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The article offers the author's insights on the studies by R. Gold and colleagues and RJ Fox and colleagues on the Placebo-controlled phase 3 study of oral BG-12 or glatiramer for relapsing multiple sclerosis. He states that in Gold's study, the relapse rate over two years was reduced by 27% for twice daily dose and 26% for the thrice daily dose compared to placebo. He says that in Fox's study, the reduction rate was 44% for the twice daily dose and 51% for the thrice daily compared to placebo.

Lymphopenia is a known adverse effect in patients with relapsing multiple sclerosis (RMS) treated with fumaric acids. We present a case series of four patients diagnosed with RMS with prolonged lymphocyte stability on dimethyl fumarate for over 1 year who developed significant lymphopenia after transitioning to diroximel fumarate. This case series highlights the need for further research to elucidate the risk of lymphopenia in patients switching between fumaric acids. [ABSTRACT FROM AUTHOR]

Background: Understanding nutrition's role in multiple sclerosis (MS) can guide recommendations and intervention-based studies. Objective: Evaluate the association between nutrition and pediatric-onset MS outcomes. Methods: Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase. Results: 353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07–1.86), and risk of T2 progression by 40% (1.40, 1.12–1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60–0.95), 45% (0.55, 0.32–0.96), and 15% (0.84, 0.74–0.96), respectively. No associations were found with EDSS. Conclusion: This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation. [ABSTRACT FROM AUTHOR]

Background: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS). Objectives: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing–remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials. Methods: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis. Results: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7–36.9]) and treatment failure (OR 10.6 [3.4–32.5]) but did not predict radiological activity (OR 1.9 [0.7–5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder. Conclusion: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully. [ABSTRACT FROM AUTHOR]

Background: Sample size calculation is a key aspect in the planning of any trial. Planning a randomized placebo-controlled trial in relapsing–remitting multiple sclerosis (RRMS) requires knowledge of the annualized relapse rate (ARR) in the placebo group.Objectives: This paper aims (i) to characterize the uncertainty in ARR by conducting a systematic review of placebo-controlled, randomized trials in RRMS and by modelling the ARR over time; and (ii) to assess the feasibility and utility of blinded sample size re-estimation (BSSR) procedures in RRMS.Methods: A systematic literature review was carried out by searching PubMed, Ovid Medline and the Cochrane Register of Controlled Trials. The placebo ARRs were modelled by negative binomial regression. Computer simulations were conducted to assess the utility of BSSR in RRMS.Results: Data from 26 placebo-controlled randomized trials were included in this analysis. The placebo ARR decreased by 6.2% per year (p < 0.0001; 95% CI (4.2%; 8.1%)) resulting in substantial uncertainty in the planning of future trials. BSSR was shown to be feasible and to maintain power at a prespecified level also if the ARR was misspecified in the planning phase.Conclusions: Our investigations confirmed previously reported trends in ARR. In this context adaptive strategies such as BSSR designs are recommended for consideration in the planning of future trials in RRMS. [ABSTRACT FROM AUTHOR]

Background: Serum neurofilament light (sNfL) reflects neuroaxonal damage and is now used as an outcome in treatment trials of relapsing-remitting multiple sclerosis (RRMS). However, the diagnostic properties of sNfL for monitoring disease activity in individual patients warrant further investigations. Method: Patients with suspected relapse and/or contrast-enhancing lesions (CELs) were consecutively included and performed magnetic resonance imaging (MRI) of the brain at baseline and weeks 28 and 48. Serum was obtained at baseline and 2, 4, 8, 16, 24, and 48 weeks. Neurofilament light concentration was measured using Single molecule array technology. Results: We included 44 patients, 40 with RRMS and 4 with clinically isolated syndrome. The median sNfL level peaked at 2 weeks post-baseline (14.6 ng/L, interquartile range (IQR); 9.3–31.6) and reached nadir at 48 weeks (9.1 ng/L, IQR; 5.5–15.0), equivalent to the median sNfL of controls (9.1 ng/L, IQR; 7.4–12). A baseline Z -score of more than 1.1 (area under the curve; 0.78, p < 0.0001) had a sensitivity of 81% and specificity of 70% to detect disease activity. Conclusion: One out of five patients with relapse and/or CELs did not change significantly in post-baseline sNfL levels. The utility of repeated sNfL measurements to monitor disease activity is complementary rather than a substitute for clinical and MRI measures. [ABSTRACT FROM AUTHOR]

Objectives: We evaluate the potential clinical and cost impacts of discontinuing disease-modifying therapy (DMT) in people with multiple sclerosis (PwMS) when age-related immunosenescence can reduce DMT efficacy while increasing associated risks. Methods: A Markov model simulated clinical and cost impacts to the patient and payers when a proportion of eligible patients with relapsing remitting multiple sclerosis (RRMS) discontinue DMT. Eligibility was defined as age >55 years, an RRMS diagnosis of >5 years, and no history of relapses for 5 years. Increasing the proportion of eligible patients willing to discontinue therapy was also modeled. Clinical and cost inputs were from published literature. Results: Difference in EDSS progression between eligible patients who did and did not attempt discontinuation was not significant. After 1 year of eligibility, per-patient costs were $96k lower in the cohort that attempted discontinuation; however a higher proportion of relapses were seen in this group. When the proportion of patients willing to discontinue DMT increased, clinical findings remained consistent while the average cost per patient decreased. Conclusion: While there are increased clinical and cost benefits as more eligible patients attempt discontinuation, the risk of relapses can increase. Timely disease monitoring is required to manage safe DMT discontinuation. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) predominantly affects women with a sex ratio of 3:1 in contrast with a 1:1 sex ratio seen in pre-pubertal onset. Thus, puberty may influence MS risk differentially in males and females. How puberty may be associated with MS clinical features and disease course remains unknown. Objective: The objective of this paper is to determine the association of menarche with disease course in girls with MS. Methods: This is a longitudinal retrospective study from the UCSF Regional Pediatric MS Center database. We categorized patients by time of disease onset: pre-menarche, peri-menarche and post-menarche. Poisson regression models were used for within-subject relapse analyses offset by follow-up time. Results: Seventy-six girls were included (pre-menarche onset = 17; peri-menarche onset = 9; post-menarche onset = 50). Age of menarche was similar in all groups (Kruskal-Wallis p = 0.19). Relapse rate was the same in all three groups during the first two years of follow-up. In girls with follow-up overlapping at least two time periods, within-subject analyses showed increased relapses during the peri-menarche compared to post-menarche period (adjusted IRR = 8.5, 95% CI 2.5–28.7, p = 0.001). Conclusion: Pubertal status may influence MS course at least in female patients. Understanding how puberty influences MS clinical features may offer new insights into important factors regulating disease processes. [ABSTRACT FROM AUTHOR]

Background: Although adding plasma exchange (PLEX) to steroids in severe neuromyelitis optica (NMO) attacks is common practice in steroid-resistant cases, the benefit of this strategy has not been previously quantified. Objective: The objective of this paper is to compare the efficacy of high-dose intravenous methylprednisolone (IVMP) versus IVMP+PLEX in treatment of acute NMO relapses. Methods: We conducted a retrospective review of the last 83 NMO admissions to the Johns Hopkins Hospital treated with IVMP alone versus IVMP+PLEX (for steroid-resistant cases). Extended Disability Status Scale (EDSS) score was calculated at baseline, at presentation, at discharge, and on follow-up. Results: Eighteen NMO relapses (16 patients, 87% female, mean age at relapse: 33.9±23.8, median baseline EDSS 2.5) were treated with IVMP alone and 65 relapses (43 patients, 95% female, mean age at relapse: 43.8±15.7, median baseline EDSS 5.75) were treated with IVMP + PLEX. Sixty-five percent of IVMP + PLEX patients achieved an EDSS equal or below their baseline at follow-up while only 35% of the IVMP-only patients achieved their baseline EDSS on follow-up (odds ratio=3.36, 95% CI 1.0657 to 10.6004, p = 0.0386). PLEX was more effective in improving EDSS in patients on preventive immunosuppressive medications at time of relapse. Conclusions: PLEX+IVMP are more likely to improve EDSS after NMO relapses compared to IVMP alone, especially in patients taking preventive medications. [ABSTRACT FROM AUTHOR]

Background: New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking. Objective: The objective of this paper is to report sample-size calculations for assessment of new lesion recovery. Methods: In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations. Results: In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions ⩾15 mm3, as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20% and statistical power of 90%. Conclusion: Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset. [ABSTRACT FROM AUTHOR]

Background: More than 100 common variants underlying multiple sclerosis (MS) susceptibility have been identified, but their effect on disease phenotype is still largely unknown. Objective: The objective of this paper is to assess whether the cumulative genetic risk score of currently known susceptibility variants affects clinical presentation. Methods: A cumulative genetic risk score was based on four human leukocyte antigen (HLA) and 106 non-HLA risk loci genotyped or imputed in 842 Belgian MS patients and 321 controls. Non-parametric analyses were applied. Results: An increased genetic risk is observed for MS patients, including subsets such as oligoclonal band-negative and primary progressive MS patients, compared to controls. Within the patient group, a stronger association between HLA risk variants and the presence of oligoclonal bands, an increased immunoglobulin G (IgG) index and female gender was apparent. Results suggest an association between a higher accumulation of non-HLA risk variants and increased relapse rate as well as shorter relapse-free intervals after disease onset. Conclusion: MS patients display a significantly increased genetic risk compared to controls, irrespective of disease course or presence of oligoclonal bands. Whereas the cumulative burden of non-HLA risk variants appears to be reflected in the relapses of MS patients, the HLA region influences intrathecal IgG levels. [ABSTRACT FROM AUTHOR]

Relapse rates and thus the impact of therapies have been decreasing. Why they decline and the impact on our ability to understand which treatments are better require more than simple math. The objective of this review is to discuss the impact of regression to the mean, changes in outcome effects and how we compare outcomes over time and among studies. This paper provides discourse on the topics of regression to the mean, some examples of the pitfalls of changes and some difficulties in the interpretation of the common percentage change in outcomes. The results show that we can often be deceived by what we think we see and they also demonstrate how such confusion evolves in the literature. This article aims to caution against the over-interpretation of changes from baseline, which are helped along by regression towards the mean and other factors. Furthermore, how we interpret changes from baseline requires care and not wishful thinking, coupled with careful digestion of seemingly reasonable explications of results. [ABSTRACT FROM AUTHOR]

Background: The role of vaccine-mediated inflammation in exacerbating multiple sclerosis (MS) is a matter of debate. Objective: In this cross-sectional study, we compared the cerebrospinal fluid (CSF) inflammation associated with MS relapses or anti-COVID-19 mRNA vaccinations in relapsing-remitting multiple sclerosis (RRMS). Methods: We dosed CSF cytokines in 97 unvaccinated RRMS patients with clinical relapse within the last 100 days. In addition, we enrolled 29 stable RRMS and 24 control patients receiving COVID-19 vaccine within the last 100 days. Results: In RRMS patients, a negative association was found between relapse distance and the CSF concentrations of the pro-inflammatory cytokines interleukin (IL)-2 (beta = −0.265, p = 0.016), IL-6 (beta = −0.284, p = 0.01), and IL-17 (beta = −0.224, p = 0.044). Conversely, vaccine distance positively correlated with a different set of cytokines including IL-12 (beta = 0.576, p = 0.002), IL-13 (beta = 0.432, p = 0.027), and IL-1ra (beta = 0.387, p = 0.05). These associations were significant also considering other clinical characteristics. No significant associations emerged between vaccine distance and CSF molecules in the control group. Conclusion: Vaccine for COVID-19 induces a central inflammatory response in RRMS patients that is qualitatively different from that associated with disease relapse. [ABSTRACT FROM AUTHOR]

Background: Due to lack of biomarkers, antibody-negative patients with features of neuromyelitis optica spectrum disorders (NMOSD) are among the most challenging to diagnose and treat. Using unsupervised clustering, we recently identified 'MS-like', 'spinal MS-like', 'classic NMOSD-like' and 'NMOSD-like with brain involvement' subgroups in this cohort. Objective: We used magnetic resonance spectroscopy (MRS) to examine differences in the level of key metabolites in the spinal cord between the four identified subgroups. Methods: Twenty-five relapsing antibody-negative patients with NMOSD features classified by the unsupervised algorithm to one of the subgroups underwent a prospective cervical spinal cord MRS. Spectra from 16 patients fulfilled quality criteria and were included in the analysis. Results: Total N -acetylaspartate (tNAA), but not total choline (tCho) or myo-inositol (Ins), was significantly different between the four subgroups (p = 0.03). In particular, tNAA was 47.8% lower in the 'MS-like' subgroup as compared with the 'classic NMOSD-like' subgroup (p = 0.02). While we found a negative overall correlation between tNAA and disability score (r = –0.514, p = 0.04) in the whole cohort, the disability score did not differ significantly between the subgroups to explain subgroup differences in tNAA level. Conclusions: Significant differences in the cervical spinal cord tNAA measurements confirm that the previously identified clinico-radiologic subgroups contain patients with distinct underlying disease processes. [ABSTRACT FROM AUTHOR]

The article discusses a study related to emergence of safe treatments and disease-modifying therapy (DMT) for multiple sclerosis (MS). It mentions that the apparent reduction in efficacy of the available DMTs in the aging MS patient should focus towards meningeal infiltrates, cortical abnormalities and microglial activation that is seen in progressive MS. It also mentions that discontinuation of medications like natalizumab may be associated with enhanced risk of recurrence.

Background: Change in ventricular volume has been suggested as surrogate measure of central brain atrophy (CBA) applicable to the everyday management of multiple sclerosis (MS) patients. Objectives: We investigated the contribution of inflammatory activity (including the severity of lesional tissue damage) to CBA. Methods: Fifty patients with relapsing–remitting multiple sclerosis (RRMS) were enrolled. Lesional activity during 4 years of follow-up was analysed using custom-build software, which segmented expanding part of the chronic lesions, new confluent lesions and new free-standing lesions. The degree of lesional tissue damage was assessed by change in mean diffusivity (MD). Volumetric change of lateral ventricles was used to measure CBA. Results: During follow-up, ventricles expanded on average by 12.6% ± 13.7% (mean ± SD). There was a significant increase of total lesion volume, 69.3% of which was due to expansion of chronic lesions. Correlation between volume of combined lesional activity and CBA (r 2 = 0.67) increased when lesion volume was adjusted by the degree of tissue damage severity (r 2 = 0.81). Regression analysis explained 90% of CBA variability, revealing that chronic lesion expansion was by far the largest contributor to ventricular enlargement. Discussion: CBA is almost entirely explained by the combination of the volume and severity of lesional activity. The expansion of chronic lesions plays a central role in this process. [ABSTRACT FROM AUTHOR]

The author comments on articles within the issue which present opposing views on the efficacy of oral versus intravenous corticosteroids in the treatment of multiple sclerosis (MS) relapses. Topics include an argument in the paper by J. D. Bowen and P. Qian about the greater impact of intravenous regimens on immune mediators of MS relapse activity and the findings by E. Le Page et al suggesting that there is no significant difference between the two routes in treating relapses.

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit–risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0–2), then DMF (Years 3–10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04–10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF (n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120–0.169)), while for PBO/DMF (n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0–2 years, 0.330 (95% CI, 0.266–0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118–0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment. [ABSTRACT FROM AUTHOR]

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ). Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively. Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses. sNfL was measured using single-molecule array (Simoa™). HAD definition was ⩾2 relapses in year before randomization and ⩾1 baseline gadolinium-enhancing lesion. Results: Baseline median sNfL levels were similar in alemtuzumab (n = 354) and SC IFNB-1a–treated (n = 159) patients (31.7 vs 31.4 pg/mL), but decreased with alemtuzumab versus SC IFNB-1a until year 2 (Y2; 13.2 vs 18.7 pg/mL; p < 0.0001); 12.7 pg/mL for alemtuzumab at Y7. Alemtuzumab-treated patients had sNfL at/below healthy control median at Y2 (72% vs 47%; p < 0.0001); 73% for alemtuzumab at Y7. HAD patients (n = 102) had higher baseline sNfL (49.4 pg/mL) versus overall population; alemtuzumab HAD patients attained similar levels (Y2, 12.8 pg/mL; Y7, 12.7 pg/mL; 75% were at/below control median at Y7). Conclusion: Alemtuzumab was superior to SC IFNB-1a in reducing sNfL, with levels in alemtuzumab patients remaining stable through Y7. ClinicalTrials.gov identifier: NCT00530348, NCT00930553, NCT02255656 [ABSTRACT FROM AUTHOR]

The article examines the best threshold for the rule of five and demonstrates the predictive validity for subsequent multiple sclerosis trials risk relapses. The study shows that the best threshold definition is a threshold of five lesions. It considers the rule of five breakage as a significant imminent relapse predictor. The discovery of lesions as important relapse predictor is also noted.

The article discusses the meta-analysis and systematic review on time-patterns of annualized relapse rates (ARR) of multiple sclerosis (MS) in randomized placebo-controlled clinical trials. It says that sytemic literature search on randomized, placebo-controlled trials in relapsing (RMS) was performed by serching PubMed. Results showed that trial ARR lessens during a trial in RMS, which is accordance with epidemiological findings.

Background: REFINE was an exploratory, dose- and frequency-blinded, prospective, randomized, dose-ranging study in relapsing–remitting multiple sclerosis (RRMS) patients. Objective: To examine the efficacy, safety, and tolerability of natalizumab administered via various regimens in RRMS patients. Methods: Clinically stable RRMS patients previously treated with 300 mg natalizumab intravenously for ⩾12 months were randomized to one of six natalizumab regimens over 60 weeks: 300 mg administered intravenously or subcutaneously every 4 weeks (Q4W), 300 mg intravenously or subcutaneously every 12 weeks (Q12W), or 150 mg intravenously or subcutaneously Q12W. The primary endpoint was the mean cumulative number of combined unique active magnetic resonance imaging (MRI) lesions at week 60. Results: In total, 290 patients were enrolled. All Q12W dosing arms were associated with increased clinical and MRI disease activity and closed early; ⩾39.5% of patients in each Q12W arm met rescue criteria. In the 300 mg intravenous and subcutaneous Q4 W arms, the mean cumulative number of combined unique active MRI lesions was 0.23 and 0.02, respectively; annualized relapse rates were 0.07 and 0.08, respectively; and trough natalizumab serum levels and α4-integrin saturation were comparable. Conclusion: Natalizumab 300 mg subcutaneous Q4W was comparable to 300 mg intravenous Q4W dosing with respect to efficacy, pharmacokinetics/pharmacodynamics, and safety. [ABSTRACT FROM AUTHOR]

Background: There are fewer multiple sclerosis (MS) relapses during pregnancy, although relapse risk increases in the early post-partum period, as has been predicted by pre-pregnancy or pregnancy disease activity in some studies. Objective: The aim of this study was to evaluate the correlation between magnetic resonance imaging (MRI) changes in the year before pregnancy and the relapse rate in the year post-partum. Methods: An observational retrospective case–control study included 172 pregnancies in 118 females with MS. Statistical analyses were used to evaluate the correlation between MRI and post-partum relapses. Clustered logistic regression was used to investigate the predictors of early post-partum relapses. Results: We found a significant correlation for an active-MRI pre-pregnancy and relapses in the first 3 months post-partum (p < 0.001). Expanded Disability Status Scale (EDSS) pre-pregnancy and relapses in the first 3 months post-partum were also significantly correlated (p = 0.009). Using a multivariate model, we predicted which women will not experience post-partum relapse by EDSS and by an active-MRI pre-pregnancy (96.7% specificity; p < 0.001). Conclusion: An active-MRI pre-pregnancy is a strong and sensitive predictor of early post-partum relapse, regardless of whether the woman had clinical evidence of disease activity prior to conception and delivery. This finding could provide clinicians with a strategy to minimize post-partum relapse risk in women with MS planning pregnancy. [ABSTRACT FROM AUTHOR]

Background: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). Objective and Methods: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5–1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo. Results: At 8 years' follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%–43.1%) of assessed participants in the IFNβ-1a–fingolimod switch group and 41.9% (36.6%–47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a–fingolimod switch group than on continuous fingolimod (5.4% [3.0%–9.5%] vs 14.2% [10.8%–18.4%], p = 0.01). Conclusion: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments. [ABSTRACT FROM AUTHOR]

Background: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. Objective: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. Methods: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile). Results: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95]; p = 0.0001) and greater whole brain volume loss during the following year (β = −0.36%; 95% CI = [−0.60, −0.13]; p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). Conclusion: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information. [ABSTRACT FROM AUTHOR]

Background: Prognostic markers are needed to guide multiple sclerosis (MS) management in the context of large availability of disease-modifying drugs (DMDs). Objective: To investigate the role of cerebrospinal fluid (CSF) markers to inform long-term MS outcomes. Methods: Demographic features, IgM index, oligoclonal IgM bands (OCMB), lipid-specific OCMB, CSF neurofilament light chain protein levels, expanded disability status scale (EDSS), relapses and DMD use over the study period and peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell plus inner plexiform layer (GCIPL) thicknesses in non-optic neuritis eyes (end of follow-up) were collected from relapsing MS (RMS) patients with CSF obtained ⩽2 years after MS onset prospectively followed at the Hospital Clinic of Barcelona. We assessed associations between CSF markers and MS outcomes using multivariable models. Results: A total of 89 patients (71 females; median 32.9 years of age) followed over a median of 9.6 years were included. OCMB were associated with a 33% increase in the annualized relapse rate (ARR; p = 0.06), higher odds for high-efficacy DMDs use (OR = 4.8; 95% CI = (1.5, 16.1)), thinner pRNFL (β = −4.4; 95% CI = (−8.6, −0.2)) and GCIPL (β = −2.9; 95% CI = (−5.9, +0.05)), and higher rates to EDSS ⩾ 3.0 (HR = 4.4; 95% CI = (1.6, 11.8)) and EDSS ⩾ 4.0 (HR = 5.4; 95% CI = (1.1, 27.1)). No overall associations were found for other CSF markers. Conclusion: The presence of OCMB was associated with unfavorable long-term outcomes. OCMB should be determined in RMS to inform long-term prognosis. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is characterized by central nervous system (CNS) infiltration of T and B cells, excess inflammatory cytokine and chemokine production and failure of immune regulation. CD19+CD24hiCD38hi transitional B cells producing interleukin (IL)-10 have been shown to suppress interferon-γ (IFNγ) and tumour necrosis factor-α (TNFα) production by CD4+ T cells and to be dysfunctional in autoimmune arthritis and systemic lupus erythematosus. Objective: We hypothesized that transitional B-cell-dependent immune regulation could be defective in MS and examined their function in healthy subjects and patients with relapsing-remitting multiple sclerosis (RRMS). Methods: A total of 62 healthy donors and 21 RRMS subjects donated peripheral blood for the study. IL-10-producing B cells, IFNγ and TNFα-producing T cells and proliferating T cells were quantified by flow cytometry. Results: In healthy individuals, CD19+CD24hiCD38hi transitional B cells produce more IL-10 than CD19+CD24+CD38+ naive and CD19+CD24hiCD38− memory B cells and are able to suppress CD4+ T-cell proliferation and IFNγ and TNFα-production. In subjects with RRMS, CD19+CD24hiCD38hi transitional B cells produce significantly less IL-10 and to fail to suppress effector T-cell function. Conclusion: CD19+CD24hiCD38hi transitional B cells physiologically represent the most potent regulatory B-cell subset and are functionally defective in patients with RRMS, an abnormality that may contribute to the immune pathological process. [ABSTRACT FROM AUTHOR]

Background: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. Objective: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. Methods: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. Results: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18–55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. Conclusion: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted. [ABSTRACT FROM AUTHOR]

The author highlights advances in the design of clinical drug trials for progressive multiple sclerosis (MS). Topics discussed include disease-modifying therapies that reduce relapses and relapse-related disability in patients with relapsing-remitting MS, the challenges to the development of effective therapies for progressive MS, and highlights of the 2017 European Committee for Treatment and Research in Multiple Sclerosis focused workshop held in Rome, Italy.

Background: B cells may be involved in the pathophysiology of multiple sclerosis (MS). Inebilizumab (formerly MEDI-551) binds to and depletes CD19+ B cells. Objectives: To assess safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of inebilizumab in adults with relapsing MS. Methods: This phase 1 trial randomised 28 patients 3:1 (21, inebilizumab; 7, placebo) to inebilizumab (2 intravenous (IV) doses, days 1 and 15: 30, 100 or 600 mg; or single subcutaneous (SC) dose on day 1: 60 or 300 mg) or matching placebo, with follow-up until at least week 24 or return of CD19+ B-cell count to ⩾80 cells/μL. Results: Complete B-cell depletion was observed across all doses. Infusion/injection (grade 1/2) reactions occurred in 6/15 patients receiving inebilizumab IV, 2/5 placebo IV and 1/6 inebilizumab SC. Serious adverse events occurred in three patients receiving inebilizumab: pyrexia, mixed-drug intoxication (unrelated to inebilizumab; resulted in death) and urinary tract infection. Mean number of cumulative new gadolinium-enhancing lesions over 24 weeks was 0.1 with inebilizumab versus 1.3 with placebo; mean numbers of new/newly enlarging T2 lesions were 0.4 and 2.4, respectively. Conclusion: Inebilizumab had an acceptable safety profile in relapsing MS patients and showed a trend in reductions in new/newly enlarging and gadolinium-enhancing lesions. [ABSTRACT FROM AUTHOR]

Background: Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments. Objective: Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE. Methods: Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the overall population and subgroups defined by baseline demographic/disease characteristics. Results: Daclizumab beta significantly reduced risk of 24-week CDP (hazard ratio (HR), 0.73; 95% confidence interval (95% CI), 0.55–0.98), risk of 24-week sustained MSFCS progression (HR, 0.80; 95% CI, 0.67–0.95), and odds of clinically meaningful worsening in MSIS-29 PHYS (odds ratio, 0.76; 95% CI, 0.60–0.95) versus IM interferon beta-1a. Point estimates showed trends favoring daclizumab beta over IM interferon beta-1a across several patient subgroups for all three outcome measures. Conclusion: Daclizumab beta showed consistent benefit versus IM interferon beta-1a across measures assessing patient disability/function and across a range of clinical baseline characteristics in patients with relapsing-remitting MS. [ABSTRACT FROM AUTHOR]

Background: Women with multiple sclerosis (MS) experience an increased risk of relapse in the postpartum period. High-dose methylprednisolone is the first-line treatment for acute relapses. Objectives: To determine the transfer of methylprednisolone into human milk in breastfeeding MS patients. Methods: Methylprednisolone therapy was given for postpartum relapse to nine patients for three consecutive days, and seven patients received a daily infusion once a month. Breast milk samples were obtained before infusion and 1, 2, 4, 8, and 12 hours after completion of infusion. Results: Methylprednisolone concentrations in milk were below detection limits immediately before infusion. Cmax was measured at 1, 2, 4, 8, and 12 hours after infusion and levels of 2.100, 1.659, 0.680, 0.174, and 0.102 µg/mL were determined, respectively. The absolute infant dose was 98.98 µg/kg/day, and the relative infant dose (RID) was 0.71% of the weight-adjusted maternal dose. Conclusion: The level of methylprednisolone transfer into breast milk is very low. The RID for methylprednisolone was lower than the generally accepted value. As methylprednisolone therapy is of short duration, infant exposure would be very low should a mother choose to breastfeed 1 hour after infusion. Waiting 2--4 hours after infusion will limit infant exposure still further. [ABSTRACT FROM AUTHOR]

Background: No randomized controlled trials have compared the efficacy of fingolimod or natalizumab as second-line treatment in patients with relapsing–remitting multiple sclerosis (RRMS). Objective: To compare clinical outcomes after escalation to fingolimod versus natalizumab in patients with clinically active RRMS. Methods: Using the registry of the Swiss Federation for Common Tasks of Health Insurances, we identified patients with RRMS and ≥1 relapse in the year before switching from interferon beta or glatiramer acetate to fingolimod or natalizumab. Propensity score matching was used to select patients with comparable baseline characteristics. Relapse and Expanded Disability Status Scale (EDSS) outcomes were compared in paired, pairwise-censored analyses. Results: Of the 547 included patients, 358 were matched (fingolimod, n = 179; natalizumab, n = 179). Median follow-up time was 1.8 years (interquartile range 0.9–2.9). Patients switching to natalizumab had a lower risk of relapses (incidence rate ratio 0.5, 95% confidence interval (CI) 0.3–0.8, p = 0.001) and were more likely to experience EDSS improvement (hazard ratio (HR) 1.8, 95% CI 1.1–2.7, p = 0.01) compared to fingolimod. We found no differences in the proportion of patients free from EDSS progression (HR 0.9, 95% CI 0.5–1.5, p = 0.62). Conclusion: Natalizumab seems to be more effective in reducing relapse rate and improving disability compared with fingolimod. [ABSTRACT FROM AUTHOR]

In the majority of relapsing multiple sclerosis patients, the disease can be quite easily controlled by already available, approved therapies. There are, however, some aggressive cases who continue to have clinical and magnetic resonance imaging (MRI) activity in spite of the treatment. These are the cases who may now receive benefit from intense immunosuppression followed by autologous haematopoietic stem cell transplantation (aHSCT). In this review, we describe the method and the rationale of aHSCT, the more recently published studies that demonstrate its efficacy in selected multiple sclerosis cases, the problems related to safety and the transplant-related mortality risk of the procedure. A description of the ideal patient who can take advantage of aHSCT is outlined and, finally, the ongoing studies which are near to completion or are close to starting are briefly reported. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the efficacy and safety of fingolimod (FTY) 0.5 mg administered every other day (FTY-EOD) compared to every day (FTY-ED) in multiple sclerosis patients. Methods: Multicentre retrospective observational study. Clinical, laboratory and neuroimaging data were consecutively collected from 60 FTY-EOD and 63 FTY-ED patients. Baseline characteristics were compared using logistic regression. Efficacy in preventing occurrence of relapses and demyelinating lesions was tested using propensity score--adjusted Cox and linear regressions. Results: Weight was inversely associated with risk of switch to FTY-EOD because of any reason (odds ratio (OR) = 0.94, 95% confidence interval (95% CI) = 0.89-0.99, p = 0.026), and female sex and lower baseline lymphocyte count were positively associated with switch because of lymphopenia. Compared to FTY-ED patients, FTY-EOD patients were at higher risk of developing relapses (hazard ratio (HR) = 2.98, 95% CI = 1.07-8.27, p = 0.036) and either relapses or new magnetic resonance imaging (MRI) demyelinating lesions (combined outcome, HR = 2.07, 95% CI = 1.06-4.08, p = 0.034). Within FTY-EOD, treatment with natalizumab before FTY and lower age were positively associated with risk of developing relapses and combined outcome, respectively (HR = 25.71, 95% CI = 3.03-217.57, p = 0.002 and HR = 0.85, 95% CI = 0.77-0.96, p = 0.005). FTY-EOD was overall well tolerated. Conclusion: Disease reactivation was observed in a significant proportion of patients treated with FTYEOD. Neurologists should be cautious when reducing FTY administration to every other day, especially in younger patients and those previously treated with natalizumab. [ABSTRACT FROM AUTHOR]

The last several decades have witnessed considerable progress in our understanding of the pathogenesis, refining diagnostic criteria, and identifying therapies of value for modifying the course of relapsing forms of multiple sclerosis. While the pace of progress has lagged for those with progressive phase disease, this now seems to be changing. This review considers those characteristics of patients with primary progressive multiple sclerosis that may contribute to phase 3 trial success and identifies some of the thorny issues that remain ahead. The larger of the studies conducted thus far have sequentially informed our understanding of "pure" primary progressive disease, and also challenge both phase 3 and especially phase 2 trial designs and participant selection for investigations going forward. This may have particular relevance for testing therapeutics directed at neuroprotection and repair in the face of ongoing progression regardless of trial participant categorization using current conventional disease phenotypes. [ABSTRACT FROM AUTHOR]

Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS. [ABSTRACT FROM AUTHOR]

Objective: Objective and reproducible evaluation of data quality is of paramount importance for studies of 'real-world' observational data. Here, we summarise a standardised data quality, density and generalisability process implemented by MSBase, a global multiple sclerosis (MS) cohort study. Methods: Error rate, data density score and generalisability score were developed using all 35,869 patients enrolled in MSBase as of November 2015. The data density score was calculated across six domains (follow-up, demography, visits, MS relapses, paraclinical data and therapy) and emphasised data completeness. The error rate evaluated syntactic accuracy and consistency of data. The generalisability score evaluated believability of the demographic and treatment information. Correlations among the three scores and the number of patients per centre were evaluated. Results: Errors were identified at the median rate of 3 per 100 patient-years. The generalisability score indicated the samples' representativeness of the known MS epidemiology. Moderate correlation between the density and generalisability scores (ρ = 0.58) and a weak correlation between the error rate and the other two scores (ρ = -0.32 to -0.33) were observed. The generalisability score was strongly correlated with centre size (ρ = 0.79). Conclusion: The implemented scores enable objective evaluation of the quality of observational MS data, with an impact on the design of future analyses. [ABSTRACT FROM AUTHOR]

Objective: To define values of normalized brain volume (NBV) that can be categorized as low, medium, or high, according to baseline characteristics of relapsing-remitting multiple sclerosis (RRMS) patients. Methods: Expected NBV (eNBV) was calculated for each patient based on age, disease duration, sex, baseline Expanded Disability Status Scale (EDSS), and T2-lesion volume, entering these variables into a multiple regression model run on 2342 RRMS patients (pooled FREEDOMS/FREEDOMS-II population). According to the difference between their observed NBV and their eNBV, patients were classified as having low NBV, medium NBV, or high NBV. We evaluated whether these NBV categories were clinically meaningful by assessing correlation with disability worsening. Results: The distribution of differences between observed NBV and eNBV was used to categorize patients as having low NBV, medium NBV or high NBV. Taking the high-NBV group as reference, the hazard ratios (HRs) for 2-year disability worsening, adjusted for treatment effect, were 1.23 (95% confidence interval (CI): 0.92-1.63, p = 0.16) for the medium NBV and 1.75 (95% CI: 1.26-2.44, p = 0.001) for the low NBV. The predictive value of NBV groups was preserved over 4 years. Treatment effect appeared more evident in low-NBV patients (HR = 0.58) than in medium-NBV (HR = 0.72) and in high-NBV (HR = 0.80) patients; however, the difference was not significant (p = 0.57). Conclusion: RRMS patients can be categorized into disability risk groups based on individual eNBV values according to baseline demographics and clinical characteristics. [ABSTRACT FROM AUTHOR]

Background and objective: The dentate nucleus, which is the largest of the cerebellar nuclei, plays a critical role in movement and cognition. The aim of our study was to assess any changes in dentate functional connectivity (FC) in adult relapsing remitting multiple sclerosis (RR-MS) patients and to investigate possible clinical correlates. Materials and methods: In all, 54 patients and 24 healthy subjects (HS) underwent multimodal magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), three-dimensional-T1-weighted and resting state (RS) functional images; they also underwent a cognitive evaluation, that is, attention and information processing speed, by means of the Paced Auditory Serial Addition Test (PASAT). Patients were also scored according to Expanded Disability Status Scale (EDSS). RS-MRI data were analysed using FMRIB Software Library (FSL) tools, with the seed-based method to identify dentate FC. Results: When compared with HS, patients exhibited brain atrophy and widespread DTI abnormalities, as well as greater FC between the dentate nucleus and cortical areas, particularly in the frontal and parietal lobes. Within these areas, FC in patients correlated inversely with clinical impairment. Finally, FC correlated inversely with lesion load and microstructural brain damage. Conclusion: Our findings indicate that dentate FC at rest is altered in MS patients. Whether these functional changes are induced by the disease and play a compensatory role remains to be established. [ABSTRACT FROM AUTHOR]

Background: Severe rebound multiple sclerosis (MS) activity is a life-threatening complication of natalizumab (NTZ) withdrawal, for which pathogenesis and treatment are still unclear. We report the immunological and pathological characterization of a case of central nervous system (CNS) inflammatory demyelination after NTZ discontinuation. Objective: To understand the pathophysiology of this neuroinflammatory condition. Methods: Antemortem blood and cerebrospinal fluid (CSF) analysis was compared with postmortem pathological studies, as well as with novel flow cytometry characterization of immune cells isolated from the CNS parenchyma. Results: Pathological analysis of the brain revealed the presence of innumerable active inflammatory demyelinating lesions typical of immunopathological pattern II. Monocytes/macrophages and B cells were enriched in the CNS parenchyma compared to the CSF. Numerous plasma cells were present in the lesions, but CD8 T lymphocytes were predominant in the parenchyma, as opposed to CD4 in the CSF. CNS-infiltrating lymphocytes expressed high levels of adhesion molecules, granzyme B (GzB), interferon-gamma (IFN-γ), and interleukin (IL)-17. Conclusions: Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS inflammation. [ABSTRACT FROM AUTHOR]

The article presents abstracts on topics related to multiple sclerosis (MS) including the not-MS diagnoses, the neurovascular coupling in relapsing-remitting MS and the use of optical coherence tomography in differentiating patients with MS and neuromyelitis optica spectrum disorder.

Background: Natalizumab and fingolimod have not been compared in controlled trials but only in observational studies, with inconclusive results. Objectives: The objective of this study is to compare the effect of natalizumab and fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Methods: We included all consecutive RRMS patients switched from first-line agents (glatiramer acetate/interferons) to natalizumab or fingolimod, with a follow-up of 24 months. Data of relapses, Expanded Disability Status Scale score and brain magnetic resonance imaging (MRI) scans were collected. We used propensity score (PS) matching and intention-to-treat analysis. Results: We retained 102 patients in each cohort after PS matching, with similar baseline characteristics. More patients discontinued natalizumab compared to fingolimod (33% vs 11%, p < 0.001), mainly for progressive multifocal leukoencephalopathy (PML) concern. No serious adverse events occurred in the two cohorts. Compared to fingolimod, the natalizumab group presented a higher percentage of relapse-free patients (66% vs 80%, p = 0.015), a higher percentage of disability-improved patients (6% vs 15%, p = 0.033), a lower percentage of MRI-active patients (38% vs 14%, p = 0.001) and a higher percentage of patients with no evidence of disease activity (NEDA-3; 44% vs 70%, p < 0.001) after 2 years of follow-up. Disability worsening was not statistically different in the two groups. Conclusion: Natalizumab is superior to fingolimod in RRMS patients non-responding to first-line agents. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of subcutaneous peginterferon beta-1a over 2 years in patients with relapsing-remitting multiple sclerosis in the ADVANCE study. Methods: Patients were randomized to placebo or 125 μg peginterferon beta-1a every 2 or 4 weeks. For Year 2 (Y2), patients originally randomized to placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks. Patients randomized to peginterferon beta-1a in Year 1 (Y1) remained on the same dosing regimen in Y2. Results: Compared with Y1, annualized relapse rate (ARR) was further reduced in Y2 with every 2 week dosing (Y1: 0.230 [95% CI 0.183-0.291], Y2: 0.178 [0.136-0.233]) and maintained with every 4 week dosing (Y1: 0.286 [0.231-0.355], Y2: 0.291 [0.231-0.368]). Patients starting peginterferon beta-1a from Y1 displayed improved efficacy versus patients initially assigned placebo, with reductions in ARR (every 2 weeks: 37%, p<0.0001; every 4 weeks: 17%, p=0.0906), risk of relapse (every 2 weeks: 39%, p<0.0001; every 4 weeks: 19%, p=0.0465), 12-week disability progression (every 2 weeks: 33%, p=0.0257; every 4 weeks: 25%, p=0.0960), and 24-week disability progression (every 2 weeks: 41%, p=0.0137; every 4 weeks: 9%, p=0.6243). Over 2 years, greater reductions were observed with every 2 week versus every 4 week dosing for all endpoints and peginterferon beta-1a was well tolerated. Conclusions: Peginterferon beta-1a efficacy is maintained beyond 1 year, with greater effects observed with every 2 week versus every 4 week dosing, and a similar safety profile to Y1. Clinicaltrials.gov Registration Number: NCT00906399. [ABSTRACT FROM AUTHOR]

The comparative clinical and demographic features of neuromyelitis optica (NMO) are not well known. In this review we analyzed peer-reviewed publications for incidence and prevalence, clinical phenotypes, and demographic features of NMO. Population-based studies from Europe, South East and Southern Asia, the Caribbean, and Cuba suggest that the incidence and prevalence of NMO ranges from 0.05–0.4 and 0.52–4.4 per 100,000, respectively. Mean age at onset (32.6–45.7) and median time to first relapse (8–12 months) was similar. Most studies reported an excess of disease in women and a relapsing course, particularly in anti-aquaporin 4 antibody (anti AQP4-IgG)-positive patients. Ethnicity may have a bearing on disease phenotype and clinical outcome. Despite limitations inherent to the review process, themes noted in clinical and demographic features of NMO among different populations promote a more global understanding of NMO and strategies to address it. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates whether the impact of fingolimod on disability progression was caused by its effects on brain volume loss and magnetic resonance imaging (MRI) lesions. The study assessed brain volume change and the effect of fingolimod therapy on disability progression in patients with multiple sclerosis (MS). The study found that the effect of fingolimod treatment on brain volume loss and relapses were both predictors of the treatment's impact on disability.

The article presents a study which investigates the occurrences of spinal cord atrophy and structural variability of the upper cervical cord in early multiple sclerosis (MS). The study measures the upper cervical cord cross-sectional area (UCCA) in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS). Results show that the UCCA was reduced in CIS and RRMS patients.

The article presents a study which aims to investigate the difference in cortical surface area, thickness and volume between early relapsing-remitting multiple sclerosis (RRMS) patients and healthy controls and explores the relationship between such measures and neurological disability, fatigue and depression. It notes the magnetic resonance imaging (MRI), neurological and neuropsychological examinations underwent by RRMS patients. It reveals that cortical thickness is affected in early RRMS.