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none 26 no Background: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial. Objective: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy. Methods: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model. Results: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06-2.84; p = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12-1.74; p = 0.003), younger age (aHR = 0.95; 95% CI 0.91-0.99; p = 0.022) and shorter DMD exposure over the follow-up (p < 0.008). Conclusion: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity. mixed Portaccio, Emilio; Tudisco, Laura; Pastò, Luisa; Razzolini, Lorenzo; Fonderico, Mattia; Bellinvia, Angelo; Ghezzi, Angelo; Annovazzi, Pietro; Zaffaroni, Mauro; Moiola, Lucia; Martinelli, Vittorio; Chisari, Clara Grazia; Patti, Francesco; Mancardi, Gianluigi; Pozzilli, Carlo; De Giglio, Laura; Totaro, Rocco; Lugaresi, Alessandra; Di Tommaso, Valeria; Paolicelli, Damiano; Cocco, Eleonora; Marrosu, Maria Giovanna; Comi, Giancarlo; Filippi, Massimo; Trojano, Maria; Amato, Maria Pia Portaccio, Emilio; Tudisco, Laura; Pastò, Luisa; Razzolini, Lorenzo; Fonderico, Mattia; Bellinvia, Angelo; Ghezzi, Angelo; Annovazzi, Pietro; Zaffaroni, Mauro; Moiola, Lucia; Martinelli, Vittorio; Chisari, Clara Grazia; Patti, Francesco; Mancardi, Gianluigi; Pozzilli, Carlo; De Giglio, Laura; Totaro, Rocco; Lugaresi, Alessandra; Di Tommaso, Valeria; Paolicelli, Damiano; Cocco, Eleonora; Marrosu, Maria Giovanna; Comi, Giancarlo; Filippi, Massimo; Trojano, Maria; Amato, Maria Pia

Metabolomic research has emerged as a promising approach to identify potential biomarkers in multiple sclerosis (MS). The aim of the present study was to determine the effect of interferon beta (IFN ß) on the metabolome of MS patients to explore possible biomarkers of disease activity and therapeutic response. Twenty-one MS patients starting IFN ß therapy (Rebif® 44 μg; s.c. 3 times per week) were enrolled. Blood samples were obtained at baseline and after 6, 12, and 24 months of IFN ß treatment and were analyzed by high-resolution nuclear magnetic resonance spectroscopy. Changes in metabolites were analyzed. After IFN ß exposure, patients were divided into responders and nonresponders according to the “no evidence of disease activity” (NEDA-3) definition (absence of relapses, disability progression, and magnetic resonance imaging activity), and samples obtained at baseline were analyzed to evaluate the presence of metabolic differences predictive of IFN ß response. The results of the investigation demonstrated differential distribution of baseline samples compared to those obtained during IFN ß exposure, particularly after 24 months of treatment (R(2)X = 0.812, R(2)Y = 0.797, Q(2) = 0.613, p = 0.003). In addition, differences in the baseline metabolome between responder and nonresponder patients with respect to lactate, acetone, 3-OH-butyrate, tryptophan, citrate, lysine, and glucose levels were found (R(2)X = 0.442, R(2)Y = 0.768, Q(2) = 0.532, p = 0.01). In conclusion, a metabolomic approach appears to be a promising, noninvasive tool that could potentially contribute to predicting the efficacy of MS therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00721-8) contains supplementary material, which is available to authorized users.

Subcutaneous (SC) interferons beta (IFN-beta) are effective therapies for the treatment of relapsing–remitting multiple sclerosis (RRMS). Factors such as dosing schedule, needle intolerance/fatigue, and side effects may impact patient satisfaction with treatment. Improvement of patient satisfaction may increase the adherence to treatment and the patient quality of life. This study was aimed at evaluating the impact of switching to “Peginterferon beta-1a (Peg-IFN beta-1a)” in patients with RRMS unsatisfied with other SC interferons. The multicenter, open-label, phase IV PLATINUM study was conducted in 32 Italian centers. The primary endpoint was changes from baseline in the score of a convenience satisfaction domain of the TSQM-9 questionnaire at 12 weeks. The secondary endpoints were patients' global satisfaction, short-term adherence to treatment, satisfaction with the injection system, effect on fatigue, disease activity, and patient inability score. A total of 193 patients were enrolled and 166 (86%) completed the study, receiving Peg-IFN beta-1a for 24 weeks. Patients switching to Peg-IFN beta-1a from other SC interferons reported a significant improvement (p < 0.001) of Convenience Score and all other scores of the TSQM-9 questionnaire at 12 and 24 weeks (p < 0.001). Peg IFN beta-1a attained very high adherence to the treatment (92 and 86% at 12 and 24 weeks, respectively) with a stable annualized relapse rate (ARR). At 24 weeks, 94% of the participants were relapse free. Adverse events (AEs), recorded on 82 patients (42%), were mild or moderate. The most common AE was flu-like syndrome (29.2%). Patients switching from SC IFN beta therapy to Peg IFN beta-1a showed high treatment satisfaction with a positive safety profile, comparable with that of other currently approved first-line injectable SC interferons. This study suggests that Peg IFN beta-1a might represent a treatment choice to improve adherence in RRMS patients unsatisfied with other SC interferons.

Background: Multiple sclerosis (MS) is a chronic immunemediated disease of the central nervous system with a highly variable clinical presentation and disease progression. In this study, we investigate the metabolomics profile of patients affected by relapsing&ndash, remitting MS (RRMS)and primary progressive MS (PPMS), in order to find potential biomarkers to distinguish between the two forms. Methods: Cerebrospinal Fluid CSF and blood samples of 34 patients (RRMS n = 22, PPMS n = 12) were collected. Nuclear magnetic resonance (1H-NMR) and mass spectrometry (coupled with a gas chromatography and liquid chromatography) were used as analytical techniques. Subsequently, a multivariate statistical analysis was performed, the resulting significant variables underwent U-Mann&ndash, Whitney test and correction for multiple comparisons. Receiver Operating Characteristic ROC curves were built and the pathways analysis was conducted. Results: The analysis of the serum and the CSF of the two classes, allowed the identification of several altered metabolites (lipids, biogenic amines, and amino acids). The pathways analysis indicated the following pathways were affected: Glutathione metabolism, nitrogen metabolism, glutamine&ndash, glutamate metabolism, arginine&ndash, ornithine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis etc. Conclusion: The analysis allowed the identification of a set of metabolites able to classify RRMS and PPMS patients, each of whom express different patterns of metabolites in the two biofluids.

Background: Gait analysis is a reliable tool to characterise ambulation in Charcot-Marie-Tooth, the obtained are complex data makes its use scarce in clinical practice. The use of synthetic measure...

Agnese Gugliandolo,1 Federica Longo,1 Maria Giovanna Marrosu,2 Giovanni Luigi Mancardi,3,4 Ilaria Gandoglia,3 Maurizio Melis,5 Fabrizio Lo Giudice,1 Placido Bramanti,1 Emanuela Mazzon1 1Department of Experimental Neurology, IRCCS Centro Neurolesi “Bonino Pulejo”, Messina, Italy; 2Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; 3Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; 4IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy; 5SC Neurologia e Stroke Unit, Azienda Ospedaliera G Brotzu, Cagliari, Italy Purpose: We performed a pharmacovigilance study of 10 drugs used in patients with relapsing-remitting multiple sclerosis (RR-MS). Our aim was to provide an overview of the safety of these drugs by the evaluation of reported expected and unexpected adverse reactions. Patients and methods: We collected and analyzed adverse drug reactions from RR-MS patients belonging to four hospitals in three Italian regions, for a period of 24months. Results: We received a total of 411 adverse reactions, of which 84.18% were expected and only 15.82% were unexpected. We found no correlation between the number of reported adverse reactions and the route of administration (injectable/intravenous drugs N=224, oral drugs N=187). However, oral agents have caused a greater number of unexpected moderate-to-severe adverse reactions while, in injectable and infusion therapies, they have been evaluated as mild–moderate adverse reactions. Conclusion: Our results underscore the importance of monitoring the safety profile of multiple sclerosis therapies, with particular attention to oral agents that have been introduced later in the clinical practice. Keywords: pharmacovigilance, relapsing-remitting multiple sclerosis, adverse drug reaction, disease-modifying therapy, safety

BACKGROUND Frequently diagnosed in young adulthood, multiple sclerosis (MS) and several MS-related factors can influence patients' unemployment status and negatively affect work productivity and daily functioning. OBJECTIVE We examined MS patients' employment status and evaluated clinical features influencing it. Furthermore, we investigated patients' burdens due to visible and invisible MS symptoms through their worsening daily functioning. METHODS The study included outpatients affected by MS according to the 2010 McDonald criteria. The co-occurrence of invisible symptoms (fatigue, depression and apathy) was stated using validated, self-administered tools: Fatigue Severity Scale (FSS); Beck Depression Inventory-Second Edition (BDI-II); Apathy Evaluation Scale (AES). Impairment in daily functioning due to MS was assessed using the Work and Social Adjustment Scale (WSAS). Descriptive statistics, hierarchical regression analyses, Pearson's correlation, and the t-test were conducted. RESULTS Of the 123 participants, 52 (42.3%) were unemployed. Results showed employment to be positively associated with higher education levels (p 0.01); female gender (p 0.03) and higher disability (p 0.02) showed negative associations with employment. No associations were found between employment and fatigue or clinically relevant depressive and apathetic symptoms. High correlations were found between WSAS score and Expanded Disability Status Scale score (r = 565, p

Background The dual task paradigm (the simultaneous performance of motor and cognitive task) is used in a laboratory setting to evaluate walking impairments that affect patients’ daily lives. Although promising, it is poorly standardized and neither the cognitive task nor the motor task have been validated in a matched healthy control group (HC) for multiple sclerosis (MS). Objective Our aim was to set up a standardized instrument to evaluate cognitive motor interference in MS using the interference test par excellence: the stroop colour word test (SCWT). Methods Patients with MS and HC underwent 3D gait analysis with a dual task protocol, using the SCWT as a cognitive task. Gait performance impairment during the dual task was evaluated by dual task cost (DTC). A MANOVA was used to verify the effect of status (MS, HC) on DTC, calculated for the spatiotemporal parameter of the gait. Results In MS, the DTC was higher for the following gait parameters: speed (p = .013), cadence (p = .004), stride time (p = .005) stance phase (p Conclusion DTC is present in MS and HC, but the motor cost in MS is higher. The present work provides a useful and validated basis for future studies about cognitive motor interference in MS.

Autologous hematopoietic stem cell transplantation (aHSCT) is used in aggressive relapsing and progressive multiple sclerosis (MS). The multicentre studies and case series reported have relatively short follow-up. To evaluate long-term effect and safety of HSCT in MS. Patients referred to the MS centre of Cagliari and undergoing HSCT were included. Variations in relapses and EDSS before and after HSCT were evaluated by Wilcoxon test. A descriptive analysis was made for other clinical data. Nine patients (female 6, males 3; 5 relapsing–remitting, 2 secondary progressive, 1 primary progressive, and 1 progressive relapsing) performed HSCT (1999–2006). The median follow-up was 11 years (11–18). Eight patients underwent aHSCT, seven using a low intensity conditioning regimen, and one an intermediate intensity. The primary progressive underwent allogeneic HSCT, due to onco hematological disease. The relapses number decreased in the 2 years following the procedure compared to the two preceding years (p = 0.041). New relapses or disease progressions were observed after a range of 7 (low intensity regimen)–118 (intermediate intensity) months. At last follow-up, the EDSS was stable in two patients, improved in two, and worse in five (maximum 2 EDSS in one patient). Six patients showed new lesions, and seven gadolinium-enhancing on brain MRI after a mean of 23.3 and 19.8 months, respectively. Two serious adverse events were reported: melanoma, and progressive multifocal leukoencephalopathy. Our results confirm in a long follow-up the efficacy of HSCT in reducing relapses and disability progression. The risk/benefit profile is better for intermediate intensity regimens.

Background The relationship between cognitive assessment results in multiple sclerosis (MS) and performance in daily activities (DAs) remains unclear. Our study aimed to evaluate the relationship between cognitive functions (CF) measured by tests, performance in DAs, and the perception of CF in patients and their caregivers (CG) in MS. Methods The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery was used to evaluate cognitive status. We created an ad hoc questionnaire (DaQ) to assess performance in DAs not requiring specific motor skills. We used the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) to measure each patient self-judgment and caregiver’s perception of CF. Results Forty-nine patients and their caregivers were included in the study. Significant correlations were found between the BICAMS and the DaQ (Symbol Digit Modalities Test (SDMT): r = − 0.48, p

Introduction: Multiple sclerosis (MS) treatment has changed considerably in recent years thanks to the introduction of ever-more-powerful drugs. Unfortunately, the higher efficacies of these therapies are associated with increased risks of severe adverse events. In this scenario, neurologists and persons with MS (pwMSs) must now balance benefits and risks when making decisions regarding MS management.Areas covered: This review highlights the importance of the risk perception of pwMSs and their neurologists in the shared decision-making process in MS management, taking into account different ways improve the empowerment and engagement of pwMSs.Expert commentary: The shared decision-making process in MS is strongly influenced by an individual’s risk perception, which is dynamic and influenced by the personal, emotional, social, and experiential factors of both the pwMSs and neurologists.

Objective: To evaluate the risk of relapses during pregnancy and in the first 3 months after delivery in 2 successive pregnancies in a cohort of French and Italian women with multiple sclerosis (MS). Methods: A total of 93 women were included if they had had 2 pregnancies followed prospectively after MS onset between January 1993 and 2013. The association of a relapse during pregnancy or the first postpartum trimester in pregnancy 1 and pregnancy 2 was evaluated by univariate logistic regression. Results: A majority of women did not experience any exacerbation in the 3 months after delivery (31.2% and 23.7%, respectively, relapsed after pregnancy 1 and 2; p = 0.32). A total of 7.6% had a relapse after both pregnancies. The risk of relapse after pregnancy 2 was not associated with the number of relapses in the prepregnancy year (odds ratio [OR] 1.52 [0.57–4.05]) or during pregnancy (OR 1.57 [0.52–4.79]) or with the occurrence of a relapse after pregnancy 1 (OR 0.86 [0.29–2.50]). Conclusions: Our work provides original data on the evolution of successive pregnancies in MS, showing a similar (and even lower) disease activity in the second pregnancy. There was no correlation of activity in successive pregnancies. Therefore, counseling of women with MS who consider having a second baby should be the same as for the first one.

Some studies have indicated the importance of considering smoking, vitamin D deficiency and obesity as negative prognostic factors for clinical and MRI outcomes in multiple sclerosis (MS). This study aimed to evaluate the possible effects of these modifiable risk factors on brain MRI lesion burden of patients with early MS, also exploring the influence on initial clinical features.MS patients were enrolled at diagnosis time and examined for smoking, body mass index (BMI), serum level of lipids and 25(OH) vitamin D. Brain MRIs' were acquired and lesion volume assessed by Jim software. Clinical data (disease course, disease duration, and EDSS score) were also collected.64 patients were enrolled, of these 4 (6.2%) had a primary progressive course. Mean age was 39.8 ± 11.1 years and mean EDSS 1.5 ± 1.1. Forty (62.5%) patients were smokers and 40 (62.5%) were overweight (BMI25). Insufficient levels of vitamin D (20 ng/mL) were reported in 36 (56.2%) patients, while 24 (37.5%) patients had an altered lipid profile with total cholesterol200 mg/dl and LDL100 mg/dl. No association between early clinical features and modifiable risk factors were reported. Multiple regression analysis showed an association between lesion burden and smoking status (p 0.003), while no association was reported with BMI, altered lipid profile and vitamin D insufficiency.Several risk factors may play a role in evolution of MS. Our results show that smoking status, probably due to chronic vascular and neurotoxic effects of the cigarette components, can affect the brain damage from the early stages of MS. No association was observed with the other explored modifiable risk factors, although an effect due to the small sample size cannot be excluded.

Cognitive impairment concerns a significant percentage of patients with multiple sclerosis (MS). A transient impairment of cognition with a simultaneous presence of non-symptomatic gadolinium (Gd)-enhancing lesions in patients with MS was previously described. Our study aimed to evaluate modifications in cognitive function before and after the occurrence of asymptomatic MRI gadolinium (Gd)-enhancing lesions in relapsing MS patients.All patients underwent a neuropsychological evaluation before (30-60 days) and after (30-60 days) brain MRI with Gd administration. Patients were classified as Gd positive (presence of enhancing-lesions) and Gd negative (absence of enhancing-lesions). We also recruited a healthy controls group underwent to the same neuropsychological assessment for two times with the same timing of MS patients.We included 84 relapsing-remitting patients and 40 healthy controls. Brain MRI results showed that 14/84 (16.7%) patients had asymptomatic Gd-enhancing-lesion. No significant variation in cognitive performance between baseline and follow-up was observed in patients with or without MRI-enhancing lesions. However, an increase between baseline and follow-up was observed in the mean scores of the Symbol Digit Modality Test (41.9 at baseline versus 46.7 at follow-up, p : 0.001). This increase was significantly lower in Gd positive patients compared to Gd negative patients (mean increase 1.1 in Gd positive versus 4.9 in Gd negative, p: 0.001) and to healthy controls groups (mean increase 7.2; p 0.001) CONCLUSIONS: In our study, the absence of a practice effect in Gd positive compared to Gd negative patients and to healthy controls suggests a possible role of focal inflammation on cognitive function of MS patients.

Background The principal biomarker of neurodegeneration in multiple sclerosis (MS) is believed to be brain volume, which is associated with cognitive functions and retinal nerve fibre layer (RNFL). A cross-sectional and longitudinal assessment of the relationship between RNFL, cognitive functions and brain volume. Methods At baseline, relapsing patients and healthy controls underwent 1.5 T MRI to estimate the normalized volume of brain (NBV), grey (NGV), white (NWV) and peripheral grey (pNGV) matter. Cognitive functions were evaluated by BICAMS, RNFL by Spectral-Domain OCT. Patients were re-evaluated after 12 months. Results Cognitive functions, brain volume, and RNFL differed between the group of 66 patients and that of 16 healthy controls. In the MS group, at baseline, an association was found between: p-NGV and symbol-digit (SDMT) (p = 0.022); temporal-RNFL and NBV (p = 0.007), NWV (p = 0.012), NGV (p = 0.048), and p-NGV (p = 0.021); papillo-macular bundle-RNFL and NBV (p = 0.013), NWV (p = 0.02), NGV (p = 0.049), and p-NGV (p = 0.032). Over the observational period, we found a reduction of brain volume (p

Several studies indicated that multiple sclerosis (MS) is frequently associated with other autoimmune diseases. However, it is little known if the coexistence of these conditions may influence the radiologic features of MS, and in particular the brain volumes. To evaluate the effect of autoimmune comorbidities on brain atrophy in a large case–control MS population. A group of MS patients affected by a second autoimmune disorder, and a control MS group without any comorbidity, were recruited. Patients underwent a brain MRI and volumes of whole brain (WB), white matter (WM), and gray matter (GM) with cortical GM were estimated by SIENAX. The sample included 286 MS patients, of which 30 (10.5%) subjects with type 1 diabetes (T1D), 53 (18.5%) with autoimmune thyroiditis (AT) and 4 (0.1%) with celiac disease. Multiple regression analysis found an association between T1D and lower GM (p = 0.038) and cortical GM (p = 0.036) volumes, independent from MS clinical features and related to T1D duration (p

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Oligoclonal IgM (OCMB) and IgG (OCGB) bands were found to be associated with poor multiple sclerosis (MS) prognosis. We aimed to evaluate the prognostic value of OCMB/OCGB in a cohort of Sardinian MS patients. We recruited patients from the University of Cagliari. They underwent lumbar puncture for diagnostic purposes. Demographic and the following clinical data were recorded: clinical course; time to reach EDSS 3 and 6; EDSS at last follow-up; and MS treatments. The influence of gender, clinical course, age at onset, treatments, and OCGB/OCMB on reaching EDSS 3 was analysed using Cox regression. Kaplan–Meier curves were used to study the time to reach EDSS 3 considering OCMB/OCGB and therapies. The enrolled number of subjects was 503. The variables influencing the achievement of EDSS 3.0 were: male gender (p = 0.005); progressive course (p = 0.001); age at onset (p

ObjectiveTo assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA).MethodsData of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed.ResultsA total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9–8.5, p < 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) was associated with lower length and weight of the babies (p < 0.001).ConclusionOur results showed that natalizumab exposure to up 12 weeks of gestation is associated with an increased risk of SA, although within the limits expected in the general population, whereas the risk of CA needs further investigation. Taking into account the high risk of disease reactivation after natalizumab suspension, pregnancy could be planned continuing natalizumab while strictly monitoring conception.Classification of evidenceThis study provides Class III evidence that in women with MS, natalizumab exposure increases the risk of spontaneous abortion as compared to IFN-β-exposed or untreated patients (OR 3.9, 95% CI 1.9–8.5).

Background Several reports suggest a higher risk of psychiatric disorders after high-dose corticosteroids (HDC), routinely used to treat clinical relapses in multiple sclerosis (MS). The present study aimed to examine the possible effect of HDC on mood in patients with MS and to determine the specific factors that influence mood changes. Methods The study included MS patients prior to receive HDC. The presence of depressive and bipolar symptoms was determined with the Beck Depression Inventory-Second Edition (BDI-II) and the Mood Disorder Questionnaire (MDQ). These assessments were made at three time points: prior to HDC initiation, after HDC completion, and 1 month after HDC. Results The study included 101 MS patients. At baseline, 32 (31.7%) patients had depressive symptoms (BDI-II scores ≥ 14) and 20 (19.8%) patients had bipolar symptoms (MDQ scores ≥ 7). While it was observed a reduction of BDI-II scores after HDC, an increase in MDQ score was found in patients with MDQ positivity at baseline, resulting associated with a higher number of HDC infusions (p 0.018). Conclusions Our results emphasize the importance of accurate screening for mood disorders in patients with MS prior to HDC initiation, and indicate that HDC should be used with caution in patients with MDQ positivity.

Introduction Cognitive motor interference (CMI) is performance impairment due to simultaneuous task execution and is measured using the dual task cost (DTC). No pathological feature of MS has to date been associated with CMI. Aim To assess the relationship between brain volumes and CMI, as measured using the DTC, in a cross-sectional study. Methods A group of persons with MS (pwMS) and an age- and sex-matched healthy control (HC) group underwent 3D gait analysis during using the dual task paradigm. Brain volumes were measured on T1-weighted gradient echo scans using SIENAX software. The relationships between brain volumes and the DTCs of spatial temporal parameters were evaluated using Pearson correlation. A multiple regression model was used to evaluate the ability to predict the DTC of cadence based on brain volume and grey matter (GM) volume. Results Forty-four patients and 16 HCs underwent MRI and gait analysis. The mean expanded disability status scale (EDSS) was 2.4 ± 1.5. Significant relationships between brain volumes and DTC were found only in the pwMS group, with higher rho scores for the DTC of mean velocity, DTC of cadence, and DTC of stride time. A statistically significant regression equation with an R 2 value of 0.684 was found using GM and Z-score on the Stroop test as predictors of the DTC of cadence ( p Conclusion Brain atrophy, especially than in the GM, is a major determinant of DTC, although other pathological markers also contribute to CMI in patients with MS.

Background: The strongest genetic determinant for multiple sclerosis (MS) is located at the human leukocyte antigen (HLA) class II DRB1 and DQB1 loci. Objectives: To investigate the possible role of predisposing HLA genotypes in determining brain atrophy. Methods: HLA genotypes were categorized as high risk (two predisposing haplotypes) or medium/low risk (one or no predisposing haplotypes). Patients underwent a brain magnetic resonance imaging (MRI) study and volumes of white matter (WM), gray matter (GM), and whole brain (WB) were estimated with SIENAX. Longitudinal atrophy was also assessed with SIENA. Results: The study included 240 MS patients. In 51/240 (21%) subjects, a high-risk HLA genotype was observed, while medium- and low-risk HLA genotypes were 109/240 (45%) and 80/240 (34%), respectively. Multiple regression analysis found that the high-risk HLA genotype was associated with significant reduction in WB ( p = 0.02) and GM ( p = 0.03) volumes compared with the medium-/low-risk HLA genotypes, independently from MS clinical features. The longitudinal study included 60 patients and showed a brain volume loss of −0.79% in high-risk HLA genotype group versus −0.56% in low-risk HLA genotype. Conclusion: Our results suggest an influence of HLA genotype on WB and GM atrophy. Further investigations are necessary to confirm these findings.

Multiple sclerosis (MS) is a complex autoimmune disease originated from the interplay between genetic and environmental factors. An overlap of clinical and neuroradiological parameters has been described between MS and an adult-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). This syndrome is caused by a trinucleotide premutation expansion of a CGG sequence in the 55–200 repeat range, which is located in the fragile-X mental retardation 1 (FMR1) gene. Female premutation carriers have an increased propensity for immune-mediated disorders. Recently, a case of co-occurrence of MS and FXTAS was reported. Assuming that the premutation expansion may play a role in the MS susceptibility, we evaluated its frequency in a cohort of MS patients from Sardinia, an island characterized by a very high frequency of MS. Nuclear DNA was extracted by standard methods, purified with bisulfite treatment and then amplified twice by PCR with specific primers. Microsatellite analysis was performed and emizogotic subjects were sequenced. Clinical data of patients were also collected. Only 1/755 MS patients exhibited the premutation expansion with a heterozygosis pattern (30/58). No pathogenic repeat expansions (>200 repeats) were found in the entire cohort. Repeats labeled as the gray zone (45–60 repeats) were observed in 15/755 patients. No specific clinical features concerning disease course, disease activity, and disability were reported for these patients. Our results do not support a possible role for premutation or gray zone alleles in MS Sardinian patients. Further studies are needed to better understand the relationship between FXTAS and MS.

Multiple sclerosis (MS) is a long-lasting neurological disease with onset in young adult age. Patients with MS are less active than healthy people, and their sedentary lifestyle might lead to secondary diseases or worsening of symptoms, disability and quality of life. In the study, we evaluated the attitude of physical activity (PA) of a group of MS patients and the differences in practice PA before and after the diagnosis. A randomly recruited group of patients with MS fulfilled a questionnaire about their attitudes towards PA before the onset and after the diagnosis of the disease. Clinical and demographic data were recorded. Out of 118 patients, 37 % practiced PA only before the diagnosis, 9 % only after and 52 % during both periods. After the diagnosis, 64 % of participants noted some negative differences in PA, in particular less physical resistance and worsening of symptoms, and 38 % stopped PA. However, patients referred benefits from PA after diagnosis. Individual exercises rather than group activities were preferred after diagnosis. Only 26 % of patients knew that adapted PA existed and the differences between adapted PA and classic physiotherapy. We observed a reduction in the practice of PA in patients after the diagnosis of MS, in particular for disease-related reasons. Nevertheless, active patients referred benefits from PA. It is important to know the point of view of patients towards developing individualized training programs. In this way, it could be possible to achieve more benefits from PA and reduce the negative effects.

Alemtuzumab (Lemtrada®) is a humanized anti-CD52 IgG1 monoclonal antibody that depletes CD52-expressing cells from the circulation. Robust clinical and radiologic data, derived from clinical trials and long-term observational studies, indicate that alemtuzumab induces a marked immunosuppression related to the depletion of circulating T and B lymphocytes. However, recent advances suggest that the long-term clinical effects of alemtuzumab are probably due to unique qualitative changes in the process of lymphocyte repopulation of the immune system. This leads to a particular rebalancing of the immune system. In this paper we review the immunomodulatory mechanisms underlying the therapeutic effect of alemtuzumab in pre-clinical models and in patients with relapsing remitting multiple sclerosis (RRMS), and stress the importance of a monoclonal antibody-based immunosuppression for treating the severe forms of RRMS. Alemtuzumab has many features of the ideal immunomodulatory drug: rapid biological and clinical actions and and long-lasting benefit. Alemtuzumab can be used as rescue therapy or as first line drug in severe-onset MS. Thus, the availability of alemtuzumab constitutes a significant step forward in the therapy of MS.

Background In people with Multiple Sclerosis (pwMS), balance assessment is essential in estimating the risk of falls, monitoring disease progression and verifying the effectiveness of rehabilitative treatment. Clinical tools and instrumental techniques are available for testing static and dynamic balance, but the relationship between such abilities is still not clear. Having information about this link would be important in properly planning the type and number of tests to administer. Methods One hundred and six pwMS (Expanded Disability Status Scale, EDSS 0−6.5) stratified in three sub-groups (Class 1 EDSS 0–1.5, Class 2 EDSS 2–4 and Class 3 EDSS 4.5–6.5) and 42 healthy controls (HC) participated in the study. All underwent static posturography and instrumented Timed-Up-and-Go (TUG) performed using a wearable inertial sensor. Raw data were processed to extract postural sway features, overall duration of TUG and its main sub-phases (i.e. sit-to-stand, 180° turns and stand-to-sit). Results All sway parameters of pwMS of Classes 2 and 3, as well as total TUG duration and time necessary to perform 180° turns, were found significantly higher than HC and Class 1 participants. However, poor correlations were found between sway and TUG parameters. When pwMS are grouped, small/moderate correlations (in the range 0.20–0.41) were found between all sway parameters and total TUG duration. Conclusions Static and dynamic balance in pwMS appear scarcely correlated, although both worsen as disability increases. This implies that they should be separately assessed using specific tests to have a complete view of postural control performance in MS.

Charcot–Marie–Tooth disease (CMT) is characterised by great variability of genetic subtypes. This study aimed to assess the genetic subtypes of CMT disease in the Sardinian population. Genetic screening was performed for CMT cases (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]). A total of 1,043 subjects (119 index cases) were evaluated. In CMT1 index cases (69/119; 58%), PMP22 duplication at 17p11.2 was the most frequent genetic diagnosis (60/69; 87%), followed by mutations in the GJB1 gene (5/69; 7.2%), in the SH3TC2 gene (3/69; 4.4%) and PMP22 Gly107Val point mutation (1/69; 1.4%). The CMT2 group (24/119; 20.1%) comprised 10/24 (41.6%) patients carrying MPZ gene Ser44Phe mutation, 6/24 (25%) with mutations in MFN2 and HSPB1, and 1/24 (4.2%) in GJB1 and LRSAM1. In the HNPP group (26/119; 21.9%), the majority of patients reported the PMP22 deletion (25/26; 96.2%). Further studies are needed to comprehend the overall picture of the disease in Mediterranean area.

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system (CNS), most probably autoimmune in origin, usually occurring in young adults with a female/male prevalence of approximately 3:1. Women with MS in the reproductive age may face challenging issues in reconciling the desire for parenthood with their condition, owing to the possible influence both on the ongoing or planned treatment with the possible consequences on the disease course and on the potential negative effects of treatments on foetal and pregnancy outcomes. At MS diagnosis, timely counselling should promote informed parenthood, while disease evolution should be assessed before making therapeutic decisions. Current guidelines advise the discontinuation of any treatment during pregnancy, with possible exceptions for some treatments in patients with very active disease. Relapses decline during pregnancy but are more frequent during puerperium, when MS therapy should be promptly resumed in most of the cases. First-line immunomodulatory agents, such as interferon-β (IFN-β) and glatiramer acetate (GA), significantly reduce the post-partum risk of relapse. Due to substantial evidence of safety with the use of GA during pregnancy, a recent change in European marketing authorization removed the pregnancy contraindication for GA. This paper reports a consensus of Italian experts involved in MS management, including neurologists, gynaecologists and psychologists. This consensus, based on a review of the available scientific evidence, promoted an interdisciplinary approach to the management of pregnancy in MS women.

Mitoxantrone is an immunosuppressive drug approved for aggressive relapsing and progressive multiple sclerosis. In recent years, its use has decreased due to the risk of severe adverse events and the introduction of novel therapies, such as natalizumab or fingolimod. Mitoxantrone is effective in reducing inflammatory activity by decreasing the number of relapses and MRI lesions and simultaneously decreasing the worsening of disability. Apart from its role as a second/third-line therapy, some studies suggest its use as an induction therapy. However, mitoxantrone use is limited because of its potential risk of severe adverse events, such as cardiotoxicity and the induction of therapy-related acute leukemia. Genetic markers are on evaluation to predict side effects and therapeutic efficacy, which is consistent with the direction of personalized treatment. Considering its efficacy and the potential risks, mitoxantrone use is limited to active patients after a careful, individualized evaluation of the risk/benefit balance.

Patients with multiple sclerosis (MS) have an increased systemic vascular resistance (SVR) response during the metaboreflex. It has been hypothesized that this is the consequence of a sedentary lifestyle secondary to MS. The purpose of this study was to discover whether a 6-month training program could reverse this hemodynamic dysregulation. Patients were randomly assigned to one of the following two groups: the intervention group (MSIT, n = 11), who followed an adapted training program; and the control group (MSCTL, n = 10), who continued with their sedentary lifestyle. Cardiovascular response during the metaboreflex was evaluated using the post-exercise muscle ischemia (PEMI) method and during a control exercise recovery (CER) test. The difference in hemodynamic variables such as stroke volume (SV), cardiac output (CO), and SVR between the PEMI and the CER tests was calculated to assess the metaboreflex response. Moreover, physical capacity was measured during a cardiopulmonary test till exhaustion. All tests were repeated after 3 and 6 months (T3 and T6, respectively) from the beginning of the study. The main result was that the MSIT group substantially improved parameters related to physical capacity (+5.31 ± 5.12 ml·min−1/kg in maximal oxygen uptake at T6) in comparison with the MSCTL group (−0.97 ± 4.89 ml·min−1/kg at T6; group effect: p = 0.0004). However, none of the hemodynamic variables changed in response to the metaboreflex activation. It was concluded that a 6-month period of adapted physical training was unable to reverse the hemodynamic dys-regulation in response to metaboreflex activation in these patients.

Alterations of the lamin A/C (LMNA) gene are associated with different clinical entities, including disorders that affect skeletal and cardiac muscle, peripheral nerves, metabolism, bones, and disorders that cause premature aging. In this article we review the clinical and genetic characteristics of cardiac and skeletal muscle diseases related to alterations in the LMNA gene. There is no single explanation of how LMNA gene alterations may cause these disorders; however, important goals have been achieved in understanding the pathogenic effects of LMNA gene mutations on cardiac and skeletal muscle.

Background Hemiplegic migraine is a rare form of migraine with aura characterized by motor aura. Although auras in hemiplegic migraine are typically complex with two or more aura symptoms, neglect has been rarely described. Case report We report the case of a 20-year-old woman with sporadic hemiplegic migraine that was investigated for the presence of unilateral spatial neglect (USN) during aura in one of her migraine attacks. Transient hemispatial neglect was observed during a right-sided migraine attack with left sensory-motor hemisyndrome; after migraine resolution there was a total recovery. Conclusions Our case demonstrates that USN may be a symptom of aura. To our knowledge, this is the first report of USN during aura in an adult with sporadic hemiplegic migraine.

The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.Genzyme (Sanofi) and Bayer Schering Pharma.

Background This study aims to verify the feasibility of use of wearable accelerometers in an ambulatory environment to assess spatiotemporal parameters of gait in people with Multiple Sclerosis (pwMS), as well as the correlation of objective data with patient-reported outcomes. Methods One hundred and five pwMS (Expanded Disability Status Scale, EDSS in the range 0–6.5) classified in three sub-groups (EDSS 0–1.5, EDSS 2–4, EDSS 4.5–6.5) and 47 healthy controls (HC) participated in the study. All the subjects were evaluated with the timed 25-foot walking test (T25FW) while wearing a commercially available accelerometer. PwMS also rated the impact of the disease on their walking abilities using the 12-item MS walking scale (MSWS-12). Results All parameters objectively measured, except stride length, were significantly modified in pwMS with higher EDSS, with respect to HC and lower disability participants. Moderate to high correlations (r =0.57–0.79) were observed between gait parameters and MSWS-12 for pwMS of higher EDSS. The correlation was found moderate for the intermediate EDSS category (r =0.42–0.62). Conclusion Wearable accelerometers are a useful tool for assessing gait performance for pwMS in a clinical setting, especially in cases of mild to moderate disability. Compared with other quantitative techniques, these devices allow patient testing under realistic conditions (i.e., fully dressed, with their usual shoes) using a simple procedure with immediate availability of data.

Elevated B lymphocyte activating factor BAFF levels have been reported in multiple sclerosis (MS) patients; moreover, disease-modifying treatments (DMT) have shown to influence blood BAFF levels in MS patients, although the significance of these changes is still controversial. In addition, BAFF levels were reported increased during infectious diseases. In our study, we wanted to investigate on the serum BAFF concentrations correlated to the antibody response against Mycobacterium avium subspecies paratuberculosis (MAP), Epstein-Barr virus (EBV) and their human homologous epitopes in MS and in patients affected with other neurological diseases (OND), divided in Inflammatory Neurological Diseases (IND), Non Inflammatory Neurological Diseases (NIND) and Undetermined Neurological Diseases (UND), in comparison to healthy controls (HCs). Our results confirmed a statistically significant high BAFF levels in MS and IND patients in comparison to HCs but not NIND and UND patients. Interestingly, BAFF levels were inversely proportional to antibodies level against EBV and MAP peptides and the BAFF levels significantly decreased in MS patients after methylprednisolone therapy. These results implicate that lower circulating BAFF concentrations were present in MS patients with humoral response against MAP and EBV. In conclusion MS patients with no IgGs against EBV and MAP may support the hypothesis that elevated blood BAFF levels could be associated with a more stable disease.

This study was aimed to describe changes of Disease-Modifying Treatments (DMT) in an Italian cohort of patients with multiple sclerosis (MS) and to identify predictors of therapeutic modifications. Patients with MS and treated with the first-line injectable DMT (interferons-IFNs or glatiramer) between 1/7/2009 and 31/10/2012 were selected from administrative databases of the MS Center of Cagliari (Sardinia, Italy). Socio-demographic, therapeutic, and clinical information was collected in the 6 months preceding the index date. All patients were followed for 36 months to evaluate therapeutic changes in terms of non-adherence, switch, temporary discontinuation, and permanent interruption. Predictors of changes were estimated by multivariable regression models. Data on 1698 patients were collected: glatiramer was prescribed in 27% of cases, IFNβ-1b in 22%, IFNβ-1a-im in 20%, IFNβ-1a-sc-44mcg in 19%, and IFNβ-1a-sc-22mcg in 12%. Non-adherence was observed in 25% of cases, therapeutic switch in 30%, discontinuation in 37%, and permanent interruption in 28%. The risk of non-adherence was higher for IFNβ-1b, compared with IFNβ-1a-im (adjOR = 1.73). Therapeutic switch occurred especially in patients recently diagnosed (each year from diagnosis causes a decrease of this risk adjHR = 0.97); the risk of discontinuation was higher with EDSS = 4–6 and 7–9 (adjHR = 1.52 and 4.42, respectively). The risk of permanent interruption increased with the augmentation of disability (adjHR = 1.67 and 5.43 for EDSS 4–6 and 7–9). This study mirrored a detailed framework of DMT prescription and identified factors related to changes in the MS therapy. These findings could support healthcare providers in the evaluation and maximization of benefits associated with a long-term DMT.

Background The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). Objective To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. Methods An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. Results Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values

Required Coefficient of Friction (RCOF) is one of the most critical gait parameters associated to the occurrence of slipping in individuals affected by neurological disorders characterized by balance impairments. This study aims to calculate RCOF in people with Multiple Sclerosis (MS) on the basis of three-dimensional Gait Analysis (GA) data.This study enrolls 22 people with MS (pwMS) who were characterized by an Expanded Disability Status Score in the range 1.5-6 and 10 healthy controls (HC). All participants underwent to three-dimensional GA from which we extracted kinematic and kinetic data (i.e. the Ground Reaction Forces, GRF, and joint moments and powers in the sagittal plane). RCOF was calculated as the ratio of the shear to normal GRF components during the stance phase of gait cycle, and normalized by the walking velocity. Thus, the following variables were extracted: first peak (named P1COF), valley (named V1COF), and second peak (named P2COF) in RCOF curve; also computating the maximum ankle dorsi-plantarflexion moment (MOMmax) and the maximum ankle joint power (PWRmax).Our data revealed that P2COF results are significantly lower in pwMS when compared to HC (p=0.043; Z=-2.025). In pwMS, the study found a moderate, positive correlation between V1COF and MOMmax (r=0.558; p0.001) and a moderate, positive correlation between EDSS score and MOMmax (rho=0.622; p=0.001). While, in HC group, the study detected a moderate positive correlation between P1COF and MOM max (r=0.636; p=0.008).Friction during mid stance and push off phases is critically important to determine whether the frictional capabilities of foot/floor interface are sufficient to prevent slips in pwMS. The impaired ankle moment in MS group causes increased P2COF in comparison to HC, increasing the risk of slipping in the critical phase of transmission of the developed forces to kinematic chain. Also, the correlation analysis among RCOF values and kinetic variables describe the interplay between V1COF and MOMmax: the higher V1COF is, the higher is MOMmax; and the different correlation the study found between COF and kinetic parameters in MS and HC group highlightes the different gait patterns of the two classes of subjects.

Mycobacterium avium subsp. paratuberculosis (MAP) and Epstein-Barr virus (EBV) epitopes elicit a consistent humoral response in serum of multiple sclerosis patients, but the cross reactivity against the homologous myelin basic protein (MBP) and human interferon regulatory factor 5 (IRF5) has not been searched within the Cerebral Spinal Fluid (CSF). We evaluated in sera and CSF of patients with MS and with other neurological diseases (OND) the humoral response against EBV/MAP peptides and the IRF5/MBP. Our data showed that EBV and MAP peptides are able to induce a specific humoral immune response in MS patients compared to OND controls both in serum and in CSF. An intrathecal specific synthesis of IgG against MBP and their EBV and MAP homologous as indicated by the antibody index was observed in MS patients. The humoral response against EBV, MAP, MBP and IRF5 was significantly higher in MS patients compared to OND both in serum and in CSF. The higher presence of antibodies against MBP and their MAP and EBV homologous in CSF during relapses suggests a possible role of the pathogens in enhancing inflammation.

Though recent progress in multiple sclerosis (MS) treatment is remarkable, numerous unmet needs remain to be addressed often inducing patients to look for complementary and alternative medicines (CAM), especially herbal remedies (HR). HR use, scarcely investigated in MS, may cause adverse reactions (AR) and interfere with conventional treatment. We performed a survey aimed at evaluating use and attitudes towards HR and factor associated to HR use. Other CAM use and attitudes have been investigated as well. Multiple-choice questionnaires were distributed to MS out patients attending 14 Italian referral Centers. Multivariable logistic regression was used to identify HR use determinants. Present/past HR use for either MS or other diseases was reported in 35.6 % of 2419 cases (95 % CI 36.0-40.0 %). CAM use was reported in 42.5 % of cases. Independent predictors of HR use were represented by higher education, geographic area, dissatisfaction with conventional treatment of diseases other than MS and benefit perception from CAM use. Both HR and CAM use were not always disclosed to the healthcare professional. In conclusion, HR and other CAM appear to be popular among MS patients. The involvement of the healthcare professionals appears to be scarce with potential risk of AR or interference with conventional treatments.

Background Notoriously the treatment of multiple sclerosis (MS) is based on the use of several different drugs, characterized by a diverse mechanism of action, efficacy and safety. Recently, progress has been made towards developing new oral immunotherapies, and dimethyl fumarate is the third oral agent approved for the treatment of relapsing-remitting forms. Case A 24-year-old patient, affected by relapsing remitting multiple sclerosis, started treatment in December 2014 with dimethyl fumarate. The common side effects (flushing and gastrointestinal events) of dimethyl fumarate occurred at the beginning of treatment, but resolved after 1 month. Six months later, the patient presented with serious recrudescence of the gastrointestinal event. In addition to this symptom, he had developed acute omphalitis–a very rare infection in adults. Conclusion The pathogenic role of dimethyl fumarate to induce this rare infection was probably related to changes in immunological surveillance as well as to the irritant effect of this agent on the gastrointestinal epithelium. Therefore, post-marketing studies in clinical practice are still needed to provide the necessary long-term safety data.

No abstract available (Neurology)

Objective: To investigate the metabolomic profiles of patients with multiple sclerosis (MS) and to define the metabolic pathways potentially related to MS pathogenesis. Methods: Plasma samples from 73 patients with MS (therapy-free for at least 90 days) and 88 healthy controls (HC) were analyzed by 1H-NMR spectroscopy. Data analysis was conducted with principal components analysis followed by a supervised analysis (orthogonal partial least squares discriminant analysis [OPLS-DA]). The metabolites were identified and quantified using Chenomx software, and the receiver operating characteristic (ROC) curves were calculated. Results: The model obtained with the OPLS-DA identified predictive metabolic differences between the patients with MS and HC (R2X = 0.615, R2Y = 0.619, Q2 = 0.476; p < 0.001). The differential metabolites included glucose, 5-OH-tryptophan, and tryptophan, which were lower in the MS group, and 3-OH-butyrate, acetoacetate, acetone, alanine, and choline, which were higher in the MS group. The suitability of the model was evaluated using an external set of samples. The values returned by the model were used to build the corresponding ROC curve (area under the curve of 0.98). Conclusion: NMR metabolomic analysis was able to discriminate different metabolic profiles in patients with MS compared with HC. With the exception of choline, the main metabolic changes could be connected to 2 different metabolic pathways: tryptophan metabolism and energy metabolism. Metabolomics appears to represent a promising noninvasive approach for the study of MS.

Introduction: In this study we describe the clinical and molecular characteristics of limb-girdle muscular dystrophy (LGMD) due to LAMA2 mutations. Methods: Five patients clinically diagnosed with LGMD and showing brain white matter hyperintensities on MRI were evaluated using laminin α2 genetic and protein testing. Results: The patients had slowly progressive, mild muscular dystrophy with various degrees of CNS involvement. Epilepsy was observed in 2, and subtle symptoms of CNS involvement (mild deficit in executive functions and low IQ scores) were noted in 3 patients. Novel LAMA2 mutations were identified in all patients. The amount of laminin α2 protein in the muscle biopsies ranged from trace to about 50% compared with controls. Conclusions: This study represents the largest series of LGMD laminin α2–deficient patients and expands the clinical phenotype associated with LAMA2 mutations. The findings suggest that brain MRI could be included in the diagnostic work-up of patients with undiagnosed LGMD. Muscle Nerve, 2011

Background Heat shock protein 27 (HSP27) mutations have been reported to cause both Charcot-Marie-Tooth disease (CMT) type 2F and distal hereditary motor neuropathy (dHMN) although never previously in a single family. Objective To analyse clinical and electrophysiological findings obtained in a single large Sardinian family bearing the HSP27 R127W mutation. Methods Twenty-one members of a five generation Sardinian family have been studied, including thirteen members affected by peroneal muscular atrophy and proved heterozygous for the known HSP27 R127W mutation. Twelve patients and eight unaffected relatives were subjected to clinical examination. A standardised electrophysiological study was performed in eleven patients and six unaffected relatives. Results Mean age at onset (±SD) was 31.2±7.2 years. Mean age at investigation was 45.2±12.9 years and mean disease duration at the time of investigation was 14±12.9 years. According to current criteria for CMT2 and dHMN, of the 10 patients who had undergone both clinical and neurophysiological examination, five were diagnosed as CMT2, two as dHMN and a further two patients were labelled as an intermediate type. Finally, due to the presence of spastic paraplegia, the index patient did not meet established criteria for the diagnosis of CMT or dHMN. Discussion Findings obtained in the present study, broadening the spectrum of clinical manifestations of disorders associated with HSP27 mutations, support the hypothesis of a continuum between CMT2 and dHMN forms and suggest a possible common spectrum between these entities and several forms of CMT plus pyramidal features (HMSN V), providing important implications for molecular genetic testing.

Neurofibromatosis 1 (NF1), also called von Recklinghausen disease or peripheral NF, is a common autosomal-dominant neurocutaneous disorder associated with mutations of the NF 1 gene. The pathogenesis is poorly understood and the disease is characterized by cafè-au-lait spots, neurofibromatous tumors of the skin, Lisch nodules of the iris and many pleiotropic manifestations. The gene responsible for the disorder has been isolated on chromosome 17q11.2. The association of multiple sclerosis with NF is rarely reported in literature. We describe a patient with NF1, who subsequently developed relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is thought to be triggered by environmental factors acting on a genetic predisposition. Sardinians share a homogeneous genetic background and boast one of the highest MS prevalence worldwide. We investigated Epstein–Barr virus (EBV) antibody prevalence in Sardinian population by ELISA. Our results show a higher serum prevalence of EBNA-1 IgG in MS patients compared to healthy controls. Moreover, analyzing a subset of patients treated for 6 months with IFN-β, we observed a decrease in their EBNA-1 specific IgG titers. These results confirm previous findings and strengthen the association between EBV and MS in Sardinia.