Sexual dysfunction in multiple sclerosis: The impact of different MSISQ-19 cut-offs on prevalence and associated risk factors.

BACKGROUND: Although multiple sclerosis (MS) Intimacy and Sexuality Questionnaire-19 (MSISQ-19) is a widely applied tool, no unique definition of sexual dysfunction (SD) based on its score exists. OBJECTIVE: To explore the impact of different MSISQ-19 cut-offs on SD prevalence and associated risk factors, providing relevant information for its application in research and clinical settings. METHODS: After defining SD according to two different MSISQ-19 cut-offs in 1155 people with MS (pwMS), we evaluated SD prevalence and association with sociodemographic and clinical features, mood status and disability via logistic regression. RESULTS: Depending on the chosen cut-off, 45% to 54% of pwMS reported SD. SD defined as MSISQ-19 score >30 was predicted by age (OR=1.01, p=0.047), cognition (OR=0.96, p=0.004) and anxiety (OR=1.03, p=0.019). SD defined as a score >3 on any MSISQ-19 item was predicted by motor disability (OR=1.12, p=0.003) and cognition (OR= 0.96, p=0.002). CONCLUSION: Applying different MSISQ-19 cut-offs influences both the estimated prevalence and the identification of risk factors for SD, a finding that should be considered during study planning and data interpretation. Preserved cognition exerts a protective effect towards SD regardless from the specific study setting, representing a key point for the implementation of preventive and therapeutic strategies.

Burden of rare coding variants in an Italian cohort of familial multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of genetic and environmental factors, and it can cluster in families. OBJECTIVE: to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families. METHODS: We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection. RESULTS: We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10-4 and 3 × 10-4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families. CONCLUSION: Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.

Transcriptomic Analysis of Peripheral Monocytes upon Fingolimod Treatment in Relapsing Remitting Multiple Sclerosis Patients.

Fingolimod (FTY), a second-line oral drug approved for relapsing remitting Multiple Sclerosis (RRMS) acts in preventing lymphocyte migration outside lymph nodes; moreover, several lines of evidence suggest that it also inhibits myeloid cell activation. In this study, we investigated the transcriptional changes induced by FTY in monocytes in order to better elucidate its mechanism of action. CD14+ monocytes were collected from 24 RRMS patients sampled at baseline and after 6 months of treatment and RNA profiles were obtained through next-generation sequencing. We conducted pathway and sub-paths analysis, followed by centrality analysis of cell-specific interactomes on differentially expressed genes (DEGs). We investigated also the predictive role of baseline monocyte transcription profile in influencing the response to FTY therapy. We observed a marked down-regulation effect (60 down-regulated vs. 0 up-regulated genes). Most of the down-regulated DEGs resulted related with monocyte activation and migration like IL7R, CCR7 and the Wnt signaling mediators LEF1 and TCF7. The involvement of Wnt signaling was also confirmed by subpaths analyses. Furthermore, pathway and network analyses showed an involvement of processes related to immune function and cell migration. Baseline transcriptional profile of the HLA class II gene HLA-DQA1 and HLA-DPA1 were associated with evidence of disease activity after 2 years of treatment. Our data support the evidence that FTY induces major transcriptional changes in monocytes, mainly regarding genes involved in cell trafficking and immune cell activation. The baseline transcriptional levels of genes associated with antigen presenting function were associated with disease activity after 2 years of FTY treatment.

Listening to the neurological teams for multiple sclerosis: the SMART project.

OBJECTIVE: Aim of the research was to define the quality of life of Italian neurologists and nurses' professional caring for multiple sclerosis, to understand their living the clinical practice and identify possible signals of compassion fatigue. MATERIAL AND METHODS: One hundred five neurologists and nurses from 30 Italian multiple sclerosis centres were involved in an online quali-quantitative survey on the organization of care, combined with the Satisfaction and Compassion Fatigue Test and a collection of narratives. Descriptive statistics of the quantitative data were integrated with the results obtained by the narrative medicine methods of analysis. RESULTS: Most of the practitioners were neurologists, 46 average years old, 69% women, 43% part time dedicated to multiple sclerosis. An increased number of patients in the last 3 years were referred in 29 centres. Differences were found between neurologists and nurses. Physicians showed higher risks of burnout, reporting intensive working paces, lack of medical personnel, and anxiety caused by the precarious employment conditions. Nurses appeared more satisfied, although the reference to the lack of spaces, and the cross professional roles risk of compassion fatigue. Both positive and negative relationships of care were depicted as influencing the professional quality of life. CONCLUSION: The interviewed neurological teams need to limit the risk of compassion fatigue, which appeared from the first years of the career. The prevalence of the risk among neurologists suggests more awareness among scientific societies and health care managers on the risk for this category, as first step to prevent it.

Structural and functional brain connectomes in patients with systemic lupus erythematosus.

BACKGROUND AND PURPOSE: Systemic lupus erythematosus (SLE) is an immune-mediated disease that may affect the nervous system. We explored the topographical organization of structural and functional brain connectivity in patients with SLE and its correlation with neuropsychiatric (NP) involvement and autoantibody profiles. METHODS: Graph theoretical analysis was applied to diffusion tensor magnetic resonance imaging (MRI) and resting-state functional MRI data from 32 patients with SLE and 32 age- and sex-matched healthy controls. Structural and functional connectivity matrices between 116 cortical/subcortical brain regions were estimated using a bivariate correlation analysis, and global and nodal network metrics were calculated. RESULTS: Structural, but not functional, global network properties (strength, transitivity, global efficiency and path length) were abnormal in patients with SLE versus controls (P < 0.0001), especially in patients with anti-double-stranded DNA (ADNA) autoantibodies (P = 0.03). No difference was found according to NP involvement or anti-phospholipid autoantibody status. Patients with SLE and controls shared identical structural hubs and the majority of functional hubs. In patients with SLE, all structural hubs showed reduced strength and clustering coefficient compared with controls (P from 0.001 to <0.0001), especially in patients with ADNA autoantibodies. Only a few differences in functional hub properties were found between patients with SLE and controls. Structural and functional hub measures did not differ according to NP involvement or anti-phospholipid autoantibody status. Significant correlations were found between clinical, MRI and network measures (r from -0.56 to 0.60, P from 0.0003 to 0.05). CONCLUSIONS: Abnormalities of global and nodal structural connectivity occur in patients with SLE, especially with ADNA autoantibodies, with a diffuse disruption of structural integrity. Functional network integrity may contribute to preserve clinical functions.

Acquired haemophilia A as a secondary autoimmune disease after alemtuzumab treatment in multiple sclerosis: A case report.

Alemtuzumab is a highly effective monoclonal antibody for the treatment of multiple sclerosis (MS). During the immune reconstitution following the use of this treatment severe secondary autoimmune diseases (SADs) can develop. We present the case of a patient affected by active MS who failed to achieve disease control with several disease-modifying drugs and was thereafter successfully treated with alemtuzumab, obtaining no evidence of disease activity and a high quality of life. Twenty months after the first infusion of alemtuzumab the patient developed acquired haemophilia A (AHA), a treatable but potentially lifethreatening condition that should be considered a possible SADs associated to this drug. In order to allow an early diagnosis and to prevent possible complications of AHA, routine coagulation tests (prothrombin time and activated partial thromboplastin time) should be included in the laboratory serological monitoring of patients treated with alemtuzumab.

Basal vitamin D levels and disease activity in multiple sclerosis patients treated with fingolimod.

BACKGROUND: Several studies have shown an association between 25-hydroxyvitamin D (25[OH]D) levels and multiple sclerosis (MS) susceptibility and/or level of disease activity in patients treated with first line drugs. AIMS: To investigate whether baseline 25[OH]D values could influence disease activity also during treatment with the second-line drug fingolimod (FTY). PATIENTS AND METHODS: We enrolled 176 MS patients who started FTY at the San Raffaele Hospital (OSR) MS center with available 25[OH]D measurement at the time of treatment start. We then prospectively followed them for 2 years with periodic clinical examinations and MRI scans. RESULTS: We found no linear correlation between baseline 25[OH]D levels and annualized relapse rate (ARR) or time to first relapse. However, we observed that patients with serum 25[OH]D ≥ 100 nmol/l showed a lower number of Gd+ and combined unique activity (CUA) lesions at baseline compared to patients with the lowest 25[OH]D levels (less than 50 nmol/l, p value < 0.05). Moreover, they showed fewer CUA lesions at 2-year follow-up also when accounting for baseline level of disease activity (p value < 0.05). CONCLUSIONS: In patients treated with FTY, those with the highest baseline 25(OH)D levels had a significantly lower number of active lesions at baseline; the same effect, even if weaker, was observed also at 2-year follow-up when adjusting for baseline disease activity. Given Vitamin D supplementation safety profile, also if a causal effect has not yet been shown, most of MS patients could probably benefit from 25[OH]D levels above those currently considered to be sufficient.

Effectiveness and baseline factors associated to fingolimod response in a real-world study on multiple sclerosis patients.

BACKGROUND: Treatment choice in multiple sclerosis (MS) is crucial for optimizing risk-benefit profile. OBJECTIVE: To assess fingolimod (FTY) effectiveness and identify baseline features associated to disease activity in a large Italian cohort of Relapsing-Remitting (RR) MS patients. METHODS: Three-hundred sixty-seven RRMS patients starting FTY treatment at San Raffaele Hospital (Milan-Italy) underwent clinical and MRI evaluations for 2 years. Treatment response was assessed considering the proportion of patients with no evidence of disease activity (NEDA) and recording the time to first relapse. Primary analyses were performed stratifying for Natalizumab (NTZ) treatment in the year before (NO_NTZ vs NTZ group), to account for post-NTZ reactivation. RESULTS: Almost half of patients were NEDA after 2 years, 53.4% in the NO_NTZ group and 36.2% in the NTZ group. Despite an opposite trend during the first 6-12 months, at 2-year follow-up the two groups were comparable for relapses and number of new/enlarging T2 and Gd-enhancing lesions. Baseline parameters of higher disease activity (ARR, Gd enhancing lesions and age at onset) were associated with increased likelihood of failing NEDA criteria or with shorter time to relapse (p < 0.05). CONCLUSIONS: Our data strengthen FTY effectiveness in everyday clinical practice, even in patients switching from NTZ treatment. Baseline parameters of inflammatory activity are the most important prognostic factors for mid-term disease reactivation also during second-line treatment with FTY, providing hints on how to select therapies towards a more personalized management.

Multiple biomarkers improve the prediction of multiple sclerosis in clinically isolated syndromes.

OBJECTIVES: Since its introduction, MRI had a major impact on the early and more precise diagnosis of multiple sclerosis (MS), and the 2010 diagnostic criteria even allow a diagnosis to be made just after a single attack if stringent MRI criteria are met. Several other clinical and paraclinical markers have been reported to be associated with an increased risk of MS independently of MRI in patients with clinically isolated syndromes (CIS), but the incremental usefulness of adding them to the current criteria has not been evaluated. In this study, we determined whether multiple biomarkers improved the prediction of MS in patients with CIS in a real-world clinical practice. MATERIALS AND METHODS: This was a retrospective study involving patients with CIS admitted to our department between 2000 and 2013. We evaluated baseline clinical, MRI, neurophysiological, and cerebrospinal fluid (CSF) data. RESULTS: During follow-up (median, 7.2 years), 127 of 243 participants (mean age, 31.6 years) developed MS. Cox proportional-hazards models adjusted for established MRI criteria, age at onset, number of T1 lesions, and presence of CSF oligoclonal bands significantly predicted the risk of developing MS at 2 and 5 years. The use of multiple biomarkers led to 29% net reclassification improvement at 2 years (P<.001) and 30% at 5 years (P<.001). CONCLUSIONS: The simultaneous addition of several biomarkers significantly improved the risk stratification for MS in patients with CIS beyond that of a model based only on established MRI criteria.

Pharmacogenetic study of long-term response to interferon-ß treatment in multiple sclerosis.

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-ß (IFNß) (4-year follow-up). We performed a genome-wide association study in 337 IFNß-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNß-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNß stimulation in HC (P=3.1 × 10-9 and 5.6 × 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNß administration (ß=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNß.

Rituximab in the treatment of Neuromyelitis optica: a multicentre Italian observational study.

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.

Neuromyelitis optica spectrum disorders: long-term safety and efficacy of rituximab in Caucasian patients.

OBJECTIVE: To assess the long-term benefit-risk profile of repeated courses of rituximab in Caucasian patients affected by neuromyelitis optica (NMO) and related disorders, in everyday clinical practice. METHODS: This is a prospective observational study performed at San Raffaele Hospital, Milan, Italy. From February 2006, we recruited 21 patients affected by NMO and NMO spectrum of disorders (NMOSD) whom underwent at least one cycle of intravenous (i.v.) rituximab and then were followed for at least 2 years. RESULTS: At a mean follow-up time of 48 months, we observed a significant reduction of the annualized relapse rate (ARR), from 2.0 to 0.16 (p < 0.01); and of the median Expanded Disability Status Scale (EDSS), from 5.5 to 4.0 (p < 0.013). There were 12 patients (57%) who remained disease free during the follow-up period. Five patients (24%) reported mild hematological adverse events. Serious infectious adverse events were reported by another four patients: These were all wheelchair bound at the beginning of their rituximab treatment. CONCLUSIONS: A fixed treatment scheme of rituximab, with re-treatment every 6 months, was efficacious for NMO and NMOSD, with a good safety profile; however, to obtain an even better benefit-risk ratio, close monitoring of CD19(+) B cells should be performed before the re-treatment of patients with high-level disability, concomitant leukopenia and hypogammaglobulinemia.

Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases.

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.

Endovascular treatment of CCSVI in patients with multiple sclerosis: clinical outcome of 462 cases.

Although it is still debated whether chronic cerebro-spinal venous insufficiency (CCSVI) plays a role in multiple sclerosis (MS) development, many patients underwent endovascular treatment (ET) of CCSVI. The objective of the study is to evaluate the outcome and safety of ET in Italian MS patients. Italian MS centers that are part of the Italian MS Study Group were all invited to participate to this retrospective study. A structured questionnaire was used to collect detailed clinical data before and after the ET. Data from 462 patients were collected in 33 centers. ET consisted of balloon dilatation (93 % of cases) or stent application. The mean follow-up duration after ET was 31 weeks. Mean EDSS remained unchanged after ET (5.2 vs. 4.9), 144 relapses occurred in 98/462 cases (21 %), mainly in RR-MS patients. Fifteen severe adverse events were recorded in 3.2 % of cases. Given the risk of severe adverse events and the lack of objective beneficial effects, our findings confirm that at present ET should not be recommended to patients with MS.

Fatigue and its relationships with cognitive functioning and depression in paediatric multiple sclerosis.

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.

Breastfeeding is not related to postpartum relapses in multiple sclerosis.

OBJECTIVE: To assess the relationship between breastfeeding and risk of puerperal relapses in a large cohort of patients with multiple sclerosis (MS). METHODS: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centers, and gathered data on breastfeeding through a standardized interview. The risk of relapses after delivery was assessed using the Cox regression analysis. RESULTS: A total of 302 out of 423 pregnancies in 298 women resulted in full-term deliveries. Patients were followed up for at least 1 year after delivery. The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not. In the multivariate analysis, adjusting for age at onset, age at pregnancy, disease duration, disability level, and relapses in the year prior to pregnancy and during pregnancy, treatment with disease-modifying drugs (DMDs), and exposure to toxics, the only significant predictors of postpartum relapses were relapses in the year before pregnancy (hazard ratio [HR] = 1.5; 95%confidence interval [CI] 1.3-1.9; p < 0.001) and during pregnancy (HR = 2.2; 95% CI 1.5-3.3; p < 0.001). CONCLUSIONS: In our sample, postpartum relapses were predicted only by relapses before and during pregnancy. Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity. Our results can assist neurologists facing the breastfeeding issue in mother counseling and shared decision-making. Especially, among patients with high risk of postpartum relapses, breastfeeding may not be feasible and early postpartum treatment should be an option.