memory test, both immediate recall and delayed recall were evaluated. MCST scoring was calculated based on the number of categories, number of perseverative and non-perseverative errors., Results: AWM-f was predictive of an impaired performance 9 years ahead in SDMT (OR 1.49, CI 1.12-1.97 p = 0.006), PASAT (OR 1.43, CI 1.14-1.80 p = 0.002), SRWL-immediate recall (OR 1.72 CI 1.35-2.20 p<0.001), SRWL-delayed recall (OR 1.61 CI 1.28-2.03 p<0.001), MCST-category (OR 1.52, CI 1.2-1.9 p<0.001), MCST-perseverative error(OR 1.51 CI 1.2-1.9 p = 0.001), MCST-non perseverative error (OR 1.26 CI 1.02-1.55 p = 0.032)., Conclusion: In our large MS cohort, focal WM damage appeared to be the most relevant predictor of the long-term cognitive outcome.

Uric acid (UA) is reduced in multiple sclerosis (MS), and possibly relates to MS outcomes, with lower UA levels in subjects experiencing a relapse or presenting higher disability scores. The present retrospective longitudinal study evaluated UA variations in MS, in relation to clinical relapses, disability progression, and cognitive functions. We included 141 subjects with relapsing-remitting MS (RRMS) and performed expanded disability status scale (EDSS), symbol digit modalities test (SDMT) and UA evaluation at baseline visit and after 2-year follow-up. Paired t test showed significantly lower UA levels after 2-year follow-up than at baseline (3.987 ± 1.135 and 4.167 ± 1.207 mg/dL, respectively) (p = 0.001). The difference in UA levels between 2-year follow-up and baseline related to EDSS sustained progression (p < 0.001; OR = 0.099), and presented a trend for clinical relapses at logistic regression (p = 0.211; OR = 0.711) and for the time to relapse at Cox regression (p = 0.236; HR = 0.792). Analysis of variance showed reduced baseline UA levels in subjects with impaired SDMT at baseline (p = 0.045; adjusted R(2) = 0.473) and after 2-year follow-up (p = 0.034; adjusted R(2) = 0.470). This is the first study showing a progressive reduction of UA levels during the course of RRMS, suggesting a progressive decrease of antioxidant reserves, in relation to relapse risk, disability progression and cognitive function.

Natalizumab-treated patients have a higher risk of developing progressive multifocal leukoencephalopathy. Exposure to John Cunningham virus (JCV) is a prerequisite for PML (progressive multifocal leukoencephalopathy). To assess JCV exposure in multiple sclerosis patients, we performed a serological examination, obtained the antibody index, performed real-time polymerase chain reaction (PCR) to detect JCV DNA in plasma and urine, and investigated the role of ultrasensitive C-reactive protein (usCRP) as a possible biological marker of JCV reactivation. We retrospectively analyzed consecutive natalizumab-treated multiple sclerosis patients who underwent a JCV antibody test through a two-step enzyme-linked immunosorbent assay (STRATIFY test) to the measure of serum usCRP levels, and to perform blood and urine JCV PCR. The studied cohort included 97 relapsing-remitting patients (60 women). Fifty-two patients (53.6%) tested positive for anti-JCV antibodies. PCR showed JCV DNA in the urine of 30 out of 83 (36.1%) patients and 28 out of 44 seropositive patients (63.6%), with a 6.7% false-negative rate for the STRATIFY test. Normalized optical density values were higher in urinary JCV DNA-positive patients (P<0.0001). Interestingly, the level of usCRP was higher in urinary JCV DNA-positive patients and correlated to the number of DNA copies in urine (P=0.028). As expected, patients' age correlated with JCV seropositivity and with JC viruria (P=0.02 and P=0.001, respectively). JC viruria was significantly correlated with a high JCV antibody index and high serum usCRP levels. We suggest that PCR and usCRP might be useful as markers of JCV reactivation, and that patients should be monitored between STRATIFY assessments.

Importance: The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS)., Objective: To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS., Design, Setting, and Participants: The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab., Interventions: Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod., Main Outcomes and Measures: The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year., Results: No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery., Conclusions and Relevance: This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug., Trial Registration: Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

The aim of the study was to investigate the Internal Jugular Veins dynamics using contrast enhanced ultrasonography in Multiple Sclerosis patients, clinically isolated syndrome patients and healthy controls. Contrast enhanced ultrasonography imaging of the Internal Jugular Vein was performed in fifty-eight patients with Multiple Sclerosis, seven clinically isolated syndrome patients and in thirteen healthy controls. Time-intensity curves were quantified using a semi-automated method and compared with clinical disease outcomes. Wash-out parameters were calculated and six Time-intensity curves shapes were created. Significantly reduction of wash-out rate in Internal Jugular Veins was detected in Multiple Sclerosis patients compared to healthy controls [22.2% (2.7%-65.9%) vs. 33.4% (16.2%-76.8%); P<0.005]. Internal Jugular Vein enhancement was heterogeneous in patients with Multiple Sclerosis and consisted of slow wash-out Time-intensity curves shapes, compared with almost only one type of Time-intensity curves shape in control subjects that correspond to fast enhancement and fast wash-out. The vein wash-in parameters were similar in Multiple Sclerosis group compared with controls. A significant correlation was found between Internal Jugular Vein wash-out and level of disability (R =  -0.402, p<0.05). Contrast enhanced ultrasonography of the Internal Jugular Vein with time intensity curve analysis revealed alterations of cerebral venous outflow in Multiple Sclerosis patients, however mechanisms that determine this condition remains unclear.

Objective: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients., Methods: A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4., Results: We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70))., Conclusions: BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.

Objective: To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS)., Methods: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months., Results: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308-0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207-0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046-0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were -0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and -0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27-0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04-0.93; p = 0.04)., Conclusions: Early BCG may benefit CIS and affect its long-term course., Classification of Evidence: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).

Natalizumab is one option for multiple sclerosis patients responding poorly to classical immunomodulators, but pilot studies did not point to its effectiveness as a second-line therapy. Aim of this study was to assess the efficacy of natalizumab as second-line therapy in patients switching from disease modifying therapies (DMTs) in a clinical setting. We retrospectively selected patients who had been treated with natalizumab for at least 12 months after switching from one or more DMTs. We collected clinical and neuroradiological data and we analysed the reduction in annualised relapse rate (ARR), the change of Expanded Disability Status Scale (EDSS) and the reduction of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI) of the brain at 12 months of natalizumab and of previous DMT therapy. Fifty patients were included in the analysis (11 males, 39 females).We observed a reduction of ARR on natalizumab (p = 0.000) and a statistically significant different trend of relapse event between the two treatments (p = 0.0149). EDSS was stable during natalizumab therapy whilst it showed an increase on DMTs (p = 0.0244). The number of CELs decreased significantly (p = 0.006) during the 12 months of treatment with natalizumab, whilst it was stable on DMTs. Natalizumab showed to decrease ARR, stabilize EDSS, increase the percentage of CELs free patients and decrease the number of CELs in a group of 50 poor responders to classical DMT, after the first 12 months of therapy.

Background: This study aimed to investigate the prevalence and clinical relevance of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (MS) patients and healthy controls using extra- and intracranial colour Doppler sonography., Methods: We examined 146 MS patients, presenting with a clinically isolated syndrome, relapsing-remitting, secondary progressive, or primary progressive MS, and 38 healthy controls. Sonographic examination was performed according to Zamboni's protocol and was performed by three independent sonographers. The results of sonographic examination were compared with clinical and demographic characteristics of the patients., Results: CCSVI, defined as the presence of at least two positive Zamboni's criteria, was found in 76% of MS patients and 16% of control subjects. B-mode anomalies of internal jugular veins, such as stenosis, malformed valves, annuli, and septa were the most common lesions detected in MS patients (80.8%) and controls (47.4%). We observed a positive correlation between sonographic diagnosis of CCSVI and the patients' age (p = 0.003). However, such a correlation was not found in controls (p = 0.635). Notably, no significant correlations were found between sonographic signs of CCSVI and clinical characteristics of MS, except for absent flow in the jugular veins, which was found more often in primary (p<0.005) and secondary (p<0.05) progressive patients compared with non-progressive patients. Absent flow in jugular veins was significantly correlated with patients' age (p < 0.0001)., Conclusions: Sonographically defined CCSVI is common in MS patients. However, CCSVI appears to be primarily associated with the patient's age, and poorly correlated with the clinical course of the disease.

Background: No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS)., Aim: To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 μg; Rebif(®) ) on clinical and radiological findings in two matched cohorts of patients with MS., Patients and Methods: We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing-remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI)., Results: In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab-treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a-treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008)., Conclusions: After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head-to-head studies would be helpful to further evaluate the differences observed in the MRI outcomes., (© 2011 John Wiley & Sons A/S.)

Purpose: To assess cerebral circulation times (CCTs) in patients with multiple sclerosis (MS) and control subjects by using contrast material-enhanced ultrasonography (US) to determine whether vascular abnormalities can be detected in this disease., Materials and Methods: This study was approved by the local ethics committee, and informed consent was obtained from all subjects. One hundred three patients with MS and 42 control subjects underwent extracranial and transcranial venous echo-color Doppler ultrasonography (US) and contrast-enhanced US. CCT was defined as the difference in arrival time of the US contrast agent bolus between the carotid artery and the internal jugular vein. The presence of chronic cerebrospinal venous insufficiency (CCSVI) was defined according to previously reported criteria for the extracranial and transcranial US techniques. Nonparametric statistics, including the Mann-Whitney U test and the Kruskal-Wallis analysis of variance, were used to compare contrast-enhanced US parameters between groups., Results: The longest and average CCTs were substantially prolonged in patients with MS compared with those in control subjects (median longest CCT in patients with MS, 6.47 seconds [range, 3.29-29.24 seconds]; that in control subjects, 5.54 seconds [range, 2.57-7.63 seconds]; P < .001; median average CCT in patients with MS, 5.76 seconds [range, 2.64-17.51 seconds]; that in control subjects, 5.01 seconds [range, 2.57-7.06 seconds]; P < .002). No correlation was found between CCTs and clinical parameters. The prevalence of CCSVI was higher in patients with MS than in control subjects (77% vs 28%, P < .0001). CCT was not significantly different between patients with MS who had CCSVI and patients with MS who did not (P = .182)., Conclusion: These results suggest that contrast-enhanced US with CCT assessment may have a role in the evaluation of cerebral blood flow in patients with MS and that a vascular impairment could be associated with MS. The finding of a prolonged CCT at contrast-enhanced US does not result from outflow impairment. Further studies are required to verify these observations and to clarify if CCT and CCSVI have any physiologic and clinical relevance in MS., (© RSNA 2012.)

Background: Insulin-like growth factor (IGF)-I has a role in remyelination, and insulin-like growth factor-binding protein-3 (IGFBP-3) might reduce its bioavailability. A role of IGFBP-3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS., Objective: To evaluate serum levels of IGF-I and IGFBP-3 in patients with relapsing-remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression., Methods: Sixty-three (41 RR and 22 SP) 'naive' MS patients and 60 age-matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF-I and IGFBP-3 were measured by ELISA., Results: Levels of IGF-I and IGFBP-3 were similar in the two MS groups. IGFBP-3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF-I/BP3 ratio (P < 0.001). Patients showing IGFBP-3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF-I or IGFBP-3 serum levels., Conclusions: Our patients showed high IGFBP-3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF-I. MSSS score was not related to IGFBP-3 levels, suggesting that IGFBP-3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)