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New therapies are being evaluated by clinical trials and, if efficacious, introduced for the treatment of adult MS. The role of these new and existing agents in the management of pediatric MS has yet to be defined. Pediatric investigation plans are now required by the Food and Drug Administration and European Medicines Agency for approval of new biological agents, providing an important opportunity to gather much-needed data for clinicians caring for children and adolescents with MS. However, challenges include the small number of patients, and the need for efficient yet comprehensive study designs incorporating factors necessary to inform the clinical care of children with MS. The elected Steering committee of the International Pediatric MS Study Group (IPMSSG) conducted a structured review of existing data on the disease-modifying therapies in pediatric MS and developed a consensus statement, which was further modified by the IPMSSG general membership, using an online survey tool. Fifty-one IPMSSG members from 21 countries responded to the survey, and 50 approved the final statement. Consensus recommendations regarding use of existing first- and second-line therapies, as well as a proposed definition for inadequate treatment response, are presented. Recommendations for the use and evaluation of emerging therapies (currently in phase III clinical trials or recently approved for adult MS) are discussed. The IPMSSG endorses the inclusion of pediatric MS patients in trials evaluating appropriate new and emerging therapies. Mechanisms for conducting high-impact, multicenter studies, including long-term follow-up in pediatric MS, are required to ensure that all MS patients, irrespective of age, benefit from advances in MS therapeutics.

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.

BackgroundThe approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting.MethodsWe collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0–10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months.ResultsA total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3–2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%).ConclusionsSativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

The snowpack is a complicated multiphase mixture with mechanical, hydraulic, and thermal properties highly variable during the year in response to climatic forcings. Bulk density is a macroscopic property of the snowpack used, together with snow depth, to quantify the water stored. In seasonal snowpacks, the bulk density is characterized by a strongly non-linear behaviour due to the occurrence of both dry and wet conditions. In the literature, bulk snow density estimates are obtained principally with multiple regressions, and snowpack models have put the attention principally on the snow depth and snow water equivalent. Here a one-dimensional model for the temporal dynamics of the snowpack, with particular attention to the bulk snow density, has been proposed, accounting for both dry and wet conditions. The model represents the snowpack as a two-constituent mixture: a dry part including ice structure, and air; and a wet part constituted by liquid water. It describes the dynamics of three variables: the depth and density of the dry part and the depth of liquid water. The model has been calibrated and validated against hourly data registered at three SNOTEL stations, western US, with mean values of the Nash–Sutcliffe coefficient ≈0.73–0.97 in the validation period.

BackgroundDimethyl-fumarate (DMF) demonstrated efficacy and safety in relapsing–remitting multiple sclerosis (MS) in randomized clinical trials.ObjectivesTo track and evaluate post-market DMF profile in real-world setting.Materials and methodsPatients receiving DMF referred to Italian MS centres were enrolled and prospectively followed, collecting demographic clinical and radiological data.ResultsAmong the 735 included patients, 45.4% were naïve to disease-modifying therapies, 17.8% switched to DMF because of tolerance, 27.4% switched to DMF because of lack of efficacy, and 9.4% switched to DMF because of safety concerns. Median DMF exposure was 17 months (0–33). DMF reduced the annual relapse rate (ARR) by 63.2%. At 12 and 24 months, 85 and 76% of patients were relapse-free. NEDA-3 status after 12 months of DMF treatment was maintained by 47.5% of patients. 89 and 70% of patients at 12 and 24 months regularly continued DMF. Most frequent adverse events (AEs) were flushing (37.2%) and gastro-enteric AEs (31.1%).ConclusionOur post-market study corroborated that DMF is a safe and effective drug. Additionally, the study suggested that naïve patients strongly benefit from DMF and that DMF improved ARR also in patients who were horizontally switched from injectable therapies due to tolerability and efficacy issues.

The three interferon beta preparations approved for treatment of relapsing-remitting multiple sclerosis (MS) differ in dose and frequency of administration. Interferon beta-1a 30 μg is administered once a week, interferon beta-1a 22 μg or 44 μg is given three times a week, and interferon beta-1b 250 μg is administered on alternate days. No clinical study directly comparing the different regimens has been published. The INCOMIN study was designed to compare the clinical and magnetic resonance imaging (MRI) benefits of on-alternate-day interferon beta-1b 250 μg with once-weekly interferon beta-1a 30 μg. INCOMIN was a 2-year, prospective, randomised, multicentre study. 188 patients with relapsing-remitting MS were assigned to interferon beta-1b (n=96) or interferon beta-1a (n=92). Primary outcome measures were the proportion of patients free from relapses and that of patients free from new proton density/T2 lesions at MRI assessment. Several secondary outcome measures were also assessed. Analysis was by intention to treat. Over 2 years, 49 (51%) individuals administered interferon beta-1b remained relapse-free compared with 33 (36%) given interferon beta-1a (relative risk of relapse 0·76; 95% Cl 0·59–0·9; p=0·03); and 42 (55%) compared with 19 (26%), respectively, remained free from new T2 lesions at MRI (relative risk of new T2 lesion 0·6; 0·45–0·8; p·0<0003). In both groups, the differences between the two treatments increased during the second year. There were also significant differences in favour of interferon beta-1b in most of the secondary outcome measures, including delay of confirmed disease progression. High-dose interferon beta-1b administered every other day is more effective than interferon beta-1a given once a week.

Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self-injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-β1a (Rebif; 22 μg), administered subcutaneously three times weekly using the RebiSmart™ electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being “Emotional functioning.” In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p  = 0.041). Significant increases were also evident for parent-reported “Psychosocial health summary score” (+ 5.90 points; p  = 0.015) and “School functioning” (+ 7.84 points; p  = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmart™ for self-administration of Rebif® can experience long-term improvements in QL.

Background: Antibodies against aquaporin-4 (AQP4), a water channel particularly expressed on perivascular astrocytic podocytes, are proposed as a marker for the diagnosis of neuromyelitis optica (NMO). However, a consensus on seroprevalence and optimal detection method has not yet been reached. Objectives: To investigate the performance of different assays to detect anti-AQP4 antibodies. Methods: We set up five different assays. Two of them were capable to detect perivascular IgG reactivity on brain tissue by immunofluorescence (NMO-IgG). Other three assays have been set to detect anti-AQP4 antibodies: immunofluorescence and flow cytometry on AQP4-expressing cells, and a radioimmunoprecipitation assay. We assessed sensitivity and specificity of these assays by interrogating sera of 33 NMO patients, 13 patients at high risk to develop NMO (hrNMO), 6 patients affected by acute partial transverse myelitis (APTM), 20 patients with multiple sclerosis (MS), and 67 age- and sex-matched healthy controls. Results: We found that the presence of serum NMO-IgG and anti-AQP4 reactivity is almost exclusively restricted to patients with NMO and hrNMO. Seroprevalence and sensitivity ranged from 30 to 47%, depending on the assay. Specificity ranged from 95 to 100%. Comparing results obtained in the five assays, we noticed lack of concordance in some samples. Conclusions: Detection of NMO-IgG or anti-AQP4 antibodies may represent a valuable tool to assist neurologists in the differential diagnosis between patients with NMO, hrNMO, APTM, or MS. The current lack of a gold standard to detect anti-AQP4 antibodies implies the necessity to standardize the detection of these antibodies.

Background: There is limited information on fatigue and its clinical and psychosocial correlates in children and adolescents with multiple sclerosis (MS). Objective: To assess the relationships between fatigue, cognitive functioning and depression in paediatric MS. Methods: The study cohort consisted of patients with MS recruited for an Italian collaborative study on cognitive and psychosocial functioning in paediatric MS. The present assessment included evaluation of fatigue on the Pediatric Quality of Life Inventory-Multidimensional Fatigue Scale, cognitive functioning on an extensive neuropsychological battery and depression on the Children’s Depression Inventory (CDI). A psychiatric interview through the Kiddie-SADS-Present and Lifetime Version was also administered. Results: In total, 57 patients with relapsing–remitting MS were compared with 70 healthy controls. Percentages of fatigued patients ranged from 9% to 14% according to self-reports, and from 23% to 39% according to parent reports. Fatigue was significantly related with higher scores on the CDI (p < 0.03). Higher levels of self-reported cognitive fatigue were associated with impaired performance on a problem-solving test, whereas higher levels of parent-reported cognitive fatigue were associated with impairment on tests of verbal learning, processing speed, complex attention and verbal comprehension. Conclusions: Our data show that fatigue can affect a sizeable proportion of paediatric MS patients, and confirm the association between fatigue and depressive symptoms in MS. They also highlight the difficulties of fatigue assessment in the paediatric population and provide a few clues to further research in the field.

Background: Limited information is available on the use of natalizumab (NA) in pediatric multiple sclerosis (ped-MS) patients. Objective: The purpose of this study was to describe the long-term effects of NA in a large cohort of active ped-MS patients. Methods: Patients with definite ped-MS were treated with NA if in the previous year they had experienced at least two relapses or a severe relapse with incomplete recovery while on immunomodulating treatment, or at least two relapses and new magnetic resonance imaging (MRI) lesions regardless of any prior treatment. Results: The study included 55 patients (mean age: 14.4 years, mean number of relapses: 4.4, pre-treatment mean disease duration: 25.5 months). They received a median number of 26 infusions. Three relapses occurred during the follow-up, one female patient continued to deteriorate in cognitive functioning. Mean Expanded Disability Status Scale (EDSS) scores decreased from 2.7 to 1.9 at the last visit (p<0.001). During the follow-up the majority of patients remained free from MRI activity. Transient and mild clinical adverse events occurred in 20 patients. Mild hematological abnormalities occurred in seven patients. Anti-JCV antibodies were detected in 20/51 tested patients. Conclusions: NA was well tolerated in all patients. A strong suppression of disease activity was observed in the majority of patients during the follow-up.