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We have described two cases of Devic's disease patients treated with rituximab with different outcomes. The results indicate that there may be early unresponsiveness in very aggressive cases. Well designed clinical trials are needed to assess treatment effects in such a rare disease. [ABSTRACT FROM AUTHOR]

Relapsing-remitting multiple sclerosis (MS) has a very fluctuating course and responsiveness to interferon beta (IFN-β) treatment in each patient is extremely difficult. Agreement exists about the negative role of neutralising antibodies (NAbs) on clinical efficacy and markers of IFN-β bioavailability have been studied; no guidelines exist yet about what to do when a patient becomes NAbs positive or IFN biological activity is lost. In this study 405 MS patients have been longitudinally studied for NAbs and MxA expression. A spontaneous disappearance of NAbs was observed in a few patients with low antibody titre; according to the clinical course, a therapeutic modification has been made in patients persistently NAbs positive; in these patients NAbs persisted over time despite the interruption of IFN therapy. [ABSTRACT FROM AUTHOR]

Background: Fingolimod (FTY) induces sequestration of lymphocytes in secondary lymphoid organs and the average lymphocyte recovery following discontinuation takes 1–2 months. It has been hypothesized that the therapeutic effects of subsequent cell-depleting agents may be compromised if initiated before lymphocyte recovery has occurred. Objective: To assess the risk of relapses following FTY discontinuation and the initiation of a B/T cell-depleting agent in relation to washout duration using data from the Italian MS Register. Methods: The risk of relapses was assessed in relation to different washout durations (< 6, 6–11, 12–17 and > / = 18 weeks) in patients starting alemtuzumab, rituximab, ocrelizumab or cladribine following FTY discontinuation. Results: We included 329 patients in the analysis (226F, 103 M; mean age 41 ± 10 years). During the cell-depleting treatment, the incidence rate ratio for a relapse was significantly greater in patients with a washout period of 12–17 and > / = 18 weeks compared to the reference period (< 6 weeks). The risk of a relapse was significantly influenced by the occurrence of relapses during FTY treatment and by washout length, with hazard ratios markedly increasing with the washout duration. Conclusion: The risk of relapses increases with the washout duration when switching from FTY to lymphocyte-depleting agents. [ABSTRACT FROM AUTHOR]

Background: MxA gene expression is one of the most appropriate markers of biological activity of exogenous interferon (IFN) beta. Methods: We quantified MxA mRNA for five consecutive days in 62 patients treated with IFN beta (16, Avonex; 10, Betaferon; 24, Rebif 22; 12, Rebif 44), by quantitative-competitive polymerase chain reaction. Every three months, IFN beta induced neutralising antibodies (NAbs) were evaluated in sera using a cytopathic effect assay. Results: Two categories of patients were identified: one group (49/62) hada sharp post-injection increase in MxA expression (defined as "IFN beta biological responder"), whereas the other group (13/62) had no MxA induction after IFN beta administrations (defined as "IFN beta biological non-responder"). In 11 / 13 biological non-responders, the persistent presence of NAbs correlated with abolished biological activity, independently of treatment regimen. The two remain in- IFN beta biological non-responders were NAb-. Among the 49 IFN beta biological responders, biological activity was comparable between the four preparations on day 2 and 3 (+12 and +36 hours post-injection), but it was greater in Betaferon and both Rebif preparations on day 1,4, and 5. In biological responders treated three times a week, only 82% (59/72) of injections were considered effective, compared with 100% (13/13) of Avonex injections. Conclusion: Our results suggest that an optimal IFN beta regimen is not yet available: Avonex, given once a week, shows lower cumulative biological activity. On the other hand, both Betaferon and Rebif, given three times a week, show 18% biologically ineffective injections and higher risk of developing NAbs, which abolish biological activity. [ABSTRACT FROM AUTHOR]

Devic's neuromyelitis optica (NMO) is a clinical entity characterised by severe transverse myelitis, optic neuropathy and monophasic or recurrent course. We report the case of a woman affected by myelitis and optic neuritis suggesting Devic's disease. Diagnosis was supported by clinical, neuroradiological and biochemical findings. In 14 months, the patient developed 5 clinical exacerbations. Six cerebrospinal fluid (CS F) examinations were performed, 3 during relapses and 3 during remitting phases: all the CSF specimens obtained during relapses showed granulocyte pleocytosis and increased protein level, whereas CSF was normal during stationary phases. Oligoclonal banding was always absent. Spinal cord MRI showed altered signal at cervical and thoracic levels. We did not find any concomitant systemic disease. The case we report underlines the importance of CSF examination during clinical relapse in NMO diagnosis. [ABSTRACT FROM AUTHOR]

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. Aims: The 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. Results: The 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a heterogeneous disease and a variable percentage of patients are non-responders to common treatment. Early diagnosis of non-responders allows change to a more useful therapy for the patient and better allocates a large amount of financial resources. Quantification of Neutralizing antibodies (Nabs) and of biological activity of IFN-β are recognized approaches to identify immuno-pharmacological non-responders. A consistent number of studies have demonstrated that quantification of Myxovirus-induced protein A (MxA) is a valid biomarker to detect immune-pharmacological non responders after one year of treatment. Persistent high titre of Nabs and absence of biological activity predict abolition of IFN-β effects in disease activity measured through MRI, number of relapses and disability. Guidelines and flow-charts including both Nabs and MxA quantification are presented. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system caused by a complex interaction between multiple genes and environmental factors. HLA region is the strongest susceptibility locus, but recent huge genome-wide association studies identified new susceptibility genes. Among these, BACH2, PTGER4, RGS1 and ZFP36L1 were highlighted. Here, a gene expression analysis revealed that three of them, namely BACH2, PTGER4 and ZFP36L1, are down-regulated in MS patients' blood cells compared to healthy subjects. Interestingly, all these genes are involved in the immune system regulation with predominant anti-inflammatory role and their reduction could predispose to MS development. [ABSTRACT FROM AUTHOR]

Abstract: We recently found a gene signature for multiple sclerosis (MS) that reverted to normal during pregnancy in MS patients and included NR4A2 and TNFAIP3, key molecules in anti-inflammatory processes. Here we focus on the expression levels of these two genes in monocytes and CD4+ T cells from healthy controls and treatment-naïve RRMS patients. Our findings show that monocytes play a key role in the dysregulated anti-inflammatory response, being the expression of both genes down-regulated in these cells in RRMS patients with respect to healthy individuals. CD4+ T cells seem to have only a marginal part, because we can observe only a slight down-regulation in NR4A2. [Copyright &y& Elsevier]

The article presents a study of the potential of early binding antibody (BAb) titers or different interferon-beta (IFN-b) biomarkers to predict neutralizing antibodies (NAb). The study included patients with multiple sclerosis (MS) or clinically isolated syndrome (CIS) that receive de novo IFN-b treatment. Results showed that BAb titers reliably predict Nabs, with CXCL-10 as a potential sensitive biomarker for IFN-b response and abrogation by anti-IFN-b antibodies.

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. [ABSTRACT FROM AUTHOR]

Abstract: There are two commonly employed types of bioassays for the detection of neutralizing antibodies (NAbs) against interferon-beta (IFNβ): the cytopatic effect assay (CPE), and the MxA (myxovirus resistance protein A) protein assay (MPA). This article describes a bioassay based on the real time PCR measurement of mRNA that results from the induction, in cultured human cells, of the MxA gene by IFNβ. Serum samples from 104 patients with multiple sclerosis (MS) treated with IFNβ were tested for NAbs using our real time PCR bioassay. NAbs also were measured in the same specimens by the MPA assay and CPE assay. The calibration range of the real time PCR bioassay is 0.125–30 LU/mL. The range of the intra- and inter-assay variations (coefficients of variation in log10) were 4.05% (range 0.88%–7.90%) and 4.42% (range 0.31%–9.15%), respectively. Samples of the three commercial preparations of IFNβ-1a and -1b were measured showing dose–response curves parallel to that of the NIH reference IFNβ (mean SD at the midpoint of the dose–response curve=5%). In addition, the assay was robust with respect to number of cells plated (i.e., increasing cell densities from 12×103/well to 384×103/well resulted in 3.03% variability in MxA expression normalized with glyceraldehyde-3 phosphate dehydrogenase). NAbs titers measured were closely comparable to those obtained by the MPA [r spearman =0.899; 89% of observed agreements; K =0.779] and the CPE [r spearman =0.7899); 86%; K =0.729] assays. Despite the obvious disadvantage of cost, when carried out according to quality assurance guidelines for molecular diagnostics the new MxA gene-expression assay (MGA) has significant advantages over the other methods for testing NAbs: it has excellent reliability and reproducibility, and utilizes equipment and methodologies already accessible in many clinical laboratories. [Copyright &y& Elsevier]

Biological activity of interferon-beta (IFNβ) can be assessed by measuring IFN-stimulated genes (ISGs). Among them, myxovirus resistance protein A (MxA) appears to have the highest specificity, but it has no role in the pathogenesis of multiple sclerosis (MS). To investigate the reliability of MxA as a biomarker, we compared its expression to that of two other ISGs: TNF-related apoptosis-inducing ligand (TRAIL) and X-linked inhibitor of apoptosis factor-1 (XAF-1). Both were shown to be involved in immunoregulatory mechanisms and might play a role in MS. Quantitative-PCR measurements were performed in peripheral blood mononuclear cells from 73 MS patients after short-term and long-term treatment with IFNβ. A time-dependent response for multiple ISGs was observed in all patients after short-term treatment. In contrast, long-term treatment induced concurrent inhibition of ISGs in 12.3% (9/73) of patients, in whom neutralizing antibodies (NAbs) were detectable. Besides, 22% (16/73) of chronically treated patients showed a non-NAbs-related abrogation of TRAIL expression. In summary, 1) MxA expression was significantly higher than both TRAIL and XAF-1, and 2) MxA was the most sensitive gene to detect decreased bioavailability due to NAbs. These findings identify MxA as an appropriate biomarker for IFNβ, although there is no evidence for a functional role of it in MS. [ABSTRACT FROM AUTHOR]

Abstract: This study is the first to evaluate biological response to first injections of interferon-beta (IFNβ) in patients with multiple sclerosis. MxA mRNA was measured in 96 patients receiving IFNβ-1a (Avonex, n=32), IFNβ-1b (Betaferon, n=19), IFNβ-1a (Rebif) 22 μg (n=30), or IFNβ-1a 44 μg (n=15). Patients were analysed before, 3 and 24 h after the first injection, and 12 h after the second administration. Results showed that up-regulation was evident within 3 h of IFNβ injection, peaked 12 h after injection, and progressively declined 24 h after administration. The cumulative responses were similar after a single administration, regardless of product/dose. Moreover, data indicate that the abolition of the biological activity detected during IFNβ therapy is due to underlying phenomena (e.g., neutralizing antibodies), because all patients were constitutively responders to IFNβ at treatment initiation. [Copyright &y& Elsevier]

Background and purpose Natalizumab discontinuation induces the recurrence of multiple sclerosis disease activity: currently no therapeutic approach has been found able to abolish disease reactivation. Methods The recurrence of disease activity after natalizumab discontinuation was retrospectively evaluated in 79 patients who had been treated with immunomodulating agents, other first-line therapies, fingolimod or not treated. Results No differences have been found in clinical or magnetic resonance imaging recurrence of disease activity amongst the groups. Interestingly, no disease reactivation was observed only in one patient treated for 6 months with monthly pulses of cyclophosphamide. Conclusion Disease modifying treatment or 'no treatment' is unable to abolish disease activity reactivation after natalizumab discontinuation. [ABSTRACT FROM AUTHOR]

Balance impairment is common in Multiple Sclerosis (MS) patients. We administered the modified Clinical Test of Sensory Interaction on Balance (mCTSIB) to 73 MS patients and 57 healthy controls, with the aim to collect normative data and compare sensitivity of mCTSIB and clinical examination in detecting balance impairment. Subjects were asked to stand quietly upright for 10 s with eyes opened and then eyes closed (EC) (3 times per condition) on a firm surface on a fixed dual forceplate. The centre of gravity (COG) sway was expressed as velocity (deg/s) and path length (mm); MS patients were examined with the Romberg Test (RT), scored according to Neurostatus. mCTSIB-EC clearly allowed to differentiate patients with positive RT (0.38 deg/s, CI 0.32–0.43) from those with negative RT (0.19 deg/s, 95% CI 0.17–0.21, p < 0.001). ROC analysis identified a cut-off value of 0.5 deg/s to define “positivity” to the mCTSIB (sensitivity 100%, specificity 95%, PPV 82%, NPV 100%). mCTSIB detected balance impairment in 19 MS patients (10 with negative RT). Compared to RT, the computerized posturographic test is more sensitive in detecting balance impairment in MS patients. It is easy to perform, fast to administer, not operator-dependent and provides objective data on postural control. [ABSTRACT FROM AUTHOR]

We investigated the Intertrial Variability and Relative Intertrial Variation (RIV) of latency and area of motor responses to High Voltage Electric Stimulation (HVES) of lumbo-sacral roots and to Transcranial Magnetic Stimulation (TMS) recorded from several sites of lower limbs. The purpose was to obtain normative variability values to detect significant changes in the individual patient in follow up studies. Maximal CMAPs to HVES of lumbo-sacral roots were obtained from 10 proximal and distal muscle districts of lower limbs; MEPs to TMS using the double cone coil were recorded from the same sites. The procedure was repeated twice, 1–2 days apart, in 30 subjects, including healthy volunteers and clinically stable multiple sclerosis patients. The use of stable recording and stimulation sites with maximal root-CMAPs and adequately stabilized MEPs allowed a significant reduction of ITV for all latency and area parameters. Mean RIV values (5th–95th percentile) for Central Motor Conduction Time and Area Ratio (MEP/CMAP) did not exceeded −14.8 and +16.0 ms and −26.0 and +33.7 mV ms, respectively. The combined monitoring of latency and areas indexes allows assessment of both conduction slowing and conduction failure, i.e the variable association of axonal damage and conduction block, which directly correlates with motor impairment. [ABSTRACT FROM AUTHOR]