Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study

PubMed Central

Rossano, Rocco; Larocca, Marilena; Trotta, Vincenzo; Mennella, Ilario; Vitaglione, Paola; Ettorre, Michele; Graverini, Antonio; De Santis, Alessandro; Di Monte, Elisabetta; Coniglio, Maria Gabriella

2016-01-01

The aim of this work was to assess the influence of nutritional intervention on inflammatory status and wellness in people with multiple sclerosis. To this end, in a seven-month pilot study we investigated the effects of a calorie-restricted, semi-vegetarian diet and administration of vitamin D and other dietary supplements (fish oil, lipoic acid, omega-3 polyunsaturated fatty acids, resveratrol and multivitamin complex) in 33 patients with relapsing-remitting multiple sclerosis and 10 patients with primary-progressive multiple sclerosis. At 0/3/6 months, patients had neurological examination, filled questionnaires and underwent anthropometric measurements and biochemical analyses. Serum fatty acids and vitamin D levels were measured as markers of dietary compliance and nutritional efficacy of treatment, whereas serum gelatinase levels were analyzed as markers of inflammatory status. All patients had insufficient levels of vitamin D at baseline, but their values did not ameliorate following a weekly administration of 5000  IU, and rather decreased over time. Conversely, omega-3 polyunsaturated fatty acids increased already after three months, even under dietary restriction only. Co-treatment with interferon-beta in relapsing-remitting multiple sclerosis was irrelevant to vitamin D levels. After six months nutritional treatment, no significant changes in neurological signs were observed in any group. However, serum levels of the activated isoforms of gelatinase matrix metalloproteinase-9 decreased by 59% in primary-progressive multiple sclerosis and by 51% in relapsing-remitting multiple sclerosis patients under nutritional intervention, including dietary supplements. This study indicates that a healthy nutritional intervention is well accepted by people with multiple sclerosis and may ameliorate their physical and inflammatory status. PMID:26785711

Anti-inflammatory nutritional intervention in patients with relapsing-remitting and primary-progressive multiple sclerosis: A pilot study.

PubMed

Riccio, Paolo; Rossano, Rocco; Larocca, Marilena; Trotta, Vincenzo; Mennella, Ilario; Vitaglione, Paola; Ettorre, Michele; Graverini, Antonio; De Santis, Alessandro; Di Monte, Elisabetta; Coniglio, Maria Gabriella

2016-03-01

The aim of this work was to assess the influence of nutritional intervention on inflammatory status and wellness in people with multiple sclerosis. To this end, in a seven-month pilot study we investigated the effects of a calorie-restricted, semi-vegetarian diet and administration of vitamin D and other dietary supplements (fish oil, lipoic acid, omega-3 polyunsaturated fatty acids, resveratrol and multivitamin complex) in 33 patients with relapsing-remitting multiple sclerosis and 10 patients with primary-progressive multiple sclerosis. At 0/3/6 months, patients had neurological examination, filled questionnaires and underwent anthropometric measurements and biochemical analyses. Serum fatty acids and vitamin D levels were measured as markers of dietary compliance and nutritional efficacy of treatment, whereas serum gelatinase levels were analyzed as markers of inflammatory status. All patients had insufficient levels of vitamin D at baseline, but their values did not ameliorate following a weekly administration of 5000  IU, and rather decreased over time. Conversely, omega-3 polyunsaturated fatty acids increased already after three months, even under dietary restriction only. Co-treatment with interferon-beta in relapsing-remitting multiple sclerosis was irrelevant to vitamin D levels. After six months nutritional treatment, no significant changes in neurological signs were observed in any group. However, serum levels of the activated isoforms of gelatinase matrix metalloproteinase-9 decreased by 59% in primary-progressive multiple sclerosis and by 51% in relapsing-remitting multiple sclerosis patients under nutritional intervention, including dietary supplements. This study indicates that a healthy nutritional intervention is well accepted by people with multiple sclerosis and may ameliorate their physical and inflammatory status. © 2016 by the Society for Experimental Biology and Medicine.

Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.

PubMed

Lublin, Fred D; Bowen, James D; Huddlestone, John; Kremenchutzky, Marcelo; Carpenter, Adam; Corboy, John R; Freedman, Mark S; Krupp, Lauren; Paulo, Corri; Hariri, Robert J; Fischkoff, Steven A

2014-11-01

Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection. PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Occipital neuralgia associates with high cervical spinal cord lesions in idiopathic inflammatory demyelinating disease.

PubMed

Kissoon, Narayan R; Watson, James C; Boes, Christopher J; Kantarci, Orhun H

2018-01-01

Background The association of trigeminal neuralgia with pontine lesions has been well documented in multiple sclerosis, and we tested the hypothesis that occipital neuralgia in multiple sclerosis is associated with high cervical spinal cord lesions. Methods We retrospectively reviewed the records of 29 patients diagnosed with both occipital neuralgia and demyelinating disease by a neurologist from January 2001 to December 2014. We collected data on demographics, clinical findings, presence of C2-3 demyelinating lesions, and treatment responses. Results The patients with both occipital neuralgia and multiple sclerosis were typically female (76%) and had a later onset (age > 40) of occipital neuralgia (72%). Eighteen patients (64%) had the presence of C2-3 lesions and the majority had unilateral symptoms (83%) or episodic pain (78%). All patients with documented sensory loss (3/3) had C2-3 lesions. Most patients with progressive multiple sclerosis (6/8) had C2-3 lesions. Of the eight patients with C2-3 lesions and imaging at onset of occipital neuralgia, five (62.5%) had evidence of active demyelination. None of the patients with progressive multiple sclerosis (3/3) responded to occipital nerve blocks or high dose intravenous steroids, whereas all of the other phenotypes with long term follow-up (eight patients) had good responses. Conclusions A cervical spine MRI should be considered in all patients presenting with occipital neuralgia. In patients with multiple sclerosis, clinical features in occipital neuralgia that were predictive of the presence of a C2-3 lesion were unilateral episodic symptoms, sensory loss, later onset of occipital neuralgia, and progressive multiple sclerosis phenotype. Clinical phenotype predicted response to treatment.

Novel Insights and Therapeutics in Multiple Sclerosis.

PubMed

Wagner, Catriona A; Goverman, Joan M

2015-01-01

The last twelve years have witnessed the development of new therapies for relapsing-remitting multiple sclerosis that demonstrate increased efficacy relative to previous therapies. Many of these new drugs target the inflammatory phase of disease by manipulating different aspects of the immune system. While these new treatments are promising, the development of therapies for patients with progressive multiple sclerosis remains a significant challenge. We discuss the distinct mechanisms that may contribute to these two types of multiple sclerosis and the implications of these differences in the development of new therapeutic targets for this debilitating disease.

[Future challenges in multiple sclerosis].

PubMed

Fernández, Óscar

2014-12-01

Multiple sclerosis occurs in genetically susceptible individuals, in whom an unknown environmental factor triggers an immune response, giving rise to a chronic and disabling autoimmune disease. Currently, significant progress is being made in our knowledge of the frequency and distribution of multiple sclerosis and its risk factors, genetics, pathology, pathogenesis, diagnostic and prognostic markers, and treatment. This has radically changed patients' and clinicians' expectations of multiple sclerosis and has raised hope that there will soon be a way to control the disease. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

A discrete-choice experiment to determine patient preferences for injectable multiple sclerosis treatments in Germany.

PubMed

Poulos, Christine; Kinter, Elizabeth; Yang, Jui-Chen; Bridges, John F P; Posner, Joshua; Gleißner, Erika; Mühlbacher, Axel; Kieseier, Bernd

2016-03-01

The aim of this study was to assess the relative importance of features of a hypothetical injectable disease-modifying treatment for patients with multiple sclerosis using a discrete-choice experiment. German residents at least 18 years of age with a self-reported physician diagnosis of multiple sclerosis completed a 25-30 minute online discrete-choice experiment. Patients were asked to choose one of two hypothetical injectable treatments for multiple sclerosis, defined by different levels of six attributes (disability progression, the number of relapses in the next 4 years, injection time, frequency of injections, presence of flu-like symptoms, and presence of injection-site reactions). The data were analyzed using a random-parameters logit model. Of 202 adults who completed the survey, results from 189 were used in the analysis. Approximately 50% of all patients reported a diagnosis of relapsing-remitting multiple sclerosis, and 31% reported secondary progressive multiple sclerosis. Approximately 71% of patients had current or prior experience with injectable multiple sclerosis medication. Approximately 53% had experienced flu-like symptoms caused by their medication, and 47% had experienced mild injection-site reactions. At least one significant difference was seen between levels in all attributes, except injection time. The greatest change in relative importance between levels of an attribute was years until symptoms get worse from 1 to 4 years. The magnitude of this difference was about twice that of relapses in the next 4 years, frequency of injections, and flu-like symptoms. Most attributes examined in this experiment had an influence on patient preference. Patients placed a significant value on improvements in the frequency of dosing and disability progression. Results suggest that changes in injection frequency can be as important as changes in efficacy and safety attributes. Understanding which attributes of injectable therapies influence patient preference could potentially improve outcomes and adherence in patients with multiple sclerosis.

Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis.

PubMed

Thomas, Katja; Proschmann, Undine; Ziemssen, Tjalf

2017-10-01

Fingolimod was the first oral and the first in class disease modifying treatment in multiple sclerosis that acts as sphingosine-1-phospathe receptor agonist. Since approval in 2010 there is a growing experience with fingolimod use in clinical practice, but also next-generation sphingosin-1-receptor agonists in ongoing clinical trials. Growing evidence demonstrates additional effects beyond impact on lymphocyte circulation, highlighting further promising targets in multiple sclerosis therapy. Areas covered: Here we present a systematic review using PubMed database searching and expert opinion on fingolimod use in clinical practice. Long-term data of initial clinical trials and post-marketing evaluations including long-term efficacy, safety, tolerability and management especially within growing disease modifying treatment options and pre-treatment constellation in multiple sclerosis patients are critically discussed. Furthermore novel findings in mechanism of actions and prospective on additional use in progressive forms in multiple sclerosis are presented. Expert opinion: There is an extensive long-term experience on fingolimod use in clinical practice demonstrating the favorable benefit-risk of this drug. Using a defined risk management approach experienced MS clinicians should apply fingolimod after critical choice of patients and review of clinical aspects. Further studies are essential to discuss additional benefit in progressive forms in multiple sclerosis.

Long-term disability progression in primary progressive multiple sclerosis: a 15-year study.

PubMed

Rocca, Maria A; Sormani, Maria Pia; Rovaris, Marco; Caputo, Domenico; Ghezzi, Angelo; Montanari, Enrico; Bertolotto, Antonio; Laroni, Alice; Bergamaschi, Roberto; Martinelli, Vittorio; Comi, Giancarlo; Filippi, Massimo

2017-11-01

Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T1-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R2 = 61% versus R2 = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers.

PubMed

Novakova, Lenka; Axelsson, Markus; Malmeström, Clas; Imberg, Henrik; Elias, Olle; Zetterberg, Henrik; Nerman, Olle; Lycke, Jan

2018-01-01

Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization. This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course. This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction. Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration. In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.

Physiotherapy Rehabilitation for People With Progressive Multiple Sclerosis: A Systematic Review.

PubMed

Campbell, Evan; Coulter, Elaine H; Mattison, Paul G; Miller, Linda; McFadyen, Angus; Paul, Lorna

2016-01-01

To assess the efficacy of physiotherapy interventions, including exercise therapy, for the rehabilitation of people with progressive multiple sclerosis. Five databases (Cochrane Library, Physiotherapy Evidence Database [PEDro], Web of Science Core Collections, MEDLINE, Embase) and reference lists of relevant articles were searched. Randomized experimental trials, including participants with progressive multiple sclerosis and investigating a physiotherapy intervention or an intervention containing a physiotherapy element, were included. Data were independently extracted using a standardized form, and methodologic quality was assessed using the PEDro scale. Thirteen studies (described by 15 articles) were identified and scored between 5 and 9 out of 10 on the PEDro scale. Eight interventions were assessed: exercise therapy, multidisciplinary rehabilitation, functional electrical stimulation, botulinum toxin type A injections and manual stretches, inspiratory muscle training, therapeutic standing, acupuncture, and body weight-supported treadmill training. All studies, apart from 1, produced positive results in at least 1 outcome measure; however, only 1 article used a power calculation to determine the sample size and because of dropouts the results were subsequently underpowered. This review suggests that physiotherapy may be effective for the rehabilitation of people with progressive multiple sclerosis. However, further appropriately powered studies are required. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C; Otto, Markus; Tumani, Hayrettin

2015-07-31

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed Central

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C.; Otto, Markus; Tumani, Hayrettin

2015-01-01

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs. PMID:26263977

[Current therapy of multiple sclerosis].

PubMed

Antonio García Merino, J

2014-12-01

Since the introduction of interferon beta 1 b for the treatment of multiple sclerosis, there has been a progressive increase in the number of drugs available for this disease. Currently, 11 drugs have been approved in Spain, and their indications depend on specific clinical characteristics. The present article reviews these indications and also discusses other medications without official approval that have also been used in multiple sclerosis. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Autologous hematopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: comparison with secondary progressive multiple sclerosis.

PubMed

Casanova, Bonaventura; Jarque, Isidro; Gascón, Francisco; Hernández-Boluda, Juan Carlos; Pérez-Miralles, Francisco; de la Rubia, Javier; Alcalá, Carmen; Sanz, Jaime; Mallada, Javier; Cervelló, Angeles; Navarré, Arantxa; Carcelén-Gadea, María; Boscá, Isabel; Gil-Perotin, Sara; Solano, Carlos; Sanz, Miguel Angel; Coret, Francisco

2017-07-01

The main objective of our work is to describe the long-term results of myeloablative autologous hematopoietic stem cell transplant (AHSCT) in multiple sclerosis patients. Patients that failed to conventional therapies for multiple sclerosis (MS) underwent an approved protocol for AHSCT, which consisted of peripheral blood stem cell mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF), followed by a conditioning regimen of BCNU, Etoposide, Ara-C, Melphalan IV, plus Rabbit Thymoglobulin. Thirty-eight MS patients have been transplanted since 1999. Thirty-one patients have been followed for more than 2 years (mean 8.4 years). There were 22 relapsing-remitting multiple sclerosis (RRMS) patients and 9 secondary progressive multiple sclerosis (SPMS) patients. No death related to AHSCT. A total of 10 patients (32.3%) had at least one relapse during post-AHSCT evolution, 6 patients in the RRMS group (27.2%) and 4 in the SPMS group (44.4%). After AHSCT, 7 patients (22.6%) experienced progression of disability, all within SP form. By contrast, no patients with RRMS experienced worsening of disability after a median follow-up of 5.4 years, 60% of them showed a sustained reduction in disability (SRD), defined as the improvement of 1.0 point in the expanded disability status scale (EDSS) sustains for 6 months (0.5 in cases of EDSS ≥ 5.5). The only clinical variable that predicted a poor response to AHSCT was a high EDSS in the year before transplant. AHSCT using the BEAM-ATG scheme is safe and efficacious to control the aggressive forms of RRMS.

[Indications for percutaneous endoscopic gastrostomy in patients with disorders of the nervous system].

PubMed

Ehler, E; Geier, P; Dostál, V; Novotná, A; Vyhnálek, P; Hájek, J; Sákra, L

2002-05-01

Percutaneous endoscopic gastrostomy (PEG) is an efficient endoscopic method that ensures enteral nutrition for a longer period of time in patients who cannot take food per os. This method is also indicated in patients suffering from disorders of the central or peripheral nervous system which developed suddenly, such as a stroke or craniocerebral injuries, or gradually, such as amyotrophic lateral sclerosis (ALS), dementia, and multiple sclerosis. It has become common practice in the cooperation between neurologists and a gastroenterologists to use PEG in patients hospitalized in a neurological ward with encephalomalacy and haemorrhage, or craniocerebral injuries (after the patient recovers from the acute stage of the disease and is transferred to a neurological ICU), as well as in patients with ALS in a progressive stage. We gradually extend the indications of PEG for other patients with neurological disorders such as patients suffering from dementia, progressive multiple sclerosis, Parkinson's disease, and progressive polyneuropathy. Of 62 patients hospitalized in a neurological ward during a period of 4.5 years, 56 patients suffered from sudden disorders of the nervous system (strokes and craniocerebral injuries) and 6 patients had gradually progressing neurological diseases (ALS, multiple sclerosis, Parkinson's disease, dementia, and polyneuropathy).

Cognitive Impairment in MS Linked to Structural and Functional Connectivity

DTIC Science & Technology

2016-10-01

AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple sclerosis (MS) is the most...9 9. Appendices……………………………………………………………9 Krupp MS130103  2  Abstract Multiple sclerosis (MS) is the most common progressive neurologic...This symptom represents a major concern for many individuals living with multiple sclerosis (MS). Unfortunately, no reliable treatments exist to

Cerebrospinal fluid ATP metabolites in multiple sclerosis.

PubMed

Lazzarino, G; Amorini, A M; Eikelenboom, M J; Killestein, J; Belli, A; Di Pietro, V; Tavazzi, B; Barkhof, F; Polman, C H; Uitdehaag, B M J; Petzold, A

2010-05-01

Increased axonal energy demand and mitochondrial failure have been suggested as possible causes for axonal degeneration and disability in multiple sclerosis. Our objective was to test whether ATP depletion precedes clinical, imaging and biomarker evidence for axonal degeneration in multiple sclerosis. The method consisted of a longitudinal study which included 21 patients with multiple sclerosis. High performance liquid chromatography was used to quantify biomarkers of the ATP metabolism (oxypurines and purines) from the cerebrospinal fluid at baseline. The Expanded Disability Status Scale, MRI brain imaging measures for brain atrophy (ventricular and parenchymal fractions), and cerebrospinal fluid biomarkers for axonal damage (phosphorylated and hyperphosphorylated neurofilaments) were quantified at baseline and 3-year follow-up. Central ATP depletion (sum of ATP metabolites >19.7 micromol/litre) was followed by more severe progression of disability if compared to normal ATP metabolites (median 1.5 versus 0, p< 0.05). Baseline ATP metabolite levels correlated with change of Expanded Disability Status Scale in the pooled cohort (r= 0.66, p= 0.001) and subgroups (relapsing-remitting patients: r= 0.79, p< 0.05 and secondary progressive/primary progressive patients: r= 0.69, p< 0.01). There was no relationship between central ATP metabolites and either biomarker or MRI evidence for axonal degeneration. The data suggests that an increased energy demand in multiple sclerosis may cause a quantifiable degree of central ATP depletion. We speculate that the observed clinical disability may be related to depolarisation associated conduction block.

Sit less and move more: perspectives of adults with multiple sclerosis.

PubMed

Aminian, Saeideh; Ezeugwu, Victor E; Motl, Robert W; Manns, Patricia J

2017-12-20

Multiple sclerosis is a chronic neurological disease with the highest prevalence in Canada. Replacing sedentary behavior with light activities may be a feasible approach to manage multiple sclerosis symptoms. This study explored the perspectives of adults with multiple sclerosis about sedentary behavior, physical activity and ways to change behavior. Fifteen adults with multiple sclerosis (age 43 ± 13 years; mean ± standard deviation), recruited through the multiple sclerosis Clinic at the University of Alberta, Edmonton, Canada, participated in semi-structured interviews. Interview audios were transcribed verbatim and coded. NVivo software was used to facilitate the inductive process of thematic analysis. Balancing competing priorities between sitting and moving was the primary theme. Participants were aware of the benefits of physical activity to their overall health, and in the management of fatigue and muscle stiffness. Due to fatigue, they often chose sitting to get their energy back. Further, some barriers included perceived fear of losing balance or embarrassment while walking. Activity monitoring, accountability, educational and individualized programs were suggested strategies to motivate more movement. Adults with multiple sclerosis were open to the idea of replacing sitting with light activities. Motivational and educational programs are required to help them to change sedentary behavior to moving more. IMPLICATIONS FOR REHABILITATION One of the most challenging and common difficulties of multiple sclerosis is walking impairment that worsens because of multiple sclerosis progression, and is a common goal in the rehabilitation of people with multiple sclerosis. The deterioration in walking abilities is related to lower levels of physical activity and more sedentary behavior, such that adults with multiple sclerosis spend 8 to 10.5 h per day sitting. Replacing prolonged sedentary behavior with light physical activities, and incorporating education, encouragement, and self-monitoring strategies are feasible approaches to manage the symptoms of multiple sclerosis.

Is impaired cerebral vasoreactivity an early marker of cognitive decline in multiple sclerosis patients?

PubMed

Metzger, Aude; Le Bars, Emmanuelle; Deverdun, Jeremy; Molino, François; Maréchal, Bénédicte; Picot, Marie-Christine; Ayrignac, Xavier; Carra, Clarisse; Bauchet, Luc; Krainik, Alexandre; Labauge, Pierre; Menjot de Champfleur, Nicolas

2018-03-01

The link between cerebral vasoreactivity and cognitive status in multiple sclerosis remains unclear. The aim of the present study was to investigate a potential decrease of cerebral vasoreactivity in multiple sclerosis patients and correlate it with cognitive status. Thirty-three patients with multiple sclerosis (nine progressive and 24 remitting forms, median age: 39 years, 12 males) and 22 controls underwent MRI with a hypercapnic challenge to assess cerebral vasoreactivity and a neuropsychological assessment. Cerebral vasoreactivity, measured as the cerebral blood flow percent increase normalised by end-tidal carbon dioxide variation, was assessed globally and by regions of interest using the blood oxygen level-dependent technique. Non-parametric statistics tests were used to assess differences between groups, and associations were estimated using linear models. Cerebral vasoreactivity was lower in patients with cognitive impairment than in cognitively normal patients (p=0.004) and was associated with education level in patients (R 2 = 0.35; p = 0.047). There was no decrease in cerebral vasoreactivity between patients and controls. Cognitive impairment in multiple sclerosis may be mediated through decreased cerebral vasoreactivity. Cerebral vasoreactivity could therefore be considered as a marker of cognitive decline in multiple sclerosis. • Cerebral vasoreactivity does not differ between multiple sclerosis patients and controls. • Cerebral vasoreactivity measure is linked to cognitive impairment in multiple sclerosis. • Cerebral vasoreactivity is linked to level of education in multiple sclerosis.

Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research

PubMed Central

Waldman, Amy; Ghezzi, Angelo; Bar-Or, Amit; Mikaeloff, Yann; Tardieu, Marc; Banwell, Brenda

2015-01-01

The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed. PMID:25142460

Exercise Training in Progressive Multiple Sclerosis: A Comparison of Recumbent Stepping and Body Weight-Supported Treadmill Training.

PubMed

Pilutti, Lara A; Paulseth, John E; Dove, Carin; Jiang, Shucui; Rathbone, Michel P; Hicks, Audrey L

2016-01-01

Background: There is evidence of the benefits of exercise training in multiple sclerosis (MS); however, few studies have been conducted in individuals with progressive MS and severe mobility impairment. A potential exercise rehabilitation approach is total-body recumbent stepper training (TBRST). We evaluated the safety and participant-reported experience of TBRST in people with progressive MS and compared the efficacy of TBRST with that of body weight-supported treadmill training (BWSTT) on outcomes of function, fatigue, and health-related quality of life (HRQOL). Methods: Twelve participants with progressive MS (Expanded Disability Status Scale scores, 6.0-8.0) were randomized to receive TBRST or BWSTT. Participants completed three weekly sessions (30 minutes) of exercise training for 12 weeks. Primary outcomes included safety assessed as adverse events and patient-reported exercise experience assessed as postexercise response and evaluation of exercise equipment. Secondary outcomes included the Multiple Sclerosis Functional Composite, the Modified Fatigue Impact Scale, and the Multiple Sclerosis Quality of Life-54 questionnaire scores. Assessments were conducted at baseline and after 12 weeks. Results: Safety was confirmed in both exercise groups. Participants reported enjoying both exercise modalities; however, TBRST was reviewed more favorably. Both interventions reduced fatigue and improved HRQOL (P ≤ .05); there were no changes in function. Conclusions: Both TBRST and BWSTT seem to be safe, well tolerated, and enjoyable for participants with progressive MS with severe disability. Both interventions may also be efficacious for reducing fatigue and improving HRQOL. TBRST should be further explored as an exercise rehabilitation tool for patients with progressive MS.

Gait Characteristics in Adolescents With Multiple Sclerosis.

PubMed

Kalron, Alon; Frid, Lior; Menascu, Shay

2017-03-01

Multiple sclerosis is a progressive autoimmune disease of the central nervous system. A presentation of multiple sclerosis before age18 years has traditionally been thought to be rare. However, during the past decade, more cases have been reported. We examined gait characteristics in 24 adolescents with multiple sclerosis (12 girls, 12 boys). Mean disease duration was 20.4 (S.D. = 24.9) months and mean age was 15.5 (S.D. = 1.1) years. The mean expanded disability status scale score was 1.7 (S.D. = 0.7) indicating minimal disability. Outcomes were compared with gait and the gait variability index value of healthy age-matched adolescents. Adolescents with multiple sclerosis walked slower with a wider base of support compared with age-matched healthy control subjects. Moreover, the gait variability index was lower in the multiple sclerosis group compared with the values in the healthy adolescents: 85.4 (S.D. = 8.1) versus 96.5 (S.D. = 7.4). We present gait parameters of adolescents with multiple sclerosis. From a clinical standpoint, our data could improve management of walking dysfunction in this relatively young population. Copyright © 2016 Elsevier Inc. All rights reserved.

Endocannabinoids in Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

PubMed

Pryce, Gareth; Baker, David

2015-01-01

There are numerous reports that people with multiple sclerosis (MS) have for many years been self-medicating with illegal street cannabis or more recently medicinal cannabis to alleviate the symptoms associated with MS and also amyotrophic lateral sclerosis (ALS). These anecdotal reports have been confirmed by data from animal models and more recently clinical trials on the ability of cannabinoids to alleviate limb spasticity, a common feature of progressive MS (and also ALS) and neurodegeneration. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have efficacy, not only in symptom relief but also as neuroprotective agents which may slow disease progression and thus delay the onset of symptoms. This review discusses what we now know about the endocannabinoid system as it relates to MS and ALS and also the therapeutic potential of cannabinoid therapeutics as disease-modifying or symptom control agents, as well as future therapeutic strategies including the potential for slowing disease progression in MS and ALS.

Exercise and Quality of Life in Women with Multiple Sclerosis

ERIC Educational Resources Information Center

Giacobbi, Peter R., Jr.; Dietrich, Frederick; Larson, Rebecca; White, Lesley J.

2012-01-01

The purpose of this study was to evaluate perceptions of quality of life after a 4-month progressive resistance training program for individuals with multiple sclerosis (MS). A second purpose was to examine participants' views about factors that facilitated or impeded exercise behavior. Qualitative interviews were conducted with eight females…

Multiple Sclerosis and Employment: A Research Review Based on the International Classification of Function

ERIC Educational Resources Information Center

Frain, Michael P.; Bishop, Malachy; Rumrill, Phillip D., Jr.; Chan, Fong; Tansey, Timothy N.; Strauser, David; Chiu, Chung-Yi

2015-01-01

Multiple sclerosis (MS) is an unpredictable, sometimes progressive chronic illness affecting people in the prime of their working lives. This article reviews the effects of MS on employment based on the World Health Organization's International Classification of Functioning, Disability and Health model. Correlations between employment and…

Self care programs and multiple sclerosis: physical therapeutics treatment - literature review.

PubMed

Demaille-Wlodyka, S; Donze, C; Givron, P; Gallien, P

2011-03-01

To clarify the therapeutic education program impact with multiple sclerosis patients, literature review. Highlight contents and efficacy. A non-systematic review on Medline, PubMed and Cochrane library databases from 1966 to 2010 using the following keywords: "multiple sclerosis", "self-care", "self-management" and specific symptoms keywords. Clinical trials and randomized clinical trials, as well as literature reviews published in English, French and German will be analyzed. Counseling is a part of the non-pharmacological management of chronic illnesses such as multiple sclerosis. Symptoms' diversity and the different clinical forms limit standardized programs of self-care management, applicable to patients. In the literature review, counseling programs have often low metrology. A behavior change with patients and medical staff could exist. To empower the patient, to reduce symptoms' impact and to improve treatment access are the aims of educational therapy. Therapeutic education program for multiple sclerosis patients could progress with their standardization and assessment, for each sign. To promote the educational therapy of multiple sclerosis patients, a specific training for medical staff, as specific financing are necessary. 2011 Elsevier Masson SAS. All rights reserved.

The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases.

PubMed

Chiurchiù, Valerio; van der Stelt, Mario; Centonze, Diego; Maccarrone, Mauro

2018-01-01

Multiple sclerosis is the most common inflammatory demyelinating disease of the central nervous system, caused by an autoimmune response against myelin that eventually leads to progressive neurodegeneration and disability. Although the knowledge on its underlying neurobiological mechanisms has considerably improved, there is a still unmet need for new treatment options, especially for the progressive forms of the disease. Both preclinical and clinical data suggest that cannabinoids, derived from the Cannabis sativa plant, may be used to control symptoms such as spasticity and chronic pain, whereas only preclinical data indicate that these compounds and their endogenous counterparts, i.e. the endocannabinoids, may also exert neuroprotective effects and slow down disease progression. Here, we review the preclinical and clinical studies that could explain the therapeutic action of cannabinoid-based medicines, as well as the medical potential of modulating endocannabinoid signaling in multiple sclerosis, with a link to other neuroinflammatory disorders that share common hallmarks and pathogenetic features. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis.

PubMed

Hofstetter, Louis; Naegelin, Yvonne; Filli, Lukas; Kuster, Pascal; Traud, Stefan; Smieskova, Renata; Mueller-Lenke, Nicole; Kappos, Ludwig; Gass, Achim; Sprenger, Till; Penner, Iris-Katharina; Nichols, Thomas E; Vrenken, Hugo; Barkhof, Frederik; Polman, Chris; Radue, Ernst-Wilhelm; Borgwardt, Stefan J; Bendfeldt, Kerstin

2014-02-01

In multiple sclerosis (MS) regional grey matter (GM) atrophy has been associated with disability progression. The aim of this study was to compare regional GM volume changes in relapsing-remitting MS (RRMS) patients with progressive and stable disability, using voxel-based morphometry (VBM). We acquired baseline and 1-year follow-up 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI) data of RRMS patients, using two 1.5-Tesla scanners. Patients were matched pair-wise with respect to age, gender, disease duration, medication, scanner and baseline Expanded Disability Status Scale (EDSS) into 13 pairs, with either progressive EDSS (≥ 1 point change y(-1)) or stable EDSS, as well as into 29 pairs with either progressive Multiple Sclerosis Functional Composite (MSFC) at ≥ 0.25% decrease in y(-1) in any component, or stable MSFC. We analysed longitudinal regional differences in GM volumes in the progressive and stable EDSS and MSFC groups, respectively, using VBM. Significant GM volume reductions occurred in the right precuneus, in the progressive EDSS group. Differential between-group effects occurred in the right precuneus and in the postcentral gyrus. Further longitudinal GM volume reductions occurred in the right orbicular gyrus, in the progressive MSFC group, but no between-group differences were observed (non-stationary cluster-wise inference, all P(corrected) < 0.05). These results suggested a direct association of disability progression and regional GM atrophy in RRMS.

SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts.

PubMed

Bove, Riley; Chitnis, Tanuja; Cree, Bruce Ac; Tintoré, Mar; Naegelin, Yvonne; Uitdehaag, Bernard Mj; Kappos, Ludwig; Khoury, Samia J; Montalban, Xavier; Hauser, Stephen L; Weiner, Howard L

2017-08-01

There is a pressing need for robust longitudinal cohort studies in the modern treatment era of multiple sclerosis. Build a multiple sclerosis (MS) cohort repository to capture the variability of disability accumulation, as well as provide the depth of characterization (clinical, radiologic, genetic, biospecimens) required to adequately model and ultimately predict a patient's course. Serially Unified Multicenter Multiple Sclerosis Investigation (SUMMIT) is an international multi-center, prospectively enrolled cohort with over a decade of comprehensive follow-up on more than 1000 patients from two large North American academic MS Centers (Brigham and Women's Hospital (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB; BWH)) and University of California, San Francisco (Expression/genomics, Proteomics, Imaging, and Clinical (EPIC))). It is bringing online more than 2500 patients from additional international MS Centers (Basel (Universitätsspital Basel (UHB)), VU University Medical Center MS Center Amsterdam (MSCA), Multiple Sclerosis Center of Catalonia-Vall d'Hebron Hospital (Barcelona clinically isolated syndrome (CIS) cohort), and American University of Beirut Medical Center (AUBMC-Multiple Sclerosis Interdisciplinary Research (AMIR)). We provide evidence for harmonization of two of the initial cohorts in terms of the characterization of demographics, disease, and treatment-related variables; demonstrate several proof-of-principle analyses examining genetic and radiologic predictors of disease progression; and discuss the steps involved in expanding SUMMIT into a repository accessible to the broader scientific community.

Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis.

PubMed

Albert, Monika; Barrantes-Freer, Alonso; Lohrberg, Melanie; Antel, Jack P; Prineas, John W; Palkovits, Miklós; Wolff, Joachim R; Brück, Wolfgang; Stadelmann, Christine

2017-11-01

In multiple sclerosis, cerebellar symptoms are associated with clinical impairment and an increased likelihood of progressive course. Cortical atrophy and synaptic dysfunction play a prominent role in cerebellar pathology and although the dentate nucleus is a predilection site for lesion development, structural synaptic changes in this region remain largely unexplored. Moreover, the mechanisms leading to synaptic dysfunction have not yet been investigated at an ultrastructural level in multiple sclerosis. Here, we report on synaptic changes of dentate nuclei in post-mortem cerebella of 16 multiple sclerosis patients and eight controls at the histological level as well as an electron microscopy evaluation of afferent synapses of the cerebellar dentate and pontine nuclei of one multiple sclerosis patient and one control. We found a significant reduction of afferent dentate synapses in multiple sclerosis, irrespective of the presence of demyelination, and a close relationship between glial processes and dentate synapses. Ultrastructurally, we show autophagosomes containing degradation products of synaptic vesicles within dendrites, residual bodies within intact-appearing axons and free postsynaptic densities opposed to astrocytic appendages. Our study demonstrates loss of dentate afferent synapses and provides, for the first time, ultrastructural evidence pointing towards neuron-autonomous and neuroglia-mediated mechanisms of synaptic degradation in chronic multiple sclerosis. © 2016 International Society of Neuropathology.

[Physical rehabilitation in multiple sclerosis: general principles and high-tech approaches].

PubMed

Peresedova, A V; Chernikova, L A; Zavalishin, I A

2013-01-01

In a chronic and disabling disease like multiple sclerosis, rehabilitation programs are of major importance for the preservation of physical, physiological, social and professional functioning and improvement of quality of life. Currently, it is generally assumed that physical activity is an important component of non-pharmacological rehabilitation in multiple sclerosis. Properly organized exercise is a safe and efficient way to induce improvements in a number of physiological functions. A multidisciplinary rehabilitative approach should be recommended. The main recommendations for the use of exercise for patients with multiple sclerosis have been listed. An important aspect of the modern physical rehabilitation in multiple sclerosis is the usage of high-tech methods. The published results of robot-assisted training to improve the hand function and walking impairment have been represented. An important trend in the rehabilitation of patients with multiple sclerosis is the reduction of postural disorders through training balance coordination. The role of transcranial magnetic stimulation in spasticity reducing is being investigated. The use of telemedicine capabilities is quite promising. Due to the fact that the decline in physical activity can lead to the deterioration of many aspects of physiological functions and, ultimately, to mobility decrease, further research of the role of physical rehabilitation as an important therapeutic approach in preventing the progression of disability in multiple sclerosis is required.

A gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging

PubMed Central

Louapre, Céline; Govindarajan, Sindhuja T.; Giannì, Costanza; Nielsen, A. Scott; Cohen-Adad, Julien; Sloane, Jacob; Kinkel, Revere P.

2015-01-01

We used a surface-based analysis of T2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2* throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (≥4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2* maps were registered to anatomical cortical surfaces for sampling T2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2* was compared with patients’ normal-appearing cortical grey matter T2* (paired t-test) and with mean cortical T2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2*, consistent with cortical myelin and iron loss. In early disease, T2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10−10 and P < 10−7), and mean cortical T2* in controls (P < 10−5 and P < 10−6). In secondary progressive multiple sclerosis, T2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface. PMID:25681411

Cognitive Impairment in MS Linked to Structural and Functional Connectivity

DTIC Science & Technology

2015-10-01

DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple sclerosis (MS) is...Requirements………………………………… 9 9. Appendices……………………………………………………………9 Krupp MS130103  2    Abstract Multiple sclerosis (MS) is the most common progressive...information processing needed to learn and solve problems. This symptom represents a major concern for many individuals living with multiple sclerosis

A passive exoskeleton can push your life up: application on multiple sclerosis patients.

PubMed

Di Russo, Francesco; Berchicci, Marika; Perri, Rinaldo Livio; Ripani, Francesca Romana; Ripani, Maurizio

2013-01-01

In the present study, we report the benefits of a passive and fully articulated exoskeleton on multiple sclerosis patients by means of behavioral and electrophysiological measures, paying particular attention to the prefrontal cortex activity. Multiple sclerosis is a neurological condition characterized by lesions of the myelin sheaths that encapsulate the neurons of the brain, spine and optic nerve, and it causes transient or progressive symptoms and impairments in gait and posture. Up to 50% of multiple sclerosis patients require walking aids and 10% are wheelchair-bound 15 years following the initial diagnosis. We tested the ability of a new orthosis, the "Human Body Posturizer", designed to improve the structural and functional symmetry of the body through proprioception, in multiple sclerosis patients. We observed that a single Human Body Posturizer application improved mobility, ambulation and response accuracy, in all of the tested patients. Most importantly, we associated these clinical observations and behavioral effects to changes in brain activity, particularly in the prefrontal cortex.

Progressive solitary sclerosis

PubMed Central

Kaufmann, Timothy J.; Weinshenker, Brian G.; Kantarci, Orhun H.; Schmalstieg, William F.; Paz Soldan, M. Mateo; Flanagan, Eoin P.

2016-01-01

Objective: To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Methods: Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. Results: The patients' median age was 48.5 years (range 23–71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15–343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Conclusions: Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. PMID:27638926

Smoking and multiple sclerosis: A systematic review and meta-analysis using the Bradford Hill criteria for causation.

PubMed

Degelman, Michelle L; Herman, Katya M

2017-10-01

Despite being one of the most common neurological disorders globally, the cause(s) of multiple sclerosis (MS) remain unknown. Cigarette smoking has been studied with regards to both the development and progression of MS. The Bradford Hill criteria for causation can contribute to a more comprehensive evaluation of a potentially causal risk factor-disease outcome relationship. The objective of this systematic review and meta-analysis was to assess the relationship between smoking and both MS risk and MS progression, subsequently applying Hill's criteria to further evaluate the likelihood of causal associations. The Medline, EMBASE, CINAHL, PsycInfo, and Cochrane Library databases were searched for relevant studies up until July 28, 2015. A random-effects meta-analysis was conducted for three outcomes: MS risk, conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS), and progression from relapsing-remitting multiple sclerosis (RRMS) to secondary-progressive multiple sclerosis (SPMS). Dose-response relationships and risk factor interactions, and discussions of mechanisms and analogous associations were noted. Hill's criteria were applied to assess causality of the relationships between smoking and each outcome. The effect of second-hand smoke exposure was also briefly reviewed. Smoking had a statistically significant association with both MS risk (conservative: OR/RR 1.54, 95% CI [1.46-1.63]) and SPMS risk (HR 1.80, 95% CI [1.04-3.10]), but the association with progression from CIS to CDMS was non-significant (HR 1.13, 95% CI [0.73-1.76]). Using Hill's criteria, there was strong evidence of a causal role of smoking in MS risk, but only moderate evidence of a causal association between smoking and MS progression. Heterogeneity in study designs and target populations, inconsistent results, and an overall scarcity of studies point to the need for more research on second-hand smoke exposure in relation to MS prior to conducting a detailed meta-analysis. This first review to supplement systematic review and meta-analytic methods with Hill's criteria to analyze the smoking-MS association provides evidence supporting the causal involvement of smoking in the development and progression of MS. Smoking prevention and cessation programs and policies should consider MS as an additional health risk when aiming to reduce smoking prevalence in the population. Copyright © 2017 Elsevier B.V. All rights reserved.

A preliminary study into the sensitivity of disease activity detection by serial weekly magnetic resonance imaging in multiple sclerosis.

PubMed Central

Lai, M; Hodgson, T; Gawne-Cain, M; Webb, S; MacManus, D; McDonald, W I; Thompson, A J; Miller, D H

1996-01-01

Long TR and gadolinium enhanced spin echo brain MRI was performed weekly for three months in three patients with relapsing-remitting or secondary progressive multiple sclerosis. During the study, 38 new enhancing lesions were seen; 11 showed enhancement for less than four weeks, and two enhanced on only one scan. All 16 new lesions seen on long TR scans showed initial enhancement. When only every fourth (monthly) scan was analysed, a total of 33 new enhancing lesions were seen. Subject to confirmation in a larger cohort, the results suggest: (a) that blood brain barrier leakage is an invariable event in new lesion development in relapsing-remitting and secondary progressive multiple sclerosis; (b) the small increase in sensitivity of weekly scanning does not justify its use in preference to monthly scanning when monitoring treatments. Images PMID:8609517

Stress and multiple sclerosis: A systematic review considering potential moderating and mediating factors and methods of assessing stress.

PubMed

Briones-Buixassa, Laia; Milà, Raimon; Mª Aragonès, Josep; Bufill, Enric; Olaya, Beatriz; Arrufat, Francesc Xavier

2015-07-01

Research about the effects of stress on multiple sclerosis has yielded contradictory results. This study aims to systematically review the evidence focusing on two possible causes: the role of stress assessment and potential moderating and mediating factors. The Web of Knowledge (MEDLINE and Web of Science), Scopus, and PsycINFO databases were searched for relevant articles published from 1900 through December 2014 using the terms "stress*" AND "multiple sclerosis." Twenty-three articles were included. Studies focused on the effect of stress on multiple sclerosis onset ( n  = 9) were mostly retrospective, and semi-structured interviews and scales yielded the most consistent associations. Studies focused on multiple sclerosis progression ( n  = 14) were mostly prospective, and self-reported diaries yielded the most consistent results. The most important modifying factors were stressor duration, severity, and frequency; cardiovascular reactivity and heart rate; and social support and escitalopram intake. Future studies should consider the use of prospective design with self-reported evaluations and the study of moderators and mediators related to amount of stress and autonomic nervous system reactivity to determine the effects of stress on multiple sclerosis.

Stress and multiple sclerosis: A systematic review considering potential moderating and mediating factors and methods of assessing stress

PubMed Central

Briones-Buixassa, Laia; Milà, Raimon; Mª Aragonès, Josep; Bufill, Enric; Olaya, Beatriz; Arrufat, Francesc Xavier

2015-01-01

Research about the effects of stress on multiple sclerosis has yielded contradictory results. This study aims to systematically review the evidence focusing on two possible causes: the role of stress assessment and potential moderating and mediating factors. The Web of Knowledge (MEDLINE and Web of Science), Scopus, and PsycINFO databases were searched for relevant articles published from 1900 through December 2014 using the terms “stress*” AND “multiple sclerosis.” Twenty-three articles were included. Studies focused on the effect of stress on multiple sclerosis onset (n = 9) were mostly retrospective, and semi-structured interviews and scales yielded the most consistent associations. Studies focused on multiple sclerosis progression (n = 14) were mostly prospective, and self-reported diaries yielded the most consistent results. The most important modifying factors were stressor duration, severity, and frequency; cardiovascular reactivity and heart rate; and social support and escitalopram intake. Future studies should consider the use of prospective design with self-reported evaluations and the study of moderators and mediators related to amount of stress and autonomic nervous system reactivity to determine the effects of stress on multiple sclerosis. PMID:28070374

Can we prevent or treat multiple sclerosis by individualised vitamin D supply?

PubMed Central

2013-01-01

Apart from its principal role in bone metabolism and calcium homeostasis, vitamin D has been attributed additional effects including an immunomodulatory, anti-inflammatory, and possibly even neuroprotective capacity which implicates a possible role of vitamin D in autoimmune diseases like multiple sclerosis (MS). Indeed, several lines of evidence including epidemiologic, preclinical, and clinical data suggest that reduced vitamin D levels and/or dysregulation of vitamin D homeostasis is a risk factor for the development of multiple sclerosis on the one hand, and that vitamin D serum levels are inversely associated with disease activity and progression on the other hand. However, these data are not undisputable, and many questions regarding the preventive and therapeutic capacity of vitamin D in multiple sclerosis remain to be answered. In particular, available clinical data derived from interventional trials using vitamin D supplementation as a therapeutic approach in MS are inconclusive and partly contradictory. In this review, we summarise and critically evaluate the existing data on the possible link between vitamin D and multiple sclerosis in light of the crucial question whether optimization of vitamin D status may impact the risk and/or the course of multiple sclerosis. PMID:23356351

Similar autobiographical memory impairment in long-term secondary progressive multiple sclerosis and Alzheimer's disease.

PubMed

Müller, S; Saur, R; Greve, B; Melms, A; Hautzinger, M; Fallgatter, A J; Leyhe, T

2013-02-01

Memory disturbance is a common symptom of multiple sclerosis (MS), but little is known about autobiographical memory deficits in the long-term course of different MS subtypes. Inflammatory activity and demyelination is pronounced in relapsing-remitting multiple sclerosis (RRMS) whereas, similar to Alzheimer's disease, neurodegeneration affecting autobiographical memory-associated areas is seen in secondary progressive multiple sclerosis (SPMS). In light of distinct disease mechanisms, we evaluated autobiographical memory in different MS subtypes and hypothesized similarities between elderly patients with SPMS and Alzheimer's disease. We used the Autobiographical Memory Interview to assess episodic and semantic autobiographical memory in 112 education- and gender-matched participants, including healthy controls and patients with RRMS, SPMS, amnesic mild cognitive impairment (aMCI) and early Alzheimer's dementia (AD). Patients with SPMS, AD, and aMCI, but not with RRMS, exhibited a pattern of episodic autobiographical memory impairment that followed Ribot's Law; older memories were better preserved than more recent memories. In contrast to aMCI and AD, neither SPMS nor RRMS was associated with semantic autobiographical memory impairment. Our neuropsychological findings suggest that episodic autobiographical memory is affected in long-term patients with SPMS, possibly due to neurodegenerative processes in functional relevant brain regions.

The US Network of Pediatric Multiple Sclerosis Centers: Development, Progress, and Next Steps.

PubMed

Casper, T Charles; Rose, John W; Roalstad, Shelly; Waubant, Emmanuelle; Aaen, Gregory; Belman, Anita; Chitnis, Tanuja; Gorman, Mark; Krupp, Lauren; Lotze, Timothy E; Ness, Jayne; Patterson, Marc; Rodriguez, Moses; Weinstock-Guttman, Bianca; Browning, Brittan; Graves, Jennifer; Tillema, Jan-Mendelt; Benson, Leslie; Harris, Yolanda

2015-09-01

Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network. © The Author(s) 2014.

Cell-based therapeutic strategies for multiple sclerosis

PubMed Central

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A; Atkins, Harold; Banwell, Brenda; Bar-Or, Amit; Bebo, Bruce; Bowen, James; Burt, Richard; Calabresi, Peter; Cohen, Jeffrey; Comi, Giancarlo; Connick, Peter; Cross, Anne; Cutter, Gary; Derfuss, Tobias; Ffrench-Constant, Charles; Freedman, Mark; Galipeau, Jacques; Goldman, Myla; Goldman, Steven; Goodman, Andrew; Green, Ari; Griffith, Linda; Hartung, Hans-Peter; Hemmer, Bernhard; Hyun, Insoo; Iacobaeus, Ellen; Inglese, Matilde; Jubelt, Burk; Karussis, Dimitrios; Küry, Patrick; Landsman, Douglas; Laule, Cornelia; Liblau, Roland; Mancardi, Giovanni; Ann Marrie, Ruth; Miller, Aaron; Miller, Robert; Miller, David; Mowry, Ellen; Muraro, Paolo; Nash, Richard; Ontaneda, Daniel; Pasquini, Marcelo; Pelletier, Daniel; Peruzzotti-Jametti, Luca; Pluchino, Stefano; Racke, Michael; Reingold, Stephen; Rice, Claire; Ringdén, Olle; Rovira, Alex; Saccardi, Riccardo; Sadiq, Saud; Sarantopoulos, Stefanie; Savitz, Sean; Scolding, Neil; Soelberg Sorensen, Per; Pia Sormani, Maria; Stuve, Olaf; Tesar, Paul; Thompson, Alan; Trojano, Maria; Uccelli, Antonio; Uitdehaag, Bernard; Utz, Ursula; Vukusic, Sandra; Waubant, Emmanuelle; Wilkins, Alastair

2017-01-01

Abstract The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. PMID:29053779

The US Network of Pediatric Multiple Sclerosis Centers: Development, Progress, and Next Steps

PubMed Central

Casper, T. Charles; Rose, John W.; Roalstad, Shelly; Waubant, Emmanuelle; Aaen, Gregory; Belman, Anita; Chitnis, Tanuja; Gorman, Mark; Krupp, Lauren; Lotze, Timothy E.; Ness, Jayne; Patterson, Marc; Rodriguez, Moses; Weinstock-Guttman, Bianca; Browning, Brittan; Graves, Jennifer; Tillema, Jan-Mendelt; Benson, Leslie; Harris, Yolanda

2014-01-01

Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network. PMID:25270659

Evidence for early neurodegeneration in the cervical cord of patients with primary progressive multiple sclerosis

PubMed Central

Schneider, Torben; Solanky, Bhavana S.; Yiannakas, Marios C.; Altmann, Dan R.; Wheeler-Kingshott, Claudia A. M.; Peters, Amy L.; Day, Brian L.; Thompson, Alan J.; Ciccarelli, Olga

2015-01-01

Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel 1H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability. Data from 21 patients with primary progressive multiple sclerosis within 6 years of disease onset, and 24 control subjects were analysed. Patients were clinically assessed on grip strength, vibration perception thresholds and postural stability, in addition to the Expanded Disability Status Scale, Nine Hole Peg Test, Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, and Modified Ashworth Scale. All subjects underwent magnetic resonance spectroscopy and q-space imaging of the cervical cord and conventional brain and spinal magnetic resonance imaging at 3 T. Multivariate analyses and multiple regression models were used to assess the differences in imaging measures between groups and the relationship between magnetic resonance imaging measures and clinical scores, correcting for age, gender, spinal cord cross-sectional area, brain T2 lesion volume, and brain white matter and grey matter volume fractions. Although patients did not show significant cord atrophy when compared with healthy controls, they had significantly lower total N-acetyl-aspartate (mean 4.01 versus 5.31 mmol/l, P = 0.020) and glutamate-glutamine (mean 4.65 versus 5.93 mmol/l, P = 0.043) than controls. Patients showed an increase in q-space imaging-derived indices of perpendicular diffusivity in both the whole cord and major columns compared with controls (P < 0.05 for all indices). Lower total N-acetyl-aspartate was associated with higher disability, as assessed by the Expanded Disability Status Scale (coefficient = −0.41, 0.01 < P < 0.05), Modified Ashworth Scale (coefficient = −3.78, 0.01 < P < 0.05), vibration perception thresholds (coefficient = −4.37, P = 0.021) and postural sway (P < 0.001). Lower glutamate-glutamine predicted increased postural sway (P = 0.017). Increased perpendicular diffusivity in the whole cord and columns was associated with increased scores on the Modified Ashworth Scale, vibration perception thresholds and postural sway (P < 0.05 in all cases). These imaging findings indicate reduced structural integrity of neurons, demyelination, and abnormalities in the glutamatergic pathways in the cervical cord of early primary progressive multiple sclerosis, in the absence of extensive spinal cord atrophy. The observed relationship between imaging measures and disability suggests that early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents to prevent the development of progressive disability. PMID:25863355

The development of an MRI lesion quantifying system for multiple sclerosis patients undergoing treatment

NASA Astrophysics Data System (ADS)

Moin, Paymann; Ma, Kevin; Amezcua, Lilyana; Gertych, Arkadiusz; Liu, Brent

2009-02-01

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that affects approximately 2.5 million people worldwide. Magnetic resonance imaging (MRI) is an established tool for the assessment of disease activity, progression and response to treatment. The progression of the disease is variable and requires routine follow-up imaging studies. Currently, MRI quantification of multiple sclerosis requires a manual approach to lesion measurement and yields an estimate of lesion volume and interval change. In the setting of several prior studies and a long treatment history, trends related to treatment change quickly become difficult to extrapolate. Our efforts seek to develop an imaging informatics based MS lesion computer aided detection (CAD) package to quantify and track MS lesions including lesion load, volume, and location. Together, with select clinical parameters, this data will be incorporated into an MS specific e- Folder to provide decision support to evaluate and assess treatment options for MS in a manner tailored specifically to an individual based on trends in MS presentation and progression.

Fingolimod Prescribed for the Treatment of Multiple Sclerosis in Patients Younger Than Age 18 Years.

PubMed

Fragoso, Yara Dadalti; Alves-Leon, Soniza Vieira; Barreira, Amilton Antunes; Callegaro, Dagoberto; Brito Ferreira, Maria Lucia; Finkelsztejn, Alessandro; Gomes, Sidney; Magno Goncalves, Marcus Vinicius; Moraes Machado, Maria Iris; Marques, Vanessa Daccach; Cunha Matta, Andre Palma; Papais-Alvarenga, Regina Maria; Apostolos Pereira, Samira Luisa; Tauil, Carlos Bernardo

2015-08-01

There have been no clinical trials for approval of medications for treating multiple sclerosis in patients younger than age 18 years. All treatments are based on personal experience and data from open observational studies. Fingolimod is an oral drug for multiple sclerosis that has been shown to be efficient and safe in adults. The aim of our study is to describe patients with multiple sclerosis who started treatment with fingolimod before the age of 18 years. Seventeen patients treated with fingolimod were identified in the Brazilian database of children and adolescents with multiple sclerosis. The average time of use of the drug was 8.6 months. Fingolimod showed a good safety and efficacy profile in these patients, all of whom had very active multiple sclerosis. After starting treatment with fingolimod, only one patient had a relapse and a new lesion on magnetic resonance imaging. The patients' degree of disability did not progress. No major adverse events were reported in relation to the first dose of the drug, nor in the short- and medium-term treatment. No patient has been followed for longer than 18 months, thus limiting long-term conclusions. Off-label use of fingolimod in patients younger than age 18 years may be a good therapeutic option for multiple sclerosis control. Copyright © 2015 Elsevier Inc. All rights reserved.

"A Group of Me's": Adult Learning through Group Process: The Experiences of Participants in a Teleconference Delivered Multiple Sclerosis Fatigue Management Program

ERIC Educational Resources Information Center

Preissner, Katharine L.

2013-01-01

Multiple sclerosis (MS) is a chronic, progressive neurological disorder that affects approximately 2.1 million people worldwide. Fatigue is one of the most common and most disabling symptoms of MS. One well-established approach to address fatigue is fatigue management education provided by an occupational therapist. Fatigue management education is…

Progressive solitary sclerosis: Gradual motor impairment from a single CNS demyelinating lesion.

PubMed

Keegan, B Mark; Kaufmann, Timothy J; Weinshenker, Brian G; Kantarci, Orhun H; Schmalstieg, William F; Paz Soldan, M Mateo; Flanagan, Eoin P

2016-10-18

To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. The patients' median age was 48.5 years (range 23-71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15-343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. © 2016 American Academy of Neurology.

Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

PubMed

Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

2017-09-01

Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental autoimmune encephalomyelitis mice, [Met 5 ]-enkephalin levels were depressed prior to the appearance of clinical disease, and were restored with low-dose naltrexone treatment. Low-dose naltrexone therapy had no effect on serum [Met 5 ]-enkephalin or β-endorphin in normal mice. Thus, [Met 5 ]-enkephalin (i.e. opioid growth factor) may be a reasonable candidate biomarker for multiple sclerosis, and may signal new pathways for treatment of autoimmune disorders. Impact statement This report presents human and animal data identifying a novel biomarker for the onset and progression of multiple sclerosis (MS). Humans diagnosed with MS have reduced serum levels of OGF (i.e. [Met 5 ]-enkephalin) relative to non-MS neurologic patients, and low-dose naltrexone (LDN) therapy restored their enkephalin levels. Serum OGF levels were reduced in mice immunized with MOG 35-55 prior to any clinical behavioral sign of experimental autoimmune encephalomyelitis, and LDN therapy restored their serum OGF levels. β-endorphin concentrations were not altered by LDN in humans or mice. Thus, blood levels of OGF may serve as a new, selective biomarker for the progression of MS, as well as response to therapy.

Multiple Sclerosis

MedlinePlus

... progression. Some drugs are taken intravenously, some by infusion, and some oral. All drugs should be prescribed ... progression. Some drugs are taken intravenously, some by infusion, and some oral. All drugs should be prescribed ...

A regenerative approach to the treatment of multiple sclerosis.

PubMed

Deshmukh, Vishal A; Tardif, Virginie; Lyssiotis, Costas A; Green, Chelsea C; Kerman, Bilal; Kim, Hyung Joon; Padmanabhan, Krishnan; Swoboda, Jonathan G; Ahmad, Insha; Kondo, Toru; Gage, Fred H; Theofilopoulos, Argyrios N; Lawson, Brian R; Schultz, Peter G; Lairson, Luke L

2013-10-17

Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.

A Systematic Review and Meta-Analysis of Strength Training in Individuals With Multiple Sclerosis Or Parkinson Disease

PubMed Central

Cruickshank, Travis M.; Reyes, Alvaro R.; Ziman, Melanie R.

2015-01-01

Abstract Strength training has, in recent years, been shown to be beneficial for people with Parkinson disease and multiple sclerosis. Consensus regarding its utility for these disorders nevertheless remains contentious among healthcare professionals. Greater clarity is required, especially in regards to the type and magnitude of effects as well as the response differences to strength training between individuals with Parkinson disease or multiple sclerosis. This study examines the effects, magnitude of those effects, and response differences to strength training between patients with Parkinson disease or multiple sclerosis. A comprehensive search of electronic databases including Physiotherapy Evidence Database scale, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL was conducted from inception to July 2014. English articles investigating the effect of strength training for individuals with neurodegenerative disorders were selected. Strength training trials that met the inclusion criteria were found for individuals with Parkinson disease or multiple sclerosis. Individuals with Parkinson disease or multiple sclerosis were included in the study. Strength training interventions included traditional (free weights/machine exercises) and nontraditional programs (eccentric cycling). Included articles were critically appraised using the Physiotherapy Evidence Database scale. Of the 507 articles retrieved, only 20 articles met the inclusion criteria. Of these, 14 were randomized and 6 were nonrandomized controlled articles in Parkinson disease or multiple sclerosis. Six randomized and 2 nonrandomized controlled articles originated from 3 trials and were subsequently pooled for systematic analysis. Strength training was found to significantly improve muscle strength in people with Parkinson disease (15%–83.2%) and multiple sclerosis (4.5%–36%). Significant improvements in mobility (11.4%) and disease progression were also reported in people with Parkinson disease after strength training. Furthermore, significant improvements in fatigue (8.2%), functional capacity (21.5%), quality of life (8.3%), power (17.6%), and electromyography activity (24.4%) were found in individuals with multiple sclerosis after strength training. The limitations of the study were the heterogeneity of interventions and study outcomes in Parkinson disease and multiple sclerosis trials. Strength training is useful for increasing muscle strength in Parkinson disease and to a lesser extent multiple sclerosis. PMID:25634170

A systematic review and meta-analysis of strength training in individuals with multiple sclerosis or Parkinson disease.

PubMed

Cruickshank, Travis M; Reyes, Alvaro R; Ziman, Melanie R

2015-01-01

Strength training has, in recent years, been shown to be beneficial for people with Parkinson disease and multiple sclerosis. Consensus regarding its utility for these disorders nevertheless remains contentious among healthcare professionals. Greater clarity is required, especially in regards to the type and magnitude of effects as well as the response differences to strength training between individuals with Parkinson disease or multiple sclerosis. This study examines the effects, magnitude of those effects, and response differences to strength training between patients with Parkinson disease or multiple sclerosis. A comprehensive search of electronic databases including Physiotherapy Evidence Database scale, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL was conducted from inception to July 2014. English articles investigating the effect of strength training for individuals with neurodegenerative disorders were selected. Strength training trials that met the inclusion criteria were found for individuals with Parkinson disease or multiple sclerosis. Individuals with Parkinson disease or multiple sclerosis were included in the study. Strength training interventions included traditional (free weights/machine exercises) and nontraditional programs (eccentric cycling). Included articles were critically appraised using the Physiotherapy Evidence Database scale. Of the 507 articles retrieved, only 20 articles met the inclusion criteria. Of these, 14 were randomized and 6 were nonrandomized controlled articles in Parkinson disease or multiple sclerosis. Six randomized and 2 nonrandomized controlled articles originated from 3 trials and were subsequently pooled for systematic analysis. Strength training was found to significantly improve muscle strength in people with Parkinson disease (15%-83.2%) and multiple sclerosis (4.5%-36%). Significant improvements in mobility (11.4%) and disease progression were also reported in people with Parkinson disease after strength training. Furthermore, significant improvements in fatigue (8.2%), functional capacity (21.5%), quality of life (8.3%), power (17.6%), and electromyography activity (24.4%) were found in individuals with multiple sclerosis after strength training. The limitations of the study were the heterogeneity of interventions and study outcomes in Parkinson disease and multiple sclerosis trials. Strength training is useful for increasing muscle strength in Parkinson disease and to a lesser extent multiple sclerosis.

No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1b therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).

PubMed

Lanzillo, Roberta; Quarantelli, Mario; Pozzilli, Carlo; Trojano, Maria; Amato, Maria Pia; Marrosu, Maria G; Francia, Ada; Florio, Ciro; Orefice, Giuseppe; Tedeschi, Gioacchino; Bellantonio, Paolo; Annunziata, Pasquale; Grimaldi, Luigi M; Comerci, Marco; Brunetti, Arturo; Bonavita, Vincenzo; Alfano, Bruno; Marini, Stefano; Brescia Morra, Vincenzo

2016-08-01

A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis. The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remitting multiple sclerosis. This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months. A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months. Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis. © The Author(s), 2015.

Biomarkers in the evolution of multiple sclerosis.

PubMed

Berger, Thomas

2017-11-01

Nonimaging biomarkers can be applied in differential diagnosis, evaluation of disease progression and therapy monitoring of multiple sclerosis (MS). Presence of oligoclonal IgG bands in cerebrospinal fluid is a diagnostic element and a negative predictor of MS evolution. AQP4 antibodies are pathogenic and diagnostic for neuromyelitis optica spectrum disorder. Antibodies to myelin oligodendrocyte glycoprotein develop in about 50% of predominantly pediatric patients with acute disseminated encephalomyelitis, but their possible role in pathogenesis is unknown. Currently, there are no individualized biomarkers suitable to track disease progression. Neutralizing antibodies against IFN-β, natalizumab and daclizumab arise with variable frequency and reduce treatment efficacy. The anti-John Cunningham virus antibody index has potential as a biomarker for risk of progressive multifocal leukoencephalopathy.

Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes.

PubMed

Ruano, Luis; Portaccio, Emilio; Goretti, Benedetta; Niccolai, Claudia; Severo, Milton; Patti, Francesco; Cilia, Sabina; Gallo, Paolo; Grossi, Paola; Ghezzi, Angelo; Roscio, Marco; Mattioli, Flavia; Stampatori, Chiara; Trojano, Maria; Viterbo, Rosa Gemma; Amato, Maria Pia

2017-08-01

There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS). The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains. A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age. CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.

[Current description of multiple sclerosis].

PubMed

Río, Jordi; Montalbán, Xavier

2014-12-01

Multiple sclerosis is a multifocal demyelinating disease leading to progressive neurodegeneration caused by an autoimmune response in genetically predisposed individuals. In the last few years, the knowledge and management of this disease has been revolutionized by a series of findings. The present article reviews pathological features of the disease, in which cortical involvement is increasingly implicated, and aspects related to novel pathogenic mechanisms, such as the role of the microbiota in the genesis of multiple sclerosis, as well as recent contributions from the fields of epidemiology and genetics. Also reviewed are the latest diagnostic criteria, which currently allow a much earlier diagnosis, with clear therapeutic implications. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Construct validity and frequency of euphoria sclerotica in multiple sclerosis.

PubMed

Fishman, Inna; Benedict, Ralph H B; Bakshi, Rohit; Priore, Roger; Weinstock-Guttman, Bianca

2004-01-01

Using the Neuropsychiatric Inventory (NPI), we studied euphoria and other behavioral changes in 75 consecutive, unselected multiple sclerosis (MS) patients and 25 healthy controls. We also assessed disease duration, clinical course, physical disability, personality, depression, insight, cognition, and caregiver distress. Factor analysis identified a cluster of symptoms--labeled euphoria/disinhibition--similar to the euphoria sclerotica syndrome originally described by Charcot and others. The euphoria/disinhibition factor score was elevated in 9% of patients and associated with secondary-progressive course, low agreeableness, poor insight, impaired cognition, and high caregiver distress. Thus, we used the NPI to validate the euphoria syndrome in multiple sclerosis (MS) and determined its frequency, and its neurological and psychological correlates.

Cell-based therapeutic strategies for multiple sclerosis.

PubMed

Scolding, Neil J; Pasquini, Marcelo; Reingold, Stephen C; Cohen, Jeffrey A

2017-11-01

The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

The development of a disease oriented eFolder for multiple sclerosis decision support

NASA Astrophysics Data System (ADS)

Ma, Kevin; Jacobs, Colin; Fernandez, James; Amezcua, Lilyana; Liu, Brent

2010-03-01

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. The chronic nature of MS necessitates multiple MRI studies to track disease progression. Currently, MRI assessment of multiple sclerosis requires manual lesion measurement and yields an estimate of lesion volume and change that is highly variable and user-dependent. In the setting of a longitudinal study, disease trends and changes become difficult to extrapolate from the lesions. In addition, it is difficult to establish a correlation between these imaged lesions and clinical factors such as treatment course. To address these clinical needs, an MS specific e-Folder for decision support in the evaluation and assessment of MS has been developed. An e-Folder is a disease-centric electronic medical record in contrast to a patient-centric electronic health record. Along with an MS lesion computer aided detection (CAD) package for lesion load, location, and volume, clinical parameters such as patient demographics, disease history, clinical course, and treatment history are incorporated to make the e-Folder comprehensive. With the integration of MRI studies together with related clinical data and informatics tools designed for monitoring multiple sclerosis, it provides a platform to improve the detection of treatment response in patients with MS. The design and deployment of MS e-Folder aims to standardize MS lesion data and disease progression to aid in decision making and MS-related research.

Neuronal and BBB damage induced by sera from patients with secondary progressive multiple sclerosis.

PubMed

Proia, Patrizia; Schiera, Gabriella; Salemi, Giuseppe; Ragonese, Paolo; Savettieri, Giovanni; Di Liegro, Italia

2009-12-01

An important component of the pathogenic process of multiple sclerosis (MS) is the blood-brain barrier (BBB) damage. We recently set an in vitro model of BBB, based on a three-cell-type co-culture system, in which rat neurons and astrocytes synergistically induce brain capillary endothelial cells to form a monolayer with permeability properties resembling those of the physiological BBB. Herein we report that the serum from patients with secondary progressive multiple sclerosis (SPMS) has a damaging effect on isolated neurons. This finding suggests that neuronal damaging in MS could be a primary event and not only secondary to myelin damage, as generally assumed. SPMS serum affects the permeability of the BBB model, as indicated by the decrease of the transendothelial electrical resistance (TEER). Moreover, as shown by both immunofluorescence and Western blot analyses, BBB breaking is accompanied by a decrease of the synthesis as well as the peripheral localization of occludin, a structural protein of the tight junctions that are responsible for BBB properties.

Cerebral blood flow and red cell delivery in normal subjects and in multiple sclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swank, R.L.; Roth, J.G.; Woody, D.C. Jr.

1983-01-01

Regional cerebral blood flow (rCBF) was determined in 77 normal females and 53 normal males of different ages and in 26 men and 45 women with multiple sclerosis by the inhalation of radioactive Xe133 method. In the normal subjects the CBF was relatively high in the teens and fell, at first rapidly and then slowly in both sexes with age. During adult life the flow in females was significantly higher than in males. The delivery of packed red cells (RCD) was determined by multiplying the CBF by the percentage concentration of red cells (HCT). The RCD for both sexes wasmore » nearly the same. In the patients with multiple sclerosis there occurred a progressive generalized decrease in CBF and in RCD with age which was significantly greater than observed in normal subjects. The rate of decrease in CBF and RCD correlated directly with the rate of progress of the disease.« less

Evidence for early neurodegeneration in the cervical cord of patients with primary progressive multiple sclerosis.

PubMed

Abdel-Aziz, Khaled; Schneider, Torben; Solanky, Bhavana S; Yiannakas, Marios C; Altmann, Dan R; Wheeler-Kingshott, Claudia A M; Peters, Amy L; Day, Brian L; Thompson, Alan J; Ciccarelli, Olga

2015-06-01

Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel (1)H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability. Data from 21 patients with primary progressive multiple sclerosis within 6 years of disease onset, and 24 control subjects were analysed. Patients were clinically assessed on grip strength, vibration perception thresholds and postural stability, in addition to the Expanded Disability Status Scale, Nine Hole Peg Test, Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, and Modified Ashworth Scale. All subjects underwent magnetic resonance spectroscopy and q-space imaging of the cervical cord and conventional brain and spinal magnetic resonance imaging at 3 T. Multivariate analyses and multiple regression models were used to assess the differences in imaging measures between groups and the relationship between magnetic resonance imaging measures and clinical scores, correcting for age, gender, spinal cord cross-sectional area, brain T2 lesion volume, and brain white matter and grey matter volume fractions. Although patients did not show significant cord atrophy when compared with healthy controls, they had significantly lower total N-acetyl-aspartate (mean 4.01 versus 5.31 mmol/l, P = 0.020) and glutamate-glutamine (mean 4.65 versus 5.93 mmol/l, P = 0.043) than controls. Patients showed an increase in q-space imaging-derived indices of perpendicular diffusivity in both the whole cord and major columns compared with controls (P < 0.05 for all indices). Lower total N-acetyl-aspartate was associated with higher disability, as assessed by the Expanded Disability Status Scale (coefficient = -0.41, 0.01 < P < 0.05), Modified Ashworth Scale (coefficient = -3.78, 0.01 < P < 0.05), vibration perception thresholds (coefficient = -4.37, P = 0.021) and postural sway (P < 0.001). Lower glutamate-glutamine predicted increased postural sway (P = 0.017). Increased perpendicular diffusivity in the whole cord and columns was associated with increased scores on the Modified Ashworth Scale, vibration perception thresholds and postural sway (P < 0.05 in all cases). These imaging findings indicate reduced structural integrity of neurons, demyelination, and abnormalities in the glutamatergic pathways in the cervical cord of early primary progressive multiple sclerosis, in the absence of extensive spinal cord atrophy. The observed relationship between imaging measures and disability suggests that early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents to prevent the development of progressive disability. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Serum levels of brain-derived neurotrophic factor (BNDF) in multiple sclerosis patients with Trichuris suis ova therapy.

PubMed

Rosche, Berit; Werner, Jonas; Benzel, Friderike Joëlle; Harms, Lutz; Danker-Hopfe, Heidi; Hellweg, Rainer

2013-01-01

We previously analysed clinical and immunological parameters under Trichuris suis ova (TSO) therapy in four patients with secondary progressive multiple sclerosis. The serum Brain-derived neurotrophic factor (BDNF) levels of these four patients were assessed before, during and after therapy with TSO and showed significant decrease of BDNF during TSO therapy (p < 0.05). © B. Rosche et al., published by EDP Sciences, 2013.

Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis.

PubMed

Snook, Erin M; Motl, Robert W

2009-02-01

The study used meta-analytic procedures to examine the overall effect of exercise training interventions on walking mobility among individuals with multiple sclerosis. A search was conducted for published exercise training studies from 1960 to November 2007 using MEDLINE, PsychINFO, CINAHL, and Current Contents Plus. Studies were selected if they measured walking mobility, using instruments identified as acceptable walking mobility constructs and outcome measures for individuals with neurologic disorders, before and after an intervention that included exercise training. Forty-two published articles were located and reviewed, and 22 provided enough data to compute effect sizes expressed as Cohen's d. Sixty-six effect sizes were retrieved from the 22 publications with 600 multiple sclerosis participants and yielded a weighted mean effect size of g = 0.19 (95% confidence interval, 0.09-0.28). There were larger effects associated with supervised exercise training ( g = 0.32), exercise programs that were less than 3 months in duration (g = 0.28), and mixed samples of relapsing-remitting and progressive multiple sclerosis (g = 0.52). The cumulative evidence supports that exercise training is associated with a small improvement in walking mobility among individuals with multiple sclerosis.

The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis.

PubMed

Shepheard, Stephanie R; Chataway, Tim; Schultz, David W; Rush, Robert A; Rogers, Mary-Louise

2014-01-01

Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A) mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno-precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9±0.5 ng/mg creatinine and this was significantly higher (p<0.001) than 12 controls (2.6±0.2 ng/mg creatinine) and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1±0.2 ng/mg creatinine). Pilot data of disease progression rates in 14 MND patients indicates that p75NTR(ECD) levels were significantly higher (p = 0.0041) in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1(G93A) mice by immuno-precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis.

Characterization of naïve, memory and effector T cells in progressive multiple sclerosis.

PubMed

Nielsen, Birgitte Romme; Ratzer, Rikke; Börnsen, Lars; von Essen, Marina Rode; Christensen, Jeppe Romme; Sellebjerg, Finn

2017-09-15

We characterized naïve, central memory (CM), effector memory (EM) and terminally differentiated effector memory (TEMRA) CD4 + and CD8 + T cells and their expression of CD49d and CD26 in peripheral blood in patients with multiple sclerosis (MS) and healthy controls. CD26 + CD28 + CD4 + TEMRA T cells were increased in all subtypes of MS, and CD26 + CD28 + CD8 + TEMRA T cells were increased in relapsing-remitting and secondary progressive MS. Conversely, in progressive MS, CD49d + CM T cells were decreased and natalizumab increased the circulating number of all six subsets but reduced the frequency of most subsets expressing CD49d and CD26. Copyright © 2017 Elsevier B.V. All rights reserved.

The Emerging Role of Zinc in the Pathogenesis of Multiple Sclerosis.

PubMed

Choi, Bo Young; Jung, Jong Won; Suh, Sang Won

2017-09-28

Our lab has previously demonstrated that multiple sclerosis-induced spinal cord white matter damage and motor deficits are mediated by the pathological disruption of zinc homeostasis. Abnormal vesicular zinc release and intracellular zinc accumulation may mediate several steps in the pathophysiological processes of multiple sclerosis (MS), such as matrix metallopeptidase 9 (MMP-9) activation, blood-brain barrier (BBB) disruption, and subsequent immune cell infiltration from peripheral systems. Oral administration of a zinc chelator decreased BBB disruption, immune cell infiltration, and spinal white matter myelin destruction. Therefore, we hypothesized that zinc released into the extracellular space during MS progression is involved in destruction of the myelin sheath in spinal cord white mater and in generation of motor deficits. To confirm our previous study, we employed zinc transporter 3 ( ZnT3 ) knockout mice to test whether vesicular zinc depletion shows protective effects on multiple sclerosis-induced white matter damage and motor deficits. ZnT3 gene deletion profoundly reduced the daily clinical score of experimental autoimmune encephalomyelitis (EAE) by suppression of inflammation and demyelination in the spinal cord. ZnT3 gene deletion also remarkably inhibited formation of multiple sclerosis-associated aberrant synaptic zinc patches, MMP-9 activation, and BBB disruption. These two studies strongly support our hypothesis that zinc release from presynaptic terminals may be involved in multiple sclerosis pathogenesis. Further studies will no doubt continue to add mechanistic detail to this process and with luck, clarify how these observations may lead to development of novel therapeutic approaches for the treatment of multiple sclerosis.

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.

PubMed

Giovannoni, Gavin; Cutter, Gary; Sormani, Maria Pia; Belachew, Shibeshih; Hyde, Robert; Koendgen, Harold; Knappertz, Volker; Tomic, Davorka; Leppert, David; Herndon, Robert; Wheeler-Kingshott, Claudia A M; Ciccarelli, Olga; Selwood, David; di Cantogno, Elisabetta Verdun; Ben-Amor, Ali-Frederic; Matthews, Paul; Carassiti, Daniele; Baker, David; Schmierer, Klaus

2017-02-01

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials. Copyright © 2016 Elsevier B.V. All rights reserved.

Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

PubMed

Cohen, Jeffrey A; Imrey, Peter B; Planchon, Sarah M; Bermel, Robert A; Fisher, Elizabeth; Fox, Robert J; Bar-Or, Amit; Sharp, Susan L; Skaramagas, Thomai T; Jagodnik, Patricia; Karafa, Matt; Morrison, Shannon; Reese Koc, Jane; Gerson, Stanton L; Lazarus, Hillard M

2018-04-01

Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest. To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS. Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 10 6 MSCs/kg were thawed and administered IV. In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 10 6 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation. Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.

A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives

PubMed Central

D’Amico, Emanuele; Patti, Francesco; Zanghì, Aurora; Zappia, Mario

2016-01-01

Using the term of progressive multiple sclerosis (PMS), we considered a combined population of persons with secondary progressive MS (SPMS) and primary progressive MS (PPMS). These forms of MS cannot be challenged with efficacy by the licensed therapy. In the last years, several measures of risk estimation were developed for predicting clinical course in MS, but none is specific for the PMS forms. Personalized medicine is a therapeutic approach, based on identifying what might be the best therapy for an individual patient, taking into account the risk profile. We need to achieve more accurate estimates of useful predictors in PMS, including unconventional and qualitative markers which are not yet currently available or practicable routine diagnostics. The evaluation of an individual patient is based on the profile of disease activity.Within the neurology field, PMS is one of the fastest-moving going into the future. PMID:27763513

Finger and foot tapping as alternative outcomes of upper and lower extremity function in multiple sclerosis.

PubMed

Tanigawa, Makoto; Stein, Jason; Park, John; Kosa, Peter; Cortese, Irene; Bielekova, Bibiana

2017-01-01

While magnetic resonance imaging contrast-enhancing lesions represent an excellent screening tool for disease-modifying treatments in relapsing-remitting multiple sclerosis (RRMS), this biomarker is insensitive for testing therapies against compartmentalized inflammation in progressive multiple sclerosis (MS). Therefore, alternative sensitive outcomes are needed. Using machine learning, clinician-acquired disability scales can be combined with timed measures of neurological functions such as walking speed (e.g. 25-foot walk; 25FW) or fine finger movements (e.g. 9-hole peg test; 9HPT) into sensitive composite clinical scales, such as the recently developed combinatorial, weight-adjusted disability scale (CombiWISE). Ideally, these complementary simplified measurements of certain neurological functions could be performed regularly at patients' homes using smartphones. We asked whether tests amenable to adaptation to smartphone technology, such as finger and foot tapping have comparable sensitivity and specificity to current non-clinician-acquired disability measures. We observed that finger and foot tapping can differentiate RRMS and progressive MS in a cross-sectional study and can also measure yearly and two-year disease progression in the latter, with better power (based on z-scores) in comparison to currently utilized 9HPT and 25FW. Replacing the 9HPT and 25FW with simplified tests broadly adaptable to smartphone technology may enhance the power of composite scales for progressive MS.

[A review of multiple sclerosis (2). Diagnosis and treatment].

PubMed

Martinez-Altarriba, M C; Ramos-Campoy, O; Luna-Calcaño, I M; Arrieta-Antón, E

2015-09-01

Multiple sclerosis is a major demyelinating disease of the central nervous system. It has a significant economic and social impact. Its etiology is unclear, although there are several hypotheses, such as infections or genetics. In its pathophysiology, it seems that immune activation attacks the myelin sheath, causing a progressive and irreversible axonal degeneration. The disease produces a variety of symptoms, and diagnosis requires fulfilling a number of criteria and the exclusion of other possible causes. The role of neuroimaging is very important, especially Magnetic Resonance Imaging. Despite the availability of disease-modifying drugs, none of them are able to halt its progress, and the most useful drugs are those designed to alleviate the symptoms of outbreaks. Overall, multiple sclerosis requires a significant effort in research to clarify not only why and how it occurs, as well as the development of new measures to improve quality of life of affected patients. Copyright © 2013 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

[A review of multiple sclerosis (1). Presentation of a case].

PubMed

Martinez-Altarriba, M C; Ramos-Campoy, O; Luna-Calcaño, I M; Arrieta-Antón, E

2015-01-01

Multiple sclerosis is a major demyelinating disease of the central nervous system. It has a significant economic and social impact. Its etiology is unclear, although there are several hypotheses, such as infections or genetics. In its pathophysiology, it seems that immune activation attacks the myelin sheath, causing a progressive and irreversible axonal degeneration. The disease produces a variety of symptoms, and diagnosis requires fulfilling a number of criteria and the exclusion of other possible causes. The role of neuroimaging, especially MRI, is very important. Despite the availability of disease-modifying drugs, none of them are able to halt its progress, and the most useful drugs are those designed to alleviate the symptoms of outbreaks. Overall, multiple sclerosis requires a significant effort in research to clarify not only why and how it occurs, but also to develop of new measures to improve the life of affected patients. Copyright © 2013 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

White matter tract abnormalities are associated with cognitive dysfunction in secondary progressive multiple sclerosis.

PubMed

Meijer, Kim A; Muhlert, Nils; Cercignani, Mara; Sethi, Varun; Ron, Maria A; Thompson, Alan J; Miller, David H; Chard, Declan; Geurts, Jeroen Jg; Ciccarelli, Olga

2016-10-01

While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind. The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients. Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS). A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance (R 2  = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients. © The Author(s), 2016.

Retinal and Optic Nerve Degeneration in Patients with Multiple Sclerosis Followed up for 5 Years.

PubMed

Garcia-Martin, Elena; Ara, Jose R; Martin, Jesus; Almarcegui, Carmen; Dolz, Isabel; Vilades, Elisa; Gil-Arribas, Laura; Fernandez, Francisco J; Polo, Vicente; Larrosa, Jose M; Pablo, Luis E; Satue, Maria

2017-05-01

To quantify retinal nerve fiber layer (RNFL) changes in patients with multiple sclerosis (MS) and healthy controls with a 5-year follow-up and to analyze correlations between disability progression and RNFL degeneration. Observational and longitudinal study. One hundred patients with relapsing-remitting MS and 50 healthy controls. All participants underwent a complete ophthalmic and electrophysiologic exploration and were re-evaluated annually for 5 years. Visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (SLP), and visual evoked potentials. Expanded Disability Status Scale (EDSS) scores, disease duration, treatments, prior optic neuritis episodes, and quality of life (QOL; based on the 54-item Multiple Sclerosis Quality of Life Scale score). Optical coherence tomography (OCT) revealed changes in all RNFL thicknesses in both groups. In the MS group, changes were detected in average thickness and in the mean deviation using the GDx-VCC nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) and in the P100 latency of visual evoked potentials; no changes were detected in visual acuity, color vision, or visual fields. Optical coherence tomography showed greater differences in the inferior and temporal RNFL thicknesses in both groups. In MS patients only, OCT revealed a moderate correlation between the increase in EDSS and temporal and superior RNFL thinning. Temporal RNFL thinning based on OCT results was correlated moderately with decreased QOL. Multiple sclerosis patients exhibit a progressive axonal loss in the optic nerve fiber layer. Retinal nerve fiber layer thinning based on OCT results is a useful marker for assessing MS progression and correlates with increased disability and reduced QOL. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Characteristics, burden of illness, and physical functioning of patients with relapsing-remitting and secondary progressive multiple sclerosis: a cross-sectional US survey.

PubMed

Gross, Hillary J; Watson, Crystal

2017-01-01

Although most patients with relapsing-remitting multiple sclerosis (RRMS) will develop secondary progressive multiple sclerosis (SPMS), little is known about the burden of multiple sclerosis by disease subtype. This study describes the burden of disease in terms of demographics, disease severity, symptoms, health care resource and disease-modifying therapy (DMT) utilization, work and activity impairment, and physical functioning of SPMS and RRMS patients. SPMS and RRMS patient responses from the 2012 and 2013 waves of the US National Health and Wellness Survey were evaluated to detect differences in demographics, disease severity, symptoms, and health care resource and DMT utilization. In addition, data from the Work Productivity and Activity Impairment and Short Form-36 questionnaires were analyzed. SPMS patients were older than RRMS patients (mean age 55.7 vs 48.9 years; P <0.001); a lower proportion were female (56.2% with SPMS vs 71.6% with RRMS; P =0.002), and fewer SPMS than RRMS patients were employed (20.0% vs 39.7%; P <0.001). SPMS patients described their disease as more severe, reporting several neurological symptoms more frequently and higher hospitalization rates than RRMS patients. A lower percentage of SPMS than RRMS patients reported DMT use. SPMS patients had greater overall work and activity impairment than RRMS patients. After controlling for baseline characteristics, impairment in physical functioning was greater in SPMS patients. Overall, SPMS patients had a higher burden of illness than RRMS patients, underscoring the need to treat RRMS patients early to delay disability progressing using therapies that are effective in real-world settings.

Can multiple sclerosis as a cognitive disorder influence patients’ dreams?

PubMed Central

Owji, Mahsa

2013-01-01

Dream should be considered as a kind of cognitive ability that is formed parallel to other cognitive capabilities like language. On the other hand, multiple sclerosis (MS) is a complex disease that can involve different aspects of our cognition. Therefore, MS may influence patients’ dreams. In fact, we do not know what the importance of dream is in MS, but further studies may introduce dream and dreaming as a sign of improvement or progression in MS disease. PMID:24250908

Is physical exercise a multiple sclerosis disease modifying treatment?

PubMed

Motl, Robert W; Pilutti, Lara A

2016-08-01

There is consensus that exercise represents a behavioral approach for the restoration of function and management of symptoms among persons with multiple sclerosis (MS). The current paper provides a review on the topic of exercise and physical activity as MS-disease modifying treatments. Firstly, metrics for evaluating disease modification and progression in MS are described. Secondly, evidence for exercise as a MS-disease modifying therapy based on individual studies, literature reviews, and meta-analyses is summarized. Finally, the paper focuses on major limitations of the existing body of research. Expert commentary: Exercise and physical activity have been associated with reduced relapse rate, mobility disability and its progression, and lesion volume, and improved neuroperformance, particularly walking outcomes. This evidence provides a positive, yet preliminary, picture for exercise having possible effects on markers of disease modification and progression in MS.

A case of lymphoma in a patient on teriflunomide treatment for relapsing multiple sclerosis.

PubMed

Landais, Anne; Alhendi, Rabi; Gouverneur, Amandine; Teron-Aboud, Brigitte

2017-10-01

Teriflunomide is an oral therapy approved for relapsing forms of multiple sclerosis which has been shown to reduce relapse rate and disability progression. We report the case of a 54-year -old black woman with multiple sclerosis who developed follicular lymphoma after about 8 months of exposure to teriflunomide. Importantly, apart from age, the patient had none of the established risk factors for follicular lymphoma. Moreover, although this is the first published case of a lymphoma on teriflunomide, it is not the first confirmed case. Ten other cases have so far been reported to pharmacovigilance worldwide, and a further 82 with leflunomide. In conclusion, an association between teriflunomide and a higher risk of lymphoma cannot be ruled out. Copyright © 2017 Elsevier B.V. All rights reserved.

The experiences of support persons of people newly diagnosed with multiple sclerosis: an interpretative phenomenological study.

PubMed

Strickland, Karen; Worth, Allison; Kennedy, Catriona

2015-12-01

This study explores the experience of the diagnosis of Multiple Sclerosis for the support person and identifies the impact on their lives. At the time of diagnosis, the support person may not be readily identified in a traditional caring role; however, the diagnosis itself brings with it the possibility of changes to the roles in the relationship and possible consequences for biographical construction. A hermeneutic phenomenological study. A convenience sample of nine support persons was interviewed between December 2008-March 2010. The data were analysed using interpretative phenomenological analysis. The participants in this study were often not readily identifiable as 'carers'; however, the diagnosis of Multiple Sclerosis implied a shift towards a caring role at some point in the future. The uncertainty surrounding the nature and progression of the condition left this identity hanging, incomplete and as such contributed to a liminal way of being. This paper reveals that biographical disruption is not limited to the person diagnosed with Multiple Sclerosis but that the support person also undergoes a transition to their sense of self to that of 'anticipatory carer'. The findings provide insight into the biographical and emotional impact of Multiple Sclerosis on the support persons early in the development of the condition. © 2015 John Wiley & Sons Ltd.

Symptomatic Therapy and Rehabilitation in Primary Progressive Multiple Sclerosis

PubMed Central

Khan, Fary; Amatya, Bhasker; Turner-Stokes, Lynne

2011-01-01

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system and a major cause of chronic neurological disability in young adults. Primary progressive MS (PPMS) constitutes about 10% of cases, and is characterized by a steady decline in function with no acute attacks. The rate of deterioration from disease onset is more rapid than relapsing remitting and secondary progressive MS types. Multiple system involvement at onset and rapid early progression have a worse prognosis. PPMS can cause significant disability and impact on quality of life. Recent studies are biased in favour of relapsing remitting patients as treatment is now available for them and they are more likely to be seen at MS clinics. Since prognosis for PPMS is worse than other types of MS, the focus of rehabilitation is on managing disability and enhancing participation, and application of a “neuropalliative” approach as the disease progresses. This chapter presents the symptomatic treatment and rehabilitation for persons with MS, including PPMS. A multidisciplinary approach optimizes the intermediate and long-term medical, psychological and social outcomes in this population. Restoration and maintenance of functional independence and societal reintegration, and issues relating to quality of life are addressed in rehabilitation processes. PMID:22013521

Characterisation of tissue-type metabolic content in secondary progressive multiple sclerosis: a magnetic resonance spectroscopic imaging study.

PubMed

Marshall, Ian; Thrippleton, Michael J; Bastin, Mark E; Mollison, Daisy; Dickie, David A; Chappell, Francesca M; Semple, Scott I K; Cooper, Annette; Pavitt, Sue; Giovannoni, Gavin; Wheeler-Kingshott, Claudia A M Gandini; Solanky, Bhavana S; Weir, Christopher J; Stallard, Nigel; Hawkins, Clive; Sharrack, Basil; Chataway, Jeremy; Connick, Peter; Chandran, Siddharthan

2018-05-30

Proton magnetic resonance spectroscopy yields metabolic information and has proved to be a useful addition to structural imaging in neurological diseases. We applied short-echo time Spectroscopic Imaging in a cohort of 42 patients with secondary progressive multiple sclerosis (SPMS). Linear modelling with respect to brain tissue type yielded metabolite levels that were significantly different in white matter lesions compared with normal-appearing white matter, suggestive of higher myelin turnover (higher choline), higher metabolic rate (higher creatine) and increased glial activity (higher myo-inositol) within the lesions. These findings suggest that the lesions have ongoing cellular activity that is not consistent with the usual assumption of 'chronic' lesions in SPMS, and may represent a target for repair therapies.

Setting a research agenda for progressive multiple sclerosis: the International Collaborative on Progressive MS.

PubMed

Fox, Robert J; Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-11-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS.

Setting a research agenda for progressive multiple sclerosis: The International Collaborative on Progressive MS

PubMed Central

Thompson, Alan; Baker, David; Baneke, Peer; Brown, Doug; Browne, Paul; Chandraratna, Dhia; Ciccarelli, Olga; Coetzee, Timothy; Comi, Giancarlo; Feinstein, Anthony; Kapoor, Raj; Lee, Karen; Salvetti, Marco; Sharrock, Kersten; Toosy, Ahmed; Zaratin, Paola; Zuidwijk, Kim

2012-01-01

Despite significant progress in the development of therapies for relapsing MS, progressive MS remains comparatively disappointing. Our objective, in this paper, is to review the current challenges in developing therapies for progressive MS and identify key priority areas for research. A collaborative was convened by volunteer and staff leaders from several MS societies with the mission to expedite the development of effective disease-modifying and symptom management therapies for progressive forms of multiple sclerosis. Through a series of scientific and strategic planning meetings, the collaborative identified and developed new perspectives on five key priority areas for research: experimental models, identification and validation of targets and repurposing opportunities, proof-of-concept clinical trial strategies, clinical outcome measures, and symptom management and rehabilitation. Our conclusions, tackling the impediments in developing therapies for progressive MS will require an integrated, multi-disciplinary approach to enable effective translation of research into therapies for progressive MS. Engagement of the MS research community through an international effort is needed to address and fund these research priorities with the ultimate goal of expediting the development of disease-modifying and symptom-relief treatments for progressive MS. PMID:22917690

Spasticity in multiple sclerosis and role of glatiramer acetate treatment

PubMed Central

Meca-Lallana, Jose Eustasio; Hernández-Clares, Rocío; Carreón-Guarnizo, Ester

2015-01-01

Introduction Spasticity is one of the most disabling and difficult-to-treat symptoms shown by patients with multiple sclerosis, who often show a suboptimal and unsatisfactory response to classic treatment and new available nonpharmacological alternatives. Due to the progressive nature of this condition, the early management should be essential to improve long-term outcomes. Methods We performed a narrative literature review of the contribution of spasticity to the burden of multiple sclerosis and the potential role of classic disease-modifying drugs. Results Added to the underlying pathophysiology of spasticity, certain external factors and drugs such as interferon may exacerbate the existing condition, hence their awareness is crucial as part of an effective management of spasticity. Furthermore, the evidence for the effectiveness of glatiramer acetate in preventing spasticity in naïve patients and in those switching from interferon should not be ignored. Conclusions This literature review proposes the examination of spasticity and the influence of classic disease-modifying agents on the level of existing condition among the variables to be considered when deciding on therapy for multiple sclerosis in clinical practice. PMID:26445705

Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis

PubMed Central

Lovato, Laura; Willis, Simon N.; Rodig, Scott J.; Caron, Tyler; Almendinger, Stefany E.; Howell, Owain W.; Reynolds, Richard; Hafler, David A.

2011-01-01

In the central nervous system of patients with multiple sclerosis, B cell aggregates populate the meninges, raising the central question as to whether these structures relate to the B cell infiltrates found in parenchymal lesions or instead, represent a separate central nervous system immune compartment. We characterized the repertoires derived from meningeal B cell aggregates and the corresponding parenchymal infiltrates from brain tissue derived primarily from patients with progressive multiple sclerosis. The majority of expanded antigen-experienced B cell clones derived from meningeal aggregates were also present in the parenchyma. We extended this investigation to include 20 grey matter specimens containing meninges, 26 inflammatory plaques, 19 areas of normal appearing white matter and cerebral spinal fluid. Analysis of 1833 B cell receptor heavy chain variable region sequences demonstrated that antigen-experienced clones were consistently shared among these distinct compartments. This study establishes a relationship between extraparenchymal lymphoid tissue and parenchymal infiltrates and defines the arrangement of B cell clones that populate the central nervous system of patients with multiple sclerosis. PMID:21216828

Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis.

PubMed

Lovato, Laura; Willis, Simon N; Rodig, Scott J; Caron, Tyler; Almendinger, Stefany E; Howell, Owain W; Reynolds, Richard; O'Connor, Kevin C; Hafler, David A

2011-02-01

In the central nervous system of patients with multiple sclerosis, B cell aggregates populate the meninges, raising the central question as to whether these structures relate to the B cell infiltrates found in parenchymal lesions or instead, represent a separate central nervous system immune compartment. We characterized the repertoires derived from meningeal B cell aggregates and the corresponding parenchymal infiltrates from brain tissue derived primarily from patients with progressive multiple sclerosis. The majority of expanded antigen-experienced B cell clones derived from meningeal aggregates were also present in the parenchyma. We extended this investigation to include 20 grey matter specimens containing meninges, 26 inflammatory plaques, 19 areas of normal appearing white matter and cerebral spinal fluid. Analysis of 1833 B cell receptor heavy chain variable region sequences demonstrated that antigen-experienced clones were consistently shared among these distinct compartments. This study establishes a relationship between extraparenchymal lymphoid tissue and parenchymal infiltrates and defines the arrangement of B cell clones that populate the central nervous system of patients with multiple sclerosis.

Microcystic macular oedema in multiple sclerosis is associated with disease severity

PubMed Central

Gelfand, Jeffrey M.; Nolan, Rachel; Schwartz, Daniel M.; Graves, Jennifer

2012-01-01

Macular oedema typically results from blood–retinal barrier disruption. It has recently been reported that patients with multiple sclerosis treated with FTY-720 (fingolimod) may exhibit macular oedema. Multiple sclerosis is not otherwise thought to be associated with macular oedema except in the context of comorbid clinical uveitis. Despite a lack of myelin, the retina is a site of inflammation and microglial activation in multiple sclerosis and demonstrates significant neuronal and axonal loss. We unexpectedly observed microcystic macular oedema using spectral domain optical coherence tomography in patients with multiple sclerosis who did not have another reason for macular oedema. We therefore evaluated spectral domain optical coherence tomography images in consecutive patients with multiple sclerosis for microcystic macular oedema and examined correlations between macular oedema and visual and ambulatory disability in a cross-sectional analysis. Participants were excluded if there was a comorbidity that could account for the presence of macular oedema, such as uveitis, diabetes or other retinal disease. A microcystic pattern of macular oedema was observed on optical coherence tomography in 15 of 318 (4.7%) patients with multiple sclerosis. No macular oedema was identified in 52 healthy controls assessed over the same period. The microcystic oedema predominantly involved the inner nuclear layer of the retina and tended to occur in small, discrete patches. Patients with multiple sclerosis with microcystic macular oedema had significantly worse disability [median Expanded Disability Score Scale 4 (interquartile range 3–6)] than patients without macular oedema [median Expanded Disability Score Scale 2 (interquartile range 1.5–3.5)], P = 0.0002. Patients with multiple sclerosis with microcystic macular oedema also had higher Multiple Sclerosis Severity Scores, a measure of disease progression, than those without oedema [median of 6.47 (interquartile range 4.96–7.98) versus 3.65 (interquartile range 1.92–5.87), P = 0.0009]. Microcystic macular oedema occurred more commonly in eyes with prior optic neuritis than eyes without prior optic neuritis (50 versus 27%) and was associated with lower visual acuity (median logMAR acuity of 0.17 versus −0.1) and a thinner retinal nerve fibre layer. The presence of microcystic macular oedema in multiple sclerosis suggests that there may be breakdown of the blood–retinal barrier and tight junction integrity in a part of the nervous system that lacks myelin. Microcystic macular oedema may also contribute to visual dysfunction beyond that explained by nerve fibre layer loss. Microcystic changes need to be assessed, and potentially adjusted for, in clinical trials that evaluate macular volume as a marker of retinal ganglion cell survival. These findings also have implications for clinical monitoring in patients with multiple sclerosis on sphingosine 1-phosphate receptor modulating agents. PMID:22539259

Vitamin D Levels Predict Multiple Sclerosis Progression

MedlinePlus

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Potential control of multiple sclerosis by cannabis and the endocannabinoid system.

PubMed

Pryce, Gareth; Baker, David

2012-08-01

For many years, multiple sclerosis (MS) patients have been self-medicating with illegal street cannabis to alleviate symptoms associated with MS. Data from animal models of MS and clinical studies have supported the anecdotal data that cannabis can improve symptoms such as limb spasticity, which are commonly associated with progressive MS, by the modulation of excessive neuronal signalling. This has lead to cannabis-based medicines being approved for the treatment of pain and spasticity in MS for the first time. Experimental studies into the biology of the endocannabinoid system have revealed that cannabinoids have activity, not only in symptom relief but also potentially in neuroprotective strategies which may slow disease progression and thus delay the onset of symptoms such as spasticity. This review appraises the current knowledge of cannabinoid biology particularly as it pertains to MS and outlines potential future therapeutic strategies for the treatment of disease progression in MS.

Exploring barriers to remaining physically active: a case report of a person with multiple sclerosis.

PubMed

Zalewski, Kathryn

2007-03-01

Physical therapy intervention for those with chronic disabling conditions typically follows an episode of care approach: therapists provide services when a decrement in functional performance occurs such that individuals require intervention to return to baseline performance. Attention to the psychosocial supports required for successful transition can be unintentionally minimized when the focus of an episode of care follows a change in physical function. The purpose of this case report is to present and discuss the challenges to successful community reintegration following physical therapy intervention with an emphasis on developing independent exercise habits in management of a person with multiple sclerosis. RW, presented in this case study, is a 52-year-old man diagnosed with progressive multiple sclerosis five years before self-referral to a pro bono physical therapy clinic.

An innovative training program based on virtual reality and treadmill: effects on gait of persons with multiple sclerosis.

PubMed

Peruzzi, Agnese; Zarbo, Ignazio Roberto; Cereatti, Andrea; Della Croce, Ugo; Mirelman, Anat

2017-07-01

In this single blind randomized controlled trial, we examined the effect of a virtual reality-based training on gait of people with multiple sclerosis. Twenty-five individuals with multiple sclerosis with mild to moderate disability were randomly assigned to either the control group (n = 11) or the experimental group (n = 14). The subjects in the control group received treadmill training. Subjects in the experimental group received virtual reality based treadmill training. Clinical measures and gait parameters were evaluated. Subjects in both the groups significantly improved the walking endurance and speed, cadence and stride length, lower limb joint ranges of motion and powers, during single and dual task gait. Moreover, subjects in the experimental group also improved balance, as indicated by the results of the clinical motor tests (p < 0.05). Between-group comparisons revealed that the experimental group improved significantly more than control group in hip range of motion and hip generated power at terminal stance at post-training. Our results support the perceived benefits of training programs that incorporate virtual reality to improve gait measures in individuals with multiple sclerosis. Implication of rehabilitation Gait deficits are common in multiple sclerosis (85%) and worsen during dual task activities. Intensive and progressive treadmill training, with and without virtual reality, is effective on dual task gait in persons with multiple sclerosis. Virtual reality-based treadmill training requiring obstacle negotiation increases the range of motion and the power generated at the hip, consequently allowing longer stride length and, consequently, higher gait speed.

Adaptive human immunity drives remyelination in a mouse model of demyelination

PubMed Central

El Behi, Mohamed; Sanson, Charles; Bachelin, Corinne; Guillot-Noël, Léna; Fransson, Jennifer; Stankoff, Bruno; Maillart, Elisabeth; Sarrazin, Nadège; Guillemot, Vincent; Abdi, Hervé; Cournu-Rebeix, Isabelle; Fontaine, Bertrand

2017-01-01

Abstract One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies. PMID:28334918

Adaptive human immunity drives remyelination in a mouse model of demyelination.

PubMed

El Behi, Mohamed; Sanson, Charles; Bachelin, Corinne; Guillot-Noël, Léna; Fransson, Jennifer; Stankoff, Bruno; Maillart, Elisabeth; Sarrazin, Nadège; Guillemot, Vincent; Abdi, Hervé; Cournu-Rebeix, Isabelle; Fontaine, Bertrand; Zujovic, Violetta

2017-04-01

One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Plasma Biomarkers Discriminate Clinical Forms of Multiple Sclerosis

PubMed Central

Tejera-Alhambra, Marta; Casrouge, Armanda; de Andrés, Clara; Seyfferth, Ansgar; Ramos-Medina, Rocío; Alonso, Bárbara; Vega, Janet; Fernández-Paredes, Lidia; Albert, Matthew L.; Sánchez-Ramón, Silvia

2015-01-01

Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients. PMID:26039252

Demographics and clinical characteristics of episodic hypothermia in multiple sclerosis.

PubMed

Toledano, Michel; Weinshenker, Brian G; Kaufmann, Timothy J; Parisi, Joseph E; Paz Soldán, M Mateo

2018-03-01

Episodic hypothermia (EH) can occur in multiple sclerosis (MS). The putative mechanism is impairment of thermoregulation due to a presumed demyelinating hypothalamic lesion. To describe a cohort of patients with MS, who developed EH. Patients were identified through review of the Mayo Clinic electronic medical record (1996 to July 2015). Search terms were [multiple sclerosis] or [MS] within the diagnoses field and [hypothermia] within any field. We reviewed records for accuracy of diagnoses and abstracted relevant data. Magnetic resonance imaging (MRI) was reviewed for presence of hypothalamic lesions. Of 156 patients, 34 had concurrent MS and hypothermia. Thirty-two (94%) had progressive disease at EH onset. Median MS duration was 19.9 years, and median expanded disability status scale (EDSS) was 8.0. Most patients presented with alterations in consciousness. Infection was suspected as the precipitating factor in 19 (56%), but clinically/laboratory supported in only 9 (28%). MRI lesions were evident within the hypothalamus in only 4 (14%). EH occurs predominantly in patients with advanced secondary progressive MS. The major manifestation is altered consciousness. Infection is often suspected as causal, but infrequently confirmed. Although commonly implicated, hypothalamic lesions were rarely evident on MRI and were absent in two post-mortem evaluations.

Phonological fluency strategy of switching differentiates relapsing-remitting and secondary progressive multiple sclerosis patients.

PubMed

Messinis, L; Kosmidis, M H; Vlahou, C; Malegiannaki, A C; Gatzounis, G; Dimisianos, N; Karra, A; Kiosseoglou, G; Gourzis, P; Papathanasopoulos, P

2013-01-01

The strategies used to perform a verbal fluency task appear to be reflective of cognitive abilities necessary for successful daily functioning. In the present study, we explored potential differences in verbal fluency strategies (switching and clustering) used to maximize word production by patients with relapsing-remitting multiple sclerosis (RRMS) versus patients with secondary progressive multiple sclerosis (SPMS). We further assessed impairment rates and potential differences in the sensitivity and specificity of phonological versus semantic verbal fluency tasks in discriminating between those with a diagnosis of MS and healthy adults. We found that the overall rate of impaired verbal fluency in our MS sample was consistent with that in other studies. However, we found no differences between types of MS (SPMS, RRMS), on semantic or phonological fluency word production, or the strategies used to maximize semantic fluency. In contrast, we found that the number of switches differed significantly in the phonological fluency task between the SPMS and RRMS subtypes. The clinical utility of semantic versus phonological fluency in discriminating MS patients from healthy controls did not indicate any significant differences. Further, the strategies used to maximize performance did not differentiate MS subgroups or MS patients from healthy controls.

Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.

PubMed

Datta, Gourab; Colasanti, Alessandro; Rabiner, Eugenii A; Gunn, Roger N; Malik, Omar; Ciccarelli, Olga; Nicholas, Richard; Van Vlierberghe, Eline; Van Hecke, Wim; Searle, Graham; Santos-Ribeiro, Andre; Matthews, Paul M

2017-11-01

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Imaging outcome measures for progressive multiple sclerosis trials

PubMed Central

Moccia, Marcello; de Stefano, Nicola; Barkhof, Frederik

2017-01-01

Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Position emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation. PMID:29041865

Associations of HLA DRB1 alleles with IgG oligoclonal bands and their influence on multiple sclerosis course and disability status.

PubMed

Balnytė, Renata; Rastenytė, Daiva; Vaitkus, Antanas; Skrodenienė, Erika; Vitkauskienė, Astra; Ulozienė, Ingrida

2016-01-01

Oligoclonal bands (OCB) may be associated with the genes of HLA complex, which allows to consider the possible interaction of genetic and immunological factors and its importance in the development and progression of multiple sclerosis (MS). The aim of this study was to evaluate the associations between HLA DRB1 alleles and oligoclonal bands (OCBs) in the disease course and disability of multiple sclerosis (MS) patients. This was a prospective study of 120 patients with MS. HLA DRB1 alleles were genotyped using the polymerase chain reaction. Matched cerebrospinal fluid (CSF) and plasma samples were analyzed using isoelectric focusing and IgG specific immunofixation to test for the presence of intrathecal specific OCB. HLA DRB1*08 allele was related to a lower degree of disability. Oligoclonal bands were an independent and significant factor that influenced disability status irrespective of HLA DRB1* 04, *07, *08, *13, *15 and *16 alleles. Age at the onset and duration of the disease were independent and significant factors for MS progression in all logistic regression models with each newly added HLA DRB1 allele. HLA DRB1*08 allele was related to 75% lower odds that relapsing remitting (RR) MS will change to a progressive course MS irrespective of the other factors investigated. Detection of OCBs in the CSF was associated with the higher possibility of RR MS progression in all cases, except when the *08 allele was present. OCBs had an influence on disability status, while HLA DRB1*08 allele was significantly associated with lower possibility that RR MS will change to progressive course MS. Copyright © 2016 The Lithuanian University of Health Sciences. Production and hosting by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Increasing bone sclerosis during bortezomib therapy in multiple myeloma patients: results of a reduced-dose whole-body MDCT study.

PubMed

Schulze, Maximilian; Weisel, Katja; Grandjean, Caroline; Oehrlein, Katharina; Zago, Manola; Spira, Daniel; Horger, Marius

2014-01-01

The objective of our study was to assess the frequency, location, extent, and patterns of bone sclerosis occurring in patients with multiple myeloma (MM) during bortezomib-based therapy. From June 2003 through December 2011, 593 whole-body reduced-dose MDCT studies were performed of 79 consecutive patients receiving bortezomib. The median surveillance time was 21 months (range, 3-67 months). Baseline studies were compared with follow-up studies during therapy (follow-up 1), at the end of therapy (follow-up 2), and 12 months after cessation of bortezomib therapy (follow-up 3). We recorded any sclerotic change occurring inside or along the margins of the osteolytic lesions, in the cancellous bone, or inside preexistent medullary or extramedullary lesions. The time point of occurrence of bone sclerosis was correlated with the best hematologic response category. Fourteen (17.7%) patients developed focal (n = 11) or diffuse (n = 3) bone sclerosis. The time window from bortezomib initiation to radiographic detection of bone sclerosis was 8 months (SD, 7 months). Sclerosis occurred at multiple sites (n = 7) or at an isolated site (n = 7). On subsequent whole-body reduced-dose MDCT studies, sclerosis further increased in seven (50%) patients. Hematologic best response during bortezomib treatment was complete response (n = 1), very good partial response (n = 2), partial response (n = 8), and stable disease (n = 3). Radiologic response at the time of sclerosis detection was partial response (n = 8), stable disease (n = 2), and progressive disease (n = 4). Bone remineralization may occur during bortezomib-based therapy for MM in a substantial proportion of patients. The extent, location, and patterns of sclerosis differ among patients and are unpredictable. Sclerosis was documented even in patients showing suboptimal hematologic response.

Axonal loss in the multiple sclerosis spinal cord revisited.

PubMed

Petrova, Natalia; Carassiti, Daniele; Altmann, Daniel R; Baker, David; Schmierer, Klaus

2018-05-01

Preventing chronic disease deterioration is an unmet need in people with multiple sclerosis, where axonal loss is considered a key substrate of disability. Clinically, chronic multiple sclerosis often presents as progressive myelopathy. Spinal cord cross-sectional area (CSA) assessed using MRI predicts increasing disability and has, by inference, been proposed as an indirect index of axonal degeneration. However, the association between CSA and axonal loss, and their correlation with demyelination, have never been systematically investigated using human post mortem tissue. We extensively sampled spinal cords of seven women and six men with multiple sclerosis (mean disease duration= 29 years) and five healthy controls to quantify axonal density and its association with demyelination and CSA. 396 tissue blocks were embedded in paraffin and immuno-stained for myelin basic protein and phosphorylated neurofilaments. Measurements included total CSA, areas of (i) lateral cortico-spinal tracts, (ii) gray matter, (iii) white matter, (iv) demyelination, and the number of axons within the lateral cortico-spinal tracts. Linear mixed models were used to analyze relationships. In multiple sclerosis CSA reduction at cervical, thoracic and lumbar levels ranged between 19 and 24% with white (19-24%) and gray (17-21%) matter atrophy contributing equally across levels. Axonal density in multiple sclerosis was lower by 57-62% across all levels and affected all fibers regardless of diameter. Demyelination affected 24-48% of the gray matter, most extensively at the thoracic level, and 11-13% of the white matter, with no significant differences across levels. Disease duration was associated with reduced axonal density, however not with any area index. Significant association was detected between focal demyelination and decreased axonal density. In conclusion, over nearly 30 years multiple sclerosis reduces axonal density by 60% throughout the spinal cord. Spinal cord cross sectional area, reduced by about 20%, appears to be a poor predictor of axonal density. © 2017 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews.

PubMed

Nielsen, Suzanne; Germanos, Rada; Weier, Megan; Pollard, John; Degenhardt, Louisa; Hall, Wayne; Buckley, Nicholas; Farrell, Michael

2018-02-13

Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects. We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms. Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.

N-acetylaspartate and neurofilaments as biomarkers of axonal damage in patients with progressive forms of multiple sclerosis.

PubMed

Trentini, Alessandro; Comabella, Manuel; Tintoré, Mar; Koel-Simmelink, Marleen J A; Killestein, Joep; Roos, Birthe; Rovira, Alex; Korth, Carsten; Ottis, Philipp; Blankenstein, Marinus A; Montalban, Xavier; Bellini, Tiziana; Teunissen, Charlotte E

2014-12-01

Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) over a long period of follow-up [median (interquartile range) 9 (5.5-12.5) years] in 19 PPMS and 4 SPMS patients, and to T2 lesion load, T1 lesion load, and brain parenchymal fraction at the time of lumbar puncture. Nf light was higher in PPMS (p < 0.005) and Nf heavy was increased in both SPMS and PPMS (p < 0.05 and p < 0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability measured by MSSS (R(2) = 0.17, β = 0.413; p < 0.05). Conversely, Nf light was the only predictor of the EDSS annual increase (R(2) = 0.195, β = 0.441; p < 0.05). The frequency of abnormal biomarkers did not differ between the two MS progressive subtypes. Our data suggest that PP and SPMS likely share similar mechanisms of axonal damage. Moreover, Nf heavy can be a biomarker of ongoing axonal damage. Conversely, Nf light can be used as a prognostic marker for accumulating disability suggesting it as a good tool for possible treatment monitoring in the progressive MS forms.

Placebo-controlled trial of oral laquinimod for multiple sclerosis.

PubMed

Comi, Giancarlo; Jeffery, Douglas; Kappos, Ludwig; Montalban, Xavier; Boyko, Alexey; Rocca, Maria A; Filippi, Massimo

2012-03-15

Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis. We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging. Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (±SE) annualized relapse rate (0.30±0.02 vs. 0.39±0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33±0.14 vs. 2.12±0.22 and 5.03±0.08 vs. 7.14±0.07, respectively; P<0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%). In this phase 3 study, oral laquinimod administered once daily slowed the progression of disability and reduced the rate of relapse in patients with relapsing-remitting multiple sclerosis. (Funded by Teva Pharmaceutical Industries; ClinicalTrials.gov number, NCT00509145.).

[The application of high-frequency and iTBS transcranial magnetic stimulation for the treatment of spasticity in the patients presenting with secondary progressive multiple sclerosis].

PubMed

Korzhova, J E; Chervyakov, A V; Poydasheva, A G; Kochergin, I A; Peresedova, A V; Zakharova, M N; Suponeva, N A; Chernikova, L A; Piradov, M A

Spasticity is considered to be a common manifestation of multiple sclerosis. Muscle relaxants are not sufficiently effective; more than that, some of them often cause a variety of adverse reactions. Transcranial magnetic stimulation (TMS) can be a promising new tool for the treatment of spasticity. The objective of the present study was to compare the effectiveness of the two TMS protocols: rhythmic (high-frequency) TMS (rTMS) and stimulation with the theta bursts (iTBS) in terms of their ability to reduce spasticity in the patients presenting with multiple sclerosis. Twenty two patients with secondary-progressive multiple sclerosis were pseudo-randomized into two groups: those in the first (high-frequency) group received the treatment with the use of rTMS therapy at a frequency of 10 Hz; the patients of the second group, underwent stimulation with the theta bursts (iTBS). All the patients received 10 sessions of either stimulation applied to the primary motor area (M1) of both legs. The effectiveness of TMS protocols was evaluated before therapy and after 10 sessions of stimulation based on the Modified Ashworth scale (MAS), the expanded disability status scale (EDSS), and the Kurtzke functional scale (Kfs). In addition, the patients were interviewed before treatment, after 10 rTMS sessions, immediately after and within 2 and 12 weeks after the completion of the treatment using questionnaires for the evaluation of spasticity (SESS) , fatigue, and dysfunction of the pelvic organs (severity of defecation and urination disorders), fatigue. The study has demonstrated a significant reduction in spasticity in the patients of both groups at the end of the TMS protocol based on the MAS scale. There was no significant difference between the outcomes of the two protocols. Both had positive effect on the concomitant «non-motor» symptoms (fatigue, dysfunction of the pelvic organs). High-frequency transcranial magnetic stimulation (10 sessions of rTMS therapy at a frequency of 10 Hz) and stimulation with the theta-bursts applied to the M1 area in both legs can be an effective alternative treatment of spasticity in the patients with secondary-progressive multiple sclerosis. Further research is needed to detect more accurately the differences between the outcomes of the two stimulation protocols and the development of indications for their application on an individual basis.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

PubMed

Ratzer, Rikke; Iversen, Pernille; Börnsen, Lars; Dyrby, Tim B; Romme Christensen, Jeppe; Ammitzbøll, Cecilie; Madsen, Camilla Gøbel; Garde, Ellen; Lyksborg, Mark; Andersen, Birgit; Hyldstrup, Lars; Sørensen, Per Soelberg; Siebner, Hartwig R; Sellebjerg, Finn

2016-06-01

There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS. © The Author(s), 2015.

Sunlight exposure and sun sensitivity associated with disability progression in multiple sclerosis.

PubMed

D'hooghe, M B; Haentjens, P; Nagels, G; Garmyn, M; De Keyser, J

2012-04-01

Sunlight and vitamin D have been inversely associated with the risk of multiple sclerosis (MS). We investigated sunlight exposure and sun sensitivity in relation to disability progression in MS. We conducted a survey among persons with MS, registered by the Flemish MS society, Belgium, and stratified data according to relapsing-onset and progressive-onset MS. We used Kaplan-Meier survival and Cox proportional hazard regression analyses with time to Expanded Disability Status Scale (EDSS) 6 as outcome measure. Hazard ratios for the time from onset and from birth were calculated for the potentially predictive variables, adjusting for age at onset, gender and immunomodulatory treatment. 704 (51.3%) of the 1372 respondents had reached EDSS 6. In relapsing-onset MS, respondents reporting equal or higher levels of sun exposure than persons of the same age in the last 10 years had a decreased risk of reaching EDSS 6. In progressive-onset MS, increased sun sensitivity was associated with an increased hazard of reaching EDSS 6. The association of higher sun exposure with a better outcome in relapsing-onset MS may be explained by either a protective effect or reverse causality. Mechanisms underlying sun sensitivity might influence progression in progressive-onset MS.

Adjustment modes in the trajectory of progressive multiple sclerosis: a qualitative study and conceptual model.

PubMed

Bogosian, Angeliki; Morgan, Myfanwy; Bishop, Felicity L; Day, Fern; Moss-Morris, Rona

2017-03-01

We examined cognitive and behavioural challenges and adaptations for people with progressive multiple sclerosis (MS) and developed a preliminary conceptual model of changes in adjustment over time. Using theoretical sampling, 34 semi-structured interviews were conducted with people with MS. Participants were between 41 and 77 years of age. Thirteen were diagnosed with primary progressive MS and 21 with secondary progressive MS. Data were analysed using a grounded theory approach. Participants described initially bracketing the illness off and carrying on their usual activities but this became problematic as the condition progressed and they employed different adjustment modes to cope with increased disabilities. Some scaled back their activities to live a more comfortable life, others identified new activities or adapted old ones, whereas at times, people disengaged from the adjustment process altogether and resigned to their condition. Relationships with partners, emotional reactions, environment and perception of the environment influenced adjustment, while people were often flexible and shifted among modes. Adjusting to a progressive condition is a fluid process. Future interventions can be tailored to address modifiable factors at different stages of the condition and may involve addressing emotional reactions concealing/revealing the condition and perceptions of the environment.

Grey matter damage in progressive multiple sclerosis versus amyotrophic lateral sclerosis: a voxel-based morphometry MRI study.

PubMed

Tavazzi, Eleonora; Laganà, Maria Marcella; Bergsland, Niels; Tortorella, Paola; Pinardi, Giovanna; Lunetta, Christian; Corbo, Massimo; Rovaris, Marco

2015-03-01

Primary progressive multiple sclerosis (PPMS) and amyotrophic lateral sclerosis (ALS) seem to share some clinical and pathological features. MRI studies revealed the presence of grey matter (GM) atrophy in both diseases, but no comparative data are available. The objective was to compare the regional patterns of GM tissue loss in PPMS and ALS with voxel-based morphometry (VBM). Eighteen PPMS patients, 20 ALS patients, and 31 healthy controls (HC) were studied with a 1.5 Tesla scanner. VBM was performed to assess volumetric GM differences with age and sex as covariates. Threshold-free cluster enhancement analysis was used to obtain significant clusters. Group comparisons were tested with family-wise error correction for multiple comparisons (p < 0.05) except for HC versus MND which was tested at a level of p < 0.001 uncorrected and a cluster threshold of 20 contiguous voxels. Compared to HC, ALS patients showed GM tissue reduction in selected frontal and temporal areas, while PPMS patients showed a widespread bilateral GM volume decrease, involving both deep and cortical regions. Compared to ALS, PPMS patients showed tissue volume reductions in both deep and cortical GM areas. This preliminary study confirms that PPMS is characterized by a more diffuse cortical and subcortical GM atrophy than ALS and that, in the latter condition, brain damage is present outside the motor system. These results suggest that PPMS and ALS may share pathological features leading to GM tissue loss.

In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI

PubMed Central

Mainero, C; Benner, T; Radding, A; van der Kouwe, A; Jensen, R; Rosen, B R.; Kinkel, R P.

2009-01-01

Objective: We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data. Methods: We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 × 033 × 1 mm3), and a 3-dimensional magnetization-prepared rapid gradient echo. Results: Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing–remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test). Conclusions: Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability. GLOSSARY ANOVA = analysis of variance; BN = background noise; CNR = contrast-to-noise ratio; DIR = double-inversion recovery; EDSS = Expanded Disability Status Scale; FLAIR = fluid-attenuated inversion recovery; FLASH = fast low-angle shot; GM = gray matter; MPRAGE = magnetization-prepared rapid gradient echo; MR = magnetic resonance; MS = multiple sclerosis; NACGM = normal-appearing cortical gray matter; RF = radiofrequency; ROI = region of interest; RRMS = relapsing–remitting multiple sclerosis; SNR = signal-to-noise ratio; SPMS = secondary progressive multiple sclerosis; TA = time of acquisition; TE = echo time; TR = repetition time; TSE = turbo spin-echo; WM = white matter. PMID:19641168

[The results of a randomized open multicenter comparative study on the tolerability and safety of gilenya (fingolimod) in patients with remitting multiple sclerosis].

PubMed

Popova, E V; Boyko, A N; Boyko, O V

2015-01-01

At the present time, disease modifying drugs (DMD) for treatment of patients with multiple sclerosis are used to reduce the risk of exacerbations and, consequently, slowing the progression of disability in accordance to treatment standards. However, the application of the first line of this therapy is not always successful. In these situations, patients receive second-line DMD. Fingolimod is one of the second-line drugs in Russia. To gain experience in using fingolimod in routine neurological practice, we have conducted a post-marketing research - GIMN.

Multiple Sclerosis: Epidemiologic, Clinical, and Therapeutic Aspects.

PubMed

Vidal-Jordana, Angela; Montalban, Xavier

2017-05-01

Multiple sclerosis (MS) is a chronic autoimmune and degenerative disease of the central nervous system that affects young people. MS develops in genetically susceptible individuals exposed to different unknown triggering factors. Different phenotypes are described. About 15% of patients present with a primary progressive course and 85% with a relapsing-remitting course. An increasing number of disease-modifying treatments has emerged. Although encouraging, the number of drugs challenges the neurologist because each treatment has its own risk-benefit profile. Patients should be involved in the decision-making process to ensure good treatment and safety monitoring adherence. Copyright © 2016 Elsevier Inc. All rights reserved.

Multiple sclerosis.

PubMed

Files, Daniel Kane; Jausurawong, Tani; Katrajian, Ruba; Danoff, Robert

2015-06-01

Multiple sclerosis (MS) is a chronic, debilitating disease that can have devastating effects. Presentation varies widely in symptoms, pace, and progression. In addition to a thorough history and physical examination, diagnostic tools required to diagnose MS and exclude other diagnoses include MRI, evoked potential testing, and cerebrospinal fluid analysis. Although the disease is not curable presently, quality of life can be improved by minimizing the frequency and severity of disease burden. Disease modification, symptom management, preservation of function, and treatment of psychosocial issues are paramount to enhance the quality of life for the patient affected with MS. Copyright © 2015 Elsevier Inc. All rights reserved.

Prognostic factors for early severity in a childhood multiple sclerosis cohort.

PubMed

Mikaeloff, Yann; Caridade, Guillaume; Assi, Saada; Suissa, Samy; Tardieu, Marc

2006-09-01

The goal was to identify prognostic factors for an early severe course in a cohort of patients with childhood-onset multiple sclerosis, for the construction of a predictive tool. The cohort consisted of 197 children from the French Kid Sclérose en Plaques neuropediatric cohort with relapsing/remitting multiple sclerosis beginning before the age of 16 years. Patients were included from 1990 to 2003. We used multivariate survival analysis (Cox model) to evaluate the prognostic value of clinical, MRI, and biological covariates at onset for the occurrence of a third attack or severe disability ("severity" outcome). The cohort was monitored for a mean of 5.5 +/- 3.6 years. The "severity" outcome was recorded for 144 patients (73%). The risk of severity was higher for girls, for a time between the first and second attacks of < 1 year, for childhood-onset multiple sclerosis MRI criteria at onset, for an absence of severe mental state changes at onset, and for a progressive course. A derived childhood-onset multiple sclerosis potential index for early severity was found to have a positive predictive value for severity of > 35% for the upper 2 quartiles. The clinical and MRI prognostic factors for early severity that were identified were used as the basis of a predictive tool, which will be validated in another cohort. This tool should make it possible to identify subgroups at risk of early severe disease and should facilitate therapeutic studies.

Up-Regulation of Soluble Axl and Mer Receptor Tyrosine Kinases Negatively Correlates with Gas6 in Established Multiple Sclerosis Lesions

PubMed Central

Weinger, Jason G.; Omari, Kakuri M.; Marsden, Kurt; Raine, Cedric S.; Shafit-Zagardo, Bridget

2009-01-01

Multiple sclerosis is a disease that is characterized by inflammation, demyelination, and axonal damage; it ultimately forms gliotic scars and lesions that severely compromise the function of the central nervous system. Evidence has shown previously that altered growth factor receptor signaling contributes to lesion formation, impedes recovery, and plays a role in disease progression. Growth arrest-specific protein 6 (Gas6), the ligand for the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl, and Mer, is important for cell growth, survival, and clearance of debris. In this study, we show that levels of membrane-bound Mer (205 kd), soluble Mer (∼150 kd), and soluble Axl (80 kd) were all significantly elevated in homogenates from established multiple sclerosis lesions comprised of both chronic active and chronic silent lesions. Whereas in normal tissue Gas6 positively correlated with soluble Axl and Mer, there was a negative correlation between Gas6 and soluble Axl and Mer in established multiple sclerosis lesions. In addition, increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin, proteins that are associated with Axl and Mer solubilization. Soluble Axl and Mer are both known to act as decoy receptors and block Gas6 binding to membrane-bound receptors. These data suggest that in multiple sclerosis lesions, dysregulation of protective Gas6 receptor signaling may prolong lesion activity. PMID:19541935

QualiCOP: real-world effectiveness, tolerability, and quality of life in patients with relapsing-remitting multiple sclerosis treated with glatiramer acetate, treatment-naïve patients, and previously treated patients.

PubMed

Ziemssen, Tjalf; Calabrese, Pasquale; Penner, Iris-Katharina; Apfel, Rainer

2016-04-01

Treatment of symptoms and signs beyond the expanded disability status scale remains a major target in multiple sclerosis. QualiCOP was an observational, non-interventional, open-label study conducted at 170 sites in Germany. Of the 754 enrolled patients, 96 % had relapsing-remitting multiple sclerosis (MS) and were either disease-modifying therapy naïve (de novo, n = 481) or previously treated (n = 237) with once-daily, subcutaneous 20-mg/mL glatiramer acetate (GA). Assessments of relapse rate, disease progression, overall functioning, quality of life (QoL), cognition, fatigue, and depression were performed over 24 months. GA treatment over 24 months was associated with reduced annual relapse rate for previously treated (from 0.98 to 0.54 relapses) and de novo (from 0.81 to 0.48 relapses) patients. Multiple Sclerosis Functional Composite scores showed slight improvement in both cohorts (all p < 0.01). Paced Auditory Serial Addition Test and Multiple Sclerosis Inventory Cognition scale scores showed robust improvement in cognition among previously treated and de novo cohorts (all p < 0.001). General Depression Scale scores showed significantly reduced depressive symptoms (p < 0.001). Disease severity, fatigue, and QoL were stable over the observational period. These real-world findings suggest that patients with MS show benefit from GA treatment in important QoL parameters beyond standard measures of relapse and disease severity.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

PubMed

Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-Ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan

2011-03-02

No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. ClinicalTrials.gov (NCT00395200).

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

PubMed Central

2011-01-01

Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). PMID:21366911

Ocrelizumab: a B-cell depleting therapy for multiple sclerosis.

PubMed

Jakimovski, Dejan; Weinstock-Guttman, Bianca; Ramanathan, Murali; Kolb, Channa; Hojnacki, David; Minagar, Alireza; Zivadinov, Robert

2017-09-01

Multiple sclerosis (MS) is the most common neurological disease responsible for early disability in the young working population. In the last two decades, based on retrospective/prospective data, the use of disease-modifying therapies has been shown to slow the rate of disability progression and prolonged the time to conversion into secondary-progressive MS (SPMS). However, despite the availability of several approved therapies, disability progression cannot be halted significantly in all MS patients. Areas covered: This article reviews the immunopathology of the B-cells, and their role in pathogenesis of MS and their attractiveness as a potential therapeutic target in MS. The review focuses on the recently published ocrelizumab phase III trials in terms of its efficacy, safety, and tolerability as well as its future considerations. Expert opinion: B lymphocyte cell depletion therapy offers a compelling and promising new option for MS patients. Nonetheless, there is a need for heightened vigilance and awareness in detecting potential long-term consequences that currently remain unknown.

Collaboration between a human group and artificial intelligence can improve prediction of multiple sclerosis course: a proof-of-principle study

PubMed Central

Ferraldeschi, Michela; Salvetti, Marco; Zaccaria, Andrea; Crisanti, Andrea; Grassi, Francesca

2017-01-01

Background: Multiple sclerosis has an extremely variable natural course. In most patients, disease starts with a relapsing-remitting (RR) phase, which proceeds to a secondary progressive (SP) form. The duration of the RR phase is hard to predict, and to date predictions on the rate of disease progression remain suboptimal. This limits the opportunity to tailor therapy on an individual patient's prognosis, in spite of the choice of several therapeutic options. Approaches to improve clinical decisions, such as collective intelligence of human groups and machine learning algorithms are widely investigated. Methods: Medical students and a machine learning algorithm predicted the course of disease on the basis of randomly chosen clinical records of patients that attended at the Multiple Sclerosis service of Sant'Andrea hospital in Rome. Results: A significant improvement of predictive ability was obtained when predictions were combined with a weight that depends on the consistence of human (or algorithm) forecasts on a given clinical record. Conclusions: In this work we present proof-of-principle that human-machine hybrid predictions yield better prognoses than machine learning algorithms or groups of humans alone. To strengthen this preliminary result, we propose a crowdsourcing initiative to collect prognoses by physicians on an expanded set of patients. PMID:29904574

Collaboration between a human group and artificial intelligence can improve prediction of multiple sclerosis course: a proof-of-principle study.

PubMed

Tacchella, Andrea; Romano, Silvia; Ferraldeschi, Michela; Salvetti, Marco; Zaccaria, Andrea; Crisanti, Andrea; Grassi, Francesca

2017-01-01

Background: Multiple sclerosis has an extremely variable natural course. In most patients, disease starts with a relapsing-remitting (RR) phase, which proceeds to a secondary progressive (SP) form. The duration of the RR phase is hard to predict, and to date predictions on the rate of disease progression remain suboptimal. This limits the opportunity to tailor therapy on an individual patient's prognosis, in spite of the choice of several therapeutic options. Approaches to improve clinical decisions, such as collective intelligence of human groups and machine learning algorithms are widely investigated. Methods: Medical students and a machine learning algorithm predicted the course of disease on the basis of randomly chosen clinical records of patients that attended at the Multiple Sclerosis service of Sant'Andrea hospital in Rome. Results: A significant improvement of predictive ability was obtained when predictions were combined with a weight that depends on the consistence of human (or algorithm) forecasts on a given clinical record. Conclusions: In this work we present proof-of-principle that human-machine hybrid predictions yield better prognoses than machine learning algorithms or groups of humans alone. To strengthen this preliminary result, we propose a crowdsourcing initiative to collect prognoses by physicians on an expanded set of patients.

Spinal cord atrophy in anterior-posterior direction reflects impairment in multiple sclerosis.

PubMed

Lundell, H; Svolgaard, O; Dogonowski, A-M; Romme Christensen, J; Selleberg, F; Soelberg Sørensen, P; Blinkenberg, M; Siebner, H R; Garde, E

2017-10-01

To investigate how atrophy is distributed over the cross section of the upper cervical spinal cord and how this relates to functional impairment in multiple sclerosis (MS). We analysed the structural brain MRI scans of 54 patients with relapsing-remitting MS (n=22), primary progressive MS (n=9), secondary progressive MS (n=23) and 23 age- and sex-matched healthy controls. We measured the cross-sectional area (CSA), left-right width (LRW) and anterior-posterior width (APW) of the spinal cord at the segmental level C2. We tested for a nonparametric linear relationship between these atrophy measures and clinical impairments as reflected by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impairment Scale (MSIS). In patients with MS, CSA and APW but not LRW were reduced compared to healthy controls (P<.02) and showed significant correlations with EDSS, MSIS and specific MSIS subscores. In patients with MS, atrophy of the upper cervical cord is most evident in the antero-posterior direction. As APW of the cervical cord can be readily derived from standard structural MRI of the brain, APW constitutes a clinically useful neuroimaging marker of disease-related neurodegeneration in MS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis.

PubMed

Peyro Saint Paul, Laure; Debruyne, Danièle; Bernard, Delphine; Mock, Donald M; Defer, Gilles L

2016-01-01

Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease. High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion. A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

High levels of 15-oxygenated steroids in circulation of patients with multiple sclerosis: fact or fiction?

PubMed

Björkhem, I; Lövgren-Sandblom, A; Piehl, F; Khademi, M; Pettersson, H; Leoni, V; Olsson, T; Diczfalusy, U

2011-01-01

15-Oxygenated cholesterol species such as 5α-cholest-8(14)ene-3β,15α-diol (15HC) and 3β-hydroxy-5α-cholest-8(14)-en-15-one (15KC) are commercially available synthetic products unlikely to occur in biological systems. Surprisingly, Farez et al. recently reported that these two steroids occur in human circulation at levels considerably higher than those of any other endogenous oxysterol [Farez, M. et al. 2009. Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nat. Immunol. 10: 958-964]. The levels were reported to be increased in patients with multiple sclerosis in a progressive phase and the authors suggested that this could be utilized diagnostically. Based on extensive in vitro experiments exposing cells to the same high levels of 15HC as found in vivo (1000 ng/ml) the authors concluded that 15HC may be an important pathogenetic factor in multiple sclerosis. Using combined gas chromatography-mass spectrometry we fail to detect significant plasma levels of 15HC either in healthy controls or in patients with multiple sclerosis (levels < 2 ng/ml). If 15KC is present in these plasma samples, the concentration of it must be <10 ng/ml. Our failure to detect significant levels of the above steroids could not be due to loss during hydrolysis and work-up because recovery of the added two oxysterols was close to 100%. Autoxidation of lipoprotein-bound cholesterol resulted in extensive conversion of cholesterol into 7-oxygenated but not 15-oxygenated sterols. We conclude that if present there are trace amounts only of the above 15-oxygenated steroids in human circulation and that the role of such oxysterols as pathogenetic factors and biomarkers must be reconsidered.

Clinical characteristics of patients with multiple sclerosis enrolled in a new registry in Egypt.

PubMed

Zakaria, Magd; Zamzam, Dina A; Abdel Hafeez, Mohamed A; Swelam, Mahmoud S; Khater, Shaimaa S; Fahmy, Mai F; Abdel Hady, Ayman; Fouad, Mohamed M; Abdel Nasser, Azza; Aref, Hany; Gadallah, Mohsen

2016-11-01

Epidemiological studies of multiple sclerosis (MS) are lacking in Egypt. To study the characteristics of Egyptian patients with multiple sclerosis in a new registry in a major tertiary referral centre in Cairo, Egypt. Patients were from the project MS database of the Multiple Sclerosis Unit at Ain Shams University Hospitals (N=950). We conducted a detailed medical history and examination including the Expanded Disability Status Scale (EDSS). Females represented 72% of subjects (female: male ratio 2.57:1). The mean age of disease onset was 26.1±7.6 years. Relapsing-remitting MS (RRMS) was the most common presentation (74.6%). Visual or sensory symptoms were the most common at presentation with RRMS, while motor symptoms were the most common presentation in other types of MS. Time to diagnosis was delayed up to 2 years in 27.8% of patients. The mean EDSS score was 3.6±2.1; 55% had EDSS≤3. About half (49%) received a disease-modifying drug. Progressive MS and motor presentation were associated with higher disability. This is the first documented MS registry from Egypt. The clinical characteristics of MS in Egypt was similar to other Arab countries and western countries. MS is more common among females in Egypt, with RRMS being the most common presentation. Visual symptoms and motor symptoms were the most common presentations in RRMS and progressive MS, respectively. Our findings also highlight the value of establishing registries in Egypt in order to be able to study, prospectively, the clinical course of the disease, the response to various DMD's and the epidemiology of MS in Egypt. Copyright © 2016 Elsevier B.V. All rights reserved.

Early-Onset Multiple Sclerosis in Isfahan, Iran: Report of the Demographic and Clinical Features of 221 Patients.

PubMed

Etemadifar, Masoud; Nourian, Sayed-Mohammadamin; Nourian, Niloofaralsadat; Abtahi, Seyed-Hossein; Sayahi, Farnaz; Saraf, Zahra; Fereidan-Esfahani, Mahboobeh

2016-06-01

It is estimated that early-onset multiple sclerosis multiple sclerosis (early-onset multiple sclerosis) approximately incorporates 3-5% of the multiple sclerosis population. In this report on early-onset multiple sclerosis, the authors aimed to define demographic, clinical and imaging features in a case-series of true-childhood multiple sclerosis and to compare its characteristics with juvenile multiple sclerosis. The authors inspected the records of multiple sclerosis patients who were registered by Isfahan MS Society. Clinical and demographic data of children with less than 16 years of age were reviewed retrospectively. Out of 4536 multiple sclerosis patients referred to the authors' center, 221 patients (4.8%) had multiple sclerosis starting at the age of 16 or less (11 true-childhood multiple sclerosis vs 210 juvenile-onset multiple sclerosis); the female to male ratio was 4.81:1. In the mean follow-up period of 6.2 years, 22 patients (10.5%) had positive family history of multiple sclerosis, 196 (88.6%) patients were classified as relapsing-remitting multiple sclerosis, the mean (± SD Expanded Disability Status Scale) was 1.5 ± 1.1 at the last evaluation. The most common initial presentation was optic nerve involvement (36.1%) and cerebellar sign and symptoms (14.6%). In all, 13 patients (5.8%) had experienced seizure in the course of multiple sclerosis. This study indicated that early-onset multiple sclerosis is not rare condition and overwhelmingly affects girls even at prepubertal onset. Physicians should consider multiple sclerosis in suspicious pediatric cases. © The Author(s) 2016.

Interferon-alpha and transfer factor in the treatment of multiple sclerosis: a double-blind, placebo-controlled trial. AUSTIMS Research Group.

PubMed Central

1989-01-01

The role of interferon-alpha (IFN-alpha) and transfer factor (TF) in the treatment of multiple sclerosis was investigated in a prospective, multi-centric, three year, double-blind, placebo-controlled trial. One hundred and eighty two patients with clinically definite multiple sclerosis were randomised into three treatment groups whose compositions were found to be similar for demographic and prognostic variables including HLA status. Subcutaneous injections of IFN-alpha (3 x 10(6) units), TF (0.5 units) manufactured from leucocytes of cohabiting donors, or placebo were given twice weekly for two months, once weekly for 10 months then fortnightly for 24 months. One hundred and fifty three patients completed the injection regimen. There was no significant difference in the progression of disability for multiple sclerosis patients in either the IFN-alpha or TF-treated groups compared with the placebo group. Similarly, change in visual evoked responses (VER), and in number of oligoclonal bands (OCB) and the level of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) over the trial period did not differ significantly between the three groups. However, the IFN-alpha-treated group had significantly more reported adverse drug reactions and patient withdrawals than either of the other two groups. PMID:2659737

Does natalizumab treatment increase the risk of herpes simplex encephalitis in multiple sclerosis? Case and discussion.

PubMed

Sharma, Kanchan; Ballham, Samantha A; Inglis, Kirsty E A; Renowden, Shelley; Cottrell, David A

2013-10-01

This report presents the 4th documented case worldwide of herpes simplex encephalitis in multiple sclerosis (MS) patients treated with natalizumab and the first case in the UK. Natalizumab is licensed for relapsing remitting multiple sclerosis in patients with high disease activity despite treatment with interferon-beta and patients with rapidly evolving severe, multiple sclerosis. Natalizumab is a monoclonal antibody targeted against alpha-4 integrin. Its proposed mechanism is attenuation of the migration of immune cells into the central nervous system. Reactivation of the JC virus causing progressive multifocal leucoencephalopathy (PML) and its association with natalizumab is well documented. This case adds support to the suggestion that natalizumab also increases the reactivation risk of CNS herpes simplex infection. A 34 year old woman was admitted with a generalized tonic-clonic seizure, fever and confusion following her 40th infusion of natalizumab. MRI demonstrated increased signal in the medial temporal lobes and EEG showed focal sharp waves over the temporal lobe. CSF PCR later confirmed herpes simplex virus. The patient made an eventual excellent recovery following 21 days of intravenous acyclovir therapy followed by 14 days of oral treatment. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells.

PubMed

Machado-Santos, Joana; Saji, Etsuji; Tröscher, Anna R; Paunovic, Manuela; Liblau, Roland; Gabriely, Galina; Bien, Christian G; Bauer, Jan; Lassmann, Hans

2018-06-04

Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain. However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations. In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls. In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse. A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen's encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest. Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis. Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells. The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions. Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen's encephalitis. Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions. Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.

Severe impulsiveness as the primary manifestation of multiple sclerosis in a young female.

PubMed

Lopez-Meza, Elmer; Corona-Vazquez, Teresa; Ruano-Calderon, Luis A; Ramirez-Bermudez, Jesus

2005-12-01

Severe impulsiveness in the absence of apparent neurological signs has rarely been reported as a clinical presentation of multiple sclerosis (MS). An 11-year-old female developed progressive and sustained personality disturbances including disinhibition, hypersexuality, drug abuse, aggressiveness and suicide attempts, without neurological signs. She was given several unsuccessful psychopharmacological and psychotherapeutic interventions. At age 21, a diagnosis of MS was made, confirmed by imaging, laboratory and neurophysiological studies. Although unusual, MS may produce pure neurobehavioral disturbances. In the present case, widespread demyelinization produced a complex behavioral disorder, with features compatible with orbitofrontal and Klüver-Bucy syndromes.

New Approaches to the Diagnosis, Clinical Course, and Goals of Therapy in Multiple Sclerosis and Related Disorders.

PubMed

Krieger, Stephen C

2016-06-01

The diagnosis, categorization, and treatment of multiple sclerosis (MS) and other demyelinating diseases have shifted over the past decade, and many of the fundamental principles of MS pathogenesis and clinical course are being rewritten. Fundamental issues include selecting the right disease-modifying therapy for someone with active disease and how, or even if, patients with purely progressive MS should be treated. This article provides an overview and introduction to the current thinking in MS diagnosis and therapy with an emphasis on the data-driven and proactive approach that has come to define the current state of the art.

Treatment optimization in MS: Canadian MS Working Group updated recommendations.

PubMed

Freedman, Mark S; Selchen, Daniel; Arnold, Douglas L; Prat, Alexandre; Banwell, Brenda; Yeung, Michael; Morgenthau, David; Lapierre, Yves

2013-05-01

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect.

PubMed

Voldsgaard, A; Bager, P; Garde, E; Åkeson, P; Leffers, A M; Madsen, C G; Kapel, C; Roepstorff, A; Thamsborg, S M; Melbye, M; Siebner, H; Søndergaard, H B; Sellebjerg, F; Sørensen, P Soelberg

2015-11-01

An observational study has suggested that relapsing-remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24-55) years, disease duration 9 (4-34) years, Expanded Disability Status Scale score 2.5 (1-5.0), and number of relapses within the last two years 3 (2-5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect. © The Author(s), 2015.

Longitudinal change in physical activity and its correlates in relapsing-remitting multiple sclerosis.

PubMed

Motl, Robert W; McAuley, Edward; Sandroff, Brian M

2013-08-01

Physical activity is beneficial for people with multiple sclerosis (MS), but this population is largely inactive. There is minimal information on change in physical activity and its correlates for informing the development of behavioral interventions. This study examined change in physical activity and its symptomatic, social-cognitive, and ambulatory or disability correlates over a 2.5-year period of time in people with relapsing-remitting multiple sclerosis. On 6 occasions, each separated by 6 months, people (N=269) with relapsing-remitting multiple sclerosis completed assessments of symptoms, self-efficacy, walking impairment, disability, and physical activity. The participants wore an accelerometer for 7 days. The change in study variables over 6 time points was examined with unconditional latent growth curve modeling. The association among changes in study variables over time was examined using conditional latent growth curve modeling, and the associations were expressed as standardized path coefficients (β). There were significant linear changes in self-reported and objectively measured physical activity, self-efficacy, walking impairment, and disability over the 2.5-year period; there were no changes in fatigue, depression, and pain. The changes in self-reported and objective physical activity were associated with change in self-efficacy (β=.49 and β=.61, respectively), after controlling for other variables and confounders. The primary limitations of the study were the generalizability of results among those with progressive multiple sclerosis and inclusion of a single variable from social-cognitive theory. Researchers should consider designing interventions that target self-efficacy for the promotion and maintenance of physical activity in this population.

Stress in multiple sclerosis: review of new developments and future directions.

PubMed

Lovera, Jesus; Reza, Tara

2013-11-01

In the experimental autoimmune encephalitis model of multiple sclerosis, the effects of stress on disease severity depend on multiple factors, including the animal's genetics and the type of stressor. The studies in humans relating stress to the risk of developing multiple sclerosis have found discordant results. The studies looking at the association of stress with relapses show a fairly consistent association, where higher stress is associated with a higher risk of relapse. Higher stress levels also appear to increase the risk of development of gadolinium-enhancing lesions. A recent randomized trial shows that reducing stress using stress management therapy (SMT), a cognitive-behavioral therapy approach, results in a statistically significant reduction in new magnetic resonance imaging lesions. The magnitude of this effect is large and comparable to the effects of existent disease-modifying therapies, but no data exist yet proving that SMT reduces relapses or clinical progression; the effect of SMT appears to be short-lived. Additional work is needed to improve the duration of this effect and make this therapy more widely accessible.

Defining active progressive multiple sclerosis.

PubMed

Sellebjerg, Finn; Börnsen, Lars; Ammitzbøll, Cecilie; Nielsen, Jørgen Erik; Vinther-Jensen, Tua; Hjermind, Lena Elisabeth; von Essen, Marina; Ratzer, Rikke Lenhard; Soelberg Sørensen, Per; Romme Christensen, Jeppe

2017-11-01

It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24). Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis.

PubMed

Romme Christensen, Jeppe; Börnsen, Lars; Khademi, Mohsen; Olsson, Tomas; Jensen, Poul Erik; Sørensen, Per Soelberg; Sellebjerg, Finn

2013-06-01

The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing-remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.

Cognitive and Language Deficits in Multiple Sclerosis: Comparison of Relapsing Remitting and Secondary Progressive Subtypes

PubMed Central

Ntoskou, Katerina; Messinis, Lambros; Nasios, Grigorios; Martzoukou, Maria; Makris, Giorgos; Panagiotopoulos, Elias; Papathanasopoulos, Panagiotis

2018-01-01

Objective: The objective of this study was to investigate the pattern and severity of cognitive and language impairment in Greek patients with Relapsing-remitting (RRMS) and Secondary Progressive Multiple Sclerosis (SPMS), relative to control participants. Method: A prospective study was conducted in 27 patients with multiple sclerosis (PwMS), (N= 15) with RRMS, (N= 12) with SPMS, and (N= 12) healthy controls. All participants were assessed with a flexible comprehensive neuropsychological – language battery of tests that have been standardized in Greece and validated in Greek MS patients. They were also assessed on measures of disability (Expanded Disability Status Scale; EDSS), fatigue (Fatigue Severity Scale; FSS) and depression (Beck Depression Inventory - fast screen; BDI-FS). Results: Our results revealed that groups were well matched on baseline demographic and clinical characteristics. The two clinical groups (RRMS; SPMS) did not differ on overall global cognitive impairment but differed in the initial encoding of verbal material, mental processing speed, response inhibition and set-shifting. RRMS patients differed from controls in the initial encoding of verbal material, learning curve, delayed recall of verbal information, processing speed, and response inhibition. SPMS patients differed in all utilized measures compared to controls. Moreover, we noted increased impairment frequency on individualized measures in the progressive SPMS group. Conclusion: We conclude that MS patients, irrespective of clinical subtype, have cognitive deficits compared to healthy participants, which become increasingly worse when they convert from RRMS to SPMS.On the contrary,the pattern of impairment remains relatively stable. PMID:29576812

Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis.

PubMed

Ravits, John; Appel, Stanley; Baloh, Robert H; Barohn, Richard; Brooks, Benjamin Rix; Elman, Lauren; Floeter, Mary Kay; Henderson, Christopher; Lomen-Hoerth, Catherine; Macklis, Jeffrey D; McCluskey, Leo; Mitsumoto, Hiroshi; Przedborski, Serge; Rothstein, Jeffrey; Trojanowski, John Q; van den Berg, Leonard H; Ringel, Steven

2013-05-01

Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS - and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease - a goal that seems increasingly achievable.

Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis.

PubMed

Healy, Brian C; Engler, David; Gholipour, Taha; Weiner, Howard; Bakshi, Rohit; Chitnis, Tanuja

2011-04-15

Identifying predictors of clinical progression in patients with relapsing-remitting multiple sclerosis (RRMS) is complicated in the era of disease modifying therapy (DMT) because patients follow many different DMT regimens. To investigate predictors of progression in a treated RRMS sample, a cohort of RRMS patients was prospectively followed in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB). Enrollment criteria were exposure to either interferon-β (IFN-β, n=164) or glatiramer acetate (GA, n=114) for at least 6 months prior to study entry. Baseline demographic and clinical features were used as candidate predictors of longitudinal clinical change on the Expanded Disability Status Scale (EDSS). We compared three approaches to account for DMT effects in statistical modeling. In all approaches, we analyzed all patients together and stratified based on baseline DMT. Model 1 used all available longitudinal EDSS scores, even those after on-study DMT changes. Model 2 used only clinical observations prior to changing DMT. Model 3 used causal statistical models to identify predictors of clinical change. When all patients were considered using Model 1, patients with a motor symptom as the first relapse had significantly larger change in EDSS scores during follow-up (p=0.04); none of the other clinical or demographic variables significantly predicted change. In Models 2 and 3, results were generally unchanged. DMT modeling choice had a modest impact on the variables classified as predictors of EDSS score change. Importantly, however, interpretation of these predictors is dependent upon modeling choice. Copyright © 2011 Elsevier B.V. All rights reserved.

Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis

PubMed Central

Solanky, Bhavana S.; Muhlert, Nils; Tur, Carmen; Edden, Richard A. E.; Wheeler-Kingshott, Claudia A. M.; Miller, David H.; Thompson, Alan J.; Ciccarelli, Olga

2015-01-01

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = −0.403 mM, 95% confidence intervals −0.792, −0.014, P = 0.043) and sensorimotor cortex (adjusted difference = −0.385 mM, 95% confidence intervals −0.667, −0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted −10.86 (95% confidence intervals −16.786 to −4.482) decrease in grip strength (kg force) (P < 0.001) and −8.74 (95% confidence intervals −13.943 to −3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis. See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article. PMID:26304151

Factors associated with clinically significant increased walking time in multiple sclerosis: results of a survival analysis of short-term follow-up data from a clinical database.

PubMed

Miller, Deborah M; Thompson, Nicolas R; Cohen, Jeffrey A; Fox, Robert J; Hartman, Jen; Schwetz, Kathleen; Conway, Devon S; Rudick, Richard A

2015-04-01

Because multiple sclerosis (MS) is variable and unpredictable, if symptom worsening could be predicted, patients may feel better prepared to manage changes in function. The objective of this paper is to study the prediction of walking impairment in MS. We retrieved data for all MS patients at our center (2008-2009), including baseline and follow-up timed 25-foot walk (T25FW) times. We assessed the incidence of ≥20% worsening in T25FW by developing two survival models: (1) disease course and (2) Multiple Sclerosis Performance Scales (MSPS) score. The outcome was days until ≥20% worsening in T25FW. Covariates were disease subtype, years since diagnosis, Patient Health Questionnaire-9 (PHQ-9) score, and demographics. Data were interval censored; missing data were handled with multiple imputation. Of 1544 patients, 309 (20%) experienced ≥20% worsening T25FW. For disease course, time to worsening was significantly shorter for secondary progressive vs. relapsing-remitting disease (p < 0.001). For MSPS, patients with lower baseline MSPS scores progressed more slowly (p = 0.001). In both models, sex, baseline T25W, and time since diagnosis were significantly associated with worsening. In the disease course model, PHQ 9 score may be related to worsening (p = 0.07). These findings suggest factors associated with worsening in T25FW and a potential approach to establishing indicators associated with clinically significant change. © The Author(s), 2014.

Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis.

PubMed

Barro, Christian; Benkert, Pascal; Disanto, Giulio; Tsagkas, Charidimos; Amann, Michael; Naegelin, Yvonne; Leppert, David; Gobbi, Claudio; Granziera, Cristina; Yaldizli, Özgür; Michalak, Zuzanna; Wuerfel, Jens; Kappos, Ludwig; Parmar, Katrin; Kuhle, Jens

2018-05-30

Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8% and 4.9% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5% (P < 0.001) and spinal cord volume of 2.5% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.

Progression, Symptoms and Psychosocial Concerns among Those Severely Affected by Multiple Sclerosis: A Mixed-Methods Cross-Sectional Study of Black Caribbean and White British People

PubMed Central

Koffman, Jonathan; Gao, Wei; Goddard, Cassie; Burman, Rachel; Jackson, Diana; Shaw, Pauline; Barnes, Fiona; Silber, Eli; Higginson, Irene J.

2013-01-01

Objective Multiple sclerosis is now more common among minority ethnic groups in the UK but little is known about their experiences, especially in advanced stages. We examine disease progression, symptoms and psychosocial concerns among Black Caribbean (BC) and White British (WB) people severely affected by MS. Design Mixed methods study of 43 BC and 43 WB people with MS (PwMS) with an Expanded Disability Status Scale (EDSS) ≥6 involving data from in clinical records, face-to-face structured interviews and a nested-qualitative component. Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) were calculated. To control for selection bias, propensity scores were derived for each patient and adjusted for in the comparative statistical analysis; qualitative data were analysed using the framework approach. Results Median EDSS for both groups was (6.5; range: 6.0–9.0). Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) based on neurological assessment of current EDSS scores identified BC PwMS were more likely to have aggressive disease (PI F = 4.04, p = 0.048, MSSS F = 10.30, p<0.001). Patients’ reports of the time required to reach levels of functional decline equivalent to different EDSS levels varied by group; EDSS 4: BC 2.7 years v/s WB 10.2 years (U = 258.50, p = 0.013), EDSS 6∶6.1 years BC v/s WB 12.7 years (U = 535.500, p = 0.011), EDSS 8: BC 8.7 years v/s WB 10.2 years. Both groups reported high symptom burden. BC PwMS were more cognitively impaired than WB PwMS (F = 9.65, p = 0.003). Thematic analysis of qualitative interviews provides correspondence with quantitative findings; more BC than WB PwMS referred to feelings of extreme frustration and unresolved loss/confusion associated with their rapidly advancing disease. The interviews also reveal the centrality, meanings and impact of common MS-related symptoms. Conclusions Delays in diagnosis should be avoided and more frequent reviews may be justified by healthcare services. Culturally acceptable interventions to better support people who perceive MS as an assault on identity should be developed to help them achieve normalisation and enhance self-identity. PMID:24098384

Progression, symptoms and psychosocial concerns among those severely affected by multiple sclerosis: a mixed-methods cross-sectional study of Black Caribbean and White British people.

PubMed

Koffman, Jonathan; Gao, Wei; Goddard, Cassie; Burman, Rachel; Jackson, Diana; Shaw, Pauline; Barnes, Fiona; Silber, Eli; Higginson, Irene J

2013-01-01

Multiple sclerosis is now more common among minority ethnic groups in the UK but little is known about their experiences, especially in advanced stages. We examine disease progression, symptoms and psychosocial concerns among Black Caribbean (BC) and White British (WB) people severely affected by MS. Mixed methods study of 43 BC and 43 WB people with MS (PwMS) with an Expanded Disability Status Scale (EDSS) ≥6 involving data from in clinical records, face-to-face structured interviews and a nested-qualitative component. Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) were calculated. To control for selection bias, propensity scores were derived for each patient and adjusted for in the comparative statistical analysis; qualitative data were analysed using the framework approach. Median EDSS for both groups was (6.5; range: 6.0-9.0). Progression Index (PI) and Multiple Sclerosis Severity Score (MSSS) based on neurological assessment of current EDSS scores identified BC PwMS were more likely to have aggressive disease (PI F = 4.04, p = 0.048, MSSS F = 10.30, p<0.001). Patients' reports of the time required to reach levels of functional decline equivalent to different EDSS levels varied by group; EDSS 4: BC 2.7 years v/s WB 10.2 years (U = 258.50, p = 0.013), EDSS 6∶6.1 years BC v/s WB 12.7 years (U = 535.500, p = 0.011), EDSS 8: BC 8.7 years v/s WB 10.2 years. Both groups reported high symptom burden. BC PwMS were more cognitively impaired than WB PwMS (F = 9.65, p = 0.003). Thematic analysis of qualitative interviews provides correspondence with quantitative findings; more BC than WB PwMS referred to feelings of extreme frustration and unresolved loss/confusion associated with their rapidly advancing disease. The interviews also reveal the centrality, meanings and impact of common MS-related symptoms. Delays in diagnosis should be avoided and more frequent reviews may be justified by healthcare services. Culturally acceptable interventions to better support people who perceive MS as an assault on identity should be developed to help them achieve normalisation and enhance self-identity.

Clinical Characteristics of Pediatric-Onset and Adult-Onset Multiple Sclerosis in Hispanic Americans.

PubMed

Langille, Megan M; Islam, Talat; Burnett, Margaret; Amezcua, Lilyana

2016-07-01

Multiple sclerosis can affect pediatric patients. Our aim was to compare characteristics between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanic Americans. This was a cross-sectional analysis of 363 Hispanic American multiple scleroses cases; demographic and clinical characteristics were analyzed. A total of 110 Hispanic patients presented with multiple sclerosis before age 18 and 253 as adult multiple sclerosis. The most common presenting symptoms for both was optic neuritis. Polyfocal symptoms, seizures, and cognitive symptoms at presentation were more prevalent in pediatric-onset multiple sclerosis (P ≤ .001). Transverse myelitis was more frequent in adult-onset multiple sclerosis (P ≤ .001). Using multivariable analysis, pediatric-onset multiple sclerosis (adjusted odds ratio, 0.3OR 95% confidence interval 0.16-0.71, P = .004) and being US born (adjusted odds ratio, 0.553, 95% confidence interval 0.3-1.03, P = .006) were less likely to have severe ambulatory disability. Results suggest that pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanics have differences that could be important for treatment and prognosis. © The Author(s) 2016.

Using a multidimensional unfolding approach to assess multiple sclerosis patient preferences for disease-modifying therapy: a pilot study

PubMed Central

Sempere, Angel Perez; Vera-Lopez, Vanesa; Gimenez-Martinez, Juana; Ruiz-Beato, Elena; Cuervo, Jesús; Maurino, Jorge

2017-01-01

Purpose Multidimensional unfolding is a multivariate method to assess preferences using a small sample size, a geometric model locating individuals and alternatives as points in a joint space. The objective was to evaluate relapsing–remitting multiple sclerosis (RRMS) patient preferences toward key disease-modifying therapy (DMT) attributes using multidimensional unfolding. Patients and methods A cross-sectional pilot study in RRMS patients was conducted. Drug attributes included relapse prevention, disease progression prevention, side-effect risk and route and schedule of administration. Assessment of preferences was performed through a five-card game. Patients were asked to value attributes from 1 (most preferred) to 5 (least preferred). Results A total of 37 patients were included; the mean age was 38.6 years, and 78.4% were female. Disease progression prevention was the most important factor (51.4%), followed by relapse prevention (40.5%). The frequency of administration had the lowest preference rating for 56.8% of patients. Finally, 19.6% valued the side-effect risk attribute as having low/very low importance. Conclusion Patients’ perspective for DMT attributes may provide valuable information to facilitate shared decision-making. Efficacy attributes were the most important drug characteristics for RRMS patients. Multidimensional unfolding seems to be a feasible approach to assess preferences in multiple sclerosis patients. Further elicitation studies using multidimensional unfolding with other stated choice methods are necessary to confirm these findings. PMID:28615928

The topographical model of multiple sclerosis

PubMed Central

Cook, Karin; De Nino, Scott; Fletcher, Madhuri

2016-01-01

Relapses and progression contribute to multiple sclerosis (MS) disease course, but neither the relationship between them nor the spectrum of clinical heterogeneity has been fully characterized. A hypothesis-driven, biologically informed model could build on the clinical phenotypes to encompass the dynamic admixture of factors underlying MS disease course. In this medical hypothesis, we put forth a dynamic model of MS disease course that incorporates localization and other drivers of disability to propose a clinical manifestation framework that visualizes MS in a clinically individualized way. The topographical model encapsulates 5 factors (localization of relapses and causative lesions; relapse frequency, severity, and recovery; and progression rate), visualized utilizing dynamic 3-dimensional renderings. The central hypothesis is that, like symptom recrudescence in Uhthoff phenomenon and pseudoexacerbations, progression clinically recapitulates prior relapse symptoms and unmasks previously silent lesions, incrementally revealing underlying lesion topography. The model uses real-time simulation software to depict disease course archetypes and illuminate several well-described but poorly reconciled phenomena including the clinical/MRI paradox and prognostic significance of lesion location and burden on disease outcomes. Utilization of this model could allow for earlier and more clinically precise identification of progressive MS and predictive implications can be empirically tested. PMID:27648465

A B Cell-Driven Autoimmune Pathway Leading to Pathological Hallmarks of Progressive Multiple Sclerosis in the Marmoset Experimental Autoimmune Encephalomyelitis Model

PubMed Central

’t Hart, Bert A.; Dunham, Jordon; Faber, Bart W.; Laman, Jon D.; van Horssen, Jack; Bauer, Jan; Kap, Yolanda S.

2017-01-01

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34–56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund’s adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund’s adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34–56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey’s immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes. PMID:28744286

Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

PubMed

Sedel, Frédéric; Bernard, Delphine; Mock, Donald M; Tourbah, Ayman

2016-11-01

Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Estimating Time to Event From Longitudinal Categorical Data: An Analysis of Multiple Sclerosis Progression.

PubMed

Mandel, Micha; Gauthier, Susan A; Guttmann, Charles R G; Weiner, Howard L; Betensky, Rebecca A

2007-12-01

The expanded disability status scale (EDSS) is an ordinal score that measures progression in multiple sclerosis (MS). Progression is defined as reaching EDSS of a certain level (absolute progression) or increasing of one point of EDSS (relative progression). Survival methods for time to progression are not adequate for such data since they do not exploit the EDSS level at the end of follow-up. Instead, we suggest a Markov transitional model applicable for repeated categorical or ordinal data. This approach enables derivation of covariate-specific survival curves, obtained after estimation of the regression coefficients and manipulations of the resulting transition matrix. Large sample theory and resampling methods are employed to derive pointwise confidence intervals, which perform well in simulation. Methods for generating survival curves for time to EDSS of a certain level, time to increase of EDSS of at least one point, and time to two consecutive visits with EDSS greater than three are described explicitly. The regression models described are easily implemented using standard software packages. Survival curves are obtained from the regression results using packages that support simple matrix calculation. We present and demonstrate our method on data collected at the Partners MS center in Boston, MA. We apply our approach to progression defined by time to two consecutive visits with EDSS greater than three, and calculate crude (without covariates) and covariate-specific curves.

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

PubMed

Kalincik, Tomas; Manouchehrinia, Ali; Sobisek, Lukas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Girard, Marc; Prat, Alexandre; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Hupperts, Raymond; Grand'Maison, Francois; Pucci, Eugenio; Boz, Cavit; Alroughani, Raed; Van Pesch, Vincent; Lechner-Scott, Jeannette; Terzi, Murat; Bergamaschi, Roberto; Iuliano, Gerardo; Granella, Franco; Spitaleri, Daniele; Shaygannejad, Vahid; Oreja-Guevara, Celia; Slee, Mark; Ampapa, Radek; Verheul, Freek; McCombe, Pamela; Olascoaga, Javier; Amato, Maria Pia; Vucic, Steve; Hodgkinson, Suzanne; Ramo-Tello, Cristina; Flechter, Shlomo; Cristiano, Edgardo; Rozsa, Csilla; Moore, Fraser; Luis Sanchez-Menoyo, Jose; Laura Saladino, Maria; Barnett, Michael; Hillert, Jan; Butzkueven, Helmut

2017-09-01

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Experimental Autoimmune Encephalomyelitis (EAE) as Animal Models of Multiple Sclerosis (MS).

PubMed

Glatigny, Simon; Bettelli, Estelle

2018-01-08

Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system (CNS) leading to the progressive destruction of the myelin sheath surrounding axons. It can present with variable clinical and pathological manifestations, which might reflect the involvement of distinct pathogenic processes. Although the mechanisms leading to the development of the disease are not fully understood, numerous evidences indicate that MS is an autoimmune disease, the initiation and progression of which are dependent on an autoimmune response against myelin antigens. In addition, genetic susceptibility and environmental triggers likely contribute to the initiation of the disease. At this time, there is no cure for MS, but several disease-modifying therapies (DMTs) are available to control and slow down disease progression. A good number of these DMTs were identified and tested using animal models of MS referred to as experimental autoimmune encephalomyelitis (EAE). In this review, we will recapitulate the characteristics of EAE models and discuss how they help shed light on MS pathogenesis and help test new treatments for MS patients. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

MRI Correlates of Disability in African-Americans with Multiple Sclerosis

PubMed Central

Howard, Jonathan; Battaglini, Marco; Babb, James Scott; Arienzo, Donatello; Holst, Brigitte; Omari, Mirza; De Stefano, Nicola; Herbert, Joseph; Inglese, Matilde

2012-01-01

Objectives Multiple sclerosis (MS) in African-Americans (AAs) is characterized by more rapid disease progression and poorer response to treatment than in Caucasian-Americans (CAs). MRI provides useful and non-invasive tools to investigate the pathological substrate of clinical progression. The aim of our study was to compare MRI measures of brain damage between AAs and CAs with MS. Methods Retrospective analysis of 97 AAs and 97 CAs with MS matched for age, gender, disease duration and age at MRI examination. Results AA patients had significantly greater T2- (p = 0.001) and T1-weighted (p = 0.0003) lesion volumes compared to CA patients. In contrast, measurements of global and regional brain volume did not significantly differ between the two ethnic groups (p>0.1). Conclusions By studying a quite large sample of well demographically and clinically matched CA and AA patients with a homogeneous MRI protocol we showed that higher lesion accumulation, rather than pronounced brain volume decrease might explain the early progress to ambulatory assistance of AAs with MS. PMID:22900088

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

PubMed

Romme Christensen, Jeppe; Komori, Mika; von Essen, Marina Rode; Ratzer, Rikke; Börnsen, Lars; Bielekova, Bibi; Sellebjerg, Finn

2018-05-01

Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Single nucleotide polymorphisms in multiple sclerosis: disease susceptibility and treatment response biomarkers.

PubMed

Pravica, Vera; Popadic, Dusan; Savic, Emina; Markovic, Milos; Drulovic, Jelena; Mostarica-Stojkovic, Marija

2012-04-01

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by unpredictable and variable clinical course. Etiology of MS involves both genetic and environmental factors. New technologies identified genetic polymorphisms associated with MS susceptibility among which immunologically relevant genes are significantly overrepresented. Although individual genes contribute only a small part to MS susceptibility, they might be used as biomarkers, thus helping to identify accurate diagnosis, predict clinical disease course and response to therapy. This review focuses on recent progress in research on MS genetics with special emphasis on the possibility to use single nucleotide polymorphism of candidate genes as biomarkers of susceptibility to disease and response to therapy.

Prognostic factors versus markers of response to treatment versus surrogate endpoints: Three different concepts.

PubMed

Sormani, Maria Pia

2017-03-01

Multiple sclerosis is a highly heterogeneous disease; the quantitative assessment of disease progression is problematic for many reasons, including the lack of objective methods to measure disability and the long follow-up times needed to detect relevant and stable changes. For these reasons, the importance of prognostic markers, markers of response to treatments and of surrogate endpoints, is crucial in multiple sclerosis research. Aim of this report is to clarify some basic definitions and methodological issues about baseline factors to be considered prognostic markers or markers of response to treatment; to define the dynamic role that variables must have to be considered surrogate markers in relation to specific treatments.

New Insights into Multiple Sclerosis Clinical Course from the Topographical Model and Functional Reserve.

PubMed

Krieger, Stephen C; Sumowski, James

2018-02-01

Clinical course in multiple sclerosis (MS) is difficult to predict on group and individual levels. We discuss the topographical model of MS as a new approach to characterizing the clinical course, with the potential to personalize disability progression based on each individual patient's pattern of disease burden (eg, lesion location) and reserve. The dynamic clinical threshold depicted in this visual model may help clinicians to educate patients about clinical phenotype and disease burden, and foster an understanding of the difference between relapses and pseudoexacerbations. There is an emphasis on building reserve against cognitive and physical decline, encouraging agency among patients. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Plasma levels of endothelial and B-cell-derived microparticles are restored by fingolimod treatment in multiple sclerosis patients.

PubMed

Zinger, Anna; Latham, Sharissa L; Combes, Valery; Byrne, Scott; Barnett, Michael H; Hawke, Simon; Grau, Georges E

2016-12-01

No molecular marker can monitor disease progression and treatment efficacy in multiple sclerosis (MS). Circulating microparticles represent a potential snapshot of disease activity at the blood brain barrier. To profile plasma microparticles by flow cytometry in MS and determine how fingolimod could impact endothelial microparticles production. In non-treated MS patients compared to healthy and fingolimod-treated patients, endothelial microparticles were higher, while B-cell-microparticle numbers were lower. Fingolimod dramatically reduced tumour necrosis factor (TNF)-induced endothelial microparticle release in vitro. Fingolimod restored dysregulated endothelial and B-cell-microparticle numbers, which could serve as a biomarker in MS. © The Author(s), 2016.

VISUALIZING IRON IN MULTIPLE SCLEROSIS

PubMed Central

Bagnato, Francesca; Hametner, Simon; Welch, Edward Brian

2012-01-01

Magnetic resonance imaging (MRI) protocols that are designed to be sensitive to iron typically take advantage of (1) iron effects on the relaxation of water protons and/or (2) iron-induced local magnetic field susceptibility changes. Increasing evidence sustains the notion that imaging iron in brain of patients with multiple sclerosis (MS) may add some specificity toward the identification of the disease pathology. The present review summarizes currently reported in vivo and post mortem MRI evidence of (1) iron detection in white matter and grey matter of MS brains, (2) pathological and physiological correlates of iron as disclosed by imaging and (3) relations between iron accumulation and disease progression as measured by clinical metrics. PMID:23347601

Personalized medicine in multiple sclerosis.

PubMed

Giovannoni, Gavin

2017-11-01

The therapeutic approach in multiple sclerosis (MS) requires a personalized medicine frame beyond the precision medicine concept, which is not currently implementable due to the lack of robust biomarkers and detailed understanding of MS pathogenesis. Personalized medicine demands a patient-focused approach, with disease taxonomy informed by characterization of pathophysiological processes. Important questions concerning MS taxonomy are: when does MS begin? When does the progressive phase begin? Is MS really two or three diseases? Does a therapeutic window truly exist? Newer evidence points to a disease spectrum and a therapeutic lag of several years for benefits to be observed from disease-modifying therapy. For personalized treatment, it is important to ascertain disease stage and any worsening of focal inflammatory lesions over time.

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

PubMed

Chevalier, Julie; Chamoux, Catherine; Hammès, Florence; Chicoye, Annie

2016-01-01

The paper aimed to estimate the incremental cost-effectiveness ratio (ICER) at the public published price for delayed-release dimethyl fumarate versus relevant Multiple Sclerosis disease-modifying therapies available in France in June 2015. The economic model was adapted to the French setting in accordance with the Haute Autorité de Santé guidelines using a model previously developed for NICE. A cohort of Relapsing Remitting Multiple Sclerosis patients was simulated over a 30-year time horizon. Twenty one health states were taken into account: Kurtzke Expanded Disability Status Scale (EDSS) 0-9 for Relapsing Remitting Multiple Sclerosis patients, EDSS 0-9 for Secondary Progressive Multiple Sclerosis patients, and death. Estimates of relative treatment efficacy were determined using a mixed-treatment comparison. Probabilities of events were derived from the dimethyl fumarate pivotal clinical trials and the London Ontario Dataset. Costs and utilities were extracted from the published literature from both the payer and societal perspectives. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model results. From both perspectives, dimethyl fumarate and interferon beta-1a (IFN beta-1a) 44 mcg were the two optimal treatments, as the other treatments (IFN beta-1a 30 mcg, IFN beta-1b 250 mcg, teriflunomide, glatiramer acetate, fingolimod) were dominated on the efficiency frontier. From the societal perspective, dimethyl fumarate versus IFN beta-1a 44 mcg incurred an incremental cost of €3,684 and an incremental quality-adjusted life year (QALY) of 0.281, corresponding to an ICER of €13,110/QALY. Despite no reference threshold for France, dimethyl fumarate can be considered as a cost-effective option as it is on the efficiency frontier.

Cognitive Implications of Deep Gray Matter Iron in Multiple Sclerosis.

PubMed

Fujiwara, E; Kmech, J A; Cobzas, D; Sun, H; Seres, P; Blevins, G; Wilman, A H

2017-05-01

Deep gray matter iron accumulation is increasingly recognized in association with multiple sclerosis and can be measured in vivo with MR imaging. The cognitive implications of this pathology are not well-understood, especially vis-à-vis deep gray matter atrophy. Our aim was to investigate the relationships between cognition and deep gray matter iron in MS by using 2 MR imaging-based iron-susceptibility measures. Forty patients with multiple sclerosis (relapsing-remitting, n = 16; progressive, n = 24) and 27 healthy controls were imaged at 4.7T by using the transverse relaxation rate and quantitative susceptibility mapping. The transverse relaxation rate and quantitative susceptibility mapping values and volumes (atrophy) of the caudate, putamen, globus pallidus, and thalamus were determined by multiatlas segmentation. Cognition was assessed with the Brief Repeatable Battery of Neuropsychological Tests. Relationships between cognition and deep gray matter iron were examined by hierarchic regressions. Compared with controls, patients showed reduced memory ( P < .001) and processing speed ( P = .02) and smaller putamen ( P < .001), globus pallidus ( P = .002), and thalamic volumes ( P < .001). Quantitative susceptibility mapping values were increased in patients compared with controls in the putamen ( P = .003) and globus pallidus ( P = .003). In patients only, thalamus ( P < .001) and putamen ( P = .04) volumes were related to cognitive performance. After we controlled for volume effects, quantitative susceptibility mapping values in the globus pallidus ( P = .03; trend for transverse relaxation rate, P = .10) were still related to cognition. Quantitative susceptibility mapping was more sensitive compared with the transverse relaxation rate in detecting deep gray matter iron accumulation in the current multiple sclerosis cohort. Atrophy and iron accumulation in deep gray matter both have negative but separable relationships to cognition in multiple sclerosis. © 2017 by American Journal of Neuroradiology.

Correlated Heterospectral Lipidomics for Biomolecular Profiling of Remyelination in Multiple Sclerosis

PubMed Central

2017-01-01

Analyzing lipid composition and distribution within the brain is important to study white matter pathologies that present focal demyelination lesions, such as multiple sclerosis. Some lesions can endogenously re-form myelin sheaths. Therapies aim to enhance this repair process in order to reduce neurodegeneration and disability progression in patients. In this context, a lipidomic analysis providing both precise molecular classification and well-defined localization is crucial to detect changes in myelin lipid content. Here we develop a correlated heterospectral lipidomic (HSL) approach based on coregistered Raman spectroscopy, desorption electrospray ionization mass spectrometry (DESI-MS), and immunofluorescence imaging. We employ HSL to study the structural and compositional lipid profile of demyelination and remyelination in an induced focal demyelination mouse model and in multiple sclerosis lesions from patients ex vivo. Pixelwise coregistration of Raman spectroscopy and DESI-MS imaging generated a heterospectral map used to interrelate biomolecular structure and composition of myelin. Multivariate regression analysis enabled Raman-based assessment of highly specific lipid subtypes in complex tissue for the first time. This method revealed the temporal dynamics of remyelination and provided the first indication that newly formed myelin has a different lipid composition compared to normal myelin. HSL enables detailed molecular myelin characterization that can substantially improve upon the current understanding of remyelination in multiple sclerosis and provides a strategy to assess remyelination treatments in animal models. PMID:29392175

Walking impairment in patients with multiple sclerosis: exercise training as a treatment option.

PubMed

Motl, Robert W; Goldman, Myla D; Benedict, Ralph H B

2010-11-16

Multiple sclerosis (MS) is a chronic disease of the central nervous system that culminates in the progression of physical and cognitive disability over time. Walking impairment is a ubiquitous feature of MS and a sentinel characteristic of the later or advanced stages of the disease. This paper presents a conceptual rationale along with empirical evidence for exercise training as a rehabilitation approach for managing walking impairment and improving walking function in persons with MS. Conceptually, MS is associated with a decrease in physical activity, which, in turn, can result in deconditioning across multiple domains of physiological functioning. The resulting deconditioning feeds back and further drives physical inactivity until a threshold is reached that likely initiates the progression of walking impairment in MS. Empirically, physical activity and exercise training have been associated with beneficial effects on walking function in persons with MS. This is based on cross-sectional, longitudinal, and experimental research that included diversity in the breadth of measures of walking, persons with MS, and exercise/physical activity characteristics. Of particular importance, future researchers might consider examining the combinatory effects of exercise training plus pharmacological agents on walking mobility in MS. Collectively, exercise training and physical activity might hold significant potential for the management of progressive mobility disability in MS.

Strategies to reduce hyperthermia in ambulatory multiple sclerosis patients.

PubMed

Edlich, Richard F; Buschbacher, Ralph M; Cox, Mary Jude; Long, William B; Winters, Kathryne L; Becker, Daniel G

2004-01-01

Approximately 400,000 Americans have multiple sclerosis. Worldwide, multiple sclerosis affects 2.5 million individuals. Multiple sclerosis affects two to three times as many women as men. The adverse effects of hyperthermia in patients with multiple sclerosis have been known since 1890. While most patients with multiple sclerosis experience reversible worsening of their neurologic deficits, some patients experience irreversible neurologic deficits. In fact, heat-induced fatalities have been encountered in multiple sclerosis patients subjected to hyperthermia. Hyperthermia can be caused through sun exposure, exercise, and infection. During the last 50 years, numerous strategies have evolved to reduce hyperthermia in individuals with multiple sclerosis, such as photoprotective clothing, sunglasses, sunscreens, hydrotherapy, and prevention of urinary tract infections. Hydrotherapy has become an essential component of rehabilitation for multiple sclerosis patients in hospitals throughout the world. On the basis of this positive hospital experience, hydrotherapy has been expanded through the use of compact aquatic exercise pools at home along with personal cooling devices that promote local and systemic hypothermia in multiple sclerosis patients. The Multiple Sclerosis Association of America and NASA have played leadership roles in developing and recommending technology that will prevent hyperthermia in multiple sclerosis patients and should be consulted for new technological advances that will benefit the multiple sclerosis patient. In addition, products recommended for photoprotection by The Skin Cancer Foundation may also be helpful to the multiple sclerosis patient's defense against hyperthermia. Infections in the urinary tract, especially detrusor-external sphincter dyssynergia, are initially managed conservatively with intermittent self-catheterization and pharmacologic therapy. In those cases, refractory to conservative therapy, transurethral external sphincterotomy followed by condom catheter drainage is recommended. However, if external urethral sphincterotomy fails to reduce residual urine and detrusor pressure, urinary diversion or bladder reconstruction may be necessary.

Employment and absenteeism in working-age persons with multiple sclerosis.

PubMed

Salter, Amber; Thomas, Nina; Tyry, Tuula; Cutter, Gary; Marrie, Ruth Ann

2017-05-01

To better understand the impact of the clinical course of multiple sclerosis (MS) and disability on employment, absenteeism, and related factors. This study included respondents to the North American Research Committee on Multiple Sclerosis Registry spring 2015 update survey who were US or Canadian residents, aged 18-65 years and reported having relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS). The RRMS and SPMS participants were combined to form the relapsing-onset MS (RMS) group and compared with the PPMS group regarding employment status, absenteeism, and disability. Multivariable logistic regression was used to examine the relationship between employment-related outcomes and factors that may affect these relationships. Of the 8004 survey respondents, 5887 (73.6%) were 18-65 years of age. The PPMS group (n = 344) had a higher proportion of males and older mean age at the time of the survey and at time of diagnosis than the RMS group (n = 4829). Female sex, age, age at diagnosis, cognitive and hand function impairment, fatigue, higher disability levels, ≥3 comorbidities, and a diagnosis of PPMS were associated with not working. After adjustment for disability, the employed PPMS sub-group reported similar levels of absenteeism to the employed RMS sub-group. Limitations of the study include self-report of information and the possibility that participants may not fully represent the working-age MS population. In MS, employment status and absenteeism are negatively affected by disability, cognitive impairment, and fatigue. These findings underscore the need for therapies that prevent disability progression and other symptoms that negatively affect productivity in persons with MS to enable them to persist in the workforce.

Total lymphoid irradiation for multiple sclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Devereux, C.K.; Vidaver, R.; Hafstein, M.P.

1988-01-01

Although chemical immunosuppression has been shown to benefit patients with chronic progressive multiple sclerosis (MS), it appears that chemotherapy has an appreciable oncogenic potential in patients with multiple sclerosis. Accordingly, we developed a modified total lymphoid irradiation (TLI) regimen designed to reduce toxicity and applied it to a randomized double blind trial of TLI or sham irradiation in MS. Standard TLI regimens were modified to reduce dose to 1,980 rad, lowering the superior mantle margin to midway between the thyroid cartilage and angle of the mandible (to avert xerostomia) and the lower margin of the mantle field to the inferiormore » margin of L1 (to reduce gastrointestinal toxicity by dividing abdominal radiation between mantle and inverted Y), limiting spinal cord dose to 1,000 rad by custom-made spine blocks in the mantle and upper 2 cm of inverted Y fields, and also protecting the left kidney even if part of the spleen were shielded. Clinical efficacy was documented by the less frequent functional scale deterioration of 20 TLI treated patients with chronic progressive MS compared to to 20 sham-irradiated progressive MS patients after 12 months (16% versus 55%, p less than 0.03), 18 months (28% versus 63%, p less than 0.03), and 24 months (44% versus 74%, N.S.). Therapeutic benefit during 3 years follow-up was related to the reduction in lymphocyte count 3 months post-irradiation (p less than 0.02). Toxicity was generally mild and transient, with no instance of xerostomia, pericarditis, herpes zoster, or need to terminate treatment in TLI patients. However, menopause was induced in 2 patients and staphylococcal pneumonia in one.« less

Reduced cellularity of bone marrow in multiple sclerosis with decreased MSC expansion potential and premature ageing in vitro.

PubMed

Redondo, Juliana; Sarkar, Pamela; Kemp, Kevin; Virgo, Paul F; Pawade, Joya; Norton, Aimie; Emery, David C; Guttridge, Martin G; Marks, David I; Wilkins, Alastair; Scolding, Neil J; Rice, Claire M

2017-05-01

Autologous bone-marrow-derived cells are currently employed in clinical studies of cell-based therapy in multiple sclerosis (MS) although the bone marrow microenvironment and marrow-derived cells isolated from patients with MS have not been extensively characterised. To examine the bone marrow microenvironment and assess the proliferative potential of multipotent mesenchymal stromal cells (MSCs) in progressive MS. Comparative phenotypic analysis of bone marrow and marrow-derived MSCs isolated from patients with progressive MS and control subjects was undertaken. In MS marrow, there was an interstitial infiltrate of inflammatory cells with lymphoid (predominantly T-cell) nodules although total cellularity was reduced. Controlling for age, MSCs isolated from patients with MS had reduced in vitro expansion potential as determined by population doubling time, colony-forming unit assay, and expression of β-galactosidase. MS MSCs expressed reduced levels of Stro-1 and displayed accelerated shortening of telomere terminal restriction fragments (TRF) in vitro. Our results are consistent with reduced proliferative capacity and ex vivo premature ageing of bone-marrow-derived cells, particularly MSCs, in MS. They have significant implication for MSC-based therapies for MS and suggest that accelerated cellular ageing and senescence may contribute to the pathophysiology of progressive MS. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this study was provided by the Medical Research Council, UK (grant no. MR/K004166/1). The ACTiMuS study is sup-ported by the Silverman Family Foundation, Multiple Sclerosis Trust, Rosetree’s Trust, Catholic Bishops of England and Wales and Friends of Frenchay and SIAMMS-II by the Sir Halley Stewart Trust. C.M.R., P.S., and K.K. received support from the Burden Neurological Institute.

Progressive multiple sclerosis patients have a higher burden of autonomic dysfunction compared to relapsing remitting phenotype.

PubMed

Adamec, Ivan; Crnošija, Luka; Junaković, Anamari; Krbot Skorić, Magdalena; Habek, Mario

2018-06-04

To determine autonomic dysfunction (AD) differences in patients with relapsing remitting multiple sclerosis (pwRRMS) and progressive MS (pwPMS). Composite autonomic scoring scale (CASS) and heart rate variability (HRV) were performed in 40 pwRRMS and 30 pwPMS. pwPMS had a significantly higher sudomotor index and total CASS score compared to pwRRMS (p < 0.001 and p < 0.001, respectively). Disease duration positively correlated with sudomotor index and total CASS (r s  = 0.409, p < 0.001 and r s  = 0.472, p < 0.001, respectively), while the Expanded Disability Status Scale (EDSS) positively correlated with sudomotor index and total CASS (r s  = 0.411, p < 0.001 and r s  = 0.402, p = 0.001, respectively) in all patients. Type of multiple sclerosis (pwRRMS or pwPMS) corrected for age, sex and disease duration, was a statistically significant predictor of CASS value (B = 1.215, p = 0.019). Compared to pwRRMS, pwPMS had a significantly lower standard deviation of NN intervals (SDNN), low frequency (LF), and high frequency (HF), during both the supine and tilt-up phases (all p-values <0.006). pwPMS had a significantly lower LF/HF (p = 0.008) during tilt-up. There is a significant difference in autonomic function in pwRRMS and pwPMS; with pwPMS having a higher burden of AD, which is particularly evident for sweating dysfunction. Further research is needed to establish whether parasympathetic and sudomotor dysfunction may serve as markers of progressive MS. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Cladribine tablets: in relapsing-remitting multiple sclerosis.

PubMed

Muir, Victoria J; Plosker, Greg L

2011-03-01

Cladribine, an immunosuppressant that selectively reduces peripheral lymphocyte levels, has potential as an oral therapy for relapsing-remitting multiple sclerosis. An oral (tablet) formulation is being investigated in clinical trials. In the large, well designed, phase III CLARITY trial, short-course treatment with oral cladribine (cumulative dose of 3.5 or 5.25 mg/kg) resulted in a significantly greater reduction in annualized relapse rates at 96 weeks compared with placebo in patients with relapsing-remitting multiple sclerosis. Improvements in the annualized relapse rate with oral cladribine were independent of key baseline patient characteristics which included age, sex, previous treatment with disease-modifying drugs and the number of relapses in the previous 12 months. In addition, a significantly higher proportion of patients were relapse-free at 96 weeks and there were significant reductions in the risk of 3-month sustained progression of disability in cladribine recipients compared with placebo recipients. The mean numbers of brain lesions on magnetic resonance imaging were also significantly reduced with cladribine compared with placebo in the CLARITY trial. Lymphocytopenia, herpes zoster infections and neoplasms (including malignancies) were more common in cladribine than placebo recipients.

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course

PubMed Central

Dhib-Jalbut, Suhayl; Dowling, Peter; Durelli, Luca; Ford, Corey; Giovannoni, Gavin; Halper, June; Harris, Colleen; Herbert, Joseph; Li, David; Lincoln, John A.; Lisak, Robert; Lublin, Fred D.; Lucchinetti, Claudia F.; Moore, Wayne; Naismith, Robert T.; Oehninger, Carlos; Simon, Jack; Sormani, Maria Pia

2012-01-01

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS. PMID:24453741

Consensus Recommendations of the Multiple Sclerosis Study Group and Portuguese Neuroradiological Society for the Use of the Magnetic Resonance Imaging in Multiple Sclerosis in Clinical Practice: Part 1.

PubMed

Abreu, Pedro; Pedrosa, Rui; Sá, Maria José; Cerqueira, João; Sousa, Lívia; Da Silva, Ana Martins; Pinheiro, Joaquim; De Sá, João; Batista, Sónia; Simões, Rita Moiron; Pereira, Daniela Jardim; Vilela, Pedro; Vale, José

2018-05-30

Magnetic resonance imaging is established as a recognizable tool in the diagnosis and monitoring of multiple sclerosis patients. In the present, among multiple sclerosis centers, there are different magnetic resonance imaging sequences and protocols used to study multiple sclerosis that may hamper the optimal use of magnetic resonance imaging in multiple sclerosis. In this context, the Group of Studies of Multiple Sclerosis and the Portuguese Society of Neuroradiology, after a joint discussion, appointed a committee of experts to create recommendations adapted to the national reality on the use of magnetic resonance imaging in multiple sclerosis. The purpose of this document is to publish the first Portuguese consensus recommendations on the use of magnetic resonance imaging in multiple sclerosis in clinical practice. The Group of Studies of Multiple Sclerosis and the Portuguese Society of Neuroradiology, after discussion of the topic in national meetings and after a working group meeting held in Figueira da Foz on May 2017, have appointed a committee of experts that have developed by consensus several standard protocols on the use of magnetic resonance imaging in the diagnosis and follow-up of multiple sclerosis. The document obtained was based on the best scientific evidence and expert opinion. Subsequently, the majority of Portuguese multiple sclerosis consultants and departments of neuroradiology scrutinized and reviewed the consensus paper; comments and suggestions were considered. Technical magnetic resonance imaging protocols regarding diagnostic, monitoring and the recommended information to be included in the magnetic resonance imaging report will be published in a separate paper. We provide some practical guidelines to promote standardized strategies to be applied in the clinical practice setting of Portuguese healthcare professionals regarding the use of magnetic resonance imaging in multiple sclerosis. We hope that these first Portuguese magnetic resonance imaging guidelines, based in the best available clinical evidence and practices, will serve to optimize multiple sclerosis management and improve multiple sclerosis patient care across Portugal.

Epidemiological study of multiple sclerosis in La Rioja.

PubMed

Bártulos Iglesias, M; Marzo Sola, M E; Estrella Ruiz, L A; Bravo Anguiano, Y

2015-01-01

Multiple sclerosis is a demyelinating disease that causes severe disability in younger patients. Many epidemiology studies have confirmed a variable prevalence. The objective of this study was to analyse the prevalence of this disease in La Rioja (Spain), using such variables as age and sex; type of progression, initial form of the disease, EDSS and number of relapses; disease-modifying treatment and reasons for treatment withdrawal; personal and family history of cancer; and incidence and mortality. Analysis of patients in La Rioja diagnosed with MS (according to Poser criteria or the 2005 McDonald criteria) during a 10-year period (2001-2011). Data were collected from hospital records, multiple sclerosis associations, and personal records kept by neurologists. The MS prevalence rate in La Rioja is 65 patients/100 000 inhabitants with an incidence rate of 3.5 cases/100 000 residents per year. Relapsing-remitting MS is present in 67.6% of the patient total. Mean age of onset is 20-29 years (range, 12 to 70). Most EDSS scores were mostly ≤ 2. Untreated MS cases account for 47.6% of the total and the most commonly used therapy is interferon. We detected 4 haematological tumours and 7 families with multiple members affected by MS. Prevalence and incidence are similar to those found in other regions Spain. The average age at onset age for primary progressive MS is slightly higher than in other papers (40-49 years). In families with multiple patients, MS may be more aggressive. Disability in these patients remains very severe. We require more epidemiology studies with a variety of data gathering methods to support findings for prevalence obtained in different provinces. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis.

PubMed

Cawley, Niamh; Solanky, Bhavana S; Muhlert, Nils; Tur, Carmen; Edden, Richard A E; Wheeler-Kingshott, Claudia A M; Miller, David H; Thompson, Alan J; Ciccarelli, Olga

2015-09-01

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population. Thirty patients with secondary progressive multiple sclerosis and 17 healthy control subjects underwent single-voxel MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) magnetic resonance spectroscopy at 3 T, to quantify gamma-aminobutyric acid levels in the prefrontal cortex, right hippocampus and left sensorimotor cortex. All subjects were assessed clinically and underwent a cognitive assessment. Multiple linear regression models were used to compare differences in gamma-aminobutyric acid concentrations between patients and controls adjusting for age, gender and tissue fractions within each spectroscopic voxel. Regression was used to examine the relationships between the cognitive function and physical disability scores specific for these regions with gamma-aminobuytric acid levels, adjusting for age, gender, and total N-acetyl-aspartate and glutamine-glutamate complex levels. When compared with controls, patients performed significantly worse on all motor and sensory tests, and were cognitively impaired in processing speed and verbal memory. Patients had significantly lower gamma-aminobutyric acid levels in the hippocampus (adjusted difference = -0.403 mM, 95% confidence intervals -0.792, -0.014, P = 0.043) and sensorimotor cortex (adjusted difference = -0.385 mM, 95% confidence intervals -0.667, -0.104, P = 0.009) compared with controls. In patients, reduced motor function in the right upper and lower limb was associated with lower gamma-aminobutyric acid concentration in the sensorimotor cortex. Specifically for each unit decrease in gamma-aminobutyric acid levels (in mM), there was a predicted -10.86 (95% confidence intervals -16.786 to -4.482) decrease in grip strength (kg force) (P < 0.001) and -8.74 (95% confidence intervals -13.943 to -3.015) decrease in muscle strength (P < 0.006). This study suggests that reduced gamma-aminobutyric acid levels reflect pathological abnormalities that may play a role in determining physical disability. These abnormalities may include decreases in the pre- and postsynaptic components of gamma-aminobutyric acid neurotransmission and in the density of inhibitory neurons. Additionally, the reduced gamma-aminobutyric acid concentration may contribute to the neurodegenerative process, resulting in increased firing of axons, with consequent increased energy demands, which may lead to neuroaxonal degeneration and loss of the compensatory mechanisms that maintain motor function. This study supports the idea that modulation of gamma-aminobutyric acid neurotransmission may be an important target for neuroprotection in multiple sclerosis.See De Stefano and Giorgio (doi:10.1093/brain/awv213) for a scientific commentary on this article. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Progressive decline of decision-making performances during multiple sclerosis.

PubMed

Simioni, Samanta; Ruffieux, Christiane; Kleeberg, Joerg; Bruggimann, Laure; du Pasquier, Renaud A; Annoni, Jean-Marie; Schluep, Myriam

2009-03-01

The purpose of this study was to evaluate longitudinally, using the Iowa Gambling Task (IGT), the dynamics of decision-making capacity at a two-year interval (median: 2.1 years) in a group of patients with multiple sclerosis (MS) (n = 70) and minor neurological disability [Expanded Disability Status Scale (EDSS) < or = 2.5 at baseline]. Cognition (memory, executive functions, attention), behavior, handicap, and perceived health status were also investigated. Standardized change scores [(score at retest-score at baseline)/standard deviation of baseline score] were computed. Results showed that IGT performances decreased from baseline to retest (from 0.3, SD = 0.4 to 0.1, SD = 0.3, p = .005). MS patients who worsened in the IGT were more likely to show a decreased perceived health status and emotional well-being (SEP-59; p = .05 for both). Relapsing rate, disability progression, cognitive, and behavioral changes were not associated with decreased IGT performances. In conclusion, decline in decision making can appear as an isolated deficit in MS.

A Comparison of Self-Hypnosis Versus Progressive Muscle Relaxation in Patients With Multiple Sclerosis and Chronic Pain1

PubMed Central

Jensen, Mark P.; Barber, Joseph; Romano, Joan M.; Molton, Ivan R.; Raichle, Katherine A.; Osborne, Travis L.; Engel, Joyce M.; Stoelb, Brenda L.; Kraft, George H.; Patterson, David R.

2009-01-01

Twenty-two patients with multiple sclerosis (MS) and chronic pain we recruited into a quasi-experimental trial comparing the effects of self-hypnosis training (HYP) with progressive muscle relaxation (PMR) on pain intensity and pain interference; 8 received HYP and the remaining 14 participants were randomly assigned to receive either HYP or PMR. HYP-condition participants reported significantly greater pre- to postsession as well as pre- to posttreatment decreases in pain and pain interference than PMR-condition participants, and gains were maintained at 3-month follow-up. Most of the participants in both conditions reported that they continued to use the skills they learned in treatment and experienced pain relief when they did so. General hypnotizability was not significantly related to treatment outcome, but treatment-outcome expectancy assessed before and after the first session was. The results support the efficacy of self-hypnosis training for the management of chronic pain in persons with MS. PMID:19234967

Failure to detect genomic material of HTLV-I or HTLV-II in mononuclear cells of Italian patients with multiple sclerosis and chronic progressive myelopathy.

PubMed

Merelli, E; Sola, P; Marasca, R; Salati, R; Torelli, G

1993-01-01

To contribute to the undecided question if a retrovirus of the human T-cell lymphotropic virus (HTLV) family may be involved in the development of multiple sclerosis (MS), we investigated by the polymerase chain reaction (PCR) the presence of HTLV-I and HTLV-II sequences in the peripheral blood mononuclear cell DNAs from 30 patients affected by MS and 15 by chronic progressive myelopathy. Moreover a control group of 14 blood donors was examined. All these patients were devoid of anti-HTLV-I antibody in the serum and cerebrospinal fluid at ELISA. For the PCR, primers and probes specific for the tax region common to HTLV-I and HTLV-II, for the pol region of HTLV-I, and for the pol region of HTLV-II were used. In spite of the high sensitivity of the technique used, the three groups of subjects were negative for HTLV-I and HTLV-II genomic sequences.

Teriflunomide: a once-daily oral medication for the treatment of relapsing forms of multiple sclerosis.

PubMed

Miller, Aaron E

2015-10-01

The purpose was to summarize US prescribing information for teriflunomide in the treatment of patients with relapsing forms of multiple sclerosis (RMS), with reference to clinical efficacy and safety outcomes. In September 2012, the US Food and Drug Administration granted approval for the use of teriflunomide, 14 mg and 7 mg once daily, to treat RMS on the basis of the results of a Phase II study and the Phase III TEMSO (Teriflunomide Multiple Sclerosis Oral) trial. After recent updates to the prescribing information (October 2014), key findings from these and 2 other Phase III clinical trials, TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) and TOPIC (Oral Teriflunomide for Patients with a First Clinical Episode Suggestive of Multiple Sclerosis), and practical considerations for physicians are summarized. Teriflunomide, 14 mg and 7 mg, significantly reduced mean number of unique active lesions on magnetic resonance imaging (MRI; P < 0.05 for both doses) in the Phase II study. In the TEMSO and TOWER studies, the 14-mg dose of teriflunomide significantly reduced annualized relapse rate (31% and 36% relative risk reduction compared with placebo, respectively; both P < 0.001) and risk of disability progression sustained for 12 weeks (hazard ratio vs placebo 0.70 and 0.69, respectively; both P < 0.05). The 7-mg dose significantly (P < 0.02) reduced annualized relapse rate in both studies, although the reduction in risk of disability progression was not statistically significant. Teriflunomide treatment was also associated with significant efficacy on MRI measures of disease activity in TEMSO; both doses significantly reduced total lesion volume and number of gadolinium-enhancing T1 lesions. TOPIC evaluated patients with a first clinical event consistent with acute demyelination and brain MRI lesions characteristic of multiple sclerosis. More patients were free of relapse in the teriflunomide 14-mg and 7-mg groups than in the placebo group (P < 0.05 for both comparisons). In safety data pooled from the 4 studies, adverse events occurring in ≥2% of patients and ≥2% higher than in the placebo group were headache, alanine aminotransferase increase, diarrhea, alopecia (hair thinning), nausea, paresthesia, arthralgia, neutropenia, and hypertension. Routine monitoring procedures before and on treatment are recommended to assess potential safety issues. Women of childbearing potential must use effective contraception and, in the event of pregnancy, undergo an accelerated elimination procedure to reduce plasma concentrations of teriflunomide. Clinical evidence suggests that teriflunomide is an effective therapeutic choice for patients with RMS, both as an initial treatment and as an alternative for patients who may have experienced intolerance or inadequate response to a previous or current disease-modifying therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Treatment against human endogenous retrovirus: a possible personalized medicine approach for multiple sclerosis.

PubMed

Curtin, François; Perron, Hervé; Faucard, Raphael; Porchet, Hervé; Lang, Alois B

2015-10-01

Human endogenous retroviruses (HERV) represent about 8 % of the human genome. Some of these genetic elements are expressed in pathological circumstances. A HERV protein, the multiple sclerosis-associated retrovirus (MSRV) envelope protein (MSRV-Env), is expressed in the blood and active brain lesions of multiple sclerosis (MS) patients. It possesses pro-inflammatory and myelinotoxic properties. The patterns of expression and pathogenic properties of MSRV-Env make it a relevant drug target for MS therapeutics-in particular for preventing neurodegeneration, a key component of progressive forms of MS. An immunoglobulin G4 monoclonal antibody (mAb), called GNbAC1, has been developed to neutralize this pathogenic target. After showing neutralizing effects in vitro and in mouse models of MS, GNbAC1 is now in phase II clinical development. MSRV-related biomarkers such as MSRV-Env and MSRV polymerase (MSRV-Pol) gene transcripts are overexpressed in the blood and cerebrospinal fluid of patients with MS. These biomarkers may have prognostic value for long-term MS evolution, and their transcription levels in blood decline during treatments with GNbAC1, which has also been reported in patients administered reference MS drugs such as natalizumab or interferon-β. GNbAC1 as a new MSRV-Env-antagonist mAb could be a specific and causal treatment for MS, with a particular application for progressive forms of the disease. For possible use in companion diagnostic tests, MSRV-associated biomarkers could open the door to a personalized therapeutic approach for MS.

Efficacy of Fish Oil on Serum of TNFα, IL-1β, and IL-6 Oxidative Stress Markers in Multiple Sclerosis Treated with Interferon Beta-1b

PubMed Central

Ramirez-Ramirez, V.; Macias-Islas, M. A.; Ortiz, G. G.; Pacheco-Moises, F.; Torres-Sanchez, E. D.; Sorto-Gomez, T. E.; Cruz-Ramos, J. A.; Orozco-Aviña, G.; Celis de la Rosa, A. J.

2013-01-01

Multiple sclerosis (MS) is a chronic inflammatory disease, which leads to focal plaques of demyelination and tissue injury in the central nervous system. Oxidative stress is also thought to promote tissue damage in multiple sclerosis. Current research findings suggest that omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapenta-enoic acid (EPA) and docosahexaenoic acid (DHA) contained in fish oil may have anti-inflammatory, antioxidant, and neuroprotective effects. The aim of the present work was to evaluate the efficacy of fish oil supplementation on serum proinflammatory cytokine levels, oxidative stress markers, and disease progression in MS. 50 patients with relapsing-remitting MS were enrolled. The experimental group received orally 4 g/day of fish oil for 12 months. The primary outcome was serum TNFα levels; secondary outcomes were IL-1β 1b, IL-6, nitric oxide catabolites, lipoperoxides, progression on the expanded disability status scale (EDSS), and annualized relapses rate (ARR). Fish oil treatment decreased the serum levels of TNFα, IL-1β, IL-6, and nitric oxide metabolites compared with placebo group (P ≤ 0.001). There was no significant difference in serum lipoperoxide levels during the study. No differences in EDSS and ARR were found. Conclusion. Fish oil supplementation is highly effective in reducing the levels of cytokines and nitric oxide catabolites in patients with relapsing-remitting MS. PMID:23861993

Care Partners and Multiple Sclerosis

PubMed Central

Quig, Mary Elizabeth; Tyry, Tuula; Marrie, Ruth Ann; Cutter, Gary; Shearin, Edward; Johnson, Kamau; Simsarian, James

2015-01-01

Background: Caring for someone with multiple sclerosis (MS) can be a stressful experience that requires clinical attention. We investigated the impact of caregiver stress on the emotional well-being and physical health of the MS care partner using the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. Methods: Care partners of NARCOMS participants were invited to complete an online questionnaire that captured demographic characteristics, health status, caregiver burden as measured by the Zarit Caregiver Burden Interview, and impact of caregiving on employment. Results: Of 1446 care partners who agreed to participate, 1333 had complete data. Most were men (n = 825, 61.9%), with a mean (SD) age of 51.1 (11.2) years. The mean (SD) Zarit total score was 24.6 (15.1), placing the overall group in the mild caregiver burden range. Compared with male care partners, female care partners reported higher levels of burden and stress and more medication use for stress/anxiety and mood disorders. Male care partners were more likely to report physical concerns. Care partners of people with primary progressive MS reported greater perceived burden than did partners of people with secondary progressive MS and relapsing-remitting MS. More than 40% of care partners (559 of 1288) had missed work during the past year owing to caregiving responsibilities. Conclusions: Care partners of people with MS have substantial physical and psychological health concerns and experience an adverse impact on employment. Future research should evaluate how to mitigate the adverse effects of caregiving and evaluate positive aspects of the role. PMID:26664330

Localized grey matter damage in early primary progressive multiple sclerosis contributes to disability.

PubMed

Khaleeli, Z; Cercignani, M; Audoin, B; Ciccarelli, O; Miller, D H; Thompson, A J

2007-08-01

Disability in primary progressive multiple sclerosis (PPMS) has been correlated with damage to the normal appearing brain tissues. Magnetization transfer ratio (MTR) and volume changes indicate that much of this damage occurs in the normal appearing grey matter, but the clinical significance of this remains uncertain. We aimed to localize these changes to distinct grey matter regions, and investigate the clinical impact of the MTR changes. 46 patients with early PPMS and 23 controls underwent MT and high-resolution T1-weighted imaging. Patients were scored on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite and subtests (Nine-Hole Peg Test, Timed Walk Test, Paced Auditory Serial Addition Test [PASAT]). Grey matter volume and MTR were compared between patients and controls, adjusting for age. Mean MTR for significant regions within the motor network and in areas relevant to PASAT performance were correlated with appropriate clinical scores, adjusting for grey matter volume. Patients showed reduced MTR and atrophy in the right pre- and left post-central gyri, right middle frontal gyrus, left insula, and thalamus bilaterally. Reduced MTR without significant atrophy occurred in the left pre-central gyrus, left superior frontal gyri, bilateral superior temporal gyri, right insula and visual cortex. Higher EDSS correlated with lower MTR in the right primary motor cortex (BA 4). In conclusion, localized grey matter damage occurs in early PPMS, and MTR change is more widespread than atrophy. Damage demonstrated by reduced MTR is clinically eloquent.

A composite measure to explore visual disability in primary progressive multiple sclerosis.

PubMed

Poretto, Valentina; Petracca, Maria; Saiote, Catarina; Mormina, Enricomaria; Howard, Jonathan; Miller, Aaron; Lublin, Fred D; Inglese, Matilde

2017-01-01

Optical coherence tomography (OCT) and magnetic resonance imaging (MRI) can provide complementary information on visual system damage in multiple sclerosis (MS). The objective of this paper is to determine whether a composite OCT/MRI score, reflecting cumulative damage along the entire visual pathway, can predict visual deficits in primary progressive multiple sclerosis (PPMS). Twenty-five PPMS patients and 20 age-matched controls underwent neuro-ophthalmologic evaluation, spectral-domain OCT, and 3T brain MRI. Differences between groups were assessed by univariate general linear model and principal component analysis (PCA) grouped instrumental variables into main components. Linear regression analysis was used to assess the relationship between low-contrast visual acuity (LCVA), OCT/MRI-derived metrics and PCA-derived composite scores. PCA identified four main components explaining 80.69% of data variance. Considering each variable independently, LCVA 1.25% was significantly predicted by ganglion cell-inner plexiform layer (GCIPL) thickness, thalamic volume and optic radiation (OR) lesion volume (adjusted R 2 0.328, p  = 0.00004; adjusted R 2 0.187, p  = 0.002 and adjusted R 2 0.180, p  = 0.002). The PCA composite score of global visual pathway damage independently predicted both LCVA 1.25% (adjusted R 2 value 0.361, p  = 0.00001) and LCVA 2.50% (adjusted R 2 value 0.323, p  = 0.00003). A multiparametric score represents a more comprehensive and effective tool to explain visual disability than a single instrumental metric in PPMS.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

PubMed

Hauser, Stephen L; Bar-Or, Amit; Comi, Giancarlo; Giovannoni, Gavin; Hartung, Hans-Peter; Hemmer, Bernhard; Lublin, Fred; Montalban, Xavier; Rammohan, Kottil W; Selmaj, Krzysztof; Traboulsee, Anthony; Wolinsky, Jerry S; Arnold, Douglas L; Klingelschmitt, Gaelle; Masterman, Donna; Fontoura, Paulo; Belachew, Shibeshih; Chin, Peter; Mairon, Nicole; Garren, Hideki; Kappos, Ludwig

2017-01-19

B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T 1 -weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Amyotrophic lateral sclerosis progression and stability of brain-computer interface communication.

PubMed

Silvoni, Stefano; Cavinato, Marianna; Volpato, Chiara; Ruf, Carolin A; Birbaumer, Niels; Piccione, Francesco

2013-09-01

Our objective was to investigate the relationship between brain-computer interface (BCI) communication skill and disease progression in amyotrophic lateral sclerosis (ALS). We sought also to assess stability of BCI communication performance over time and whether it is related to the progression of neurological impairment before entering the locked-in state. A three years follow-up, BCI evaluation in a group of ALS patients (n = 24) was conducted. For a variety of reasons only three patients completed the three years follow-up. BCI communication skill and disability level, using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, were assessed at admission and at each of the three follow-ups. Multiple non-parametric statistical methods were used to ensure reliability of the dependent variables: correlations, paired test and factor analysis of variance. Results demonstrated no significant relationship between BCI communication skill (BCI-CS) and disease evolution. The patients who performed the follow-up evaluations preserved their BCI-CS over time. Patients' age at admission correlated positively with the ability to achieve control over a BCI. In conclusion, disease evolution in ALS does not affect the ability to control a BCI for communication. BCI performance can be maintained in the different stages of the illness.

Treatment of Cognitive Impairment in Multiple Sclerosis

PubMed Central

Pierson, Susan H.; Griffith, Nathan

2006-01-01

Cognitive impairment in multiple sclerosis is an increasingly recognized entity. This article reviews the cognitive impairment of multiple sclerosis, its prevalence, its relationship to different types of multiple sclerosis, and its contribution to long-term functional prognosis. The discussion also focuses on the key elements of cognitive dysfunction in multiple sclerosis which distinguish it from other forms of cognitive impairment. Therapeutic interventions potentially effective for the cognitive impairment of multiple sclerosis are reviewed including the effects of disease modifying therapies and the use of physical and cognitive interventions. PMID:16720960

Quantitative analysis of the pendulum test: application to multiple sclerosis patients treated with botulinum toxin.

PubMed

Bianchi, L; Monaldi, F; Paolucci, S; Iani, C; Lacquaniti, F

1999-01-01

The aim of this study was to develop quantitative analytical methods in the application of the pendulum test to both normal and spastic subjects. The lower leg was released by a torque motor from different starting positions. The resulting changes in the knee angle were fitted by means of a time-varying model. Stiffness and viscosity coefficients were derived for each half-cycle oscillation in both flexion and extension, and for all knee starting positions. This method was applied to the assessment of the effects of Botulinum toxin A (BTX) in progressive multiple sclerosis patients in a follow-up study. About half of the patients showed a significant decrement in stiffness and viscosity coefficients.

The Gas6/TAM System and Multiple Sclerosis.

PubMed

Bellan, Mattia; Pirisi, Mario; Sainaghi, Pier Paolo

2016-10-28

Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done in the understanding of the biological activities of this highly pleiotropic system, which plays a role in the regulation of immune response, inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Recent findings have further related Gas6 and TAM receptors to neuroinflammation in general and, specifically, to multiple sclerosis (MS). In this paper, we review the biology of the Gas6/TAM system and the current evidence supporting its potential role in the pathogenesis of MS.

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.

PubMed

Ball, Susan; Vickery, Jane; Hobart, Jeremy; Wright, Dave; Green, Colin; Shearer, James; Nunn, Andrew; Cano, Mayam Gomez; MacManus, David; Miller, David; Mallik, Shahrukh; Zajicek, John

2015-02-01

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. Twenty-seven UK sites. Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. Three and 6 months, and then 6-monthly up to 36 or 42 months. Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. Current Controlled Trials ISRCTN62942668. The National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

Proteomic Analysis of Cerebrospinal Fluid in a Fulminant Case of Multiple Sclerosis

PubMed Central

Füvesi, Judit; Hanrieder, Jörg; Bencsik, Krisztina; Rajda, Cecilia; Kovács, S. Krisztián; Kaizer, László; Beniczky, Sándor; Vécsei, László; Bergquist, Jonas

2012-01-01

Multiple Sclerosis (MS) is a chronic disease, but in rare fulminant cases rapid progression may lead to death shortly after diagnosis. Currently there is no diagnostic test to predict disease course. The aim of this study was to identify potential biomarkers/proteins related to rapid progression. We present the case history of a 15-year-old male MS patient. Cerebrospinal fluid (CSF) was taken at diagnosis and at the time of rapid progression leading to the patient’s death. Using isobaric tag labeling and nanoflow liquid chromatography in conjunction with matrix assisted laser desorption/ionization time of flight tandem mass spectrometry we quantitatively analyzed the protein content of two CSF samples from the patient with fulminant MS as well as one relapsing-remitting (RR) MS patient and one control headache patient, whose CSF analysis was normal. Seventy-eight proteins were identified and seven proteins were found to be more abundant in both fulminant MS samples but not in the RR MS sample compared to the control. These proteins are involved in the immune response, blood coagulation, cell proliferation and cell adhesion. In conclusion, in this pilot study we were able to show differences in the CSF proteome of a rapidly progressing MS patient compared to a more typical clinical form of MS and a control subject. PMID:22837721

Role of dimethyl fumarate in oxidative stress of multiple sclerosis: A review.

PubMed

Suneetha, A; Raja Rajeswari, K

2016-04-15

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS affecting both white and grey matter. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis. Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapy with dimethyl fumarate. The clinical utility of DMF in multiple sclerosis is being explored through phase III trials with BG-12, which is an oral therapeutic agent. Currently a wide research is going on to find out the exact mechanism of DMF, till date it is not clear. Based on strong signals of nephrotoxicity in non-humans and the theoretical risk of renal cell cancer from intracellular accumulation of fumarate, post-marketing study of a large population of patients will be necessary to fully assess the long-term safety of dimethyl fumarate. The current treatment goals are to shorten the duration and severity of relapses, prolong the time between relapses, and delay progression of disability. In this regard, dimethyl fumarate offers a promising alternative to orally administered fingolimod (GILENYA) or teriflunomide (AUBAGIO), which are currently marketed in the United States under FDA-mandated Risk Evaluation and Mitigation Strategy (REMS) programs because of serious safety concerns. More clinical experience with all three agents will be necessary to differentiate the tolerability of long-term therapy for patients diagnosed with multiple sclerosis. This write-up provides the detailed information of dimethyl fumarate in treating the neuro disease, multiple sclerosis and its mechanism involved via oxidative stress pathway. The rapid screening methods are also need to be developed to estimate DMF in biological samples to perform and proceed for further investigations. Copyright © 2016 Elsevier B.V. All rights reserved.

Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis.

PubMed

Singh, Shailender; Dallenga, Tobias; Winkler, Anne; Roemer, Shanu; Maruschak, Brigitte; Siebert, Heike; Brück, Wolfgang; Stadelmann, Christine

2017-03-17

Axonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination. Wallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions. Furthermore, we studied the effects of Wallerian degeneration blockage on clinical severity, inflammatory pathology, acute axonal damage, and long-term axonal loss in experimental autoimmune encephalomyelitis using Wallerian degeneration slow (Wld S ) mutant mice. The highest numbers of axons undergoing Wallerian degeneration were found in the perilesional white matter of multiple sclerosis patients early in the disease course and with actively demyelinating lesions. Furthermore, Wallerian degeneration was more abundant in patients harboring chronic active as compared to chronic inactive lesions. No co-localization of neuropeptide Y-Y1 receptor, a bona fide immunohistochemical marker of Wallerian degeneration, with amyloid precursor protein, frequently used as an indicator of acute axonal transport disturbance, was observed in human and mouse tissue, indicating distinct axon-degenerative processes. Experimentally, a delay of Wallerian degeneration, as observed in Wld S mice, did not result in a reduction of clinical disability or acute axonal damage in experimental autoimmune encephalomyelitis, further supporting that acute axonal damage as reflected by axonal transport disturbances does not share common molecular mechanisms with Wallerian degeneration. Furthermore, delaying Wallerian degeneration did not result in a net rescue of axons in late lesion stages of experimental autoimmune encephalomyelitis. Our data indicate that in multiple sclerosis, ongoing demyelination in focal lesions is associated with axonal degeneration in the perilesional white matter, supporting a role for focal pathology in diffuse white matter damage. Also, our results suggest that interfering with Wallerian degeneration in inflammatory demyelination does not suffice to prevent acute axonal damage and finally axonal loss.

Self-reported levels of education and disability progression in multiple sclerosis.

PubMed

D'hooghe, M B; Haentjens, P; Van Remoortel, A; De Keyser, J; Nagels, G

2016-12-01

The purpose of our study is to investigate whether socioeconomic indicators such as education, financial concerns, employment, and living status are associated with disease progression in relapsing-onset and progressive-onset Multiple Sclerosis (MS). We performed a cross-sectional survey among individuals with MS, registered by the Flemish MS society and included socioeconomic indicators. A Cox proportional hazard regression was performed with the time from MS onset and from birth to reach an ambulatory disability milestone corresponding to Expanded Disability Status Scale (EDSS) 6 (requiring a cane) as outcome measure, adjusted for gender, age at MS onset, and immunomodulatory treatment. Among the participants with relapsing-onset MS, subjects reporting education for more than 12 years had a reduced risk of reaching EDSS 6 compared to subjects reporting education for less than 12 years [HR from onset 0.68 (95% CI 0.49-0.95); HR from birth 0.71 (95% CI 0.51-0.99)]. In progressive-onset MS, longer education was associated with an increased hazard to reach EDSS 6 [HR from onset 1.25 (95% CI 0.91-1.70); HR from birth 1.39 (95% CI 1.02-1.90)]. Our study shows an association of self-reported levels of education with disability progression in MS, with the highest level being protective in relapsing-onset MS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

CSF profile in primary progressive multiple sclerosis: Re-exploring the basics.

PubMed

Abdelhak, Ahmed; Hottenrott, Tilman; Mayer, Christoph; Hintereder, Gudrun; Zettl, Uwe K; Stich, Oliver; Tumani, Hayrettin

2017-01-01

The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS). The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease. The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS. We present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role.

Treatment of multiple sclerosis with interferon β: an appraisal of cost-effectiveness and quality of life

PubMed Central

Parkin, D.; Jacoby, A.; McNamee, P.; Miller, P.; Thomas, S.; Bates, D.

2000-01-01

OBJECTIVE—To evaluate the cost-effectiveness of interferon beta-1b (IFβ-1b) for relapsing-remitting multiple sclerosis (RRMS).
METHODS—Construction of a cost-effectiveness model using published data on IFβ-1b effectiveness and the natural history of RRMS, and new data on costs and quality of life (QoL) from a sample of 102patients with RRMS and resident in northern England.
RESULTS—Poorer QoL was found for patients with multiple sclerosis compared with the general population; those who had had a relapse; those with worse states identified by a clinical measure (expanded disability status scale (EDSS)). Relapses have effects over several months. Health state valuations were higher than in the general population. Costs were higher in relapse than remission and for worse EDSS states. IFβ-1b costs were larger than cost savings. The best cost-effectiveness estimate was £28 700 per relapse avoided, which is £809 900 per QALY gained; or £328 300 per QALY gained allowing for effects of progression over 5 years. Estimates were robust to changes in assumptions.
CONCLUSIONS—The impact of multiple sclerosis on QoL is substantial. Future trials should base outcomes measurement on QoL and be better linked to natural history and cost data. IFβ-1b produces important occasional short term QoL gains, but small gains in QALYs overall and large additional costs.

 PMID:10644777

Multiple sclerosis affects the frequency content in the vertical ground reaction forces during walking.

PubMed

Wurdeman, Shane R; Huisinga, Jessie M; Filipi, Mary; Stergiou, Nicholas

2011-02-01

Multiple sclerosis is a progressive neurological disease that results in a high incident of gait disturbance. Exploring the frequency content of the ground reaction forces generated during walking may provide additional insights to gait in patients with multiple sclerosis that could lead to specific tools for differential diagnosis. The purpose of this study was to investigate differences in the frequency content of these forces in an effort to contribute to improved clinical management of this disease. Eighteen patients and eighteen healthy controls walked across a 10 meter long walkway. The anterior-posterior and vertical ground reaction forces generated during the stance phase of gait were evaluated in the frequency domain using fast Fourier transformation. T-tests were utilized for comparison of median frequency, the 99.5% frequency, and the frequency bandwidth between patients and healthy controls and also for comparisons between patients with mild and moderate severity. Patients with multiple sclerosis had significantly lower 99.5% frequency (P=0.006) and median frequency (P<0.001) in the vertical ground reaction force. No differences were found in the anterior-posterior reaction force frequency content. There were no differences between patients with mild and moderate severity. The lower frequency content suggests lesser vertical oscillation of the center of gravity. Lack of differences between severities may suggest presence of differences prior to currently established diagnosis timelines. Analysis of the frequency content may potentially serve to provide earlier diagnostic assessment of this debilitating disease. Copyright © 2010 Elsevier Ltd. All rights reserved.

"Disease modifying nutricals" for multiple sclerosis.

PubMed

Schmitz, Katja; Barthelmes, Julia; Stolz, Leonie; Beyer, Susanne; Diehl, Olaf; Tegeder, Irmgard

2015-04-01

The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3-gallate, curcumin and the mustard oil glycoside from e.g. broccoli and sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF-κB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. Copyright © 2014 Elsevier Inc. All rights reserved.

Global and 3D Spatial Assessment of Neuroinflammation in Rodent Models of Multiple Sclerosis

PubMed Central

Gupta, Shashank; Utoft, Regine; Hasseldam, Henrik; Schmidt-Christensen, Anja; Hannibal, Tine Dahlbaek; Hansen, Lisbeth; Fransén-Pettersson, Nina; Agarwal-Gupta, Noopur; Rozell, Björn; Andersson, Åsa; Holmberg, Dan

2013-01-01

Multiple Sclerosis (MS) is a progressive autoimmune inflammatory and demyelinating disease of the central nervous system (CNS). T cells play a key role in the progression of neuroinflammation in MS and also in the experimental autoimmune encephalomyelitis (EAE) animal models for the disease. A technology for quantitative and 3 dimensional (3D) spatial assessment of inflammation in this and other CNS inflammatory conditions is much needed. Here we present a procedure for 3D spatial assessment and global quantification of the development of neuroinflammation based on Optical Projection Tomography (OPT). Applying this approach to the analysis of rodent models of MS, we provide global quantitative data of the major inflammatory component as a function of the clinical course. Our data demonstrates a strong correlation between the development and progression of neuroinflammation and clinical disease in several mouse and a rat model of MS refining the information regarding the spatial dynamics of the inflammatory component in EAE. This method provides a powerful tool to investigate the effect of environmental and genetic forces and for assessing the therapeutic effects of drug therapy in animal models of MS and other neuroinflammatory/neurodegenerative disorders. PMID:24124545

Effect of optic neuritis on progressive axonal damage in multiple sclerosis patients.

PubMed

Garcia-Martin, E; Pueyo, V; Ara, J R; Almarcegui, C; Martin, J; Pablo, L; Dolz, I; Sancho, E; Fernandez, F J

2011-07-01

The objective of this research was to study the effect of optic neuritis (ON) on axonal damage in multiple sclerosis (MS) patients. Specifically, we compared changes over 2 years in the retinal nerve fibre layer (RNFL) between affected and contralateral eyes in MS patients with a prior history of ON. Thirty-four patients with one unilateral definitive episode of ON were included and underwent a complete ophthalmic examination, optical coherence tomography (OCT), scanning laser polarimetry, visual evoked potentials (VEP) and pattern electroretinogram (pERG). All patients were re-evaluated at 12 and 24 months. Parameters were compared between ON-affected and contralateral eyes in an initial exploration and over the course of the follow-up. Correlations between parameter changes were analysed. RNFL thickness and functional parameters showed more affection in ON eyes (p ≤ 0.05), but changes in measurements during the study were similar between both groups of eyes. Progressive axonal loss can be detected in the optic nerve, but ON is not a risk factor for increased chronic damage in MS patients without ophthalmic relapses. Loss of the RNFL is caused by progressive degeneration associated with the disease.

Information processing efficiency in patients with multiple sclerosis.

PubMed

Archibald, C J; Fisk, J D

2000-10-01

Reduced information processing efficiency, consequent to impaired neural transmission, has been proposed as underlying various cognitive problems in patients with Multiple Sclerosis (MS). This study employed two measures developed from experimental psychology that control for the potential confound of perceptual-motor abnormalities (Salthouse, Babcock, & Shaw, 1991; Sternberg, 1966, 1969) to assess the speed of information processing and working memory capacity in patients with mild to moderate MS. Although patients had significantly more cognitive complaints than neurologically intact matched controls, their performance on standard tests of immediate memory span did not differ from control participants and their word list learning was within normal limits. On the experimental measures, both relapsing-remitting and secondary-progressive patients exhibited significantly slowed information processing speed relative to controls. However, only the secondary-progressive patients had an additional decrement in working memory capacity. Depression, fatigue, or neurologic disability did not account for performance differences on these measures. While speed of information processing may be slowed early in the disease process, deficits in working memory capacity may appear only as there is progression of MS. It is these latter deficits, however, that may underlie the impairment of new learning that patients with MS demonstrate.

In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis.

PubMed

Granberg, Tobias; Fan, Qiuyun; Treaba, Constantina Andrada; Ouellette, Russell; Herranz, Elena; Mangeat, Gabriel; Louapre, Céline; Cohen-Adad, Julien; Klawiter, Eric C; Sloane, Jacob A; Mainero, Caterina

2017-11-01

Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems

PubMed Central

Herrando-Grabulosa, Mireia; Mulet, Roger; Pujol, Albert; Mas, José Manuel; Navarro, Xavier; Aloy, Patrick; Coma, Mireia; Casas, Caty

2016-01-01

Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis. PMID:26807587

Supratentorial lesions contribute to trigeminal neuralgia in multiple sclerosis.

PubMed

Fröhlich, Kilian; Winder, Klemens; Linker, Ralf A; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Hilz, Max J; Schwab, Stefan; Seifert, Frank

2018-06-01

Background It has been proposed that multiple sclerosis lesions afflicting the pontine trigeminal afferents contribute to trigeminal neuralgia in multiple sclerosis. So far, there are no imaging studies that have evaluated interactions between supratentorial lesions and trigeminal neuralgia in multiple sclerosis patients. Methods We conducted a retrospective study and sought multiple sclerosis patients with trigeminal neuralgia and controls in a local database. Multiple sclerosis lesions were manually outlined and transformed into stereotaxic space. We determined the lesion overlap and performed a voxel-wise subtraction analysis. Secondly, we conducted a voxel-wise non-parametric analysis using the Liebermeister test. Results From 12,210 multiple sclerosis patient records screened, we identified 41 patients with trigeminal neuralgia. The voxel-wise subtraction analysis yielded associations between trigeminal neuralgia and multiple sclerosis lesions in the pontine trigeminal afferents, as well as larger supratentorial lesion clusters in the contralateral insula and hippocampus. The non-parametric statistical analysis using the Liebermeister test yielded similar areas to be associated with multiple sclerosis-related trigeminal neuralgia. Conclusions Our study confirms previous data on associations between multiple sclerosis-related trigeminal neuralgia and pontine lesions, and showed for the first time an association with lesions in the insular region, a region involved in pain processing and endogenous pain modulation.

Therapeutic neuroprotective agents for amyotrophic lateral sclerosis

PubMed Central

Pandya, Rachna S.; Zhu, Haining; Li, Wei; Bowser, Robert; Friedlander, Robert M.

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a fatal chronic neurodegenerative disease whose hallmark is proteinaceous, ubiquitinated, cytoplasmic inclusions in motor neurons and surrounding cells. Multiple mechanisms proposed as responsible for ALS pathogenesis include dysfunction of protein degradation, glutamate excitotoxicity, mitochondrial dysfunction, apoptosis, oxidative stress, and inflammation. It is therefore essential to gain a better understanding of the underlying disease etiology and search for neuroprotective agents that might delay disease onset, slow progression, prolong survival, and ultimately reduce the burden of disease. Because riluzole, the only Food and Drug Administration (FDA)-approved treatment, prolongs the ALS patient’s life by only 3 months, new therapeutic agents are urgently needed. In this review, we focus on studies of various small pharmacological compounds targeting the proposed pathogenic mechanisms of ALS and discuss their impact on disease progression. PMID:23864030

The "Yin" and "Yang" of Cell Cycle Progression and Differentiation in the Oligodendroglial Lineage

ERIC Educational Resources Information Center

Nguyen, Laurent; Borgs, Laurence; Vandenbosch, Renaud; Mangin, Jean-Marie; Beukelaers, Pierre; Moonen, Gustave; Gallo, Vittorio; Malgrange, Brigitte; Belachew, Shibeshih

2006-01-01

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor cells involves errors in the sequence of events that normally occur during development when progenitors proliferate, migrate through the white…

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study.

PubMed

Kappos, Ludwig; Bar-Or, Amit; Cree, Bruce A C; Fox, Robert J; Giovannoni, Gavin; Gold, Ralf; Vermersch, Patrick; Arnold, Douglas L; Arnould, Sophie; Scherz, Tatiana; Wolf, Christian; Wallström, Erik; Dahlke, Frank

2018-03-31

No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3·0-6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65-0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Novartis Pharma AG. Copyright © 2018 Elsevier Ltd. All rights reserved.

Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm.

PubMed

Giovannoni, Gavin

2018-06-01

The treatment of multiple sclerosis is evolving rapidly with 11 classes of disease-modifying therapies (DMTs). This article provides an overview of a new classification system for DMTs and treatment paradigm for using these DMTs effectively and safely. A summary of research into the use of more active approaches to early and effective treatment of multiple sclerosis with defined treatment targets of no evident disease activity (NEDA). New insights are discussed that is allowing the field to begin to tackle more advanced multiple sclerosis, including people with multiple sclerosis using wheelchairs. However, the need to modify expectations of what can be achieved in more advanced multiple sclerosis are discussed; in particular, the focus on neuronal systems with reserve capacity, for example, upper limb, bulbar and visual function. The review describes a new more active way of managing multiple sclerosis and concludes with a call to action in solving the problem of slow adoption of innovations and the global problem of untreated, or undertreated, multiple sclerosis.

Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions

PubMed Central

Mehta, Veela; Pei, Wei; Yang, Grant; Li, Suyang; Swamy, Eashwar; Boster, Aaron; Schmalbrock, Petra; Pitt, David

2013-01-01

MRI phase imaging in multiple sclerosis (MS) patients and in autopsy tissue have demonstrated the presence of iron depositions in white matter lesions. The accumulation of iron in some but not all lesions suggests a specific, potentially disease-relevant process, however; its pathophysiological significance remains unknown. Here, we explore the role of lesional iron in multiple sclerosis using multiple approaches: immunohistochemical examination of autoptic MS tissue, an in vitro model of iron-uptake in human cultured macrophages and ultra-highfield phase imaging of highly active and of secondary progressive MS patients. Using Perls' stain and immunohistochemistry, iron was detected in MS tissue sections predominantly in non-phagocytosing macrophages/microglia at the edge of established, demyelinated lesions. Moreover, iron-containing macrophages but not myelin-laden macrophages expressed markers of proinflammatory (M1) polarization. Similarly, in human macrophage cultures, iron was preferentially taken up by non-phagocytosing, M1-polarized macrophages and induced M1 (super) polarization. Iron uptake was minimal in myelin-laden macrophages and active myelin phagocytosis led to depletion of intracellular iron. Finally, we demonstrated in MS patients using GRE phase imaging with ultra-highfield MRI that phase hypointense lesions were significantly more prevalent in patients with active relapsing than with secondary progressive MS. Taken together, our data provide a basis to interpret iron-sensitive GRE phase imaging in MS patients: iron is present in non-phagocytosing, M1-polarized microglia/macrophages at the rim of chronic active white matter demyelinating lesions. Phase imaging may therefore visualize specific, chronic proinflammatory activity in established MS lesions and thus provide important clinical information on disease status and treatment efficacy in MS patients. PMID:23516409

Nutraceuticals against Neurodegeneration: A Mechanistic Insight.

PubMed

Dadhania, Vivekkumar P; Trivedi, Priyanka P; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer`s disease (AD), Parkinson`s disease (PD), Huntington`s disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.

Nutraceuticals against Neurodegeneration: A Mechanistic Insight

PubMed Central

Dadhania, Vivekkumar P.; Trivedi, Priyanka P.; Vikram, Ajit; Tripathi, Durga Nand

2016-01-01

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca2+ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways. PMID:26725888

Coexistence of multiple sclerosis and ankylosing spondylitis: Report of four cases from Russia and review of the literature.

PubMed

Fominykh, Vera; Shevtsova, Tatyana; Arzumanian, Narine; Brylev, Lev

2017-10-01

Multiple sclerosis is a chronic demyelinating disorder of the central nervous system. There are many cases of multiple sclerosis - like syndrome and demyelinating disorders in systemic lupus erythematosus, Sjogren disease, Behcet disease and other autoimmune conditions. Coexistence of ankylosing spondylitis and multiple sclerosis usually is rare but in this article we report 4 Russian patients with concomitant multiple sclerosis and ankylosing spondylitis diseases. None of these patients received anti-tumor necrosis factor alpha therapy prior to diagnosis of multiple sclerosis. Pathogenesis, diagnostic and treatment challenges are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood.

PubMed

Keshari, Pankaj K; Harbo, Hanne F; Myhr, Kjell-Morten; Aarseth, Jan H; Bos, Steffan D; Berge, Tone

2016-04-14

Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown. Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele. Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.

A web-based decision support tool for prognosis simulation in multiple sclerosis.

PubMed

Veloso, Mário

2014-09-01

A multiplicity of natural history studies of multiple sclerosis provides valuable knowledge of the disease progression but individualized prognosis remains elusive. A few decision support tools that assist the clinician in such task have emerged but have not received proper attention from clinicians and patients. The objective of the current work is to implement a web-based tool, conveying decision relevant prognostic scientific evidence, which will help clinicians discuss prognosis with individual patients. Data were extracted from a set of reference studies, especially those dealing with the natural history of multiple sclerosis. The web-based decision support tool for individualized prognosis simulation was implemented with NetLogo, a program environment suited for the development of complex adaptive systems. Its prototype has been launched online; it enables clinicians to predict both the likelihood of CIS to CDMS conversion, and the long-term prognosis of disability level and SPMS conversion, as well as assess and monitor the effects of treatment. More robust decision support tools, which convey scientific evidence and satisfy the needs of clinical practice by helping clinicians discuss prognosis expectations with individual patients, are required. The web-based simulation model herein introduced proposes to be a step forward toward this purpose. Copyright © 2014 Elsevier B.V. All rights reserved.

Does vagotomy protect against multiple sclerosis?

PubMed

Sundbøll, Jens; Horváth-Puhó, Erzsébet; Adelborg, Kasper; Svensson, Elisabeth

2017-07-01

To examine the association between vagotomy and multiple sclerosis. We conducted a matched cohort study of all patients who underwent truncal or super-selective vagotomy and a comparison cohort, by linking Danish population-based medical registries (1977-1995). Hazard ratios (HRs) for multiple sclerosis, adjusting for potential confounders were computed by means of Cox regression analysis. Median age of multiple sclerosis onset corresponded to late onset multiple sclerosis. No association with multiple sclerosis was observed for truncal vagotomy (0-37 year adjusted HR=0.91, 95% confidence interval [CI]: 0.48-1.74) or super-selective vagotomy (0-37 year adjusted HR=1.28, 95% CI: 0.79-2.09) compared with the general population. We found no association between vagotomy and later risk of late onset multiple sclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Which symptoms contribute the most to patients' perception of health in multiple sclerosis?

PubMed

Green, Rivka; Cutter, Gary; Friendly, Michael; Kister, Ilya

2017-01-01

Multiple sclerosis is a polysymptomatic disease. Little is known about relative contributions of the different multiple sclerosis symptoms to self-perception of health. To investigate the relationship between symptom severity in 11 domains affected by multiple sclerosis and self-rated health. Multiple sclerosis patients in two multiple sclerosis centers assessed self-rated health with a validated instrument and symptom burden with symptoMScreen, a validated battery of Likert scales for 11 domains commonly affected by multiple sclerosis. Pearson correlations and multivariate linear regressions were used to investigate the relationship between symptoMScreen scores and self-rated health. Among 1865 multiple sclerosis outpatients (68% women, 78% with relapsing-remitting multiple sclerosis, mean age 46.38 ± 12.47 years, disease duration 13.43 ± 10.04 years), average self-rated health score was 2.30 ('moderate to good'). Symptom burden (composite symptoMScreen score) highly correlated with self-rated health ( r  = 0.68, P  < 0.0001) as did each of the symptoMScreen domain subscores. In regression analysis, pain ( t  = 7.00), ambulation ( t  = 6.91), and fatigue ( t  = 5.85) contributed the highest amount of variance in self-rated health ( P  < 0.001). Pain contributed the most to multiple sclerosis outpatients' perception of health, followed by gait dysfunction and fatigue. These findings suggest that 'invisible disability' may be more important to patients' sense of wellbeing than physical disability, and challenge the notion that physical disability should be the primary outcome measure in multiple sclerosis.

Dietary intake of nutrients and its correlation with fatigue in multiple sclerosis patients

PubMed Central

Bitarafan, Sama; Harirchian, Mohammad-Hossein; Nafissi, Shahriar; Sahraian, Mohammad-Ali; Togha, Mansoureh; Siassi, Fereydoun; Saedisomeolia, Ahmad; Alipour, Elham; Mohammadpour, Nakisa; Chamary, Maryam; Honarvar, Niyaz Mohammadzadeh

2014-01-01

Background The role of nutrition in the progression of multiple sclerosis (MS) and related complications such as fatigue has been reported by several studies. The aim of this study is the assessment of nutritional status and its relationship with fatigue in multiple sclerosis patients. Methods This is a cross-sectional study, in which 101 relapsing-remitting MS patients were enrolled. The fatigue status was determined using the validated Persian version of of the Modified Fatigue Impact Scale (MFIS). Dietary intake was assessed using a 3-day food record questionnaire and compared to dietary reference intake (DRI) values. Association between variables was determined using Pearson Correlation Coefficient. Results In the preset study, 25 men and 76 women (total = 101) were enrolled. Analysis of dietary intake showed that daily intake of vitamin D, folate, calcium, and magnesium were significantly lower than DRI in all of patients. In men, zinc intake was significantly lower than DRI; while, in women, iron was significantly below the DRI level. After adjusting for energy, MFIS and its physical subscale were highly correlated with intake of folate and magnesium. Conclusion Our findings support that lower magnesium and folate diets are correlated with higher fatigue scores in MS patients. PMID:24800044

Relationships between trunk performance, gait and postural control in persons with multiple sclerosis.

PubMed

Freund, Jane E; Stetts, Deborah M; Vallabhajosula, Srikant

2016-06-30

Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system. Compared to healthy individuals, persons with multiple sclerosis (PwMS) have increased postural sway in quiet stance, decreased gait speed and increased fall incidence. Trunk performance has been implicated in postural control, gait dysfunction, and fall prevention in older adults. However, the relationship of trunk performance to postural control and gait has not been adequately studied in PwMS. To compare trunk muscle structure and performance in PwMS to healthy age and gendered-matched controls (HC); to determine the effects of isometric trunk endurance testing on postural control in both populations; and to determine the relationship of trunk performance with postural control, gait and step activity in PwMS. Fifteen PwMS and HC completed ultrasound imaging of trunk muscles, 10 m walk test, isometric trunk endurance tests, and postural sway test. Participants wore a step activity monitor for 7 days. PwMS had worse isometric trunk endurance compared to HC. PwMS trunk flexion endurance negatively correlated to several postural control measures and positively correlated to gait speed and step activity. Clinicians should consider evaluation and interventions directed at impaired trunk endurance in PwMS.

Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice.

PubMed

Yamamoto, Shinji; Gotoh, Mari; Kawamura, Yuuki; Yamashina, Kota; Yagishita, Sosuke; Awaji, Takeo; Tanaka, Motomu; Maruyama, Kei; Murakami-Murofushi, Kimiko; Yoshikawa, Keisuke

2014-10-15

Multiple sclerosis is a chronic demyelinating disease of the central nervous system leading to progressive cognitive and motor dysfunction, which is characterized by neuroinflammation, demyelination, astrogliosis, loss of oligodendrocytes, and axonal pathologies. Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. In this study, we investigated the effects of cPA on cuprizone-induced demyelination, which is a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, astrocyte and microglial activation, and motor dysfunction. Simultaneous administration of cPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction. These data indicate that cPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis. cPA is a potential lead compound in the development of drugs for the treatment of this devastating disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Conduction block in the peripheral nervous system in experimental allergic encephalomyelitis

NASA Astrophysics Data System (ADS)

Pender, M. P.; Sears, T. A.

1982-04-01

Experimental allergic encephalomyelitis (EAE) has been widely studied as a model of multiple sclerosis, a central nervous system (CNS) disease of unknown aetiology. The clinical features of both EAE and multiple sclerosis provide the only guide to the progress and severity of these diseases, and are used to assess the response to treatment. In such comparisons the clinical features of EAE are assumed to be due to lesions in the CNS, but in this disease there is also histological evidence of damage to the peripheral nervous system1-8. However, the functional consequences of such peripheral lesions have been entirely ignored. To examine this we have studied nerve conduction in rabbits with EAE. We report here that most of the large diameter afferent fibres are blocked in the region of the dorsal root ganglion and at the dorsal root entry zone, thus accounting for the loss of tendon jerks and also, through the severe loss of proprioceptive information, the ataxia of these animals. We conclude that whenever clinical comparisons are made between EAE and multiple sclerosis, the pathophysiology associated with the histological damage of the peripheral nervous system must be taken into account.

Progranulin genetic polymorphisms influence progression of disability and relapse recovery in multiple sclerosis.

PubMed

Vercellino, Marco; Fenoglio, Chiara; Galimberti, Daniela; Mattioda, Alessandra; Chiavazza, Carlotta; Binello, Eleonora; Pinessi, Lorenzo; Giobbe, Dario; Scarpini, Elio; Cavalla, Paola

2016-07-01

Progranulin (GRN) is a multifunctional protein involved in inflammation and repair, and also a neurotrophic factor critical for neuronal survival. Progranulin is strongly expressed in multiple sclerosis (MS) brains by macrophages and microglia. In this study we evaluated GRN genetic variability in 400 MS patients, in correlation with clinical variables such as disease severity and relapse recovery. We also evaluated serum progranulin levels in the different groups of GRN variants carriers. We found that incomplete recovery after a relapse is correlated with an increased frequency of the rs9897526 A allele (odds ratio (OR) 4.367, p = 0.005). A more severe disease course (Multiple Sclerosis Severity Score > 5) is correlated with an increased frequency of the rs9897526 A allele (OR 1.886, p = 0.002) and of the rs5848 T allele (OR 1.580, p = 0.019). Carriers of the variants associated with a more severe disease course (rs9897526 A, rs5848 T) have significantly lower levels of circulating progranulin (80.5 ± 9.1 ng/mL vs. 165.7 ng/mL, p = 0.01). GRN genetic polymorphisms likely influence disease course and relapse recovery in MS. © The Author(s), 2015.

Gray Matter Pathology in MS: Neuroimaging and Clinical Correlations

PubMed Central

Honce, Justin Morris

2013-01-01

It is abundantly clear that there is extensive gray matter pathology occurring in multiple sclerosis. While attention to gray matter pathology was initially limited to studies of autopsy specimens and biopsies, the development of new MRI techniques has allowed assessment of gray matter pathology in vivo. Current MRI techniques allow the direct visualization of gray matter demyelinating lesions, the quantification of diffuse damage to normal appearing gray matter, and the direct measurement of gray matter atrophy. Gray matter demyelination (both focal and diffuse) and gray matter atrophy are found in the very earliest stages of multiple sclerosis and are progressive over time. Accumulation of gray matter damage has substantial impact on the lives of multiple sclerosis patients; a growing body of the literature demonstrates correlations between gray matter pathology and various measures of both clinical disability and cognitive impairment. The effect of disease modifying therapies on the rate accumulation of gray matter pathology in MS has been investigated. This review focuses on the neuroimaging of gray matter pathology in MS, the effect of the accumulation of gray matter pathology on clinical and cognitive disability, and the effect of disease-modifying agents on various measures of gray matter damage. PMID:23878736

Sclerosing bone dysplasias: genetic, clinical and radiology update of hereditary and non-hereditary disorders

PubMed Central

Boulet, Cedric; Madani, Hardi; Lenchik, Leon; Vanhoenacker, Filip; Amalnath, Deepak S; de Mey, Johan

2016-01-01

There is a wide variety of hereditary and non-hereditary bone dysplasias, many with unique radiographic findings. Hereditary bony dysplasias include osteopoikilosis, osteopathia striata, osteopetrosis, progressive diaphyseal dysplasia, hereditary multiple diaphyseal sclerosis and pyknodysostosis. Non-hereditary dysplasias include melorheostosis, intramedullary osteosclerosis and overlap syndromes. Although many of these dysplasias are uncommon, radiologists should be familiar with their genetic, clinical and imaging findings to allow for differentiation from acquired causes of bony sclerosis. We present an overview of hereditary and non-hereditary bony dysplasias with focus on the pathogenesis, clinical and radiographic findings of each disorder. PMID:26898950

A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology

PubMed Central

Kolasinski, James; Chance, Steven A.; DeLuca, Gabriele C.; Esiri, Margaret M.; Chang, Eun-Hyuk; Palace, Jacqueline A.; McNab, Jennifer A.; Jenkinson, Mark; Miller, Karla L.; Johansen-Berg, Heidi

2012-01-01

Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies. PMID:23065787

[Revision of McDonald's new diagnostic criteria for multiple sclerosis].

PubMed

Wiendl, H; Kieseier, B C; Gold, R; Hohlfeld, R; Bendszus, M; Hartung, H-P

2006-10-01

In 2001, an international panel suggested new diagnostic criteria for multiple sclerosis (MS). These criteria integrate clinical, imaging (MRI), and paraclinical results in order to facilitate diagnosis. Since then, these so-called McDonald criteria have been broadly accepted and widely propagated. In the meantime a number of publications have dealt with the sensitivity and specificity for MS diagnosis and with implementing these new criteria in clinical practice. Based on these empirical values and newer data on MS, an international expert group recently proposed a revision of the criteria. Substantial changes affect (1) MRI criteria for the dissemination of lesions over time, (2) the role of spinal cord lesions in the MRI and (3) diagnosis of primary progressive MS. In this article we present recent experiences with the McDonald and revised criteria.

Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis.

PubMed

Kroth, Julia; Ciolac, Dumitru; Fleischer, Vinzenz; Koirala, Nabin; Krämer, Julia; Muthuraman, Muthuraman; Luessi, Felix; Bittner, Stefan; Gonzalez-Escamilla, Gabriel; Zipp, Frauke; Meuth, Sven G; Groppa, Sergiu

2017-12-01

Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSF IgA and CSF IgM showed higher functional disability at follow-up. CSF markers of blood-brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.

Iron in Multiple Sclerosis and Its Noninvasive Imaging with Quantitative Susceptibility Mapping

PubMed Central

Stüber, Carsten; Pitt, David; Wang, Yi

2016-01-01

Iron is considered to play a key role in the development and progression of Multiple Sclerosis (MS). In particular, iron that accumulates in myeloid cells after the blood-brain barrier (BBB) seals may contribute to chronic inflammation, oxidative stress and eventually neurodegeneration. Magnetic resonance imaging (MRI) is a well-established tool for the non-invasive study of MS. In recent years, an advanced MRI method, quantitative susceptibility mapping (QSM), has made it possible to study brain iron through in vivo imaging. Moreover, immunohistochemical investigations have helped defining the lesional and cellular distribution of iron in MS brain tissue. Imaging studies in MS patients and of brain tissue combined with histological studies have provided important insights into the role of iron in inflammation and neurodegeneration in MS. PMID:26784172

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

PubMed

Pryce, Gareth; Riddall, Dieter R; Selwood, David L; Giovannoni, Gavin; Baker, David

2015-06-01

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

Progressive multiple sclerosis, cognitive function, and quality of life.

PubMed

Højsgaard Chow, Helene; Schreiber, Karen; Magyari, Melinda; Ammitzbøll, Cecilie; Börnsen, Lars; Romme Christensen, Jeppe; Ratzer, Rikke; Soelberg Sørensen, Per; Sellebjerg, Finn

2018-02-01

Patients with progressive multiple sclerosis (MS) often have cognitive impairment in addition to physical impairment. The burden of cognitive and physical impairment progresses over time, and may be major determinants of quality of life. The aim of this study was to assess to which degree quality of life correlates with physical and cognitive function in progressive MS. This is a retrospective study of 52 patients with primary progressive ( N  = 18) and secondary progressive MS ( N  = 34). Physical disability was assessed using the Expanded Disability Status Scale, Timed 25 Foot Walk (T25FW) test and 9-Hole Peg Test (9HPT). Cognitive function was assessed using Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test, and Trail Making Test B (TRAIL-B). In addition, quality of life was assessed by the Short Form 36 (SF-36) questionnaire. Only measures of cognitive function correlated with the overall SF-36 quality of life score and the Mental Component Summary score from the SF-36. The only physical measure that correlated with a measure of quality of life was T25FW test, which correlated with the Physical Component Summary from the SF-36. We found no other significant correlations between the measures of cognitive function and the overall physical measures but interestingly, we found a possible relationship between the 9HPT score for the nondominant hand and the SDMT and TRAIL-B. Our findings support inclusion of measures of cognitive function in the assessment of patients with progressive MS as these correlated closer with quality of life than measures of physical impairment.

Exploring Wellness Interventions in Progressive Multiple Sclerosis: an Evidence-Based Review.

PubMed

Venasse, Myriam; Edwards, Thomas; Pilutti, Lara A

2018-04-10

There has been recent interest in the role of lifestyle and wellness-based approaches in the treatment and management of multiple sclerosis (MS). These approaches may be particularly relevant for patients with progressive MS, considering limited therapeutic options currently available. The purpose of this review is to examine the role of wellness-based interventions including exercise training, emotional well-being therapies, and dietary modification in patients with progressive MS. We conducted a literature search on the efficacy of wellness-based interventions in patients with progressive MS published between 1985 and July 2017. The level of evidence for each trial was evaluated using the American Academy of Neurology criteria. Overall, 21 articles reporting on 16 wellness-based interventions were identified: ten trials involved exercise training, three involved emotional wellness therapies, two involved dietary modification, and one was a combined wellness intervention. There is level C evidence (possibly effective; one class II study) for the efficacy of aerobic exercise training on cardiorespiratory fitness in patients with progressive MS. There is level B evidence (probably effective; one class I study) for the efficacy of mindfulness training on psychological distress, depression, anxiety, pain, and quality of life in patients with progressive MS. There is inadequate evidence (level U) for efficacy of dietary modification (one class III study and one class IV study) and combined wellness interventions involving exercise training, meditation, and dietary modification (one class IV study). High-quality research is needed to provide evidence-based recommendations for wellness behaviors and lifestyle change in patients with progressive MS.

The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients.

PubMed

Morel, Agnieszka; Miller, Elzbieta; Bijak, Michal; Saluk, Joanna

2016-09-01

Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase-dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS.

Cytokine Profile in Patients with Progressive Multiple Sclerosis and Its Association with Disease Progression and Disability.

PubMed

Kallaur, Ana Paula; Oliveira, Sayonara Rangel; Simão, Andréa Name Colado; Alfieri, Daniela Frizon; Flauzino, Tamires; Lopes, Josiane; de Carvalho Jennings Pereira, Wildea Lice; de Meleck Proença, Caio; Borelli, Sueli Donizete; Kaimen-Maciel, Damacio Ramón; Maes, Michael; Reiche, Edna Maria Vissoci

2017-05-01

Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability. We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay. IL-1β, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1β and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patients with progressive MS with disease progression presented higher TNF-α, IFN-γ, and IL-10 levels than those without disease progression. Patients with progressive MS with disease progression showed a higher frequency of positive gadolinium-enhanced lesions in MRI; higher TNF-α, IFN-γ, and IL-17 levels; and decreased IL-12 levels compared with RRMS patients with progression. There was a significant inverse correlation between IL-10 levels and EDSS score in patients with progressive MS. The results underscore the complex cytokine network imbalance exhibited by progressive MS patients and show the important involvement of TNF-α, IFN-γ, and IL-17 in the pathophysiology and progression of the disease. Moreover, serum IL-10 levels were inversely associated with disability in patients with progressive MS.

Improvements in cognition, quality of life, and physical performance with clinical Pilates in multiple sclerosis: a randomized controlled trial

PubMed Central

Küçük, Fadime; Kara, Bilge; Poyraz, Esra Çoşkuner; İdiman, Egemen

2016-01-01

[Purpose] The aim of this study was to determine the effects of clinical Pilates in multiple sclerosis patients. [Subjects and Methods] Twenty multiple sclerosis patients were enrolled in this study. The participants were divided into two groups as the clinical Pilates and control groups. Cognition (Multiple Sclerosis Functional Composite), balance (Berg Balance Scale), physical performance (timed performance tests, Timed up and go test), tiredness (Modified Fatigue Impact scale), depression (Beck Depression Inventory), and quality of life (Multiple Sclerosis International Quality of Life Questionnaire) were measured before and after treatment in all participants. [Results] There were statistically significant differences in balance, timed performance, tiredness and Multiple Sclerosis Functional Composite tests between before and after treatment in the clinical Pilates group. We also found significant differences in timed performance tests, the Timed up and go test and the Multiple Sclerosis Functional Composite between before and after treatment in the control group. According to the difference analyses, there were significant differences in Multiple Sclerosis Functional Composite and Multiple Sclerosis International Quality of Life Questionnaire scores between the two groups in favor of the clinical Pilates group. There were statistically significant clinical differences in favor of the clinical Pilates group in comparison of measurements between the groups. Clinical Pilates improved cognitive functions and quality of life compared with traditional exercise. [Conclusion] In Multiple Sclerosis treatment, clinical Pilates should be used as a holistic approach by physical therapists. PMID:27134355

Improvements in cognition, quality of life, and physical performance with clinical Pilates in multiple sclerosis: a randomized controlled trial.

PubMed

Küçük, Fadime; Kara, Bilge; Poyraz, Esra Çoşkuner; İdiman, Egemen

2016-03-01

[Purpose] The aim of this study was to determine the effects of clinical Pilates in multiple sclerosis patients. [Subjects and Methods] Twenty multiple sclerosis patients were enrolled in this study. The participants were divided into two groups as the clinical Pilates and control groups. Cognition (Multiple Sclerosis Functional Composite), balance (Berg Balance Scale), physical performance (timed performance tests, Timed up and go test), tiredness (Modified Fatigue Impact scale), depression (Beck Depression Inventory), and quality of life (Multiple Sclerosis International Quality of Life Questionnaire) were measured before and after treatment in all participants. [Results] There were statistically significant differences in balance, timed performance, tiredness and Multiple Sclerosis Functional Composite tests between before and after treatment in the clinical Pilates group. We also found significant differences in timed performance tests, the Timed up and go test and the Multiple Sclerosis Functional Composite between before and after treatment in the control group. According to the difference analyses, there were significant differences in Multiple Sclerosis Functional Composite and Multiple Sclerosis International Quality of Life Questionnaire scores between the two groups in favor of the clinical Pilates group. There were statistically significant clinical differences in favor of the clinical Pilates group in comparison of measurements between the groups. Clinical Pilates improved cognitive functions and quality of life compared with traditional exercise. [Conclusion] In Multiple Sclerosis treatment, clinical Pilates should be used as a holistic approach by physical therapists.

Monitoring My Multiple Sclerosis

PubMed Central

Namey, Marie; Halper, June

2011-01-01

Optimal health of people with multiple sclerosis (MS) can be promoted by patients' sharing of health information gained through periodic self-monitoring with their health-care providers. The purpose of this study was to develop a valid and reliable self-administered scale to obtain information about MS patients' health status and the impact of the disease on their daily lives. We named this scale “Monitoring My Multiple Sclerosis” (MMMS). A cross-sectional survey was conducted of 171 MS patients who completed the MMMS and Patient-Determined Disease Steps (PDDS) scales and provided information on their MS disease classification and demographic characteristics. Data analysis included several parametric procedures. Factor analysis of the 26-item MMMS resulted in four factors with satisfactory α reliability coefficients for the total scale (0.90) and factored subscales: Physical (0.85), Relationships (0.80), Energy (0.70), and Cognitive/Mental (0.67). Analysis of variance demonstrated that the total scale and the Physical subscale, but not the Relationships subscale, showed significantly worse functioning for patients with either moderate or severe disability as measured by the PDDS than for patients with mild disability (P < .001). The Cognitive/Mental subscale showed significantly worse functioning for patients with moderate disability than for patients with mild disability (P < .05). However, the Energy subscale showed significantly worse functioning among moderately disabled patients than among severely disabled patients (P < .01). Independent t tests demonstrated that patients classified as having secondary progressive multiple sclerosis had significantly worse scores on the total MMMS (P < .05) and the Physical subscale (P < .001) than those classified as having relapsing-remitting multiple sclerosis. The MMMS demonstrated satisfactory reliability and validity and is recommended for use by MS patients and their health-care providers as a mechanism to promote the sharing of health information, to the benefit of both patients and providers. PMID:24453717

Blood-Brain Barrier Permeability and Monocyte Infiltration in Experimental Allergic Encephalomyelitis

ERIC Educational Resources Information Center

Floris, S.; Blezer, E. L. A.; Schreibelt, G.; Dopp, E.; van der Pol, S. M. A.; Schadee-Eestermans, I. L.; Nicolay, K.; Dijkstra, C. D.; de Vries, H. E.

2004-01-01

Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive…

A prospective study of physical trauma and multiple sclerosis.

PubMed Central

Sibley, W A; Bamford, C R; Clark, K; Smith, M S; Laguna, J F

1991-01-01

During an eight year period 170 multiple sclerosis (MS) patients and 134 controls without physical impairment were followed closely to record all episodes of physical trauma and to measure their effect on exacerbation rate and progression of MS. There was a total of 1407 instances of trauma, which were sorted into various categories. Overall there was no significant correlation between all-traumas and disease activity. There was, however, a statistically significant negative correlation between traumatic episodes and exacerbations in 95 patients who had exacerbations during the programme, due primarily to less activity of the disease during a three month period following surgical procedures and fractures. Electrical injury had a significant positive association with exacerbation using a three month at-risk period, but there were no other significant positive correlations in any other category of trauma, including minor head injuries; there were no cases of head injury with prolonged unconsciousness. There was no linkage between the frequency of trauma and progression of disability. MS patients had two to three times more trauma than controls. PMID:1895121

Inactivation of JNK1 enhances innate IL-10 production and dampens autoimmune inflammation in the brain.

PubMed

Tran, Elise H; Azuma, Yasu-Taka; Chen, Manchuan; Weston, Claire; Davis, Roger J; Flavell, Richard A

2006-09-05

Environmental insults such as microbial pathogens can contribute to the activation of autoreactive T cells, leading to inflammation of target organs and, ultimately, autoimmune disease. Various infections have been linked to multiple sclerosis and its animal counterpart, autoimmune encephalomyelitis. The molecular process by which innate immunity triggers autoreactivity is not currently understood. By using a mouse model of multiple sclerosis, we found that the genetic loss of the MAPK, c-Jun N-terminal kinase 1 (JNK1), enhances IL-10 production, rendering innate myeloid cells unresponsive to certain microbes and less capable of generating IL-17-producing, encephalitogenic T cells. Moreover, JNK1-deficient central nervous system myeloid cells are unable to respond to effector T cell inflammatory cytokines, preventing further progression to neuroinflammation. Thus, we have identified the JNK1 signal transduction pathway in myeloid cells to be a critical component of a regulatory circuit mediating inflammatory responses in autoimmune disease. Our findings provide further insights into the pivotal MAPK-regulated network of innate and adaptive cytokines in the progression to autoimmunity.

Diabetes insipidus as a rare cause of acute cognitive impairment in multiple sclerosis.

PubMed

Tiedje, V; Schlamann, M; Führer, D; Moeller, L C

2013-10-01

Multiple sclerosis (MS) is a complex neurodegenerative disease presenting with a diversity of clinical symptoms including palsy and cognitive impairment. We present a 59-year-old woman with a history of secondary progressive MS since 1987, who was referred to our department because of recent onset of confusion and polydipsia. Initial lab tests showed mildly elevated serum sodium levels and low urine osmolality. Under water deprivation, diuresis and low urine osmolality persisted and serum sodium levels rose above 150 mmol/l. Oral desmopressin resulted in normalisation of serum sodium as well as urine osmolarity, confirming a diagnosis of central diabetes insipidus. As drug-induced diabetes could be excluded, pituitary magnetic resonance imaging (MRI) was performed. A demyelinating lesion was detected in the hypothalamus. The patient was started on oral desmopressin treatment (0.2 mg/day). Fluid intake and serum sodium levels have since remained normal. In summary, we report the rare case of a patient presenting with diabetes insipidus due to progressive MS. Diabetes insipidus should be considered in MS patients who develop new onset of polydipsia.

The importance of studying sex differences in disease: The example of multiple sclerosis.

PubMed

Golden, Lisa C; Voskuhl, Rhonda

2017-01-02

To date, scientific research has often focused on one sex, with assumptions that study of the other sex would yield similar results. However, many diseases affect males and females differently. The sex of a patient can affect the risk for both disease susceptibility and progression. Such differences can be brought to the laboratory bench to be investigated, potentially bringing new treatments back to the clinic. This method of research, known as a "bedside to bench to bedside" approach, has been applied to studying sex differences in multiple sclerosis (MS). Females have greater susceptibly to MS, while males have worse disease progression. These two characteristics of the disease are influenced by the immune system and the nervous system, respectively. Thus, sex differences in each system must be studied. Personalized medicine has been at the forefront of research recently, and studying sex differences in disease fits with this initiative. This review will discuss the known sex differences in MS and highlight how investigating them can lead to new insights and potential treatments for both men and women. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A systematic review about the epidemiology of primary progressive multiple sclerosis in Latin America and the Caribbean.

PubMed

Rojas, Juan Ignacio; Romano, Marina; Patrucco, Liliana; Cristiano, Edgardo

2018-02-24

Novel epidemiological data has appeared in recent years in Latin America (LATAM) regarding the epidemiology of multiple sclerosis (MS); however, most of this information is related to all MS subtypes, and no specific data was collected regarding the primary progressive form of MS (PPMS). The objective of this study was to perform an updated systematic review of the epidemiology of PPMS in LATAM. We conducted a systematic review of published epidemiological articles of PPMS from January 1997 to June 2017. No incidence data were found regarding PPMS. Differentiated prevalence was reported in 7 studies and ranged from 0.13 to 1.1 cases of PPMS per 100,000 inhabitants. Regarding subtype frequency, PPMS was observed in 10% of affected patients in proportional meta-analysis. No data about mortality were found. The study provides information on discriminated epidemiological features of PPMS in the region. The frequency observed was low in terms of prevalence. Follow up studies considering survival milestones and incidence data could provide a better understanding of the disease in the region. Copyright © 2018. Published by Elsevier B.V.

Prolonged-release fampridine treatment improved subject-reported impact of multiple sclerosis: Item-level analysis of the MSIS-29.

PubMed

Gasperini, Claudio; Hupperts, Raymond; Lycke, Jan; Short, Christine; McNeill, Manjit; Zhong, John; Mehta, Lahar R

2016-11-15

Prolonged-release (PR) fampridine is approved to treat walking impairment in persons with multiple sclerosis (MS); however, treatment benefits may extend beyond walking. MOBILE was a phase 2, 24-week, double-blind, placebo-controlled exploratory study to assess the impact of 10mg PR-fampridine twice daily versus placebo on several subject-assessed measures. This analysis evaluated the physical and psychological health outcomes of subjects with progressing or relapsing MS from individual items of the Multiple Sclerosis Impact Scale (MSIS-29). PR-fampridine treatment (n=68) resulted in greater improvements from baseline in the MSIS-29 physical (PHYS) and psychological (PSYCH) impact subscales, with differences of 89% and 148% in mean score reduction from baseline (n=64) at week 24 versus placebo, respectively. MSIS-29 item analysis showed that a higher percentage of PR-fampridine subjects had mean improvements in 16/20 PHYS and 6/9 PSYCH items versus placebo after 24weeks. Post hoc analysis of the 12-item Multiple Sclerosis Walking Scale (MSWS-12) improver population (≥8-point mean improvement) demonstrated differences in mean reductions from baseline of 97% and 111% in PR-fampridine MSIS-29 PHYS and PSYCH subscales versus the overall placebo group over 24weeks. A higher percentage of MSWS-12 improvers treated with PR-fampridine showed mean improvements in 20/20 PHYS and 8/9 PSYCH items versus placebo at 24weeks. In conclusion, PR-fampridine resulted in physical and psychological benefits versus placebo, sustained over 24weeks. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Prognostic value of free light chains lambda and kappa in early multiple sclerosis.

PubMed

Voortman, Margarete M; Stojakovic, Tatjana; Pirpamer, Lukas; Jehna, Margit; Langkammer, Christian; Scharnagl, Hubert; Reindl, Markus; Ropele, Stefan; Seifert-Held, Thomas; Archelos, Juan-Jose; Fuchs, Siegrid; Enzinger, Christian; Fazekas, Franz; Khalil, Michael

2017-10-01

Cerebrospinal fluid (CSF) immunoglobulin free light chains (FLC) have been suggested as quantitative alternative to oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS). However, little is known on their role in predicting clinical and paraclinical disease progression, particularly in early stages. To assess the prognostic value of FLC in OCB-positive patients with clinically isolated syndrome (CIS) suggestive of MS and early MS. We determined FLC kappa (KFLC) and lambda (LFLC) in CSF and serum by nephelometry in 61 patients (CIS ( n = 48), relapsing-remitting multiple sclerosis ( n = 13)) and 60 non-inflammatory neurological controls. Median clinical follow-up time in CIS was 4.8 years (interquartile range (IQR), 1.5-6.5 years). Patients underwent 3T magnetic resonance imaging (MRI) at baseline and follow-up (median time interval, 2.2 years; IQR, 1.0-3.7 years) to determine T2 lesion load (T2LL) and percent brain volume change (PBVC). CSF FLC were significantly increased in CIS/MS compared to controls (all p < 0.001). A lower KFLC/LFLC CSF ratio was associated with CIS-clinically definite multiple sclerosis (CDMS) conversion (hazard ratio (HR) = 2.89; 95% confidence interval (CI) = 1.17-7.14; p < 0.05). No correlations were found for FLC variables with T2LL or PBVC. Our study confirms increased intrathecal synthesis of FLC in CIS/MS which supports their diagnostic contribution. The KFLC/LFLC CSF ratio appears to have a prognostic value in CIS beyond OCB.

MIF functional polymorphisms (-794 CATT5-8 and -173 G>C) are associated with MIF serum levels, severity and progression in male multiple sclerosis from western Mexican population.

PubMed

Castañeda-Moreno, V A; De la Cruz-Mosso, U; Torres-Carrillo, N; Macías-Islas, M A; Padilla-De la Torre, O; Mireles-Ramírez, M A; González-Pérez, O; Ruiz-Sandoval, J L; Huerta, M; Trujillo, X; Ortuño-Sahagún, D; Muñoz-Valle, J F

2018-07-15

Macrophage migration inhibitory factor (MIF) is a cytokine associated with tissue damage in multiple autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis. The role of MIF in multiple sclerosis (MS) and the contribution of its polymorphisms are unknown in our population. Therefore, we decided to investigate the genetic association of -794 CATT 5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms with MS, clinical variables and MIF serum levels in the population of western Mexico. 230 MS patients diagnosed according to McDonald criteria and 248 control subjects (CS) were recruited for this study, both polymorphisms were genotyped by PCR and PCR-RFLP and MIF serum levels were measured by ELISA kit. Severity and progression of MS were evaluated by EDSS and MSSS scores, respectively. Genotypes carrying the 5 repeats alleles of -794 CATT 5-8 MIF polymorphism present higher MIF serum levels in comparison with no carriers, and the presence of 5,7 heterozygous genotype contribute to the increase of disease severity and damage progression in MS patients. Notably when we stratified by sex, an effect of risk alleles (7 repeats and -173*C) of both MIF polymorphisms on EDSS and MSSS scores on males was found (p < 0.01). This study suggests that polymorphic alleles of MIF polymorphisms could act as sex-specific disease modifiers that increase the severity and progression of MS in male Mexican-Mestizo western population. Copyright © 2018 Elsevier B.V. All rights reserved.

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

PubMed

Tourbah, Ayman; Lebrun-Frenay, Christine; Edan, Gilles; Clanet, Michel; Papeix, Caroline; Vukusic, Sandra; De Sèze, Jerome; Debouverie, Marc; Gout, Olivier; Clavelou, Pierre; Defer, Gilles; Laplaud, David-Axel; Moreau, Thibault; Labauge, Pierre; Brochet, Bruno; Sedel, Frédéric; Pelletier, Jean

2016-11-01

Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated. © The Author(s), 2016.

A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis.

PubMed

Wootla, Bharath; Denic, Aleksandar; Watzlawik, Jens O; Warrington, Arthur E; Rodriguez, Moses

2015-04-29

Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology. (1)H-magnetic resonance spectroscopy (MRS) showed that treatment with HIgM12 significantly increased brainstem NAA concentrations compared to controls in TMEV-infected mice. Pathologic analysis demonstrated a significant preservation of axons in the spinal cord of animals treated with HIgM12. This study links drug efficacy of slowing deficits with axon preservation and NAA concentrations in the brainstem in a model of progressive MS. HIgM12-mediated changes of NAA concentrations in the brainstem are a surrogate marker of axon injury/preservation throughout the spinal cord. This study provides proof-of-concept that a neuron-reactive human IgM can be therapeutic and provides a biomarker for clinical trials.

Usefulness of optic nerve ultrasound to predict clinical progression in multiple sclerosis.

PubMed

Pérez Sánchez, S; Eichau Madueño, S; Rus Hidalgo, M; Domínguez Mayoral, A M; Vilches-Arenas, A; Navarro Mascarell, G; Izquierdo, G

2018-03-21

Progressive neuronal and axonal loss are considered the main causes of disability in patients with multiple sclerosis (MS). The disease frequently involves the visual system; the accessibility of the system for several functional and structural tests has made it a model for the in vivo study of MS pathogenesis. Orbital ultrasound is a non-invasive technique that enables various structures of the orbit, including the optic nerve, to be evaluated in real time. We conducted an observational, ambispective study of MS patients. Disease progression data were collected. Orbital ultrasound was performed on all patients, with power set according to the 'as low as reasonably achievable' (ALARA) principle. Optical coherence tomography (OCT) data were also collected for those patients who underwent the procedure. Statistical analysis was conducted using SPSS version 22.0. Disease progression was significantly correlated with ultrasound findings (P=.041 for the right eye and P=.037 for the left eye) and with Expanded Disability Status Scale (EDSS) score at the end of the follow-up period (P=.07 for the right eye and P=.043 for the left eye). No statistically significant differences were found with relation to relapses or other clinical variables. Ultrasound measurement of optic nerve diameter constitutes a useful, predictive factor for the evaluation of patients with MS. Smaller diameters are associated with poor clinical progression and greater disability (measured by EDSS). Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

High doses of biotin in chronic progressive multiple sclerosis: a pilot study.

PubMed

Sedel, Frédéric; Papeix, Caroline; Bellanger, Agnès; Touitou, Valérie; Lebrun-Frenay, Christine; Galanaud, Damien; Gout, Olivier; Lyon-Caen, Olivier; Tourbah, Ayman

2015-03-01

No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis.

PubMed

Cree, B A C; Khan, O; Bourdette, D; Goodin, D S; Cohen, J A; Marrie, R A; Glidden, D; Weinstock-Guttman, B; Reich, D; Patterson, N; Haines, J L; Pericak-Vance, M; DeLoa, C; Oksenberg, J R; Hauser, S L

2004-12-14

African American (AA) individuals are thought to develop multiple sclerosis (MS) less frequently than Caucasian American (CA) individuals. To compare the clinical characteristics of AA and CA patients with MS. The clinical features of MS were compared in a large retrospective cohort of AA (n = 375) and CA (n = 427) subjects. The proportion of women to men was similar in AA and CA subjects (81% [AA] vs 77% [CA]; p = 0.122). There were no differences in the proportions of subjects with relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. The median time to diagnosis was 1 year after symptom onset in AA subjects and 2 years after symptom onset in CA subjects (p = 0.0013). The age at onset was approximately 2.5 years later in AA than CA subjects (33.7 vs 31.1 years; p = 0.0001). AA subjects presented with multisite signs and symptoms at disease onset more often than CA subjects (p = 0.018). Clinical involvement restricted to the optic nerves and spinal cord (opticospinal MS) occurred in 16.8% of AA patients compared with 7.9% of CA patients (p < 0.001). Transverse myelitis also occurred more frequently in AA subjects (28 vs 18%; p = 0.001). Survival analysis revealed that AA subjects were at higher risk for development of ambulatory disability than CA subjects. After adjusting for baseline variations and differences in therapeutic interventions, AAs were at 1.67-fold greater risk for requiring a cane to ambulate than CA patients (p < 0.001). There was a trend suggesting that AAs were also at greater risk for development of wheelchair dependency (p = 0.099). Adjusted Cox proportional hazard models showed that this effect was in part attributable to the older age at onset in AAs (p < 0.001). Compared with multiple sclerosis (MS) in Caucasian Americans, African American patients with MS have a greater likelihood of developing opticospinal MS and transverse myelitis and have a more aggressive disease course.

Subcutaneous interferon β-1a three times weekly and the natural evolution of gadolinium-enhancing lesions into chronic black holes in relapsing and progressive multiple sclerosis: Analysis of PRISMS and SPECTRIMS trials.

PubMed

Traboulsee, A; Li, Dkb; Tam, R; Zhao, G; Riddehough, A; Fang, J; Dangond, F; Kappos, L

2017-01-01

Evolution of gadolinium-enhancing lesions into chronic black holes (CBH) may be reduced by interferon (IFN) therapy. The objective of this paper is to assess the effect of IFN β-1a and placebo on CBH evolution and disability in patients with relapsing-remitting multiple sclerosis (RRMS), as well as CBH evolution in patients with secondary progressive multiple sclerosis (SPMS). A post hoc, exploratory analysis of patients with RRMS and SPMS with monthly MRI scans (months -1 to 9) from two separate placebo-controlled clinical trials of IFN β-1a was conducted. In RRMS patients, the risk of ≥1 evolved CBH was lower for IFN β-1a versus placebo (odds ratio 0.42; p  = 0.024); volume of newly evolved CBH was numerically reduced. A numerically higher proportion of patients with ≥1 evolving CBH vs no evolving CBH had confirmed three-month disability progression (four-year rate 55.8% vs 43.1%, respectively). Proportion of lesions evolving into CBH (patient level: 34.7% vs 12.6%, p  < 0.0001; lesion level: 28.8% vs 11.0%, p  < 0.0001) and evolved CBH volume (median 33.5 mm 3 (Quartile 1, 0.0; Quartile 3, 173.4) vs 0.0 mm 3 (0.0; 52.4); p  = 0.0008) was higher for SPMS than RRMS patients treated with IFN β-1a. In RRMS, IFN β-1a significantly decreased the proportion of new T1 Gd+ lesions evolving into CBH and the risk of developing a CBH. In patients with SPMS, more lesions develop to CBH, indicating reduced repair capacity, and the natural history of lesion development appears to be unaffected by IFN β-1a treatment.

Multiple sclerosis

MedlinePlus

... this page: //medlineplus.gov/ency/article/000737.htm Multiple sclerosis To use the sharing features on this page, please enable JavaScript. Multiple sclerosis (MS) is an autoimmune disease that affects the ...

Use of the 2010 McDonald criteria can facilitate early diagnosis of pediatric multiple sclerosis in a predominantly black cohort.

PubMed

Williams, Mitchel T; Tapos, Daniela O; Juhász, Csaba

2014-12-01

Pediatric-onset multiple sclerosis represents around 3-5% of all patients with multiple sclerosis. Both the 2005 and 2010 McDonald criteria for multiple sclerosis have been suggested for the possible use in pediatric-onset multiple sclerosis. Modifications incorporated into the 2010 criteria enabled the fulfillment of dissemination in time to be met with the initial magnetic resonance imaging. The present study was designed to compare the diagnostic sensitivity of these criteria at initial presentation, the time to fulfilling them, and secondary effects of ethnicity in pediatric-onset multiple sclerosis. Twenty-five children with clinically definite multiple sclerosis (mean age, 14.6 ± 3.1 years; 15 girls) from a single center between 2005 and 2012 were analyzed using both the 2005 and 2010 McDonald criteria based on initial clinical presentation and neuroimaging findings comparing diagnostic sensitivity, time interval to meet diagnosis, and ethnicity. Initial multiple sclerosis diagnosis rates applying the 2005 McDonald criteria were 32% compared with 92% for the 2010 criteria (P = 0.0003). The mean time after initial signs until the 2005 and 2010 McDonald criteria for multiple sclerosis were met was 5.0 vs 0.7 months, respectively (P = 0.001). Time to diagnosis using the 2010 criteria was shorter in black children than the European white (P = 0.005). The 2010 McDonald criteria are an appropriate tool for the timely diagnosis of pediatric multiple sclerosis, especially in black children, potentially allowing an earlier initiation of disease-modifying therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets.

PubMed

De Stefano, Nicola; Giorgio, Antonio; Battaglini, Marco; De Leucio, Alessandro; Hicking, Christine; Dangond, Fernando; Giovannoni, Gavin; Sormani, Maria Pia

2018-02-01

Neuroimaging studies have used magnetic resonance imaging-derived methods to assess brain volume loss in multiple sclerosis (MS) as a reliable measure of diffuse tissue damage. In the CLARITY study ( ClinicalTrials.gov NCT00213135), the effect of 2 years' treatment with cladribine tablets on annualized percentage brain volume change (PBVC/y) was evaluated in patients with relapsing MS (RMS). Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa. Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.

The development of hematopoietic and mesenchymal stem cell transplantation as an effective treatment for multiple sclerosis

PubMed Central

Holloman, Jameson P; Ho, Calvin C; Hukki, Arushi; Huntley, Jennifer L; Gallicano, G Ian

2013-01-01

This article examines the current use and future implications of stem cell therapy in treating Multiple Sclerosis (MS). MS is the most common neurological disease in young adults, affecting approximately two million people worldwide. Currently there is no cure for MS. The standard treatment of MS involves disease-modifying drugs, which work to alleviate the symptoms of MS. However, these drugs carry adverse side effects and are ineffective in preventing disease progression in many MS patients. Hematopoietic stem cell transplantation (HSCT) was first used in 1995 to treat patients with severe rapidly progressing MS. The HSCT treatment protocol has evolved into a less intense conditioning regimen that is currently demonstrating efficacy in treating patients with variable disease severity—with best results in early-stage rapidly progressing MS patients with active CNS inflammation. Mesenchymal stem cell therapy (MSCT) is an experimental stem cell therapy currently undergoing clinical trials. Animal models and early clinical trials have shown promise that MSCT might be a low risk treatment to precipitate neuroregeneration and immunomodulation in MS patients. Specifically, neuroprogenitor and placental-derived mesenchymal stem cells offer the best hope for a practical treatment for MS. Stem cell therapy, and perhaps a combinatorial therapeutic approach, holds promise for a better treatment for MS. PMID:23862098

Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage.

PubMed

Morel, Agnieszka; Bijak, Michał; Miller, Elżbieta; Rywaniak, Joanna; Miller, Sergiusz; Saluk, Joanna

2015-01-01

Multiple sclerosis (MS) is the autoimmune disease of the central nervous system with complex pathogenesis, different clinical courses and recurrent neurological relapses and/or progression. Despite various scientific papers that focused on early stage of MS, our study targets selective group of late stage secondary progressive MS patients. The presented work is concerned with the reactivity of blood platelets in primary hemostasis in SP MS patients. 50 SP MS patients and 50 healthy volunteers (never diagnosed with MS or other chronic diseases) were examined to evaluate the biological activity of blood platelets (adhesion, aggregation), especially their response to the most important physiological agonists (thrombin, ADP, and collagen) and the effect of oxidative stress on platelet activity. We found that the blood platelets from SP MS patients were significantly more sensitive to all used agonists in comparison with control group. Moreover, the platelet hemostatic function was advanced in patients suffering from SP MS and positively correlated with increased production of O2 (-∙) in these cells, as well as with Expanded Disability Status Scale. We postulate that the increased oxidative stress in blood platelets in SP MS may be primarily responsible for the altered haemostatic properties of blood platelets.

Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage

PubMed Central

Bijak, Michał; Miller, Elżbieta; Miller, Sergiusz

2015-01-01

Multiple sclerosis (MS) is the autoimmune disease of the central nervous system with complex pathogenesis, different clinical courses and recurrent neurological relapses and/or progression. Despite various scientific papers that focused on early stage of MS, our study targets selective group of late stage secondary progressive MS patients. The presented work is concerned with the reactivity of blood platelets in primary hemostasis in SP MS patients. 50 SP MS patients and 50 healthy volunteers (never diagnosed with MS or other chronic diseases) were examined to evaluate the biological activity of blood platelets (adhesion, aggregation), especially their response to the most important physiological agonists (thrombin, ADP, and collagen) and the effect of oxidative stress on platelet activity. We found that the blood platelets from SP MS patients were significantly more sensitive to all used agonists in comparison with control group. Moreover, the platelet hemostatic function was advanced in patients suffering from SP MS and positively correlated with increased production of O2 −∙ in these cells, as well as with Expanded Disability Status Scale. We postulate that the increased oxidative stress in blood platelets in SP MS may be primarily responsible for the altered haemostatic properties of blood platelets. PMID:26064417

Marginal Structural Cox Models for Estimating the Association Between β-Interferon Exposure and Disease Progression in a Multiple Sclerosis Cohort

PubMed Central

Karim, Mohammad Ehsanul; Gustafson, Paul; Petkau, John; Zhao, Yinshan; Shirani, Afsaneh; Kingwell, Elaine; Evans, Charity; van der Kop, Mia; Oger, Joel; Tremlett, Helen

2014-01-01

Longitudinal observational data are required to assess the association between exposure to β-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the “real-world” clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995–2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed “normalized stabilized” weights were found to be the most appropriate choice of weights. Using this model, no association between β-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings. PMID:24939980

Immunosuppressive therapy reduces axonal damage in progressive multiple sclerosis.

PubMed

Axelsson, Markus; Malmeström, Clas; Gunnarsson, Martin; Zetterberg, Henrik; Sundström, Peter; Lycke, Jan; Svenningsson, Anders

2014-01-01

In progressive multiple sclerosis (PMS), disease-modifying therapies have not been shown to reduce disability progression. The impact from immunosuppressive therapy in PMS was explored by analyzing cerebrospinal fluid (CSF) biomarkers of axonal damage (neurofilament light protein, NFL), astrogliosis (glial fibrillary acidic protein, GFAP), and B-cell regulation (CXCL13). CSF was obtained from 35 patients with PMS before and after 12-24 months of mitoxantrone (n=30) or rituximab (n=5) treatment, and from 14 age-matched healthy control subjects. The levels of NFL, GFAP, and CXCL13 were determined by immunoassays. The mean NFL level decreased by 51% (1781 ng/l, SD 2018 vs. 874 ng/l, SD 694, p=0.007), the mean CXCL13 reduction was 55% (9.71 pg/ml, SD 16.08, vs. 4.37 pg/ml, SD 1.94, p=0.008), while GFAP levels remained unaffected. Subgroup analysis showed that the NFL reduction was confined to previously untreated patients (n=20) and patients with Gd-enhancing lesions on magnetic resonance imaging (n=12) prior to study baseline. Our data imply that 12-24 months of immunosuppressive therapy reduces axonal damage in PMS, particularly in patients with ongoing disease activity. Determination of NFL levels in CSF is a potential surrogate marker for treatment efficacy and as endpoint in phase II trials of MS.

Markers of oxidative/nitrative damage of plasma proteins correlated with EDSS and BDI scores in patients with secondary progressive multiple sclerosis.

PubMed

Morel, Agnieszka; Bijak, Michał; Niwald, Marta; Miller, Elżbieta; Saluk, Joanna

2017-11-01

The objective of the present study was to evaluate oxidative/nitrative stress in the plasma of 50 patients suffering from the secondary progressive course of multiple sclerosis (MS), and to verify its correlation with physical and mental disability as assessed by the Expanded Disability Status Scale (EDSS), and the Beck Depression Inventory (BDI). Oxidative and nitrative damage to proteins was determined by the level of carbonyl groups and 3-nitrotyrosine using ELISA test. Based on the reaction with Ellman's reagent, we estimated the concentration of oxidized thiol groups. Additionally, we measured the level of lipid peroxidation. In plasma drawn from MS patients, we observed a significantly higher level of 3-NT (92%; P < 0.0003), carbonyl groups (29%; P < 0.0001) and thiobarbituric acid reactive substances (73%; P < 0.0001), as well as a lower concentration of thiol groups (33%; P < 0.0001), in comparison to healthy subjects. We noted positive correlations between the level of carbonyl groups or 3-NT and both diagnostic parameters, EDSS and BDI. Negative correlations were observed between concentration of -SH groups and EDSS and BDI. Our results indicate that impaired red-ox balance can significantly promote neurodegeneration in secondary progressive MS.

Late-onset multiple sclerosis presenting with cognitive dysfunction and severe cortical/infratentorial atrophy.

PubMed

Calabrese, Massimiliano; Gajofatto, Alberto; Gobbin, Francesca; Turri, Giulia; Richelli, Silvia; Matinella, Angela; Oliboni, Eugenio Simone; Benedetti, Maria Donata; Monaco, Salvatore

2015-04-01

Although cognitive dysfunction is a relevant aspect of multiple sclerosis (MS) from the earliest disease phase, cognitive onset is unusual thus jeopardizing early and accurate diagnosis. Here we describe 12 patients presenting with cognitive dysfunction as primary manifestation of MS with either mild or no impairment in non-cognitive neurological domains. Twelve patients with cognitive onset who were subsequently diagnosed with MS (CI-MS) were included in this retrospective study. Twelve cognitively normal MS patients (CN-MS), 12 healthy controls and four patients having progressive supranuclear palsy (PSP) served as the reference population. Ten CI-MS patients had progressive clinical course and all patients had late disease onset (median age = 49 years; range = 40-58 years). Among cognitive functions, frontal domains were the most involved. Compared to CN-MS and healthy controls, significant cortical and infratentorial atrophy characterized CI-MS patients. Selective atrophy of midbrain tegmentum with relative sparing of pons, known as "The Hummingbird sign," was observed in eight CI-MS and in three PSP patients. Our observation suggests that MS diagnosis should be taken into consideration in case of cognitive dysfunction, particularly when associated with slowly progressive disease course and severe cortical, cerebellar and brainstem atrophy even in the absence of other major neurological symptoms and signs. © The Author(s), 2014.

Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis.

PubMed

Planchon, Sarah M; Lingas, Karen T; Reese Koç, Jane; Hooper, Brittney M; Maitra, Basabi; Fox, Robert M; Imrey, Peter B; Drake, Kylie M; Aldred, Micheala A; Lazarus, Hillard M; Cohen, Jeffrey A

2018-01-01

Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 × 10 6 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration.

Impact of multiple sclerosis on employment and use of job-retention strategies: The situation in France in 2015.

PubMed

Fantoni-Quinton, Sophie; Kwiatkowski, Arnaud; Vermersch, Patrick; Roux, Bastien; Hautecoeur, Patrick; Leroyer, Ariane

2016-06-13

The main objective of this survey of persons with multiple sclerosis was to describe their employment situation. Secondary objectives were to ascertain when and how multiple sclerosis symptoms first impact employment per se and what strategies persons with multiple sclerosis use to cope with their employment problems. A retrospective survey was conducted to collect data from persons with multiple sclerosis aged 18 years and over, using a computer-assisted web tool. A total of 941 respondents were working at the time of multiple sclerosis diagnosis or had worked subsequently. Median time since diagnosis was 10 years. Multiple sclerosis had an impact on employment for 74.3% of respondents. The overall employment rate at the time of the survey was 68.1%; 27.2% had discontinued their occupational activity for a multiple sclerosis-related reason. Median time from diagnosis to multiple sclerosis-related cessation of occupational activity was 24.0 years (95% confidence interval (CI) 21.7-26.3 years). Respondents were poorly aware of available tools designed to assist them in retaining employment. This study highlights the importance of early intervention by the occupational medicine physician in order to favour job retention and use of available tools by all workers with MS and not only those with a recognized status as a disabled worker.

The Latest Innovations in the Drug Pipeline for Multiple Sclerosis.

PubMed

Radick, Lea; Mehr, Stanton R

2015-11-01

Several new medications are being investigated in late-phase studies for the treatment of patients with relapsing or progressive multiple sclerosis (MS). These agents represent a variety of mechanisms of action and provide not only lower relapse rates but also improvement in disabilities. The majority of investigational trials involve selective sphingosine-1-phosphate receptor 1 immunomodulators, such as laquinimod, ozanimod, ponesimod, and siponimod, in an effort to build on the success of fingolimod. Ocrelizumab is a CD20-positive B-cell-targeting monoclonal antibody with a promising new mechanism of action. Ofatumumab is also a CD20 inhibitor. Daclizumab, an interleukin-2 inhibitor, has evidence of good efficacy but is associated with unfavorable side effects. Masitinib is a mast-cell inhibitor that also has shown efficacy in Alzheimer's disease and amyotrophic lateral sclerosis. Phase 3 trials for some of these agents will conclude in the next 12 months, and their manufacturers are expected to apply for US Food and Drug Administration approval soon thereafter. This review article summarizes data for newly approved and late-phase investigational agents for the treatment of patients with MS.

The Latest Innovations in the Drug Pipeline for Multiple Sclerosis

PubMed Central

Radick, Lea; Mehr, Stanton R.

2015-01-01

Several new medications are being investigated in late-phase studies for the treatment of patients with relapsing or progressive multiple sclerosis (MS). These agents represent a variety of mechanisms of action and provide not only lower relapse rates but also improvement in disabilities. The majority of investigational trials involve selective sphingosine-1-phosphate receptor 1 immunomodulators, such as laquinimod, ozanimod, ponesimod, and siponimod, in an effort to build on the success of fingolimod. Ocrelizumab is a CD20-positive B-cell–targeting monoclonal antibody with a promising new mechanism of action. Ofatumumab is also a CD20 inhibitor. Daclizumab, an interleukin-2 inhibitor, has evidence of good efficacy but is associated with unfavorable side effects. Masitinib is a mast-cell inhibitor that also has shown efficacy in Alzheimer's disease and amyotrophic lateral sclerosis. Phase 3 trials for some of these agents will conclude in the next 12 months, and their manufacturers are expected to apply for US Food and Drug Administration approval soon thereafter. This review article summarizes data for newly approved and late-phase investigational agents for the treatment of patients with MS. PMID:26702336

Application of Item Response Theory to Modeling of Expanded Disability Status Scale in Multiple Sclerosis.

PubMed

Novakovic, A M; Krekels, E H J; Munafo, A; Ueckert, S; Karlsson, M O

2017-01-01

In this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients' (unobserved) disability using a logistic model. Longitudinal data from placebo arms were used to describe the disease progression over time, and the model was then extended to cladribine arms to characterize the drug effect. Sensitivity with respect to patient disability was calculated as Fisher information for each EDSS item, which were ranked according to the amount of information they contained. The IRT model was able to describe baseline and longitudinal EDSS data on item and total level. The final model suggested that cladribine treatment significantly slows disease-progression rate, with a 20% decrease in disease-progression rate compared to placebo, irrespective of exposure, and effects an additional exposure-dependent reduction in disability progression. Four out of eight items contained 80% of information for the given range of disabilities. This study has illustrated that IRT modeling is specifically suitable for accurate quantification of disease status and description and prediction of disease progression in phase 3 studies on RRMS, by integrating EDSS item-level data in a meaningful manner.

Brain reserve against physical disability progression over 5 years in multiple sclerosis.

PubMed

Sumowski, James F; Rocca, Maria A; Leavitt, Victoria M; Meani, Alessandro; Mesaros, Sarlota; Drulovic, Jelena; Preziosa, Paolo; Habeck, Christian G; Filippi, Massimo

2016-05-24

The brain reserve hypothesis links larger maximal lifetime brain growth (MLBG, estimated with intracranial volume [ICV]) with lower risk for cognitive decline/dementia. We examined whether larger MLBG is also linked to less physical disability progression over 5 years in a prospective sample of treatment-naive patients with multiple sclerosis (MS). Physical disability was measured with the Expanded Disability Status Scale (EDSS) at baseline and 5-year follow-up in 52 treatment-naive Serbian patients with MS. MRI measured disease burden (cerebral atrophy, T2 lesion volume) and MLBG: a genetically determined, premorbid (established during adolescence, stable thereafter) patient characteristic estimated with ICV (adjusted for sex). Logistic regression tested whether MLBG (smaller vs larger) predicts disability progression (stable vs worsened) independently of disease burden. Disability progression was observed in 29 (55.8%) patients. Larger MLBG predicted lower risk for progression (odds ratio 0.13, 95% confidence interval 0.02-0.78), independently of disease burden. We also calculated absolute change in EDSS scores, and observed that patients with smaller MLBG showed worse EDSS change (0.91 ± 0.71) than patients with larger MLBG (0.42 ± 0.87). Larger MLBG was linked to lower risk for disability progression in patients with MS over 5 years, which is the first extension of the brain reserve hypothesis to physical disability. MLBG (ICV) represents a clinically available metric that may help gauge risk for future disability in patients with MS, which may advance the science and practice of early intervention. Potential avenues for future research are discussed. © 2016 American Academy of Neurology.

Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis.

PubMed

Jafari, Naghmeh; Broer, Linda; Hoppenbrouwers, Ilse A; van Duijn, Cornelia M; Hintzen, Rogier Q

2010-11-01

Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10( -5)). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 (p = 0.003) for HLA-A. HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

Neurotoxicity

MedlinePlus

... disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Also being studied are the mechanisms ... disorders such as Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and dementia. Also being studied are the mechanisms ...

Spasticity

MedlinePlus

... in association with spinal cord injury, multiple sclerosis, cerebral palsy, stroke, brain or head trauma, amyotrophic lateral sclerosis, ... in association with spinal cord injury, multiple sclerosis, cerebral palsy, stroke, brain or head trauma, amyotrophic lateral sclerosis, ...

Determining Changes in Neural Circuits in Tuberous Sclerosis

DTIC Science & Technology

2013-05-01

features of human Tuberous Sclerosis including mosaicism, autism and epilepsy. This research progress deepened our understanding of Tuberous Sclerosis by... autism and epilepsy. This research progress deepened our understanding of Tuberous Sclerosis by linking temporal gene function, mTOR function, physiology...of function of Tsc1 in the brain causes intellectual disability, seizures, sleep disorders, and autism . We took advantage of our CreER/loxP based

Orthodontic treatment for a patient with multiple sclerosis

PubMed Central

Bakathir, Manal A

2017-01-01

Multiple sclerosis (MS) is a chronic, autoimmune inflammatory disorder of the central nervous system (CNS) that affects myelinated axons, destroying the myelin and damaging axons to varying degrees. The course of MS is highly varied and unpredictable. Metals used during orthodontic treatment can negatively affect imaging techniques used to diagnose and monitor the progression of MS, while medications used to treat MS can negatively affect orthodontic tooth movement. The present case report highlights some of the challenges encountered during orthodontic treatment of a patient with MS and how to overcome them. The patient was a 20-year-old woman with complaints of diastema and spacing in the upper arch. Although closing the spaces was challenging due to some of the MS medications, she was treated successfully, without complications, within 20 months using closing loops. PMID:28717636

Multiple sclerosis masquerading as Alzheimer-type dementia: Clinical, radiological and pathological findings.

PubMed

Tobin, W O; Popescu, B F; Lowe, V; Pirko, I; Parisi, J E; Kantarci, K; Fields, J A; Bruns, M B; Boeve, B F; Lucchinetti, C F

2016-04-01

We report a comprehensive clinical, radiological, neuropsychometric and pathological evaluation of a woman with a clinical diagnosis of AD dementia (ADem), but whose autopsy demonstrated widespread demyelination, without Alzheimer disease (AD) pathology. Initial neuropsychometric evaluation suggested amnestic mild cognitive impairment (aMCI). Serial magnetic resonance images (MRI) images demonstrated the rate of increase in her ventricular volume was comparable to that of 46 subjects with aMCI who progressed to ADem, without accumulating white matter disease. Myelin immunohistochemistry at autopsy demonstrated extensive cortical subpial demyelination. Subpial lesions involved the upper cortical layers, and often extended through the entire width of the cortex. Multiple sclerosis (MS) can cause severe cortical dysfunction and mimic ADem. Cortical demyelination is not well detected by standard imaging modalities and may not be detected on autopsy without myelin immunohistochemistry. © The Author(s), 2015.

Characteristics and correlates of coping with multiple sclerosis: a systematic review.

PubMed

Keramat Kar, Maryam; Whitehead, Lisa; Smith, Catherine M

2017-10-10

The purpose of this systematic review was to examine coping strategies that people with multiple sclerosis use, and to identify factors that influence their coping pattern. This systematic review followed the Joanna Briggs Institute guidelines for synthesizing descriptive quantitative research. The following databases were searched from the inception of databases until December 2016: Ovid (Medline, Embase, CINAHL, and PsycINFO), Science Direct, Web of Science, and Scopus. Manual search was also conducted from the reference lists of retrieved articles. Findings related to the patterns of coping with multiple sclerosis and factors influencing coping with multiple sclerosis were extracted and synthesized. The search of the database yielded 455 articles. After excluding duplicates (n = 341) and studies that did not meet the inclusion criteria (n = 27), 71 studies were included in the full-text review. Following the full-text, a further 21 studies were excluded. Quality appraisal of 50 studies was completed, and 38 studies were included in the review. Synthesis of findings indicated that people with multiple sclerosis use emotional and avoidance coping strategies more than other types of coping, particularly in the early stages of the disease. In comparison to the general population, people with multiple sclerosis were less likely to use active coping strategies and used more avoidance and emotional coping strategies. The pattern of coping with multiple sclerosis was associated with individual, clinical and psychological factors including gender, educational level, clinical course, mood and mental status, attitude, personality traits, and religious beliefs. The findings of this review suggest that considering individual or disease-related factors could help healthcare professionals in identifying those less likely to adapt to multiple sclerosis. This information could also be used to provide client-centered rehabilitation for people living with multiple sclerosis based on their individual responses and perceptions for coping. Implications for rehabilitation Engagement in coping with multiple sclerosis has been associated with individual factors and neuropsychological functions. Considering individual and disease-related factors would allow healthcare professionals to provide more tailored interventions to maintain and master coping with multiple sclerosis. People living with multiple sclerosis should be empowered to appraise and manage ability to cope based on the contextual evidence (individual and clinical condition). Rehabilitation services should move beyond physical management incorporating behavioral aspects for better functioning in living with multiple sclerosis.

Multiple Sclerosis

MedlinePlus

Multiple sclerosis (MS) is a nervous system disease that affects your brain and spinal cord. It damages the ... attacks healthy cells in your body by mistake. Multiple sclerosis affects women more than men. It often begins ...

Episodic Mood Changes Preceding an Exacerbation of Multiple Sclerosis

PubMed Central

Sharma, Priya; Morrow, Sarah A.; Owen, Richard J.

2015-01-01

Multiple sclerosis is a neurologic inflammatory disease that can manifest with psychiatric symptoms. Although depression is the most common psychiatric diagnosis in patients with multiple sclerosis, how depression develops is not fully understood. We present the case of an individual who displayed episodic mood changes preceding an exacerbation of multiple sclerosis symptoms. The clinical and research implications of this association are discussed. PMID:26835163

Mobilization of Neural Precursors in the Circulating Blood of Patients with Multiple Sclerosis

DTIC Science & Technology

2012-07-01

circulating blood of patients with multiple sclerosis PRINCIPAL INVESTIGATOR: Ernesto R. Bongarzone, Ph.D... multiple sclerosis 5b. GRANT NUMBER W81XWH-09-1-0427 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Ernesto R. Bongarzone...NOTES 14. ABSTRACT Relapsing remitting multiple sclerosis (RRMS) is demyelinating disease that affects both men and women and is characterized by

Physical activity and exercise priorities in community dwelling people with multiple sclerosis: a Delphi study.

PubMed

Stennett, Andrea; De Souza, Lorraine; Norris, Meriel

2018-07-01

Exercise and physical activity have been found to be beneficial in managing disabilities caused by multiple sclerosis. Despite the known benefits, many people with multiple sclerosis are inactive. This study aimed to identify the prioritised exercise and physical activity practices of people with multiple sclerosis living in the community and the reasons why they are engaged in these activities. A four Round Delphi questionnaire scoped and determined consensus of priorities for the top 10 exercise and physical activities and the reasons why people with multiple sclerosis (n = 101) are engaged in these activities. Data were analysed using content analysis, descriptive statistics, and non-parametric tests. The top 10 exercise and physical activity practices and the top 10 reasons why people with multiple sclerosis (n = 70) engaged in these activities were identified and prioritised. Consensus was achieved for the exercise and physical activities (W = 0.744, p < .0001) and for the reasons they engaged in exercise and physical activity (W = 0.723, p < .0001). The exercise and physical activity practices and the reasons people with multiple sclerosis engaged in exercise and physical activity were diverse. These self-selected activities and reasons highlighted that people with multiple sclerosis might conceptualise exercise and physical activity in ways that may not be fully appreciated or understood by health professionals. Considerations of the views of people with multiple sclerosis may be essential if the goal of increasing physical activity in this population is to be achieved. Implications for Rehabilitation Health professionals should work collaboratively with people with multiple sclerosis to understand how they prioritise activities, the underlying reasons for their prioritisations and embed these into rehabilitation programmes. Health professionals should utilise activities prioritised by people with multiple sclerosis in the community as a way to support, promote, and sustain exercise and physical activity in this population. Rehabilitation interventions should include both the activities people with multiple sclerosis prioritise and the reasons why they engage in exercise and physical activity as another option for increasing physical activity levels and reducing sedentary behaviours.

Development and validation of a patient self-assessed questionnaire on satisfaction with communication of the multiple sclerosis diagnosis.

PubMed

Solari, A; Mattarozzi, K; Vignatelli, L; Giordano, A; Russo, P M; Uccelli, M Messmer; D'Alessandro, R

2010-10-01

We describe the development and clinical validation of a patient self-administered tool assessing the quality of multiple sclerosis diagnosis disclosure. A multiple sclerosis expert panel generated questionnaire items from the Doctor's Interpersonal Skills Questionnaire, literature review, and interviews with neurology inpatients. The resulting 19-item Comunicazione medico-paziente nella Sclerosi Multipla (COSM) was pilot tested/debriefed on seven patients with multiple sclerosis and administered to 80 patients newly diagnosed with multiple sclerosis. The resulting revised 20-item version (COSM-R) was debriefed on five patients with multiple sclerosis, field tested/debriefed on multiple sclerosis patients, and field tested on 105 patients newly diagnosed with multiple sclerosis participating in a clinical trial on an information aid. The hypothesized monofactorial structure of COSM-R section 2 was tested on the latter two groups. The questionnaire was well accepted. Scaling assumptions were satisfactory in terms of score distributions, item-total correlations and internal consistency. Factor analysis confirmed section 2's monofactorial structure, which was also test-retest reliable (intraclass correlation coefficient [ICC] 0.73; 95% CI 0.54-0.85). Section 1 had only fair test-retest reliability (ICC 0.45; 95% CI 0.12-0.69), and three items had 8-21% missed responses. COSM-R is a brief, easy-to-interpret MS-specific questionnaire for use as a health care indicator.

[Effects of nutritional status on the multiple sclerosis disease: systematic review].

PubMed

Ródenas Esteve, Irene; Wanden-Berghe, Carmina; Sanz-Valero, Javier

2018-01-19

To review the available scientific literature about the effects of nutritional status on the multiple sclerosis disease. A systematic review of the scientific literature in the Medline (PubMed), Scopus, Cochrane Library and Web of Science databases through November 2016. Search equation: ("Multiple Sclerosis"[Mesh] OR "Multiple Sclerosis"[Title/Abstract] OR "Disseminated Sclerosis"[Title/Abstract] OR "Multiple Sclerosis Acute Fulminating"[Title/Abstract]) AND ("Nutritional Status"[Mesh] OR "Nutritional Status"[Title/Abstract] OR "Nutrition Status"[Title/Abstract]). The quality of the selected articles was discussed using the STROBE questionnaire. The search was completed through experts inquiry and additional review of the bibliographic references included in the selected papers. The concordance between authors (Kappa index) had to be higher than 80% for inclusion in this review. Of the 160 references recovered, after applying inclusion and exclusion criteria, 29 articles were selected for review. Concordance between evaluators was 100.00%. The most studies established vitamin D levels. Others focused their research on finding out which nutrient deficits might be related to the multiple sclerosis development. Vitamin D may influence multiple sclerosis improvement. Sunlight and physical activity would be important factors, with nutritional status, in the course of this disease. It is necessary to produce new specific works that will delve into the subject to find out more about the relationship between nutritional status and multiple sclerosis.

Multiple sclerosis - discharge

MedlinePlus

... this page: //medlineplus.gov/ency/patientinstructions/000129.htm Multiple sclerosis - discharge To use the sharing features on this ... Your doctor has told you that you have multiple sclerosis (MS). This disease affects the brain and spinal ...

Microglia activation in multiple sclerosis black holes predicts outcome in progressive patients: an in vivo [(11)C](R)-PK11195-PET pilot study.

PubMed

Giannetti, Paolo; Politis, Marios; Su, Paul; Turkheimer, Federico; Malik, Omar; Keihaninejad, Shiva; Wu, Kit; Reynolds, Richard; Nicholas, Richard; Piccini, Paola

2014-05-01

The pathophysiological correlates and the contribution to persisting disability of hypointense T1-weighted MRI lesions, black holes (BH), in multiple sclerosis (MS) are still unclear. In order to study the in vivo functional correlates of this MRI finding, we used 11C-PK11195 PET (PK-PET) to investigate changes in microglial activity. Ten relapsing and 9 progressive MS subjects had a PK-PET scan and a MRI scan alongside a full clinical assessment, including the expanded disability status scale (EDSS) for evaluation of disability. We studied the PK binding potential of the specifically bound radioligand relative to the non-displaceable radioligand in tissue (BPND) in T1 BHs. Out of a total of 1242 BHs identified, 947 were PK enhancing. The PKBPND was correlated with the EDSS (r=0.818; p<0.05) only in the progressive group. In the relapsing patients there was an inverse correlation between PKBPND and BH total lesion volume in whole brain (r=-0.781; p<0.05). When progressive patients were grouped according to the disability outcome at 2years from the PK-PET scan, the total PKBPND in BHs was found to be a significant outcome predictor of disability (p<0.01). Our findings show that relapsing and progressive patients have heterogeneous patterns of PKBPND in T1 BHs and indicate that BHs are not just "holes" representing loss of axons and myelin, but display inflammatory activity in the form of activated microglia. The significant association between PKBPND, neurological impairment and outcome in progressive subjects supports a role for activated microglia in disability progression. Copyright © 2014 Elsevier Inc. All rights reserved.

Chronic Cerebrospinal Vascular Insufficiency Is Not Associated with HLA DRB1*1501 Status in Multiple Sclerosis Patients

PubMed Central

Weinstock-Guttman, Bianca; Zivadinov, Robert; Cutter, Gary; Tamaño-Blanco, Miriam; Marr, Karen; Badgett, Darlene; Carl, Ellen; Elfadil, Makki; Kennedy, Cheryl; Benedict, Ralph H. B.; Ramanathan, Murali

2011-01-01

Background Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients. Methodology/Principal Findings This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients. Conclusions/Significance The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS. PMID:21340025

Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations from the 2015 Strategic Planning Conference

PubMed Central

Sahin, Mustafa; Henske, Elizabeth P.; Manning, Brendan D.; Ess, Kevin C.; Bissler, John J.; Klann, Eric; Kwiatkowski, David J.; Roberds, Steven L.; Silva, Alcino J.; Hillaire-Clarke, Coryse St.; Young, Lisa R.; Zervas, Mark; Mamounas, Laura A.

2016-01-01

On March 10–12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland to assess progress and new opportunities for research in tuberous sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis (http://www.ninds.nih.gov/about_ninds/plans/tscler_research_plan.htm). In addition to the National Institute of Neurological Disorders and Stroke and Tuberous Sclerosis Alliance, participants in the strategic planning effort and workshop included representatives from six other Institutes of the National Institutes of Health, the Department of Defense Tuberous Sclerosis Complex Research Program and a broad cross-section of basic scientists and clinicians with expertise in tuberous sclerosis complex along with representatives from the pharmaceutical industry. This review summarizes outcomes from the extensive pre-meeting deliberations and final workshop recommendations, and includes: 1) progress in the field since publication of the initial 2003 research plan for tuberous sclerosis complex; 2) the key gaps, needs and challenges that hinder progress in tuberous sclerosis complex research; and 3) a new set of research priorities along with specific recommendations for addressing the major challenges in each priority area. The new research plan is organized around both short-term and long-term goals with the expectation that progress toward specific objectives can be achieved within a five- to ten-year timeframe. PMID:27267556

Multiple Sclerosis: Can It Cause Seizures?

MedlinePlus

... Is there any connection between multiple sclerosis and epilepsy? Answers from B Mark Keegan, M.D. Epileptic ... E, et al. The prevalence and characteristics of epilepsy in patients with multiple sclerosis in Nordland County, ...

[Chronically ill and unemployed? A review on vocational status in multiple sclerosis].

PubMed

Kern, S; Kühn, M; Ziemssen, T

2013-02-01

Multiple sclerosis (MS) is one of the most common neurological disorders in young adults. It is characterised by a chronic progressive course with far reaching implications on the patient's private and professional life. Based on the current literature, employment status is analysed in relation to disease-specific, therapeutic, psychosocial, and socioeconomic factors. A special emphasis is placed on the vocational status of MS patients in Germany. According national and international studies, around 40 % of all MS patients are currently unemployed. Main reasons for early retirement are disease-specific factors such as impaired mobility, disability in the upper extremities, fatigue, and cognitive impairment. According to the German Multiple Sclerosis Registry (GMSR), these symptoms are still insufficiently treated. In patients with minor motoric impairment (EDSS ≤ 3.0), depressive symptoms seem to have a major impact on employment status. Disease progression, older age at diagnosis, and hard physical work are negative predictors in terms of employment situation. The lack of flexible working hours, the inability to have flexible resting times at work, a lack of understanding from colleagues and employers as well as the personal attitude were main non-disease-specific reasons for early retirement. The current knowledge on the vocational status in MS is mainly based on international studies (e. g., Scandinavia, England, USA, Australia, MSIF Survey). For Germany, only the GMSR supports significant information on the employment status of MS patients. According to the GMSR, ataxia, fatigue and cognitive dysfunction are still insufficiently treated - a situation that is at least partly due to insufficient treatment options. Comprehensive studies that focus on a broad range of possible influencing factors on vocational status of German MS patients are currently lacking. © Georg Thieme Verlag KG Stuttgart · New York.

Sex-Based Differences in Multiple Sclerosis (MS): Part II: Rising Incidence of Multiple Sclerosis in Women and the Vulnerability of Men to Progression of this Disease.

PubMed

Dunn, Shannon E; Gunde, Eva; Lee, Hyunwoo

2015-01-01

It is well known that a number of autoimmune diseases including multiple sclerosis (MS) predominantly affect women and there has been much attention directed toward understanding why this is the case. Past research has revealed a number of sex differences in autoimmune responses that can account for the female bias in MS. However, much less is known about why the incidence of MS has increased exclusively in women over the past half century. The recency of this increase suggests that changing environmental or lifestyle factors are interacting with biological sex to increase MS risk predominantly in females. Indeed, a number of recent studies have identified sex-specific differences in the effect of environmental factors on MS incidence. The first part of this chapter will overview this evidence and will discuss the possible scenarios of how the environment may be interacting with autoimmune mechanisms to contribute to the preferential rise in MS incidence in women. Despite the strong female bias in MS incidence, culminating evidence from natural history studies, and imaging and pathology studies suggests that males who develop MS may exhibit a more rapid decline in disability and cognitive functioning than women. Very little is known about the biological basis of this more rapid deterioration, but some insights have been provided by studies in rodent models of demyelination/remyelination. The second part of this chapter will overview the evidence that males with relapsing-onset MS undergo a more rapid progression of disease than females and will discuss potential biological mechanisms that account for this sex difference.

Effect of alpha-lipoic acid on asymmetric dimethylarginine and disability in multiple sclerosis patients: A randomized clinical trial.

PubMed

Khalili, Mohammad; Soltani, Madjid; Moghadam, Shirin Amiri; Dehghan, Parvin; Azimi, Amirreza; Abbaszadeh, Omid

2017-07-01

Multiple Sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system. Oxidative stress plays a major role in the onset and progression of MS. Asymmetric dimethylarginine (ADMA) formation is dependent on oxidative stress status. We examined whether alpha-lipoic acid (ALA) as a potent antioxidant could improve the Expanded Disability Status Scale (EDSS) and decrease plasma level of ADMA in multiple sclerosis patients. In a randomized, double-blinded clinical trial conducted at Sina Hospital in Tehran, Iran, from September 2009 to July 2011, 24 patients with relapsing-remitting MS were divided into a treatment group receiving ALA (1200mg/day) for 12 weeks and a control group receiving placebo. Then patients' EDSS and Plasma levels of ADMA were measured at baseline and 12 weeks later. Statistical analysis was done by SPSS software version 16 using the K-S test, Chi square, Mann-Whitney U-test and Wilcoxon test. The plasma levels of ADMA in the intervention group were decreased significantly (p=0.04). Also, no patient had increased EDSS score in the supplement group, where 2 out of 12 patients in the placebo group experienced so. Comparing the serum level of ADMA between the two groups failed to show any significant change in the supplement group compared with the control group. Considering that ADMA is produced by oxidative stress in MS patients and leads to increase of inflammation, ALA may have the potential of beneficial effects in them, in part, by decreasing the plasma level of ADMA and stopping progression. The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: No. IRCT138812222602N2. The authors received no financial support for the research, authorship, and/or publication of this article.

Detection of Brain Reorganization in Pediatric Multiple Sclerosis Using Functional MRI

DTIC Science & Technology

2015-10-01

Page | 2 AWARD NUMBER: W81XWH-13-1-0464 TITLE: Detection of Brain Reorganization in Pediatric Multiple Sclerosis Using Functional MRI...Sep 2014 – 29 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Detection of Brain Reorganization in Pediatric Multiple Sclerosis Using Functional...findings include: 1) detection of brain organization in a cohort of 24 pediatric onset multiple sclerosis patients (POMS) and 25 healthy controls

Plasma Endothelial Microparticles in Multiple Sclerosis: A Novel Metric Assay of Disease Activity and Response to Treatment

DTIC Science & Technology

2011-09-01

direct link to a source of increased tissue iron deposition which is characteristic for multiple sclerosis . The results of these data and their... Multiple Sclerosis : A Novel Metric Assay of Disease Activity and Response to Treatment PRINCIPAL INVESTIGATOR: Jonathan Steven...SUBTITLE 5a. CONTRACT NUMBER Plasma Endothelial Microparticles in Multiple Sclerosis : A Novel Metric Assay of Disease Activity and Response to

Illness trajectories in patients with amyotrophic lateral sclerosis: How illness progression is related to life narratives and interpersonal relationships.

PubMed

Cipolletta, Sabrina; Gammino, Giorgia Rosamaria; Palmieri, Arianna

2017-12-01

To identify illness trajectories in amyotrophic lateral sclerosis by analysing personal, social and functional dimensions related to amyotrophic lateral sclerosis progression. Previous studies have considered some psychological distinct variables that may moderate illness progression, but no research has combined an extensive qualitative understanding of amyotrophic lateral sclerosis patients' psychological characteristics and illness progression. A mixed-methods approach was used to combine quantitative and qualitative measures. Illness progression was assessed through a longitudinal design. Eighteen patients with amyotrophic lateral sclerosis attending a Neurology Department in northern Italy participated in the study. Semi-structured interviews to explore personal experience, and dependency grids to assess the distribution of dependency; ALSFRS-R and neuropsychological screening were, respectively, used to measure physical and cognitive impairment. To assess the progression of the disease, ALSFRS-R was re-administered after 8 months and mortality rate was considered. Data were analysed using the grounded theory approach. Illness progression changed according to the perception of the disease, the trust placed in medical care, self-construction and the distribution of dependency. Based on these categories, cases that had similar experiences were grouped, and four illness trajectories were identified: aggressiveness, threat, constriction and guilt. The findings suggest that it is possible to identify different illness trajectories in amyotrophic lateral sclerosis. Personalised intervention strategies may be construed based on the different trajectories identified. © 2017 John Wiley & Sons Ltd.

Living with uncertainty and hope: A qualitative study exploring parents' experiences of living with childhood multiple sclerosis.

PubMed

Hinton, Denise; Kirk, Susan

2017-06-01

Background There is growing recognition that multiple sclerosis is a possible, albeit uncommon, diagnosis in childhood. However, very little is known about the experiences of families living with childhood multiple sclerosis and this is the first study to explore this in depth. Objective Our objective was to explore the experiences of parents of children with multiple sclerosis. Methods Qualitative in-depth interviews with 31 parents using a grounded theory approach were conducted. Parents were sampled and recruited via health service and voluntary sector organisations in the United Kingdom. Results Parents' accounts of life with childhood multiple sclerosis were dominated by feelings of uncertainty associated with four sources; diagnostic uncertainty, daily uncertainty, interaction uncertainty and future uncertainty. Parents attempted to manage these uncertainties using specific strategies, which could in turn create further uncertainties about their child's illness. However, over time, ongoing uncertainty appeared to give parents hope for their child's future with multiple sclerosis. Conclusion Illness-related uncertainties appear to play a role in generating hope among parents of a child with multiple sclerosis. However, this may lead parents to avoid sources of information and support that threatens their fragile optimism. Professionals need to be sensitive to the role hope plays in supporting parental coping with childhood multiple sclerosis.

Economic burden of multiple sclerosis and the role of managed sare organizations in multiple sclerosis management.

PubMed

Owens, Gary M

2016-06-01

Multiple sclerosis (MS) is disease that has an early age of onset and may intensify and subside with disease relapses or exacerbations interrupted by periods of stability. Because of this, patients, their families and caregivers, employers, and the entire healthcare system carry substantial clinical and economic burdens associated with the disease over of a period of many years. Although most patients with MS are covered by health insurance, the management landscape has become increasingly complex over the past decade with the introduction and approval of several new disease-modifying therapies that, while remarkably effective and well tolerated, usually come with a very high cost. Whereas the main goal of treating patients with MS is to prevent disease progression and disability, healthcare and benefit providers are faced with an ever-tipping balance point between effectively managing the disease and maximizing the value of high-cost disease-modifying therapies in an already overburdened healthcare system. Treatment of MS should be individualized, and shared decision making between patients and healthcare providers must be preserved. Healthcare providers and payers need to collaborate to ensure that resources are used optimally and not wasted, reducing both the clinical and economic burdens related to this complex chronic disorder.

Work Change in Multiple Sclerosis as Motivated by the Pursuit of Illness-Work-Life Balance: A Qualitative Study.

PubMed

Vijayasingham, Lavanya; Jogulu, Uma; Allotey, Pascale

2017-01-01

Individuals with multiple sclerosis have a tendency to make early decisions for work change, even in reversible, episodic, or mild disease stages. To better understand how a multiple sclerosis (MS) diagnosis influences perceptions of work and motivations for work changes, we conducted a hermeneutic phenomenology study to explore the work lives of ten individuals with MS in Malaysia. The interpretive analysis and cumulative narratives depict an overarching change in their concept of ideal work and life aspirations and how participants make preemptive work changes to manage illness-work-life futures in subjectively meaningful ways. Discussions on their integrated pursuit of finding dynamic and subjective illness-work-life balance include reconciling the problem of hard work and stress on disease activity and progress, making positive lifestyle changes as health management behaviour, and the motivational influence of their own life and family roles: the consideration of their spouses, parents, and children. At an action level, work change was seen as moral and necessary for the management of illness futures. Our findings contribute insights on how individual perceptions and holistic life management decisions contribute to on-going and disrupted work trajectories, which can inform practice and policy on early interventions to support continued employment.

Work Change in Multiple Sclerosis as Motivated by the Pursuit of Illness-Work-Life Balance: A Qualitative Study

PubMed Central

Jogulu, Uma

2017-01-01

Individuals with multiple sclerosis have a tendency to make early decisions for work change, even in reversible, episodic, or mild disease stages. To better understand how a multiple sclerosis (MS) diagnosis influences perceptions of work and motivations for work changes, we conducted a hermeneutic phenomenology study to explore the work lives of ten individuals with MS in Malaysia. The interpretive analysis and cumulative narratives depict an overarching change in their concept of ideal work and life aspirations and how participants make preemptive work changes to manage illness-work-life futures in subjectively meaningful ways. Discussions on their integrated pursuit of finding dynamic and subjective illness-work-life balance include reconciling the problem of hard work and stress on disease activity and progress, making positive lifestyle changes as health management behaviour, and the motivational influence of their own life and family roles: the consideration of their spouses, parents, and children. At an action level, work change was seen as moral and necessary for the management of illness futures. Our findings contribute insights on how individual perceptions and holistic life management decisions contribute to on-going and disrupted work trajectories, which can inform practice and policy on early interventions to support continued employment. PMID:29348937

Genome-Wide Association Study of Multiple Sclerosis Confirms a Novel Locus at 5p13.1

PubMed Central

Sanna, Serena; Gayán, Javier; Urcelay, Elena; Zara, Ilenia; Pitzalis, Maristella; Cavanillas, María L.; Arroyo, Rafael; Zoledziewska, Magdalena; Marrosu, Marisa; Fernández, Oscar; Leyva, Laura; Alcina, Antonio; Fedetz, Maria; Moreno-Rey, Concha; Velasco, Juan; Real, Luis M.; Ruiz-Peña, Juan Luis; Cucca, Francesco

2012-01-01

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80–0.89; p = 1.36×10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS. PMID:22570697

What's new in multiple sclerosis spasticity research? Poster session highlights.

PubMed

Linker, Ralf

2017-11-01

Each year at the Multiple Sclerosis Experts Summit, relevant research in the field of multiple sclerosis spasticity is featured in poster sessions. The main studies presented at this year's meeting are summarized herein.

Accelerated Cure Project for Multiple Sclerosis

MedlinePlus

... main content Accelerating research toward a cure for multiple sclerosis Toggle navigation Search form Search Connect Volunteer Donate ... is to accelerate efforts toward a cure for multiple sclerosis by rapidly advancing research that determines its causes ...

Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.

PubMed

Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas

2017-10-01

Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Effectiveness of multiple sclerosis treatment with current immunomodulatory drugs.

PubMed

Milo, Ron

2015-04-01

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS of a putative autoimmune origin characterized by neurologic dysfunction disseminated in space and time due to demyelination and axonal loss that results in progressive disability. Recent advances in understanding the immune pathogenesis of the disease resulted in the introduction of numerous effective immunomodulatoty drugs having diverse mechanisms of action, modes of administration and risk-benefit profiles. This results in more complex albeit more promising treatment selection and choices. The epidemiology, clinical features, pathogenesis and diagnosis of the disease are discussed. The mode of action and main characteristics of current immunomodulatory drugs for MS and their place in the therapeutic algorithm of the disease based on evidence from clinical trials are described. Speculation on new paradigms, treatment goals and outcome measures aimed at improving the landscape of MS treatment is presented. Multiple disease, drug and patient-related factors should be taken into consideration when selecting the appropriate drug and treatment strategy to the appropriate patient, thus paving the road for personalized medicine in MS.

Epidemiological and clinical characteristics of multiple sclerosis in paediatric population in Slovenia: A descriptive nation-wide study.

PubMed

Bizjak, Neli; Osredkar, Damjan; Perković Benedik, Mirjana; Šega Jazbec, Saša

2017-11-01

Although multiple sclerosis usually affects young adults, paediatric-onset multiple sclerosis (pMS) is increasingly recognized in the past ten years. The aim of the present study was to evaluate the incidence of pMS in Slovenia and to characterize the clinical, laboratory and neuroradiological characteristics of pMS at the disease onset. We performed a national retrospective descriptive study including all patients diagnosed with pMS between January 1992 and June 2017. We reviewed data of all patients younger than 18 years at the first demyelinating event. The estimated incidence of pMS was 0.66/100,000 children per year. We included 61 patients (77% were female) with a median age at diagnosis of 16.3 years. In 4 patients, onset of pMS was before the age of 12 years old (childhood-onset pMS). Relapsing-remitting multiple sclerosis was most prevalent, with only 2 patients presenting a primary progressive pMS. Polysymptomatic pMS was found at onset in 59% of patients and monosymptomatic in 41%. In the cerebrospinal fluid study, 88% of patients had positive oligoclonal bands. Brain magnetic resonance imaging studies showed a predominant supratentorial involvement (100% of patients). The clinical pattern of pMS in our cohort of patients was characterized by polysymptomatic presentation and predominantly sensory symptoms at onset, developing a relapsing-remitting pMS pattern. It is important to gather more information about the incidence of pMS and its initial presentation and clinical course to improve early recognition and appropriate initiation of immunomodulatory treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Disability-Specific Atlases of Gray Matter Loss in Relapsing-Remitting Multiple Sclerosis.

PubMed

MacKenzie-Graham, Allan; Kurth, Florian; Itoh, Yuichiro; Wang, He-Jing; Montag, Michael J; Elashoff, Robert; Voskuhl, Rhonda R

2016-08-01

Multiple sclerosis (MS) is characterized by progressive gray matter (GM) atrophy that strongly correlates with clinical disability. However, whether localized GM atrophy correlates with specific disabilities in patients with MS remains unknown. To understand the association between localized GM atrophy and clinical disability in a biology-driven analysis of MS. In this cross-sectional study, magnetic resonance images were acquired from 133 women with relapsing-remitting MS and analyzed using voxel-based morphometry and volumetry. A regression analysis was used to determine whether voxelwise GM atrophy was associated with specific clinical deficits. Data were collected from June 28, 2007, to January 9, 2014. Voxelwise correlation of GM change with clinical outcome measures (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite scores). Among the 133 female patients (mean [SD] age, 37.4 [7.5] years), worse performance on the Multiple Sclerosis Functional Composite correlated with voxelwise GM volume loss in the middle cingulate cortex (P < .001) and a cluster in the precentral gyrus bilaterally (P = .004). In addition, worse performance on the Paced Auditory Serial Addition Test correlated with volume loss in the auditory and premotor cortices (P < .001), whereas worse performance on the 9-Hole Peg Test correlated with GM volume loss in Brodmann area 44 (Broca area; P = .02). Finally, voxelwise GM loss in the right paracentral lobulus correlated with bowel and bladder disability (P = .03). Thus, deficits in specific clinical test results were directly associated with localized GM loss in clinically eloquent locations. These biology-driven data indicate that specific disabilities in MS are associated with voxelwise GM loss in distinct locations. This approach may be used to develop disability-specific biomarkers for use in future clinical trials of neuroprotective treatments in MS.

[The overall assessment of psychological well - being of patients with multiple sclerosis after the application of physical therapy. Part 2].

PubMed

Kubsik-Gidlewska, Anna; Klimkiewicz, Robert; Klimkiewicz, Paulina; Janczewska, Katarzyna; Jankowska, Agnieszka; Nowakowski, Tomasz; Woldańska-Okońska, Marta

2017-01-01

Multiple sclerosis is a chronic demyelinating disease of the central nervous system, which results a progressive disability. The disease reduces the quality of life of patients, changes the general health perceptions, and also limits performing social roles because of emotional problems. Evaluation of the impact of the methods of rehabilitation to improve the mental health of patients with multiple sclerosis, and also to change individual parameters included in the overall assessment of mental health. The study was conducted in 2010-2014 at the Department of Physical Medicine and Rehabilitation in Lodz. The study included 120 patients with multiple sclerosis. Patients were classified into 4 test groups: in the first was used the laser, in the second - laser and magnetostimulation, in the third - kinesiotherapy, and in the fourth - magnetostimulation. The tests were carried out three times. To evaluate the quality of life was used Quality of Life Questionnaire (MSQOL-54), analyzed the overall assessment of mental health. The improvement in a range of parameters, an overall assessment of the quality of mental health has allowed to get a better overall psychological well-being. ,There was oserved a statistically significant difference at the level of p<0.001 between groups in 4/5 investigated parameters, statistically significant differences weren't obserwed at the evaluation of cognitive functions. The greatest improvement was observed in Group II and Group IV. In the examination it was confirmed an effectiveness of physical treatment, such a the laser radiation and magnetostimulation. Synergism of both methods in their biological activity, allows for evoke of hysteresis fenomenon, resulting in the maintenance of the treatment effects after cessation of rehabilitation. Applying the classical kinesiotherapy only doesn't allow to get long-term effects.

[The overall assessment of the quality of the physical health of patients with multiple sclerosis after the application of physical therapy. Part 1].

PubMed

Kubsik, Anna; Klimkiewicz, Robert; Klimkiewicz, Paulina; Janczewska, Katarzyna; Jankowska, Agnieszka; Kociuga, Natalia; Woldańska-Okońska, Marta

2016-01-01

Multiple sclerosis is one of the demyelinating diseases of the central nervous system. The biggest problem of patients affected by this disease are physical limitations which force many times to changes in employment and dependent on their families.The progressive disability significantly reduces the quality of life of patients with MS. The study involved 120 patients with multiple sclerosis at the age of 21 - 81 years. Patients were divided into four groups, and the test was performed three times. In the first group was used laser therapy, group II laser and magnetostimulation, in the third group kinesiotherapy in the fourth group magnetostimulation. In all patients MSQOL (Quality of Life Questionnaire-54) was carried out, this survey analyzed overall assessment of physical health. In all test groups was observed tends to decrease as a result of a point in Quality of Life Questionnaire MSQOL-54 and continuation in this relationship even after cessation of use of these therapies. The correlation between the two groups showed a statistically significant result at the level of p <0.001 in the group I and II in relation to group III and IV. Synergic action of laser radiation and magnetic stimulation, causing a plurality of changes at the cellular and tissue level, has a beneficial effect on improving functional status, and thereby improves the quality of life of patients with multiple sclerosis. Thanks to physical therapy, it is possible to achieve long-term effects of therapy, which proves the biological hysteresis phenomenon. Such results can not be achieved with using monotherapy only - by kinesiotherapy.

Randomized study combining interferon and glatiramer acetate in multiple sclerosis.

PubMed

Lublin, Fred D; Cofield, Stacey S; Cutter, Gary R; Conwit, Robin; Narayana, Ponnada A; Nelson, Flavia; Salter, Amber R; Gustafson, Tarah; Wolinsky, Jerry S

2013-03-01

A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis. A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. Combination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences. Copyright © 2013 American Neurological Association.

A network meta-analysis of randomized controlled trials for comparing the effectiveness and safety profile of treatments with marketing authorization for relapsing multiple sclerosis.

PubMed

Hadjigeorgiou, G M; Doxani, C; Miligkos, M; Ziakas, P; Bakalos, G; Papadimitriou, D; Mprotsis, T; Grigoriadis, N; Zintzaras, E

2013-12-01

The relative effectiveness and safety profile of the treatments with marketing authorization for relapsing multiple sclerosis (MS) are not well known because randomized controlled trials with head-to-head comparisons between these treatments do not exist. Thus, a network of multiple-treatments meta-analysis was performed using four clinical outcomes: 'patients free of relapse', 'patients without disease progression', 'patients without MRI progression' and 'patients with adverse events'. Randomized controlled trials (RCTs) on MS were systematically searched in PubMed and Cochrane Central Register of Controlled Trial. The network analysis performed pairwise comparisons between the marketed treatments (Betaferon 250mcg, Avonex 30mcg, Rebif 44mcg, Rebif 22mcg, Aubagio 7 mg, Aubagio 14 mg, Copaxone 20 mg, Tysabri 300 mg, Gilenya 0·5 mg and Novantrone 12 mg/m(2)) using direct and indirect analyses. The analysis included 48 articles, involving 20 455 patients with MS. The direct analysis showed better response for more than one outcome for Gilenya compared with Avonex ('patients free of relapse' and 'patients without MRI progression') and for Betaferon compared with Avonex ('patients without disease progression' and 'patients without MRI progression'). The indirect analysis indicated that Tysabri may have better relative effectiveness compared with the other treatments for two outcomes: 'patients free of relapse' and 'patients without MRI progression'. Regarding 'patients with adverse events', no data were available for all comparisons to make fair inferences. This was an attempt, for the first time, to compare the efficacy and safety profile of existing approved treatments for relapsing MS. Although some treatments have shown better response, the results of the network analysis should be interpreted with caution because of the lack of RCTs with head-to-head comparisons between treatments. © 2013 John Wiley & Sons Ltd.

78 FR 17613 - Special Local Regulations and Safety Zones; Recurring Events in Northern New England

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-22

... Multiple Sclerosis Event Type: Regatta and Sailboat Regatta. Race Sponsor: Maine Chapter, Multiple...]13'51'' W 8.7 Multiple Sclerosis Event Type: Power Boat Race Harborfest Lobster Boat/ Sponsor: Maine Chapter, National Tugboat Races. Multiple Sclerosis Society [[Page 17619

Differential diagnosis of Mendelian and mitochondrial disorders in patients with suspected multiple sclerosis

PubMed Central

Katz Sand, Ilana B.; Honce, Justin M.; Lublin, Fred D.

2015-01-01

Several single gene disorders share clinical and radiologic characteristics with multiple sclerosis and have the potential to be overlooked in the differential diagnostic evaluation of both adult and paediatric patients with multiple sclerosis. This group includes lysosomal storage disorders, various mitochondrial diseases, other neurometabolic disorders, and several other miscellaneous disorders. Recognition of a single-gene disorder as causal for a patient’s ‘multiple sclerosis-like’ phenotype is critically important for accurate direction of patient management, and evokes broader genetic counselling implications for affected families. Here we review single gene disorders that have the potential to mimic multiple sclerosis, provide an overview of clinical and investigational characteristics of each disorder, and present guidelines for when clinicians should suspect an underlying heritable disorder that requires diagnostic confirmation in a patient with a definite or probable diagnosis of multiple sclerosis. PMID:25636970

Visual field impairment captures disease burden in multiple sclerosis.

PubMed

Ortiz-Perez, Santiago; Andorra, Magí; Sanchez-Dalmau, Bernardo; Torres-Torres, Rubén; Calbet, David; Lampert, Erika J; Alba-Arbalat, Salut; Guerrero-Zamora, Ana M; Zubizarreta, Irati; Sola-Valls, Nuria; Llufriu, Sara; Sepúlveda, María; Saiz, Albert; Villoslada, Pablo; Martinez-Lapiscina, Elena H

2016-04-01

Monitoring disease burden is an unmeet need in multiple sclerosis (MS). Identifying patients at high risk of disability progression will be useful for improving clinical-therapeutic decisions in clinical routine. To evaluate the role of visual field testing in non-optic neuritis eyes (non-ON eyes) as a biomarker of disability progression in MS. In 109 patients of the MS-VisualPath cohort, we evaluated the association between visual field abnormalities and global and cognitive disability markers and brain and retinal imaging markers of neuroaxonal injury using linear regression models adjusted for sex, age, disease duration and use of disease-modifying therapies. We evaluated the risk of disability progression associated to have baseline impaired visual field after 3 years of follow-up. Sixty-two percent of patients showed visual field defects in non-ON eyes. Visual field mean deviation was statistically associated with global disability; brain (normalized brain parenchymal, gray matter volume and lesion load) and retinal (peripapillary retinal nerve fiber layer thickness and macular ganglion cell complex thickness) markers of neuroaxonal damage. Patients with impaired visual field had statistically significative greater disability, lower normalized brain parenchymal volume and higher lesion volume than patients with normal visual field testing. MS patients with baseline impaired VF tripled the risk of disability progression during follow-up [OR = 3.35; 95 % CI (1.10-10.19); p = 0.033]. The association of visual field impairment with greater disability and neuroaxonal injury and higher risk of disability progression suggest that VF could be used to monitor MS disease burden.

'You are just left to get on with it': qualitative study of patient and carer experiences of the transition to secondary progressive multiple sclerosis.

PubMed

Davies, F; Edwards, A; Brain, K; Edwards, M; Jones, R; Wallbank, R; Robertson, N P; Wood, F

2015-07-22

Although the transition to secondary progressive multiple sclerosis (SPMS) is known to be a period of uncertainty for clinicians, who may find progressive disease challenging to objectively identify, little research has explored the experiences of patients and carers specifically during this transition period. Our objective was to explore what patients and their carers understand about their disease stage and describe their experiences and perspectives on the transition to SPMS. Semistructured qualitative interviews and subsequent validation focus groups were analysed using inductive thematic analysis. South East Wales, UK. 20 patients with MS and 13 carers were interviewed. Eight patients and two carers participated in focus groups. Four main themes around disease progression were identified. 'Realisation' describes how patients came to understand they had SPMS while 'reaction' describes their response to this realisation. The 'realities' of living with SPMS, including dealing with the healthcare system during this period, were described along with 'future challenges' envisaged by patients and carers. Awareness that the transition to SPMS has occurred, and subsequent emotional reactions and coping strategies, varied widely between patients and their carers. The process of diagnosing the transition was often not transparent and some individuals wanted information to help them understand what the transition to SPMS meant for them. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Impaired neurosteroid synthesis in multiple sclerosis

PubMed Central

Noorbakhsh, Farshid; Ellestad, Kristofor K.; Maingat, Ferdinand; Warren, Kenneth G.; Han, May H.; Steinman, Lawrence; Baker, Glen B.

2011-01-01

High-throughput technologies have led to advances in the recognition of disease pathways and their underlying mechanisms. To investigate the impact of micro-RNAs on the disease process in multiple sclerosis, a prototypic inflammatory neurological disorder, we examined cerebral white matter from patients with or without the disease by micro-RNA profiling, together with confirmatory reverse transcription–polymerase chain reaction analysis, immunoblotting and gas chromatography-mass spectrometry. These observations were verified using the in vivo multiple sclerosis model, experimental autoimmune encephalomyelitis. Brains of patients with or without multiple sclerosis demonstrated differential expression of multiple micro-RNAs, but expression of three neurosteroid synthesis enzyme-specific micro-RNAs (miR-338, miR-155 and miR-491) showed a bias towards induction in patients with multiple sclerosis (P < 0.05). Analysis of the neurosteroidogenic pathways targeted by micro-RNAs revealed suppression of enzyme transcript and protein levels in the white matter of patients with multiple sclerosis (P < 0.05). This was confirmed by firefly/Renilla luciferase micro-RNA target knockdown experiments (P < 0.05) and detection of specific micro-RNAs by in situ hybridization in the brains of patients with or without multiple sclerosis. Levels of important neurosteroids, including allopregnanolone, were suppressed in the white matter of patients with multiple sclerosis (P < 0.05). Induction of the murine micro-RNAs, miR-338 and miR-155, accompanied by diminished expression of neurosteroidogenic enzymes and allopregnanolone, was also observed in the brains of mice with experimental autoimmune encephalomyelitis (P < 0.05). Allopregnanolone treatment of the experimental autoimmune encephalomyelitis mouse model limited the associated neuropathology, including neuroinflammation, myelin and axonal injury and reduced neurobehavioral deficits (P < 0.05). These multi-platform studies point to impaired neurosteroidogenesis in both multiple sclerosis and experimental autoimmune encephalomyelitis. The findings also indicate that allopregnanolone and perhaps other neurosteroid-like compounds might represent potential biomarkers or therapies for multiple sclerosis. PMID:21908875

Vitamin D and Multiple Sclerosis (MS): Is There Any Connection?

MedlinePlus

... protective effect and lower the risk of developing multiple sclerosis (MS). Another study conducted at Maastricht University in ... D. Raghuwanshi A, et al. Vitamin D and multiple sclerosis. Journal of Cell Biochemistry. 2008;105:338. Ramagopalan ...

Brain-derived neurotrophic factor levels under chronic natalizumab treatment in multiple sclerosis. A preliminary report.

PubMed

Văcăraş, Vitalie; Major, Zoltán Zsigmond; Buzoianu, Anca Dana

Our main purpose was to investigate if the chronic treatment with the disease-modifying drug natalizumab shows quantifiable effect on BDNF levels in multiple sclerosis patients. BDNF plasma concentration was evaluated using enzyme-linked immunosorbent assay in healthy individuals, not treated multiple sclerosis patients and patients treated with natalizumab. Multiple sclerosis patients have a significantly lower amount of peripheral BDNF than healthy individuals. Patients treated with natalizumab have significantly higher BDNF levels than not treated patients. Chronic natalizumab treatment is associated with significantly increased plasma BDNF concentration in multiple sclerosis. Copyright © 2017 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

[Coincidence of juvenile idiopathic arthritis and multiple sclerosis: case report].

PubMed

Puszczewicz, Mariusz J; Tuchocka-Piotrowska, Aleksandra; Majewski, Dominik; Kołczewska, Aleksandra

2006-01-01

Juvenile idiopathic arthritis is a systemic pathology of connective tissue characterized by a chronic inflammatory process with an autoimmune background whereas multiple sclerosis is a demyelination disease with an important role of immune disorders in its pathogenesis. The etiology in both cases remains unknown. The coincidence of juvenile idiopathic arthritis and multiple sclerosis was described a just a few patients. We now report on a 31-year-old woman with juvenile idiopathic arthritis and multiple sclerosis. In the present case, the main problem was to find the right proper medication for a very, aggressive course of multiple sclerosis and for arthritis. Treatment with interferon-beta and methylprednisolone led to remission with just minor side-effects.

Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease.

PubMed

Yamamoto, Shinji; Yamashina, Kota; Ishikawa, Masaki; Gotoh, Mari; Yagishita, Sosuke; Iwasa, Kensuke; Maruyama, Kei; Murakami-Murofushi, Kimiko; Yoshikawa, Keisuke

2017-07-21

Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis. To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. We demonstrated that 2ccPA suppressed the CoCl 2 -induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model. We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE. These data indicate that 2ccPA may be a promising compound for the development of new drugs to treat demyelinating disease and ameliorate the symptoms of multiple sclerosis.

[Assessment of the pain patients with the multiple sclerosis after applying the physiotherapy treatment].

PubMed

Kubsik, Anna; Klimkiewicz, Robert; Klimkiewicz, Paulina; Janczewska, Katarzyna; Jankowska, Agnieszka; Łukasiak, Adam; Woldańska-Okońska, Marta

2016-04-01

Multiple sclerosis is one of the most common demyelinating disease of the CNS connected with the autoimmune action. The effect of the disease is progressive disability, and one of the symptoms is pain. In relieving pain in the course of MS physical procedures and exercises of physiotherapy are used. The aim of the study was assessment of the pain in patients with the multiple sclerosis after applying laser radiation, magnetostimulation and kinesiotherapy. The studied material was consisted of 120 patients with multiple sclerosis of both sexes (82 women and 38 men) aged 21-81 years. Patients were randomly divided into 4 treatment groups and the assesment was performed three times. In the first group laser therapy, in the group II laser and magnetostimulation, in the third group kinesiotherapy, in the fourth group magnetostimulation was used. The same program of physiotherapy in all groups was used. All patients were performed the following tests to assess of the pain: The Laitinen Modified Questionnaire Indicators of Pain of and the Visual- Analogue Scale (VAS). In all treatment groups was observed tends to decrease a result of a point in The Laitinen Modified Questionnaire Indicators of Pain and the Visual-Analogue Scale (VAS). Correlation between groups demonstrated statistically significant result on the level p<0.05 in the group where the laser treatment was applied towards group II assessed with parameter of the Questionnaire of Pain according to Laitinen, as well as towards group II and III assessed with parameter - of the Visual Analogue Scale (VAS). The good result, i.e. the reduction of the spot value, after the III examination towards the preliminary examination were got in the group II. Laser radiation is an effective method which has an analgesisc action. The combination of laser radiation and magnetostimulation reduces pain in patients with multiple sclerosis, and also allows to maintain a therapeutic effect even after the cessation of the application of these procedures, which indicates the possibility to elicitation the biological phenomenon of hysteresis in these methods. © 2016 MEDPRESS.

Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference.

PubMed

Sahin, Mustafa; Henske, Elizabeth P; Manning, Brendan D; Ess, Kevin C; Bissler, John J; Klann, Eric; Kwiatkowski, David J; Roberds, Steven L; Silva, Alcino J; Hillaire-Clarke, Coryse St; Young, Lisa R; Zervas, Mark; Mamounas, Laura A

2016-07-01

On March 10 to March 12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland, to assess progress and new opportunities for research in tuberous sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis (http://www.ninds.nih.gov/about_ninds/plans/tscler_research_plan.htm). In addition to the National Institute of Neurological Disorders and Stroke and Tuberous Sclerosis Alliance, participants in the strategic planning effort and workshop included representatives from six other Institutes of the National Institutes of Health, the Department of Defense Tuberous Sclerosis Complex Research Program, and a broad cross-section of basic scientists and clinicians with expertise in tuberous sclerosis complex along with representatives from the pharmaceutical industry. Here we summarize the outcomes from the extensive premeeting deliberations and final workshop recommendations, including (1) progress in the field since publication of the initial 2003 research plan for tuberous sclerosis complex, (2) the key gaps, needs, and challenges that hinder progress in tuberous sclerosis complex research, and (3) a new set of research priorities along with specific recommendations for addressing the major challenges in each priority area. The new research plan is organized around both short-term and long-term goals with the expectation that progress toward specific objectives can be achieved within a five to ten year time frame. Copyright © 2016 Elsevier Inc. All rights reserved.

Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-1-0524 TITLE:Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis PRINCIPAL INVESTIGATOR: Jeffrey D...29 Sep 2015 4. TITLE AND SUBTITLE Oligodendroglial MCT1 and Metabolic Support of Axons in Multiple Sclerosis 5a. CONTRACT NUMBER W81XWH-14-1-0524...MCT1 in injured oligodendroglia of multiple sclerosis patients contributes to axon neurodegeneration and that increasing MCT1 will be protective in the

Gut microbiota in multiple sclerosis: possible influence of immunomodulators.

PubMed

Cantarel, Brandi L; Waubant, Emmanuelle; Chehoud, Christel; Kuczynski, Justin; DeSantis, Todd Z; Warrington, Janet; Venkatesan, Arun; Fraser, Claire M; Mowry, Ellen M

2015-06-01

Differences in gut bacteria have been described in several autoimmune disorders. In this exploratory pilot study, we compared gut bacteria in patients with multiple sclerosis and healthy controls and evaluated the influence of glatiramer acetate and vitamin D treatment on the microbiota. Subjects were otherwise healthy white women with or without relapsing-remitting multiple sclerosis who were vitamin D insufficient. Patients with multiple sclerosis were untreated or were receiving glatiramer acetate. Subjects collected stool at baseline and after 90 days of vitamin D3 (5000 IU/d) supplementation. The abundance of operational taxonomic units was evaluated by hybridization of 16S rRNA to a DNA microarray. While there was overlap of gut bacterial communities, the abundance of some operational taxonomic units, including Faecalibacterium, was lower in patients with multiple sclerosis. Glatiramer acetate-treated patients with multiple sclerosis showed differences in community composition compared with untreated subjects, including Bacteroidaceae, Faecalibacterium, Ruminococcus, Lactobacillaceae, Clostridium, and other Clostridiales. Compared with the other groups, untreated patients with multiple sclerosis had an increase in the Akkermansia, Faecalibacterium, and Coprococcus genera after vitamin D supplementation. While overall bacterial communities were similar, specific operational taxonomic units differed between healthy controls and patients with multiple sclerosis. Glatiramer acetate and vitamin D supplementation were associated with differences or changes in the microbiota. This study was exploratory, and larger studies are needed to confirm these preliminary results.

Addressing the targeting range of the ABILHAND-56 in relapsing-remitting multiple sclerosis: A mixed methods psychometric study.

PubMed

Cleanthous, Sophie; Strzok, Sara; Pompilus, Farrah; Cano, Stefan; Marquis, Patrick; Cohan, Stanley; Goldman, Myla D; Kresa-Reahl, Kiren; Petrillo, Jennifer; Castrillo-Viguera, Carmen; Cadavid, Diego; Chen, Shih-Yin

2018-01-01

ABILHAND, a manual ability patient-reported outcome instrument originally developed for stroke patients, has been used in multiple sclerosis clinical trials; however, psychometric analyses indicated the measure's limited measurement range and precision in higher-functioning multiple sclerosis patients. The purpose of this study was to identify candidate items to expand the measurement range of the ABILHAND-56, thus improving its ability to detect differences in manual ability in higher-functioning multiple sclerosis patients. A step-wise mixed methods design strategy was used, comprising two waves of patient interviews, a combination of qualitative (concept elicitation and cognitive debriefing) and quantitative (Rasch measurement theory) analytic techniques, and consultation interviews with three clinical neurologists specializing in multiple sclerosis. Original ABILHAND was well understood in this context of use. Eighty-two new manual ability concepts were identified. Draft supplementary items were generated and refined with patient and neurologist input. Rasch measurement theory psychometric analysis indicated supplementary items improved targeting to higher-functioning multiple sclerosis patients and measurement precision. The final pool of Early Multiple Sclerosis Manual Ability items comprises 20 items. The synthesis of qualitative and quantitative methods used in this study improves the ABILHAND content validity to more effectively identify manual ability changes in early multiple sclerosis and potentially help determine treatment effect in higher-functioning patients in clinical trials.

Defining the clinical course of multiple sclerosis

PubMed Central

Reingold, Stephen C.; Cohen, Jeffrey A.; Cutter, Gary R.; Sørensen, Per Soelberg; Thompson, Alan J.; Wolinsky, Jerry S.; Balcer, Laura J.; Banwell, Brenda; Barkhof, Frederik; Bebo, Bruce; Calabresi, Peter A.; Clanet, Michel; Comi, Giancarlo; Fox, Robert J.; Freedman, Mark S.; Goodman, Andrew D.; Inglese, Matilde; Kappos, Ludwig; Kieseier, Bernd C.; Lincoln, John A.; Lubetzki, Catherine; Miller, Aaron E.; Montalban, Xavier; O'Connor, Paul W.; Petkau, John; Pozzilli, Carlo; Rudick, Richard A.; Sormani, Maria Pia; Stüve, Olaf; Waubant, Emmanuelle; Polman, Chris H.

2014-01-01

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. PMID:24871874

Multiple Sclerosis: Immunopathology and Treatment Update

PubMed Central

Dargahi, Narges; Katsara, Maria; Tselios, Theodore; Androutsou, Maria-Eleni; Matsoukas, John

2017-01-01

The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include β-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumab, ocrelizumab, alemtuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS. PMID:28686222

Plasma exchange therapy in steroid-unresponsive relapses in patients with multiple sclerosis.

PubMed

Trebst, Corinna; Reising, Ansgar; Kielstein, Jan T; Hafer, Carsten; Stangel, Martin

2009-01-01

Plasma exchange (PE) is well established for conditions such as rapid progressive vasculitis associated with autoantibodies against neutrophil cytoplasmic antigens (ANCA), anti-glomerular basement membrane (GBM) antibody disease, or thrombotic thrombocytopenic purpura (TTP). Also, several neurological disorders, such as acute worsening in myasthenia gravis, Guillan-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), can successfully be treated with PE. Only small case series have previously shown that PE is also effective in relapses in patients with multiple sclerosis (MS). We report our experiences of PE therapy in a series of 20 patients with 21 steroid unresponsive MS relapses. A marked-to-moderate clinical response with clear gain of function in 76% of patients with uni- or bilateral optic neuritis and in 87.5% of patients with relapses other than optic neuritis was observed. PE is an effective and well tolerated therapeutic option for steroid-unresponsive MS relapses.

Gut-CNS-Axis as Possibility to Modulate Inflammatory Disease Activity-Implications for Multiple Sclerosis.

PubMed

Fleck, Ann-Katrin; Schuppan, Detlef; Wiendl, Heinz; Klotz, Luisa

2017-07-14

In the last decade the role of environmental factors as modulators of disease activity and progression has received increasing attention. In contrast to classical environmental modulators such as exposure to sun-light or fine dust pollution, nutrition is an ideal tool for a personalized human intervention. Various studies demonstrate a key role of dietary factors in autoimmune diseases including Inflammatory Bowel Disease (IBD), rheumatoid arthritis or inflammatory central nervous system (CNS) diseases such as Multiple Sclerosis (MS). In this review we discuss the connection between diet and inflammatory processes via the gut-CNS-axis. This axis describes a bi-directional communication system and comprises neuronal signaling, neuroendocrine pathways and modulation of immune responses. Therefore, the gut-CNS-axis represents an emerging target to modify CNS inflammatory activity ultimately opening new avenues for complementary and adjunctive treatment of autoimmune diseases such as MS.

Churg–Strauss syndrome in a patient previously diagnosed with multiple sclerosis

PubMed Central

Sarkar, Pamela; Ibitoye, Richard Tolulope; Promnitz, Douglas Anthony

2011-01-01

A lady in her 70s with a background of multiple sclerosis (MS) and late-onset asthma was admitted with a 2-week history of cough and shortness of breath, progressive right-sided weakness and functional decline. Investigation revealed eosinophilia, elevated myeloperoxidase antineutrophil cytoplasmic antibody, CT sinuses showed long-standing inflammatory changes consistent with sinonasal polyposis and MRI head showed lesions consistent with vasculitis. She then developed left-sided weakness and increased wheeze. Review of her case notes demonstrated that, the eosinophilia was long-standing, her asthma was severe and steroid-dependent, and her neurologic syndrome was atypical for MS. Intravenous methylprednisolone then cyclophosphamide were administered. She demonstrated remarkable improvement, becoming more alert, with improvement in left-sided weakness. A diagnosis of Churg–Strauss syndrome was established. She was discharged to a nursing home with outpatient rheumatology follow-up. The diagnosis of MS was revisited. PMID:22679315

Trust, Protocol, Gender, and Power in Interwar British Biomedical Research: Kathleen Chevassut and the “Germ” of Multiple Sclerosis

PubMed Central

Casper, Stephen T.

2011-01-01

In March 1930, reports of the discovery of an organism causative of multiple sclerosis circulated in the British press. At the same time, news of a therapeutically efficacious vaccine also reached the ears of neurologists and patients afflicted with the debilitating degenerative disease. It was soon shown that no organism had been discovered. The events leading up to this ultimately painful episode reveal many of the central problems created when social conventions and a sense of decorum scripted received understanding of good scientific practice rather than actual regulatory frameworks. In the absence of such frameworks, few means were present to censor inappropriate scientific conduct. This story thus provides a window into an emergent world of state-sponsored biomedical research; a world where recrimination, gossip, misogyny, uncertainty, exaggeration, and dreams and delusions of scientific and therapeutic progress were collapsed together. PMID:20478897

Staying on the job: The relationship between work performance and cognition in individuals diagnosed with multiple sclerosis.

PubMed

Baughman, Brandon C; Basso, Michael R; Sinclair, Robert R; Combs, Dennis R; Roper, Brad L

2015-01-01

People with multiple sclerosis (MS) are apt to become unemployed as the disease progresses, and most research implies that this is due to diminishing mobility. Some studies have shown that presence of cognitive impairment also predicts employment status. Yet, no studies have examined how neuropsychological factors predict vocational performance among individuals with MS who remain employed. We assessed employer- and self-rated work performance, mobility status, and neuropsychological function in a sample of 44 individuals diagnosed with MS. Results suggest that cognitive impairment is common in these employed individuals, despite largely intact mobility status. Moreover, a significant interaction emerged, such that cognitively impaired individuals' work performance was rated more poorly by supervisors. In contrast, self-ratings of work performance were higher in cognitively impaired than in unimpaired participants. These novel findings suggest that cognitive impairment may influence work performance, even in patients whose physical disability status is relatively intact.

Disease activity return after natalizumab cessation in multiple sclerosis.

PubMed

Rasenack, Maria; Derfuss, Tobias

2016-05-01

Natalizumab (NAT) was the first monoclonal antibody to be approved for the treatment of relapsing-remitting multiple sclerosis. Its considerable and sustained efficacy has been demonstrated in two phase III studies. However, there are several reasons why its use is limited in clinical practice. The main argument for stopping use of the drug is the risk of the rare but serious progressive multifocal leukencephalopathy. Other reasons are neutralizing antibodies and pregnancy. There is compelling evidence from some clinical trials and many case series that disease activity returns upon suspension or cessation of NAT. Several therapeutic strategies that have been tested to prevent or reduce the recurrence of disease activity will be reviewed in this article. Considering these data, it is evident that the decision to stop NAT treatment has different implications and consequences. A subsequent therapy after cessation of NAT is needed to reduce the risk of disease recurrence.

MRI in the assessment and monitoring of multiple sclerosis: an update on best practice

PubMed Central

Kaunzner, Ulrike W.; Gauthier, Susan A.

2017-01-01

Magnetic resonance imaging (MRI) has developed into the most important tool for the diagnosis and monitoring of multiple sclerosis (MS). Its high sensitivity for the evaluation of inflammatory and neurodegenerative processes in the brain and spinal cord has made it the most commonly used technique for the evaluation of patients with MS. Moreover, MRI has become a powerful tool for treatment monitoring, safety assessment as well as for the prognostication of disease progression. Clinically, the use of MRI has increased in the past couple decades as a result of improved technology and increased availability that now extends well beyond academic centers. Consequently, there are numerous studies supporting the role of MRI in the management of patients with MS. The aim of this review is to summarize the latest insights into the utility of MRI in MS. PMID:28607577

Estimate of the cost of multiple sclerosis in Spain by literature review.

PubMed

Fernández, Oscar; Calleja-Hernández, Miguel Angel; Meca-Lallana, José; Oreja-Guevara, Celia; Polanco, Ana; Pérez-Alcántara, Ferran

2017-08-01

Multiple Sclerosis (MS) is a progressive disease leading to increasing disability and costs. A literature review was carried out to identify MS costs and to estimate its economic burden in Spain. Areas Covered: The public electronic databases PubMed, ScienceDirect and IBECS were consulted and a manual review of communications presented at related congresses was carried out. A total of 225 references were obtained, of which 43 were finally included in the study. Expert Commentary: Three major cost groups were identified: direct healthcare costs, direct non-healthcare costs and indirect costs. There is a direct relationship between disease progression and increased costs, mainly direct non-healthcare costs (greater need for informal care) and indirect costs (greater loss of productivity). The total cost associated with MS in Spain is €1,395 million per year, and that the mean annual cost per patient is €30,050. Beyond costs, a large impact on the quality of life of patients, with an annual loss of up to 13,000 quality-adjusted life years was also estimated. MS has a large economic impact on Spanish society and a significant impact on the quality of life of patients.

Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis

PubMed Central

Kuenz, Bettina; Lutterotti, Andreas; Ehling, Rainer; Gneiss, Claudia; Haemmerle, Monika; Rainer, Carolyn; Deisenhammer, Florian; Schocke, Michael; Berger, Thomas; Reindl, Markus

2008-01-01

Background There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS). Methodology/Principal Findings In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD138−) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matrix metalloproteinase (MMP)-9 and the B cell chemokine CxCL-13. Conclusions Our data support an important role of CSF B cells in acute brain inflammation in CIS and RRMS. PMID:18596942

Improving quality of life in multiple sclerosis: an unmet need.

PubMed

Zwibel, Howard L; Smrtka, Jennifer

2011-05-01

Multiple sclerosis (MS) affects approximately 400,000 people in the United States and 2.1 million people worldwide. It is the most common chronic, non-traumatic neurological disorder afflicting young people during their peak productive ages. MS can diminish quality of life (QOL) by interfering with the ability to work, pursue leisure activities, and carry on usual life roles. Symptoms that affect QOL may include impaired mobility, fatigue, depression, pain, spasticity, cognitive impairment, sexual dysfunction, bowel and bladder dysfunction, vision and hearing problems, seizures, and sDwallowing and breathing difficulties. Direct medical costs of MS in the United States are estimated in excess of $10 billion per year. Indirect costs of MS include costs of reduced employment or unemployment, assistive equipment, disability related home modifications, and paid and unpaid personal care. Although direct medical costs predominate in the earlier stages of MS, indirect costs of productivity loss are responsible for higher costs later. Disease-modifying therapies (DMTs) lessen symptoms, reduce relapses, and delay disability progression. Unfortunately, many DMTs might produce only modest improvements in QOL. Although symptom-specific therapies do not delay disease progression, they may delay unemployment and dependency, thereby reducing indirect costs.

Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions

PubMed Central

Gillen, Kelly M.; Mubarak, Mayyan; Nguyen, Thanh D.; Pitt, David

2018-01-01

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression. PMID:29515576

Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden

PubMed Central

Westerlind, Helga; Ramanujam, Ryan; Uvehag, Daniel; Kuja-Halkola, Ralf; Boman, Marcus; Bottai, Matteo; Lichtenstein, Paul

2014-01-01

Data on familial recurrence rates of complex diseases such as multiple sclerosis give important hints to aetiological factors such as the importance of genes and environment. By linking national registries, we sought to avoid common limitations of clinic-based studies such as low numbers, poor representation of the population and selection bias. Through the Swedish Multiple Sclerosis Registry and a nationwide hospital registry, a total of 28 396 patients with multiple sclerosis were identified. We used the national Multi-Generation Registry to identify first and second degree relatives as well as cousins, and the Swedish Twin Registry to identify twins of patients with multiple sclerosis. Crude and age corrected familial risks were estimated for cases and found to be in the same range as previously published figures. Matched population-based controls were used to calculate relative risks, revealing lower estimates of familial multiple sclerosis risks than previously reported, with a sibling recurrence risk (λs = 7.1; 95% confidence interval: 6.42–7.86). Surprisingly, despite a well-established lower prevalence of multiple sclerosis amongst males, the relative risks were equal among maternal and paternal relations. A previously reported increased risk in maternal relations could thus not be replicated. An observed higher transmission rate from fathers to sons compared with mothers to sons suggested a higher transmission to offspring from the less prevalent sex; therefore, presence of the so-called ‘Carter effect’ could not be excluded. We estimated the heritability of multiple sclerosis using 74 757 twin pairs with known zygosity, of which 315 were affected with multiple sclerosis, and added information from 2.5 million sibling pairs to increase power. The heritability was estimated to be 0.64 (0.36–0.76), whereas the shared environmental component was estimated to be 0.01 (0.00–0.18). In summary, whereas multiple sclerosis is to a great extent an inherited trait, the familial relative risks may be lower than usually reported. PMID:24441172

Effects of Acupuncture on Gait of Patients with Multiple Sclerosis.

PubMed

Criado, Maria Begoña; Santos, Maria João; Machado, Jorge; Gonçalves, Arminda Manuela; Greten, Henry Johannes

2017-11-01

Multiple sclerosis is considered a complex and heterogeneous disease. Approximately 85% of patients with multiple sclerosis indicate impaired gait as one of the major limitations in their daily life. Acupuncture studies found a reduction of spasticity and improvement of fatigue and imbalance in patients with multiple sclerosis, but there is a lack of studies regarding gait. We designed a study of acupuncture treatment, according to the Heidelberg model of Traditional Chinese Medicine (TCM), to investigate if acupuncture can be a useful therapeutic strategy in patients with gait impairment in multiple sclerosis of relapsing-remitting type. The sample consisted of 20 individuals with diagnosis of multiple sclerosis of relapsing-remitting type. Gait impairment was evaluated by the 25-foot walk test. The results showed differences in time to walk 25 feet following true acupuncture. In contrast, there was no difference in time to walk 25 feet following sham acupuncture. When using true acupuncture, 95% of cases showed an improvement in 25-foot walk test, compared with 45% when sham acupuncture was done. Our study protocol provides evidence that acupuncture treatment can be an attractive option for patients with multiple sclerosis, with gait impairment.

A multigenerational family with multiple sclerosis.

PubMed

Dyment, D A; Cader, M Z; Willer, C J; Risch, N; Sadovnick, A D; Ebers, G C

2002-07-01

We report a family with 15 individuals affected with multiple sclerosis present in three and possibly four generations. The segregation of multiple sclerosis within this pedigree is consistent with an autosomal dominant mode of inheritance with reduced penetrance. The clinical characteristics of the affected individuals are indistinguishable from those seen in sporadic multiple sclerosis with respect to sex ratio, age at onset, onset symptom, MRI and clinical course. Eleven of 14 cases (78.6%) were positive for the known multiple sclerosis-associated major histocompatibility complex (MHC) Class II HLA DRB1*15 allele. Parametric linkage analysis gave a non-significant LOD score of 0.31 (theta; = 0.33) for the DRB1 gene. However, among 11 affected children with at least one DRB1*15 bearing parent, all 11 out of 11 received at least one copy of this known susceptibility allele. A transmission disequilibrium test analysis was significant for the DRB1*15 allele within this single family; P = 0.0054. The inheritance pattern in this family suggests the presence of a single major locus responsible for multiple sclerosis susceptibility, with DRB1 acting as an important modifier. This family could be an important resource for the identification of a multiple sclerosis susceptibility gene.

77 FR 23601 - Special Local Regulations and Safety Zones; Recurring Events in Northern New England

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-20

... Multiple Sclerosis Regatta......... Event Type: Regatta and Sailboat Race. Sponsor: Maine Chapter, Multiple...'' W. 8.7 Multiple Sclerosis Harborfest Event Type: Power Boat Tugboat Race. Race. Sponsor: Maine Chapter, National Multiple Sclerosis Society. Date: A one day event on Sunday during the third week of...

"Cure" for multiple sclerosis (MS)-Evolving views of therapy goals in patients on different stages of the disease: A pilot study in a cohort of Polish MS patients.

PubMed

Chacińska, Weronika; Brzostowska, Marta; Nojszewska, Monika; Podlecka-Piętowska, Aleksandra; Jędrzejczak, Wiesław W; Snarski, Emilian

2017-06-01

New aggressive treatments promise improvement of results in the treatment of multiple sclerosis (MS), however, with high risk of serious complications. In this study, we analyzed patients' acceptance for risks connected with the MS treatment. The study was designed as a prospective nonanonymous online questionnaire. Responders were asked about the definition of the "cure" for MS and crucial goals in the treatment. One hundred and eighty patients filled in the questionnaire (129 women and 51 men), and the mean age was 33 years ( SD  = 10.29). The MS forms were as follows: relapsing-remitting (65%), secondary progressive (14%), primary progressive (10%), and other (11%), with mean EDSS score of 3 points ( SD  = 2.6). For 50% of the patients, relief of symptoms such as fatigue (72%), paresis (66%), and balance disorders (65%) was synonymous with "cure." The patients with faster progression of the disease were likely to accept risky "curative" treatments-with average 68% accepted mortality risk ( p  = .003). Over 81% of patients accepted mortality rates over 1% for the treatment that achieves self-defined cure. The study shows that the MS patients are likely to accept even very risky treatments as long as they promise patient-defined "cure."

Cognitive impairment at diagnosis predicts 10-year multiple sclerosis progression.

PubMed

Moccia, Marcello; Lanzillo, Roberta; Palladino, Raffaele; Chang, Kiara Chu-Mei; Costabile, Teresa; Russo, Cinzia; De Rosa, Anna; Carotenuto, Antonio; Saccà, Francesco; Maniscalco, Giorgia Teresa; Brescia Morra, Vincenzo

2016-04-01

Cognitive impairment occurs from the early phases of multiple sclerosis (MS), and more frequently affects secondary progressive (SP) subjects than relapsing-remitting (RR). To investigate relationships between cognitive dysfunctions in newly diagnosed RRMS, and long-term MS-related outcomes. The present 10-year retrospective longitudinal study included 155 RRMS subjects, tested with the Rao Brief Repeatable Battery at MS diagnosis. The reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded. 67 subjects (43.2%) reached EDSS 4.0, and 34 subjects (21.9%) converted to SP during a follow-up period of 10.0±1.8 years. Subjects with cognitive impairment at diagnosis had a rate of reaching EDSS 4.0 more than three times greater (p<0.001; HR=3.183), and a rate of SP conversion more than two times greater, as compared to cognitively preserved subjects (p=0.008; HR=2.535). In particular, better scores in the Selective Reminding Test-Delayed Recall and in the Symbol Digit Modalities Test at baseline were associated with lower SP conversion rates during the follow-up period (p=0.018; HR=0.835; and p=0.001; HR=0.941, respectively). Cognitive impairment, with particular involvement of processing speed and memory, predicts disability progression and SP conversion in newly diagnosed RRMS, highlighting the importance of cognitive assessment from the beginning of MS. © The Author(s), 2015.

Diffusion Tensor Imaging as a Biomarker to Differentiate Acute Disseminated Encephalomyelitis From Multiple Sclerosis at First Demyelination.

PubMed

Aung, Wint Yan; Massoumzadeh, Parinaz; Najmi, Safa; Salter, Amber; Heaps, Jodi; Benzinger, Tammie L S; Mar, Soe

2018-01-01

There are no clinical features or biomarkers that can reliably differentiate acute disseminated encephalomyelitis from multiple sclerosis at the first demyelination attack. Consequently, a final diagnosis is sometimes delayed by months and years of follow-up. Early treatment for multiple sclerosis is recommended to reduce long-term disability. Therefore, we intend to explore neuroimaging biomarkers that can reliably distinguish between the two diagnoses. We reviewed prospectively collected clinical, standard MRI and diffusion tensor imaging data from 12 pediatric patients who presented with acute demyelination with and without encephalopathy. Patients were followed for an average of 6.5 years to determine the accuracy of final diagnosis. Final diagnosis was determined using 2013 International Pediatric MS Study Group criteria. Control subjects consisted of four age-matched healthy individuals for each patient. The study population consisted of six patients with central nervous system demyelination with encephalopathy with a presumed diagnosis of acute disseminated encephalomyelitis and six without encephalopathy with a presumed diagnosis of multiple sclerosis or clinically isolated syndrome at high risk for multiple sclerosis. During follow-up, two patients with initial diagnosis of acute disseminated encephalomyelitis were later diagnosed with multiple sclerosis. Diffusion tensor imaging region of interest analysis of baseline scans showed differences between final diagnosis of multiple sclerosis and acute disseminated encephalomyelitis patients, whereby low fractional anisotropy and high radial diffusivity occurred in multiple sclerosis patients compared with acute disseminated encephalomyelitis patients and the age-matched controls. Fractional anisotropy and radial diffusivity measures may have the potential to serve as biomarkers for distinguishing acute disseminated encephalomyelitis from multiple sclerosis at the onset. Copyright © 2017 Elsevier Inc. All rights reserved.

Physical Activity and Its Correlates in Youth with Multiple Sclerosis.

PubMed

Grover, Stephanie A; Sawicki, Carolyn P; Kinnett-Hopkins, Dominique; Finlayson, Marcia; Schneiderman, Jane E; Banwell, Brenda; Till, Christine; Motl, Robert W; Yeh, E Ann

2016-12-01

To investigate physical activity levels in youth with multiple sclerosis and monophasic acquired demyelinating syndromes ([mono-ADS], ie, children without relapsing disease) compared with healthy controls and to determine factors that contribute to engagement in physical activity. We hypothesized that greater physical activity goal setting and physical activity self-efficacy would be associated with greater levels of vigorous physical activity in youth with multiple sclerosis. A total of 68 consecutive patients (27 multiple sclerosis, 41 mono-ADS) and 37 healthy controls completed fatigue, depression, Physical Activity Self-Efficacy Scale, perceived disability, Exercise Goal-Setting scale, and physical activity questionnaires, and wore an accelerometer for 7 days. All patients had no ambulatory limitations (Expanded Disability Status Scale, scores all <4). Youth with multiple sclerosis engaged in fewer minutes per day of vigorous (P = .009) and moderate and vigorous physical activity (P = .048) than did patients with mono-ADS and healthy controls. A lower proportion of the group with multiple sclerosis (63%) reported participating in any strenuous physical activity than the mono-ADS (85%) and healthy control (89%) groups (P = .020). When we adjusted for age and sex, the Physical Activity Self-Efficacy Scale and Exercise Goal-Setting scale were associated positively with vigorous physical activity in the group with multiple sclerosis. Fatigue and depression did not predict physical activity or accelerometry metrics. Youth with multiple sclerosis participate in less physical activity than their counterparts with mono-ADS and healthy controls. Physical activity self-efficacy and exercise goal setting serve as potentially modifiable correlates of physical activity, and are measures suited to future interventions aimed to increase physical activity in youth with multiple sclerosis. Copyright © 2016 Elsevier Inc. All rights reserved.

[Current aspects of therapy conversion for multiple sclerosis].

PubMed

Kolber, P; Luessi, F; Meuth, S G; Klotz, L; Korn, T; Trebst, C; Tackenberg, B; Kieseier, B; Kümpfel, T; Fleischer, V; Tumani, H; Wildemann, B; Lang, M; Flachenecker, P; Meier, U; Brück, W; Limmroth, V; Haghikia, A; Hartung, H-P; Stangel, M; Hohlfeld, R; Hemmer, B; Gold, R; Wiendl, H; Zipp, F

2015-10-01

In recent years the approval of new substances has led to a substantial increase in the number of course-modifying immunotherapies available for multiple sclerosis. Therapy conversion therefore represents an increasing challenge. The treatment options sometimes show complex adverse effect profiles and necessitate a long-term and comprehensive monitoring. This article presents an overview of therapy conversion of immunotherapies for multiple sclerosis in accordance with the recommendations of the Disease-Related Competence Network for Multiple Sclerosis and the German Multiple Sclerosis Society as well as the guidelines on diagnostics and therapy for multiple sclerosis of the German Society of Neurology and the latest research results. At the present point in time it should be noted that no studies have been carried out for most of the approaches for therapy conversion given here; however, the recommendations are based on theoretical considerations and therefore correspond to recommendations at the level of expert consensus, which is currently essential for the clinical daily routine.

Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression

PubMed Central

Christensen, Jeppe Romme; Börnsen, Lars; Ratzer, Rikke; Piehl, Fredrik; Khademi, Mohsen; Olsson, Tomas; Sørensen, Per Soelberg; Sellebjerg, Finn

2013-01-01

Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4+ and CD8+T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS+TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor+CD4+T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN+ and CD83+B-cells in SPMS. ICOS+TFH-cells and DC-SIGN+B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4+T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS. PMID:23469245

Nurse-led immunotreatment DEcision Coaching In people with Multiple Sclerosis (DECIMS) - Feasibility testing, pilot randomised controlled trial and mixed methods process evaluation.

PubMed

Rahn, A C; Köpke, S; Backhus, I; Kasper, J; Anger, K; Untiedt, B; Alegiani, A; Kleiter, I; Mühlhauser, I; Heesen, C

2018-02-01

Treatment decision-making is complex for people with multiple sclerosis. Profound information on available options is virtually not possible in regular neurologist encounters. The "nurse decision coach model" was developed to redistribute health professionals' tasks in supporting immunotreatment decision-making following the principles of informed shared decision-making. To test the feasibility of a decision coaching programme and recruitment strategies to inform the main trial. Feasibility testing and parallel pilot randomised controlled trial, accompanied by a mixed methods process evaluation. Two German multiple sclerosis university centres. People with suspected or relapsing-remitting multiple sclerosis facing immunotreatment decisions on first line drugs were recruited. Randomisation to the intervention (n = 38) or control group (n = 35) was performed on a daily basis. Quantitative and qualitative process data were collected from people with multiple sclerosis, nurses and physicians. We report on the development and piloting of the decision coaching programme. It comprises a training course for multiple sclerosis nurses and the coaching intervention. The intervention consists of up to three structured nurse-led decision coaching sessions, access to an evidence-based online information platform (DECIMS-Wiki) and a final physician consultation. After feasibility testing, a pilot randomised controlled trial was performed. People with multiple sclerosis were randomised to the intervention or control group. The latter had also access to the DECIMS-Wiki, but received otherwise care as usual. Nurses were not blinded to group assignment, while people with multiple sclerosis and physicians were. The primary outcome was 'informed choice' after six months including the sub-dimensions' risk knowledge (after 14 days), attitude concerning immunotreatment (after physician consultation), and treatment uptake (after six months). Quantitative process evaluation data were collected via questionnaires. Qualitative interviews were performed with all nurses and a convenience sample of nine people with multiple sclerosis. 116 people with multiple sclerosis fulfilled the inclusion criteria and 73 (63%) were included. Groups were comparable at baseline. Data of 51 people with multiple sclerosis (70%) were available for the primary endpoint. In the intervention group 15 of 31 (48%) people with multiple sclerosis achieved an informed choice after six months and 6 of 20 (30%) in the control group. Process evaluation data illustrated a positive response towards the coaching programme as well as good acceptance. The pilot-phase showed promising results concerning acceptability and feasibility of the intervention, which was well perceived by people with multiple sclerosis, most nurses and physicians. Delegating parts of the immunotreatment decision-making process to trained nurses has the potential to increase informed choice and participation as well as effectiveness of patient-physician consultations. Copyright © 2017 Elsevier Ltd. All rights reserved.

A combined inspiratory and expiratory muscle training program improves respiratory muscle strength and fatigue in multiple sclerosis.

PubMed

Ray, Andrew D; Udhoji, Supriya; Mashtare, Terry L; Fisher, Nadine M

2013-10-01

To determine the effects of a short-duration, combined (inspiratory and expiratory), progressive resistance respiratory muscle training (RMT) protocol on respiratory muscle strength, fatigue, health-related quality of life, and functional performance in individuals with mild-to-moderate multiple sclerosis (MS). Quasi-experimental before-after trial. University rehabilitation research laboratory. Volunteers with MS (N=21) were divided into 2 groups: RMT (n=11; 9 women, 2 men; mean age ± SD, 50.9 ± 5.7y, mean Expanded Disability Status Scale score ± SD, 3.2 ± 1.9) and a control group that did not train (n=10; 7 women, 3 men; mean age ± SD, 56.2 ± 8.8y, mean Expanded Disability Status Scale score ± SD, 4.4 ± 2.1). Expanded Disability Status Scale scores ranged from 1 to ≤6.5. No patients withdrew from the study. Training was a 5-week combined progressive resistance RMT program, 3d/wk, 30 minutes per session. The primary outcome measures were maximal inspiratory pressure and expiratory pressure and the Modified Fatigue Impact Scale. All subjects completed secondary measures of pulmonary function, the six-minute walk test, the timed stair climb, the Multiple Sclerosis Self-Efficacy Scale, the Medical Outcomes Study 36-Item Short-Form Health Survey, and the Physical Activity Disability Scale. Maximal inspiratory pressure and expiratory pressure (mean ± SD) increased 35% ± 22% (P<.001) and 26% ± 17% (P<.001), respectively, whereas no changes were noted in the control group (12% ± 23% and -4% ± 17%, respectively). RMT improved fatigue (Modified Fatigue Impact Scale, P<.029), with no change or worsening in the control group. No changes were noted in the six-minute walk test, stair climb, Multiple Sclerosis Self-Efficacy Scale, or Physical Activity Disability Scale in the RMT group. The control group had decreases in emotional well-being and general health (Medical Outcomes Study 36-Item Short-Form Health Survey). A short-duration, combined RMT program improved inspiratory and expiratory muscle strength and reduced fatigue in patients with mild to moderate MS. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Diagnosis and treatment of latent tuberculosis in patients with multiple sclerosis, expert consensus. On behalf of the Colombian Association of Neurology, Committee of Multiple Sclerosis.

PubMed

Navas, Carlos; Torres-Duque, Carlos A; Munoz-Ceron, Joe; Álvarez, Carlos; García, Juan R; Zarco, Luis; Vélez, Lázaro A; Awad, Carlos; Castro, Carlos Alberto

2018-01-01

Multiple sclerosis is an inflammatory and neurodegenerative demyelinating disease. Current treatment of multiple sclerosis focuses on the use of immunomodulatory, immunosuppressant, and selective immunosuppressant agents. Some of these medications may result in high risk of opportunistic infections including tuberculosis. The purpose of this study was to obtain consensus from a panel of neurologists, pulmonologists, infectious disease specialists, and epidemiology experts regarding the diagnosis, treatment, and monitoring of latent tuberculosis in patients with multiple sclerosis. A panel of experts in multiple sclerosis and tuberculosis was established. The methodological process was performed in three phases: definition of questions, answer using Delphi methodology, and the discussion of questions not agreed. Tuberculosis screening is suggested when multiple sclerosis drugs are prescribed. The recommended tests for latent tuberculosis are tuberculin and interferon gamma release test. When an anti-tuberculosis treatment is indicated, monitoring should be performed to determine liver enzyme values with consideration of age as well as comorbid conditions such as a history of alcoholism, age, obesity, concomitant hepatotoxic drugs, and history of liver disease. Latent tuberculosis should be considered in patients with multiple sclerosis who are going to be treated with immunomodulatory and immunosuppressant medications. Transaminase level monitoring is required on a periodic basis depending on clinical and laboratory characteristics. In addition to the liver impairment, other side effects should be considered when Isoniazid is prescribed.

[Effect of preventive treatment on cognitive performance in patients with multiple sclerosis].

PubMed

Shorobura, Maria S

2018-01-01

Introduction: cognitive, emotional and psychopathological changes play a significant role in the clinical picture of multiple sclerosis and influence the effectiveness of drug therapy, working capacity, quality of life, and the process of rehabilitation of patients with multiple sclerosis. The aim: investigate the changes in cognitive function in patients with multiple sclerosis, such as information processing speed and working memory of patients before and after treatment with immunomodulating drug. Materials and methods:33 patients examined reliably diagnosed with multiple sclerosis who were treated with preventive examinations and treatment from 2012 to 2016. For all patients with multiple sclerosis had clinical-neurological examination (neurological status using the EDSS scale) and the cognitive status was evaluated using the PASAT auditory test. Patient screening was performed before, during and after the therapy. Statistical analysis of the results was performed in the system Statistica 8.0. We used Student's t-test (t), Mann-Whitney test (Z). Person evaluated the correlation coefficients and Spearman (r, R), Wilcoxon criterion (T), Chi-square (X²). Results: The age of patients with multiple sclerosis affects the growth and EDSS scale score decrease PASAT to treatment. Duration of illness affects the EDSS scale score and performance PASAT. Indicators PASAT not significantly decreased throughout the treatment. Conclusions: glatiramer acetate has a positive effect on cognitive function, information processing speed and working memory patients with multiple sclerosis, which is one of the important components of the therapeutic effect of this drug.

Primary Sjogren's syndrome with central nervous system involvement.

PubMed

Alhomoud, Iftetah A; Bohlega, Saeed A; Alkawi, Mohammed Z; Alsemari, Abdulaziz M; Omer, Saleh M; Alsenani, Fahmi M

2009-08-01

To describe the clinical, laboratory, and radiological features of Primary Sjogren's syndrome (PSS) with central nervous system (CNS) involvement. A retrospective case series of 12 female patients with PSS and CNS involvement at King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia from 1991-2009. The diagnosis of PSS is defined by the American-European Diagnostic Criteria. We analyzed the clinical, radiological, and immunological features. The mean age was 40 years (range 16-58 years); all patient were females and presented with active neurological symptoms. The neurological involvement preceded the classic sicca symptoms (33%). Eight patients (66%) presented with myelopathy, 9 patients (75%) had optic neuritis, and the rest had variable neurological signs. Immunological tests (anti-Sjogren's syndrome A and anti-Sjogren's syndrome B) were high in 7 patients (58%). Minor salivary gland biopsy revealed inflammatory cell infiltrate in 11 patients (92%). Brain MRI showed scattered white matter changes in 7 patients (58%). Spine MRI showed multiple foci of hyperintensity in T2-weighted image in 6 patients (50%), and long segment of hyperintensity at the cervical spinal cord in 2 patients (16%). Our findings demonstrate that CNS involvements in PSS have great clinical variability and could precede the classic sicca symptoms by years. Primary Sjogren's syndrome can mimic multiple sclerosis (primary progressive multiple sclerosis or relapsing remitting multiple sclerosis), therefore a screening test for PSS should be considered in suspected cases. A well-defined management protocol awaits studies with larger case numbers.

White matter microstructural alterations in clinically isolated syndrome and multiple sclerosis.

PubMed

Huang, Jing; Liu, Yaou; Zhao, Tengda; Shu, Ni; Duan, Yunyun; Ren, Zhuoqiong; Sun, Zheng; Liu, Zheng; Chen, Hai; Dong, Huiqing; Li, Kuncheng

2018-07-01

This study aims to determine whether and how diffusion alteration occurs in the earliest stage of multiple sclerosis (MS) and the differences in diffusion metrics between CIS and MS by using the tract-based spatial statistics (TBSS) method based on diffusion tensor imaging (DTI). Thirty-six CIS patients (mean age ± SD: 34.0 years ± 12.6), 36 relapsing-remitting multiple sclerosis (RRMS) patients (mean age ± SD: 35.0 years ± 9.4) and 36 age- and gender-matched normal controls (NCs) were included in this study. Voxel-wise analyses were performed with TBSS using multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ 1 ) and radial diffusivity (λ 23 ). In the CIS patients, TBSS analyses revealed diffusion alterations in a few white matter (WM) regions including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, body and splenium of the corpus callosum, internal capsule, external capsule, and cerebral peduncle. MS patients showed more widespread diffusion changes (decreased FA, increased λ 1 , λ 23 and MD) than CIS. Exploratory analyses also revealed the possible associations between WM diffusion metrics and clinical variables (Expanded Disability Status Scale and disease duration) in the patients. This study provided imaging evidence for DTI abnormalities in CIS and MS and suggested that DTI can improve our knowledge of the path physiology of CIS and MS and clinical progression. Copyright © 2018 Elsevier Ltd. All rights reserved.

Current and Emerging Therapies in Multiple Sclerosis: Implications for the Radiologist, Part 1-Mechanisms, Efficacy, and Safety.

PubMed

McNamara, C; Sugrue, G; Murray, B; MacMahon, P J

2017-09-01

Imaging for the diagnosis and follow-up of patients with suspected or confirmed multiple sclerosis is a common scenario for many general radiologists and subspecialty neuroradiologists. The field of MS therapeutics has rapidly evolved with multiple new agents now being used in routine clinical practice. To provide an informed opinion in discussions concerning newer MS agents, radiologists must have a working understanding of the strengths and limitations of the various novel therapies. The role of imaging in MS has advanced beyond monitoring and surveillance of disease activity to include treatment complications. An understanding of the new generation of MS drugs in conjunction with the key role that MR imaging plays in the detection of disease progression, opportunistic infections, and drug-related adverse events is of vital importance to the radiologist and clinical physician alike. Radiologists are in a unique position to detect many of the described complications well in advance of clinical symptoms. Part 1 of this review outlines recent developments in the treatment of MS and discusses the published clinical data on the efficacy and safety of the currently approved and emerging therapies in this condition as they apply to the radiologist. Part 2 will cover pharmacovigilance and the role the neuroradiologist plays in monitoring patients for signs of opportunistic infection and/or disease progression. © 2017 by American Journal of Neuroradiology.

Multiple sclerosis and human T-cell lymphotropic retroviruses

NASA Astrophysics Data System (ADS)

Koprowski, Hilary; Defreitas, Elaine C.; Harper, Mary E.; Sandberg-Wollheim, Magnhild; Sheremata, William A.; Robert-Guroff, Marjorie; Saxinger, Carl W.; Feinberg, Mark B.; Wong-Staal, Flossie; Gallo, Robert C.

1985-11-01

A combination of different types of data suggests that some multiple sclerosis patients respond immunologically to, and have cerebrospinal T cells containing, a retrovirus that is related to, but distinct from, the three types of human T-cell lymphotropic viruses. The role of this virus in multiple sclerosis is uncertain.

Disconnection as a Mechanism for Cognitive Dysfunction in Multiple Sclerosis

ERIC Educational Resources Information Center

Dineen, R. A.; Vilisaar, J.; Hlinka, J.; Bradshaw, C. M.; Morgan, P. S.; Constantinescu, C. S.; Auer, D. P.

2009-01-01

Disconnection of cognitively important processing regions by injury to the interconnecting white matter provides a potential mechanism for cognitive dysfunction in multiple sclerosis. The contribution of tract-specific white matter injury to dysfunction in different cognitive domains in patients with multiple sclerosis has not previously been…

Demyelination of subcortical nuclei in multiple sclerosis

NASA Astrophysics Data System (ADS)

Krutenkova, E.; Aitmagambetova, G.; Khodanovich, M.; Bowen, J.; Gangadharan, B.; Henson, L.; Mayadev, A.; Repovic, P.; Qian, P.; Yarnykh, V.

2016-02-01

Myelin containing in basal ganglia in multiple sclerosis patients was evaluated using new noninvasive quantitative MRI method fast whole brain macromolecular proton fraction mapping. Myelin level in globus pallidus and putamen significantly decreased in multiple sclerosis patients as compared with healthy control subjects but not in substantia nigra and caudate nucleus.

Multiple Sclerosis and the Family Physician

PubMed Central

Sky, Ruth

1977-01-01

Multiple sclerosis is difficult to diagnose since it develops over a period of time and the symptoms and signs are scattered throughout the central nervous system. Because there is no specific treatment, the problems of management are especially challenging. Case histories are presented to support the concept that multiple sclerosis is a family and community concern. Family physicians are urged to maintain a supportive role and an interested attitude towards patients with multiple sclerosis. These patients and their families have urgent and continuing needs for their doctors' skills. PMID:21304869

Antecedents of Coping with the Disease in Patients with Multiple Sclerosis: A Qualitative Content Analysis

PubMed Central

Dehghani, Ali; Dehghan Nayeri, Nahid; Ebadi, Abbas

2017-01-01

ABSTRACT Background: Due to many physical and mental disorders that occur in multiple sclerosis patients, identifying the factors affecting coping based on the experiences of patients using qualitative study is essential to improve their quality of life. This study was conducted to explore the antecedents of coping with the disease in patients with multiple sclerosis. Methods: This is a qualitative study conducted on 11 patients with multiple sclerosis in 2015 in Tehran, Iran. These patients were selected based on purposive sampling. Data were collected using semi-structured and in-depth interviews and coded. These data were analyzed using the conventional content analysis. The rigor of qualitative data using the criteria proposed by Guba and Lincoln were assessed. Results: Five main categories were revealed: (1) social support, (2) lenience, (3) reliance on faith, (4) knowledge of multiple sclerosis and modeling, and (5) economic and environmental situation. Each category had several distinct sub-categories. Conclusions: The results of this study showed that coping with multiple sclerosis is a complex, multidimensional and contextual concept that is affected by various factors in relation to the context of Iran. The findings of the study can provide the healthcare professionals with deeper recognition and understanding of these antecedents to improve successful coping in Iranian patients suffering from multiple sclerosis. PMID:28097178

'Normal' and 'failing' mothers: Women's constructions of maternal subjectivity while living with multiple sclerosis.

PubMed

Parton, Chloe; Katz, Terri; Ussher, Jane M

2017-10-01

Multiple sclerosis causes physical and cognitive impairment that can impact women's experiences of motherhood. This study examined how women construct their maternal subjectivities, or sense of self as a mother, drawing on a framework of biographical disruption. A total of 20 mothers with a multiple sclerosis diagnosis took part in semi-structured interviews. Transcripts were analysed using thematic decomposition to identify subject positions that women adopted in relation to cultural discourses of gender, motherhood and illness. Three main subject positions were identified: 'The Failing Mother', 'Fear of Judgement and Burdening Others' and 'The Normal Mother'. Women's sense of self as the 'Failing Mother' was attributed to the impact of multiple sclerosis, contributing to biographical disruption and reinforced through 'Fear of Judgement and Burdening Others' within social interactions. In accounts of the 'Normal Mother', maternal subjectivity was renegotiated by adopting strategies to manage the limitations of multiple sclerosis on mothering practice. This allowed women to self-position as 'good' mothers. Health professionals can assist women by acknowledging the embodied impact of multiple sclerosis on maternal subjectivities, coping strategies that women employ to address potential biographical disruption, and the cultural context of mothering, which contributes to women's experience of subjectivity and well-being when living with multiple sclerosis.

Visual Search as a Tool for a Quick and Reliable Assessment of Cognitive Functions in Patients with Multiple Sclerosis

PubMed Central

Utz, Kathrin S.; Hankeln, Thomas M. A.; Jung, Lena; Lämmer, Alexandra; Waschbisch, Anne; Lee, De-Hyung; Linker, Ralf A.; Schenk, Thomas

2013-01-01

Background Despite the high frequency of cognitive impairment in multiple sclerosis, its assessment has not gained entrance into clinical routine yet, due to lack of time-saving and suitable tests for patients with multiple sclerosis. Objective The aim of the study was to compare the paradigm of visual search with neuropsychological standard tests, in order to identify the test that discriminates best between patients with multiple sclerosis and healthy individuals concerning cognitive functions, without being susceptible to practice effects. Methods Patients with relapsing remitting multiple sclerosis (n = 38) and age-and gender-matched healthy individuals (n = 40) were tested with common neuropsychological tests and a computer-based visual search task, whereby a target stimulus has to be detected amongst distracting stimuli on a touch screen. Twenty-eight of the healthy individuals were re-tested in order to determine potential practice effects. Results Mean reaction time reflecting visual attention and movement time indicating motor execution in the visual search task discriminated best between healthy individuals and patients with multiple sclerosis, without practice effects. Conclusions Visual search is a promising instrument for the assessment of cognitive functions and potentially cognitive changes in patients with multiple sclerosis thanks to its good discriminatory power and insusceptibility to practice effects. PMID:24282604

Disease-specific molecular events in cortical multiple sclerosis lesions

PubMed Central

Wimmer, Isabella; Höftberger, Romana; Gerlach, Susanna; Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Mahad, Don; Binder, Christoph J.; Krumbholz, Markus; Bauer, Jan; Bradl, Monika

2013-01-01

Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. PMID:23687122

New insights into the burden and costs of multiple sclerosis in Europe

PubMed Central

Kobelt, Gisela; Thompson, Alan; Berg, Jenny; Gannedahl, Mia; Eriksson, Jennifer

2017-01-01

Background: The current focus in multiple sclerosis (MS) is on early diagnosis and drug intervention, with a view to modifying disease progression. Consequently, healthcare costs have shifted from inpatient care and rehabilitation to outpatient care. Objectives: This European burden of illness study provides data that can be combined with other evidence to assess whether management approaches provide value to society. Methods: A cross-sectional study was conducted in 16 countries. Patients reported on their disease, health-related quality of life (HRQoL) and resource consumption. Descriptive analyses were performed by disease severity. Costs are reported from a societal perspective in 2015€ PPP (adjusted for purchasing power parity). Results: The 16,808 participants had a mean age of 51.5 years, and 52% had relapsing–remitting multiple sclerosis (RRMS). Work capacity declined from 82% to 8%, and utility declined from normal population values to less than zero with advancing disease. Mean costs were 22,800€ PPP in mild, 37,100€ PPP in moderate and 57,500€ PPP in severe disease; healthcare accounted for 68%, 47% and 26%, respectively. Fatigue and cognitive difficulties were reported by 95% and 71% of participants, respectively; both had a significant independent effect on utility. Conclusion: Costs and utility were highly correlated with disease severity, but resource consumption was heavily influenced by healthcare systems organisation and availability of services. PMID:28273775

Cognitive reserve in multiple sclerosis: Protective effects of education.

PubMed

Martins Da Silva, Ana; Cavaco, Sara; Moreira, Inês; Bettencourt, Andreia; Santos, Ernestina; Pinto, Cláudia; Gonçalves, Alexandra; Coutinho, Ester; Samões, Raquel; Dias, Cláudia C; Teixeira-Pinto, Armando; Da Silva, Berta Martins; Montalban, Xavier

2015-09-01

Recent data suggest that cognitive reserve modulates the adverse effects of multiple sclerosis (MS) pathology on cognitive functioning; however, the protective effects of education in MS are still unclear. To explore education as an indicator of cognitive reserve, while controlling for demographic, clinical and genetic features. A total of 419 MS patients and 159 healthy comparison (HC) subjects underwent a comprehensive neuropsychological (NP) assessment, and answered the Hospital Anxiety and Depression Scale. Based on the HC data, MS patients' NP scores were adjusted for sex, age and education; and the estimated 5(th) percentile (or 95(th) percentile, when appropriate) was used to identify any deficits. Patients also performed the Mini-Mental State Examination (MMSE); and their human leucocyte antigen HLA-DRB1 and apolipoprotein E (ApoE) genotypes were investigated. Patients with higher education were less likely (p < 0.05) to have cognitive deficits than those with lower education, even when controlling for other covariates. Other significant predictors of cognitive deficit were: age, Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), and a progressive course. No significant association was found with the HLA-DRB1*15:01 or ApoE ε4 alleles. These results provide support to the use of education as a proxy of cognitive reserve in MS and stress the need to take into account education when approaching cognition in MS. © The Author(s), 2015.

Review of the novelties from the 32nd ECTRIMS Congress, 2016, presented at the 9th Post-ECTRIMS Meeting (II).

PubMed

Fernandez, O; Oterino, A; Oreja-Guevara, C; Prieto, J M; Mendibe-Bilbao, M M; Garcia-Merino, J A; Ramio-Torrenta, Ll; Ginestal, R; Meca-Lallana, J E; Romero-Pinel, L; Munoz, D; Oliva-Nacarino, P; Calles-Hernandez, M C; Izquierdo, G; Martinez-Gines, M L; Saiz, A; Comabella, M; Casanova-Estruch, B; Brieva, Ll; Arroyo, R; Rodriguez-Antiguedad, A

2017-07-16

For the ninth year in a row the Post-ECTRIMS Meeting has been held in Madrid (Spain) with the aim of presenting and discussing the hottest issues debated at the ECTRIMS Congress by renowned specialists in multiple sclerosis in our country. One outcome of this scientific activity, endorsed by the Spanish Neurology Society, is this review article, which is published in two parts. This second part reflects the current controversy over the management of multiple sclerosis, especially as regards the progressive forms and their differential diagnosis. The work presents the latest advances in remyelination, where the use of the micropillar technique in laboratory stands out, and in neuroprotection, which is reviewed through a study of the optic nerve. Anti-CD20 antibodies are a very promising development and we find ourselves before a new mechanism of action and therapeutic target in cells to which little attention has been paid to date. Another notable fact is the high correlation between the levels of neurofilaments in cerebrospinal fluid and in serum, which could make it possible to avoid the use of cerebrospinal fluid as a biological sample in future studies of biomarkers. The review also provides a preview of the advances in clinical research, which will converge in clinical practice in the future, thereby conditioning the steps that should be taken in the therapeutic management of multiple sclerosis.

Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis

PubMed Central

Benedict, Ralph HB; DeLuca, John; Phillips, Glenn; LaRocca, Nicholas; Hudson, Lynn D; Rudick, Richard

2017-01-01

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful. This topical review provides an overview of research on one particular cognitive measure, the Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude. PMID:28206827

Cerebellar contribution to motor and cognitive performance in multiple sclerosis: An MRI sub-regional volumetric analysis.

PubMed

D'Ambrosio, Alessandro; Pagani, Elisabetta; Riccitelli, Gianna C; Colombo, Bruno; Rodegher, Mariaemma; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo; Rocca, Maria A

2017-08-01

To investigate the role of cerebellar sub-regions on motor and cognitive performance in multiple sclerosis (MS) patients. Whole and sub-regional cerebellar volumes, brain volumes, T2 hyperintense lesion volumes (LV), and motor performance scores were obtained from 95 relapse-onset MS patients and 32 healthy controls (HC). MS patients also underwent an evaluation of working memory and processing speed functions. Cerebellar anterior and posterior lobes were segmented using the Spatially Unbiased Infratentorial Toolbox (SUIT) from Statistical Parametric Mapping (SPM12). Multivariate linear regression models assessed the relationship between magnetic resonance imaging (MRI) measures and motor/cognitive scores. Compared to HC, only secondary progressive multiple sclerosis (SPMS) patients had lower cerebellar volumes (total and posterior cerebellum). In MS patients, lower anterior cerebellar volume and brain T2 LV predicted worse motor performance, whereas lower posterior cerebellar volume and brain T2 LV predicted poor cognitive performance. Global measures of brain volume and infratentorial T2 LV were not selected by the final multivariate models. Cerebellar volumetric abnormalities are likely to play an important contribution to explain motor and cognitive performance in MS patients. Consistently with functional mapping studies, cerebellar posterior-inferior volume accounted for variance in cognitive measures, whereas anterior cerebellar volume accounted for variance in motor performance, supporting the assessment of cerebellar damage at sub-regional level.

New insights into the burden and costs of multiple sclerosis in Europe.

PubMed

Kobelt, Gisela; Thompson, Alan; Berg, Jenny; Gannedahl, Mia; Eriksson, Jennifer

2017-07-01

The current focus in multiple sclerosis (MS) is on early diagnosis and drug intervention, with a view to modifying disease progression. Consequently, healthcare costs have shifted from inpatient care and rehabilitation to outpatient care. This European burden of illness study provides data that can be combined with other evidence to assess whether management approaches provide value to society. A cross-sectional study was conducted in 16 countries. Patients reported on their disease, health-related quality of life (HRQoL) and resource consumption. Descriptive analyses were performed by disease severity. Costs are reported from a societal perspective in 2015€ PPP (adjusted for purchasing power parity). The 16,808 participants had a mean age of 51.5 years, and 52% had relapsing-remitting multiple sclerosis (RRMS). Work capacity declined from 82% to 8%, and utility declined from normal population values to less than zero with advancing disease. Mean costs were 22,800€ PPP in mild, 37,100€ PPP in moderate and 57,500€ PPP in severe disease; healthcare accounted for 68%, 47% and 26%, respectively. Fatigue and cognitive difficulties were reported by 95% and 71% of participants, respectively; both had a significant independent effect on utility. Costs and utility were highly correlated with disease severity, but resource consumption was heavily influenced by healthcare systems organisation and availability of services.

Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis.

PubMed

Benedict, Ralph Hb; DeLuca, John; Phillips, Glenn; LaRocca, Nicholas; Hudson, Lynn D; Rudick, Richard

2017-04-01

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful. This topical review provides an overview of research on one particular cognitive measure, the Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

Substantial adverse association of visual and vascular comorbidities on visual disability in multiple sclerosis.

PubMed

Marrie, Ruth Ann; Cutter, Gary; Tyry, Tuula

2011-12-01

Visual comorbidities are common in multiple sclerosis (MS) but the impact of visual comorbidities on visual disability is unknown. We assessed the impact of visual and vascular comorbidities on severity of visual disability in MS. In 2006, we queried participants of the North American Research Committee on Multiple Sclerosis (NARCOMS) about cataracts, glaucoma, uveitis, hypertension, hypercholesterolemia, heart disease, diabetes and peripheral vascular disease. We assessed visual disability using the Vision subscale of Performance Scales. Using Cox regression, we investigated whether visual or vascular comorbidities affected the time between MS symptom onset and the development of mild, moderate and severe visual disability. Of 8983 respondents, 1415 (15.9%) reported a visual comorbidity while 4745 (52.8%) reported a vascular comorbidity. The median (interquartile range) visual score was 1 (0-2). In a multivariable Cox model the risk of mild visual disability was higher among participants with vascular (hazard ratio [HR] 1.45; 95% confidence interval [CI]: 1.39-1.51) and visual comorbidities (HR 1.47; 95% CI: 1.37-1.59). Vascular and visual comorbidities were similarly associated with increased risks of moderate and severe visual disability. Visual and vascular comorbidities are associated with progression of visual disability in MS. Clinicians hearing reports of worsening visual symptoms in MS patients should consider visual comorbidities as contributing factors. Further study of these issues using objective, systematic neuro-ophthalmologic evaluations is warranted.

Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study

PubMed Central

2012-01-01

Background Treatment options for patients suffering from progressive forms of multiple sclerosis (MS) remain inadequate. Mast cells actively participate in the pathogenesis of MS, in part because they release large amounts of various mediators that sustain the inflammatory network. Masitinib, a selective oral tyrosine kinase inhibitor, effectively inhibits the survival, migration and activity of mast cells. This exploratory study assessed the safety and clinical benefit of masitinib in the treatment of primary progressive MS (PPMS) or relapse-free secondary progressive MS (rfSPMS). Methods Multicenter, randomized, placebo-controlled, proof-of-concept trial. Masitinib was administered orally at 3 to 6 mg/kg/day for at least 12 months, with dose adjustment permitted in event of insufficient response with no toxicity. The primary response endpoint was the change relative to baseline in the multiple sclerosis functional composite score (MSFC). Clinical response was defined as an increase in MSFC score relative to baseline of > 100%. Results Thirty-five patients were randomized to receive masitinib (N = 27) or placebo (N = 8). Masitinib was relatively well tolerated with the most common adverse events being asthenia, rash, nausea, edema, and diarrhea. The overall frequency of adverse events was similar to the placebo group, however, a higher incidence of severe and serious events was associated with masitinib treatment. Masitinib appeared to have a positive effect on MS-related impairment for PPMS and rfSPMS patients, as evidenced by an improvement in MSFC scores relative to baseline, compared with a worsening MSFC score in patients receiving placebo; +103% ± 189 versus -60% ± 190 at month-12, respectively. This positive, albeit non-statistically significant response was observed as early as month-3 and sustained through to month-18, with similar trends seen in the PPMS and rfSPMS subpopulations. A total of 7/22 (32%) assessable masitinib patients reported clinical response following 12 months of treatment (according to the modified intent-to-treat population, observed cases) compared with none in the placebo group. The Expanded Disability Status Scale remained stable for both treatment groups. Conclusion These data suggest that masitinib is of therapeutic benefit to PPMS and rfSPMS patients and could therefore represent an innovative avenue of treatment for this disease. This exploratory trial provides evidence that may support a larger placebo-controlled investigation. PMID:22691628

Enantioselectivity in the Metabolism of Cyclophosphamide in Patients With Multiple or Systemic Sclerosis.

PubMed

de Castro, Francine Attié; Simões, Belinda Pinto; Coelho, Eduardo Barbosa; Lanchote, Vera Lucia

2017-06-01

The aim of this study was to evaluate the enantioselective pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide and carboxyethylphosphoramide mustard in patients with systemic or multiple sclerosis. Patients with systemic sclerosis (n = 10) or multiple sclerosis (n = 10), genotyped for the allelic variants of CYP2C9*2 and CYP2C9*3 and of the CYP2B6 G516T polymorphism, were treated with 50 mg cyclophosphamide/kg daily for 4 days. Serial blood samples were collected up to 24 hours after administration of the last cyclophosphamide dose. Cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide enantiomers were analyzed in plasma samples using liquid chromatography-tandem mass spectrometry coupled to chiral column Chiralcel OD-R or Chiralpak AD-RH. Cytokines IL-2, IL-4, IL-6, IL-8, IL-10, IL- 12p70, IL-17, TNF-α, and INT-δ in the plasma samples collected before cyclophosphamide infusion were analyzed by Milliplex MAP human cytokine/chemokine. Pharmacokinetic parameters showed higher plasma concentrations of (S)-(-)-cyclophosphamide (AUC 215.0 vs 186.2 μg·h/mL for multiple sclerosis patients and 219.1 vs 179.2 μg·h/mL for systemic sclerosis patients) and (R)-4-hydroxycyclophosphamide (AUC 5.6 vs 3.7 μg·h/mL for multiple sclerosis patients and 6.3 vs 5.6 μg·h/mL for systemic sclerosis patients) when compared to their enantiomers in both groups of patients, whereas the pharmacokinetics of the carboxyethylphosphoramide metabolite was not enantioselective. Cytokines' plasma concentrations were similar between multiple and systemic sclerosis groups. The pharmacokinetics of cyclophosphamide is enantioselective in patients with systemic sclerosis and multiple sclerosis, with higher plasma concentrations of the (S)-(-)-cyclophosphamide enantiomer due to the preferential formation of the (R)-4-hydroxycyclophosphamide metabolite. © 2017, The American College of Clinical Pharmacology.

Complement is activated in progressive multiple sclerosis cortical grey matter lesions.

PubMed

Watkins, Lewis M; Neal, James W; Loveless, Sam; Michailidou, Iliana; Ramaglia, Valeria; Rees, Mark I; Reynolds, Richard; Robertson, Neil P; Morgan, B Paul; Howell, Owain W

2016-06-22

The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression. We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls. Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions. Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.

Glucose uptake heterogeneity of the leg muscles is similar between patients with multiple sclerosis and healthy controls during walking.

PubMed

Kindred, John H; Ketelhut, Nathaniel B; Rudroff, Thorsten

2015-02-01

Difficulties in ambulation are one of the main problems reported by patients with multiple sclerosis. A previous study by our research group showed increased recruitment of muscle groups during walking, but the influence of skeletal muscle properties, such as muscle fiber activity, has not been fully elucidated. The purpose of this investigation was to use the novel method of calculating glucose uptake heterogeneity in the leg muscles of patients with multiple sclerosis and compare these results to healthy controls. Eight patients with multiple sclerosis (4 men) and 8 healthy controls (4 men) performed 15 min of treadmill walking at a comfortable self-selected speed following muscle strength tests. Participants were injected with ≈ 8 mCi of [(18)F]-fluorodeoxyglucose during walking after which positron emission tomography/computed tomography imaging was performed. No differences in muscle strength were detected between multiple sclerosis and control groups (P>0.27). Within the multiple sclerosis, group differences in muscle volume existed between the stronger and weaker legs in the vastus lateralis, semitendinosus, and semimembranosus (P<0.03). Glucose uptake heterogeneity between the groups was not different for any muscle group or individual muscle of the legs (P>0.16, P≥0.05). Patients with multiple sclerosis and healthy controls showed similar muscle fiber activity during walking. Interpretations of these results, with respect to our previous study, suggest that walking difficulties in patients with multiple sclerosis may be more associated with altered central nervous system motor patterns rather than alterations in skeletal muscle properties. Published by Elsevier Ltd.

The interpretation of physical activity, exercise, and sedentary behaviours by persons with multiple sclerosis.

PubMed

Kinnett-Hopkins, Dominique; Learmonth, Yvonne; Hubbard, Elizabeth; Pilutti, Lara; Roberts, Sarah; Fanning, Jason; Wójcicki, Thomas; McAuley, Edward; Motl, Robert

2017-11-07

This study adopted a qualitative research design with directed content analysis and examined the interpretations of physical activity, exercise, and sedentary behaviour by persons with multiple sclerosis. Fifty three persons with multiple sclerosis who were enrolled in an exercise trial took part in semi-structured interviews regarding personal interpretations of physical activity, exercise, and sedentary behaviours. Forty three percent of participants indicated a consistent understanding of physical activity, 42% of participants indicated a consistent understanding of exercise, and 83% of participants indicated a consistent understanding of sedentary behaviour with the standard definitions. There was evidence of definitional ambiguity (i.e., 57, 58, and 11% of the sample for physical activity, exercise, and sedentary behaviour, respectively); 6% of the sample inconsistently defined sedentary behaviour with standard definitions. Some participants described physical activity in a manner that more closely aligned with exercise and confused sedentary behaviour with exercise or sleeping/napping. Results highlight the need to provide and utilise consistent definitions for accurate understanding, proper evaluation and communication of physical activity, exercise, and sedentary behaviours among persons with multiple sclerosis. The application of consistent definitions may minimise ambiguity, alleviate the equivocality of findings in the literature, and translate into improved communication about these behaviours in multiple sclerosis. Implications for Rehabilitation The symptoms of multiple sclerosis can be managed through participation in physical activity and exercise. Persons with multiple sclerosis are not engaging in sufficient levels of physical activity and exercise for health benefits. Rehabilitation professionals should use established definitions of physical activity, exercise, and sedentary behaviours when communicating about these behaviours among persons with multiple sclerosis.

Striving for balance between caring and restraint: young adults' experiences with parental multiple sclerosis.

PubMed

Moberg, Julie Y; Larsen, Dorte; Brødsgaard, Anne

2017-05-01

To explore and describe how young adults between 18-25 years of age experienced growing up with a parent with multiple sclerosis and how these experiences continue to influence their daily lives. Chronic parental illness is occurring in about 10% of families worldwide, but little is known about how the children experience growing up with a parent with multiple sclerosis during their childhood and into young adulthood. We chose a qualitative design using a phenomenological approach based on Giorgi. Exploratory and open-ended interviews with 14 young adults were conducted. The essence of the phenomenon of having a parent with multiple sclerosis was synthesized into 'Striving for balance between caring and restraint' from two themes 'caring' and 'restraint' and eight subthemes. Participants' experiences of caring for parents with multiple sclerosis continued influencing their other close relationships, in which they tended to assume responsibility while concealing some of their feelings and desires. Most participants showed restraint among parents with and without multiple sclerosis, friends and partners. It seems that one of the greatest challenges of having a parent with multiple sclerosis is achieving a balance between caring for others and asserting one's own desires. Healthcare professionals can support the family by encouraging family members to participate in consultations and to assist the parents in providing information about multiple sclerosis and its symptoms to the children. Parents might need assistance in applying for help with domestic chores or referrals to support groups for their children or other family members. © 2016 John Wiley & Sons Ltd.

Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings.

PubMed

Leavitt, V M; Cirnigliaro, C; Cohen, A; Farag, A; Brooks, M; Wecht, J M; Wylie, G R; Chiaravalloti, N D; DeLuca, J; Sumowski, J F

2014-01-01

Multiple sclerosis leads to prominent hippocampal atrophy, which is linked to memory deficits. Indeed, 50% of multiple sclerosis patients suffer memory impairment, with negative consequences for quality of life. There are currently no effective memory treatments for multiple sclerosis either pharmacological or behavioral. Aerobic exercise improves memory and promotes hippocampal neurogenesis in nonhuman animals. Here, we investigate the benefits of aerobic exercise in memory-impaired multiple sclerosis patients. Pilot data were collected from two ambulatory, memory-impaired multiple sclerosis participants randomized to non-aerobic (stretching) and aerobic (stationary cycling) conditions. The following baseline/follow-up measurements were taken: high-resolution MRI (neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Intervention was 30-minute sessions 3 times per week for 3 months. Aerobic exercise resulted in 16.5% increase in hippocampal volume and 53.7% increase in memory, as well as increased hippocampal resting-state functional connectivity. Improvements were specific, with no comparable changes in overall cerebral gray matter (+2.4%), non-hippocampal deep gray matter structures (thalamus, caudate: -4.0%), or in non-memory cognitive functioning (executive functions, processing speed, working memory: changes ranged from -11% to +4%). Non-aerobic exercise resulted in relatively no change in hippocampal volume (2.8%) or memory (0.0%), and no changes in hippocampal functional connectivity. This is the first evidence for aerobic exercise to increase hippocampal volume and connectivity and improve memory in multiple sclerosis. Aerobic exercise represents a cost-effective, widely available, natural, and self-administered treatment with no adverse side effects that may be the first effective memory treatment for multiple sclerosis patients.

A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis.

PubMed

Colpitts, Sara L; Kasper, Eli J; Keever, Abigail; Liljenberg, Caleb; Kirby, Trevor; Magori, Krisztian; Kasper, Lloyd H; Ochoa-Repáraz, Javier

2017-11-02

The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

PubMed Central

Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah; Villar, Luisa Maria; Reynolds, Richard; Mikol, Daniel

2016-01-01

Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing–remitting disease course, typically progressing over time to a phase of relentless advancement in secondary progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood–brain barrier and is followed by a cascade of events, including persistent microglial activation that may lead to chronic demyelination and neurodegeneration associated with irreversible disability. In patients with relapsing forms of MS, natalizumab therapy is known to significantly reduce intrathecal inflammatory responses which results in reductions in brain lesions and brain atrophy as well as beneficial effects on clinical measures, such as reduced frequency and severity of relapse and reduced accumulation of disability. Natalizumab treatment also reduces levels of cerebrospinal fluid chemokines and other biomarkers of intrathecal inflammation, axonal damage and demyelination, and has demonstrated the ability to reduce innate immune activation and intrathecal immunoglobulin synthesis in patients with MS. The efficacy of natalizumab therapy in SPMS is currently being investigated in a randomized, double-blind, placebo-controlled trial. PMID:26788129

Symptomatic therapy in multiple sclerosis

PubMed Central

Frohman, Teresa C.; Castro, Wanda; Shah, Anjali; Courtney, Ardith; Ortstadt, Jeffrey; Davis, Scott L.; Logan, Diana; Abraham, Thomas; Abraham, Jaspreet; Remington, Gina; Treadaway, Katherine; Graves, Donna; Hart, John; Stuve, Olaf; Lemack, Gary; Greenberg, Benjamin; Frohman, Elliot M.

2011-01-01

Multiple sclerosis is the most common disabling neurological disease of young adults. The ability to impact the quality of life of patients with multiple sclerosis should not only incorporate therapies that are disease modifying, but should also include a course of action for the global multidisciplinary management focused on quality of life and functional capabilities. PMID:21694806

Endogenous Task Shift Processes in Relapsing-Remitting Multiple Sclerosis

ERIC Educational Resources Information Center

Stablum, F.; Meligrana, L.; Sgaramella, T.; Bortolon, F.; Toso, V.

2004-01-01

This paper reports a study that was aimed to evaluate executive functions in relapsing-remitting multiple sclerosis patients. The groups tested comprised 22 relapsing-remitting multiple sclerosis patients, and 22 non-brain damaged controls. When one is engaged in two speeded tasks, not simultaneously but with some form of alternation, it is slower…

The Relevance of Depressive Symptoms and Social Support to Disability in Women with Multiple Sclerosis or Fibromyalgia

ERIC Educational Resources Information Center

Phillips, Lorraine J.

2010-01-01

Multiple sclerosis and fibromyalgia syndrome may spur substantial disability for those affected. Using structural equation modeling, this secondary analysis examined predictors of disability in women with multiple sclerosis (n = 118) and fibromyalgia syndrome (n = 197) recruited for separate wellness studies. Greater functional limitations, lower…

78 FR 40632 - Drawbridge Operation Regulation; Trent River, New Bern, NC

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-08

... navigation position for one hour on two consecutive days to accommodate the annual Bike Multiple Sclerosis... INFORMATION: The Event Director for the Bike Multiple Sclerosis: Historic New Bern Bike Ride, with approval... safe passage for cyclists during the Bike Multiple Sclerosis: Historic New Bern Bike Ride. The US 70...

Oxidative Stress is Increased in Serum from Mexican Patients with Relapsing-Remitting Multiple Sclerosis

PubMed Central

Ortiz, Genaro Gabriel; Macías-Islas, Miguel Ángel; Pacheco-Moisés, Fermín P.; Cruz-Ramos, José A.; Sustersik, Silvia; Barba, Elías Alejandro; Aguayo, Adriana

2009-01-01

Objective: To determine the oxidative stress markers in serum from patients with relapsing-remitting multiple sclerosis. Methods: Blood samples from healthy controls and 22 patients 15 women (7 aged from 20 to 30 and 8 were > 40 years old) and 7 men (5 aged from 20 to 30 and 2 were > 40 years old) fulfilling the McDonald Criteria and classified as having Relapsing-Remitting Multiple Sclerosis accordingly with Lublin were collected for oxidative stress markers quantification. Results: Nitric oxide metabolites (nitrates/nitrites), lipid peroxidation products (malondialdehyde plus 4-hidroxialkenals), and glutathione peroxidase activity were significantly increased in serum of subjects with relapsing-remitting multiple sclerosis in comparison with that of healthy controls. These data support the hypothesis that multiple sclerosis is a component closely linked to oxidative stress. PMID:19242067

Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism.

PubMed

Davis, Peter E; Peters, Jurriaan M; Krueger, Darcy A; Sahin, Mustafa

2015-07-01

Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD). Tremendous progress in understanding the pathogenesis of TSC has been made in recent years, along with initial trials of medical treatment aimed specifically at the underlying mechanism of the disorder. At the cellular level, loss of TSC1 or TSC2 results in upregulation of the mechanistic target of rapamycin (mTOR) pathway. At the circuitry level, TSC and mTOR play crucial roles in axonal, dendritic, and synaptic development and function. In this review, we discuss the molecular mechanism underlying TSC, and how this disease results in aberrant neural connectivity at multiple levels in the central nervous system, leading to ASD symptoms. We then review recent advances in mechanism-based treatments of TSC, and the promise that these treatments provide for future mechanism-based treatment of ASD. Because of these recent advances, TSC represents an ideal model for how to make progress in understanding and treating the mechanisms that underlie ASD in general.

High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial.

PubMed

Beck, Roy W; Trobe, Jonathan D; Moke, Pamela S; Gal, Robin L; Xing, Dongyuan; Bhatti, M Tariq; Brodsky, Michael C; Buckley, Edward G; Chrousos, Georgia A; Corbett, James; Eggenberger, Eric; Goodwin, James A; Katz, Barrett; Kaufman, David I; Keltner, John L; Kupersmith, Mark J; Miller, Neil R; Nazarian, Sarkis; Orengo-Nania, Silvia; Savino, Peter J; Shults, William T; Smith, Craig H; Wall, Michael

2003-07-01

To identify factors associated with a high and low risk of developing multiple sclerosis after an initial episode of optic neuritis. Three hundred eighty-eight patients who experienced acute optic neuritis between July 1, 1988, and June 30, 1991, were followed up prospectively for the development of multiple sclerosis. Consenting patients were reassessed after 10 to 13 years. The 10-year risk of multiple sclerosis was 38% (95% confidence interval, 33%-43%). Patients (160) who had 1 or more typical lesions on the baseline magnetic resonance imaging (MRI) scan of the brain had a 56% risk; those with no lesions (191) had a 22% risk (P<.001, log rank test). Among the patients who had no lesions on MRI, male gender and optic disc swelling were associated with a lower risk of multiple sclerosis, as was the presence of the following atypical features for optic neuritis: no light perception vision; absence of pain; and ophthalmoscopic findings of severe optic disc edema, peripapillary hemorrhages, or retinal exudates. The 10-year risk of multiple sclerosis following an initial episode of acute optic neuritis is significantly higher if there is a single brain MRI lesion; higher numbers of lesions do not appreciably increase that risk. However, even when brain lesions are seen on MRI, more than 40% of the patients will not develop clinical multiple sclerosis after 10 years. In the absence of MRI lesions, certain demographic and clinical features seem to predict a very low likelihood of developing multiple sclerosis. This natural history information is a critical input for estimating a patient's 10-year multiple sclerosis risk and for weighing the benefit of initiating prophylactic treatment at the time of optic neuritis or other initial demyelinating events in the central nervous system.

Use of the Godin leisure-time exercise questionnaire in multiple sclerosis research: a comprehensive narrative review.

PubMed

Sikes, Elizabeth Morghen; Richardson, Emma V; Cederberg, Katie J; Sasaki, Jeffer E; Sandroff, Brian M; Motl, Robert W

2018-01-17

The Godin Leisure-Time Exercise Questionnaire has been a commonly applied measure of physical activity in research among persons with multiple sclerosis over the past decade. This paper provides a comprehensive description of its application and inclusion in research on physical activity in multiple sclerosis. This comprehensive, narrative review included papers that were published between 1985 and 2017, written in English, involved participants with multiple sclerosis as a primary population, measured physical activity, and cited one of the two original Godin papers. There is a broad scope of research that has included the Godin Leisure-Time Exercise Questionnaire in persons with multiple sclerosis. Overall, 8 papers evaluated its psychometric properties, 21 evaluated patterns of physical activity, 24 evaluated correlates or determinants of physical activity, 28 evaluated outcomes or consequences of physical activity, and 15 evaluated physical activity interventions. The Godin Leisure-Time Exercise Questionnaire is a valid self-report measure of physical activity in persons with multiple sclerosis, and further is an appropriate, simple, and effective tool for describing patterns of physical activity, examining correlates and outcomes of physical activity, and provides a sensitive outcome for measuring change in physical activity after an intervention. Implications for rehabilitation There is increasing interest in physical activity and its benefits in multiple sclerosis. The study of physical activity requires appropriate and standardized measures. The Godin Leisure-Time Exercise Questionnaire is a common self-report measure of physical activity for persons with multiple sclerosis. Godin Leisure-Time Exercise Questionnaire scores are reliable measures of physical activity in persons with multiple sclerosis. The Godin Leisure-Time Exercise Questionnaire further is an appropriate, simple, and effective tool for describing patterns of physical activity, examining correlates and outcomes of physical activity participation, and is an advantageous primary outcome for measuring change in physical activity in response to an intervention.

Clinical benefits to vestibular rehabilitation in multiple sclerosis. Report of 4 cases.

PubMed

Zeigelboim, Bianca; Liberalesso, Paulo; Jurkiewicz, Ari; Klagenberg, Karlin

2010-01-01

Balance difficulties are common among multiple sclerosis patients. To evaluate the effectiveness of the Cawthorne and Cooksey protocol of vestibular rehabilitation (VR) exercises in reducing the physical, functional and emotional impact of multiple sclerosis among individuals who complained of vertigo. Four patients with remittent-recurrent multiple sclerosis underwent an interview, otorhinolaryngological and vestibular evaluation, VR exercises and the Dizziness Handicap Inventory pre- and post-intervention. There was significant improvement in the physical, functional and emotional aspects of the DHI after the completion of the VR. The VR exercises appeared useful in reducing subjective complaints of the study participants.

Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.

PubMed

Jurynczyk, Maciej; Geraldes, Ruth; Probert, Fay; Woodhall, Mark R; Waters, Patrick; Tackley, George; DeLuca, Gabriele; Chandratre, Saleel; Leite, Maria I; Vincent, Angela; Palace, Jacqueline

2017-03-01

Brain imaging characteristics of MOG antibody disease are largely unknown and it is unclear whether they differ from those of multiple sclerosis and AQP4 antibody disease. The aim of this study was to identify brain imaging discriminators between those three inflammatory central nervous system diseases in adults and children to support diagnostic decisions, drive antibody testing and generate disease mechanism hypotheses. Clinical brain scans of 83 patients with brain lesions (67 in the training and 16 in the validation cohort, 65 adults and 18 children) with MOG antibody (n = 26), AQP4 antibody disease (n = 26) and multiple sclerosis (n = 31) recruited from Oxford neuromyelitis optica and multiple sclerosis clinical services were retrospectively and anonymously scored on a set of 29 predefined magnetic resonance imaging features by two independent raters. Principal component analysis was used to perform an overview of patients without a priori knowledge of the diagnosis. Orthogonal partial least squares discriminant analysis was used to build models separating diagnostic groups and identify best classifiers, which were then tested on an independent cohort set. Adults and children with MOG antibody disease frequently had fluffy brainstem lesions, often located in pons and/or adjacent to fourth ventricle. Children across all conditions showed more frequent bilateral, large, brainstem and deep grey matter lesions. MOG antibody disease spontaneously separated from multiple sclerosis but overlapped with AQP4 antibody disease. Multiple sclerosis was discriminated from MOG antibody disease and from AQP4 antibody disease with high predictive values, while MOG antibody disease could not be accurately discriminated from AQP4 antibody disease. Best classifiers between MOG antibody disease and multiple sclerosis were similar in adults and children, and included ovoid lesions adjacent to the body of lateral ventricles, Dawson's fingers, T1 hypointense lesions (multiple sclerosis), fluffy lesions and three lesions or less (MOG antibody). In the validation cohort patients with antibody-mediated conditions were differentiated from multiple sclerosis with high accuracy. Both antibody-mediated conditions can be clearly separated from multiple sclerosis on conventional brain imaging, both in adults and children. The overlap between MOG antibody oligodendrocytopathy and AQP4 antibody astrocytopathy suggests that the primary immune target is not the main substrate for brain lesion characteristics. This is also supported by the clear distinction between multiple sclerosis and MOG antibody disease both considered primary demyelinating conditions. We identify discriminatory features, which may be useful in classifying atypical multiple sclerosis, seronegative neuromyelitis optica spectrum disorders and relapsing acute disseminated encephalomyelitis, and characterizing cohorts for antibody discovery. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL)

ClinicalTrials.gov

2018-05-01

FTLD; Progressive Supranuclear Palsy (PSP); Frontotemporal Dementia (FTD); Corticobasal Degeneration (CBD); PPA Syndrome; Behavioral Variant Frontotemporal Dementia (bvFTD); Semantic Variant Primary Progressive Aphasia (svPPA); Nonfluent Variant Primary Progressive Aphasia (nfvPPA); FTD With Amyotrophic Lateral Sclerosis (FTD/ALS); Amyotrophic Lateral Sclerosis (ALS); Oligosymptomatic PSP (oPSP); Corticobasal Syndrome (CBS)

Advancing drug delivery systems for the treatment of multiple sclerosis.

PubMed

Tabansky, Inna; Messina, Mark D; Bangeranye, Catherine; Goldstein, Jeffrey; Blitz-Shabbir, Karen M; Machado, Suly; Jeganathan, Venkatesh; Wright, Paul; Najjar, Souhel; Cao, Yonghao; Sands, Warren; Keskin, Derin B; Stern, Joel N H

2015-12-01

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. It is characterized by demyelination of neurons and loss of neuronal axons and oligodendrocytes. In MS, auto-reactive T cells and B cells cross the blood-brain barrier (BBB), causing perivenous demyelinating lesions that form multiple discrete inflammatory demyelinated plaques located primarily in the white matter. In chronic MS, cortical demyelination and progressive axonal transections develop. Treatment for MS can be stratified into disease-modifying therapies (DMTs) and symptomatic therapy. DMTs aim to decrease circulating immune cells or to prevent these cells from crossing the BBB and reduce the inflammatory response. There are currently 10 DMTs approved for the relapsing forms of MS; these vary with regard to their efficacy, route and frequency of administration, adverse effects, and toxicity profile. Better drug delivery systems are being developed in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells. Here, we address the uses and benefits of advanced drug delivery systems, including nanoparticles, microparticles, fusion antibodies, and liposomal formulations. By altering the properties of therapeutic particles and enhancing targeting, breakthrough drug delivery technologies potentially applicable to multiple disease treatments may rapidly emerge.

Therapeutics for multiple sclerosis symptoms.

PubMed

Ben-Zacharia, Aliza Bitton

2011-01-01

Symptoms management in multiple sclerosis is an integral part of its care. Accurate assessment and addressing the different symptoms provides increased quality of life among patients with multiple sclerosis. Multiple sclerosis symptoms may be identified as primary, secondary, or tertiary symptoms. Primary symptoms, such as weakness, sensory loss, and ataxia, are directly related to demyelination and axonal loss. Secondary symptoms, such as urinary tract infections as a result of urinary retention, are a result of the primary symptoms. Tertiary symptoms, such as reactive depression or social isolation, are a result of the social and psychological consequences of the disease. Common multiple sclerosis symptoms include fatigue and weakness; decreased balance, spasticity and gait problems; depression and cognitive issues; bladder, bowel, and sexual deficits; visual and sensory loss; and neuropathic pain. Less-common symptoms include dysarthria and dysphagia, vertigo, and tremors. Rare symptoms in multiple sclerosis include seizures, hearing loss, and paralysis. Symptom management includes nonpharmacological methods, such as rehabilitation and psychosocial support, and pharmacological methods, ie, medications and surgical procedures. The keys to symptom management are awareness, knowledge, and coordination of care. Symptoms have to be recognized and management needs to be individualized. Multiple sclerosis therapeutics include nonpharmacological strategies that consist of lifestyle modifications, rehabilitation, social support, counseling, and pharmacological agents or surgical procedures. The goal is vigilant management to improve quality of life and promote realistic expectations and hope. © 2011 Mount Sinai School of Medicine.

Internal jugular vein blood flow in multiple sclerosis patients and matched controls.

PubMed

Mancini, Marcello; Lanzillo, Roberta; Liuzzi, Raffaele; Di Donato, Orlando; Ragucci, Monica; Monti, Serena; Salvatore, Elena; Morra, Vincenzo Brescia; Salvatore, Marco

2014-01-01

The aim of the study was to investigate the Internal Jugular Veins dynamics using contrast enhanced ultrasonography in Multiple Sclerosis patients, clinically isolated syndrome patients and healthy controls. Contrast enhanced ultrasonography imaging of the Internal Jugular Vein was performed in fifty-eight patients with Multiple Sclerosis, seven clinically isolated syndrome patients and in thirteen healthy controls. Time-intensity curves were quantified using a semi-automated method and compared with clinical disease outcomes. Wash-out parameters were calculated and six Time-intensity curves shapes were created. Significantly reduction of wash-out rate in Internal Jugular Veins was detected in Multiple Sclerosis patients compared to healthy controls [22.2% (2.7%-65.9%) vs. 33.4% (16.2%-76.8%); P<0.005]. Internal Jugular Vein enhancement was heterogeneous in patients with Multiple Sclerosis and consisted of slow wash-out Time-intensity curves shapes, compared with almost only one type of Time-intensity curves shape in control subjects that correspond to fast enhancement and fast wash-out. The vein wash-in parameters were similar in Multiple Sclerosis group compared with controls. A significant correlation was found between Internal Jugular Vein wash-out and level of disability (R =  -0.402, p<0.05). Contrast enhanced ultrasonography of the Internal Jugular Vein with time intensity curve analysis revealed alterations of cerebral venous outflow in Multiple Sclerosis patients, however mechanisms that determine this condition remains unclear.

Diffusion tensor imaging of the optic tracts in multiple sclerosis: association with retinal thinning and visual disability.

PubMed

Dasenbrock, Hormuzdiyar H; Smith, Seth A; Ozturk, Arzu; Farrell, Sheena K; Calabresi, Peter A; Reich, Daniel S

2011-04-01

Visual disability is common in multiple sclerosis, but its relationship to abnormalities of the optic tracts remains unknown. Because they are only rarely affected by lesions, the optic tracts may represent a good model for assessing the imaging properties of normal-appearing white matter in multiple sclerosis. Whole-brain diffusion tensor imaging was performed on 34 individuals with multiple sclerosis and 26 healthy volunteers. The optic tracts were reconstructed by tractography, and tract-specific diffusion indices were quantified. In the multiple-sclerosis group, peripapillary retinal nerve-fiber-layer thickness and total macular volume were measured by optical coherence tomography, and visual acuity at 100%, 2.5%, and 1.25% contrast was examined. After adjusting for age and sex, optic-tract mean and perpendicular diffusivity were higher (P=.002) in multiple sclerosis. Lower optic-tract fractional anisotropy was correlated with retinal nerve-fiber-layer thinning (r=.51, P=.003) and total-macular-volume reduction (r=.59, P=.002). However, optic-tract diffusion indices were not specifically correlated with visual acuity or with their counterparts in the optic radiation. Optic-tract diffusion abnormalities are associated with retinal damage, suggesting that both may be related to optic-nerve injury, but do not appear to contribute strongly to visual disability in multiple sclerosis. Copyright © 2010 by the American Society of Neuroimaging.

Diffusion Tensor Imaging of the Optic Tracts in Multiple Sclerosis: Association with Retinal Thinning and Visual Disability

PubMed Central

Dasenbrock, Hormuzdiyar H.; Smith, Seth A.; Ozturk, Arzu; Farrell, Sheena K.; Calabresi, Peter A.; Reich, Daniel S.

2009-01-01

Background and purpose Visual disability is common in multiple sclerosis, but its relationship to abnormalities of the optic tracts remains unknown. Because they are only rarely affected by lesions, the optic tracts may represent a good model for assessing the imaging properties of normal-appearing white matter in multiple sclerosis. Methods Whole-brain diffusion tensor imaging was performed on 34 individuals with multiple sclerosis and 26 healthy volunteers. The optic tracts were reconstructed by tractography, and tract-specific diffusion indices were quantified. In the multiple-sclerosis group, peripapillary retinal nerve-fiber-layer thickness and total macular volume were measured by optical coherence tomography, and visual acuity at 100%, 2.5%, and 1.25% contrast was examined. Results After adjusting for age and sex, optic-tract mean and perpendicular diffusivity were higher (p=0.002) in multiple sclerosis. Lower optic-tract fractional anisotropy was correlated with retinal nerve-fiber-layer thinning (r=0.51, p=0.003) and total-macular-volume reduction (r=0.59, p=0.002). However, optic-tract diffusion indices were not specifically correlated with visual acuity or with their counterparts in the optic radiation. Conclusions Optic-tract diffusion abnormalities are associated with retinal damage, suggesting that both may be related to optic-nerve injury, but do not appear to contribute strongly to visual disability in multiple sclerosis. PMID:20331501

Clustering of multiple sclerosis in Galion, Ohio, 1982-1985

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ingalls, T.H.

1989-09-01

Epidemiologic evidence indicates that the outbreak of 30-40 cases of multiple sclerosis and other demyelinating syndromes in Galion, Ohio, USA, during 1982-1985 was related to an excess concentration of heavy-metal wastes, especially of cadmium and chromium in sewage and river water. Both multiple sclerosis and myasthenia gravis were diagnosed by board-certified neurologists.

Clinical commentary on "Paroxysmal kinesigenic dyskinesia-like phenotype in multiple sclerosis" and "Secondary paroxysmal dyskinesia in multiple sclerosis: Clinical-radiological features and treatment. Case report of seven patients".

PubMed

Pareés, Isabel

2017-11-01

This clinical commentary discusses the phenomenology and treatment of paroxysmal dyskinesia in patients with multiple sclerosis. It calls for a consensus on the definition as well as for larger studies to better understand this unusual clinical association.

Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis

DTIC Science & Technology

2017-10-01

Insulin, Symbol Digit Modalities Test , Minimal Assessment of Cognitive Function in Multiple Sclerosis 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...going to evaluate if intranasal insulin improves cognition in people with MS, as assessed by standardized cognitive assessment tests . 2. KEYWORDS...Multiple Sclerosis, Cognitive Impairment, Neurodegenerative diseases, Intranasal Insulin, Symbol Digit Modalities Test , Minimal Assessment of Cognitive

Reliability and Clinical Significance of Mobility and Balance Assessments in Multiple Sclerosis

ERIC Educational Resources Information Center

Learmonth, Yvonne C.; Paul, Lorna; McFadyen, Angus K.; Mattison, Paul; Miller, Linda

2012-01-01

The aim of the study was to establish the test-retest reliability, clinical significance and precision of four mobility and balance measures--the Timed 25-Foot Walk, Six-minute Walk, Timed Up and Go and the Berg Balance Scale--in individuals moderately affected by multiple sclerosis. Twenty four participants with multiple sclerosis (Extended…

76 FR 17530 - Special Local Regulations and Safety Zones; Recurring Events in Northern New England

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-30

...'' N 069[deg] 31'56'' W. 8.6 Multiple Sclerosis Regatta.... Event Type: Regatta and Sailboat Race. Sponsor: Maine Chapter, Multiple Sclerosis Society. Date: A one day event on Saturday during the third... 070[deg] 13'51'' W. 8.7 Multiple Sclerosis Harborfest Event Type: Power Boat Tugboat Race. Race...

75 FR 32280 - Safety Zones; Marine Events Within the Captain of the Port Sector Northern New England Area of...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-08

.... Sponsor: Maine Chapter, Multiple Sclerosis Society. Date: August 21, 2010. Time: 11 am to 2 pm. Location... Sailboat Race. Sponsor: Maine Chapter, Multiple Sclerosis Society. Date: August 21, 2010. Time: 10 am to 4... Tugboat Muster. Event Type: Power Boat Race. Sponsor: Maine Chapter, National Multiple Sclerosis Society...

Is Hypovitaminosis D One of the Environmental Risk Factors for Multiple Sclerosis?

ERIC Educational Resources Information Center

Pierrot-Deseilligny, Charles; Souberbielle, Jean-Claude

2010-01-01

The role of hypovitaminosis D as a possible risk factor for multiple sclerosis is reviewed. First, it is emphasized that hypovitaminosis D could be only one of the risk factors for multiple sclerosis and that numerous other environmental and genetic risk factors appear to interact and combine to trigger the disease. Secondly, the classical…

Epstein Barr Virus and Blood Brain Barrier in Multiple Sclerosis

DTIC Science & Technology

2013-07-01

Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Multiple sclerosis (MS) is a chronic, autoimmune neurodegenerative disease . Epstein - Barr ...of EBV in MS disease . 15. SUBJECT TERMS Blood-brain-barrier, Epstein - Barr virus ; EBV; BBB; MS, Multiple sclerosis 16. SECURITY CLASSIFICATION OF...AD_________________ Award Number: W81XWH-12-1-0225 TITLE: Epstein Barr virus and blood brain

[Assessment of exposure to tobacco smoke in a selected group of patients with multiple sclerosis from the Upper Silesia region].

PubMed

Dobosz, Cezary; Tyrpień, Krystyna; Pierzchała, Krystyna

2012-01-01

In recent years, the increase in the incidence of multiple sclerosis (MS - Multiple Sclerosis) is observed. and the direct cause of the symptoms of multiple sclerosis is myelin nerves damage. It can be concluded that the environmental factor is at least partly responsible for the occurrence of this disease. For the development of this disease are responsible, in addition to genetic factors, compounds present in many parts of the environment. Many of these compounds may adversely affect the redox equilibrium of the body, exacerbating radicalgenesis and decreasing antioxidant defenses. Multiple sclerosis is usually diagnosed in early adulthood, during most daily activities. Effects of SM on living standards includes not only the medical aspect, but also social, economic and emotional aspect. Polish population is a high risk zone regarding multiple sclerosis. The aim of this study was a preliminary assessment of selected environmental exposure factors in the pathogenesis of multiple sclerosis with regard to exposure to tobacco smoke with the author's survey of patients from the region of Upper Silesia. Most MS patients (32) in the study group (suffering from MS from 2 to 44 years) are inhabitants of agglomeration of over 50 thousand citizens, from the area of Gliwice, Bytom and Zabrze (43.75%). In investigated group 46.88% MS patients from Silesia region were exposed to tobacco smoke, of which 21.88% actively smoke. Patients with MS, in order not to worsen their disease manifestation, should stop smoking and increase, if possible, any physical activities. These data will be incorporated into a wide-ranging research to clarify the role of selected environmental factors in a very complex and still not fully explored the pathogenesis of multiple sclerosis in Upper Silesia.

Childhood infections and risk of multiple sclerosis.

PubMed

Bager, Peter; Nielsen, Nete Munk; Bihrmann, Kristine; Frisch, Morten; Hjalgrim, Henrik; Wohlfart, Jan; Koch-Henriksen, Nils; Melbye, Mads; Westergaard, Tine

2004-11-01

Multiple sclerosis has been hypothesized to be the result from an aberrant immune response possibly triggered by delayed exposure to a common childhood infection. Because the vast majority of previous studies testing this hypothesis have been based on a history of childhood infections recalled years to decades later in adulthood, we investigated whether age at six common childhood infections was associated with risk of multiple sclerosis, using information recalled in the childhood of a historical cohort of school children in Denmark. Cases included all individuals with multiple sclerosis in the country born between 1940 and 1975, who had attended school in the capital, Copenhagen. Controls were age- and sex-matched peers. School health records were obtained for all subjects. The records contained information on measles, pertussis, scarlet fever, birth order, sibship size, social class of the father, school years, and name of school and attended school classes for children born since 1940 (n(cases) = 455, n(controls) = 1801). For children born since 1950, the records also contained information on rubella, varicella and mumps (n(cases) = 182, n(controls) = 690). Neither age at infection with measles, rubella, varicella, mumps, pertussis and scarlet fever (upper age limit, 14 years) nor the cumulative number of these infections between the ages of 10 and 14 years was associated with the risk of multiple sclerosis. In addition, the risk of multiple sclerosis was not associated with birth order or social class. No clustering of multiple sclerosis in school classes was observed. Our findings suggest that measles, rubella, mumps, varicella, pertussis and scarlet fever, even if acquired late in childhood, are not associated with increased risk of multiple sclerosis later in life.

Disconnection mechanism and regional cortical atrophy contribute to impaired processing of facial expressions and theory of mind in multiple sclerosis: a structural MRI study.

PubMed

Mike, Andrea; Strammer, Erzsebet; Aradi, Mihaly; Orsi, Gergely; Perlaki, Gabor; Hajnal, Andras; Sandor, Janos; Banati, Miklos; Illes, Eniko; Zaitsev, Alexander; Herold, Robert; Guttmann, Charles R G; Illes, Zsolt

2013-01-01

Successful socialization requires the ability of understanding of others' mental states. This ability called as mentalization (Theory of Mind) may become deficient and contribute to everyday life difficulties in multiple sclerosis. We aimed to explore the impact of brain pathology on mentalization performance in multiple sclerosis. Mentalization performance of 49 patients with multiple sclerosis was compared to 24 age- and gender matched healthy controls. T1- and T2-weighted three-dimensional brain MRI images were acquired at 3Tesla from patients with multiple sclerosis and 18 gender- and age matched healthy controls. We assessed overall brain cortical thickness in patients with multiple sclerosis and the scanned healthy controls, and measured the total and regional T1 and T2 white matter lesion volumes in patients with multiple sclerosis. Performances in tests of recognition of mental states and emotions from facial expressions and eye gazes correlated with both total T1-lesion load and regional T1-lesion load of association fiber tracts interconnecting cortical regions related to visual and emotion processing (genu and splenium of corpus callosum, right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, uncinate fasciculus). Both of these tests showed correlations with specific cortical areas involved in emotion recognition from facial expressions (right and left fusiform face area, frontal eye filed), processing of emotions (right entorhinal cortex) and socially relevant information (left temporal pole). Thus, both disconnection mechanism due to white matter lesions and cortical thinning of specific brain areas may result in cognitive deficit in multiple sclerosis affecting emotion and mental state processing from facial expressions and contributing to everyday and social life difficulties of these patients.

"Always looking for a new balance": toward an understanding of what it takes to continue working while being diagnosed with relapsing-remitting multiple sclerosis.

PubMed

Meide, Hanneke van der; Gorp, Dennis van; van der Hiele, Karin; Visser, Leo

2017-06-22

The aim of this study was to gain insight into the meaning of work in the everyday lives of people with relapsing-remitting multiple sclerosis, and the barriers and facilitators to staying in work. Nineteen employed adults diagnosed with relapsing-remitting multiple sclerosis participated in narrative interviews. All interviews were transcribed and coded for thematic analysis. For people with relapsing-remitting multiple sclerosis, continuing to work was a precarious balancing act. Five themes influenced this balance: becoming familiar with the disease, adjusting expectations, having an understanding and realistic line manager, seeing work as meaningful life activity and strategic considerations. People receiving a diagnosis of relapsing-remitting multiple sclerosis have to refamiliarize themselves with their own body in a meaningful way to be able to continue their work. Rehabilitation professionals can support them herein by taking into account not merely functional capabilities but also identity aspects of the body. Medication that stabilizes symptoms supports making the necessary adjustments. A trusting relationship with the line manager is vital for this adaptation process. Additionally, a match between being adequately challenged by work, while still having the capacity to meet those work demands, is needed, as is long-term financial stability. Implications for rehabilitation Rehabilitation professionals can support employees with relapsing-remitting multiple sclerosis by taking into account not merely functional capabilities but also identity aspects of the body. A trusting relationship with the line manager, including a timely disclosure of the diagnosis, is vital for people with relapsing-remitting multiple sclerosis to remain at work. For people with relapsing-remitting multiple sclerosis, there is a delicate balance between being adequately challenged by work while still having the capacity to meet work demands.

An ImmunoChip study of multiple sclerosis risk in African Americans

PubMed Central

Isobe, Noriko; Madireddy, Lohith; Khankhanian, Pouya; Matsushita, Takuya; Caillier, Stacy J.; Moré, Jayaji M.; Gourraud, Pierre-Antoine; McCauley, Jacob L.; Beecham, Ashley H.; Piccio, Laura; Herbert, Joseph; Khan, Omar; Cohen, Jeffrey; Stone, Lael; Santaniello, Adam; Cree, Bruce A. C.; Onengut-Gumuscu, Suna; Rich, Stephen S.; Hauser, Stephen L.; Sawcer, Stephen

2015-01-01

The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10−4), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10−5). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk. PMID:25818868

An ImmunoChip study of multiple sclerosis risk in African Americans.

PubMed

Isobe, Noriko; Madireddy, Lohith; Khankhanian, Pouya; Matsushita, Takuya; Caillier, Stacy J; Moré, Jayaji M; Gourraud, Pierre-Antoine; McCauley, Jacob L; Beecham, Ashley H; Piccio, Laura; Herbert, Joseph; Khan, Omar; Cohen, Jeffrey; Stone, Lael; Santaniello, Adam; Cree, Bruce A C; Onengut-Gumuscu, Suna; Rich, Stephen S; Hauser, Stephen L; Sawcer, Stephen; Oksenberg, Jorge R

2015-06-01

The aims of this study were: (i) to determine to what degree multiple sclerosis-associated loci discovered in European populations also influence susceptibility in African Americans; (ii) to assess the extent to which the unique linkage disequilibrium patterns in African Americans can contribute to localizing the functionally relevant regions or genes; and (iii) to search for novel African American multiple sclerosis-associated loci. Using the ImmunoChip custom array we genotyped 803 African American cases with multiple sclerosis and 1516 African American control subjects at 130 135 autosomal single nucleotide polymorphisms. We conducted association analysis with rigorous adjustments for population stratification and admixture. Of the 110 non-major histocompatibility complex multiple sclerosis-associated variants identified in Europeans, 96 passed stringent quality control in our African American data set and of these, >70% (69) showed over-representation of the same allele amongst cases, including 21 with nominally significant evidence for association (one-tailed test P < 0.05). At a further eight loci we found nominally significant association with an alternate correlated risk-tagging single nucleotide polymorphism from the same region. Outside the regions known to be associated in Europeans, we found seven potentially associated novel candidate multiple sclerosis variants (P < 10(-4)), one of which (rs2702180) also showed nominally significant evidence for association (one-tailed test P = 0.034) in an independent second cohort of 620 African American cases and 1565 control subjects. However, none of these novel associations reached genome-wide significance (combined P = 6.3 × 10(-5)). Our data demonstrate substantial overlap between African American and European multiple sclerosis variants, indicating common genetic contributions to multiple sclerosis risk. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Older age, higher perceived disability and depressive symptoms predict the amount and severity of work-related difficulties in persons with multiple sclerosis.

PubMed

Raggi, Alberto; Giovannetti, Ambra Mara; Schiavolin, Silvia; Brambilla, Laura; Brenna, Greta; Confalonieri, Paolo Agostino; Cortese, Francesca; Frangiamore, Rita; Leonardi, Matilde; Mantegazza, Renato Emilio; Moscatelli, Marco; Ponzio, Michela; Torri Clerici, Valentina; Zaratin, Paola; De Torres, Laura

2018-04-16

This cross-sectional study aims to identify the predictors of work-related difficulties in a sample of employed persons with multiple sclerosis as addressed with the Multiple Sclerosis Questionnaire for Job Difficulties. Hierarchical linear regression analysis was conducted to identify predictors of work difficulties: predictors included demographic variables (age, formal education), disease duration and severity, perceived disability and psychological variables (cognitive dysfunction, depression and anxiety). The targets were the questionnaire's overall score and its six subscales. A total of 177 participants (108 females, aged 21-63) were recruited. Age, perceived disability and depression were direct and significant predictors of the questionnaire total score, and the final model explained 43.7% of its variation. The models built on the questionnaire's subscales show that perceived disability and depression were direct and significant predictors of most of its subscales. Our results show that, among patients with multiple sclerosis, those who were older, with higher perceived disability and higher depression symptoms have more and more severe work-related difficulties. The Multiple Sclerosis Questionnaire for Job Difficulties can be fruitfully exploited to plan tailored actions to limit the likelihood of near-future job loss in persons of working age with multiple sclerosis. Implications for rehabilitation Difficulties with work are common among people with multiple sclerosis and are usually addressed in terms of unemployment or job loss. The Multiple Sclerosis Questionnaire for Job Difficulties is a disease-specific questionnaire developed to address the amount and severity of work-related difficulties. We found that work-related difficulties were associated to older age, higher perceived disability and depressive symptoms. Mental health issues and perceived disability should be consistently included in future research targeting work-related difficulties.

The multiple sclerosis work difficulties questionnaire: translation and cross-cultural adaptation to Turkish and assessment of validity and reliability.

PubMed

Kahraman, Turhan; Özdoğar, Asiye Tuba; Honan, Cynthia Alison; Ertekin, Özge; Özakbaş, Serkan

2018-05-09

To linguistically and culturally adapt the Multiple Sclerosis Work Difficulties Questionnaire-23 (MSWDQ-23) for use in Turkey, and to examine its reliability and validity. Following standard forward-back translation of the MSWDQ-23, it was administered to 124 people with multiple sclerosis (MS). Validity was evaluated using related outcome measures including those related to employment status and expectations, disability level, fatigue, walking, and quality of life. Randomly selected participants were asked to complete the MSWDQ-23 again to assess test-retest reliability. Confirmatory factor analysis on the MSWDQ-23 demonstrated a good fit for the data, and the internal consistency of each subscale was excellent. The test-retest reliability for the total score, psychological/cognitive barriers, physical barriers, and external barriers subscales were high. The MSWDQ-23 and its subscales were positively correlated with the employment, disability level, walking, and fatigue outcome measures. This study suggests that the Turkish version of MSWDQ-23 has high reliability and adequate validity, and it can be used to determine the difficulties faced by people with multiple sclerosis in workplace. Moreover, the study provides evidence about the test-retest reliability of the questionnaire. Implications for rehabilitation Multiple sclerosis affects young people of working age. Understanding work-related problems is crucial to enhance people with multiple sclerosis likelihood of maintaining their job. The Multiple Sclerosis Work Difficulties Questionnaire-23 (MSWDQ-23) is a valid and reliable measure of perceived workplace difficulties in people with multiple sclerosis: we presented its validation to Turkish. Professionals working in the field of vocational rehabilitation may benefit from using the MSWDQ-23 to predict the current work outcomes and future employment expectations.

The liminal self in people with multiple sclerosis: an interpretative phenomenological exploration of being diagnosed.

PubMed

Strickland, Karen; Worth, Allison; Kennedy, Catriona

2017-06-01

To explore the lived experience of the meaning of being diagnosed with multiple sclerosis on the individual's sense of self. The time leading up to and immediately following the diagnosis of multiple sclerosis has been identified as a time period shrouded by uncertainty and one where individuals have a heightened desire to seek accurate information and support. The diagnosis brings changes to the way one views the self which has consequences for biographical construction. A hermeneutic phenomenological study. In-depth qualitative interviews were conducted with 10 people recently diagnosed with multiple sclerosis. The data were analysed using interpretative phenomenological analysis. This study presents the three master themes: the 'road to diagnosis', 'the liminal self' and 'learning to live with multiple sclerosis'. The diagnosis of multiple sclerosis may be conceptualised as a 'threshold moment' where the individual's sense of self is disrupted from the former taken-for-granted way of being and propose a framework which articulates the transition. The findings highlight the need for healthcare professionals to develop interventions to better support people affected by a new diagnosis of multiple sclerosis. The conceptual framework which has been developed from the data and presented in this study provides a new way of understanding the impact of the diagnosis on the individual's sense of self when affected by a new diagnosis of multiple sclerosis. This framework can guide healthcare professionals in the provision of supportive care around the time of diagnosis. The findings provide practitioners with a new way of understanding the impact of the diagnosis on the individual's sense of self and a framework which can guide them in the provision of supportive care around the time of diagnosis. © 2016 John Wiley & Sons Ltd.

Physical activity and pediatric multiple sclerosis: Developing a research agenda.

PubMed

Yeh, E Ann; Kinnett-Hopkins, Dominique; Grover, Stephanie A; Motl, Robert W

2015-11-01

Three-quarters of children with multiple sclerosis (MS) experience fatigue or depression, and progressive neurocognitive decline may be seen as early as two years after MS diagnosis. Furthermore, a higher magnetic resonance imaging disease burden is seen in pediatric-onset MS compared with adult-onset MS. To date, limited knowledge exists regarding behavioral methods for managing symptoms and disease progression in pediatric MS. To that end, this paper builds an evidence-based argument for the possible symptomatic and disease-modifying effects of exercise and physical activity in pediatric MS. This will be accomplished through: (a) a review of pediatric MS and its consequences; (b) a brief overview of physical activity and its consequences in children and adults with MS; and (c) a selective review of research on the neurological benefits of physical activity in pediatric populations. This topical review concludes with a list of 10 questions to guide future research on physical activity and pediatric MS. The objective of this paper is the provision of a research interest, focus and agenda involving pediatric MS and its lifelong management though exercise and physical activity behavior. Such an agenda is critical as the effects and maintenance of physical activity and exercise track across the lifespan, particularly when developed in the early stages of life. © The Author(s), 2015.

Therapeutic plasma exchange in the treatment of neuroimmunologic disorders: review of 50 cases.

PubMed

Yücesan, Canan; Arslan, Onder; Arat, Mutlu; Yücemen, Nezih; Ayyildiz, Erol; Ilhan, Osman; Mutluer, Nermin

2007-02-01

Therapeutic plasma exchange (TPE) has been used for the treatment of neurologic diseases in which autoimmunity plays a major role. We reviewed the medical records of our patients who had consecutively been treated by TPE between January 1998 and June 2000. Neurological indications included myasthenia gravis (30 patients), multiple sclerosis attack (6 patients with remitting-relapsing course and 3 patients with secondary progressive course), Guillain-Barrè syndrome (6 patients), paraproteinemic neuropathy (2 patients), and chronic inflammatory demyelinating neuropathy (CIDP), transverse myelitis due to systemic lupus erythematosus, acute disseminated encephalomyelitis in one patient each. Continuous flow cell separators were used for TPE. TPE was generally given every other day for all of the patients and one plasma volume was exchanged for each cycle. Although the patients with secondary progressive multiple sclerosis (3 patients) and paraproteinemic neuropathy (2 patients) did not show any improvement after TPE, other patients' targeted neurological deficits were improved by TPE. During the TPE procedures, no patient had any morbidity or mortality, and the complications were mild and manageable such as hypotension, hypocalcemia and mild anemia; three patients had septicemia due to the venous catheter used for TPE. TPE is an effective treatment in neurologic diseases in which autoimmunity plays an important role in pathogenesis, and it is safe when performed in experienced centers.

Validating Neuro-QoL short forms and targeted scales with people who have multiple sclerosis.

PubMed

Miller, Deborah M; Bethoux, Francois; Victorson, David; Nowinski, Cindy J; Buono, Sarah; Lai, Jin-Shei; Wortman, Katy; Burns, James L; Moy, Claudia; Cella, David

2016-05-01

Multiple sclerosis (MS) is a chronic, progressive, and disabling disease of the central nervous system with dramatic variations in the combination and severity of symptoms it can produce. The lack of reliable disease-specific health-related quality of life (HRQL) measures for use in clinical trials prompted the development of the Neurology Quality of Life (Neuro-QOL) instrument, which includes 13 scales that assess physical, emotional, cognitive, and social domains, for use in a variety of neurological illnesses. The objective of this research paper is to conduct an initial assessment of the reliability and validation of the Neuro-QOL short forms (SFs) in MS. We assessed reliability, concurrent validity, known groups validity, and responsiveness between cross-sectional and longitudinal data in 161 recruited MS patients. Internal consistency was high for all measures (α = 0.81-0.95) and ICCs were within the acceptable range (0.76-0.91); concurrent and known groups validity were highest with the Global HRQL question. Longitudinal assessment was limited by the lack of disease progression in the group. The Neuro-QOL SFs demonstrate good internal consistency, test-re-test reliability, and concurrent and known groups validity in this MS population, supporting the validity of Neuro-QOL in adults with MS. © The Author(s), 2015.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy. MS Neurology Group of the Australian and New Zealand Association of Neurologists.

PubMed

Broadley, Simon A; Barnett, Michael H; Boggild, Mike; Brew, Bruce J; Butzkueven, Helmut; Heard, Robert; Hodgkinson, Suzanne; Kermode, Allan G; Lechner-Scott, Jeannette; Macdonell, Richard A L; Marriott, Mark; Mason, Deborah F; Parratt, John; Reddel, Stephen W; Shaw, Cameron P; Slee, Mark; Spies, Judith; Taylor, Bruce V; Carroll, William M; Kilpatrick, Trevor J; King, John; McCombe, Pamela A; Pollard, John D; Willoughby, Ernest

2014-11-01

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Thalamic lesions in multiple sclerosis by 7T MRI: Clinical implications and relationship to cortical pathology.

PubMed

Harrison, Daniel M; Oh, Jiwon; Roy, Snehashis; Wood, Emily T; Whetstone, Anna; Seigo, Michaela A; Jones, Craig K; Pham, Dzung; van Zijl, Peter; Reich, Daniel S; Calabresi, Peter A

2015-08-01

Pathology in both cortex and deep gray matter contribute to disability in multiple sclerosis (MS). We used the increased signal-to-noise ratio of 7-tesla (7T) MRI to visualize small lesions within the thalamus and to relate this to clinical information and cortical lesions. We obtained 7T MRI scans on 34 MS cases and 15 healthy volunteers. Thalamic lesion number and volume were related to demographic data, clinical disability measures, and lesions in cortical gray matter. Thalamic lesions were found in 24/34 of MS cases. Two lesion subtypes were noted: discrete, ovoid lesions, and more diffuse lesional areas lining the periventricular surface. The number of thalamic lesions was greater in progressive MS compared to relapsing-remitting (mean ±SD, 10.7 ±0.7 vs. 3.0 ±0.7, respectively, p < 0.001). Thalamic lesion burden (count and volume) correlated with EDSS score and measures of cortical lesion burden, but not with white matter lesion burden or white matter volume. Using 7T MRI allows identification of thalamic lesions in MS, which are associated with disability, progressive disease, and cortical lesions. Thalamic lesion analysis may be a simpler, more rapid estimate of overall gray matter lesion burden in MS. © The Author(s), 2015.

Newly diagnosed multiple sclerosis in state of Qatar.

PubMed

Akhtar, N; Elsetouhy, A; Deleu, D; Kamran, S; AlHail, H; Elalamy, O; Mesraoua, B; Sokrab, T; Kamil, H; Melikyan, G; D'souza, A; Osman, Y; Imam, Y

2013-08-01

Epidemiologic studies on multiple sclerosis (MS) are well-documented in the western population but to a lesser extent in Arab world. To study the demographics, clinical aspects, radiologic and laboratory features along with the degree of disability inflicted, and factors affecting disease progression and outcome of newly diagnosed MS patients at our institution. Data from all newly diagnosed MS patients fulfilling McDonald criteria from January 01, 2005 to December 31, 2010 were collected and analyzed. A total of 142 patients were identified, in which 82 (58%) were Qataris, and 90 (64%) females. Mean age was 31 years, and mean duration of symptoms was 24 days (median 15 days). Most common symptoms were sensory (63%), followed by visual (45%) and motor (43%). Mean EDSS was 2.3 at presentation. Treatment was given to 127 (89%), and relapse observed in 49%. Gadolinium enhancing lesions on follow-up MRI brain and relapsing remitting MS were associated with increased radiologic disease burden, while weakness at onset, EDSS of ≥2.5 and ≥3 clinical relapse was associated with clinical disease progression. MS in Qatar is an emerging disorder especially in the native population. The pattern of disease differs from other Middle Eastern countries by its milder clinical and aggressive radiologic disease presentation. Copyright © 2013 Elsevier B.V. All rights reserved.

Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis - A case report.

PubMed

Dalbjerg, Sara Maria; Tsakiri, Anna; Frederiksen, Jette Lautrup

2016-07-01

Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis associated with Interferon-beta treatment. We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved. Clinicians should be aware of the possibility of rhabdomyolysis occurring during Interferon-beta-1-alpha therapy. In cases where patients complain of severe myalgia, and in particular if weakness is reported, creatine kinase activity should be measured to prevent irreversible rhabdomyolysis during Interferon-beta-1-alpha therapy in patients with multiple sclerosis. Copyright © 2016 Elsevier B.V. All rights reserved.

Evolution of multiple sclerosis in France since the beginning of hepatitis B vaccination.

PubMed

Le Houézec, Dominique

2014-12-01

Since the implementation of the mass vaccination campaign against hepatitis B in France, the appearance of multiple sclerosis, sometimes occurring in the aftermath of vaccinations, led to the publication of epidemiological international studies. This was also justified by the sharp increase in the annual incidence of multiple sclerosis reported to the French health insurance in the mid-1990s. Almost 20 years later, a retrospective reflection can be sketched from these official data and also from the national pharmacovigilance agency. Statistical data from these latter sources seem to show a significant correlation between the number of hepatitis B vaccinations performed and the declaration to the pharmacovigilance of multiple sclerosis occurring between 1 and 2 years later. The application of the Hill's criteria to these data indicates that the correlation between hepatitis B vaccine and multiple sclerosis may be causal.

Latin American algorithm for treatment of relapsing-remitting multiple sclerosis using disease-modifying agents.

PubMed

Finkelsztejn, Alessandro; Gabbai, Alberto Alain; Fragoso, Yara Dadalti; Carrá, Adriana; Macías-Islas, Miguel Angel; Arcega-Revilla, Raul; García-Bonitto, Juan; Oehninger-Gatti, Carlos Luis; Orozco-Escobar, Geraldine; Tarulla, Adriana; Vergara, Fernando; Vizcarra, Darwin

2012-10-01

It is estimated that circa 50,000 individuals have relapsing-remitting multiple sclerosis in Latin America. European and North-American algorithms for the treatment of multiple sclerosis do not foresee our regional difficulties and the access of patients to treatment. The Latin American Multiple Sclerosis Forum is an independent and supra-institutional group of experts that has assessed the latest scientific evidence regarding efficacy and safety of disease-modifying treatments. Accesses to treatment and pharmacovigilance programs for each of the eight countries represented at the Forum were also analyzed. A specific set of guidelines based upon evidence-based recommendations was designed for Latin America. Future perspectives of multiple sclerosis treatment were also discussed. The present paper translated an effort from representatives of eight countries discussing a matter that cannot be adapted to our region directly from purely European and North-American guidelines for treatment.

The Practice of Sport in Multiple Sclerosis: Update.

PubMed

Donze, Cecile; Massot, Caroline; Hautecoeur, Patrick; Cattoir-Vue, Helene; Guyot, Marc-Alexandre

The practice of sport by multiple sclerosis patients has long been controversial. Recent studies, however, show that both sport and physical activity are essential for these patients. Indeed, they help to cope with the effects of multiple sclerosis, such as fatigue, reduced endurance, loss of muscle mass, and reduction of muscle strength. The beneficial effects of physical activity on these patients have been underlined in several studies, whereas those of practicing sport have been the subject of fewer evaluations and assessments. The aim of this update is to report on the effects of sport on multiple sclerosis patients. The benefits of sport have been demonstrated in several studies. It helps multiple sclerosis patients to increase their balance, resistance to fatigue, mobility and quality of life. Several biases in these studies do not enable us to recommend the practice of some of these sports on a routine basis.

Early disturbances in multimodal evoked potentials as a prognostic factor for long-term disability in relapsing-remitting multiple sclerosis patients.

PubMed

London, Frédéric; El Sankari, Souraya; van Pesch, Vincent

2017-04-01

The aim of this study was to investigate whether early alterations in evoked potentials (EPs) have a prognostic value in relapsing-remitting multiple sclerosis (RRMS). We retrospectively selected 108 early MS patients with a neurological follow-up ranging from 5 to 15years, in whom multimodal EPs (visual, brainstem auditory, somatosensory and motor) were performed at diagnosis. A conventional ordinal score was used to quantify the observed abnormalities. The extent of change in the composite EP score was well correlated to the Expanded Disability Status Scale (EDSS) at ten years (Y 10 ) and up to 15years (Y 11-15 ) after disease onset. Analysis of the predictive value of the EP score showed an increased risk of disability progression at Y 10 and Y 11-15 of 60% (p<0.0001) and 73% (p<0.0001) respectively in patients with an EP score >4. Conversely, the risk of disability progression at Y 10 and Y 11-15 associated with a lower EP score (⩽4) was reduced to 16% and 20% respectively. Our data support the good predictive value for long-term disability progression of multimodal EPs performed early after disease onset in RRMS patients. This study, performed in a homogeneous RRMS cohort with long term follow-up, demonstrates the value of an early comprehensive neurophysiological assessment as a marker for future disability. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

A longitudinal model for disease progression was developed and applied to multiple sclerosis

PubMed Central

Lawton, Michael; Tilling, Kate; Robertson, Neil; Tremlett, Helen; Zhu, Feng; Harding, Katharine; Oger, Joel; Ben-Shlomo, Yoav

2015-01-01

Objectives To develop a model of disease progression using multiple sclerosis (MS) as an exemplar. Study Design and Settings Two observational cohorts, the University of Wales MS (UoWMS), UK (1976), and British Columbia MS (BCMS) database, Canada (1980), with longitudinal disability data [the Expanded Disability Status Scale (EDSS)] were used; individuals potentially eligible for MS disease-modifying drugs treatments, but who were unexposed, were selected. Multilevel modeling was used to estimate the EDSS trajectory over time in one data set and validated in the other; challenges addressed included the choice and function of time axis, complex observation-level variation, adjustments for MS relapses, and autocorrelation. Results The best-fitting model for the UoWMS cohort (404 individuals, and 2,290 EDSS observations) included a nonlinear function of time since onset. Measurement error decreased over time and ad hoc methods reduced autocorrelation and the effect of relapse. Replication within the BCMS cohort (978 individuals and 7,335 EDSS observations) led to a model with similar time (years) coefficients, time [0.22 (95% confidence interval {CI}: 0.19, 0.26), 0.16 (95% CI: 0.10, 0.22)] and log time [−0.13 (95% CI: −0.39, 0.14), −0.15 (95% CI: −0.70, 0.40)] for BCMS and UoWMS, respectively. Conclusion It is possible to develop robust models of disability progression for chronic disease. However, explicit validation is important given the complex methodological challenges faced. PMID:26071892

Intervening to reduce the risk of future disability from multiple sclerosis: are we there yet?

PubMed

Dahdaleh, Maurice; Alroughani, Raed; Aljumah, Mohammed; AlTahan, Abdulrahman; Alsharoqi, Issa; Bohlega, Saeed A; Daif, Abdulkader; Deleu, Dirk; Inshasi, Jihad; Karabudak, Rana; Sahraian, Mohammed A; Taha, Karim; Yammout, Bassem I; Zakaria, Magd

2017-10-01

Disease-modifying therapies (DMTs) delay or may prevent the progression of patients with high-risk clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (MS), and from relapsing-remitting MS to secondary progressive MS. Current evidence on the effects of DMT on disability in MS is supported by the use of the Expanded Disability Status Scale (EDSS), which is dominated by ambulation, and usually used as a secondary outcome measure. Less is known about the long-term effects of DMTs on other aspects of functional status, particularly cognition, which is a key determinant of ability to work. The time scale for measurements of disability is at most a few years, with scant data from more than 10 years of observation. Longer prospective follow-up of large numbers of patients with CIS is needed to determine whether early intervention with a DMT influences long-term disease progression. Finally, the emergence of the radiologically isolated syndrome (RIS) as a clinical entity has shifted the debate about when to intervene to an even earlier time frame. Balancing the significant side-effects associated with DMT in general and the expected outcome of pharmacologic intervention is increasingly problematic for managing patients with uncertain prognosis, as many patients may have low-risk CIS, benign MS or patients with RIS only. Preventing long-term disability in MS should be recognised more clearly as an important outcome in its own right, with disability measured more consistently with more sensitive instruments beyond the use of the EDSS.

Natural history of multiple sclerosis from the Indian perspective: Experience from a tertiary care hospital.

PubMed

Jena, Subhransu S; Alexander, Mathew; Aaron, Sanjith; Mathew, Vivek; Thomas, Maya Mary; Patil, Anil K; Sivadasan, Ajith; Muthusamy, Karthik; Mani, Sunithi; Rebekah, J Grace

2015-01-01

Multiple sclerosis (MS) has a spectrum of heterogeneity, as seen in western and eastern hemispheres, in the clinical features, topography of involvement and differences in natural history. To study the clinical spectrum, imaging, and electrophysiological as well as cerebrospinal fluid (CSF) characteristics and correlate them with outcome. Retrospective analysis of MS patients during a period of 20 years. Cases were selected according to recent McDonald's criteria (2010), They were managed in the Department of Neurology, Christian Medical College, Vellore. Chi-square and Fisher's exact tests were used for categorical variables. Multiple binary logistic regressions were done to assess significance. Kaplan-Meier curves were drawn to estimate the time to irreversible disability. A total of 157 patients with female preponderance (55%) were included. The inter quartile range duration of follow-up was 9.1 (8.2, 11) years for 114 patients, who were included for final outcome analysis. Relapsing remitting MS (RRMS) (54.1%) was the most common type of MS seen. RRMS had a significantly better outcome (odds ratio: 0.12, 95% confidence interval: 0.02-0.57, P = 0.008) compared to progressive form of MS (primary progressive, secondary progressive). The Expanded Disability Status Scale score of patients at presentation and at final follow-up was 4.4 ± 1.31 and 4.1 ± 2.31, respectively. During the first presentation, polysymptomatic manifestations like motor and sphincteric involvement, incomplete recovery from the first attack; and, during the disease course, bowel, bladder, cerebellar and pyramidal affliction, predicted a worse outcome. A high incidence of optico-spinal presentation, predominance of RRMS and a low yield on cerebrospinal fluid (CSF) studies are the major findings of our study. A notable feature was the analysis of prognostic markers of disability.

Triple dose of gadolinium-DTPA and delayed MRI in patients with benign multiple sclerosis.

PubMed Central

Filippi, M; Capra, R; Campi, A; Colombo, B; Prandini, F; Marcianò, N; Gasparotti, R; Comi, G

1996-01-01

OBJECTIVES--To evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) or delayed MRI increase the number, size, and conspicuousness of enhancing lesions in patients with benign multiple sclerosis. METHODS--T1 weighted brain MRI was carried out on 20 patients with benign multiple sclerosis (expanded disability status scale < 3 with a disease duration > 10 years) in two sessions. In the first session, one scan was obtained before and two scans five to seven minutes and 20-30 minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, the same procedure was repeated with 0.3 mmol/kg Gd-DTPA (triple dose). RESULTS--Nine enhancing lesions were found in seven patients (35%) using the standard dose of Gd-DTPA. The numbers of enhancing lesions increased to 13 (P = 0.03) and the number of patients with such lesions to eight (40%) on the delayed standard dose scans. On the early triple dose scans, we found 19 enhancing lesions in 10 patients (50%). The number of enhancing lesions was significantly higher (P = 0.01) than that obtained with the early standard dose. The number of enhancing lesions was 18 and the number of "active" patients 11 (55%) on the delayed triple dose scans. The enhancing areas increased progressively from the early standard dose scans to the delayed triple dose scans. The contrast ratios of the lesions detected in early standard dose scans was lower than those of lesions present in the early (P = 0.01) and delayed (P = 0.04) triple dose scans. CONCLUSIONS--More enhancing lesions were detected in patients with benign multiple sclerosis with both delay of MRI and the use of triple dose of Gd-DTPA suggesting that the amount of inflammation in the lesions of such patients is mild and heterogeneous. Images PMID:8778257

Alternative source of stem cells derived from human periodontal ligament: a new treatment for experimental autoimmune encephalomyelitis.

PubMed

Trubiani, Oriana; Giacoppo, Sabrina; Ballerini, Patrizia; Diomede, Francesca; Piattelli, Adriano; Bramanti, Placido; Mazzon, Emanuela

2016-01-04

Multiple sclerosis is a demyelinating disease mostly of autoimmune origin that affects and damages the central nervous system, leading to a disabling condition. The aim of the present study was to investigate whether administration of mesenchymal stem cells from human periodontal ligament (hPDLSCs) could ameliorate multiple sclerosis progression by exerting neuroprotective effects in an experimental model of autoimmune encephalomyelitis (EAE). EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55 in C57BL/6 mice. After immunization, mice were observed every 48 hours for signs of EAE and weight loss. At the onset of disease, approximately 14 days after immunization, EAE mice were subjected to a single intravenous injection of hPDLSCs (10(6) cells/150 μl) into the tail vein. At the point of animal sacrifice on day 56 after EAE induction, spinal cord and brain tissues were collected in order to perform histological evaluation, immunohistochemistry and western blotting analysis. Achieved results reveal that treatment with hPDLSCs may exert neuroprotective effects against EAE, diminishing both clinical signs and histological score typical of the disease (lymphocytic infiltration and demyelination) probably through the production of neurotrophic factors (results focused on brain-derived neurotrophic factor and nerve growth factor expression). Furthermore, administration of hPDLSCs modulates expression of inflammatory key markers (tumor necrosis factor-α, interleukin (IL)-1β, IL-10, glial fibrillary acidic protein, Nrf2 and Foxp3), the release of CD4 and CD8α T cells, and the triggering of apoptotic death pathway (data shown for cleaved caspase 3, p53 and p21). In light of the achieved results, transplantation of hPDLSCs may represent a putative novel and helpful tool for multiple sclerosis treatment. These cells could have considerable implication for future therapies for multiple sclerosis and this study may represent the starting point for further investigations.

Stem cell transplantation and mesenchymal cells to treat autoimmune diseases.

PubMed

Tyndall, Alan; van Laar, Jacob M

2016-06-01

Since the start of the international stem cell transplantation project in 1997, over 2000 patients have received a haematopoietic stem cell transplant (HSCT), mostly autologous, as treatment for a severe autoimmune disease, the majority being multiple sclerosis (MS), systemic sclerosis (SSc) and Crohn's disease. There was an overall 85% 5-year survival and 43% progression-free survival. Around 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many cases, e.g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. It is hoped that the results of the three running large prospective randomized controlled trials will allow modification of the protocols to reduce the high transplant-related mortality which relates to regimen intensity, age of patient, and comorbidity. Mesenchymal stromal cells (MSC), often incorrectly called stem cells, have been the intense focus of in vitro studies and animal models of rheumatic and other diseases over more than a decade. Despite multiple plausible mechanisms of action and a plethora of positive in vivo animal studies, few randomised controlled clinical trials have demonstrated meaningful clinical benefit in any condition so far. This could be due to confusion in cell product terminology, complexity of clinical study design and execution or agreement on meaningful outcome measures. Within the rheumatic diseases, SLE and rheumatoid arthritis (RA) have received most attention. Uncontrolled multiple trial data from over 300 SLE patients have been published from one centre suggesting a positive outcome; one single centre comparative study in 172 RA was positive. In addition, small numbers of patients with Crohn's disease, multiple sclerosis, primary Sjögren's disease, polymyositis/dermatomyositis and type II diabetes mellitus have received MSC therapeutically. The possible reasons for this apparent mismatch between expectation and clinical reality will be discussed. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Analysis of macular and nerve fiber layer thickness in multiple sclerosis patients according to severity level and optic neuritis episodes.

PubMed

Soler García, A; Padilla Parrado, F; Figueroa-Ortiz, L C; González Gómez, A; García-Ben, A; García-Ben, E; García-Campos, J M

2016-01-01

Quantitative assessment of macular and nerve fibre layer thickness in multiple sclerosis patients with regard to expanded disability status scale (EDSS) and presence or absence of previous optic neuritis episodes. We recruited 62 patients with multiple sclerosis (53 relapsing-remitting and 9 secondary progressive) and 12 disease-free controls. All patients underwent an ophthalmological examination, including quantitative analysis of the nerve fibre layer and macular thickness using optical coherence tomography. Patients were classified according to EDSS as A (lower than 1.5), B (between 1.5 and 3.5), and C (above 3.5). Mean nerve fibre layer thickness in control, A, B, and C groups was 103.35±12.62, 99.04±14.35, 93.59±15.41, and 87.36±18.75μm respectively, with statistically significant differences (P<.05). In patients with no history of optic neuritis, history of episodes in the last 3 to 6 months, or history longer than 6 months, mean nerve fibre layer thickness was 99.25±13.71, 93.92±13.30 and 80.07±15.91μm respectively; differences were significant (P<.05). Mean macular thickness in control, A, B, and C groups was 220.01±12.07, 217.78±20.02, 217.68±20.77, and 219.04±24.26μm respectively. Differences were not statistically significant. The mean retinal nerve fibre layer thickness in multiple sclerosis patients is related to the EDSS level. Patients with previous optic neuritis episodes have a thinner retinal nerve fibre layer than patients with no history of these episodes. Mean macular thickness is not correlated to EDSS level. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis.

PubMed

Radue, Ernst-Wilhelm; O'Connor, Paul; Polman, Chris H; Hohlfeld, Reinhard; Calabresi, Peter; Selmaj, Krystof; Mueller-Lenke, Nicole; Agoropoulou, Catherine; Holdbrook, Frederick; de Vera, Ana; Zhang-Auberson, Lixin; Francis, Gordon; Burtin, Pascale; Kappos, Ludwig

2012-10-01

To assess the impact of fingolimod (FTY720) therapy on magnetic resonance imaging measures of inflammatory activity and tissue damage in patients participating in a 2-year, placebo-controlled, phase 3 study. Patients with active relapsing-remitting multiple sclerosis were randomized to receive fingolimod, 0.5 mg; fingolimod, 1.25 mg; or placebo for 2 years. Standardized magnetic resonance imaging scans were obtained at months 0, 6, 12, and 24 and centrally evaluated for number and volume of T1 gadolinium-enhancing, T2 hyperintense, and T1 hypointense lesions and for percentage of brain volume change. Findings were compared across subgroups by treatment and baseline characteristics. Worldwide, multicenter clinical trial. Patients were part of the fingolimod FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial for relapsing-remitting multiple sclerosis (N=1272). We measured the effect of therapy on acute inflammatory activity, burden of disease, and irreversible loss of brain volume. Fingolimod therapy resulted in rapid and sustained reductions in inflammatory lesion activity as assessed by gadolinium-enhancing and new/newly enlarged T2 lesions after 6, 12, and 24 months of therapy (P.001, all comparisons vs placebo). Changes in T2 hyperintense and T1 hypointense lesion volume also significantly favored fingolimod (P.05, all comparisons). Fingolimod, 0.5 mg (licensed dose), significantly reduced brain volume loss during months 0 to 6, 0 to 12, 12 to 24, and 0 to 24 (P.05, all comparisons) vs placebo, and subgroup analyses confirmed these effects over 2 years irrespective of the presence/absence of gadolinium-enhancing lesions, T2 lesion load, previous treatment status, or level of disability. These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution. clinicaltrials.gov Identifier: NCT00289978

Lockhart Clarke’s contribution to the description of amyotrophic lateral sclerosis

PubMed Central

Turner, Martin R.; Swash, Michael; Ebers, George C.

2011-01-01

The definition of the clinicopathological entity of amyotrophic lateral sclerosis evolved over half a century. Although the definitive term amyotrophic lateral sclerosis that acknowledged both upper and lower motor neuron involvement was attributed to Jean-Martin Charcot in 1874, his initial case was published nearly a decade earlier; and it is accepted that, from at least the 1830s, several others (including Charles Bell, François-Amilcar Aran and Jean Cruveilhier) had already recognized a progressive lower motor neuron-only syndrome within a broader, clinically-defined group of disorders, termed progressive muscular atrophy. Although William Gowers first grouped the three phenotypes of amyotrophic lateral sclerosis, progressive muscular atrophy and progressive bulbar palsy together as part of the same syndrome, the term motor neuron disease, as an over-arching label, was not suggested until nearly a century later by W. Russell Brain. Augustus Jacob Lockhart Clarke (1817–80) is best known for his descriptions of spinal cord anatomy. However, in two detailed case reports from the 1860s, he carried out rigorous post-mortem neuropathological studies of what appear to be classical cases of amyotrophic lateral sclerosis. Furthermore, he recognized the additional involvement of the corticospinal tracts that distinguished this from progressive muscular atrophy. Several aspects of the exquisite clinical histories documented as part of both studies, one by Charles Bland Radcliffe, resonate with contemporary debates concerning the evolution of disease in amyotrophic lateral sclerosis. These ‘past masters’ still have much to teach us. PMID:20576696

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

PubMed

Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C A; Patsopoulos, Nikolaos A; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E; Edkins, Sarah; Gray, Emma; Booth, David R; Potter, Simon C; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Céline; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D'alfonso, Sandra; Blackburn, Hannah; Martinelli Boneschi, Filippo; Liddle, Jennifer; Harbo, Hanne F; Perez, Marc L; Spurkland, Anne; Waller, Matthew J; Mycko, Marcin P; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J; Barcellos, Lisa F; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P; Brassat, David; Broadley, Simon A; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M; Cavalla, Paola; Celius, Elisabeth G; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Françoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B; Cozen, Wendy; Cree, Bruce A C; Cross, Anne H; Cusi, Daniele; Daly, Mark J; Davis, Emma; de Bakker, Paul I W; Debouverie, Marc; D'hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Bénédicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F A; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G; Kilpatrick, Trevor J; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S; Leone, Maurizio A; Leppä, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R; Link, Jenny; Liu, Jianjun; Lorentzen, Aslaug R; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L; Ramsay, Patricia P; Reunanen, Mauri; Reynolds, Richard; Rioux, John D; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P; Rückert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J; Sellebjerg, Finn; Selmaj, Krzysztof W; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M A; Smestad, Cathrine; Sørensen, Per Soelberg; Søndergaard, Helle Bach; Stankovich, Jim; Strange, Richard C; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvänen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A; Tronczynska, Ewa; Casas, Juan P; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S; Wang, Kai; Mathew, Christopher G; Wason, James; Palmer, Colin N A; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C; Yaouanq, Jacqueline; Viswanathan, Ananth C; Zhang, Haitao; Wood, Nicholas W; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R; Pericak-Vance, Margaret A; Haines, Jonathan L; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J; De Jager, Philip L; Peltonen, Leena; Stewart, Graeme J; Hafler, David A; Hauser, Stephen L; McVean, Gil; Donnelly, Peter; Compston, Alastair

2011-08-10

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

76 FR 1568 - Special Local Regulations and Safety Zones; Recurring Events in Northern New England

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-11

..., 069[deg]31[min]29[sec] W;43[deg]52[min]09[sec] N, 069[deg]31[min]56[sec] W. 8.6 Multiple Sclerosis Event Type: Regatta and Sailboat Regatta. Race. Sponsor: Maine Chapter, Multiple Sclerosis Society. Date...]51[sec] W. 8.7 Multiple Sclerosis Event Type: Power Boat Race. Harborfest Tugboat Race. Sponsor...

76 FR 80850 - Special Local Regulations and Safety Zones; Recurring Events in Northern New England

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-27

...[deg]31'29'' W. 43[deg]52'09'' N, 069[deg]31'56'' W. 8.6 Multiple Sclerosis Regatta......... Event Type: Regatta and Sailboat Race. Sponsor: Maine Chapter, Multiple Sclerosis Society. Date: A one day event on..., 070[deg]13'51'' W. 8.7 Multiple Sclerosis Harborfest Event Type: Power Boat Tugboat Race. Race...

78 FR 47555 - Special Local Regulations and Safety Zones; Recurring Events in Northern New England

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-06

...]52'35'' N, 069[deg]31'29'' W. 43[deg]52'09'' N, 069[deg]31'56'' W. 8.6 Multiple Sclerosis Regatta......... Event Type: Regatta and Sailboat Race. Sponsor: Maine Chapter, Multiple Sclerosis Society. Date: A one..., National Multiple Sclerosis Society. Date: A one day event on the third Sunday of August.* Time...

Multiple sclerosis: Left advantage for auditory laterality in dichotic tests of central auditory processing and relationship of psychoacoustic tests with the Multiple Sclerosis Disability Scale-EDSS.

PubMed

Peñaloza López, Yolanda Rebeca; Orozco Peña, Xóchitl Daisy; Pérez Ruiz, Santiago Jesús

2018-04-03

To evaluate the central auditory processing disorders in patients with multiple sclerosis, emphasizing auditory laterality by applying psychoacoustic tests and to identify their relationship with the Multiple Sclerosis Disability Scale (EDSS) functions. Depression scales (HADS), EDSS, and 9 psychoacoustic tests to study CAPD were applied to 26 individuals with multiple sclerosis and 26 controls. Correlation tests were performed between the EDSS and psychoacoustic tests. Seven out of 9 psychoacoustic tests were significantly different (P<.05); right or left (14/19 explorations) with respect to control. In dichotic digits there was a left-ear advantage compared to the usual predominance of RDD. There was significant correlation in five psychoacoustic tests and the specific functions of EDSS. The left-ear advantage detected and interpreted as an expression of deficient influences of the corpus callosum and attention in multiple sclerosis should be investigated. There was a correlation between psychoacoustic tests and specific EDSS functions. Copyright © 2018 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Publicado por Elsevier España, S.L.U. All rights reserved.

Vision and vision-related outcome measures in multiple sclerosis

PubMed Central

Balcer, Laura J.; Miller, David H.; Reingold, Stephen C.

2015-01-01

Visual impairment is a key manifestation of multiple sclerosis. Acute optic neuritis is a common, often presenting manifestation, but visual deficits and structural loss of retinal axonal and neuronal integrity can occur even without a history of optic neuritis. Interest in vision in multiple sclerosis is growing, partially in response to the development of sensitive visual function tests, structural markers such as optical coherence tomography and magnetic resonance imaging, and quality of life measures that give clinical meaning to the structure-function correlations that are unique to the afferent visual pathway. Abnormal eye movements also are common in multiple sclerosis, but quantitative assessment methods that can be applied in practice and clinical trials are not readily available. We summarize here a comprehensive literature search and the discussion at a recent international meeting of investigators involved in the development and study of visual outcomes in multiple sclerosis, which had, as its overriding goals, to review the state of the field and identify areas for future research. We review data and principles to help us understand the importance of vision as a model for outcomes assessment in clinical practice and therapeutic trials in multiple sclerosis. PMID:25433914

Efficacy of aquatic therapy for multiple sclerosis: a systematic review.

PubMed

Corvillo, Iluminada; Varela, Enrique; Armijo, Francisco; Alvarez-Badillo, Antonio; Armijo, Onica; Maraver, Francisco

2017-12-01

Multiple sclerosis (MS) is a chronic, inflammatory, progressive, disabling autoimmune disease affecting the central nervous system. Symptoms and signs of MS vary widely and patients may lose their ability to walk. To date the benefits of aquatic therapy often used for rehabilitation in MS patients have not been reviewed. The aim of this study was to systematically review the current state of aquatic treatment for persons with MS (hydrotherapy, aquatic therapy, aquatic exercises, spa therapy) and to evaluate the scientific evidence supporting the benefits of this therapeutic option. The databases PubMed, Scopus, WoS and PEDro were searched to identify relevant reports published from January 1, 2011 to April 30, 2016. Of 306 articles identified, only 10 fulfilled the inclusion criteria: 5 randomized controlled, 2 simple randomized quasi-experimental, 1 semi-experimental, 1 blind controlled pilot and 1 pilot. Evidence that aquatic treatment improves quality of life in affected patients was very good in two studies, good in four, fair in two and weak in two.

A rare presentation of atypical demyelination: tumefactive multiple sclerosis causing Gerstmann’s syndrome

PubMed Central

2014-01-01

Background Tumefactive demyelinating lesions are a rare manifestation of multiple sclerosis (MS). Differential diagnosis of such space occupying lesions may not be straightforward and sometimes necessitate brain biopsy. Impaired cognition is the second most common clinical manifestation of tumefactive MS; however complex cognitive syndromes are unusual. Case presentation We report the case of a 30 year old woman who presented with Gerstmann’s syndrome. MRI revealed a large heterogeneous contrast enhancing lesion in the left cerebral hemisphere. Intravenous corticosteroids did not stop disease progression. A tumour or cerebral lymphoma was suspected, however brain biopsy confirmed inflammatory demyelination. Following diagnosis of tumefactive MS treatment with natalizumab effectively suppressed disease activity. Conclusions The case highlights the need for clinicians, radiologists and surgeons to appreciate the heterogeneous presentation of tumefactive MS. Early brain biopsy facilitates rapid diagnosis and management. Treatment with natalizumab may be useful in cases of tumefactive demyelination where additional evidence supports a diagnosis of relapsing MS. PMID:24694183

Advising patients seeking stem cell interventions for multiple sclerosis.

PubMed

von Wunster, Beatrice; Bailey, Steven; Wilkins, Alastair; Marks, David I; Scolding, Neil J; Rice, Claire M

2018-05-30

Given the intuitive potential of stem cell therapy and limitations of current treatment options for progressive multiple sclerosis (MS), it is not surprising that patients consider undertaking significant clinical and financial risks to access stem cell transplantation. However, while increasing evidence supports autologous haematopoietic stem cell transplantation (AHSCT) in aggressive relapsing-remitting MS, interventions employing haematopoietic or other stem cells should otherwise be considered experimental and recommended only in the context of a properly regulated clinical study. Understandably, most neurologists are unfamiliar with AHSCT procedures and the specific requirements for quality assurance and safety standards, as well as post-procedure precautions and follow-up. Consequently they may feel ill-equipped to advise patients. Here, we highlight important points for discussion in consultations with patients considering stem cell 'tourism' for MS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Goals Set After Completing a Teleconference-Delivered Program for Managing Multiple Sclerosis Fatigue

PubMed Central

Asano, Miho; Preissner, Katharine; Duffy, Rose; Meixell, Maggie

2015-01-01

Setting goals can be a valuable skill to self-manage multiple sclerosis (MS) fatigue. A better understanding of the goals set by people with MS after completing a fatigue management program can assist health care professionals with tailoring interventions for clients. This study aimed to describe the focus of goals set by people with MS after a teleconference-delivered fatigue management program and to evaluate the extent to which participants were able to achieve their goals over time. In total, 485 goals were set by 81 participants. Over a follow-up period, 64 participants rated 284 goals regarding progress made toward goal achievement. Approximately 50% of the rated goals were considered achieved. The most common type of goal achieved was that of instrumental activities of daily living. Short-term goals were more likely to be achieved. This study highlights the need for and importance of promoting and teaching goal-setting skills to people with MS. PMID:25871602

G protein-coupled receptors as therapeutic targets for multiple sclerosis

PubMed Central

Du, Changsheng; Xie, Xin

2012-01-01

G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future. PMID:22664908

Multi-output decision trees for lesion segmentation in multiple sclerosis

NASA Astrophysics Data System (ADS)

Jog, Amod; Carass, Aaron; Pham, Dzung L.; Prince, Jerry L.

2015-03-01

Multiple Sclerosis (MS) is a disease of the central nervous system in which the protective myelin sheath of the neurons is damaged. MS leads to the formation of lesions, predominantly in the white matter of the brain and the spinal cord. The number and volume of lesions visible in magnetic resonance (MR) imaging (MRI) are important criteria for diagnosing and tracking the progression of MS. Locating and delineating lesions manually requires the tedious and expensive efforts of highly trained raters. In this paper, we propose an automated algorithm to segment lesions in MR images using multi-output decision trees. We evaluated our algorithm on the publicly available MICCAI 2008 MS Lesion Segmentation Challenge training dataset of 20 subjects, and showed improved results in comparison to state-of-the-art methods. We also evaluated our algorithm on an in-house dataset of 49 subjects with a true positive rate of 0.41 and a positive predictive value 0.36.

Effect of physical exercise on brain and lipid metabolism in mouse models of multiple sclerosis.

PubMed

Houdebine, Léo; Gallelli, Cristina Anna; Rastelli, Marialetizia; Sampathkumar, Nirmal Kumar; Grenier, Julien

2017-10-01

Multiple sclerosis (MS) is a central nervous demyelinating disease characterized by cyclic loss and repair of myelin sheaths associated with chronic inflammation and neuronal loss. This degenerative pathology is accompanied by modified levels of oxysterols (oxidative derivatives of cholesterol, implicated in cholesterol metabolism), highlighted in the brain, blood and cerebrospinal fluid of MS patients. The pathological accumulation of such derivatives is thought to participate in the onset and progression of the disease through their implication in inflammation, oxidative stress, demyelination and neurodegeneration. In this context, physical exercise is envisaged as a complementary resource to ameliorate therapeutic strategies. Indeed, physical activity exerts beneficial effects on neuronal plasticity, decreases inflammation and oxidative stress and improves blood-brain integrity in extents that could be beneficial for brain health. The present review attempts to summarize the available data on the positive effect of physical exercise to highlight possible links between physical activity and modulation of cholesterol/oxysterol homeostasis in MS. Copyright © 2017 Elsevier B.V. All rights reserved.

Prospective memory impairment in multiple sclerosis: a review.

PubMed

Rouleau, Isabelle; Dagenais, Emmanuelle; Tremblay, Alexandra; Demers, Mélanie; Roger, Élaine; Jobin, Céline; Duquette, Pierre

2017-08-04

Multiple sclerosis (MS) is a progressive disease of the central nervous system affecting information processing speed, episodic memory, attention, and executive functions. MS patients also often report prospective memory (PM) failures that directly impact their functional autonomy, including professional and social life. The purpose of this paper was to review the literature concerning the assessment and remediation of PM deficits in MS. The literature pertaining to PM impairment in MS was carefully reviewed using PubMed, PsyINFO, and Google Scholar, as well as cross-references from the articles published on this topic. Since PM rehabilitation in MS patients is still in its infancy, this review mainly focuses on studies that have directly assessed PM through various measures including questionnaires, standardized clinical tests, and experimental procedures. This literature review confirms the presence of PM deficits in MS patients, even in the early stages of the disease. A further need for controlled studies on PM assessment and PM interventions in patients with MS is stressed.

Iron deposition and inflammation in multiple sclerosis. Which one comes first?

PubMed Central

2011-01-01

Whether iron deposition is an epiphenomenon of the multiple sclerosis (MS) disease process or may play a primary role in triggering inflammation and disease development remains unclear at this time, and should be studied at the early stages of disease pathogenesis. However, it is difficult to study the relationship between iron deposition and inflammation in early MS due to the delay between the onset of symptoms and diagnosis, and the poor availability of tissue specimens. In a recent article published in BMC Neuroscience, Williams et al. investigated the relationship between inflammation and iron deposition using an original animal model labeled as "cerebral experimental autoimmune encephalomyelitis", which develops CNS perivascular iron deposits. However, the relative contribution of iron deposition vs. inflammation in the pathogenesis and progression of MS remains unknown. Further studies should establish the association between inflammation, reduced blood flow, iron deposition, microglia activation and neurodegeneration. Creating a representative animal model that can study independently such relationship will be the key factor in this endeavor. PMID:21699686

Pregnancy and childbirth in a patient with multiple sclerosis: A case report of successful management.

PubMed

Wang, Chun-Kai; Lin, Chi-Kang; Wang, Tun-Jun; Wang, Chen-Yu; Hsu, Po-Chao; Su, Her-Young

2018-06-01

Multiple sclerosis (MS) preferentially affects females of reproductive age, making reproduction an important issue for women with MS. An increased incidence of poor labor progress often results in assisted vaginal delivery or a cesarean section. However, with good pre-pregnancy counseling and management, women with MS can conceive and give birth safely. Here, we present a case of pregnancy with MS, which was carried to term uneventfully and ended with unassisted vaginal delivery. A 36-year-old woman was treated for MS for three years before she conceived. Because of her mild clinical presentation, medication was discontinued when her pregnancy was confirmed. Counseling was completed, and she had a smooth pregnancy course and gave birth vaginally at 38 weeks and two days. Based on this case report, women with mild clinical presentation of MS before pregnancy can conceive and carry successfully to term with no or improved disease presentation. Copyright © 2018. Published by Elsevier B.V.

Urinary Urea, Uric Acid and Hippuric Acid as Potential Biomarkers in Multiple Sclerosis Patients.

PubMed

Atya, Hanaa B; Ali, Sahar A; Hegazy, Mohamed I; El Sharkawi, Fathia Z

2018-04-01

Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, noninvasive, inexpensive, and efficient diagnostic tool for various human diseases. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). The objective was to investigate the level of some urinary metabolites (urea, uric acid and hippuric acid) in patients with MS and correlate their levels to the severity of the disease, MS subtypes and MS treatment. The urine samples were collected from 73 MS patients-48 with RRMS and 25 with SPMS- and age matched 75 healthy controls. The values of urinary urea, uric acid and hippuric acid in MS patients were significantly decreased, and these metabolites in SPMS pattern showed significantly decrease than RRMS pattern. Also showed significant inverse correlation with expanded disability status scale and number of relapses. Accordingly, they may act as a potential urinary biomarkers for MS, and correlate to disease progression.

Atypical Initial Presentation of Painful Muscle Cramps in a Patient with Amyotrophic Lateral Sclerosis: A Case Report and Brief Review of the Literature.

PubMed

Kuzel, Aaron R; Lodhi, Muhammad Uzair; Syed, Intekhab Askari; Rahim, Mustafa

2017-11-10

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized clinically by progressive muscle weakness that can occur proximally or distally in either the upper or lower extremities. It includes both upper motor neuron signs (spasticity, hyperreflexia, clonus, and Babinski sign) and lower motor neuron signs (atrophy, weakness, and muscle fasciculation). Initial presentation of progressively painful muscle cramps should lead the physician to screen for other signs of amyotrophic lateral sclerosis. We report the case of a 51-year-old male, who presented with dull muscle cramps in the right upper shoulder and arm. After a careful history and physical exam, it was found that patient had both upper and lower motor neuron signs; therefore, a diagnosis of amyotrophic lateral sclerosis was made. Amyotrophic lateral sclerosis should strongly be considered in the differential diagnosis of patients presenting with an atypical initial presentation of progressively painful muscle cramps.

Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis

PubMed Central

Elliott, Christina; Lindner, Maren; Arthur, Ariel; Brennan, Kathryn; Jarius, Sven; Hussey, John; Chan, Andrew; Stroet, Anke; Olsson, Tomas; Willison, Hugh; Barnett, Susan C.; Meinl, Edgar

2012-01-01

Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from patients with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in patients with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of patients with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments. PMID:22561643

[Magnetic Resonance Imaging Conversion Predictors of Clinically Isolated Syndrome to Multiple Sclerosis].

PubMed

Peixoto, Sara; Abreu, Pedro

2016-11-01

Clinically isolated syndrome may be the first manifestation of multiple sclerosis, a chronic demyelinating disease of the central nervous system, and it is defined by a single clinical episode suggestive of demyelination. However, patients with this syndrome, even with long term follow up, may not develop new symptoms or demyelinating lesions that fulfils multiple sclerosis diagnostic criteria. We reviewed, in clinically isolated syndrome, what are the best magnetic resonance imaging findings that may predict its conversion to multiple sclerosis. A search was made in the PubMed database for papers published between January 2010 and June 2015 using the following terms: 'clinically isolated syndrome', 'cis', 'multiple sclerosis', 'magnetic resonance imaging', 'magnetic resonance' and 'mri'. In this review, the following conventional magnetic resonance imaging abnormalities found in literature were included: lesion load, lesion location, Barkhof's criteria and brain atrophy related features. The non conventional magnetic resonance imaging techniques studied were double inversion recovery, magnetization transfer imaging, spectroscopy and diffusion tensor imaging. The number and location of demyelinating lesions have a clear role in predicting clinically isolated syndrome conversion to multiple sclerosis. On the other hand, more data are needed to confirm the ability to predict this disease development of non conventional techniques and remaining neuroimaging abnormalities. In forthcoming years, in addition to the established predictive value of the above mentioned neuroimaging abnormalities, different clinically isolated syndrome neuroradiological findings may be considered in multiple sclerosis diagnostic criteria and/or change its treatment recommendations.

Correlation between white matter damage and gray matter lesions in multiple sclerosis patients.

PubMed

Han, Xue-Mei; Tian, Hong-Ji; Han, Zheng; Zhang, Ce; Liu, Ying; Gu, Jie-Bing; Bakshi, Rohit; Cao, Xia

2017-05-01

We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. We analyzed the correlation between fractional anisotropy values and changes in whole-brain gray matter volume. The participants included 20 patients with relapsing-remitting multiple sclerosis and 20 healthy volunteers as controls. All subjects underwent head magnetic resonance imaging and diffusion tensor imaging. Our results revealed that fractional anisotropy values decreased and gray matter volumes were reduced in the genu and splenium of corpus callosum, left anterior thalamic radiation, hippocampus, uncinate fasciculus, right corticospinal tract, bilateral cingulate gyri, and inferior longitudinal fasciculus in multiple sclerosis patients. Gray matter volumes were significantly different between the two groups in the right frontal lobe (superior frontal, middle frontal, precentral, and orbital gyri), right parietal lobe (postcentral and inferior parietal gyri), right temporal lobe (caudate nucleus), right occipital lobe (middle occipital gyrus), right insula, right parahippocampal gyrus, and left cingulate gyrus. The voxel sizes of atrophic gray matter positively correlated with fractional anisotropy values in white matter association fibers in the patient group. These findings suggest that white matter fiber bundles are extensively injured in multiple sclerosis patients. The main areas of gray matter atrophy in multiple sclerosis are the frontal lobe, parietal lobe, caudate nucleus, parahippocampal gyrus, and cingulate gyrus. Gray matter atrophy is strongly associated with white matter injury in multiple sclerosis patients, particularly with injury to association fibers.

The effectiveness of Robot-Assisted Gait Training versus conventional therapy on mobility in severely disabled progressIve MultiplE sclerosis patients (RAGTIME): study protocol for a randomized controlled trial.

PubMed

Straudi, Sofia; Manfredini, Fabio; Lamberti, Nicola; Zamboni, Paolo; Bernardi, Francesco; Marchetti, Giovanna; Pinton, Paolo; Bonora, Massimo; Secchiero, Paola; Tisato, Veronica; Volpato, Stefano; Basaglia, Nino

2017-02-27

Gait and mobility impairments affect the quality of life (QoL) of patients with progressive multiple sclerosis (MS). Robot-assisted gait training (RAGT) is an effective rehabilitative treatment but evidence of its superiority compared to other options is lacking. Furthermore, the response to rehabilitation is multidimensional, person-specific and possibly involves functional reorganization processes. The aims of this study are: (1) to test the effectiveness on gait speed, mobility, balance, fatigue and QoL of RAGT compared to conventional therapy (CT) in progressive MS and (2) to explore changes of clinical and circulating biomarkers of neural plasticity. This will be a parallel-group, randomized controlled trial design with the assessor blinded to the group allocation of participants. Ninety-eight (49 per arm) progressive MS patients (EDSS scale 6-7) will be randomly assigned to receive twelve 2-h training sessions over a 4-week period (three sessions/week) of either: (1) RAGT intervention on a robotic-driven gait orthosis (Lokomat, Hocoma, Switzerland). The training parameters (torque of the knee and hip drives, treadmill speed, body weight support) are set during the first session and progressively adjusted during training progression or (2) individual conventional physiotherapy focusing on over-ground walking training performed with the habitual walking device. The same assessors will perform outcome measurements at four time points: baseline (before the first intervention session); intermediate (after six training sessions); end of treatment (after the completion of 12 sessions); and follow-up (after 3 months from the end of the training program). The primary outcome is gait speed, assessed by the Timed 25-Foot Walk Test. We will also assess walking endurance, balance, depression, fatigue and QoL as well as instrumental laboratory markers (muscle metabolism, cerebral venous hemodynamics, cortical activation) and circulating laboratory markers (rare circulating cell populations pro and anti-inflammatory cytokines/chemokines, growth factors, neurotrophic factors, coagulation factors, other plasma proteins suggested by transcriptomic analysis and metabolic parameters). The RAGT training is expected to improve mobility compared to the active control intervention in progressive MS. Unique to this study is the analysis of various potential markers of plasticity in relation with clinical outcomes. ClinicalTrials.gov, identifier: NCT02421731 . Registered on 19 January 2015 (retrospectively registered).

Association study of four polymorphisms in the interleukin-7 receptor alpha gene with multiple sclerosis in Eastern Iran.

PubMed

Haj, Mehrdad Sadeghi; Nikravesh, Abbas; Kakhki, Majid Pahlevan; Rakhshi, Nahid

2015-06-01

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) with unknown etiology. Various genetics and environmental factors contribute to the pathogenesis of the disease. The interleukin-7 receptor alpha chain (IL-7Ra) was identified as the first non-major histocompatibility complex (non-MHC) MS susceptibility locus. In this study we are trying to find the association of IL-7Ra gene polymorphisms with MS susceptibility in Eastern Iran. A case-control study was performed in two provinces Sistan & Baluchistan and Khorasan with 219 patients and 258 unrelated matched healthy controls, using PCR-RFLP method for four single nucleotide polymorphisms (SNPs) rs7718919, rs11567685, rs11567686 and rs6897932 of IL-7Ra gene. We found a tendency toward association with genotyping analyses in SNP rs7718919 (P=0.048, OR=4.344, and 95% CI=0.892-21.146); also genotype and allele frequency in gender and MS subtype stratification were shown to have significant association with MS. Analysis of two provinces separately showed a significant difference in results of the allele and genotype frequencies. Moreover, haplotyping analysis showed that (GTGC) has an association only in the male secondary-progressive multiple sclerosis (SPMS) patients in comparison to the healthy controls (P=0.043, OR=0.413, and 95% CI=0.179-0.955). IL7-Ra could be a susceptible gene to MS within the Eastern Iran population especially after MS and gender stratification.

Gallium-67 uptake by the thyroid associated with progressive systemic sclerosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sjoberg, R.J.; Blue, P.W.; Kidd, G.S.

1989-01-01

Although thyroidal uptake of gallium-67 has been described in several thyroid disorders, gallium-67 scanning is not commonly used in the evaluation of thyroid disease. Thyroidal gallium-67 uptake has been reported to occur frequently with subacute thyroiditis, anaplastic thyroid carcinoma, and thyroid lymphoma, and occasionally with Hashimoto's thyroiditis and follicular thyroid carcinoma. A patient is described with progressive systemic sclerosis who, while being scanned for possible active pulmonary involvement, was found incidentally to have abnormal gallium-67 uptake only in the thyroid gland. Fine needle aspiration cytology of the thyroid revealed Hashimoto's thyroiditis. Although Hashimoto's thyroiditis occurs with increased frequency in patientsmore » with progressive systemic sclerosis, thyroidal uptake of gallium-67 associated with progressive systemic sclerosis has not, to our knowledge, been previously described. Since aggressive thyroid malignancies frequently are imaged by gallium-67 scintigraphy, fine needle aspiration cytology of the thyroid often is essential in the evaluation of thyroidal gallium-67 uptake.« less

Atrophied Brain Lesion Volume: A New Imaging Biomarker in Multiple Sclerosis.

PubMed

Dwyer, Michael G; Bergsland, Niels; Ramasamy, Deepa P; Jakimovski, Dejan; Weinstock-Guttman, Bianca; Zivadinov, Robert

2018-06-01

Lesion accrual in multiple sclerosis (MS) is an important and clinically relevant measure, used extensively as an imaging trial endpoint. However, lesions may also shrink or disappear entirely due to atrophy. Although generally ignored or treated as a nuisance, this phenomenon may actually be an important stand-alone imaging biomarker. Therefore, we investigated the rate of brain lesion loss due to atrophy (atrophied lesion volume) in MS subtypes compared to baseline lesion volume and to new and enlarging lesion volumes, and evaluated the independent predictive value of this phenomenon for clinical disability. A total of 192 patients (18 clinically isolated syndrome, 126 relapsing-remitting MS, and 48 progressive) received 3T magnetic resonance imaging at baseline and 5 years. Lesions were quantified at baseline, and new/enlarging lesion volumes were calculated over the study interval. Atrophied lesion volume was calculated by combining baseline lesion masks with follow-up SIENAX-derived cerebrospinal fluid partial volume maps. Measures were compared between disease subgroups, and correlations with disability change (Expanded Disability Status Scale [EDSS]) were evaluated. Hierarchical regression was employed to determine the unique additive value of atrophied lesion volume. Atrophied lesion volume was different between MS subtypes (P = .02), and exceeded new lesion volume accumulation in progressive MS (298.1 vs. 75.5 mm 3 ). Atrophied lesion volume was the only significant correlate of EDSS change (r = .192 relapsing, r = .317 progressive, P < .05), and explained significant additional variance when controlling for brain atrophy and new/enlarging lesion volume (R 2 .092 vs. .045, P = .003). Atrophied lesion volume is a unique and clinically relevant imaging marker in MS, with particular promise in progressive MS. Copyright © 2018 by the American Society of Neuroimaging.

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

PubMed

Rae-Grant, Alexander; Day, Gregory S; Marrie, Ruth Ann; Rabinstein, Alejandro; Cree, Bruce A C; Gronseth, Gary S; Haboubi, Michael; Halper, June; Hosey, Jonathan P; Jones, David E; Lisak, Robert; Pelletier, Daniel; Potrebic, Sonja; Sitcov, Cynthia; Sommers, Rick; Stachowiak, Julie; Getchius, Thomas S D; Merillat, Shannon A; Pringsheim, Tamara

2018-04-24

To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms. Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used. Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers. © 2018 American Academy of Neurology.

Exercising away the blues: can it help multiple sclerosis-related depression?

PubMed

Feinstein, Anthony; Rector, Neil; Motl, Robert

2013-12-01

The present review focuses on exercise as a treatment for depression in multiple sclerosis. While exercise has emerged as a potentially useful treatment in the general psychiatry-depression literature, the findings from a small number of multiple sclerosis-related treatment trials are equivocal. Methodological limitations, including the absence of depression as a primary endpoint, characterize all the studies completed to date. Given that limitations in study design can be rectified, it is time to put exercise to the test once more. Depressed multiple sclerosis patients and those involved in their care are looking for guidance here because the prevailing zeitgeist promotes the benefits of exercise to mood. But first, some clarity is needed.

Azathioprine therapy in a case of pediatric multiple sclerosis that was seropositive for MOG-IgG.

PubMed

Zhou, Yifan; Huang, Qiao; Lu, Tingting; Sun, Xiaobo; Fang, Ling; Lu, Zhengqi; Hu, Xueqiang; Kermode, Allan; Qiu, Wei

2017-04-01

There is a lack of evidence for treatment of pediatric multiple sclerosis (PedMS). Treatment using azathioprine for PedMS has not been reported. A 10-year-old boy with multiple sclerosis who was seropositive for antibodies against myelin oligodendrocyte glycoprotein (MOG)-IgG was treated with azathioprine plus oral methylprednisolone. The patient showed clinical and magnetic resonance imaging stability, with MOG-IgG seroconversion. There were no major side effects over a 5-year period. Azathioprine may be a treatment option, particularly in poor medical resource areas, for pediatric patients with multiple sclerosis who are seropositive for MOG-IgG. Copyright © 2017 Elsevier Ltd. All rights reserved.

Deficits in Social Cognition: An Unveiled Signature of Multiple Sclerosis.

PubMed

Chalah, Moussa A; Ayache, Samar S

2017-03-01

Multiple sclerosis (MS) is a chronic progressive inflammatory disease of the central nervous system, representing the primary cause of non-traumatic disability in young adults. Cognitive dysfunction can affect patients at any time during the disease process and might alter the six core functional domains. Social cognition is a multi-component construct that includes the theory of mind, empathy and social perception of emotions from facial, bodily and vocal cues. Deficits in this cognitive faculty might have a drastic impact on interpersonal relationships and quality of life (QoL). Although exhaustive data exist for non-social cognitive functions in MS, only a little attention has been paid for social cognition. The objectives of the present work are to reappraise the definition and anatomy of social cognition and evaluate the integrity of this domain across MS studies. We will put special emphasis on neuropsychological and neuroimaging studies concerning social cognitive performance in MS. Studies were selected in conformity with PRISMA guidelines. We looked for computerized databases (PubMed, Medline, and Scopus) that index peer-reviewed journals to identify published reports in English and French languages that mention social cognition and multiple sclerosis, regardless of publication year. We combined keywords as follows: (facial emotion or facial expression or emotional facial expressions or theory of mind or social cognition or empathy or affective prosody) AND multiple sclerosis AND (MRI or functional MRI or positron emission tomography or functional imaging or structural imaging). We also scanned references from articles aiming to get additional relevant studies. In total, 26 studies matched the abovementioned criteria (26 neuropsychological studies including five neuroimaging studies). Available data support the presence of social cognitive deficits even at early stages of MS. The increase in disease burden along with the "multiple disconnection syndrome" resulting from gray and white matters pathology might exceed the "threshold for cerebral tolerance" and can manifest as deficits in social cognition. Admitting the impact of the latter on patients' social functioning, a thorough screening for such deficits is crucial to improving patients' QoL. (JINS, 2017, 23, 266-286).

Most Scottish neurologists do not apply the 2010 McDonald criteria when diagnosing multiple sclerosis.

PubMed

Lumley, R; Davenport, R; Williams, A

2015-03-01

The diagnostic criteria for multiple sclerosis have evolved over time and currently the 2010 McDonald criteria are the most widely accepted. These criteria allow the diagnosis of multiple sclerosis to be made at the clinically isolated syndrome stage provided certain criteria are met on a single magnetic resonance brain scan. Our hypothesis was that neurologists in Scotland did not use these criteria routinely. We sent a SurveyMonkey questionnaire to all Scottish neurologists (consultants and trainees) regarding the diagnosis of multiple sclerosis. Our questionnaire response rate was 65/99 (66%). Most Scottish neurologists were aware of the criteria and 31/58 (53%) felt that they were using these routinely. However, in a clinical vignette designed to test the application of these criteria, only 5/57 (9%) of neurologists appeared to use them. Scottish neurologists' use of the 2010 McDonald criteria for diagnosis of multiple sclerosis varies from practitioners' perception of their use of these criteria.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

PubMed Central

Beecham, Ashley H; Patsopoulos, Nikolaos A; Xifara, Dionysia K; Davis, Mary F; Kemppinen, Anu; Cotsapas, Chris; Shahi, Tejas S; Spencer, Chris; Booth, David; Goris, An; Oturai, Annette; Saarela, Janna; Fontaine, Bertrand; Hemmer, Bernhard; Martin, Claes; Zipp, Frauke; D’alfonso, Sandra; Martinelli-Boneschi, Filippo; Taylor, Bruce; Harbo, Hanne F; Kockum, Ingrid; Hillert, Jan; Olsson, Tomas; Ban, Maria; Oksenberg, Jorge R; Hintzen, Rogier; Barcellos, Lisa F; Agliardi, Cristina; Alfredsson, Lars; Alizadeh, Mehdi; Anderson, Carl; Andrews, Robert; Søndergaard, Helle Bach; Baker, Amie; Band, Gavin; Baranzini, Sergio E; Barizzone, Nadia; Barrett, Jeffrey; Bellenguez, Céline; Bergamaschi, Laura; Bernardinelli, Luisa; Berthele, Achim; Biberacher, Viola; Binder, Thomas M C; Blackburn, Hannah; Bomfim, Izaura L; Brambilla, Paola; Broadley, Simon; Brochet, Bruno; Brundin, Lou; Buck, Dorothea; Butzkueven, Helmut; Caillier, Stacy J; Camu, William; Carpentier, Wassila; Cavalla, Paola; Celius, Elisabeth G; Coman, Irène; Comi, Giancarlo; Corrado, Lucia; Cosemans, Leentje; Cournu-Rebeix, Isabelle; Cree, Bruce A C; Cusi, Daniele; Damotte, Vincent; Defer, Gilles; Delgado, Silvia R; Deloukas, Panos; di Sapio, Alessia; Dilthey, Alexander T; Donnelly, Peter; Dubois, Bénédicte; Duddy, Martin; Edkins, Sarah; Elovaara, Irina; Esposito, Federica; Evangelou, Nikos; Fiddes, Barnaby; Field, Judith; Franke, Andre; Freeman, Colin; Frohlich, Irene Y; Galimberti, Daniela; Gieger, Christian; Gourraud, Pierre-Antoine; Graetz, Christiane; Graham, Andrew; Grummel, Verena; Guaschino, Clara; Hadjixenofontos, Athena; Hakonarson, Hakon; Halfpenny, Christopher; Hall, Gillian; Hall, Per; Hamsten, Anders; Harley, James; Harrower, Timothy; Hawkins, Clive; Hellenthal, Garrett; Hillier, Charles; Hobart, Jeremy; Hoshi, Muni; Hunt, Sarah E; Jagodic, Maja; Jelčić, Ilijas; Jochim, Angela; Kendall, Brian; Kermode, Allan; Kilpatrick, Trevor; Koivisto, Keijo; Konidari, Ioanna; Korn, Thomas; Kronsbein, Helena; Langford, Cordelia; Larsson, Malin; Lathrop, Mark; Lebrun-Frenay, Christine; Lechner-Scott, Jeannette; Lee, Michelle H; Leone, Maurizio A; Leppä, Virpi; Liberatore, Giuseppe; Lie, Benedicte A; Lill, Christina M; Lindén, Magdalena; Link, Jenny; Luessi, Felix; Lycke, Jan; Macciardi, Fabio; Männistö, Satu; Manrique, Clara P; Martin, Roland; Martinelli, Vittorio; Mason, Deborah; Mazibrada, Gordon; McCabe, Cristin; Mero, Inger-Lise; Mescheriakova, Julia; Moutsianas, Loukas; Myhr, Kjell-Morten; Nagels, Guy; Nicholas, Richard; Nilsson, Petra; Piehl, Fredrik; Pirinen, Matti; Price, Siân E; Quach, Hong; Reunanen, Mauri; Robberecht, Wim; Robertson, Neil P; Rodegher, Mariaemma; Rog, David; Salvetti, Marco; Schnetz-Boutaud, Nathalie C; Sellebjerg, Finn; Selter, Rebecca C; Schaefer, Catherine; Shaunak, Sandip; Shen, Ling; Shields, Simon; Siffrin, Volker; Slee, Mark; Sorensen, Per Soelberg; Sorosina, Melissa; Sospedra, Mireia; Spurkland, Anne; Strange, Amy; Sundqvist, Emilie; Thijs, Vincent; Thorpe, John; Ticca, Anna; Tienari, Pentti; van Duijn, Cornelia; Visser, Elizabeth M; Vucic, Steve; Westerlind, Helga; Wiley, James S; Wilkins, Alastair; Wilson, James F; Winkelmann, Juliane; Zajicek, John; Zindler, Eva; Haines, Jonathan L; Pericak-Vance, Margaret A; Ivinson, Adrian J; Stewart, Graeme; Hafler, David; Hauser, Stephen L; Compston, Alastair; McVean, Gil; De Jager, Philip; Sawcer, Stephen; McCauley, Jacob L

2013-01-01

Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals. PMID:24076602

Determining the IgM and IgG antibody titer against CMV and helicobacter pylori in the serum of multiple sclerosis patients comparing to the control group in Hamadan.

PubMed

Salim, Masome Afiati; Eftekharian, Mohammad Mahdi; Taheri, Mohammad; Yousef Alikhani, Mohammad

2017-07-19

Multiple sclerosis (MS) is a chronic autoimmune disease that disables central nervous system (CNS) system. Cytomegalovirus (CMV) probably has an important role in the MS pathology. The infection with helicobacter pylori also is recognized as a protective agent against MS in female. Serum samples were isolated and frozen at -70∘C. The earlier mentioned anti-virus antibodies and antibacterial antibodies were quantified by Elisa kit. The results showed that IgG antibody average value against cytomegalovirus in the blood of multiple sclerosis patients not only decreased but also was significant statistically (p< 0.05). IgM and IgG antibodies average value in the blood of multiple sclerosis patients against helicobacter pylori shown a statistically significant decrease (p< 0.05). Therefore it may be considered that probably helicobacter pylori presence in the individuals especially in female can alleviate MS signs. CMV infection can intensify the symptoms in multiple sclerosis patients.

Interleukin 35 and Hepatocyte Growth Factor; as a novel combined immune gene therapy for Multiple Sclerosis disease.

PubMed

Moghadam, Samira; Erfanmanesh, Maryam; Esmaeilzadeh, Abdolreza

2017-11-01

An autoimmune demyelination disease of the Central Nervous System, Multiple Sclerosis, is a chronic inflammation which mostly involves young adults. Suffering people face functional loss with a severe pain. Most current MS treatments are focused on the immune response suppression. Approved drugs suppress the inflammatory process, but factually, there is no definite cure for Multiple Sclerosis. Recently developed knowledge has demonstrated that gene and cell therapy as a hopeful approach in tissue regeneration. The authors propose a novel combined immune gene therapy for Multiple Sclerosis treatment using anti-inflammatory and remyelination of Interleukine-35 and Hepatocyte Growth Factor properties, respectively. In this hypothesis Interleukine-35 and Hepatocyte Growth Factor introduce to Mesenchymal Stem Cells of EAE mouse model via an adenovirus based vector. It is expected that Interleukine-35 and Hepatocyte Growth Factor genes expressed from MSCs could effectively perform in immunotherapy of Multiple Sclerosis. Copyright © 2017. Published by Elsevier Ltd.

The Validity and Test-Retest Reliability of the Leeds Multiple Sclerosis Quality of Life Scale in Turkish Patients

ERIC Educational Resources Information Center

Akbiyik, Derya Iren; Sumbuloglu, Vildan; Guney, Zafer; Armutlu, Kadriye; Korkmaz, Nilufer; Keser, Ilke; Yuksel, Muazzez Merve; Karabudak, Rana

2009-01-01

The aim of the study was to translate and test the reliability and validity of the Leeds Multiple Sclerosis Quality of Life Scale (LMSQoL) in Turkish patients with multiple sclerosis (MS). Demographic data of MS patients who had a registration in and followed up by a university hospital were recorded. The LMSQoL and Turkish Quality of Life…

The Effects of Gain- versus Loss-Framed Messages Following Health Risk Information on Physical Activity in Individuals With Multiple Sclerosis.

PubMed

Lithopoulos, Alexander; Bassett-Gunter, Rebecca L; Martin Ginis, Kathleen A; Latimer-Cheung, Amy E

2017-06-01

Few people with multiple sclerosis engage in physical activity. Messaging interventions may motivate more physical activity among these individuals. The purpose of this online study was to evaluate an intervention presenting participants with multiple sclerosis (N = 237) with risk information (i.e., information demonstrating people with multiple sclerosis are more likely to experience certain health issues) or no risk information followed by gain- or loss-framed physical activity messages. Participants completed questionnaires on Days 1, 6, and 28 and received information material on Days 2-5. The dependent variables were as follows: physical activity intentions and behavior, response and task efficacy, perceived threat (i.e., perception of threat to health issues relevant to people with multiple sclerosis), and avoidance (i.e., avoiding thinking about/doing something about the health issues presented in the messages). Analyses indicated physical activity and response efficacy increased over time. Also, participants receiving risk information had higher levels of physical activity and perceived threat. However, manipulation checks showed no differences between participants regarding perceptions of risk information or gain/loss-framed messages. Despite the lack of impact of the framing intervention, this study suggests that a brief informational intervention can positively influence physical activity and certain correlates of physical activity among people with multiple sclerosis.

Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial.

PubMed

Khalili, Mohammad; Eghtesadi, Shahryar; Mirshafiey, Abbas; Eskandari, Ghazaleh; Sanoobar, Meisam; Sahraian, Mohamad Ali; Motevalian, Abbas; Norouzi, Abbas; Moftakhar, Shirin; Azimi, Amirreza

2014-01-01

Multiple sclerosis is a neurodegenerative and demyelinating disease of central nervous system. High levels of oxidative stress are associated with inflammation and play an important role in pathogenesis of multiple sclerosis. This double-blind, randomized controlled clinical study was carried out to determine the effect of daily consumption of lipoic acid on oxidative stress among multiple sclerosis patients. A total of 52 relapsing-remitting multiple sclerosis patients, aged 18-50 years with Expanded Disability Status Scale ≤5.5 were assigned to consume either lipoic acid (1200 mg/day) or placebo capsules for 12 weeks. Fasting blood samples were collected before the first dose taken and 12 hours after the last. Dietary intakes were obtained by using 3-day dietary records. Consumption of lipoic acid resulted in a significant improvement of total antioxidant capacity (TAC) in comparison to the placebo group (P = 0.004). Although a significant change of TAC (-1511 mmol/L, P = 0.001) was found within lipoic acid group, other markers of oxidative stress including superoxide dismutase activity, glutathione peroxidase activity, and malondialdehyde levels were not affected by lipoic acid consumption. These results suggest that 1200 mg of lipoic acid improves serum TAC among multiple sclerosis patients but does not affect other markers of oxidative stress.

Physician compensation for industry-sponsored clinical trials in multiple sclerosis influences patient trust.

PubMed

Klein, E; Solomon, A J; Corboy, J; Bernat, J

2016-07-01

Perceived physician financial conflicts of interest of can affect patient trust. Payment to physicians for industry sponsored clinical trials in multiple sclerosis is a relatively new potential source of physician conflict of interest. There is limited available data on how physician payment for trial involvement in multiple sclerosis clinical trials may influence patient trust. To understand how patient trust is influenced by information about physician payment for multiple sclerosis clinical trials. An anonymous online instrument was developed. 597 people with multiple sclerosis participated in the study. The study found that 61% of patients who had not previously participated in a clinical trial estimated that they would have lower levels of trust in their physician if the physician was paid for involvement in their clinical trial. Among former clinical trial participants, 38% self-reported a lower level of trust. Other potential physician-industry relationships, such as industry consulting or giving industry-sponsored talks, also adversely affected trust, though to a lesser extent than physician payment for subject participation in clinical trials. Results of this study demonstrate that physician payment for study participation in multiple sclerosis clinical trials is a potential conflict that can adversely affect patient trust. Copyright © 2016 Elsevier B.V. All rights reserved.

Lateral interactions and speed of information processing in highly functioning multiple sclerosis patients.

PubMed

Nagy, Helga; Bencsik, Krisztina; Rajda, Cecília; Benedek, Krisztina; Janáky, Márta; Beniczky, Sándor; Kéri, Szabolcs; Vécsei, László

2007-06-01

Visual impairment is a common feature of multiple sclerosis. The aim of this study was to investigate lateral interactions in the visual cortex of highly functioning patients with multiple sclerosis and to compare that with basic visual and neuropsychologic functions. Twenty-two young, visually unimpaired multiple sclerosis patients with minimal symptoms (Expanded Disability Status Scale <2) and 30 healthy controls subjects participated in the study. Lateral interactions were investigated with the flanker task, during which participants were asked to detect the orientation of a low-contrast Gabor patch (vertical or horizontal), flanked with 2 collinear or orthogonal Gabor patches. Stimulus exposure time was 40, 60, 80, and 100 ms. Digit span forward/backward, digit symbol, verbal fluency, and California Verbal Learning Test procedures were used for background neuropsychologic assessment. Results revealed that patients with multiple sclerosis showed intact visual contrast sensitivity and neuropsychologic functions, whereas orientation detection in the orthogonal condition was significantly impaired. At 40-ms exposure time, collinear flankers facilitated the orientation detection performance of the patients resulting in normal performance. In conclusion, the detection of briefly presented, low-contrast visual stimuli was selectively impaired in multiple sclerosis. Lateral interactions between target and flankers robustly facilitated target detection in the patient group.

Incidence of multiple sclerosis among European Economic Area populations, 1985-2009: the framework for monitoring

PubMed Central

2013-01-01

Background A debate surrounding multiple sclerosis epidemiology has centred on time-related incidence increases and the need of monitoring. The purpose of this study is to reassess multiple sclerosis incidence in the European Economic Area. Methods We conducted a systematic review of literature from 1965 onwards and integrated elements of original research, including requested or completed data by surveys authors and specific analyses. Results The review of 5323 documents yielded ten studies for age- and sex-specific analyses, and 21 studies for time-trend analysis of single data sets. After 1985, the incidence of multiple sclerosis ranged from 1.12 to 6.96 per 100,000 population, was higher in females, tripled with latitude, and doubled with study midpoint year. The north registered increasing trends from the 1960s and 1970s, with a historic drop in the Faroe Islands, and fairly stable data in the period 1980-2000; incidence rose in Italian and French populations in the period 1970-2000, in Evros (Greece) in the 1980s, and in the French West Indies in around 2000. Conclusions We conclude that the increase in multiple sclerosis incidence is only apparent, and that it is not specific to women. Monitoring of multiple sclerosis incidence might be appropriate for the European Economic Area. PMID:23758972

Internet-based home training is capable to improve balance in multiple sclerosis: a randomized controlled trial.

PubMed

Frevel, D; Mäurer, M

2015-02-01

Balance disorders are common in multiple sclerosis. Aim of the study is to investigate the effectiveness of an Internet-based home training program (e-Training) to improve balance in patients with multiple sclerosis. A randomized, controlled study. Academic teaching hospital in cooperation with the therapeutic riding center Gut Üttingshof, Bad Mergentheim. Eighteen multiple sclerosis patients (mean EDSS 3,5) took part in the trial. Outcome of patients using e-Training (N.=9) was compared to the outcome of patients receiving hippotherapy (N.=9), which can be considered as an advanced concept for the improvement of balance and postural control in multiple sclerosis. After simple random allocation patients received hippotherapy or Internet-based home training (balance, postural control and strength training) twice a week for 12 weeks. Assessments were done before and after the intervention and included static and dynamic balance (primary outcome). Isometric muscle strength of the knee and trunk extension/flexion (dynamometer), walking capacity, fatigue and quality of life served as secondary outcome parameters. Both intervention groups showed comparable and highly significant improvement in static and dynamic balance capacity, no difference was seen between the both intervention groups. However looking at fatigue and quality of life only the group receiving hippotherapy improved significantly. Since e-Training shows even comparable effects to hippotherapy to improve balance, we believe that the established Internet-based home training program, specialized on balance and postural control training, is feasible for a balance and strength training in persons with multiple sclerosis. We demonstrated that Internet-based home training is possible in patients with multiple sclerosis.

Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis

PubMed Central

Srivastava, Rajneesh; Aslam, Muhammad; Kalluri, Sudhakar Reddy; Schirmer, Lucas; Buck, Dorothea; Tackenberg, Björn; Rothhammer, Veit; Chan, Andrew; Gold, Ralf; Berthele, Achim; Bennett, Jeffrey L.; Korn, Thomas; Hemmer, Bernhard

2016-01-01

BACKGROUND Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known. METHODS We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. RESULTS Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. CONCLUSIONS KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.) PMID:22784115

T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention.

PubMed

van Langelaar, Jamie; van der Vuurst de Vries, Roos M; Janssen, Malou; Wierenga-Wolf, Annet F; Spilt, Isis M; Siepman, Theodora A; Dankers, Wendy; Verjans, Georges M G M; de Vries, Helga E; Lubberts, Erik; Hintzen, Rogier Q; van Luijn, Marvin M

2018-05-01

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

PubMed

Metz, Luanne M; Li, David K B; Traboulsee, Anthony L; Duquette, Pierre; Eliasziw, Misha; Cerchiaro, Graziela; Greenfield, Jamie; Riddehough, Andrew; Yeung, Michael; Kremenchutzky, Marcelo; Vorobeychik, Galina; Freedman, Mark S; Bhan, Virender; Blevins, Gregg; Marriott, James J; Grand'Maison, Francois; Lee, Liesly; Thibault, Manon; Hill, Michael D; Yong, V Wee

2017-06-01

On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T 2 -weighted MRI, cumulative number of new lesions enhanced on T 1 -weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T 1 -weighted MRI plus new and newly enlarged lesions on T 2 -weighted MRI]). A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

What Is Leukodystrophy

MedlinePlus

... having the disease. Are the leukodystrophies related to Multiple Sclerosis? The leukodystrophies do share some common features with multiple sclerosis (MS). Like the leukodystrophies, MS is caused by ...

Disease Modifying Therapy in Multiple Sclerosis

PubMed Central

Williams, U. E.; Oparah, S. K.; Philip-Ephraim, E. E.

2014-01-01

Multiple sclerosis is an autoimmune disease of the central nervous system characterized by inflammatory demyelination and axonal degeneration. It is the commonest cause of permanent disability in young adults. Environmental and genetic factors have been suggested in its etiology. Currently available disease modifying drugs are only effective in controlling inflammation but not prevention of neurodegeneration or accumulation of disability. Search for an effective neuroprotective therapy is at the forefront of multiple sclerosis research. PMID:27355035

Immunology and Oxidative Stress in Multiple Sclerosis: Clinical and Basic Approach

PubMed Central

Ortiz, Genaro G.; Pacheco-Moisés, Fermín P.; Bitzer-Quintero, Oscar K.; Ramírez-Anguiano, Ana C.; Flores-Alvarado, Luis J.; Ramírez-Ramírez, Viridiana; Macias-Islas, Miguel A.; Torres-Sánchez, Erandis D.

2013-01-01

Multiple sclerosis (MS) exhibits many of the hallmarks of an inflammatory autoimmune disorder including breakdown of the blood-brain barrier (BBB), the recruitment of lymphocytes, microglia, and macrophages to lesion sites, the presence of multiple lesions, generally being more pronounced in the brain stem and spinal cord, the predominantly perivascular location of lesions, the temporal maturation of lesions from inflammation through demyelination, to gliosis and partial remyelination, and the presence of immunoglobulin in the central nervous system and cerebrospinal fluid. Lymphocytes activated in the periphery infiltrate the central nervous system to trigger a local immune response that ultimately damages myelin and axons. Pro-inflammatory cytokines amplify the inflammatory cascade by compromising the BBB, recruiting immune cells from the periphery, and activating resident microglia. inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in the demyelination and free radical-mediated tissue injury in the pathogenesis of MS. The inflammatory environment in demyelinating lesions leads to the generation of oxygen- and nitrogen-free radicals as well as proinflammatory cytokines which contribute to the development and progression of the disease. Inflammation can lead to oxidative stress and vice versa. Thus, oxidative stress and inflammation are involved in a self-perpetuating cycle. PMID:24174971

Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.

PubMed

Pryce, Gareth; Ahmed, Zubair; Hankey, Deborah J R; Jackson, Samuel J; Croxford, J Ludovic; Pocock, Jennifer M; Ledent, Catherine; Petzold, Axel; Thompson, Alan J; Giovannoni, Gavin; Cuzner, M Louise; Baker, David

2003-10-01

Multiple sclerosis is increasingly being recognized as a neurodegenerative disease that is triggered by inflammatory attack of the CNS. As yet there is no satisfactory treatment. Using experimental allergic encephalo myelitis (EAE), an animal model of multiple sclerosis, we demonstrate that the cannabinoid system is neuroprotective during EAE. Mice deficient in the cannabinoid receptor CB1 tolerate inflammatory and excitotoxic insults poorly and develop substantial neurodegeneration following immune attack in EAE. In addition, exogenous CB1 agonists can provide significant neuroprotection from the consequences of inflammatory CNS disease in an experimental allergic uveitis model. Therefore, in addition to symptom management, cannabis may also slow the neurodegenerative processes that ultimately lead to chronic disability in multiple sclerosis and probably other diseases.

Design of Chemical Conjugate for Targeted Therapy of Multiple Sclerosis Based of Constant Fragment of Human Antibody Heavy Chain and Peptoid Analog of Autoantigen MOG35-55.

PubMed

Lomakin, Y A; Stepanov, A V; Balabashin, D S; Ponomarenko, N A; Smirnov, I V; Belogurov, A A

2017-04-01

Elimination of B cells producing autoantibodies to neuroantigens is considered as beneficial in the treatment of multiple sclerosis. Myelin oligodendrocyte glycoprotein (MOG) is a significant autoantigen in multiple sclerosis. It was shown that MOG-like peptoid AMogP3 can bind autoantibodies produced by pathological lymphocytes. We propose a structure of an innovative drug for targeted elimination of the pool of autoreactive B cells responsible for multiple sclerosis pathogenesis; this compound is a complex of peptoid AMogP3 with Fc fragment of human immunoglobulin. The obtained Fc-PEG-AMogP3 conjugate effectively interact with autoreactive antibodies, which attests to their high therapeutic potential.

Gestational bisphenol-A exposure lowers the threshold for autoimmunity in a model of multiple sclerosis.

PubMed

Rogers, James A; Mishra, Manoj K; Hahn, Jennifer; Greene, Catherine J; Yates, Robin M; Metz, Luanne M; Yong, V Wee

2017-05-09

Environmental and hormonal factors are implicated in dysimmunity in multiple sclerosis. We investigated whether bisphenol-A, a prominent contaminant with endocrine-disrupting capabilities, altered susceptibility in an inflammatory model of multiple sclerosis. We found that gestational, but not adult, exposure to bisphenol-A increased the development of experimental autoimmune encephalomyelitis in adulthood in male, but not female, mice when a suboptimal disease-inducing immunization was used. Gestational bisphenol-A in male mice primed macrophages in adulthood and raised granulocyte-colony stimulating factor and neutrophil counts/activity postsuboptimal immunization. Neutralizing granulocyte-colony stimulating factor blocked susceptibility to disease in bisphenol-A mice. Early life exposure to bisphenol-A may represent an environmental consideration in multiple sclerosis.