Two Small Studies Find Benefits of Exercise for People with MS with Moderate to Severe Problems with Movement

Summary

• Two small studies report on the benefits of exercise for people with MS who have moderate to severe mobility impairments. This research shows the importance of physical activity in enabling people with all forms of MS to live their best lives.
• The National MS Society provides resources on exercise for people living with all forms of MS, as well as for healthcare providers. Further information on increasing physical activity in adults with disabilities is available from the Centers for Disease Control.

Details
Background: Growing evidence suggests that exercise is good for a person’s overall health and for reducing other health conditions (co-morbidities).  Research in MS has also suggested that exercise training is effective for improving aerobic capacity and muscle strength, mobility, quality of life, and may benefit cognition, fatigue and depression. However, research is limited on exercise options for people with MS who have moderate or severe mobility impairments. Two recent, small studies begin to address this gap.

Exercise for severe mobility impairments: Investigators randomly assigned 12 people with progressive MS to receive total-body recumbent stepper training (similar to climbing stairs) or body weight–supported treadmill training. Both are used for people with severe mobility impairments, but the authors wanted to see if stepper training showed similar benefit to treadmill training, because it is significantly less costly to use and maintain the equipment. Participants completed three weekly 30-minute sessions for 12 weeks. Both training programs were safe, and although participants enjoyed both, stepper training was reviewed more favorably. There were no changes in physical function, but both reduced fatigue and improved quality of life.

The team (Lara A. Pilutti, PhD, now at the University of Ottawa, and former colleagues at the University of Illi­nois at Urbana-Champaign) has published results in the International Journal of MS Care (2016;18:221–229).

A cycling option for non-ambulatory people: Functional electrical stimulation (FES) offers people with significant weakness and mobility problems a cycling option, using low-level electrical impulses to stimulate the activation of leg muscles. Researchers evaluated whether this type of cycling improved symptoms and quality of life in 16 people with moderate to severe MS who were unable to walk. Participants cycled for 30 minutes, two to three times a week for one month. Significant improvements were noted in cycling performance, and physical and psychosocial aspects of fatigue, as well as reductions in reported pain. There were no significant changes in spasticity, cognitive aspects of fatigue, or muscle strength. Further research in larger numbers of people would help to clarify how benefits might be optimized.

The team (Deborah Backus, PhD, PT, and colleagues at the Shepherd Center, Atlanta, GA) report their results in the International Journal of MS Care (Published online, August 9, 2016).

Read More: The National MS Society provides resources on exercise for people living with all forms of MS, as well as for healthcare providers. Further information on increasing physical activity in adults with disabilities is available from the Centers for Disease Control.

New research strengthens genetics, MS link

In a large-scale, genome-wide analysis of more than 110,000 samples, researchers identified 200 genetic loci associated with multiple sclerosis. The study authors said that while the research highlights the role of several different immune cells that contribute to the initiation of this inflammatory disease, the mechanisms that lead this inflammatory disease to target the brain and spinal cord remain unclear.
By comparing the genomes of people with and without MS, the researchers identified 200 variants that were significantly more common among those with the disease. Most of these variants implicate genes that are associated with immune cells and immune system function, including a few potentially specific to brain-related functions.
Interestingly, many of the genes identified were known to also be involved in other autoimmune diseases, such as rheumatoid arthritis, Type I diabetes, and ulcerative colitis. This raises intriguing questions about why these diseases target different organs and have different clinical manifestations.
The findings were presented at the American Society of Human Genetics (ASHG) 2016 annual meeting in Vancouver, B.C.

World’s Largest MS Research Conference Highlights Advances in Progressive MS, Gut Microbiome, Managing Symptoms, and New Approaches to Restoring Function

Results from clinical trials, including new approaches to treating progressive MS, lifestyle and wellness research and myelin repair strategies were among more than 2,000 presentations made at the European Committee for Treatment and Research in MS (ECTRIMS) meeting held in London, England in September.
The world’s largest gathering of MS researchers convened more than 9,000 scientists and clinicians and industry representatives from across the globe, including many National MS Society-funded researchers, meeting and presenting on cutting-edge MS research progress. In addition, the European Rehabilitation in MS network met jointly with ECTRIMS this year.

• Read blogs and announcements from the meeting
• Explore scientific summaries (abstracts) on the ECTRIMS Website 

During the conference, the International Progressive MS Alliance announced new investments of over $14 million US dollars to support three Collaborative Network Awards. These international teams were selected to accelerate the pace of research in key areas to speed new therapies for progressive MS.

Below are highlights of presentations focused on stopping MS, restoring function, and ending MS forever. In most cases, studies presented are considered preliminary. Many will be analyzed more thoroughly, and likely published in peer-reviewed journals.

STOPPING MS

Many presentations showed continued benefits of available therapies and longer-term safety information, as well as more evidence that early and ongoing treatment with a disease-modifying therapy has long-term benefits for controlling disease activity, delaying accumulation of disability, and protecting quality of life.

Siponimod in secondary progressive MS: More details were presented from a 60-month, phase 3 clinical trial of the experimental oral therapy siponimod (Novartis Pharmaceuticals AG) involving 1,651 people with secondary progressive MS. The trial met its primary endpoint, with those on active treatment showing a modest 21% reduced risk of disability progression compared to those on placebo. Secondary endpoints suggested that those on active therapy had 23.4% lower average change in brain volume and reduced MRI-detected lesion volume. The medication showed a similar safety profile to others that work by preventing white blood cells from entering the central nervous system. (Abstract #250)

More details from trial of lipoic acid in secondary progressive MS: Dr. Rebecca Spain and colleagues (Oregon Health & Science University) presented results from a small, controlled clinical trial on the oral anti-oxidant supplement called lipoic acid in people with secondary progressive MS. The lipoic acid group had 66% less brain tissue shrinkage, or atrophy, than the group taking inactive placebo pills. This pilot study suggests potential benefits if they hold up in a larger trial. (Abstract #222)

New results on gut bacteria: Efforts are advancing to pinpoint bacteria in the gut that may drive inflammatory immune system activity in MS and others that can suppress it, which may open the door to novel probiotic or other therapeutic approaches to treating MS.

• Drs. Yan Wang, Lloyd Kasper and colleagues (Dartmouth Medical School and Eastern Washington University) reported that treating mice with the gut-related molecule called polysaccharide A (PSA) expanded a type of immune cells called “Regulatory B cells” (Bregs) which promote an immune response that prevents mice from getting MS-like disease. (Abstract #181) Members of this team also reported that PSA had positive effects in mice with progressive MS-like disease. (Abstract #P465) 
• Dr. Sergio Baranzini (University of California, San Francisco) and other collaborators in the National MS Society-supported MS Microbiome Consortium are analyzing gut bacteria to unearth clues about MS susceptibility and progression. They analyzed bacteria in stool samples from 64 people with MS who had received treatment for MS, and 68 people without MS. Certain bacteria were increased in people with MS, and those bacteria increased immune cells (T helper 1 cells) that are major players in MS immune attacks. Another type of bacteria that could suppress the immune attack was reduced. (Abstract #179) 

Disappointing results for nerve-protection approaches: A small two-year clinical trial of fluoxetine (same compound as the anti-depressant Prozac) did not meet its goal of improving walking speed in people with progressive MS. The multi-center team from Belgium is still analyzing other results, such as changes in MRI and cognition. (Abstract #253) Likewise, a trial conducted at the University of Oxford tested the ability of amiloride to protect against nerve damage in people with acute optic neuritis (often an early sign of MS) failed to show any neuroprotective benefit. (Abstract #102) Additional trials of neuroprotective approaches to MS are ongoing.

Vitamin D deficiency and smoking linked to progression: Dr. Maria Isabel Zuluaga and team (Vall d’Hebron University, Barcelona) explored the independent impacts of smoking and vitamin D deficiency in a large group of people followed over time. They found that those with severe vitamin D deficiency (defined as blood levels at less than 8 ng/ml) showed an increased risk for MS disability, and active smokers also had an increased risk for disability progression. (Abstract #252) Graduate student Ms. Eva Rosa Petersen (Danish MS Center, Copenhagen) also found that smoking intensity was linked with higher frequency of relapses among people taking interferon beta. Smoking one pack of cigarettes per day increased relapse rates by 25%. (Abstract #178)

Vitamin D added to Rebif: A large international trial did not show a statistical difference between treatment groups after adding vitamin D (14,000 IU [350 µg] vitamin D3 daily) or placebo to Rebif therapy in relapsing MS, in terms of the percent of participants who were free from disease activity after 48 weeks. Dr. Raymond Hupperts (Orbis Medical Centre, Sittard-Geleen, The Netherlands), who presented results, noted that both groups were stable, which likely contributed to the inconclusive results. (Abstract #166)

Biomarkers under development: Teams are making headway toward having a simple test that can predict a person’s disease course, progression and response to therapy. Dr. Bibiana Bielekova (National Institute of Neurological Diseases and Stroke) and team examined proteins in the spinal fluid of people with neurological diseases, including all types of MS, and identified a “signature” of markers that distinguished MS from other diseases, and also differentiated relapsing MS from progressive MS. (Abstract #219). Other investigators also reported progress in this area, including advances using “neurofilament light chain” as a biomarker. (Such as Abstracts #183, #249) These early results need further development but indicate that  sensitive biomarkers for predicting disease course and response to therapy may become useful tools for the clinical management of MS.

RESTORING FUNCTION – WELLNESS, LIFESTYLE, SYMPTOMS

Home-based rehabilitation can work: With funding from the National MS Society, Dr. Gabriel Pardo (Oklahoma Medical Research Foundation) and colleagues compared the benefits of three approaches to rehabilitation for gait and balance in a small study: unsupervised home-based exercise 5 times/week; home-based exercise supervised remotely by a physical therapist 2-3 times per week via audio and visual conferencing; and home-based exercise plus in-person physical therapy 2-3 times/week. They found that all participants improved, and that the telerehabilitation program worked as well as the onsite program to improve gait and balance. Further research in larger trials could make telerehabilitation a cost-effective and more accessible alternative for people with MS. (Abstract #120)

Tackling fatigue: Dr. Vincent de Groot (VU University Medical Center, Amsterdam) reported results from three clinical trials testing different strategies over 16 weeks to lessen fatigue, in 90 people with MS: aerobic training, cognitive behavioral therapy, and energy conservation management. Only cognitive behavioral therapy effectively reduced severe fatigue in this short-term study. This is a commonly available type of psychotherapy. (Abstract #142) Read more about managing fatigue

Pain more common than previously reported: Dr. Carolyn Young (University of Liverpool) and colleagues found that nearly 66% of over 700 people with MS reported nerve pain. Higher levels were found in those who had MS for a longer time, had more severe disability, or were not working. (Abstract #P337) Read more about addressing pain in MS

New trial confirms Ampyra (fampridine) benefits: Dr. Jeremy Hobart (Plymouth Hospitals NHS Trust) presented results from a large clinical trial of fampridine, a twice-a-day oral therapy that was previously approved for its ability to improve walking.. This trial wanted to show evidence that its benefits include meaningful functional improvements for people. The results over 6 months showed that 43% of those on active therapy had significantly better self-reported walking ability, mobility, and balance than those on placebo, with no new safety issues reported. (Abstract #254)

Cognitive rehabilitation enhances brain connections: Several studies showed that rehabilitation to improve cognition goes hand-in-hand with changes in brain connectivity (how areas of the brain interact). While many of these treatments are still experimental, some are available from rehabilitation specialists such as speech pathologists or neuropsychologists. Discuss options with your MS doctor:

• Dr. Brian Sandroff (Kessler Foundation, West Orange, NJ) and colleagues showed that treadmill training improved information processing speed and brain connectivity in a small pilot study funded by the Society. (Abstract #P796) 
• Dr. Pietro Iaffaldano (University of Bari, Italy) and colleagues showed that a home-based computerized training program that targeted specific cognitive issues improved overall cognitive function significantly more than a non-specific program. Also, those who had less function in certain brain areas showed greater improvement after cognitive training. (Abstract #145) 
• Oiane Rilo (University of Deusto, Bilbao, Spain) and colleagues showed that a three-month, group-based cognitive rehabilitation program improved working memory, information processing speed, verbal memory and executive function (which is important in problem solving and planning), and altered brain connectivity. (Abstract #144)  

Emerging treatment for muscle spasticity: Dr. Daniel Kantor (Kantor Neurology, Ponte Vedra Beach, FL) and colleagues report that in a trial of 354 people with relapsing-remitting or secondary progressive MS, Arbaclofen Extended Release Tablets (Osmotica Pharmaceuticals) significantly reduced spasticity compared to baclofen. The extended-release tablets caused significantly less sleepiness, drowsiness and dizziness than baclofen. (Abstract #128) The company reports that it has filed for FDA approval of Arbaclofen.

RESTORING FUNCTION – NERVOUS SYSTEM REPAIR

More Anti-LINGO Results: In June 2016 Biogen announced that its phase 2 clinical trial of anti-LINGO (proposed name opicinumab), an approach to repair myelin, did not meet its primary endpoint of improvement in physical function, cognitive function, or disability. The trial involved 418 people with relapsing MS who were taking interferon beta-1a (Avonex) plus one of several doses of intravenous opicinumab or placebo for 72 weeks. Dr. Diego Cadavid from the company described ongoing evaluations from the extensive testing and monitoring during the trial, which are helping to pinpoint the patient population, dosage and outcome measures that would inform the design of any future trials of anti-LINGO.  (Abstract #192)

Myelin repair in pediatric and adult MS: Dr. Sabine Pfeifenbring (University of Göttingen, Germany) and an international team analyzed brain biopsies from children who had been diagnosed with MS and compared the extent of damage and natural myelin repair against those of adults with MS. They found that children showed less damage to myelin-making cells and more evidence of myelin repair than adults. However, some myelin repair was found to occur at virtually all ages in MS. (Abstract #194)

Exercise enhances myelin repair in mice: To investigate some reasons why exercise promotes benefits in people with MS, Drs. S. Jensen and Wee Yong (University of Calgary) did a study where mice with myelin damage in their spinal cords used running wheels soon after the injury. They reported finding more evidence of generation of myelin-making cells and myelin repair in the active mice than those that did not use the running wheels after injury. (Abstract: #P1210)

Emerging approaches to protection and repair:  Dr. Martin Sanders (Io therapeutics) presented results from mice suggesting that the compound IRX4204 promotes repair of damaged myelin in mice. He noted that previous studies suggested that IRX4204 also showed signs of reducing immune attacks and protecting against nerve loss. This work was supported in part by a National MS Society’s Fast Forward investment. (Abstract #193)

Drs. Sarah Starossom, Samia Khoury and team (Brigham and Women’s Hospital, Boston) reported on studies of Chi3l3, a naturally occurring molecule in the brain that can stimulate the transformation of resident stem cells into myelin-making cells. The team noted that it plays an important role in recovery from the MS-like disease in mice, and may have potential for development as a new treatment approach in MS. (Abstract #195)
 

Positive Results Announced from Clinical Trial of BAF-312 (Siponimod) in Secondary Progressive MS

Summary

Results presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) provided additional details from a 60-month, phase III clinical trial of the experimental oral therapy siponimod (BAF312, Novartis Pharmaceuticals AG) involving 1,651 people with secondary progressive MS.

The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression compared to those on placebo. Secondary endpoints suggested that those on active therapy had 23.4% lower average change in brain volume and reduced lesion volume.

The therapy was generally well tolerated and similar to adverse events reported for similar compounds. 

Details

Background: Siponimod (BAF312) is an experimental immune system-modulating therapy that was designed to be a more selective sphingosine 1-phosphate receptor modulator than Gilenya® (fingolimod, Novartis International AG). Gilenya, was approved in 2010 for adults with relapsing forms of MS to reduce the frequency of clinical relapses and to delay the accumulation of physical disability. Siponimod previously demonstrated safety and efficacy on MRI scans in a phase II study in people with relapsing-remitting MS (The Lancet Neurology, 2013 Aug;12(8):756-67).  Siponimod is thought to act by retaining certain white blood cells in the body’s lymph nodes, keeping them out of circulation and from entering the central nervous system. Siponimod also distributes effectively to the central nervous system (brain and spinal cord) where it may have direct anti-inflammatory or other effects.

The Study: Participants were randomly assigned to take siponimod or placebo capsules daily for up to 60 months. The primary endpoint of the study was reducing the risk of disability progression, as measured by the EDSS scale at three months. Secondary endpoints included reducing the risk of disability progression as measured by the EDSS at six months versus placebo, the risk of worsening mobility as measured by the timed 25-foot walk test, disease activity as observed on MRI scans, relapse rate, and safety/ tolerability.

Results:  Results were presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on September 17, 2016. The trial met its primary endpoint of reducing the risk of disability progression compared with inactive placebo. Those on active treatment had a 21% reduced risk of disability progression (confirmed at 3 months) compared to those on placebo. Secondary endpoints suggested that those on active therapy had at 26% reduced risk of disability progression (confirmed at 6 months), a 23.4% lower average change in brain volume, and reduced MRI-detected brain lesion volume. There was no significant difference seen between groups in the timed 25-foot walk. Relapse rates were significantly lower in those taking siponimod.

Safety: The therapy was generally well tolerated and similar to adverse events reported for similar compounds. Serious adverse events occurred in 16.7% of participants. The serious adverse events reported to be more likely for those taking siponimod included nervous system disorders and infections.

Comment: “These results suggest a modest benefit for people with secondary progressive MS, which is a positive step forward in the global effort to speed solutions for people living with this chronic form of the disease,” said Timothy Coetzee, PhD, Chief Advocacy, Services and Research Officer at the National MS Society. “We look forward to learning additional details about its potential benefit and safety.”

Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial

Publication History

Published Online: July 06, 2016

http://www.msard-journal.com/article/S2211-0348(16)30100-6/fulltext#s0005

 

The role of diet in ameliorating the severity of multiple sclerosis (MS) has been long debated, but there remains a paucity of relevant research. Observational studies by Dr. Roy Swank, published between 1953 and 2003, suggested significantly reduced MS disease activity and disability progression and longer survival in people following a diet low in total and saturated fat compared with those who did not (Swank, 1953, Swank and Goodwin, 2003, Swank, 1970). Swank's diet book, last published in 1987, remains popular among patients with MS. However, this approach to treating MS has never been subjected to a well-controlled clinical trial.

The supposed large clinical effect of the Swank low fat diet led to our hypothesis that a very-low-fat, plant-based diet might have a large effect on MRI activity. We conducted a pilot study to explore the tolerability and potential benefits of a very-low saturated fat, plant-based diet followed for 12 months by people with relapsing-remitting MS (RRMS) with the primary endpoint being brain MRI disease activity.

Study suggests antibody may have therapeutic effect on MS

Researchers have developed an antibody with potential therapeutic effects against multiple sclerosis. The discovery opens up a new strategy for controlling the disease.

For the cells of the immune system circulating in the bloodstream to reach the central nervous system, they must penetrate the blood-brain barrier and blood-spinal cord barrier. During previous work, the authors studied a factor involved in opening the blood-brain barrier, the NMDA receptor. They found that blocking the interaction of this receptor with tPA has beneficial effects linked with maintaining the integrity of the barrier.

Scientists at the Institut National de la Santé et de la Recherche Médicale, in France, developed a monoclonal antibody (Glunomab) directed against the specific site on the NMDA receptor to which tPA binds. In cellular models of the human blood-brain and blood-spinal cord barriers, the use of this antibody prevented opening of the barrier under inflammatory conditions, limiting the entry of lymphocytes. The team then tested the therapeutic effects of the antibody in an experimental mouse model of MS. After intravenous injection of Glunomab, the progression of partial or total paralysis of the limbs – as assessed by a clinical score – was blocked. In these treated mice, this effect was linked with reduced infiltration of lymphocytes into the nervous tissue, and reduced demyelination.

Results of mouse model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, the authors argue that by preventing myelin destruction by the cells of the immune system, this strategy might represent a promising therapy for the control of MS.

The study was published in the journal Brain.