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Background and purpose: The long-term impact of gadolinium retention in the dentate nuclei of patients undergoing administration of seriate gadolinium-based contrast agents is still widely unexplored. The aim of this study was to evaluate the impact of gadolinium retention on motor and cognitive disability in patients with MS during long-term follow-up. Materials and methods: In this retrospective study, clinical data were obtained from patients with MS followed in a single center from 2013 to 2022 at different time points. These included the Expanded Disability Status Scale score to evaluate motor impairment and the Brief International Cognitive Assessment for MS battery to investigate cognitive performances and their respective changes with time. The association with qualitative and quantitative MR imaging signs of gadolinium retention (namely, the presence of dentate nuclei T1-weighted hyperintensity and changes in longitudinal relaxation R1 maps, respectively) was probed using different General Linear Models and regression analyses. Results: No significant differences in motor or cognitive symptoms emerged between patients showing dentate nuclei hyperintensity and those without visible changes on T1WIs (P = .14 and 0.92, respectively). When we tested possible relationships between quantitative dentate nuclei R1 values and both motor and cognitive symptoms, separately, the regression models including demographic, clinical, and MR imaging features explained 40.5% and 16.5% of the variance, respectively, without any significant effect of dentate nuclei R1 values (P = .21 and 0.30, respectively). Conclusions: Our findings suggest that gadolinium retention in the brains of patients with MS is not associated with long-term motor or cognitive outcomes.

Introduction: Disease modifying treatments are commonly used in the treatment of multiple sclerosis. As different opportunistic infections have been reported, concerns are also raised regarding the risk of invasive fungal infections. Areas covered: Both clinical trials and observational studies on safety and efficacy of diseases modifying treatment for multiple sclerosis were reviewed and data regarding the occurrence of invasive fungal infections were reported. Papers evaluating the following drugs were reviewed: rituximab, ocrelizumab, alemtuzumab, fingolimod, natalizumab, dimethyl fumarate, interferon, glatiramer acetate, cladribine, teriflunomide. Expert opinion: Overall, the occurrence of invasive fungal infections was low, with most infective events reported among patients treated with monoclonal antibodies and fingolimod. Aspergillosis and cryptococcal meningitidis were the most representative fungal infections. Although not common, these infections may be difficult to diagnose and their fatality rate is often high. For this reason, screening protocols for fungal infections must be implemented in the clinical practice when managing patients with MS.

Background: No uniform criteria for a sensitive identification of the transition from relapsing–remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available. Objective: To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA). Methods: Relapsing-onset MS patients ( n = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models. Results: SPMS identified by the DDA ( n = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability ( p 40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0. Conclusion: A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.

Background/objectives Several studies supported the beneficial effects of the Mediterranean diet (MeDi) on chronic diseases. In Multiple Sclerosis (MS), the MeDi might interfere with systemic inflammatory state, gut microbiota, and comorbidities. The Med Diet Score (MDS) estimates the adherence to the MeDi and the cardiovascular (CV) risk. Aims of our study were i) to photograph lifestyle and diet habits of a southern Italy cohort of people with MS (pwMS), and ii) to investigate the impact of the MeDi on MS clinical outcomes. Subjects/methods We conducted a multi-center, cross-sectional study, enrolling 435 consecutive consenting pwMS, attending the outpatient clinics for routine follow-up visits. Participants underwent a clinical examination and a 29-item self-administered questionnaire on life and dietary habits. Disease phenotype, Expanded Disability Status Scale (EDSS), MS Severity Score (MSSS), waist circumference (WC), Body Mass Index (BMI), therapies, and comorbidities, were updated. MDS was assessed and correlated with current and retrospective clinical data. Results 75.8% of respondents were interested in nutrition, 72.8% were non-smokers, 52.9% performed physical activity, and 45.6% used food supplements. MDS was higher in pwMS with normal WC (p = 0.031), and inversely correlated with MSSS (p = 0.013) and EDSS (p = 0.012) at survey time. MDS did not correlate with the total number of relapses (before and after diagnosis) (p = 0.372). Metabolic comorbidities were associated with an increased 10-year CV risk (r = 0.85, p = 0.002). Conclusion Our findings suggest a putative beneficial effect of the MeDi on WC, MS course and disability. Given the role of chronic systemic inflammation in maintenance of autoimmunity and secondary neurodegeneration, both involved in long-term disability, we may suppose a beneficial effect of the MeDi on MS long-term disability outcomes, probably mediated by a modulation of the gut microbiota and the low-grade chronic systemic inflammation.

BACKGROUND AND PURPOSE: Conventional MR imaging explains only a fraction of the clinical outcome variance in multiple sclerosis. We aimed to evaluate machine learning models for disability prediction on the basis of radiomic, volumetric, and connectivity features derived from routine brain MR images. MATERIALS AND METHODS: In this retrospective cross-sectional study, 3T brain MR imaging studies of patients with multiple sclerosis, including 3D T1-weighted and T2-weighted FLAIR sequences, were selected from 2 institutions. T1-weighted images were processed to obtain volume, connectivity score (inferred from the T2 lesion location), and texture features for an atlas-based set of GM regions. The site 1 cohort was randomly split into training (n = 400) and test (n = 100) sets, while the site 2 cohort (n = 104) constituted the external test set. After feature selection of clinicodemographic and MR imaging–derived variables, different machine learning algorithms predicting disability as measured with the Expanded Disability Status Scale were trained and cross-validated on the training cohort and evaluated on the test sets. The effect of different algorithms on model performance was tested using the 1-way repeated-measures ANOVA. RESULTS: The selection procedure identified the 9 most informative variables, including age and secondary-progressive course and a subset of radiomic features extracted from the prefrontal cortex, subcortical GM, and cerebellum. The machine learning models predicted disability with high accuracy (r approaching 0.80) and excellent intra- and intersite generalizability (r ≥ 0.73). The machine learning algorithm had no relevant effect on the performance. CONCLUSIONS: The multidimensional analysis of brain MR images, including radiomic features and clinicodemographic data, is highly informative of the clinical status of patients with multiple sclerosis, representing a promising approach to bridge the gap between conventional imaging and disability.

Background : Fingolimod (FTY720, Gilenya) is a second line therapy to treat relapsing MS not responding to first-line treatments and/or with a high disease activity (according to Italian Regulatory authorities). Before starting Fingolimod, patients’ immunity to varicella zoster virus (VZV) needs to be assessed and seronegative patients vaccinated. To test susceptibility and response, IgG antibodies are tested after immunization. Since Fingolimod determines a reduction of circulating B lymphocytes and immunoglobulins, we aimed at describing the trend of VZV antibodies in seronegative vaccinated patients with MS before and after treatment. Methods : A total of 23 patients vaccinated for VZV before starting Fingolimod treatment, were recruited in this observational retrospective study involving five MS Centers in Campania (Italy). Of these, 12 patients were excluded for missing data. Patients received two doses of Varivax® Vaccine. After vaccination patients were re-tested and were all positive for IgG-VZV. We re-tested IgG-VZV in the same laboratory after a mean time of 2.42 years from Fingolimod therapy start. Results : During Fingolimod therapy we observed a global reduction of antibody titer and a disappearance in 7/11 patients. Titer disappearance was more probable in patients with lower post-vaccination titer. Of the 7 patients with vanishing IgG-VZV, three suspended Fingolimod for adverse event. In two of them, we observed a reappearance of antibody titer after treatment cessation. In one patient chickenpox infection occurred one year later. Discussion and conclusions : Our observational study shows that Fingolimod could influence antibody titer probably through its effect on B lymphocytes, but the efficacy of the vaccination should be verified. In conclusion, it is necessary to pay attention to therapies acting on B lymphocytes as they could influence the antibody titer and efficacy of vaccination making the search for other markers of vaccine efficacy desirable such as cell-mediated immunity with proliferation and induction of memory T lymphocytes in response to viral glycoproteins.

Background: Patient-reported outcomes (PROs) may help patients and clinicians in selecting disease-modifying therapies (DMTs) for multiple sclerosis (MS). Objective: To evaluate PRO differences among first-line DMTs for relapsing-remitting (RR) people with MS (pwMS). Methods: Multicenter study. RR pwMS on first-line DMTs completed Fatigue Severity Scale (FSS), PROs Indices for MS (PRIMUS), 36-item Short-Form Health Survey (SF-36), treatment satisfaction questionnaire for medication (TSQM), Beck Depression Inventory-II (BDI-II), and Symbol Digit Modalities Test (SDMT). Differences among PROs across DMTs were tested by ANOVA. Multivariable linear regressions were used to investigate associations between PROs and the treatment group. Results: Two-hundred eighty pwMS were enrolled: 56% were on interferons (INF), 22% on dimethylfumarate (DMF), 13% on glatiramer acetate, and 9% on teriflunomide (Teri). Compared with INF, pwMS on Teri were the oldest, with higher disability, worst depression at BDI, worst cognitive performances at SDMT (p = 0.001), fatigue at FSS (p = 0.001), and activity limitation and quality of life respectively at PRIMUS (p = 0.005) and SF-36 Mental Composite Score (p < 0.001); pwMS on DMF reported highest side effects and, together with pwMS on Teri, better treatment satisfaction at TSQM. Conclusions: Compared with INF-treated patients, pwMS on DMF and Teri reported the best treatment satisfaction, although DMF-treated pwMS reported higher side effects and those on Teri the worst QoL and fatigue; however, the older age, higher disability and depression, and worse cognitive performance of pwMS on Teri suggest to be careful in evaluating these results.

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

Background: Dimethyl-fumarate (DMF) was effective and safe in relapsing–remitting multiple sclerosis (MS) in randomized clinical trials. We aimed to evaluate the efficacy and safety of DMF and factors related to drug response in real-life setting. Methods: We analysed prospectively collected demographic and clinical data for patients treated with DMF in six multiple sclerosis (MS) centers from 2015 to 2017 in Campania region, Italy. We performed univariate and multivariate analyses to assess relationships between baseline parameters and DMF efficacy outcomes, Annualized Relapse Rate (ARR), Expanded Disability Status Scale (EDSS) progression and No Evidence of Disease Activity (NEDA-3) status. Results: we analyzed data of 456 patients (67% female subjects, mean age 40 ± 12 years, mean disease duration 9 ± 9 years, mean treatment duration 18 ± 11 months, median EDSS 2.5, 0–8). Proportion of Naïve versus pretreated with other DMTs patients was 149/307 (32.7%), with 122 patients switching to DMF for disease activity (26.7%) and 185 for safety and tolerability issues (40.6%). During treatment with DMF, the annualized relapse rate was reduced by 75% respect to the pre-treatment ARR [incidence-rate-ratio (IRR) = 0.25, p < 0.001, CI 0.18–0.33]. Factors influencing ARR rate while on DMF were relapsing remitting (RR) MS course (IRR = 2.0, p =

Background Multiple sclerosis (MS) is an heterogenous disease whose prevalence varies in Europe. Hereby, we aimed to estimate prevalence of MS in the Campania Region of Italy. Methods To identify individuals with MS living in the Campania Region of Italy, we extracted data from the following healthcare administrative databases: hospital discharge records, regional drug registry, and specialist outpatient visits from Jan-2015 to 3Dec-2017. Individuals alive on the 1-Jan-2018 were included to capture prevalence on this date. Age-sex standardised prevalence rates were calculated using the direct standardisation method; the European population in 2018 was considered as reference population. To assess differences in the prevalence ratios across the five provinces of the region, standardised morbility ratios (SMR) were calculated. To calculate 95% confidence intervals (95%CI) for the standardised rates, the Byar’s approximation method based on the Poisson distribution was used. Results We identified 5,361 individuals with MS (females 64.5%, age 45.6±12.7 years). Standardised prevalence rate per 100,000 people was 90.0 cases (95%CI=87.60, 92.40) (112.07 for females [95%CI=108.36, 115.88] and 66.20 for males [95%CI=63.26, 69.25]). The SMR in the province of Naples, the most densely populated, was 0.90 (95%CI=0.86, 0.96), whereas the highest SMR was found in the province of Salerno (SMR=1.30; 95%CI=1.23, 1.38), and the lowest in the province of Caserta (SMR=0.89; 95%CI=0.82-0.96). Conclusions Prevalence of MS in the Campania Region is lower than previous estimates from smaller areas in the North of Italy, suggesting a longitudinal gradient. Differences within the Region could be explained by genetic/environmental background and healthcare organization (e.g., missing diagnoses). In the future, healthcare administrative databases could be used to monitor MS prevalence/incidence and to plan healthcare resource utilization. Key messages Prevalence of MS in the Campania Region is 90 cases per 100,000 people. It is lower than previous estimates from smaller areas in the North of Italy, suggesting a longitudinal gradient. Differences within the Region could be explained by genetic/environmental background and healthcare organization (e.g., missing diagnoses).

To investigate the effects of Glatiramer Acetate (GA) on B cells by an integrated computational and experimental approach. GA is an immunomodulatory drug approved for the treatment of multiple sclerosis (MS). GA effect on B cells is yet to be fully elucidated. We compared transcriptional profiles of B cells from treatment-naïve relapsing remitting MS patients, treated or not with GA for 6 hours in vitro, and of B cells before and after six months of GA administration in vivo. Microarrays were analyzed with two different computational approaches, one for functional analysis of pathways (Gene Set Enrichment Analysis) and one for the identification of new drug targets (Mode-of-action by Network Analysis). GA modulates the expression of genes involved in immune response and apoptosis. A differential expression of genes encoding ion channels, mostly regulating Ca2+ homeostasis in endoplasmic reticulum (ER) was also observed. Microfluorimetric analysis confirmed this finding, showing a specific GA effect on ER Ca2+ concentration. Our findings unveils a GA regulatory effect on the immune response by influencing B cell phenotype and function. In particular, our results highlight a new functional role for GA in modulating Ca2+ homeostasis in these cells.

BACKGROUND AND PURPOSE Vascular pathology is increasingly acknowledged as a risk factor for multiple sclerosis (MS). Vascular density (VD) is reduced in the eyes of patients with MS on optical coherence tomography (OCT) angiography. We performed a 1-year prospective study to estimate VD variations over time and possible clinical correlates. METHODS A total of 50 patients with MS underwent spectral domain-OCT and OCT angiography at baseline and after 1-year follow-up. Mixed-effect linear regression models were used to assess variations of each OCT measure and its relation to treatment and clinical outcomes. RESULTS We observed an increase in parafovea VD (coefficient, 1.147; 95% confidence interval, 0.081-2.214; P = 0.035). Reduction in parafovea VD was associated with increase in Expanded Disability Status Scale score (coefficient, -0.969; 95% confidence interval, -1.732/-0.207; P = 0.013). CONCLUSIONS Retinal VD can improve over time in MS, particularly in patients experiencing disease stability. Longer follow-up, inclusion of early MS cases and combination with conventional markers of MS severity (i.e. brain atrophy) are needed to better define VD as a potential new biomarker.

Background Over the last few decades, patients have increasingly been searching for health information on the Internet. This aspect of information seeking is 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. A professional approach is imperative to maintain confidentiality, honesty, and trust in the medical profession. Objective we aimed to examine, in a medically supervised Italian web community (SMsocialnetwotk.com) dedicated to people with Multiple Sclerosis (pwMS), the posts shared by users and to verify the reliability of contents of posts shared by users pinpointed as Influencers through an online questionnaire. Methods we grouped the posts published on SMsocialnetwork from April to June 2015 into those with medical content (scientifically correct or fake news), and those related to social interactions. Later, we gave a questionnaire to the community asking to identify the three users/Influencers providing the most reliable advice for everyday life with MS and the three users/Influencers providing the most useful information about MS treatments. Results 308 posts reported scientific and relevant medical information, whereas 72 posts included pieces of fake news. 1420 posts were of general interest. Four out of the 6 Influencers had written only posts with correct medical information (3 were pwMS, 1 was a Neurologist) and never any fake news. The remaining 2 appointed Influencers (2 pwMS) had written only posts about general interests. Conclusion the identification of fake news and their authors has shown that the latter are never appointed as Influencers. SMsocialnetwork.com acted as a “web safe environment” where the Influencers contributed by sharing only correct medical information and never fake news. We speculate that the presence of neurologists and psychologists supervising the information flow might have contributed to reduce the risk of fake news spreading and to avoid their acquisition of authoritative meaning.

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.

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 naive 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.

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.

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.

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

ackground: 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) (40e54%) 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 13e18 and 19e25 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 (

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

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.

No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS).To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 ??g; Rebif(®) ) on clinical and radiological findings in two matched cohorts of patients with MS.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).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).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.

OBJECTIVE: To describe the effect of natalizumab in the treatment of subjects with active multiple sclerosis (MS) treated before the age of 18 years. METHODS: Nineteen pediatric subjects with MS (mean age 14.6 +/- 2.2 years, mean number of attacks 5.2 +/- 1.9 during the pretreatment phase of 27.7 +/- 19.7 months, median pretreatment Expanded Disability Status Scale score [EDSS] 2.5, range 1.0-5.0) were treated with natalizumab at the dose of 300 mg every 28 days. After treatment initiation, patients were reassessed clinically every month; brain MRI was performed at baseline and every 6 months. RESULTS: Patients received a median number of 15 infusions (range 6-26). A transient reversible worsening of preexisting symptoms occurred in 1 subject during and following the first infusion. All the patients remained relapse-free during the whole follow-up. The median EDSS decreased from 2.5 to 2.0 at the last visit (p < 0.001). EDSS remained stable in 5 cases, decreased by at least 0.5 point in 6 cases, and decreased by at least 1 point in 8 cases. At baseline, the mean number of gadolinium-enhancing lesions was 4.1 (range 1-20). During the follow-up, no gadolinium-enhancing lesions were detected (p = 0.008); 3 patients developed new T2-visible lesions at month 6 scan but the overall number of T2 lesions remained stable during the subsequent follow-up. Transient and mild side effects occurred in 8 patients. CONCLUSIONS: Natalizumab was well-tolerated in all subjects. A strong suppression of disease activity was observed in all subjects during the follow-up. Classification of evidence: This study provides Class IV evidence that natalizumab, 300 mg IV once every 28 days, decreased EDSS scores in pediatric patients with MS over a mean treatment period of 15.2 months.

Previous studies have shown a preferential loss of grey matter in fronto-temporal regions in patients with multiple sclerosis. Studies of correlates of disease severity are more controversial, because some studies have suggested an association between sensorimotor cortex atrophy and Expanded Disability Status Scale score, while others did not find such a correlation. The objective of this study was to assess the correlation of regional loss of grey matter and white matter with indexes of clinical and radiological severity in relapsing—remitting multiple sclerosis, including the Expanded Disability Status Scale and lesion load. Correlations between Expanded Disability Status Scale, lesion load and disease duration were assessed in 128 patients with relapsing—remitting multiple sclerosis (Expanded Disability Status Scale range 1.0—6.0) using optimized voxel-based morphometry. Bilateral loss of grey matter in sensorimotor cortices was correlated with Expanded Disability Status Scale, and tissue loss also involved adjacent white matter, extending along pyramidal tracts to the brainstem. Increasing lesion load was correlated with loss of deep grey matter and white matter. No specific region of grey matter or white matter showed a significant correlation with disease duration. These findings support the hypothesis that motor neuron involvement plays a major role in the progression of physical disability. Lesion load accrual affects mainly highly interconnected subcortical structures, while disease duration has a less significant impact on brain atrophy, probably owing to the inter-subject heterogeneity of the clinical course of the disease.

Background To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression. Methods Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points. Results The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression. Conclusions In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.

Cognitive dysfunction occurs in patients suffering from multiple sclerosis also at the beginning of disease. This impairment has clinical relevance during progression of disease and has major impact on social functioning. In this critical review we take into account the cognitive and emotional-behavioural changes usually observed in multiple sclerosis and we discuss these aspects considering recent studies using functional imaging approach.

The prevalence of primary headache (PH) in a multiple sclerosis (MS) sample vs. control healthy subjects was investigated at a neurological clinic in 2004-2005: 122 of 238 (51%) MS patients and 57 of 238 (23%) controls proved to be affected by headache. The groups did not differ for the rates of PH types. Headache types of MS patients were comparable to those of PH patients that were observed at the same institute in a case-control comparison. First symptoms of headache preceded those of MS in two thirds of cases. Headache features did not significantly change after MS onset. Comorbidity of MS and PH could be explained by some common clinical and biological traits.

Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of interferon beta-1a (IFNb-1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFNb-1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 ± 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with £2 relapses in the previous 2 years and with baseline EDSS scores of £2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFNb-1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome. Introduction Interferon b-1a (IFNb-1a, Avonex; Biogen Idec, Inc, Cambridge, MA, USA) has shown beneficial effects in patients with multiple sclerosis (MS), reducing relapses and disability progression [1,2], and in patients with a first demyelinating event, reducing the rate of developing clinically definite MS [3]. However, long-term efficacy, safety, and compliance to IFNb-1a have not been sufficiently demonstrated [4], as randomized, blinded, controlled trials are expensive and usually last for a short time. Disease modifying treatments systemic effects are usually monitored through blood analysis. The effects of all the available IFNs have been studied giving controversial results. The most frequent effects are liver enzymes changes, thyroid function alterations, hematological effect and blood lipid changes. A multicenter, dose-comparison study to assess differences in therapeutic response between two doses of weekly IFNb-1a has been reported [5,6], and is the only study to provide information about longterm (> 3 years) therapy with weekly intramuscular (i.m.) IFNb-1a. Several studies

Disabling tremor is frequent in multiple sclerosis (MS) and its treatment remains challenging. We conducted an open-label trial to evaluate the effect of levetiracetam (LEV) to treat cerebellar tremor in MS patients.Fourteen MS patients, aged 27 to 57 years, with cerebellar tremor. Tremor duration ranged from 3 to 14 years. The tremor clinical rating scale, the spiral drawings scale, and ataxia clinical scale were used to assess the severity of tremor. Data about the tremor-induced disability were obtained by using the specific Activities of Daily Living Questionnaire (ADL). LEV was orally administered at a starting dose of 500 mg twice daily for one week followed by increments of 500 mg twice daily each week up to the target dose of 50 mg/Kg/day. Patients were evaluated at baseline and two weeks after the end of titration phase. The Wilcoxon matched-pairs test was used for statistical analysis.Eleven patients completed the trial. LEV administration was associated with subjective and objective improvement of the tremor, with significant lowering of all tremor measurements' sum of scores as well as of ADL mean score between the baseline and follow-up. No correlation was found between the degree of improvement of the tremor and the disease duration or progression. LEV was well tolerated by subjects who completed the study.LEV could be useful for the management of cerebellar tremor in MS and the good tolerability makes it easy to test. LEV long-term efficacy should be confirmed in extended studies.

Global grey matter (GM) loss has been reported in multiple sclerosis (MS). We addressed the question of if and where GM loss is localized by means of optimized voxel-based morphometry, applied to MRI studies of 51 patients with clinically defined relapsing-remitting MS and 34 age-matched normal subjects, segmented into normal and abnormal brain tissues using a multiparametric approach. Segmented GM volumes were subsequently compared on a voxel-by-voxel basis to highlight regions of relative GM loss (P < 0.05, corrected for multiple comparisons at AnCova). Additionally, localized differences in brain asymmetry between the MS and the control groups were assessed by comparing on a voxel-by-voxel basis maps of GM differences between the two hemispheres (P < 0.05 corrected for multiple comparisons). In MS patients, GM volume was significantly decreased at the level of the left fronto-temporal cortex and precuneus, as well as of anterior cingulate gyrus and of caudate nuclei bilaterally. The only cortical region of significant GM loss in the right hemisphere was located in the postcentral area. Furthermore, GM loss regions were colocalized with increased GM asymmetries (Left < Right) in MS, confirming a preferential left-sided GM loss. Caudate atrophy correlated with lesion load, while no correlation between cortical regional GM loss and disease duration, clinical status or lesion load emerged. Our findings suggest that in RR-MS cortical GM reduction preferentially involves left fronto-temporal structures and deep GM, the latter correlating preferentially to global lesion load.

Despite clinical similitude, there is a tendency to consider trigeminal pain in multiple sclerosis (MS) as a distinct condition. To evaluate clinical differences in trigeminal pain presentation in patients with and without underlying MS, we compared clinical characteristics of facial pain found in 15 consecutive MS patients with those reported by 13 consecutive subjects diagnosed with classical trigeminal neuralgia. The only significant difference between MS and non-MS neuralgic patients was the age of onset of pain (43.4+/-10.5 in MS vs. 59.6+/-11.50 in non-MS patients, p=0.000629, unpaired Student's t-test). No differences were observed for side, duration and quality of pain, trigeminal branches involved, presence of trigger areas or factors, pain refractive period, remitting-relapsing or chronic course. There was only a trend without statistical significance in interval pain and trigeminal hypoesthesia, more frequent in MS population. Only one patient in the MS group presented with long-lasting episodes (45-60 min) of atypical odontalgia. Our findings support the view of a common pathogenetic mechanism underlying TN in the two groups, possibly related to demyelination of the trigeminal entry root in the pons. Typical TN in MS patients should be considered as "symptomatic trigeminal neuralgia".

Interferon-β (IFNβ) has been widely used as a disease-modifying therapy for multiple sclerosis (MS) and other diseases. Some studies reported increased triglyceride plasma levels during interferon therapy, whereas conflicting data are reported about total cholesterol levels.1–3⇓⇓ The aim of this study was to evaluate cholesterol and triglyceride plasma levels during a 1-year follow-up period in a large cohort of patients with MS treated with IFNβ1a (IM and subcutaneous) and IFNβ1b (subcutaneous). Two hundred fifty-three consecutive patients with MS were prospectively enrolled in the study after informed consent was obtained. No patient was taking immunomodulatory agents for at least 1 month before inclusion in the study. Patients were treated with IFNβ1a (6 million U/week, IM; Avonex, Biogen, Cambridge, MA), IFNβ1b (8 million U every other day, subcutaneous; Betaferon, Schering, Berlin, Germany), or IFNβ1a (22 and 44 μg subcutaneously three times per week; Rebif, Ares-Serono, Geneva, Switzerland). Treatment was chosen based on clinical experience, laboratory data, and after discussion with the patient. Blood samples …

Epileptic seizures occur more frequently in multiple sclerosis (MS) patients than in the general population. We evaluated clinical, electroencephalographic (EEG) and magnetic resonance imaging (MRI) findings, as well as EEG-MRI correlations and the response to antiepileptic drugs (AEDs) in 270 consecutive patients with definite MS referred to our Department from 1995 to 2002. Thirteen (4.8%) subjects experienced epileptic seizures. In four cases, seizures manifested within 1-2 years ("early-onset"), and in six cases within 8-23 years ("late-onset") of MS diagnosis. Seizures were usually partial with secondary generalization. Thus, acute symptomatic seizures occurred in three cases. Epilepsy usually appeared late in the course of disease, although a single episode or a cluster of seizures can represent the onset symptom or a relapse of MS. Prognosis of epilepsy during the course of MS is usually good but the choice of AEDs remains a matter of debate.

Primitive reflexes (PRs) are present in newborns; they disappear as the brain matures and increase in frequency in healthy elderly individuals. Primitive reflexes are more frequent in some neurological disorders than in age-matched controls. The aim of this study was to investigate the effect of diabetes on some PRs. We examined three PRs (glabellar tap, snout and palmomental reflexes) in 376 subjects: 111 normal age-matched controls, 60 patients with cerebrovascular disease (CVD) and 205 patients with type 2 diabetes mellitus. The latter patients were divided into three groups: (1) diabetics without neurological complications (D); (2) diabetics with cerebrovascular disease (D-CVD); and (3) diabetics with polyneuropathy (D-PN). The frequency of PRs was increased in CVD, unchanged in D-CVD (except palmomental) and greatly reduced in D and D-PN. It is possible that the vascular lesions in perforating arteries of the pons in diabetic subjects, previously studied in some pathological reports, can account for the reduced occurrence of primitive reflex responses.

The involvement of sensory pathways in patients suffering from amyotrophic lateral sclerosis (ALS) is well reported in histopathological studies. Several laboratories have also used evoked potentials to evidentiate subtle dysfunctions of sensory systems in such patients. However, conflicting results have been presented in studies using evoked potentials. In the present experiment we have evaluated multimodality evoked potentials in subjects with sure diagnosis of sporadic ALS, by means of the Bonferroni multiple comparisons procedure. Our principal findings are: a) no statistical difference between patients and controls in BAEP and VEP recordings; b) a reduction of N13 amplitude and a prolonged P22 latency in SEP recordings. Due to the sources of N13 and P22, these latter alterations, however, do not implicate the involvement of somatosensory pathway. In conclusion, the current investigation does not provide an electrophysiological support for the involvement of sensory systems in the sporadic ALS.

Pulmonary function tests were performed before and at different times after 250 mg L-Dopa in 12 patients with Parkinson's disease (PD). Six were de-novo patients, the other six patients had been taking L-Dopa over different periods. All patients had an abnormal basal flow-volume loop, which significantly improved only in de-novo patients. This improvement occurred early and was independent on improvement of neurological symptoms. The effect of L-Dopa on pulmonary function could be a useful test in differentiating PD from related extrapyramidal syndromes.