Multiple Sclerosis Newsletter

Multiple Sclerosis Newsletter
Northern Colorado Edition

October - November 2003

Research Updates

RESEARCHERS TACKLE MS PROGRESSION:WHAT CAN WE DO TO STOP IT?
NMSS Progress in Research (Fall 2003) By Sara N. Bernstein

Why do the symptoms of MS sometimes get worse, or progress, over time? Although we still don't have an answer to this important and long-standing question, investigators are beginning to make headway in terms of why it occurs, and clinicians now have better tools than ever to fight progressive disability. Here is an overview of this existing work, focusing on the pathology underlying progressive MS, efforts to measure MS progression, and work to develop treatments.

Why Does MS Progress?
MS is a highly unpredictable disease. Not only are the symptoms or even timing of attacks unpredictable, there are no laboratory or clinical tests that can predict the future course of this life-long disease. People newly diagnosed with MS most often have a relapsing-remitting (RR) form of the disease, in which attacks alternate with complete or partial remission. Many will eventually develop secondary-progressive (SP) MS, characterized by a steady declined in neurological function with or without acute attacks. Other courses - primary-progressive (PP) and progressive-relapsing (PR) MS - show progression of disability from onset.

MS involves an immune-system attack against nerve tissues, primarily the myelin that coats and insulates nerve fibers. Evidence is mounting, however, of the crucial role that damage to nerve fibers, or axons, plays in the progression of MS. In January 1998, Bruce Trapp, PhD (Cleveland Clinic) reported in The New England Journal of Medicine that the loss of nerve fibers was common in MS lesions, or areas of myelin damage.

This publication reminded the MS community that (as suggested by Professor Jean-Martin Charcot in the mid-1800s) nerve fiber destruction is a key, and early, part of the disease pathology in MS. This and other evidence forced a re-thinking about treatment strategies, with a focus on the earliest possible treatment to help forestall permanent damage. Trapp received the National MS Society/American Academy of Neurology's 2003 John Dystel Prize for MS Research or his major contributions in this area.

Trapp's team recently reported that in a mouse model with chronic EAE (an MS-like disease), the first attack of neurologic disability was associated with immune system activity. However. long-standing neurological impairment in this model, such as occurs during progressive MS, correlated with a loss of axons (Journal of Neuropathology and Experimental Neurology, January 2002). Trapp was assisted in these efforts by Carl Bjartmar, MD, PhD, a postdoctoral fellow funded by the National MS Society.

Trapp and colleagues believe that axonal loss begins early in MS as a result of the inflammation, but that repair mechanisms can compensate for this damage early in the disease. Eventually, however, these repair capabilities are exhausted, and cumulative loss of axons becomes the "major determinant" of the neurologic disability that occurs in people with progressive forms of Multiple Sclerosis, says Trapp in the February 15, 2003 issue of the Journal of the Neurological Sciences, February 15, 2003.

"Picturing" MS Progression.
A serious dilemma in MS diagnosis and treatment is the inability to predict the future course and progression of the disease. Current imaging techniques cannot reliably distinguish between injury to myelin and to the underlying nerve fibers. If disease progression is more closely tied to nerve fiber damage, a non-invasive method of measuring this damage is essential to understanding more about MS progression. Researchers are using novel technologies to resolve this dilemma.

Diffusion tensor imaging (DTI) reveals how many protons in water molecules are moving in tissue, and in what direction. If fatty myelin is intact, then water should be repelled, but if it is damaged, water will infiltrate the tissue. In a Society-funded pilot research project, Sheng-Kwei Song, PhD (Washington University in St. Louis) studied DTI in a rodent model similar to MS. Song's team found that the rate of water movement is modulated differently in different directions, depending on whether just myelin was damaged, or both myelin and nerve fibers were damaged.

Song's findings are the basis for a new Collaborative MS Research Center Award funded by the Society. A team of neurologists, radiologists, biophysicists, biomedical engineers and pharmacologists at Washington University are using DTI to differentiate types of tissue damage and repair in lesions--first in mice and eventually in people with MS. A better understanding of how DTI pictures correlate to tissue destruction in experimental models may help to obtain a more accurate picture of tissue damage in people with MS as the disease progresses.

An advanced technology called magnetic resonance spectroscopy (MRS) identifies damage to axons in people with MS by detecting a drop in levels of N-acetyl aspartate (NAA), a chemical that indicates when nerve fibers are not functioning properly. This may be an additional way to measure progression at the tissue level in a non-invasive function.

James Garbern, MD, PhD (Wayne State University, Detroit) is utilizing MRS to study axonal damage in genetically altered mice born without a specific protein in myelin known as "PLP." His team has shown that humans and mice lacking PLP develop progressive axonal loss, without myelin damage (Brain, March 2002). They propose that disruption in the interaction between myelin-making and nerve cells could be responsible for the axonal loss in progressive MS, even in the absence of the immune attack on myelin. Garbern further reports that NAA itself, although produced by nerve cells, is involved in myelin formation. His team presented these findings at the American Academy of Neurology Annual Meeting (AAN), 2003. This new understanding of how myelin and nerve fibers interact might lead to new treatment avenues for progressive multiple sclerosis.

Richard Rudick, MD (Mellen Center, Cleveland Clinic Foundation) and colleagues had previously confirmed that, in the course of MS, even early in the disease, there is progressive loss of brain volume. Understanding what underlies this loss, how it correlates with clinical disability, and how to prevent it are key issues. With a Society-funded research grant, Rudick is continuing his use of a new method of analyzing MRI scans called "brain parenchymal fraction" (BPF) to track brain tissue loss in a large group of people with MS. He is also determining whether early tissue loss predicts disease progression.

Rudick and colleagues recently reported that, as measured by BPF, tissue loss increased 1.4-fold in people with a single episode of "demyelinating disease" who are at high risk to develop clinical MS compared with healthy controls; 5.2-fold in people with RR MS; and 6.3-fold in people with SP MS (Reported in AAN 2003). This finding indicates reduced brain volume measured by BPF is associated with MS, in all of its forms, and that it may be more severe in more progressive forms of disease.

Clinical Studies in Progressive MS
As research reveals more about why and how MS progresses, it forms the groundwork for applying approved treatments to progressive MS and for developing new ones. In October, 2000, Novantrone® (mitoxantrone) became the first therapy approved by the U.S. FDA for SP MS, specifically for "worsening" forms of MS, including SP MS. And, in March 2003, the FDA approved revised labeling of Betaseron® (interferon beta-1b approved to treat RR MS) to extend its use to treat "relapsing forms of MS,": including individuals with SP MS who experience relapses.

Here are several studies that recently yielded results in people with progressive forms of MS (for more information on recently completed, ongoing, and planned studies, see our section on Clinical Trials):

Hemopoietic stem cell (bone marrow) transplantation: people get transplants of their own (autologous) blood stem cells after immune cells are destroyed, to reconstitute the immune system. There is a high risk of infections, and the mortality rate has been higher than expected in MS. Richard Burt, MD (Northwestern University, Chicago, IL) and colleagues presented findings at AAN 2003 from a study of 28 people, most with worsening SP MS. Those with mild to moderate disability scores tended to stabilize, at least temporarily; those with higher scores tended to progress. Long-term effects are not known. If radiation is used to kill immune cells, this may harm brain tissue in the long term.

Cytoxan ® (Cyclophosphamide): a chemotherapeutic agent that suppresses the immune system. This agent has been used for years by some physicians, especially for patients who did not respond to other treatments, but it haze potential risks and no widely agreed-upon benefit. In a review of 490 cases, monthly treatment for at least one year stabilized or improved the course of disease in 80% (SP MS) and 74% (PP MS). Those who did not respond well after six months were unlikely to respond after one year. Helene Zephir, MD (INSERM, Lille, France) and colleagues reported these findings at AAN 2003.

Rilutek ® (riluzole): an agent that protects nerve cells. A pilot study of 16 people with PP MS reported by Nynke Kalkers, MD, PhD (VU Medical Center, Amsterdam) and colleagues suggested a favorable effect on MRI indications of axonal loss after 12 months (Multiple Sclerosis, December 2002). Further trials are needed to determine clinical benefit.

Zenapax ® (daclizumab): a laboratory-created monoclonal antibody that blocks the activity of a key immune activator in MS. Two studies were presented at AAN 2003. In 11 people with RR and SP MS, John Rose, MD (University of Utah, Salt Lake City) found that Zenapax, alone or along with interferon beta, resulted in stability or improvement of disability and no new brain lesions. Bibiana Bielekova, MD (National Institutes of Health, Bethesda, MD) reported that Zenapax and interferon beta reduced disease activity in 10 people (RR and SP MS) by over 70%. Larger, more definitive trials are planned to determine clinical benefit.

Researchers are making strides toward understanding the unpredictable progression of MS. Although much work remains, these strides give hope for finding new ways to diagnose and treat people with progressive MS.

NEW STUDY SUGGESTS LINK BETWEEN INCREASED SUN EXPOSURE AND DECREASED RISK OF MS
NMSS (Aug. 8, 2003)

Australian researchers report new evidence that increased sun exposure during ages 6 to 15 is associated with a decreased risk of multiple sclerosis, an autoimmune disease of unknown cause. Dr. I.A.F. van der Mei and colleagues (University of Tasmania, Hobart, Australia) report their efforts in the August 9 issue of the British Medical Journal (2003;327:316).

MS occurs with much greater frequency in temperate zones farther from the equator than in tropical zones closer to the equator. One possible explanation for this is that an environmental factor associated with latitude (distance from the equator) may contribute to the development of MS, or protect against it. MS is less common in tropical areas, which are exposed to greater ultraviolet radiation (UVR, a form of radiation that has shorter wavelengths than visible light and therefore carries more energy) than temperate zones. Recent research indicates that UVR (or vitamin D which is synthesized in the body as a result of UVR exposure) can dampen the immune attack. This might provide a biological explanation for reduced frequency of MS where UVR exposure is higher.

Dr. van der Mei's team examined 136 people with MS and 272 controls without MS who were residents of the island of Tasmania, the part of Australia most distant from the equator. Participants were asked about the amount of time they spent in the sun in the winter and summer, as well as measures used to protect against the sun and use of vitamin D supplements at ages 10 to 15 years. The approximate age of sun exposure also was determined. The investigators obtained silicone casts of the hand, which measure "actinic damage" - damage from chemically active sun rays. The results show that higher sun exposure during ages 6 to 15 was associated with a lower risk of MS. Greater actinic damage was also associated with a decreased risk of MS.

Although this was a relatively small study in a limited geographic area, it formed the basis for a new research grant awarded by the National MS Society to Anthony J. McMichael, MBBS, PhD (The Australian National University, Canberra). Dr. McMichael's study will examine the association between UVR exposure and both MS and "first demyelinating event" (a single, isolated neurologic event suggesting demyelination, loss of nerve-fiber insulation). In addition, his study will not be confined to Tasmania, a temperate zone, but will extend throughout the tropical areas of Australia where UVR exposure is likely to be higher.

Colleen Hayes, PhD (University of Wisconsin-Madison) is investigating possible mechanisms for a link between sun exposure and MS. She has evidence that Vitamin D can lead to the production of beneficial immune chemicals, or cytokines, in mice with an MS-like disease, and reverse or prevent its occurrence. With funding from a Society research grant, she is examining how vitamin D thus may stop the immune attack in MS.

These studies may provide new insights into factors that make people susceptible to the development of MS and may suggest new avenues for treatment or prevention.

CAN A BLOOD TEST PREDICT MS?
NMSS Bulletins (July 9, 2003)

A new study by Austrian scientists, if confirmed, may help doctors predict whether a person experiencing a single episode of specific neurological symptoms will ultimately develop clinically defined multiple sclerosis (MS), an unpredictable disease of the central nervous system that can be difficult to diagnose. The group analyzed the blood for antibodies (immune system proteins) that attach to two proteins in myelin, the nerve insulating material which is damaged by an immune attack in MS. Thomas Berger, MD, and colleagues (University of Innsbruck, Austria) report their results in the July 10, 2003 issue of The New England Journal of Medicine (2003;349:139-45).

Speeding the diagnosis of MS is an important and necessary goal. The diagnosis of clinically definite MS requires evidence of two neurological events suggesting inflammation and loss of myelin in the brain and/or spinal cord separated in time and in location. Studies have shown that individuals who experience "clinically isolated syndrome" - CIS, a single occurrence of a sign or symptom of myelin loss and multiple clinically ""silent" MRI-detected brain lesions - are at high risk for developing clinically definite MS within several years.

Dr. Berger's team took blood samples from 103 people with CIS, MRI lesions suggestive of MS, and positive findings on cerebrospinal fluid analysis - all highly predictive of MS - to determine the presence of antibodies to two major proteins in myelin. Individuals who had antibodies against these proteins tended to experience a second clinical event significantly earlier than people without these antibodies.

Individuals in this study were selected because they had a high risk of eventually developing clinically definite MS. In fact, the U.S. FDA recently extended the labeling of Avonex (interferon beta-1a), one of several therapies available for treating MS, to include those who experience their first clinical episode and have MRI-detected brain lesions consistent with MS. While the presence of antibodies may help predict how soon the conversion to clinically definite MS may occur, an earlier diagnosis of MS may ultimately be made in the absence of antibodies, using specific MRI parameters, and such have recently been incorporated into formal revised diagnostic criteria.

In an accompanying editorial, Jack P. Antel, MD, and Amit Bar-Or, MD (McGill University, Montreal) note that - if confirmed - these findings could improve the quality of diagnostic information that can be used to guide treatment in MS, and enhance insight into the development of disease. At present, the practical implications of this study and the potential for influencing early diagnosis or treatment remains to be determined. The laboratory test to detect the antibodies is not commercially available.

COPING SKILLS
Mayo Clinic Staff (January 7, 2003)

As is true with other chronic diseases, living with multiple sclerosis can place you on a roller coaster of emotions. Here are some suggestions to help you even out the ups and downs:

If MS impairs your ability to do things you enjoy, talk with your doctor about possible ways to get around the obstacles.

Remember that your physical health can directly impact your mental health. Denial, anger and frustration are not uncommon when you learn life has dealt you something painful and unexpected. Professionals such as therapists or behavioral psychologists may help you put things in perspective. They can also teach you coping skills and relaxation techniques that may be helpful.

Sometimes, joining a support group, where you can share experiences and feelings with other people, is a good approach. Ask your doctor what support groups are available in your community.

In addition, many chronic illnesses are associated with an increased risk of depression. This isn't a failure to cope but may indicate a disruption in the body's neurochemistry that can be helped with appropriate medical treatment.

If you have a chronic illness such as MS, there's no denying that it affects your life. But how much you allow it to determine the quality of your life depends, to some extent, on the way you choose to live day to day.

SELF-CARE
Mayo Clinic Staff (January 7, 2003)

These steps may help you relieve symptoms of multiple sclerosis.

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*This material is provided as general medical information and is not intended as advice for individual patients;
please contact your physician for specific recommendations.

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