September 2011

What Triggers MS in Kids? Pediatric Network and Other Sites Recruiting for Study of Environmental and Genetic Risk Factors

Investigators nationwide are recruiting 640 children with early relapsing-remitting MS or CIS (clinically isolated syndrome, a single episode of MS-like symptoms) and 1280 children without MS or CIS for a four-year study to determine environmental and genetic risk factors that make children susceptible to developing MS. The study, funded by the National Institutes of Health, leverages the National MS Society’s support of the Promise: 2010 Pediatric Network of Centers of Excellence.
Background: This study takes advantage of the collaborative efforts of the Pediatric Network. Although the initial grants end this year, there is funding through 2012 to support a data coordination and analysis center so the Network can continue to collect data and study pediatric MS and related disorders. The Network produced over 150 papers, posters and presentations on pediatric MS and network members are the lead authors and editors of a textbook on Pediatric MS from Cambridge Press.
The five-year, $3.2 million grant to lead investigator Dr. Emmanuelle Waubant (University of California, San Francisco Pediatric MS Center) from the NIH is based on pilot data collected by the Network in a study of 180 children with MS. That study confirmed previous reports that the Epstein-Barr virus (which causes infectious mononucleosis and other disorders) was associated with higher risk of MS. They also reported that cytomegalovirus was associated with a lower risk of developing MS, and that herpes simplex virus type 1was associated with increased risk in children who did not have a specific immune-related gene.)
These findings and other factors are being investigated further in the new study, which should help us understand more about how MS begins in children and can eventually be applied to adult forms of MS.
The Study: Those under age 18 who had disease onset (MS or CIS) in the last two years may enroll in this study with the consent of their parents. Children without MS or CIS can enroll if they are 19 or younger and don’t have a demyelinating disease or an autoimmune disorder (except asthma).
Participants are providing blood samples to test for genetic and environmental risk factors that may be associated with pediatric MS. Next, all participants are completing questionnaires about relevant environmental factors. Investigators also will draw information from participants’ medical records.
Investigators specifically are looking at genes, Epstein Barr and other common viruses, vitamin D levels, and exposure to cigarette smoking. They are attempting to confirm these risk factors separately and to determine whether there are any interactions between them.

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"News" articles are derived from research releases made by the National MS Society"

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August 2011

Study of Laquinimod Does Not Meet Primary Endpoint: Initial Results Announced in Press Release

Teva Pharmaceutical Industries Ltd. and Active Biotech announced in a press release that the phase III BRAVO study, in which the experimental oral drug laquinimod was tested against inactive placebo in a study involving over 1300 people with relapsing-remitting MS, did not reach its primary goal of reducing the average number of relapses in a year. However, when the investigators adjusted the data to correct for differences in magnetic resonance imaging characteristics at the start of the study, a significant reduction in average annual relapse rate was observed in the group receiving the laquinimod. Further analysis is ongoing, and the results are being submitted for presentation at a scientific meeting later this year. The companies state that they plan to submit applications to regulatory authorities for the treatment of MS in the United States and European Union.
Background: Multiple sclerosis occurs when the immune system mistakenly attacks nerve fiber-insulating myelin and other brain and spinal cord tissues. Laquinimod is a monoclonal antibody believed to affect the immune attack. In an earlier phase II study involving 306 people with relapsing-remitting MS, oral laquinimod reduced disease activity by 40.4% compared with inactive placebo. (Lancet 2008; 371: 2085–92) In one phase III study – the ALLEGRO study – laquinimod reduced the annual relapse rate in those completing the trial by 23%, compared to those on placebo. (Late-Breaking News – American Academy of Neurology, 2011)
The Study: In the BRAVO study, participants were randomly assigned to receive either laquinimod 0.6 mg (one capsule daily), inactive placebo, or Avonex® (interferon beta-1a, Biogen Idec) 30 mcg/wk for 24 months. The primary goal of the study was to determine the effect of laquinimod on the rate of relapses. Secondary goals included impacts on disease activity as observed on MRI scans, and accumulation of disability. Laquinimod was not directly compared to Avonex, but just to the inactive placebo.
Laquinimod did not reduce the annualized relapse rate significantly more than placebo. According to the press release, there were differences in MRI characteristics between the treatment groups at the beginning of the study, and when the data were adjusted to account for these differences, laquinimod was found to reduce annualized relapse rate, disability progression (as measured by the EDSS scale of disease activity), and brain tissue volume loss significantly more than placebo. No details were released related to safety, except to state that “laquinimod demonstrated a favorable safety and tolerability profile compared to placebo.”
According to the companies, further analysis is ongoing, and the results are being submitted for presentation at a scientific meeting later in the year. The companies plan to submit applications to regulatory authorities for the treatment of MS in the United States and European Union. The complete data from the BRAVO and ALLEGRO studies should help define the safety and promise of laquinimod as a potential new oral therapy for relapsing-remitting MS.

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"News" articles are derived from research releases made by the National MS Society"

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July 2011

Positive Results Announced from First Phase III Study of Alemtuzumab in MS

Sanofi and its subsidiary Genzyme have announced that the experimental intravenous therapy alemtuzumab (with a proposed brand name Lemtrada,™) met one of two primary endpoints by significantly reducing relapse rates in a two-year study comparing two annual cycles of alemtuzumab against standard subcutaneous dosing of Rebif® (interferon beta-1a, EMD Serono Inc. and Pfizer). The study, called CARE-MS I, involved 581 people with early relapsing-remitting MS. The study did not meet its second primary endpoint of slowing disease progression compared to Rebif. The results were announced in July 11 press release. Data analysis is ongoing and the company expects to provide a full report at an upcoming medical meeting. Another trial of alemtuzumab, called CARE-MS-II, is currently underway.

Background: Multiple sclerosis involves immune system attacks against brain and spinal cord tissues. Alemtuzumab is a humanized monoclonal antibody directed at CD52 (a protein on the surface of immune cells) that is currently approved by the U.S. FDA for the treatment of B-cell chronic lymphocytic leukemia. Its ability to target immune cells led investigators to test its potential as a treatment for relapsing-remitting MS. An earlier phase II study compared two dose levels of alemtuzumab with Rebif in 334 subjects with relapsing-remitting MS who had never taken any other disease-modifying therapies. Those taking alemtuzumab had a 74% reduction in the risk of MS relapse compared with those on Rebif, and a 71% reduction in the risk for sustained accumulation of disability (New England Journal of Medicine 2008 359;17: 30-45).
Dosing was temporarily suspended in the Phase II study due to the occurrence of immune thrombocytopenic purpura (ITP), a rare condition in which low blood platelet counts can lead to abnormal bleeding. After the first cases of ITP occurred, one of which was fatal, Genzyme implemented a patient safety monitoring program which includes patient and physician education and regular contacts with patients. Two phase III studies comparing alemtuzumab with Rebif were then launched.
In June 2010, it was announced that alemtuzumab had been designated by the FDA as a “Fast Track Product.” This designation should expedite its future review by the FDA after the company submits results of the phase III trials. The press release stated that the company expects to file for regulatory approval of alemtuzumab for MS in early 2012.

This Study: In the CARE-MS I study, approximately 581 people with early, active relapsing-remitting MS, who had never received disease-modifying therapy to treat their MS, were randomly assigned to receive alemtuzumab or Rebif. Alemtuzumab was given by intravenous infusion for 5 days initially and for 3 days one year later. Those on Rebif received the standard dose of 3-times weekly subcutaneous injections. According to the press release, after two years the relapse rate of those on alemtuzumab was reduced by 55 percent compared to those on Rebif. After two years, 8 percent of those on alemtuzumab had an increase in their EDSS score (a standard scale of physical disability) compared to 11 percent on Rebif – a difference that was not statistically significant.

According to the press release, the most common adverse event associated with alemtuzumab in the CARE-MS I study included reactions associated with infusions (such as headache, rash, fever, flushing, hives and chills). There were more infections in those taking alemtuzumab, predominantly mild to moderate, and there were no fatal infections. Less than 20 percent on alemtuzumab developed autoimmune thyroid-related problems and less than one percent developed ITP.

In the ongoing CARE-MS II study, approximately 1200 subjects at over 250 study sites have been randomly assigned to receive one of two alemtuzumab treatment regimens, or Rebif.

Comment: These positive results are the first reported from this Phase III study of alemtuzumab. Full details and evaluation of this study, and from another Phase III study now underway, should help define the safety and promise of alemtuzumab as a potential new therapy for relapsing MS.

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"News" articles are derived from research releases made by the National MS Society"

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June 2011

Positive Results Announced from Phase 3 Study of Oral BG-12

Biogen Idec announced that the experimental oral therapy BG-12 significantly reduced the proportion of people with MS who experienced relapses in a two-year study of more than 1200 people with relapsing-remitting MS. Although its exact mode of action is not known, BG-12 is thought to inhibit immune cells and molecules involved in MS attacks on the brain and spinal cord. The results were announced in an April 11 press release. Data analysis is ongoing and the company expects to provide a full report at an upcoming medical meeting. Another trial of BG-12 is currently underway.
Background: Multiple sclerosis involves immune system attacks against brain and spinal cord tissues. Although its exact mechanism of action is not known, BG-12, an oral drug, is thought to inhibit immune cells and molecules and may be protective against damage to the brain and spinal cord. In an earlier phase 2 study, compared to inactive placebo, the highest tested BG-12 dose led to a 69% reduction in active inflammation on MRI scans from weeks 12 to 24. Side effects (formally known as adverse events) included abdominal pain, flushing, headache, fatigue, and feeling hot
This Study: The primary goal of the DEFINE study was to determine whether BG-12 could decrease the proportion of participants experiencing relapses and whether the agent was safe and well tolerated. Secondary objectives included assessing BG-12’s effects on the frequency of relapses, disability progression, and disease activity detected by MRI.

Participants were randomly assigned to one of two treatment groups receiving different doses, or a group receiving placebo. According to the press release, in both groups taking BG-12, the primary endpoint was met, meaning a significant reduction in the proportion of people experiencing relapses at 2 years. All secondary endpoints were met as well in these groups, with significant reductions in relapse rate, disease activity on MRI scans, and in disability progression as detected by the EDSS, a standard scale that measures disability. According to the press release, adverse events were similar to those experienced during the Phase 2 study (those included abdominal pain, flushing, headache, fatigue, and feeling hot):
Comment: These positive results are the first reported from this large, Phase 3 study of BG-12. Full details and evaluation of this study, and from another Phase 3 study now underway, should help define the safety and promise of BG-12 as a potential therapy for relapsing MS.

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"News" articles are derived from research releases made by the National MS Society"

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May 2011

Canbex Therapeutics Receives $2.8 Million Dollar Translation Award

The National MS Society is pleased to report that Canbex Therapeutics Ltd. (Canbex) announced today that it has received a Translation Award of up to 1.75 million ($2.8 million) from the Wellcome Trust to support development of a therapy for the treatment of the debilitating muscle spasms associated with multiple sclerosis and potentially other disorders.
The award will facilitate further preclinical development of Canbex’s VSN series of compounds and the progression into clinical trials.  It is anticipated that a Phase I trial of lead compound VSN16R could begin in December 2012.
“We are very grateful to the Wellcome Trust for its support, and are very excited to be moving our lead compound VSN16R forward towards clinical trials,” said Stephane Mery, CEO of Canbex. 
Preclinical studies have shown that VSN16R treatment reduces muscle spasms in an animal model of MS spasticity, with a far lower burden of side effects than the decades-old compounds that are currently in clinical use.  Even at high doses, animals treated with of VSN16R did not show the limpness and muscle flaccidity, know as the “rag doll effect”, that is a characteristic of existing compounds. 
“Multiple sclerosis (MS) patients urgently need more tolerable treatments for the painful and debilitating muscle spasms that many of them suffer, and we believe that VSN16R has the potential to meet that need, and enhance the quality of life for people living with MS” Mery added.
MS is a serious and typically progressive chronic disease for which no satisfactory cure is in sight. Spasticity, characterized by sudden and uncontrollable movements of limb and torso musculature, is among the most painful, damaging and debilitating symptoms of the disease.  It can manifest itself in the form of gait disorders, fatigue, spasms and pain. Spasticity can also occur in other conditions, including bladder dysfunction and spinal cord injury. 
Current forms of treatment for spasticity are unsatisfactory, and a drug against spasticity that is well tolerated and effective could make a substantial difference to quality of life for MS patients and potentially many others. 
Canbex has been developing its VSN series of compounds with the support of interested investors including Fast Forward LLC, a not for profit organization established by the National Multiple Sclerosis Society, USA, to accelerate the development of treatments for MS.  “Fast Forward’s support has been a uniquely powerful endorsement of our efforts, one which has encouraged other funders and the MS community to engage with us,” Stephane Mery said.
"Fast Forward is very pleased that Canbex has been able to leverage its support and the support of others to secure investment from the Wellcome Trust.  This will enable Canbex to make substantial progress in advancing a potentially promising therapy that could significantly improve the quality of life for people living with MS," said Dr. Timothy Coetzee, Chief Research Officer at the National MS Society.

About Canbex Therapeutics Ltd.
Founded in 2005, Canbex Therapeutics Ltd is a spinout company from The Wolfson Institute for Biomedical Research at UCL (University College London) that is focused on the development of novel small molecule treatments for spasticity in MS and other neurological disorders. The novel orally active lead compound, VSN16R, is effective against spasticity in the Chronic Relapsing EAE mouse model of MS and has the potential to be substantially more tolerable than existing anti-spastic agents. The original work on this compound was conducted in the labs of the founders Professor David Selwood and Professor David Baker (now at Queen Mary University of London) by Dr Cristina Visintin, Dr Masahiro Okuyama and Dr Gareth Pryce.
Canbex is a virtual, low-burn company that was set up as a vehicle for the development of the VSN compounds. Building on the expertise of its founders Canbex has assembled a highly experienced team with expertise in pharmacology, medicinal chemistry, preclinical and clinical development, finance and business development. In addition to the Wellcome Trust investment, other shareholders and investors include Fast Forward LLC (an affiliate of the US National Multiple Sclerosis Foundation), the Bloomsbury Bioseed Fund; Esperante Ventures; and UCL Business PLC.  Operational and business development activities are managed by UCL Business PLC, the commercialization company for UCL.
About the Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust’s breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.

About Fast Forward, LLC
Fast Forward, LLC is a nonprofit organization established by the National Multiple Sclerosis Society in order to accelerate the development of treatments for MS. Fast Forward will accomplish its mission by connecting university-based MS research with private-sector drug development and by funding small biotechnology/pharmaceutical companies to develop innovative new MS therapies and repurpose FDA-approved drugs as new treatments for MS.
The National MS Society addresses the challenges of each person affected by MS by funding cutting-edge research, driving change through advocacy, facilitating professional education, collaborating with MS organizations around the world, and providing programs and services designed to help people with MS and their families move their lives forward.

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"News" articles are derived from research releases made by the National MS Society"

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April 2011

$17.5 Million in New Research Projects Launched to Stop MS, Restore Function and End it Forever

50 new grants part of nearly $40 million 2011 investment in cutting-edge research projects moving us closer to a world free of MS
The National MS Society has just committed $17.5 million to support 50 new MS research projects as part of its comprehensive strategy to stop MS in its tracks, restore function that has been lost, and end the disease forever. This financial commitment is part of the Society’s nearly $40 million 2011 investment in cutting-edge research projects. 
Worldwide, over 2.1 million people live with the unpredictable challenges of multiple sclerosis.  To find the best research projects, the National MS Society relies on more than 70 world-class scientists. These scientists volunteer their time to carefully evaluate hundreds of proposals every year. 
The new projects support the comprehensive research goals outlined in the Society’s five-year Strategic Response, including an increased focus on understanding and stopping disease progression, supporting development of new therapies, identifying rehabilitation and other strategies to restore function, and getting more researchers and scientists focusing on MS. The new projects include: 

• clinical trials testing whether vitamin D can stop MS activity
• a clinical trial to evaluate whether a repurposed drug, phenytoin, can protect the nervous system from MS damage;
• investigations of mechanisms that may lead the immune system to turn against the nervous system 
• studies of natural molecules that may stimulate repair of the nervous system to restore function; 
• studies exploring novel exercise programs to combat MS symptoms; and
• a study comparing the activity of several viruses, including Epstein-Barr virus, that may be involved in triggering immune attacks in people with MS, which may lead to clues to ending MS through prevention.

There are FDA-approved therapies that can impact the underlying disease course in people with the more common forms of MS. However, none of these can stop or reverse the damage to restore function. The National MS Society-funded research helped lead to the development of many of these therapies, and continues to be a driving force of MS research.

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"News" articles are derived from research releases made by the National MS Society"

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March 2011

Small, Uncontrolled Study Looks at Long-Term Effects of Bone Marrow Stem Cell Transplantation for MS

In a small uncontrolled study, 35 people with MS underwent bone marrow stem cell transplantation aimed at “rebooting” the immune system, and were followed for two to 15 years. Two deaths occurred which were attributed to the treatment, and three other patients died over the follow-up period, two of which were attributed to complications of their MS. The treatment showed the most benefit in people considered to have aggressive disease. This procedure is experimental, and is the subject of ongoing clinical trials to determine its benefits and risks in people with MS. 
Bone marrow transplantation is a lifesaving treatment for certain cancers. It is variously called “hematopoietic stem cell therapy” and “autologous stem cell transplantation.” People are given infusions of their own bone marrow stem cells, which are first extracted and treated. Chemotherapy and sometimes whole-body radiation are used to wipe out the person’s immune system before the bone marrow cells are reintroduced by injection. The hope is that the new immune cells will no longer attack myelin or other brain tissue, so that the person develops a new more tolerant immune system. 
This procedure is strictly investigational. In clinical trials over the years, it has produced some good results in MS, usually for younger, less disabled people, however, others have seen their MS return, and experienced more progression. And, sadly, a few have died.
The team from Greece conducted 35 transplants from June 1995 until May 2001 in people whose MS symptoms had progressed in the year preceding treatment. Two people died from transplant-related complications at two months and 2.5 years after the procedure, and three others died over the follow-up period, two of which were attributed to complications of their MS. Sixteen people improved on the EDSS scale measuring disability, with improvements lasting for a median of 2 years. Two of the individuals stabilized and remained improved over 7 and 8 years, respectively. Seven worsened during follow-up but remained better than their disability level at baseline, while seven others worsened compared to their disability level at baseline. The results appeared to be most beneficial in those who had evidence of active areas of disease activity (“gadolinium-enhancing lesions”) on MRI scans at the time of the transplant. 
The most impressive results in this series were observed in very active “aggressive” MS cases, but whether bone marrow transplantation is superior to conventional treatments cannot be answered on the basis of this this study, note the authors, because of the methods used. This was an uncontrolled and unblinded study, meaning that no other treatment or sham procedure was used for comparison, and all participants and clinicians knew what therapy was being administered (blinding is used to control bias). Furthermore, the duration of follow-up varied widely, and many individuals who initially improved following treatment worsened to varying degrees during follow-up. The treatment-related deaths, which occurred in 6% of the study population, are of concern, and warrant caution in pursuing such experimental therapy outside of a clinical trial setting.

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Early Clinical Trial Results and Observational Study Support Further Research of “Probiotic” Parasitic Worm Treatment Approach in MS

Two recently published studies are reporting results related to parasitic worms, called helminths, and their possible implications for treating multiple sclerosis. Further study, including the second phase of the reported clinical trial supported by the National MS Society, should determine whether a “probiotic” treatment approach using relatively harmless parasitic worms to alter immune activity will benefit people with MS.
Background: Scientists have noted that autoimmune diseases and allergies are less common in underdeveloped regions. Some researchers have noted that early exposure to common infectious agents – such as that which occurs to people in regions with poor sanitation – may stimulate immune regulation in a positive way and aid healthy immune responses. Because MS is more prevalent in regions with high standards of hygiene, researchers have been testing the “hygiene hypothesis” – the idea that lack of exposure to common innocuous agents at an early age may cause the immune system to over-react and trigger MS.
Studies in MS-like disease in lab rodents and preliminary clinical trials in Crohn’s disease, an autoimmune disease of the bowel, suggest that drinking a concoction containing eggs from parasitic worms might alter immune attacks and improve these conditions.
Wisconsin Study: In the first phase of a clinical trial supported by the National MS Society, John Fleming, MD, and colleagues (University of Wisconsin, Madison) administered a drink containing harmless helminth eggs to five people with MS over three months to determine the safety and preliminary impact of the treatment in relapsing-remitting MS.
The eggs hatch and mature inside the body, reaching about the size of an eyelash. When they reach the large intestine, the larvae interact with the immune system and are then killed. MRI scans were taken by a radiologist who was blinded to the treatments taken to determine increases in MS disease activity.
The results – which compared data before and after treatment – showed that the egg solution was tolerated well. Three out of the five participants had mild gastrointestinal symptoms 30 days after the first dose. These symptoms resolved spontaneously within six days. No worsening in neurological symptoms occurred. The number of participants and study design make it difficult to draw firm conclusions about the treatment’s effectiveness, but beneficial trends were noted in relation to MRI and immune activity. Immunologic analyses indicate that a vigorous immune response was mounted in response to the treatment.

The authors note, “Only follow-up studies of longer duration and with larger numbers of subjects will adequately determine safety and efficacy…We strongly discourage administration of this or other helminth preparations outside of clinical trials.”
A second, follow-up study is underway. Dr. Fleming’s team is recruiting 20 patients at two Wisconsin sites (University of Wisconsin, Madison; Marshfield Clinic). Participants are drinking the egg solution every two weeks for 10 months, and are undergoing MRI scans to determine the effects on MS disease activity.

Argentina Study: Jorge Correale, MD, and Mauricio Farez, MD (Institute for Neurological Research, Buenos Aires) observed 12 people with MS and parasitic infections as a follow up to a study they reported in 2007. In the previous study, they reported observations of 12 people with MS and parasitic infections, and they compared clinical, MRI, and immunologic data with 12 uninfected people with MS. Over four years of observation, the infected individuals showed signs of benefit including lower number of relapses, minimal changes in disability scores, and significantly lower MRI activity compared with uninfected people.
Correale and Farez report on further observations of the 12 infected people with MS, compared with 12 uninfected individuals with MS, and 12 controls without MS. After 5.25 years, four of the infected individuals experienced a worsening of infection-related symptoms, and required anti-parasitic treatment. After treatment, MS symptoms and disease-related MRI activity increased to that which was observed in the uninfected people with MS, and blood work showed signs of increased inflammatory immune activity.
The authors note the limitations of this study, in that it included only a small number of people, and no blinding; all participants and clinicians knew who was infected and who was not. (Studies generally use blinding to avoid potential bias.)
Comment: Further research, which is now ongoing, should help shed light on the potential of this probiotic approach for treating MS.

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International Panel Revises “McDonald Criteria” for Diagnosing MS

An international panel has revised and simplified the “McDonald Criteria” commonly used to diagnose multiple sclerosis, incorporating new data that should speed the diagnosis without compromising accuracy. The International Panel on Diagnosis of MS, organized and supported by the National MS Society and the European Committee for Treatment and Research in Multiple Sclerosis, was chaired by Chris H. Polman, MD, PhD (Free University of Amsterdam).
“Treating MS early and effectively is likely our best way to prevent permanent damage to the nervous system, so speeding the diagnosis of MS without compromising accuracy is a key goal,” stated National MS Society Chief Medical Officer Aaron Miller, MD, Professor of Neurology and Medical Director of the MS Center at Mount Sinai Medical Center in New York City. “These updated diagnostic criteria appear to achieve this goal.”
The National MS Society is developing materials to help neurologists understand and apply the 2010 revised diagnostic criteria in practice. These include plans to produce pocket cards summarizing the new criteria.
Background: MS is a chronic, often disabling disease that attacks the central nervous system. Its progress, severity, and specific symptoms are unpredictable and vary from one person to another. Determining if an individual has MS can be difficult because there is no single test that can accurately determine the diagnosis. Generally the process of diagnosis involves obtaining evidence from patient history, clinical examination, a variety of laboratory tests, and magnetic resonance imaging (MRI) scans, all intended to rule out other possible causes of disease and to gather data consistent with a diagnosis of MS. The newly revised 2010 McDonald Criteria incorporate updated information on using MRI as a tool for speeding diagnosis.
The McDonald Criteria for Diagnosis of MS were originally published in 2001. They were named for the chair of the original panel, the late neurologist W. Ian McDonald, MB, ChB, PhD. Dr. Polman chaired the panels responsible for the 2005 and 2010 revisions. The previous versions have been the subject of extensive debate and testing. A significant body of new information about the utility of the Criteria has been published. The International Panel reconvened in May 2010 in Dublin to consider these new data and to develop consensus for revising and updating the McDonald Criteria, with an eye toward speeding and easing diagnosis without compromising accuracy.

Diagnosis of MS - The Basics Still Apply: The diagnosis of MS is a partly subjective process, and is best made by an expert who is familiar with the disease and who can interpret imaging and laboratory evidence that can supplement the clinical diagnostic process. The requirement remains that there must be no better explanation than MS for the clinical and laboratory findings – other possible diagnoses must be considered and excluded. The key to an MS diagnosis has been, and remains, the objective demonstration of dissemination of typical disease signs and symptoms in time and space. The 2010 revisions maintain this requirement, but offer several ways of using imaging to determine dissemination. It remains the case that while the use of paraclinical and laboratory examination can speed an MS diagnosis, a solid diagnosis can be made on clinical grounds alone.
No single test can provide adequate information to support an MS diagnosis. Therefore, supportive and confirmatory paraclinical examinations – including analysis of lesions by MRI, of cerebrospinal fluid (CSF), and sometimes of evoked potentials – are still important in helping to confirm an MS diagnosis.
What Has Changed: There is new emphasis that the McDonald Criteria should only be applied to those who present with a clinically isolated syndrome (CIS) suggestive of MS, or who have symptoms consistent with a central nervous system inflammatory demyelinating disease. The panel also considered how well the Criteria can be applied to specific populations such as childhood MS (pediatric MS) and Asian and Latin American populations. They concluded that the 2010 Revised Criteria would apply to the majority of these populations, but the paper describes specific situations in which further considerations and tests would be recommended to properly diagnose MS in these groups.

In past versions of the McDonald Criteria, guidelines were presented for using MRI to demonstrate dissemination of disease in time and space, based on earlier studies. For the 2010 Revised Criteria, published recommendations from the European MAGNIMS multicenter collaboration have been incorporated (Swanton JK, Rovira A, Tintoré M, et al. Lancet Neurol 2007;6:677-686; Swanton JK Fernando K, Dalton CM, et al. J Neurol Neurosurg Psychiatry 2006;77:830-833.) These indicate that:

• Dissemination in time can be demonstrated by a new T2 or gadolinium-enhancing lesion on a follow-up MRI, with reference to a baseline scan, regardless of when the baseline MRI was obtained. (Previous versions had specified that the reference scan be performed at least 30 days after the initial clinical event; this is no longer a requirement.)
• Dissemination in space can be demonstrated with at least one T2 lesion in at least two our of four areas of the central nervous system: periventricular, juxtacortical, infratentorial, or spinal cord. These lesions need not be gadolinium enhanced.

In the case of diagnosing primary-progressive MS, aspects of the previous criteria remain, but the MAGNIMS recommendations for demonstrating dissemination in space were incorporated to harmonize with other 2010 updates. As shown in Table 1, diagnosing primary-progressive MS requires one year of disease progression (determined retrospectively or prospectively), plus at least 2 out of these 3 criteria: dissemination in space in the brain based on at least 1 T2 lesion in periventricular, juxtacortical or infratentorial regions; dissemination in space in the spinal cord based on at least 2 T2 lesions; or positive cerebrospinal fluid (CSF) findings.

While the International Panel has provided revised and simplified criteria for MS diagnosis, recommendations for further testing of the Criteria are made as well, to bolster the scientific evidence supporting the 2010 recommendations.

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"News" articles are derived from research releases made by the National MS Society"

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February 2011

Risk of Having a First Neurologic Event is Decreased with Increased Sun Exposure and Higher Blood Levels of Vitamin D, Society-Supported Australian Study Suggests

Findings in line with others suggesting these factors may lower the risk for MS
Higher levels of sun exposure and higher blood levels of vitamin D were both associated with decreased risk of having a first demyelinating event that can be the first indicator of multiple sclerosis, in a comprehensive study undertaken in Australia, called the Ausimmune Study. (A first demyelinating event, in this study called FDE, is also known as clinically isolated syndrome (CIS), a first neurologic episode caused by inflammation/demyelination in the brain or spinal cord.) Some of these individuals developed MS during the study and others did not, however findings were similar in either case. Robyn Lucas, PhD, Anthony McMichael, PhD (The Australian National University, Canberra) and colleagues across Australia report their findings in Neurology. This study was supported by the National MS Society, the National Health and Medical Research Council of Australia, the ANZ William Buckland Foundation, and MS Research Australia.
The findings provide additional support for previous suggestions that sun exposure and vitamin D may help protect against developing MS. It remains to be seen whether safe and effective strategies can be developed that utilize this potential protection without the risks involved in overexposure to the sun or overdoses of vitamin D supplements, and whether these findings have relevance for individuals who already have MS.
Background: In all parts of the world, MS is more common at latitudes that are farther from the equator and less common in areas closer to the equator. This latitude effect has been under investigation for many years. Previous studies have found evidence suggesting that higher lifetime exposure to sunlight (through which the skin makes vitamin D) and higher blood levels of vitamin D may reduce a person’s risk of developing MS. This is an active area of continued research.
The Ausimmune study was undertaken to investigate whether increased exposure to sunlight in those living closer to the equator and the vitamin D that is produced in part by sunlight may be protective against MS. Rather than studying people who had already been diagnosed with definite MS, which could alter a person’s lifestyle and recollection of past events, the team investigated sun exposure and vitamin D levels in people who had not yet been diagnosed with MS, but who had experienced a CIS. A CIS often, but not always, leads to a diagnosis of MS.
The Study: The investigators recruited participants who were aged 18–59 years and lived in four geographic regions of Australia between November 1, 2003, and December 31, 2006. The four regions were characterized by differing distance from the equator. A total of 216 people were enrolled who had experienced a CIS. A total of 395 controls were randomly selected from the Australian Electoral Roll and matched to the CIS cases in age, gender, and study region.
Sun exposure was measured in several ways, including by participant reports on how much time they spent in the sun during different periods of life starting from age 6, and also by more objective means, such as examination of the skin for sun damage (actinic skin damage) and measurements of skin pigment (melanin). The latitude and longitude of participants’ residence were also recorded as an indicator of ambient ultraviolet (UV) light. Vitamin D levels were measured by a blood sample taken at entry into the study.
The results show that higher recent or lifetime sun exposure and higher blood levels of vitamin D at study entry were independently linked with a reduced risk of CIS. The investigators reported that people with most evidence of skin damage from sun exposure were 60% less likely to develop a CIS than those with the least damage. People with the highest levels of vitamin D at entry also were less likely to have a CIS than those with the lowest levels. As reported in other parts of the world, this study confirmed a latitude effect in Australia. Taken together, differences in sun exposure, vitamin D levels, and skin type accounted for a 32.4% increase in CIS incidence from the low to high latitude regions of Australia.
Comment: This carefully designed and executed study adds important evidence for a protective impact of sun exposure and vitamin D. The authors note that early life sun exposure alone was not associated with CIS risk in this study, and that frequency of ultraviolet light exposure may be more important. They point out that sun exposure and vitamin D levels were independently associated with the risk of developing a CIS, but caution that only a single vitamin D measurement at study entry was available, and that further study is required to determine which of these factors may be more important to this protective effect, and at what stage of a person’s life.
This study does not address the question of whether increasing sun exposure or vitamin D levels through supplements may reduce MS symptoms in people already living with the disease. Also, further research is needed to determine whether safe and effective strategies can be developed that utilize this potential protection without the risks involved in overexposure to the sun or overdoses of vitamin D supplements.
Studies are underway to address those questions. For example, the National MS Society is funding studies of vitamin D, including two clinical trials. Christopher Eckstein, MD (The Johns Hopkins Hospital, Baltimore, MD) and colleagues are testing the impact of different formulas and doses of vitamin D and how it alters the immune system in people who have MS. Ellen Mowry, MD, has just been funded to launch a multi-center, double-blind clinical trial to determine whether high-dose vitamin D added to glatiramer acetate (a standard MS therapy) reduces the frequency of relapses of MS.
“This carefully designed study involving a large collaboration of investigators is exactly the type of research we need to help determine what environmental factors contribute to MS susceptibility,” said Timothy Coetzee, PhD, Chief Research Officer of the National MS Society. “Identifying and understanding risk and triggering factors that cause MS is vital if we’re going to find a way to end MS forever,” he added.
Clinicians who treat people with MS should become familiar with current vitamin D information so that they are able to educate their patients, and, if appropriate, diagnose and treat vitamin D deficiency.

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Nerve Repair Teams Convened to Share Exciting Progress and Plan Next Steps

A cure for MS means not just stopping and ending the disease but repairing damage and restoring lost function. The Nervous System Repair and Protection Initiative, funded through the National MS Society’s Promise: 2010 Campaign, was launched in 2005 to address what was then an underexplored area. This bold initiative involved the largest grants ever offered by the Society and set the stage for translating basic lab discoveries into clinical efforts to restore nerve function in people with MS. The results have been impressive: it jump-started the field, trained scores of promising young investigators, produced over 150 research papers, and leveraged millions of dollars in new funding.

These four multinational, interdisciplinary teams met recently in New York City to discuss their accomplishments during the last five years, and to look toward the future. “It’s remarkable,” said Timothy Coetzee, PhD, Chief Research Officer of the National MS Society. “We launched this initiative to set the stage for clinical trials of neuroprotection in MS, and five years later, we are seeing these studies come to life.”
Repair and Protection: What they mean
During the course of MS, the immune system attacks the brain and spinal cord. Nerve cells have wires, or axons, that allow them to send and receive signals. The axons have a coating on them, which can be likened to insulation on a wire, which nourishes the axons and speeds nerve conduction. That coating is myelin. Myelin is a main target in MS, but axons are also damaged. Damage to axons is probably what causes progressive disability or worsening in people with MS. The focus of “protection” efforts is to stop the destruction of myelin and axons; the focus of “repair” efforts is to restore those tissues.
Drs. Peter Calabresi (Johns Hopkins University, Baltimore), Ian D. Duncan (University of Wisconsin, Madison), Charles ffrench-Constant (University of Edinburgh) and Gavin Giovannoni (Queen Mary University of London) and their team members reported on their progress in all three goals of the repair initiative with the ultimate goal of paving the way for clinical trials to protect the nervous system, repair the damage and restore function in people with MS. Read more about the four teams.
Goal 1: Develop new disease models to screen repair and protection techniques
Team members made great strides in developing new tools to investigate myelin damage and repair. It is now possible to grow nerves and myelin-making cells in lab dishes and explore molecular signals engaged in repair. New treatment strategies cannot be tested without therapeutic targets being discovered and without the development of animal models for testing safety and effectiveness before studies can begin in people. Teams reported numerous exciting developments in this goal area.

Investigators used the latest in “omics” technology – such as genomics, which screens multiple genes simultaneously – to identify new targets for MS therapies. Drs. Stephen P. J. Fancy, David Rowitch (University of California, San Francisco [UCSF]), Robin J. M. Franklin (Cambridge University, UK) and colleagues conducted high-tech screens to detect the activity of genes, called transcription factors, that control other genes. Among 1,040 transcription factor genes that were active in mice during the process of myelin repair, they pinpointed the “Wnt signaling pathway.” Further experiments showed that this pathway may play an important role in the failure of myelin to repair itself in people with MS.
Drs. Jeffrey K. Huang (Cambridge), ffrench-Constant, Franklin and colleagues created a “transcriptome” – a complete picture of RNA activity during spontaneous myelin repair. RNA, ribonucleic acid, is the chemical that delivers the instructions from a gene to a cell. The results showed high levels of activity for the gene that controls a molecule called retinoid acid receptor-gamma, and further study showed that this molecule that appears to stimulate the brain’s natural ability to repair myelin in rodents.
Investigators funded through this initiative have propelled research on cell-based therapies forward, reporting groundbreaking results. Dr. Steven A. Goldman and colleagues (University of Rochester, NY) transplanted human immature myelin-making cells into mice born without myelin, resulting in widespread myelin formation and restoration of neurological deficits. Read more here. Dr. Gianvito Martino and colleagues (San Raffaele Scientific Institute, Italy) transplanted nerve stem cells into models with MS-like disease, stimulating repair and reducing inflammation. This team is nearing a phase 1 study of this strategy in people with MS.
Drs. Siddharthan Chandran (Cambridge), David Baker (Queen Mary) and colleagues studied the “Biozzi” mouse model, and confirmed that this is the model of choice for studying secondary-progressive MS. The model replicates the chronic myelin damage and nerve fiber loss found in later phases of MS, without the inflammation of early disease. This is an invaluable tool for studying the safety and benefits of neuroprotective drugs in progressive MS.
Dr. Duncan and colleagues studied a model where a neurological disease can be induced and resolved through spontaneous repair, restoring neurological function to normal; this model will help to understand the natural mechanisms of repair and how they translate to symptoms experienced by people with MS. In a truly exciting effort, Dr. Franklin and collaborators showed that cells from young mice could enhance myelin repair in older mice, giving us new information on a possible role of aging in nervous system damage, and new possibilities for inducing repair.
Goal 2: Apply advanced MRI and other non-invasive monitoring tools to detect nervous system protection and repair
What if a new therapy was developed to protect brain cells from damage and even regenerate new cells to repair damage caused by MS, but there was no way to prove that it works? Developing ways to measure damage and repair was another goal of this initiative, with results ranging from simple tests of function to cutting edge technology. 

Laura Balcer (University of Pennsylvania), Elliott Frohman (Southwestern Medical Center, Dallas), and Calabresi, Lauren Talman, and colleagues confirmed that optical coherence tomography, or OCT, can measure the health of the nerve fibers in the back of the eye. This simple, quick method can show how much nerve fibers in the eye are damaged. Changes can be observed in people with MS, even if they don’t have eye inflammation). Drs. D.M. Harrison (Johns Hopkins), Calabresi, Daniel Reich (NIH), and colleagues showed that other novel imaging technologies – such as diffusion tensor imaging (DTI), which measures the flow of water particles in tissue, and magnetization transfer, which measures the transfer of energy particles – could specifically detect myelin and nerve fiber damage and track them over time. These methods will be useful in tracking treatment success or failure during clinical trials.
Drs. Sharmilee Gnanapavan (Queen Mary) and Giovannoni searched for biomarkers that would indicate tissue damage or repair via a blood or spinal fluid sample. This research has indicated several possibilities, including neurofilament, a threadlike molecule found in nerve cells that can be measured in spinal fluid. Neurofilament levels may be a good indication of whether nerve cells are being damaged, and whether disease is progressing. If validated in further research, measuring neurofilament may prove to be a quick measure of whether potentially neuroprotective drugs are working, enabling faster clinical trials.
Drs. Aaron Field, Andrew Alexander (University of Wisconsin-Madison) and colleagues reported on an effort to combine DTI and diffusion spectrum imaging, which enabled them to examine nerve fibers that intersect each other. The team has been able to minimize the imaging time necessary for this hybrid approach and increase its accuracy.)
Scientists also reported progress in using clinical tests that can assess symptoms simply, but may correlate with underlying disease activity. For example, Drs. Kathleen M. Zackowski, Calabresi (Johns Hopkins) and colleagues showed that “sensorimotor” dysfunction that was picked up by testing vibration sensation and ankle strength correlated with disease activity on advanced MRI technology. Also, Dr. Balcer’s research indicates that tests of visual acuity (perception of light gray letters of progressively smaller size on a white background) correlate with OCT and other imaging results. These tests may be quick, simple ways of measuring outcomes in clinical studies.

Goal 3: Design human clinical trials of repair and protection therapies.
The ultimate goal of this initiative was to lay the groundwork for clinical trials of strategies to protect and repair the nervous system: Mission accomplished. 

Here is a sampling of studies that are underway or planned in collaboration with team members of this initiative:
• Dr. Chandran has completed A Phase 1 safety study of mesenchymal cells in optic neuritis. Results are nearing publication.
• Dr. Rowitch is conducting an industry-backed Phase 1 study to study the safety of neural stem cell transplantation in children born with a lack of myelin; this small, early study would also serve as a “proof of principal” for this strategy in MS.
• Dr. Raj Kapoor (National Hospital for Neurology and. Neurosurgery, Queen Square, London) is launching a Phase 2 study of phenyltoin to determine its effects on neuroprotection in optic neuritis (funded by the National MS Society and the MS Society of Great Britain and Northern Ireland); the study design takes lessons learned from a failed study of lamotrigine in SP MS.) Both these drugs are sodium channel blockers, drugs that enable tiny pores along nerve fibers to improve nerve impulse conduction.
• Dr. John Zajicek (Peninsula Medical School, Plymouth, UK) and colleagues are expected to report results later this year from a large multicenter study exploring whether cannabis can slow disease progression in 500 people with primary-progressive and secondary-progressive MS.
• Dr. Reich and colleagues are beginning NIH-funded studies of the antioxidant idebenone for PP MS and the monoclonal antibody rituximab for SP MS; studies will collect much data on these types of MS as well.
The initiative also has spawned important progress aimed at enhancing clinical research in this area. Team members are among those involved in a new clinical trials network in the United Kingdom to speed up the translation of neuroprotective therapies for people with progressive MS. And guidelines were established for the design and conduct of clinical trials using cell therapies in MS, in collaboration with some team members and several MS Societies worldwide.
The Value of Collaboration
Team leaders unanimously agreed that this collaboration has moved the field of repair in MS forward exponentially.
“The kind of infrastructure that we’ve established is helping to move things forward more quickly,” said Dr. Calabresi of his team. “We can specialize, much in the way a factory does. No one scientist has to think about all the problems that are necessary to move a target, validate it and then get it into clinical trials.”
Dr. ffrench-Constant agreed. “Two things we've done have made a huge difference. We've used the internet extensively to keep everybody in contact. Also, we've recruited post docs and graduate students who have spent time in all of the different labs. This increases the amount of collaboration, and secondly, it trains the next generation of the scientists that we need in multiple sclerosis.”
As the research continues and proceeds towards clinical trials of new MS treatment strategies, team leaders and members were eager to see the momentum continue, and provided several suggestions for further collaborations, including:
• Hold future nerve repair conferences (investigators have been meeting every two years)
• Create a shared resource that produces stem cells for all stem cell clinical trials.
• Develop an initiative comparing the value of different types of imaging technology in monitoring repair.
• Find creative ways to continue encourage young researchers to enter this field.
Dr. Giovannoni emphasized the importance of investigator meetings in particular. “A meeting focused on repair, just by itself, is a catalyst for further innovation. A lot comes out of these meetings in terms of ideas, hypotheses, and exchanges of research.” Dr. Duncan concurred. “You hear colleagues present interesting information and you realize that you’re quite close; it would just take some kind of joint experiment between the two of you sharing the expertise.”
Dr. Coetzee noted that the Society is evaluating program outcomes to determine how to sustain the momentum created by these teams. “We are going to continue to move our work forward and share it worldwide in order to continue to speed research to repair the nervous system in MS. The dream is stopping MS in its tracks and of restoring function that has been lost. This is topmost in the hearts and minds of people who have MS, as well as their loved ones.”

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"News" articles are derived from research releases made by the National MS Society"

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January 2011

Researchers Report MS-Related Gene in More Women than Men

Reporting on a study tracing MS in 1,055 families, investigators suggest that a gene long known to have association to MS susceptibility (HLA-DRB1*15) may be more likely to be found in women with the disease than men, and that women with this gene variation may be more likely to transmit it to other women in their families than to men. If confirmed by other investigators, the findings might help explain why women are more likely than men to develop MS, and reinforce the idea that factors other than genes, such as the environment, influence whether a person develops MS. Drs. Michael Chao, George Ebers and colleagues (University of Oxford, U.K.) report their findings in the January 5, 2011, online issue of (Neurology). The study was supported by the MS Society of Canada and the MS Society of Great Britain and Northern Ireland.
Background: While the cause of MS is still not known, scientists believe that a combination of several factors may be involved. While MS is not directly inherited, genes are known to make people susceptible to developing the disease. Studies are ongoing in the areas of genetics, immunology (the science of the body’s immune system) and epidemiology (who gets MS) in an effort to answer this important question.
Understanding the genetics of MS involves a multifaceted approach. One part of the effort to understand the genetic underpinnings of MS is genome analysis, involving the scanning of all genes in the body to find “hot spots” of gene activity relevant to MS. A dozen or so gene variations have been confirmed as being linked to MS susceptibility. Currently the International MS Genetics Consortium is completing the largest scan ever – with funding from the Wellcome Trust, the National MS Society and other agencies – which should identify all common genetic variations that play roles in MS susceptibility.
As MS susceptibility genes are identified, they provide possible clues to how MS is triggered, and possible ways to block those pathways to prevent the disease.
Another approach to studying MS genes involves focusing on the activity of these specific genes in groups of people with MS. In the current study, the genes under study are part of the MHC or “major histocompatibility complex,” which helps determine immune responses. MHC genes – particularly the gene HLA-DRB1*15 – have been linked to MS susceptibility.
Epidemiologic studies have revealed that MS affects women two to three times more often than men. Some research also suggests that this preponderance of women with MS may be growing, at least in some regions. Exploring gender differences is yielding new insight into the course of MS and possible therapeutic strategies involving sex hormones. In the current study, the authors were seeking to determine if the gender bias in MS is influenced by MHC genes.
The Study: The team examined the MHC genes of 1,055 families with more than one person with MS. In all, they tested the genes of 7,093 people, including 2,127 people with MS. The researchers looked at what MHC genes were active in people with and without MS, whether people with MS inherited the genes from their mother or their father, and what the relationship was between people in the same family with MS.
In this analysis, the authors found that women with MS might be more likely to have the HLA-DRB1*15 gene than men with MS. They also reported that women with this genetic variation were more likely to transmit it to other women in their families than to men. The authors suggest that their findings may help account for why women are more likely to develop MS than men.
Comment: If these results are confirmed by other investigators, they indicate an association between the gender bias in MS and genes, writes Orhun H. Kantarci, MD (Mayo Clinic, Rochester, MN) in an accompanying editorial. He notes that the findings lend evidence to the existence of “epigenetic” factors in the development of MS. Epigenetic factors are changes in how a gene functions that can be inherited, but are separate from the DNA itself, and can be influenced by environmental factors. This is a growing area of interest in MS genetics.

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Risk of Having a First Neurologic Event is Decreased with Increased Sun Exposure and Higher Blood Levels of Vitamin D

Findings in line with others suggesting these factors may lower the risk for MS
Higher levels of sun exposure and higher blood levels of vitamin D were both associated with decreased risk of having a first demyelinating event that can be the first indicator of multiple sclerosis, in a comprehensive study undertaken in Australia, called the Ausimmune Study. (A first demyelinating event, in this study called FDE, is also known as clinically isolated syndrome (CIS), a first neurologic episode caused by inflammation/demyelination in the brain or spinal cord.) Some of these individuals developed MS during the study and others did not, however findings were similar in either case.
The findings provide additional support for previous suggestions that sun exposure and vitamin D may help protect against developing MS. It remains to be seen whether safe and effective strategies can be developed that utilize this potential protection without the risks involved in overexposure to the sun or overdoses of vitamin D supplements, and whether these findings have relevance for individuals who already have MS.

Background: In all parts of the world, MS is more common at latitudes that are farther from the equator and less common in areas closer to the equator. This latitude effect has been under investigation for many years. Previous studies have found evidence suggesting that higher lifetime exposure to sunlight (through which the skin makes vitamin D) and higher blood levels of vitamin D may reduce a person’s risk of developing MS. This is an active area of continued research.
The Ausimmune study was undertaken to investigate whether increased exposure to sunlight in those living closer to the equator and the vitamin D that is produced in part by sunlight may be protective against MS. Rather than studying people who had already been diagnosed with definite MS, which could alter a person’s lifestyle and recollection of past events, the team investigated sun exposure and vitamin D levels in people who had not yet been diagnosed with MS, but who had experienced a CIS. A CIS often, but not always, leads to a diagnosis of MS.

The Study: The investigators recruited participants who were aged 18–59 years and lived in four geographic regions of Australia between November 1, 2003, and December 31, 2006. The four regions were characterized by differing distance from the equator. A total of 216 people were enrolled who had experienced a CIS. A total of 395 controls were randomly selected from the Australian Electoral Roll and matched to the CIS cases in age, gender, and study region.
Sun exposure was measured in several ways, including by participant reports on how much time they spent in the sun during different periods of life starting from age 6, and also by more objective means, such as examination of the skin for sun damage (actinic skin damage) and measurements of skin pigment (melanin). The latitude and longitude of participants’ residence were also recorded as an indicator of ambient ultraviolet (UV) light. Vitamin D levels were measured by a blood sample taken at entry into the study.
The results show that higher recent or lifetime sun exposure and higher blood levels of vitamin D at study entry were independently linked with a reduced risk of CIS. The investigators reported that people with most evidence of skin damage from sun exposure were 60% less likely to develop a CIS than those with the least damage. People with the highest levels of vitamin D at entry also were less likely to have a CIS than those with the lowest levels. As reported in other parts of the world, this study confirmed a latitude effect in Australia. Taken together, differences in sun exposure, vitamin D levels, and skin type accounted for a 32.4% increase in CIS incidence from the low to high latitude regions of Australia.

Comment: This carefully designed and executed study adds important evidence for a protective impact of sun exposure and vitamin D. The authors’ note that early life sun exposure alone was not associated with CIS risk in this study, and that frequency of ultraviolet light exposure may be more important. They point out that sun exposure and vitamin D levels were independently associated with the risk of developing a CIS, but caution that only a single vitamin D measurement at study entry was available, and that further study is required to determine which of these factors may be more important to this protective effect, and at what stage of a person’s life.
This study does not address the question of whether increasing sun exposure or vitamin D levels through supplements may reduce MS symptoms in people already living with the disease. Also, further research is needed to determine whether safe and effective strategies can be developed that utilize this potential protection without the risks involved in overexposure to the sun or overdoses of vitamin D supplements.
Studies are underway to address those questions. For example, the National MS Society is funding studies of vitamin D, including two clinical trials. Christopher Eckstein, MD (The Johns Hopkins Hospital, Baltimore, MD) and colleagues are testing the impact of different formulas and doses of vitamin D and how it alters the immune system in people who have MS. Ellen Mowry, MD, has just been funded to launch a multi-center, double-blind clinical trial to determine whether high-dose vitamin D added to glatiramer acetate (a standard MS therapy) reduces the frequency of relapses of MS.
“This carefully designed study involving a large collaboration of investigators is exactly the type of research we need to help determine what environmental factors contribute to MS susceptibility,” said Timothy Coetzee, PhD, Chief Research Officer of the National MS Society. “Identifying and understanding risk and triggering factors that cause MS are vital if we’re going to find a way to end MS forever,” he added.

Clinicians who treat people with MS should become familiar with current vitamin D information so that they are able to educate their patients, and, if appropriate, diagnose and treat vitamin D deficiency.

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"News" articles are derived from research releases made by the National MS Society"

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2010: A Year of Significant Progress in MS Research

Exciting progress was made in 2010 in virtually every field of MS research. Progress toward finding new therapies for MS is highlighted by the availability of the first disease-modifying therapy for MS taken orally. Progress was also made toward finding ways to restore function and improving quality of life and specific MS symptoms through exercise, meditation, rehabilitation and medications, including the first therapy specifically approved to treat a symptom of MS (Ampyra). And our understanding of factors that influence whether a person develops MS deepened this year, bringing us closer to finding ways to prevent the disease.
The National MS Society continues to propel research forward with a comprehensive research strategy and program. This year we provided $36 million to support some 325 new and ongoing projects, including everything from discovery research to the Society’s commercial drug development efforts through Fast Forward. In addition, thanks to the efforts of our MS activists, $4.5 million was specifically set aside for funding MS research out of the 2010 Department of Defense budget.
This year the Society launched new projects focusing on discovering risk factors that lead to progressive disability, projects aimed at speeding diagnosis, research on protective mechanisms of vitamin D and estrogen, tests determining whether a new device can improve walking ability, and many more.
To develop our Strategic Response for the next five years, the National MS Society reached out and heard the hopes and expectations of more than 10,000 people affected by MS. The Society remains committed to being a driving force in MS research, and aims to understand mechanisms that drive MS progression and find new therapies to treat it; discover how nerve cells are damaged and how to repair them to restore function; find better rehabilitation and treatment for symptoms to improve quality of life; identify the cause of MS to find a way to prevent it; and expand the quantity and quality of research worldwide to drive discovery and treatments.
Here is just a small sample of many important, potentially high-impact research results that occurred this year, presented according to three research approaches: stopping MS, restoring function, and ending MS forever.
Toward Stopping MS
Exciting progress was made toward finding better therapies for MS, including the availability of the first disease-modifying therapy for MS taken by mouth.
• Gilenya™ (Novartis International AG) capsules were approved by the FDA for reducing the frequency of clinical relapses and delaying the accumulation of physical disability in relapsing forms of MS, making it the first oral disease-modifying therapy for the treatment of multiple sclerosis. Cleveland Clinic doctors voted this among the top 10 medical breakthroughs of the year. 
• Researchers at the University of Bristol, UK, reported results of a Phase I safety/feasibility clinical trial involving six people with long-standing MS, testing intravenous injections of the patients’ own adult bone marrow cells containing a mix of stem cells. After one year, the investigators found the treatment safe, but because it was a small, open-label trial with no controls, they report that firm conclusions cannot be drawn about its effectiveness. 
• Positive results from the phase III trial of oral Cladribine (EMD Serono), known as the CLARITY study, were published showing that it reduced relapse rates compared to placebo by up to 57.6% in a study involving 1,326 people with relapsing-remitting MS, and also showed other benefits. Cladribine can interfere with the activity of lymphocytes, a subset of white blood cells. Additional studies are underway, and the company has applied to the FDA for marketing approval.
• Teriflunomide (sanofi-aventis) is a novel oral compound that inhibits the function of specific immune cells. Results from a two-year, phase III trial in 1,088 people with relapsing MS (the TEMSO trial), comparing two doses against placebo, showed that both doses significantly reduced the rate of MS relapses by up to 31.5% relative to placebo, and the higher dose was found to reduce the risk of disability progression by 29.8% compared to placebo. MRI scanning showed reduced risk of new MS lesions and reduced disease activity. The most common side effects were nausea, diarrhea, mildly elevated liver enzymes and thinning of the hair. Additional trials of teriflunomide are underway.
• In a study supported by the National MS Society, the Department of Veterans Affairs and others, researchers at the Oregon Health & Science University in Portland investigated lipoic acid, an antioxidant that previous studies suggest can benefit mice with MS-like disease in part by inhibiting immune cells from entering the brain. In a lab model of acute optic neuritis, they found that lipoic acid could reduce damage to myelin and to nerve fibers, and also reduced inflammation. This group is planning more research to determine whether lipoic acid may provide benefits for people with MS.
• Over $2.4 million was committed by the National MS Society (USA) and the MS Society of Canada to support 7 grants on CCSVI (chronic cerebrospinal venous insufficiency) to determine its role in the MS disease process. The applications underwent a rigorous expedited review process by an international review panel that included experts drawn from all key relevant disciplines including radiology, vascular surgery and neurology. The studies, launched July 1, were deemed necessary because it is not known yet whether, or if so how, CCSVI contributes to MS disease activity.
• Results of the phase II CHOICE study – in which 230 people with relapsing MS taking interferon beta and having disease activity were administered one of two doses of daclizumab (Biogen Idec and Abbott) or placebo – were published, showing that the higher dose reduced disease activity on MRI scans by 72% and the lower dose by 25%. Phase 3 studies of this immune modulator are underway.
• At least two small clinical trials are currently underway – one at the University of Wisconsin supported with funding from the National MS Society – testing the idea that infection with intestinal parasites may reduce immune attacks in MS. This relates to the “hygiene hypothesis,” the idea that MS may be less common in underdeveloped regions because early exposure to common infections stimulates immune responses that help offset the attack on the brain and spinal cord in MS.
• The Society invited investigators to submit proposals for designing studies to identify risk factors that influence MS progression in large groups of people with MS. This initiative is supported by special funds provided by the Society’s Greater Delaware Valley Chapter. Two teams were recommended for funding; one team comprises MS centers around the globe, and the other is taking advantage of a longstanding consortium of MS centers in one state.
• In a study of over 5,000 people with MS, researchers identified characteristics that may help predict the rate of disease progression, or worsening. Motor symptoms at onset (such as muscle stiffness known as spasticity) and male gender were associated with a faster progression from relapsing-remitting MS to secondary-progressive MS. The investigators, at the University Medical Centre Groningen, The Netherlands, the University of British Columbia and elsewhere, were funded by the National MS Society, the MS Society of Canada and others.
• Two published studies strengthened the idea that neuromyelitis optica (NMO), a disease closely related to MS, is an autoimmune disease that targets one or more specific proteins in the brain, and provided a rationale for new treatment approaches that could also have implications for treating MS. The separate studies were done by researchers at the University of Colorado Denver School of Medicine and the Medical University Vienna, Center for Brain Research.
• A provocative study by investigators at the University of Sydney suggested that the earliest activity seen in the brain in MS is the destruction of cells that make myelin (oligodendrocytes), occurring before the onset of immune activity usually blamed for triggering the disease. This study, co-funded by many sources including the National MS Society, opens up new possibilities for finding the cause of the disease and developing new treatments. 
• Another new clue to the nerve tissue damage that occurs in MS came from an ongoing international collaboration studying brain tissue from people who had MS in their lifetimes. A detailed analysis of MS lesions from people with different forms of MS suggested a surprising amount of inflammation associated with the pathology of progressive stages of MS. They also found signs that nerve fiber damage occurred at the same time as inflammation. While additional studies are needed, these and other new findings may have important implications for developing new therapies that address the needs of people with progressive forms of MS.
• The Society convened a think tank in Boston, bringing together MS investigators, research funding agencies and industry representatives to map out next steps to move the field toward better understanding of factors underlying MS progression and to increase the number and quality of clinical trials in progressive MS.
• The Society’s annual listing of Clinical Trials in MS 2010, featuring ongoing MS trials, as well as those that are being planned or that have been recently completed, lists 129 studies including studies of oral therapies for treating MS or its symptoms, novel agents such as green tea extracts, and a study of the antioxidant idebenone in people with primary-progressive MS.
Toward Restoring Function
Progress was made toward finding ways to repair nervous system damage and toward improving quality of life and specific MS symptoms through exercise, meditation, rehabilitation and medications, including the first therapy specifically approved to treat a symptom of MS (Ampyra).
• International consensus on the future of stem cell transplantation research for people with MS were published, paving the way for coordinated global research efforts and potentially better, and quicker, patient access to stem cell clinical trials. The guidelines, developed by an international panel of MS experts with input from MS Societies around the world, spell out hope for the future of MS stem cell research and debunk myths about overseas stem cell clinics claiming to cure the condition.
• Researchers co-funded by the National MS Society have identified a molecule that appears to stimulate the brain’s natural ability to repair myelin in rodents. Myelin is the insulating coating on nerve fibers that is damaged in MS. The finding, which needs further research to translate to human disease, resulted from a massive hi-tech screening system to identify new strategies to repair nervous system damage in MS. Collaborators at the University of Cambridge, University of Edinburgh, and others were funded by the National MS Society.
• The FDA cleared the way for the first human clinical trials of experimental stem cell-based therapy aimed at healing spinal cord injury, to be conducted by Geron Corporation. This may have future implications for MS because the cells to be tested in this small safety trial are progenitor cells from which oligodendrocytes arise. Oligodendrocytes make the insulating and nourishing myelin that wraps around nerve fibers, and these are among the cells that are damaged during the course of MS.
• The FDA approved the marketing of Ampyra™ (dalfampridine, formerly known as fampridine SR, from Acorda Therapeutics) for its ability to improve walking in people with any type of multiple sclerosis. This is the first therapy specifically approved to treat a symptom of MS, and it represents a big step forward for the many people who may benefit.
• The first drug specifically developed to treat uncontrollable laughing or crying, also called pseudobulbar affect, or PBA, was approved by the FDA. Nuedexta™ (dextromethorphan hydrobromide and quinidine sulfate, formerly called AVP-923, Avanir Pharmaceuticals) is an oral therapy shown to significantly reduce episodes in people with MS, ALS and other disorders.

• A pilot clinical trial conducted by University of California at San Francisco researchers, involving 60 people with all types of MS, tested low-dose Naltrexone, a drug approved for treating addiction. Results suggested that it may improve several measures of mental health quality of life and pain, and that further testing in larger numbers of individuals may be warranted.
• A University of California at Los Angeles team funded by the National MS Society found that depression is linked to brain volume loss in specific subregions of the “hippocampus,” an area of the brain known to be important in memory. Tissue loss in this area was linked as well with abnormal secretion patterns of the stress-related hormone cortisol. The results warrant further study, but are an important clue to a symptom that can interfere greatly with the quality of life of people with MS.

• The largest study of its kind showed that mindfulness-based meditation significantly improved health-related quality of life, depression, and fatigue in a study involving 150 people with relapsing-remitting and secondary-progressive MS. This controlled study by University Hospital (Basel, Switzerland) researchers shows the value of an alternative treatment and highlights the importance of focusing on quality of life issues to improve well being.
• Investigators at the University of California at Los Angeles, with a Health Care Delivery & Policy contract from the National MS Society, explored how to measure quality MS health care to establish better standards of care for people with MS. The most highly rated indicators were appropriateness and timeliness of the diagnostic work-up, bladder dysfunction, cognition dysfunction, depression, disease-modifying agent use, fatigue, and spasticity. These will be further explored to help clinicians and healthcare systems in evaluating the quality of the MS care they are providing.
• To evaluate sleep disorders and fatigue in people with MS, investigators at the Klinikum Stralsund used polysomnography – a diagnostic tool used in sleep medicine. They found that 25 of 26 people reporting higher levels of fatigue actually had sleep disorders, such as insomnia, restless legs syndrome or sleep apnea. Twelve had two different sleep disorders. The investigators urged health care professionals treating people with MS to evaluate fatigued patients for the presence of sleep disorders, which are likely to improve with the appropriate treatments.
• A unique study suggested that memory training can enhance signs of brain function. A National MS Society-supported postdoctoral researcher training at the Kessler Medical Rehabilitation Research & Education Corporation in West Orange, New Jersey, found that in people with MS who had learning impairment, those who underwent learning using imagery and contextual strategies to code story material had signs on brain imaging scans (DTI) suggesting significantly enhanced tissue integrity in specific brain areas over those in a control group.
• Clues from a series of basic experiments have propelled a leap forward that has implications for new strategies to treat MS and other conditions. An international team from Mount Sinai School of Medicine (New York), Singapore Immunology Network and others traced the developmental origins of microglia, which are the only immune/inflammatory cells resident in the brain. Microglia are suspected to play a role in either causing or even repairing lesions (damaged areas) in MS. They were found to develop completely apart from all other immune cells in the mouse embryo and remain a separate population throughout life. This finding will focus attention on microglia and lead toward new treatment strategies to inhibit injury and promote repair in the central nervous system.
Toward Ending MS Forever
Understanding of factors that influence whether a person develops MS deepened this year, bringing us closer to finding ways to prevent the disease.
• Two new studies added to evidence for a possible role for Epstein-Barr virus (EBV) in the development of MS. In one, Harvard School of Public Health investigators showed that an EBV-positive blood test preceded MS diagnosis in a large sample of MS cases identified through U.S. military databases. In another, an international team reported that reactions to a specific protein associated with EBV were increased in people with MS compared with siblings who did not have MS.
• Harvard School of Public Health researchers showed that two individual factors that were previously identified as increasing the likelihood of developing MS – exposure to Epstein-Barr virus and tobacco smoking – may interact and multiply to substantially increase the risk of developing MS in those with both risk factors. The results warrant confirmation in further studies.
• MRI-detected MS disease activity was increased 2 to 3 times during the months of March to August compared with other times of the year, reported researchers at Harvard’s Brigham and Women’s Hospital, Boston. These increases correlated with warmer temperature and increased solar radiation levels. The study highlights the influence of environmental factors on MS and also suggests that seasonal variations should be accounted for in future clinical trials.
• Understanding how a person’s genes make them susceptible to developing MS will go a long way toward finding ways to prevent it. Reporting at the AAN meeting, investigators at the University of Boulder described a new Web site www.msgene.org launched by the International MS Genetics Consortium that summarizes over 800 MS gene association studies. The strongest associations appear to be exerted by immune system genes. This collection can help to prioritize future genetic studies.
• A preliminary list of some 50 common gene variations, most immune in nature, was presented by members of the International MS Genetics Consortium, funded in part by the National MS Society, and being done in collaboration with other consortia. The 50 still need to be validated with an additional genome-wide association screen now being done, and although these genes will not necessarily determine any person’s risk for inheriting MS, they will deepen our understanding of what goes wrong in MS and new pathways for fixing it.

                   These and many other efforts by researchers around the world reflect the rapid pace of MS research today.

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"News" articles are derived from research releases made by the National MS Society"