Search

Increasing systemic prolactin levels improves remyelination and neuronal survival in animal models of Multiple Sclerosis (MS), but it has been suggested that this therapeutic strategy may also increase inflammatory responses, and potentially harm patients. We analyzed serum prolactin and cytokine, chemokine and growth factor levels in sera from MS patients enrolled in two clinical trials who were treated with domperidone, a generic drug that increases systemic prolactin levels. In patients treated with domperidone, molecule levels changed little during follow up, while prolactin levels increased several-fold. We found no significant association between prolactin levels and radiological or clinical outcome., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Accurate segmentation of MS lesions on MRI is difficult and, if performed manually, time consuming. Automatic segmentations rely strongly on the image contrast and signal-to-noise ratio. Literature examining segmentation tool performances in real-world multi-site data acquisition settings is scarce., Objective: FLAIR 2 , a combination of T 2 -weighted and fluid attenuated inversion recovery (FLAIR) images, improves tissue contrast while suppressing CSF. We compared the use of FLAIR and FLAIR 2 in LesionTOADS, OASIS and the lesion segmentation toolbox (LST) when applied to non-homogenized, multi-center 2D-imaging data., Methods: Lesions were segmented on 47 MS patient data sets obtained from 34 sites using LesionTOADS, OASIS and LST, and compared to a semi-automatically generated reference. The performance of FLAIR and FLAIR 2 was assessed using the relative lesion volume difference (LVD), Dice coefficient (DSC), sensitivity (SEN) and symmetric surface distance (SSD). Performance improvements related to lesion volumes (LVs) were evaluated for all tools. For comparison, LesionTOADS was also used to segment lesions from 3 T single-center MR data of 40 clinically isolated syndrome (CIS) patients., Results: Compared to FLAIR, the use of FLAIR 2 in LesionTOADS led to improvements of 31.6% (LVD), 14.0% (DSC), 25.1% (SEN), and 47.0% (SSD) in the multi-center study. DSC and SSD significantly improved for larger LVs, while LVD and SEN were enhanced independent of LV. OASIS showed little difference between FLAIR and FLAIR 2 , likely due to its inherent use of T 2 w and FLAIR. LST replicated the benefits of FLAIR 2 only in part, indicating that further optimization, particularly at low LVs is needed. In the CIS study, LesionTOADS did not benefit from the use of FLAIR 2 as the segmentation performance for both FLAIR and FLAIR 2 was heterogeneous., Conclusions: In this real-world, multi-center experiment, FLAIR 2 outperformed FLAIR in its ability to segment MS lesions with LesionTOADS. The computation of FLAIR 2 enhanced lesion detection, at minimally increased computational time or cost, even retrospectively. Further work is needed to determine how LesionTOADS and other tools, such as LST, can optimally benefit from the improved FLAIR 2 contrast., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Genetic research in multiple sclerosis (MS) mostly compares patients with MS with healthy controls, but does not differentiate between MS disease courses. We compared peripheral blood gene expression patterns between extremes of MS phenotypes, i.e. patients with mild relapsing-remitting MS (mRRMS) and primary progressive MS (PPMS)., Methods: We analyzed global gene expression profiles of peripheral blood samples of age- and gender-matched patients with mRRMS and PPMS. Detailed bioinformatic and gene set enrichment analysis, pathway and principle component analyses were used to identify differentially expressed genes and pathways., Results: A total of 84 genes were significantly deregulated between the groups. Of those, 19 had been previously reported to be deregulated in patients with MS as compared with healthy controls, including major histocompatibility complex, interferon receptor 2 and interleukin 6 receptor. Detailed molecular pathway analysis revealed significant up-regulation of antigen processing and presentation, leukocyte transendothelial migration, nucleotide-binding oligomerization domain-like receptor signaling, chemokine signaling and down-regulation of RNA transport, spliceosome and aminoacyl-tRNA biosynthesis pathways in PPMS compared with mRRMS., Conclusion: Our analyses show significant differences between mRRMS and PPMS gene expression. Surprisingly, the differentially expressed genes were mostly involved in immunological and inflammatory pathways, suggesting that the difference in MS phenotypes is caused primarily by a difference in immune responses. It should be kept in mind that our analyses were in peripheral blood only, and that the observed differences in inflammatory pathways may be a substrate of the analysed tissue. Further research into gene expression differences between disease courses including analyses in central nervous system tissue is warranted., (© 2018 EAN.)

Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3T in 8 stable relapsing-remitting (RR) MS patients treated with minocycline over 3years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r=-0.94, P=0.02). This correlation was strongest in the head of caudate (r=-0.95, P=0.01) and putamen (r=-0.89, P=0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r=-0.72, P=0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients., (Copyright 2010 Elsevier B.V. All rights reserved.)

Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing-remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo-controlled study by determining the total number of T1 gadolinium-enhanced lesions at months 8 and 9 in patients who were starting glatiramer acetate and had at least one T1 gadolinium-enhanced lesion on screening magnetic resonance imaging. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study. Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63% (mean 1.47 versus 2.95; p = 0.08), the total number of new and enlarging T2 lesions by 65% (mean 1.84 versus 5.14; p = 0.06), and the total T2 disease burden (p = 0.10). A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group (0.19 versus 0.41; p = NS). Treatment was safe and well tolerated. We conclude that efficacy endpoints showed a consistent trend favoring combination treatment. As minocycline is a relatively safe oral therapy, further study of this combination is warranted in relapsing-remitting multiple sclerosis.

Background: Glucocorticoid treatment improves the speed of functional recovery of acute multiple sclerosis (MS) relapses but has not been shown to provide any long-term functional benefit. There is currently no convincing evidence that the clinical benefit is influenced by the route of administration or the dosage of glucocorticoid, or the particular glucocorticoid prescribed. Recent studies support similarities in the bioequivalence and in the clinical effect of high dose oral corticosteroids for MS relapses., Objective: This survey aimed to determine the relapse treatment preferences of clinicians in Canadian MS clinics., Methods: Members of the Canadian Network of MS Clinics are linked by an email server. A one page survey was distributed to the group to determine and report use of corticosteroids to manage MS relapses amongst Canadian MS specialists., Results: Fifty-one clinicians from 17 MS clinics were surveyed. 32 (63%) surveys were returned representing 16 clinics. Five doses are most commonly prescribed, usually without a taper. Three or four doses and the use of a corticosteroid taper, however, are not uncommon. Gastric cytoprotection and sedatives are often prescribed for use as needed., Conclusion: This survey illustrates that when Canadian clinicians with expertise in managing MS treat MS relapses they choose high dose corticosteroids, either oral or i.v. The results therefore represent Canadian practice as these clinicians provide direct patient care and influence care by community neurologists. Until evidence clearly identifies a superior practice all options should be available to clinicians and their patients.

Background: A new formulation of subcutaneous (s.c.) interferon-beta-1a has been developed (Rebif New Formulation, RNF), produced without fetal bovine serum and without human serum albumin as an excipient, with the aim of improving injection tolerability, and reducing immunogenicity., Objectives: This article reports 96-week analyses of a Phase IIIb, open-label study of the safety and immunogenicity of RNF compared with historical (EVIDENCE study) and recent (REGARD study) data on the original formulation., Methods: Patients with relapsing multiple sclerosis (McDonald criteria) and an Expanded Disability Status Scale score < 6.0 received RNF, 44 microg s.c. three times weekly., Results: The proportion of neutralizing antibody-positive (NAb+) patients (serum NAb status >or=20 neutralizing units/mL) at week 96 (last observation carried forward; primary endpoint) was 17.4% (exact 95% confidence interval [CI]: 13.0-22.5), compared with 21.4% (95% CI: 17.2-26.2) in the EVIDENCE study, and 27.3% (95% CI: 22.8-32.1) in the REGARD study. The proportion of patients NAb+ at any time during the 96 weeks was 18.9% (95% CI: 14.4-24.2), compared with 27.1% (95% CI: 22.4-32.2) and 33.7% (95% CI: 28.9-38.7), respectively. Most pre-specified categories of adverse events were reported by patients in the RNF study at a similar or lower proportion than in the EVIDENCE and REGARD studies. Injection-site reactions were experienced by fewer patients than in the EVIDENCE and REGARD studies., Conclusions: RNF has improved overall immunogenicity and safety profiles compared with the original formulation.

Objective: To examine the effect of allogeneic hematopoietic cell transplantation (HCT) on disease activity in a patient with multiple sclerosis (MS)., Design: Case report, prospective study, and autopsy., Setting: Departments of Clinical Neurosciences, Internal Medicine, and Pathology at the University of Calgary, Alberta, Canada., Patient: A 39-year-old woman with chronic myelogenous leukemia and concurrent mild MS., Interventions: Hematopoietic cell transplantation from a healthy unrelated donor., Results: After HCT the patient developed graft-vs-host disease and experienced worsening, but not new, neurological symptoms. Her circulating leukocytes were 100% of donor origin. Magnetic resonance imaging showed increased lesion burden. She died of adenovirus hepatitis 20 weeks after HCT. An autopsy revealed demyelinating-inflammatory activity in active lesions and chronic active lesions., Conclusion: Despite high-dose, cytotoxic, immunosuppressive therapy and exchange of a presumed autoreactive immune system with a healthy immune system, MS in this patient continued to be active.

Background: Randomized controlled trials incorporating validated depression scales have failed to identify an association between interferon beta treatment and depression in MS. This is surprising since interferons used in other clinical contexts are considered capable of causing depression. The negative results in MS could be due inadequate power in the published trials., Methods: In this study, longitudinal data from an IMS Health Canada database called the Therapy Dynamics database were analyzed. The database contains information about prescriptions filled at outpatient pharmacies in Canada, linked at the individual level over time periods as long as 36 months. Antidepressant prescriptions were used as a proxy indicator for depressive disorders. The frequency of antidepressant use was compared in cohorts treated with glatiramer acetate and interferon beta., Results: No differences in the frequency of antidepressant treatment were observed. A large proportion (approximately 40%) in all treatment cohorts were treated with antidepressants at some time over the study interval. The proportions remained comparable after adjustment for age and sex and in a time-to-event analysis of new antidepressant prescriptions. Among patients receiving prescriptions exclusively from Neurologists, the frequency of exposure to antidepressants was much lower (2.4%)., Conclusions: This analysis uncovered no evidence that antidepressant treatment occurs more often in people treated with interferon beta than in those treated with glatiramer acetate. These results help to confirm that depression is not associated with interferon beta treatment in MS.

T2 hypointensity (black T2, BT2) in the deep grey matter of multiple sclerosis (MS) patients correlate weakly with disability at 1.5 T. BT2 is likely to be caused by abnormal iron deposition. We compared the correlation between disability and deep grey matter BT2 measured on 3 T MRI and on 1.5 T MRI in 17 MS patients. We observed a significant correlation between expanded disability status scale and signal intensity on 3 T MRI in the globus pallidus and the caudate nucleus (r = -0.5, P < 0.05). BT2 at 3 T may be a useful MRI measure associated with disability in MS and warrants further study.

The past decade has witnessed a revolution in the treatment of multiple sclerosis (MS), the most common demyelinating disorder of the human CNS. After being considered as an untreatable disease for more than a century, six disease-modifying treatments have been approved between 1993 and 2006. Glatiramer acetate (GA) is a worldwide drug approved for the treatment of relapsing-remitting MS in 1996. The drug is a synthetic copolymer of four amino acids based on the composition of myelin basic protein, one of several putative autoantigens implicated in the pathogenesis of MS. Three separate double-blind, placebo-controlled trials have established its efficacy in relapsing-remitting MS. Observations from an ongoing study, the longest prospective study in MS therapeutics so far, suggest that the effect of GA in reducing the relapse rate and neurological disability is maintained over a 10-year period. Independent investigators have identified several putative immunological mechanisms of action of GA, with the unique observation of the generation of GA-reactive T-helper 2 (anti-inflammatory) polarised lymphocytes within days to weeks of initiating therapy and sustaining an anti-inflammatory milieu for years in the peripheral immune system and, presumably, in the CNS. Emerging data from immunological and imaging studies quantifying axonal injury in the brain point towards neuroprotective abilities of GA. Combined with its remarkable safety and tolerability, long-term efficacy and neuroprotective effect, GA presents it self as a first-line choice in relapsing-remitting MS, and holds immense promise in developing its potential as a combination therapy in MS, as well as extending its indications to other neurodegenerative diseases.

Background: Tactile temporal thresholds, which represent the time separating the onset of two tactile stimuli when they are judged as simultaneous, can differentiate a group of people with multiple sclerosis (MS) from normal controls. Demyelination, axonal injury and loss, and altered information processing all occur in MS and may cause these increased thresholds. Thus, tactile temporal thresholds may be a useful outcome measure in MS. Our objective was to assess whether tactile temporal thresholds reflect change during a MS relapse., Methods: During a study to evaluate the stability of tactile temporal thresholds in people with MS, two participants suffered relapses. Both events were associated with prolonged thresholds (i.e., significantly increased thresholds)., Conclusions: Tactile temporal thresholds can detect neurologic worsening and thus warrant further evaluation as a useful method to facilitate in the monitoring of disease change in people with MS.

The presence of depression is an important concern for patients with multiple sclerosis who are candidates for disease-modifying treatment, since depression may affect treatment adherence. The authors evaluated the positive predictive value of the Center for Epidemiologic Studies Depression Rating Scale (CES-D) in detecting depression among patients who were candidates for disease-modifying multiple sclerosis treatment. Of 47 patients who scored >/=16 on the CES-D, 74.5% (N=38) were found to have a depressive disorder. The results of the study indicate that case-finding for depressive disorders among multiple sclerosis patients can be facilitated by use of the CES-D scale.

Background: Once weekly interferon beta-1a for multiple sclerosis (OWIMS) demonstrated modest, but significant, magnetic resonance imaging (MRI) benefit of once-weekly (qw) interferon (IFN) beta-1a at 48 weeks, but no significant effect on relapses., Objective: An OWIMS extension permitted assessment of longer-term efficacy/safety of qw IFN beta-1a in relapsing-remitting multiple sclerosis (RRMS)., Methods: Placebo patients were rerandomized to IFN beta-1a, 22 or 44 mcg qw, for two additional 48-week intervals. Primary outcome was MRI lesion activity. Relapse rate and other MRI measures were secondary outcomes., Results: After three years, median (mean) T2 lesion count/patient/scan was 1.3 (2.6) for 44 mcg, 1.7 (3.3) for 22 mcg, 1.7 (3.4) for placebo/22 mcg, 2.0 (3.6) for placebo/44 mcg (all differences not significant). Annualized relapse rates were lowest for 44 mcg (0.77) versus other groups (0.83-0.86, not significant). Persistent neutralizing antibodies did not affect relapse rates, but MRI active lesions were increased in antibody-positive patients receiving 44 mcg compared to antibody negative patients., Conclusions: In RRMS, once weekly IFN beta-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen. In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN beta-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing.

Objective: To assess the effects of glatiramer acetate and beta interferon on fatigue in multiple sclerosis., Methods: Fatigue was measured at baseline and six months using the fatigue impact scale (FIS). Groups (glatiramer acetate and beta interferon) were evaluated for the proportion improved, using Fisher's exact test. Logistic regression analysis assessed the relation between treatment group and improvement and controlled for confounding variables., Results: Six month paired FIS assessments were available for 218 patients (76% female). Ages ranged between 19 and 61 years, with 86% having relapsing-remitting disease. Glatiramer acetate was used by 61% and beta interferon by 39%. At baseline, total FIS and subscale scores were comparable in the two groups. More patients improved on glatiramer acetate than on beta interferon on total FIS (24.8% v 12.9%, p = 0.033; adjusted odds ratio = 2.36, 95% confidence interval 1.03 to 5.42), and on physical (28.6% v 14.1%, p = 0.013) and cognitive subscales (21.1% v 10.6%, p = 0.045). Logistic regression analysis confirmed the association between glatiramer acetate use and improved fatigue, after accounting for baseline group differences., Conclusions: The odds of reduced multiple sclerosis fatigue were around twice as great with glatiramer acetate treatment as with beta interferon. Confirmation of this result is required.

Background: Relapses in multiple sclerosis (MS) can cause significant neurologic disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by blocking binding of alpha4beta1-integrin to vascular cell adhesion molecule-1., Objective: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses., Methods: In this randomized, double-blind, multicenter trial, the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks., Results: There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups. In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group. A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo., Conclusions: A single dose of IV natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment. These MRI findings are consistent with prior studies of natalizumab and support its further investigation as an agent for the treatment of MS.