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Rituximab (RTX) efficacy in NMO is suggested by several case series. No consensus exists on optimal dosing strategies. At present the treatment schedules more frequently used are 375 mg/m2/week iv for 4 weeks (RTX-A) and 1000 mg iv twice, 2 weeks apart (RTX-B). Aim of this study is to confirm RTX efficacy and safety in the treatment of NMO and to evaluate whether a most favourable dosage regimen exists. Data on RTX-treated NMO patients were collected from 13 Italian Hospitals. 73 patients (64 F), were enlisted. RTX-A was administered in 42/73 patients, RTX-B in 31/73. Median follow-up was 27 months (range 7–106). Mean relapse rate in the previous year before RTX start was 2.2 ± 1.3 for RTX-A and 2.3 ± 1.2 for RTX-B. ARR in the first year of treatment was 0.8 ± 0.9 for RTX-A and 0.2 ± 0.4 for RTX-B, in the second year of treatment was 0.9 ± 1.5 for RTX-A and 0.4 ± 0.8 for RTX-B patients ( p  = 0.001 for the first year, ns (0.09) for the second year). RTX-B was more effective in delaying the occurrence of a relapse (HR 2.2 (95 % IC 1.08–4.53) p  = 0.02). Adverse events were described in 19/73 patients (mainly urinary tract and respiratory infections, and infusion reactions). Two deaths were reported in severely disabled patients. Though with the limitations of an observational study, our data support RTX efficacy in NMO and suggest that high dose pulses might be more effective than a more fractioned dose.

Two analyses, a cost-minimization and a budget impact, were conducted to estimate the economic and financial impact of subcutaneous (SC) vs intravenous (IV) natalizumab in terms of administration times and costs in the Italian setting from the perspective of multiple sclerosis (MS) center, patient, and society. Cost minimization analysis (CMA) adopted a Markov model with three different states, and it is based on the results of REFINE study and its post-hoc analysis, which evaluated and demonstrated the non-inferiority of natalizumab SC vs IV formulation. The economic inputs came mainly from EASIER study, that estimated the administration time, resource consumption, and costs of natalizumab SC vs IV. A lifetime horizon was considered. Budget impact analysis (BIA) was conducted with a cost calculator approach and compared a base scenario (without SC natalizumab) with an alternative scenario (with SC natalizumab). The inputs were shared with the CMA and a 3-year time horizon was considered. A progressive increase in the number of patients treated with natalizumab SC was estimated from the 1st to the 2nd to the 3rd year after reimbursement in Italy. CMA estimated that savings due to the use of SC instead of IV natalizumab would be €2,824, €1,137, and €9,170 per patient from the perspectives of MS center, patient, and society, respectively, thus depicting a weak dominance (lower costs and non-inferiority efficacy). BIA estimated that the savings were approximately 3.2 million euros from the perspective of MS centers and around 10.3 million euros from the perspective of society in the first 3 years following reimbursement. Administering natalizumab subcutaneously rather than intravenously to treatment-eligible patients would result in administration time and cost savings thus determining a favorable impact for the MS center, the patient and the society.

Background and objective: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor imaging, and clinical impairments. Methods: Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons. Results: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. Conclusions: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities.

Background: Multiple sclerosis (MS) frequently affects women of childbearing age. While short-term effects of pregnancy on MS course are well-known, whether pregnancy may influence long-term disability progression is debated. Methods: A two-centre retrospective study to investigate long-term effect of pregnancy on disability was performed in a population of MS women. Survival analyses and multivariate Cox proportional regression models (including early predictors of MS severity and exposure to disease-modifying treatments) were performed to compare time to reach well-established disability milestones in nulliparous women and in those with pregnancies after MS onset (‘parous’). Women with pregnancies before MS onset were excluded from analyses as they represent a heterogeneous group. Results: Data about 445 women (261 nulliparous, 184 ‘parous’) were analysed. A longer time to reach Expanded Disability Status Scale (EDSS) 4.0 and 6.0 was observed in parous women; Cox regression models revealed a lower risk for ‘parous’ than nulliparous women in reaching EDSS 4.0 and 6.0 (HR = 0.552, p = 0.008 and HR = 0.422, p = 0.012 respectively). Conclusion: Our findings suggest that pregnancy after MS onset is associated with a slower long-term disability progression. Whether this represents a biological/immunological effect, or reflects a higher propensity toward childbearing in women with milder disease, it remains uncertain deserving further investigations.

Objective : To determine whether additional physiotherapy increases botulinum toxin type A effects in reducing spasticity in patients with multiple sclerosis. Design : A single-blind, randomized, controlled pilot trial with a 12-week study period. Subjects : Thirty-eight patients with progressive multiple sclerosis affected by focal spasticity and who were observed at the Multiple Sclerosis Centre operating in the S. Andrea Hospital in Rome. Interventions : For intervention all patients received botulinum toxin type A; the treatment group also received additional physiotherapy to optimize management through passive or active exercise and stretching regimens. Main measures : To measure objective and subjective level of spasticity, patients were assessed at baseline, 2, 4 and 12 weeks post treatment by Modified Ashworth Scale and visual analogue scale. Results : When compared with the control group, we found a significant decrease of spasticity by Modified Ashworth Scale (P < 0.01 by t-test) in the treatment group at week 2 (2.73 versus 3.22), week 4 (2.64 versus 3.33) and week 12 (2.68 versus 3.33). The mean (%) difference in Modified Ashworth Scale score between baseline and the end of follow-up was —0.95 (26.1) in the treatment group and —0.28 (7.7) in the control group (P < 0.01). The combined treatment proved also to be more effective by visual analogue scale (P < 0.01) at week 4 (6.95 versus 5.50) and at week 12 (7.86 versus 6.56) but not at week 2 (5.18 versus 5.50; P = 0.41). Conclusions : Our data suggest that physiotherapy in combination with botulinum toxin type A injection can improve overall response to botulinum toxin.

Background. The role of prolactin (PRL) on tissue injury and repair mechanisms in multiplesclerosis (MS) remains unclear. The aim of this work was to investigate the relationship between PRL plasma levels and brain damage as measured by magnetic resonance imaging (MRI). Methods. We employed a chemiluminescence immunoassay for measuring plasma levels of PRL. We used a 1.5 T scanner to acquire images and Jim 4.0 and SIENAX software to analyse them. Results. We included 106 women with relapsing remitting (RR) MS and stable disease in the lasttwo months. There was no difference in PRL plasma levels between patients with and without gadolinium enhancement on MRI. PRL plasma levels correlated with white matter volume (WMV) (rho = 0.284, p=0.014) but not with grey matter volume (GMV). Moreover, PRL levels predicted changes in WMV (Beta: 984, p=0.034). Conclusions. Our data of a positive association between PRL serum levels and WMV support the role of PRL in promoting myelin repair as documented in animal models of demyelination. The lack of an increase of PRL in the presence of gadolinium enhancement, contrasts with the view considering this hormone as an immune-stimulating and detrimental factor in the inflammatory process associated with MS.

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient’s empowerment in the decision-making process.AimsThe aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice.ResultsThe new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.

The aim of this study was to identify clinical, magnetic resonance imaging (MRI) and biological markers predictive of long-term clinical response to interferon beta (IFN beta) therapy in patients with relapsing-remitting multiple sclerosis (RRMS). Sixty-eight patients treated with IFN beta were followed over a 6-year period. Relapse rate and disability progression were evaluated throughout the study. We considered suboptimal clinical response to be either the presence of sustained disability progression, or more than two relapses. Baseline and 12-month demographic, clinical and MRI findings, as well as the development of neutralizing antibodies (NAbs) against IFN beta during the first year of therapy were analyzed as predictors of long-term clinical outcome. \"Black holes\" on MRI were the best baseline predictor of disability progression (odds ratio [OR] 6.8; p < 0.001). At 1 year, both male gender (OR 4.9; p = 0.009) and NAbs (OR 7.3; p = 0.003) were independently associated with a high risk of developing subsequent disability. The presence of gadolinium enhancement, both at baseline (OR 4.7; p = 0.005) and on the 1-year MRI scan (OR 7.9; p = 0.002), was the unique variable associated with the number of relapses over the study period. Variables assessable within the first year of treatment significantly influence relapse rate and disability progression in patients with RRMS treated with IFN beta. These findings may help clinicians to make decisions regarding therapy regimen over time, and highlight the need for a prognostic algorithm.

Objective. Gait impairment is commonly in people with multiple sclerosis (MS). The 12-item MS walking scale (MSWS-12) assesses patients’ measurement of walking quality. The aim of this study was to cross-culturally adapt and validate the MSWS-12 for the Italian population with MS. Methods. Six MS out-patient clinics across Italy enrolled subjects between June 2013 and December 2013. Construct validity of MSWS-12 was determined by examining correlations with the Italian version of the EDSS, the timed 25-foot walk (T25FW), and the Fatigue Severity Scale (FSS). Results. 321 MS subjects were enrolled. Mean age was 47.55 years and mean disease duration was 13.8 years. Mean EDSS score was 4.46. 185 subjects had a relapsing-remitting course, 92 were secondary progressive, 43 were primary progressive, and 1 had a clinically isolated syndrome. The mean total score of the MSWS-12 was 49.6 (SD: 31) with values ranging between 0 and 100. Correlations between the MSWS-12 with age, disease duration, and disease course were found but not with gender. Values of the MSWS-12/IT were significantly related to EDSS (0.71), to the T25FW (0.65), and to the FSS (0.51). Conclusion. MSWS-12/IT has been adapted and validated, it is a reliable and reproducible scale for Italian patients with MS.

We reported a post-marketing experience of 190 patients affected by relapsing multiple sclerosis on treatment with natalizumab. Clinical findings during pre-treatment period and throughout the study were documented. Magnetic resonance imaging (MRI) scans were performed at baseline and at 6, 12, and 24 months of therapy. Cumulative proportions of patients disease activity free (i.e. absence of relapses, disability progression, MRI activity) were measured as efficacy endpoints. Despite that the baseline characteristics suggested a more severe course of disease in our sample than that of the AFFIRM trial, data on effectiveness of natalizumab were comparable. At 1 year of treatment we found 80 and 70% patients free from relapses and MRI activity, respectively, that is similar to 75 and 62% detected in the AFFIRM trial. Moreover, only 5% of our patients showed a progression of disability after a mean follow-up time of 15 months. Finally, the presence of antibodies anti-Natalizumab was strongly related to the occurrence of relapses ( p  = 0.002) and MRI activity ( p  < 0.001) even in the post-marketing experience.