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Objective: Multiple sclerosis (MS) is an autoimmune disease affecting the brain and spinal cord by demyelination and neurodegeneration. Although the cause of the disease is not known exactly due to its heterogeneous etiology, it is thought that inflammatory processes can be effective in the formation and progression of the MS pathology. Herein, the present study's aim was to evaluate the changes in inflammation-related proteins, which have a crucial role in the formation of neuroinflammation, according to the period of MS. Materials and Methods: The study included 33 MS patients, 8 of whom were in relapse and 25 in remission, and 10 healthy individuals. Lymphocytes were isolated from peripheral blood. After RNA isolation and cDNA conversion, NLRP3, ASC, NLRX1, IL-1β, and IL-18 gene expressions were measured in real time-polymerase chain reaction. In addition, the protein levels of the NLRP3 and ASC were determined from serum samples by enzyme-linked immunosorbent assay. Results: The expression of the NLRX1 gene was significantly decreased in the patient groups compared to the controls. The levels of NLRP3, ASC, and IL-18 gene expressions of patients were not significantly different from controls in the remission and relapse periods. Although IL-1β gene expressions of the patients in the remission period increased in value, it was not statistically significant compared to that of healthy controls. Conclusion: Our findings showed that anti-inflammatory NLRX1 protein can be considered as a strong biomarker in the diagnosis and treatment of MS, where neuroinflammation is the main cause.

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuroprotective and anti-inflammatory molecules of the central nervous system (CNS). Both bind to three G protein-coupled receptors, namely PAC1, VPAC1 and VPAC2, to elicit their beneficial effects in various CNS diseases, including multiple sclerosis (MS). In this study, we assessed the expression and distribution of PACAP/VIP receptors in the normal-appearing white matter (NAWM) of MS donors with a clinical history of either relapsing–remitting MS (RRMS), primary MS (PPMS), secondary progressive MS (SPMS) or in aged-matched non-MS controls. Gene expression studies revealed MS-subtype specific changes in PACAP and VIP and in the receptors' levels in the NAWM, which were partly corroborated by immunohistochemical analyses. Most PAC1 immunoreactivity was restricted to myelin-producing cells, whereas VPAC1 reactivity was diffused within the neuropil and in axonal bundles, and VPAC2 in small vessel walls. Within and around lesioned areas, glial cells were the predominant populations showing reactivity for the different PACAP/VIP receptors, with distinctive patterns across MS subtypes. Together, these data identify the differential expression patterns of PACAP/VIP receptors among the different MS clinical entities. These results may offer opportunities for the development of personalized therapeutic approaches to treating MS and/or other demyelinating disorders. [ABSTRACT FROM AUTHOR]

Objective: Multiple sclerosis (MS) is an autoimmune disease affecting the brain and spinal cord by demyelination and neurodegeneration. Although the cause of the disease is not known exactly due to its heterogeneous etiology, it is thought that inflammatory processes can be effective in the formation and progression of the MS pathology. Herein, the present study’s aim was to evaluate the changes in inflammation-related proteins, which have a crucial role in the formation of neuroinflammation, according to the period of MS. Materials and Methods: The study included 33 MS patients, 8 of whom were in relapse and 25 in remission, and 10 healthy individuals. Lymphocytes were isolated from peripheral blood. After RNA isolation and cDNA conversion, NLRP3, ASC, NLRX1, IL-1β, and IL-18 gene expressions were measured in real time-polymerase chain reaction. In addition, the protein levels of the NLRP3 and ASC were determined from serum samples by enzyme-linked immunosorbent assay. Results: The expression of the NLRX1 gene was significantly decreased in the patient groups compared to the controls. The levels of NLRP3, ASC, and IL-18 gene expressions of patients were not significantly different from controls in the remission and relapse periods. Although IL-1β gene expressions of the patients in the remission period increased in value, it was not statistically significant compared to that of healthy controls. Conclusion: Our findings showed that anti-inflammatory NLRX1 protein can be considered as a strong biomarker in the diagnosis and treatment of MS, where neuroinflammation is the main cause. [ABSTRACT FROM AUTHOR]

There is wide variation in the time from the onset to secondary progressive multiple sclerosis (MS) and some controversy regarding the clinical characteristics of the courses (phenotypes) of MS. The present study aimed to characterize demographic and clinical factors that potentially influence long-term disability progression in the cohort of Latvian MS patients. A descriptive longitudinal incidence study was conducted using a cohort of 288 MS patients beginning in 2011 (disease duration from 1 to 51 years). Socio-demographic and clinical information from the first visit to 15/20 years was analysed in groups stratified by gender and visits at five-time points (the first visit; after a year or 2; after 5 ± 1 year; after 10 ± 2 years; after 15–20 years). Our study was dominated by patients from urban areas and non-smokers. The female/male ratio was 2.4:1; the distribution of clinical courses at the first visit was consistent with most European studies. The most common symptom at presentation in our study was optic manifestations, followed by sensory disturbances and motor deficits. In the Latvian study, gender was not a significant influencing factor on the rate of disease progression; however, patient age was statistically significantly associated with EDSS (Expanded Disability Status Scale) value at the first visit. Early clinical features of MS are important in predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Latvian patients are similar to other regions of the world. [ABSTRACT FROM AUTHOR]

Abstract Introduction MicroRNAs (miR or miRNA) are short regulatory RNAs, which modulate post-transcriptional gene expression. Dysregulation of these molecules contributes to pathogenicity of autoimmune disorders, such as multiple sclerosis (MS). Aims This study was conducted to investigate changed expression pattern of miRNA-145 and miRNA-155 in MS. Methods We collected blood samples of 75 patients with relapsing-remitting MS patients and 75 healthy controls. Ficoll-Hypaque density gradient method was used to isolate peripheral blood mononuclear cells. Also, total RNA was extracted and subjected to RT-PCR analysis. We used the Mann–Whitney U test to evaluate the differences in expression levels of target miRNAs between the groups. Results We found that expression of miRNA-145 (P = 0.012) and miRNA-155 (P = 0.005) were partly reduced in patients with relapse-remitting MS in comparison with healthy controls. The miRNA-145 had an area under curve (AUC) of 0.621 (P = 0.01) and miRNA-155 levels had an AUC of 0.625 (P = 0.008). Conclusion Decreased expression of miRNA-145 and miRNA-155 contributes to development of relapse-remitting MS, while further large scale observational studies and meta-analyses are required.

Background: Multiple Sclerosis (MS) is a chronic, autoimmune inflammatory disease of the CNS. It is the most common chronic disabling disease of the CNS in young adults, affecting 2.3 million people worldwide. It is two times more common in females than in males and its onset is usually at young ages, namely around 30 years of age. Its most frequent and typical initial forms of presentation are neuritis optica or arrays of sensory-motor symptoms. Nevertheless, a small minority of patients (about 1%) experience changes in mood, behaviour, personality, or cognition as initial manifestations of MS. In contrast, as cases of MS progress, neuropsychiatric symptoms are very likely to appear; estimates indicate that they will affect two-thirds of all patients at some point. Objective: To determine the percent and severity of neurotic disorders in a sample of Egyptian multiple sclerosis patients. Patients and Methods: We conducted this observational cross sectional study at Nasr City health insurance outpatient clinic and MS unit at Ain Shams university Hospitals. We included 100MS patients of all types according to McDonald's criteria (The 2017 revisions), adult age group above 18 years old. We excluded patients with other diseases that could clearly affect the patient psychiatric condition prior to the diagnosis of MS and patients with recent drug intake that could clearly affect psychiatric condition other than for documented psychiatric disease or MS. Results: The current study shows that anxiety, and OCD are frequent among patients with MS in Egypt. There was significant relationship between development of neurotic illnesses and feeling pain/discomfort, also between development of neurotic illnesses and reporting anxiety/depression. Conclusion: The current study shows that depression, anxiety, and OCD are frequent among patients with MS in Egypt. The results of this study are important for the improvement of the clinical management of MS patients. The psychiatric state of patients in this group should be investigated systematically, simultaneously with the assessment of their neurological state. Clinicians should have more focus on neurotic symptoms among people with MS disease to develop appropriate treatments for those patients. Finally, support programs should be made available for patients with MS to ensure adequate coping with the disease. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRs) are involved in the autoimmune and neurological diseases, including multiple sclerosis (MS), through modulating post-transcriptional gene regulation. Accumulating evidence indicates that miR-10, miR-24a, miR-124, and miR-21 play an imperative role in MS pathogenesis. Therefore, the current research aimed to analyze the expression of the selected miRNAs for MS in Iranian population. Methods and Results: Blood sample of 75 relapsing-remitting MS (RRMS) patients and 75 healthy individuals suffering no neurodegenerative illness was collected. Subsequently, the isolation of peripheral blood mononuclear cells (PBMCs) was performed by employing Ficoll-Hypaque density gradient method. Afterward, total RNA was extracted and subjected to qRT-PCR analysis. The obtained results evidenced that the relative expression of miR-10 (P = 0.0002), miR-21 (P = 0.0014), and miR-124 (P = 0.0091) significantly decreased in RRMS patients compared to healthy participants. On the contrary, no notable change was observed between the studies groups regarding miR-24a expression levels (P = 0.107). ROC curve analysis estimated an area under the curve (AUC) value equal to 0.75 with P = 0.0006 for miR-10, while it was decreased for miR-21 (AUC = 0.67 and P = 0.0054) and miR-124 (AUC = 0.66 and P = 0.012). Conclusion: The change in miR-10, miR-124, and miR-21 expression patterns was implied to participate in MS development. Further large scale observational studies are recommended. [ABSTRACT FROM AUTHOR]

Purpose: Promising advances have been made in mesenchymal stem cell transplantation to reinducethe immune tolerance in neuroinflammatory animal models and multiple sclerosis (MS)patients. The available evidence demonstrated that immunomodulatory effects of mesenchymalstem cell are particularly exerted through releasing exosomes to their environment. Wetherefore, aimed to comparatively assess the potential effect of mesenchymal stem cells andmesenchymal stem cells-derived exosomes on proliferation and function of the CD4+CD25−conventional T cells, isolated from relapsing-remitting MS patients.Methods: Mesenchymal stem cells were isolated from human umbilical cord tissues and usedfor exosome isolation via ultracentrifugation. Both mesenchymal stem cells and mesenchymalstem cells-derived exosomes were evaluated for their anti-inflammatory effects againstthe proliferation of T cells isolated from two groups of individuals in vitro, MS patients andhealthy subjects. Cytokine production of conventional T cells (interferon-γ, interleukin-10, andinterleukin-17) was also assessed, using flow cytometry for the patients and healthy individuals.Results: Here, evidence shows that MSCs and MSC-derived exosomes dampen proliferationand percentage of conventional T cells that produce IFN-γ (healthy control: P

Introduction: MicroRNAs (miR or miRNA) are short regulatory RNAs, which modulate post-transcriptional gene expression. Dysregulation of these molecules contributes to pathogenicity of autoimmune disorders, such as multiple sclerosis (MS).Aims: This study was conducted to investigate changed expression pattern of miRNA-145 and miRNA-155 in MS.Methods: We collected blood samples of 75 patients with relapsing-remitting MS patients and 75 healthy controls. Ficoll-Hypaque density gradient method was used to isolate peripheral blood mononuclear cells. Also, total RNA was extracted and subjected to RT-PCR analysis. We used the Mann-Whitney U test to evaluate the differences in expression levels of target miRNAs between the groups.Results: We found that expression of miRNA-145 (P = 0.012) and miRNA-155 (P = 0.005) were partly reduced in patients with relapse-remitting MS in comparison with healthy controls. The miRNA-145 had an area under curve (AUC) of 0.621 (P = 0.01) and miRNA-155 levels had an AUC of 0.625 (P = 0.008).Conclusion: Decreased expression of miRNA-145 and miRNA-155 contributes to development of relapse-remitting MS, while further large scale observational studies and meta-analyses are required. [ABSTRACT FROM AUTHOR]

Selective depletion of CD20+ B cells by anti-CD20 monoclonal antibodies as monotherapy in multiple sclerosis (MS) profoundly suppresses acute inflammatory disease activity and signifies an important advance in the treatment of relapsing-remitting MS. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is also the first proven therapy to lessen disability progression in primary progressive MS-a breakthrough for patients with a disease that had no proven therapy. Ocrelizumab is generally well tolerated, with the most common adverse events experienced being infusion reactions and infections. In ocrelizumab trials in MS a numerical imbalance in the risk of malignancies was observed. In this article, we review advances in anti-CD20 B-cell-depleting biological therapies for MS, including ocrelizumab, rituximab, and ofatumumab.

Background and purpose: Treatment success in relapsing–remitting multiple sclerosis (RRMS) is generally determined using relapse frequency and magnetic resonance imaging (MRI) activity in the first 6 or 12 months on treatment. The association of these definitions of short‐term treatment success with disability worsening and disease activity in the longer term is unclear. In this study, we investigated risk factors associated with early first‐line treatment failure in RRMS, and the association of early treatment failure with subsequent disability worsening or "no evidence of disease activity" (NEDA‐3) status. Methods: We used data from CombiRx (clinicaltrials.gov identifier NCT00211887) to investigate risk factors associated with early treatment failure, and the association of early treatment failure at 6 and 12 months with subsequent disability worsening or NEDA‐3 at 36 months. Results: CombiRx included 1008 treatment‐naïve participants with RRMS, who were randomly assigned to treatment with glatiramer acetate, interferon beta, or the combination of both. Early treatment failure at 6 or 12 months by several definitions was associated with NEDA‐3 failure at 36 months, but not with subsequent disability worsening at 36 months. Expanded Disability Status Scale (EDSS) was the only baseline characteristic associated with the risk of disability worsening at 36 months. Approximately 70% of NEDA‐3 failures occurred due to MRI activity, and <10% occurred due to EDSS worsening. Conclusions: Our investigation shows that current definitions of early treatment failure in RRMS are unrelated to patient‐relevant disability worsening at 36 months of follow‐up. Further research into useful definitions of treatment success and failure in RRMS is needed. [ABSTRACT FROM AUTHOR]

Purpose: Promising advances have been made in mesenchymal stem cell transplantation to reinduce the immune tolerance in neuroinflammatory animal models and multiple sclerosis (MS) patients. The available evidence demonstrated that immunomodulatory effects of mesenchymal stem cell are particularly exerted through releasing exosomes to their environment. We therefore, aimed to comparatively assess the potential effect of mesenchymal stem cells and mesenchymal stem cells-derived exosomes on proliferation and function of the CD4+CD25-conventional T cells, isolated from relapsing-remitting MS patients. Methods: Mesenchymal stem cells were isolated from human umbilical cord tissues and used for exosome isolation via ultracentrifugation. Both mesenchymal stem cells and mesenchymal stem cells-derived exosomes were evaluated for their anti-inflammatory effects against the proliferation of T cells isolated from two groups of individuals in vitro, MS patients and healthy subjects. Cytokine production of conventional T cells (interferon-γ, interleukin-10, and interleukin-17) was also assessed, using flow cytometry for the patients and healthy individuals. Results: Here, evidence shows that MSCs and MSC-derived exosomes dampen proliferation and percentage of conventional T cells that produce IFN-γ (healthy control: P<0.001) and interleukin-17 (healthy control: P <0.001, MS patients: P <0.001), with a significant increase of IL-10 producing cells in the patients and healthy individuals. Surprisingly, MSC-derived exosomes demonstrated higher immune-modulating properties on conventional T cells responses, compared to mesenchymal stem cells (MSCs). Conclusion: The current study, provides a novel approach of exocytosis on autoimmune therapy. In particular, Mesenchymal stem cell -derived exosomes, which are cell-derived biologics, could be considered as an alternative for Mesenchymal stem cells in treating MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a central nervous system (CNS) degenerative disorder which is caused by a targeted autoimmune‐mediated attack on myelin proteins. Previously, mesenchymal stem cells were considered as a novel and successful treatment of MS. One of the underlying mechanisms behind their immunomodulatory function is the release of extracellular vesicles, particularly exosomes. In this study, we aimed to evaluate the suppressive efficacy of MSCs and their exosomes on the proliferation of peripheral mononuclear blood cells (PBMC) in relapsing‐remitting MS (RRMS) patients and healthy subjects. To do, mesenchymal stem cells were derived from human umbilical cord tissues and used for exosome isolation through ultracentrifugation. Suppressive function of MSCs and MSC‐derived exosomes was examined in a coculture with CFSE‐labelled PBMCs in vitro. PBMC proliferation of the patients and healthy individuals was measured using flow cytometry. We first demonstrated that proliferation of PBMCs decreased in the presence of MSCs and suppression was more efficient by MSC‐derived exosomes, with a minimum alloreaction rate. However, suppression capacity of MSCs and their exosomes significantly decreased during extensive sub‐culturing. The present study showed that MSC‐derived exosomes as an effective cell‐free therapy could prevent proliferation of PBMCs. However, further evaluations are need to move towards a functional approach that can be translated to the clinic. [ABSTRACT FROM AUTHOR]

Patients with human immunodeficiency virus (HIV) infection have a decreased risk of developing multiple sclerosis (MS) and MS patients very rarely contract HIV infection. We report on a 35-year-old woman with relapsing-remitting MS, who acquired HIV infection 8 years after MS onset. During 7 years of follow-up without combined antiretroviral therapy (cART), CD4+ counts decreased and HIV viremia increased progressively, but slightly. These trends reverted after starting cART, with optimal viro-immunological control. While the patient had many MS relapses before acquiring HIV infection, she had then only one relapse, shortly after HIV infection, despite irregular or no MS therapy. This case contributes to the discussion about MS and HIV potential interactions and describes for the first time the effects of the MS-targeting drug natalizumab in an HIV-positive patient. [ABSTRACT FROM AUTHOR]

Background: The CLARINET-MS study assessed the long-term effectiveness of cladribine tablets by following patients with multiple sclerosis (MS) in Italy, using data from the Italian MS Registry. Methods: Real-world data (RWD) from Italian MS patients who participated in cladribine tablets randomised clinical trials (RCTs; CLARITY, CLARITY Extension, ONWARD or ORACLE-MS) across 17 MS centres were obtained from the Italian MS Registry. RWD were collected during a set observation period, spanning from the last dose of cladribine tablets during the RCT (defined as baseline) to the last visit date in the registry, treatment switch to other disease-modifying drugs, date of last Expanded Disability Status Scale recording or date of the last relapse (whichever occurred last). Time-to-event analysis was completed using the Kaplan–Meier (KM) method. Median duration and associated 95% confidence intervals (CI) were estimated from the model. Results: Time span under observation in the Italian MS Registry was 1–137 (median 80.3) months. In the total Italian patient population (n = 80), the KM estimates for the probability of being relapse-free at 12, 36 and 60 months after the last dose of cladribine tablets were 84.8%, 66.2% and 57.2%, respectively. The corresponding probability of being progression-free at 60 months after the last dose was 63.7%. The KM estimate for the probability of not initiating another disease-modifying treatment at 60 months after the last dose of cladribine tablets was 28.1%, and the median time-to-treatment change was 32.1 (95% CI 15.5–39.5) months. Conclusion: CLARINET-MS provides an indirect measure of the long-term effectiveness of cladribine tablets. Over half of MS patients analysed did not relapse or experience disability progression during 60 months of follow-up from the last dose, suggesting that cladribine tablets remain effective in years 3 and 4 after short courses at the beginning of years 1 and 2. [ABSTRACT FROM AUTHOR]

Background: Multiple Sclerosis (MS) is a neurodegenerative disease that produces plaques throughout the central nervous system. MS can present in four different clinical courses. Of these, Relapsing-Remitting MS (RRMS) is the main clinical course, especially at early stages of the disease. Rapidly evolving severe (RES) RRMS is a form of RRMS in which an individual has two or more disabling relapses in one year and evidence of increasing lesions on two consecutive MRI scans. MS affects the cortical and subcortical pathways of the brain leading to impairment in both physical and cognitive skills. Speech, language and communication deficits more broadly, have been acknowledged in the MS literature, but relatively little research has focused on these symptoms. Aims: To examine communication deficits in people with (RES) RRMS, with specific focus on anomic symptoms – difficulties in word retrieval, examining measures of both accuracy and latency (time intervals for accurate word retrieval). Methods & Procedures: A communication screening assessment was conducted with 100 participants with (RES) RRMS. This screening assessment consisted of the ACE-R cognitive screen, a bespoke picture naming task, reading words aloud from the National Adult Reading Test (NART) and the Pyramids and Palm Trees Test. The picture naming task obtained timed naming responses for sixty pictures of objects from the International Picture Naming Project (IPNP). Results for participants with MS (PWMS) were compared to matched neurotypical control participants (n = 40) and normative test data. Outcomes & Results: The group mean performance for PWMS was below the lower end of the neuro-typical control range for the cognitive screen and picture naming tasks. The reading aloud and semantic association mean scores were within the neuro-typical range but towards the lower end of this range. Anomic symptoms for PWMS presented as both lapses in word retrieval and reduced speed of word retrieval. Word retrieval latency was on average 26% slower for PWMS. Within the anomic symptoms, there were instances of inaccuracy (42% of participants) as well as slow naming latency (31% of participants) in retrieving words. There was evidence of mild dysarthria for 33% of participants. Regression analyses suggested the anomic symptoms were most strongly associated with semantic processing deficits. Conclusions: Anomic symptoms are common in (RES) RRMS, and present as inaccuracy as well as slow word retrieval latency. The prevalence and cognitive nature of anomic symptoms require further research across the range of presentations of MS. [ABSTRACT FROM AUTHOR]

This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN β-1a) 44 µg 3 × weekly (tiw) in patients appearing to transition from relapsing–remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0–5.0; ≥ 2 relapses in previous 2 years), and the SPECTRIMS study included 618 patients with SPMS (EDSS 3.0–6.5 and ≥ 1-point increase in previous 2 years [≥ 0.5 point if 6.0–6.5]) randomly assigned to sc IFN β-1a 44 or 22 µg or placebo for 2–3 years, respectively. These post hoc analyses examined five subgroups of MS patients with EDSS 4.0–6.0: PRISMS (n = 59), PRISMS/SPECTRIMS (n = 335), PRISMS/SPECTRIMS with baseline disease activity (n = 195; patients with either ≥ 1 relapse within 2 years before baseline or ≥ 1 gadolinium-enhancing lesion at baseline), PRISMS/SPECTRIMS without baseline disease activity (n = 140), and PRISMS/SPECTRIMS with disease activity during the study (n = 202). In the PRISMS and PRISMS/SPECTRIMS subgroups, sc IFN β-1a delayed disability progression, although no significant effect was observed in PRISMS/SPECTRIMS subgroups with activity at baseline or activity during the study (regardless of baseline activity). In the PRISMS/SPECTRIMS subgroup, over year 1 (0–1) and 2 (0–2), sc IFN β-1a 44 µg tiw significantly reduced annualized relapse rate (p ≤ 0.001), and relapse risk (p < 0.05) versus placebo. Similar results were seen for the PRISMS/SPECTRIMS with baseline disease activity subgroup. Subcutaneous IFN β-1a reduced T2 burden of disease and active T2 lesions in the PRISMS/SPECTRIMS subgroups overall, with and without baseline activity. In conclusion, these post hoc analyses indicate that effects of sc IFN β-1a 44 µg tiw on clinical/MRI endpoints are preserved in a patient subgroup appearing to transition between RRMS and SPMS. [ABSTRACT FROM AUTHOR]

BACKGROUND: Memory impairments commonly afflict individuals with MS. While evidence-based cognitive rehabilitation treatments are available in English, the lack of such interventions in Spanish is an important barrier to care for Hispanics with MS. There is class I evidence that the modified Story Memory Technique (mSMT) improves learning in English. This intervention has been translated and adapted into Spanish. OBJECTIVE: To examine the preliminary efficacy of the Spanish mSMT to improve learning in Mexicans with MS. METHODS: Twenty individuals with relapsing-remitting MS were randomized to treatment (n = 10) or placebo control (n = 10) groups. The Spanish mSMT is a 10-session intervention that teaches imagery and context to facilitate learning. The control condition was matched to the treatment condition in treatment duration, and stimulus content and presentation. Participants completed baseline and post-treatment neuropsychological assessments. RESULTS: Individuals who received the Spanish mSMT showed significant improvements in learning and life satisfaction relative to the control group. Also observed were a near-moderate effect size on perceived memory complaints and a moderate-to-large effect size on the family's perception of the patient's competency. CONCLUSIONS: The Spanish mSMT showed preliminary efficacy in improving learning deficits in Mexicans with MS, and such improvements may extend to other domains. [ABSTRACT FROM AUTHOR]

Selective depletion of CD20+ B cells by anti-CD20 monoclonal antibodies as monotherapy in multiple sclerosis (MS) profoundly suppresses acute inflammatory disease activity and signifies an important advance in the treatment of relapsing-remitting MS. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is also the first proven therapy to lessen disability progression in primary progressive MS-a breakthrough for patients with a disease that had no proven therapy. Ocrelizumab is generally well tolerated, with the most common adverse events experienced being infusion reactions and infections. In ocrelizumab trials in MS a numerical imbalance in the risk of malignancies was observed. In this article, we review advances in anti-CD20 B-cell-depleting biological therapies for MS, including ocrelizumab, rituximab, and ofatumumab. [ABSTRACT FROM AUTHOR]

Purpose: Few data are available regarding the optimal treatment of multiple sclerosis (MS)-related uveitis. The aim of this study was to describe clinical features of MS-associated uveitis and determine how MS treatment affects the course of uveitis.Methods: Retrospective, multicenter study. Patients were divided into two groups according to the use (group 2) or not (group 1) of immunomodulatory drugs. Characteristics of uveitis and treatment were reviewed.Results: A total of 68 eyes from 36 patients (17 in group 1 and 19 in group 2) were included. All patients were treated with topical and/or systemic steroids for uveitis. Uveitis occurred 1-17 years prior to neurologic symptoms in 78% of patients. Uveitis was more severe in group 2 (p<0.05), with a tendency toward a higher rate of chronic uveitis (p = 0.06).Conclusions: MS-related uveitis has often a favorable evolution. Patients on interferon-beta have more severe and chronic uveitis. As far as we are concerned, interferon-beta given on the sole indication of uveitis is not recommended. If steroid-sparing agent is required for intraocular inflammation, immunosuppressive drugs should be considered. [ABSTRACT FROM AUTHOR]

Purpose: Multiple sclerosis (MS) requires long-term therapy and can affect many aspects of a patient's life, including quality of life. MS patients score lower on health-related quality of life (HRQoL) measures. The efficacy of subcutaneous interferon (IFN) β-1a has been extensively evaluated by using objective measures but its impact on HRQoL is currently unclear. In this observational study, we evaluated HRQoL of Iranian patients with relapsing-remitting MS (RRMS) treated with IFN β-1a by using short-form 36 (SF-36) and multiple sclerosis international quality of life (MusiQoL) questionnaires.Methods: Four hundred recruited RRMS patients were treated with human serum album free IFN β-1a for 1 year. Patients were required to fill in SF-36 and MusiQoL questionnaires at the first visit and at each follow-up visit. Expanded disability status scale (EDSS) evaluation was performed at baseline and at each visit. Comparisons in HRQoL between visits were calculated using Cohen'sdeffect size. The relationship between change in EDSS score and the score of each questionnaire was calculated using Pearson correlation coefficients.Results: Three-hundred and eighty three completed the study. Two-hundred and thirty nine were female. Mean (SD) age was 28.75 (±5.49). After 1 year, overall MusiQoL Index score effect size was −0.16 and SF-36 physical component and mental component showed overall effect sizes of −0.28 and −0.53, respectively. Mean (range) EDSS change was 1 (1–4). Three-hundred and seventy four were clinically stable with mean (range) EDSS change of 0.1 (−2–0.5). Increase in EDSS was linked to a decrease in both MusiQoL and SF-36.Conclusion: We found that, HRQoL did not change significantly over the first year of therapy. Furthermore, decreases in HRQoL were inversely correlated with increases in EDSS score. [ABSTRACT FROM PUBLISHER]

Background: Dendritic cells (DCs) rendered suppressive by treatment with mitomycin C and loaded with the autoantigen myelin basic protein demonstrated earlier their ability to prevent experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). This provides an approach for prophylactic vaccination against autoimmune diseases. For clinical application such DCs are difficult to generate and autoantigens hold the risk of exacerbating the disease.Methods: We replaced DCs by peripheral mononuclear cells and myelin autoantigens by glatiramer acetate (Copaxone(®)), a drug approved for the treatment of MS. Spleen cells were loaded with Copaxone(®), incubated with mitomycin C (MICCop) and injected into mice after the first bout of relapsing-remitting EAE. Immunosuppression mediated by MICCop was investigated in vivo by daily assessment of clinical signs of paralysis and in in vitro restimulation assays of peripheral immune cells. Cytokine profiling was performed by enzyme-linked immunosorbent assay (ELISA). Migration of MICCop cells after injection was examined by biodistribution analysis of (111)Indium-labelled MICCop. The number and inhibitory activity of CD4(+)CD25(+)FoxP3(+) regulatory T cells were analysed by histology, flow cytometry and in vitro mixed lymphocyte cultures. In order to assess the specificity of MICCop-induced suppression, treated EAE mice were challenged with the control protein ovalbumin. Humoral and cellular immune responses were then determined by ELISA and in vitro antigen restimulation assay.Results: MICCop cells were able to inhibit the harmful autoreactive T-cell response and prevented mice from further relapses without affecting general immune responses. Administered MICCop migrated to various organs leading to an increased infiltration of the spleen and the central nervous system with CD4(+)CD25(+)FoxP3(+) cells displaying a suppressive cytokine profile and inhibiting T-cell responses.Conclusion: We describe a clinically applicable cell therapeutic approach for controlling relapses in autoimmune encephalomyelitis by specifically silencing the deleterious autoimmune response. [ABSTRACT FROM AUTHOR]

• Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS). • Repeated low-dose RTX therapy is effective and safe for RRMS. • RTX at lower dose may be a promising option for MS with an ideal risk/benefit ratio. Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS), whereas the induction and maintenance regimens vary widely among studies. Few data are available on efficacy and safety of repeated low-dose RTX therapy in MS patients. This study aimed to evaluate the efficacy and safety of repeated low-dose RTX therapy for relapsing-remitting MS (RRMS), the most common form of MS affecting approximately 85% of patients. Nine RRMS patients were enrolled and the medical records were retrospectively reviewed. RTX at 100 mg per week for three consecutive weeks was used as induction therapy. Maintenance therapy was reinfusions of RTX at 100 mg every 6 months during the first year, followed by 100 mg every 6 to 12 months. Main outcome measures included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, and T2 lesion burden on MRI for evaluating the efficacy of low-dose RTX regimen. Meanwhile, adverse events (AEs) were recorded to assess the safety of repeated RTX infusions. All patients were females with an average onset age of 25.4 ± 6.7 years. The median disease duration before the first RTX infusion was 56 (range, 3–108) months and the median follow-up period was 30 (range, 15–40) months. No relapses were recorded in all patients after RTX therapy. Repeated low-dose RTX therapy resulted in a dramatic reduction of median ARR (pre-RTX vs post-RTX, 1.1 vs 0, p = 0.012), median EDSS score (2.0 vs 0, p = 0.007), and the number of T2 lesions on MRI (35.6 ± 18.0 vs 29.4 ± 18.1, p = 0.001). A total of 35 episodes of AEs occurred during repeated low-dose RTX therapy, and all of them were mild and transient. Repeated low-dose RTX therapy is cost-effective for RRMS patients and shows a good safety profile. It may be a promising option for those having no access or poor response to first-line disease-modified drugs (DMDs), particularly in low- or middle-income countries. [ABSTRACT FROM AUTHOR]

Animal models simulate different aspects of human diseases and are essential to get a better understanding of the disease, studying treatments and producing new drugs. Experimental autoimmune encephalomyelitis (EAE) is a preferred model in multiple sclerosis research. Common EAE model in Lewis rats is induced using MBP peptide as a myelin antigen which results in a monophasic disease course. In the present study, EAE was induced in Lewis rats by homogenized guinea pig spinal cord along with or without pertussis toxin (PT). When PT was used, EAE turned into remitting–relapsing form and worsen the clinical symptoms. Higher inflammation and oxidative stress marker gene expression was observed when PT was administrated. [ABSTRACT FROM AUTHOR]

The article discusses neurodegeneration in multiple sclerosis (MS). Topics discussed include clinical evidence supporting the primacy of inflammation as predictor of secondary neurodegeneration in MS, grey matter inflammation which causes disability accumulation in MS, and inadequate detection of inflammation. It also discusses the need for biomarkers in relapsing MS, the need for better inflammatory biomarkers, and the need for neuroprotection.

Background and aims Multiple sclerosis (MS) is an inflammatory condition of the central nervous system, with genetic and environmental factors having a role in its etiology. The condition is characterized by demyelination, acute inflammation, and chronic and acute lesions in the central nervous system. Human and experimental studies have shown that T-helper cells, and pro-inflammatory cytokines have a major role in the pathogenesis of MS. Recent researches have shown that IL-17 secreting T (Th17) cells have a role in inflammation and demyelination of the central nervous system. In the present study, the role of Interleukin-17A (IL-17A) and Interleukin-17F (IL-17F) in the immunopathogenesis and follow-up of the MS disease was evaluated. Materials and methods Thirty-five relapsing remitting (RR) form of MS patients were included in the present study. Blood samples were taken from 35 MS patients and 35 healthy individuals as controls. Enzyme-Linked Immunosorbent Assay (ELISA) was used to determine IL-17A and IL-17F serum levels. Results A statistically significant increase was noted in the serum levels of IL-17A and IL-17F in MS patients compared to the controls ( P < 0.001). There was a significant positive correlation of IL-17F serum levels with the number of relapses (rs = 0.717, P < 0.001). However, there was no significant relationship between the serum levels of these cytokines and Expanded Standard Disability Stated Scale (EDSS) and disease Progression Index (PI). Conclusion The data of the present study revealed a significant increase in the serum levels of IL-17A and IL-17F in MS patients compared with healthy controls and a significant positive correlation of IL-17F serum levels with the number of relapses. It appears that increased serum levels of IL-17 and especially IL-17F may lead to a raised risk of MS. [ABSTRACT FROM AUTHOR]

Conversion of active lesions to black holes has been associated with disability progression in subjects with relapsing-remitting multiple sclerosis (RRMS) and represents a complementary approach to evaluating clinical efficacy. The objective of this study was to assess the conversion of new active magnetic resonance imaging (MRI) lesions, identified 6 months after initiating treatment with glatiramer acetate 40 mg/mL three-times weekly (GA40) or placebo, to T1-hypointense black holes in subjects with RRMS. Subjects received GA40 ( n = 943) or placebo ( n = 461) for 12 months. MRI was obtained at baseline and Months 6 and 12. New lesions were defined as either gadolinium-enhancing T1 or new T2 lesions at Month 6 that were not present at baseline. The adjusted mean numbers of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a negative binomial model; adjusted proportions of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a logistic regression model. Of 1,292 subjects with complete MRI data, 433 (50.3 %) GA-treated and 247 (57.2 %) placebo-treated subjects developed new lesions at Month 6. Compared with placebo, GA40 significantly reduced the mean number (0.31 versus 0.45; P = .0258) and proportion (15.8 versus 19.6 %; P = .006) of new lesions converting to black holes. GA significantly reduced conversion of new active lesions to black holes, highlighting the ability of GA40 to prevent tissue damage in RRMS. [ABSTRACT FROM AUTHOR]

The article presents a study on the characterization of cerebrospinal fluid (CSF) biomarkers of amyloid precursor protein (APP) degradation in multiple sclerosis (MS). It mentions that CFS samples were gathered from 87 MS patients, who underwent treatment of natalizumab or mitoxantrone. The study found that MS patients had reduced their CSF soluble (s)APP but increased their gain after treatment of natalizumab.

The article presents a study which examines the relationship between reward-related cognition and fatigue in multiple sclerosis (MS). The study examines the usefulness of reward perception testing in 104 fatigued and 70 fatigue-free relapsing-remitting MS patients to predict the efficacy of monoamine-modulating drugs on fatigue. Results reveal that fatigued MS patients have lower reward responsiveness which provide significant information to guide individualized treatment for fatigue in MS.

Abstract: Objective: To compare the long-term effect of disease-modifying therapies (DMT) on brain volume loss in relapsing–remitting MS (RRMS) patients. Methods: We conducted a study to examine the effect of daily glatiramer acetate (GA), weekly low dose interferon beta (LD-IFNB), and high-dose high-frequency interferon beta disease (HD-IFNB) on brain volume loss over 5years in RRMS patients. All patients were previously treatment naïve, had disease duration ≤5years at the time of initiating DMT, and subsequently received the same DMT for 5years continuously. The percentage change in brain volume (PCBV) was measured using fully automated software. MRI analysis was performed blinded to treatment allocation. Results: The adjusted PCBV from baseline to year 5 was −2.27% in GA, −2.62% in LD-IFNB, and −3.21% in the HD-IFNB groups (−2.27 vs −2.62, p=0.0036; −2.27 vs −3.21, p<0.0001; −2.62 vs −3.21, p<0.0001). These data remained unchanged from year 1 to year 5, after adjusting for pseudoatrophy in the first year. A group of RRMS patients that remained untreated for a period ranging from 8 to 24months, served as controls. All treatment groups were significantly better than the rate of projected brain volume loss in the untreated group over 5years (p<0.0001). Conclusions: Global brain volume loss is a dynamic process even in relatively early RRMS patients that occurs despite intervention with therapy. However, all DMT significantly reduced the loss of brain volume compared to no treatment. The GA-treated group experienced the least reduction in brain volume over 5years, compared to the LD-IFNB and HD-IFNB treated groups. These differences could be partly related to the immunologic consequences of GA therapy in RRMS. [Copyright &y& Elsevier]

Patients with multiple sclerosis have a lifelong disease for which no cure is currently available. Treatments for MS should demonstrate sustained efficacy to slow or stop the inflammation, demyelination or axonal damage in the central nervous system. The development of interferon beta (IFNB) preparations and glatiramer acetate (GA) as treatments for MS represents a critical milestone in the care of patients with this potentially disabling disease. Interferons for MS have been available in the Turkish market since 1995, and GA - since 1999. Since those days, many clinical trials have been conducted in order to understand the efficacy, safety, tolerability, as well as the adverse effects of IFNB and GA in different clinical courses of the disease and ethnic groups. These studies revealed that IFNBs and GA are efficient and safe therapies as the first-line treatment, particularly for relapsing-remitting MS. Although there are other recently developed drugs, it is expected that IFNBs and GA will continue to be available in the market for patients with MS. Most patients with clinically definite MS and a history of relapses should be considered for treatment with these agents while the search for better agents is ongoing. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hypoperfusion has been reported in lesions, normal-appearing white (NAWM) and gray matter (NAGM) of patients with clinically definite multiple sclerosis (MS) by using perfusion MRI. However, it is still unknown how early such changes in perfusion occur. The aim of our study was to assess the presence of hemodynamic changes in the NAWM and subcortical NAGM of patients with clinically isolated syndrome (CIS) in comparison to healthy controls and to patients with early relapsing-remitting (RR) MS. Methods: Absolute cerebral blood flow (CBF), blood volume (CBV) and mean transit time (MTT) were measured in the periventricular and frontal NAWM, thalamus and putamen nuclei of 12 patients with CIS, 12 with early RR-MS and 12 healthy controls using dynamic susceptibility contrast enhanced (DSC) T2⁎-weighted MRI. Results: Compared to controls, CBF was significantly decreased in the periventricular NAWM of CIS patients and in the periventricular NAWM and putamen of RR-MS patients. Compared to CIS, RR-MS patients showed a significant CBF decrease in the putamen. Conclusions: CBF was decreased in the NAWM of both CIS and RR-MS patients and in the subcortical NAGM of RR-MS patients suggesting a continuum of tissue perfusion decreases beginning in white matter and spreading to gray matter, as the disease progresses. [Copyright &y& Elsevier]

Background During the last 15 years, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has globally been performed for severe multiple sclerosis (MS). Most patients have been in progressive phase with long disease duration. As a rule, treatment effect has been minor or moderate. Patients Since 2004, we have performed HSCT in nine young patients with "malignant" relapsing-remitting MS. Criteria for treatment were short duration of disease; very frequent, severe relapses; recent improvement periods indicating potential for recovery after strong immunosuppression. Findings Median age at treatment was 27 (range 9-34) years, MS duration 26 (4-100) months, and annualized relapse rate 10 (4-12). Median Disability Status Scale (extended disability status scale, EDSS) at HSCT was 7.0 (3.5-8.0). Median follow-up time April 2008 is 29 (23-47) months. Median EDSS improvement is 3.5 (1.0-7.0), clearly surpassing most previous reports. One patient relapsed mildly with rapid recovery 7 months after HSCT. All patients are otherwise stable, median EDSS being 2.0 (0-6.0). Before HSCT, 61 relapses occurred in 82 patient months; during follow-up, one relapse in 289 patient months. Conclusion This small series of patients with "malignant" relapsing-remitting MS suggests HSCT to be an effective treatment option for this relatively rare disease course. It further suggests that future criteria for HSCT in MS should be close to the present ones. [ABSTRACT FROM AUTHOR]

Summary: Magnetic resonance imaging (MRI) is the most important paraclinical test in the diagnosis of multiple sclerosis (MS) and for delineating its natural history. We investigate MRIs from a longitudinal study of 24 relapsing-remitting MS patients who had monthly MRI examinations for one year, and were not receiving active MS therapy during this period. We hypothesized that lesions occur randomly throughout the brain, and that patients are homogeneous with regard to spatial patterns of lesion presentation. We recorded the numbers and locations of enhancing lesions and hypointense lesions (black holes) in all scans, and found asymmetrical patterns of lesions about the mid-transaxial, mid-coronal, and mid-sagittal planes. Furthermore, in distinct subsets of patients, enhancing lesions and black holes tend to occur in the same locations. Clustering in lesion locations may be of functional significance, with consequent therapeutic implications. [Copyright &y& Elsevier]

Although multiple sclerosis (MS) is an immune-mediated disorder, serological testing to aid in its diagnosis has not been developed. To test the hypothesis that the pathological changes in MS can be detected by analyzing a molecular signature of serum proteomic patterns, we tested sera from 25 newly diagnosed relapsing-remitting MS patients and 25 healthy controls with matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry, following albumin depletion and desalting. Analysis of MALDI-TOF/mass spectrometry data, using proteomic spectral pattern recognition software, revealed a distinct proteomic pattern in the MS group determined by 3 biomarkers at 8687, 8773, and 8818 mass-to-charge ratios. Although our data are representative of analysis on a small number of samples and are preliminary, we conclude that MALDI-TOF/mass spectrometry, in combination with serum proteomic pattern analysis, could be useful in the diagnosis of MS, and a larger, masked trial to identify proteomic spectral patterns characteristic of relapsing-remitting, primary progressive and secondary progressive variants of MS is justified. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are implicated in the pathogenesis of multiple sclerosis (MS). Nine relapsing–remitting MS (RRMS) patients along with age, sex, and NK responder status matched controls were studied serially. Although the average NK cell functional activity (FA) was not significantly different between both groups, four clinical relapses in RRMS patients were associated with the development of ‘novel’ valleys in FA. These valleys are of greater depth and duration than cyclical valleys observed in both RRMS and controls, precede the onset of clinical attacks, and are observed in RRMS but not controls.In both RRMS and controls, cyclical peaks and valleys in FA are determined by the number of CD33+, CD3−CD56+, and to a lessor extent CD3+CD56+ cells capable of binding targets and inducing cell-mediated cytotoxicity (CMC). In contrast, ‘novel’ valleys in FA result from a reduction in the ability of CD3−CD56+ bound to targets to induce CMC.The results suggest that RRMS patients are at greater risk for clinical relapses during ‘novel’ valleys in FA. Furthermore, these valleys are the result of cells with a NK cell phenotype being unable to deliver a ‘lethal’ hit to targets. [Copyright &y& Elsevier]

Lumbar CSF and serum pairs of untreated multiple sclerosis patients (MS; n=47) were analyzed on admission. On average, higher CSF leukocyte (lymphocyte and monocyte) counts, IgG index, CSF IgG contents, but not of TNF-α, IL-1β, IL-6, IL-8 in CSF and serum, were revealed in all MS or patients with long disease course (LO-MS) compared with controls. In primary progressive MS (PP-MS) cell counts were low, but IgG contents were high, when compared to relapsing-remitting MS (RR-MS). In clinically probable MS (CP-MS) both contents were low, in clinically definite MS (CD-MS) high. Spearman’s correlation with the four monokines and the basic indices in CSF revealed activation patterns known for microglia/macrophages in the four MS subgroups, for astrocytes in CP-MS and RR-MS, for CSF lymphocytes in CP-MS and PP-MS, for cells of blood–brain barrier (BBB) in CP-MS, for intrathecal IgG synthesis in PP-MS and for lymphocyte transfer in CD-MS. Correlations between CSF and serum parameters indicated CNS disease processes to be associated with systemic processes of inflammation (acute, chronic) in CD-MS, RR-MS, and PP-MS in different ways. CSF IgG content, IgG index and systemic markers of inflammation correlated with overall disability scores in LO-MS; increasing levels may indicate a bad outcome. [Copyright &y& Elsevier]

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Objective – β-chemokines were recently demonstrated in active MS-lesions. We tested whether MCP-1 and RANTES can also be detected in CSF and serum of patients with MS and whether release is associated with inflammatory disease activity. Materials and methods – CSF and serum from 34 patients with newly diagnosed relapsing–remitting MS (RR-MS), 17 patients with viral meningitis (VM) and 19 patients with non-inflammatory neurological diseases (NIND) were investigated by ELISA. RR-MS patients underwent lumbar puncture and Gd-enhanced MRI examinations within 2 days. Results – MCP-1 was strong intrathecally released in all patients. Compared to NIND CSF-levels were increased in VM (P<0.001) and were decreased in RR-MS (P<0.05). RANTES was only detected in serum in all patients. Levels were higher in VM and RR-MS compared to NIND (P<0.05). A total of 14/34 RR-MS patients exhibited active Gd-enhancing lesions on MRI. They had lower MCP-1 levels in CSF (P<0.001) and serum (P<0.05) and higher serum levels of RANTES (P<0.05) as compared to patients without active lesions. Conclusions – MCP-1 and RANTES are differentially released during acute attacks of RR-MS, which might reflect different immunregulatory roles of these β-chemokines in RR-MS. [ABSTRACT FROM AUTHOR]

Abstract: Importance: Natalizumab was approved in 2004 by the US Food and Drug Administration (US-FDA) for treatment of multiple sclerosis (MS), however it was temporarily withdrawn after its use was associated with progressive multifocal leukoencephalopathy (PML). Other reported adverse events have included melanoma, primary central nervous system (CNS) lymphoma, and gastrointestinal cryptosporidiosis. An MS exacerbation may occur after discontinuation and immune reconstitution inflammatory syndrome (IRIS), particularly in the setting of PML, is also possible. We present the first case of cryptococcal meningitis in a patient taking natalizumab. Managements of both cryptococcal meningitis and MS after discontinuation of natalizumab are the focus of this report. Observations: This is a case report describing a 49-year old Caucasian man with relapsing–remitting MS (RR-MS) on natalizumab. On the twenty-fourth month of natalizumab treatment, he developed cryptococcal meningitis, prompting its discontinuation. Two months later, off natalizumab, while on antifungal treatment, he developed an MS exacerbation. Cerebrospinal fluid (CSF) JC virus polymerase chain reaction (PCR) and human immunodeficiency virus (HIV) serology were repeatedly negative. Conclusions and relevance: Although specific recommendations for treating natalizumab-associated cryptococcal meningitis do not exist, our patient discontinued natalizumab and started conventional anti-fungal treatment. Two months later, he was treated with steroids due to worsening neurologic status from a presumed MS attack. Subsequently, he improved with successful treatment of the cryptococcal meningitis, with no new clinical or radiographic exacerbations. [Copyright &y& Elsevier]

Previously, we determined that training with vibrotactile feedback (VTfb) of trunk sway improves MS patients' balance impairment. Here, we posed 5 questions: 1) How many weeks of VTfb training are required to obtain the best short-term carry over effect (CoE) with VTfb? 2) How long does the CoE last once VTfb training terminates? 3) Is the benefit similar for stance and gait? 4) Is position or velocity based VTfb more effective in reducing trunk sway? 5) Do patients' subjective assessments of balance control improve? Balance control of 16 MS patients was measured with gyroscopes at the lower trunk. The gyroscopes drove directionally active VTfb in a head-band. Patients trained twice per week with VTfb for 4 weeks to determine when balance control with and without VTfb stopped improving. Thereafter, weekly assessments without VTfb over 4 weeks and at 6 months determined when CoEs ended. A 20% improvement in balance to normal levels occurred with VTfb. Short term CoEs improved from 15 to 20% (p ≤ 0.001). Medium term (1–4 weeks) CoEs were constant at 19% (p ≤ 0.001). At 6 months improvement was not significant, 9%. Most improvement was for lateral sway. Equal improvement occurred when angle position or velocity drove VTfb. Subjectively, balance improvements peaked after 3 weeks of training (32%, p ≤ 0.05). 3–4 weeks VTfb training yields clinically relevant sway reductions and subjective improvements for MS patients during stance and gait. The CoEs lasted at least 1 month. Velocity-based VTfb was equally effective as position-based VTfb. • Described the effects of vibrotactile feedback training (VTfbT) on MS patients' balance. • Gyroscopes drove directionally active VTfb in a head-band and measured trunk sway. • A 20% improvement in balance to normal levels occurred with VTfbT. • Medium term (1-4 weeks) carry-over effects post-VTfbT were constant at 19%. • 3-4 weeks of VTfbT yielded both trunk sway reductions and subjective improvements. [ABSTRACT FROM AUTHOR]

Introduction: Dynamic functional connectivity (dFC) allows capturing recurring patterns (states) of interaction among functional networks. In this study, we investigated resting state (RS) dFC abnormalities across the different clinical phenotypes of multiple sclerosis (MS) and assessed their correlation with motor and cognitive performances. Methods: RS functional magnetic resonance imaging (fMRI) and 3D T1-weighted MRI data were acquired from 128 MS patients (69 relapsing-remitting [RR] MS, 34 secondary progressive [SP] MS, and 25 primary progressive [PP] MS) and 40 healthy controls (HC). RS fMRI data underwent independent component analysis and sliding-window correlations, to identify recurring dFC states and between-group dFC differences in the main networks. Results: dFC identified three recurring connectivity states: State 1 (frequency of appearance during fMRI acquisition = 57%, low dFC strength), State 2 (frequency = 19%, middle-high dFC strength), and State 3 (frequency = 24%, high sensorimotor and visual dFC strength). Compared to HC, MS (as a whole), RRMS, and PPMS patients exhibited lower State1/State 3 dFC ( p  = 0.0001, corrected) between sensorimotor, cerebellar, and cognitive networks, and some dFC increments ( p  = 0.001-0.05, uncorrected) in sensorimotor, visual, default-mode, and frontal/attention networks in States 2 and 3. Similar results were observed in SPMS versus RRMS patients. In MS, dFC decrease in sensorimotor, default-mode, and frontal/attention networks was correlated with worse motor and cognitive performances. Conclusions: MS patients exhibited overall lower dFC, and marginally higher dFC in sensorimotor/cognitive networks in the less-frequent middle/high-connected States. dFC abnormalities became more severe in progressive MS and correlated with motor and cognitive impairment, suggesting the presence of maladaptive mechanisms concomitant with accumulation of damage. Impact statement This is the first study exploring reorganization of dynamic functional connectivity in patients with multiple sclerosis (MS) across the main clinical phenotypes of the disease. Here, we demonstrated abnormalities of connectivity dynamism, which were present at all disease stages, but became more severe in progressive MS and correlated with worse motor and cognitive performances. These findings suggested that progressive MS patients might experience a maladaptive neuronal response to transient loss of dynamic coordination and flexibility among sensory and cognitive brain regions, leading to the progression of clinical impairment.

Background: Compared to the adult onset of multiple sclerosis (AOMS), both early-onset (EOMS) and late-onset (LOMS) are much less frequent, but are often under- or misdiagnosed. The aims of the present study were: 1. To compare demographic and clinical features of individuals with EOMS, AOMS and LOMS, and 2. To identify predictors for disability progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS). Method: Data were taken from the Isfahan Hakim MS database. Cases were classified as EOMS (MS onset ≤ 18 years), LOMS (MS onset >50 years) and AOMS (MS >18 and ≤ 50 years). Patients' demographic and clinical (initial symptoms; course of disease; disease patterns from MRI; disease progress) information were gathered and assessed. Kaplan–Meier and Cox proportional hazard regressions were conducted to determine differences between the three groups in the time lapse in conversion from relapsing remitting MS to secondary progressive MS. Results: A total of 2627 MS cases were assessed; of these 127 were EOMS, 84 LOMS and 2416 AOMS. The mean age of those with EOMS was 14.5 years; key symptoms were visual impairments, brain stem dysfunction, sensory disturbances and motor dysfunctions. On average, 24.6 years after disease onset, 14.2% with relapsing remitting MS (RRMS) were diagnosed with secondary progressive MS (SPMS). The key predictor variable was a higher Expanded Disability Status Scale (EDSS) score at disease onset. Compared to individuals with AOMS and LOMS, those with EOMS more often had one or two relapses in the first two years, and more often gadolinium-enhancing brain lesions. For individuals with AOMS, mean age was 29.4 years; key symptoms were sensory disturbances, motor dysfunctions and visual impairments. On average, 20.5 years after disease onset, 15.6% with RRMS progressed to SPMS. The key predictors at disease onset were: a higher EDSS score, younger age, a shorter inter-attack interval and spinal lesions. Compared to individuals with EOMS and LOMS, individuals with AOMS more often had either no or three and more relapses in the first two years. For individuals with LOMS, mean age was 53.8 years; key symptoms were motor dysfunctions, sensory disturbances and visual impairments. On average, 14 years after disease onset, 25.3% with RRMS switched to an SPMS. The key predictors at disease onset were: occurrence of spinal lesions and spinal gadolinium-enhancement. Compared to individuals with EOMS and AOMS, individuals with LOMS more often had no relapses in the first two years, and higher EDSS scores at disease onset and at follow-up. Conclusion: Among a large sample of MS sufferers, cases with early onset and late onset are observable. Individuals with early, adult and late onset MS each display distinct features which should be taken in consideration in their treatment. [ABSTRACT FROM AUTHOR]