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Medicine | IN THE LAB

10-year study targets the mysteries of MS

Researchers want to know what causes the disorder, how it progresses and why it takes different forms.

June 21, 2004|Linda Marsa | Special to The Times

Multiple sclerosis is a puzzling disorder. It's the leading cause of paralysis in Western nations, but scientists don't know what causes it.

Nor do they know why the disease strikes women twice as frequently as men, why it hits mostly people in their 20s and early 30s or why it takes different forms. Some people experience only mild symptoms for decades; many have periodic attacks for years that suddenly switch to a precipitous decline; and a few deteriorate rapidly and must use wheelchairs within a few years of diagnosis.

An ongoing Harvard study, which researchers hope will ultimately include 1,000 patients, may unravel some of these mysteries, providing insights into the condition's underlying mechanisms and eventually leading to more effective treatments for the nation's 400,000 people with MS.

"We're tracking the natural progression of the disease in patients from the earliest stages," says Dr. Howard L. Weiner, the study's lead investigator and director of the Partners Multiple Sclerosis Center at Brigham and Women's Hospital in Boston. "Our goal is to create a disease model that will answer a lot of the big questions."

The study, which started in 2000, has already enrolled 300 participants, all in the early stages of the disease. For 10 years, volunteers will undergo annual physical and neurological exams to monitor the progress of their disease. They'll have MRI scans to detect brain damage and nerve activity, blood tests to check immune response and DNA analysis to identify genetic patterns.

Some of the participants have benign MS, meaning they experience only mild symptoms. Researchers hope to identify the factors that enable them to escape the worst ravages of this disease, says Weiner, a neurologist at Harvard Medical School.

Scientists know that MS is an autoimmune disorder, in which the immune system dispatches certain white blood cells to attack myelin, the fatty insulation around nerve cells in the brain. This damage interferes with the efficient transmission of electrical impulses, which doctors believe leads to the problems with balance, walking, vision, sensation and speech that characterize MS.

Current treatments consist of anti-inflammatory drugs, like interferon, to dampen this immune response. These medications can ease symptoms and halt new attacks for some patients but not all, and the relief the drugs provide is often only temporary. As a consequence, most MS experts, including Weiner, suspect something else is at play.

Research in the late 1990s revealed that nerve fibers, or axons, are injured in the earliest stages of the disease, suggesting that aggressive treatment is necessary from the beginning.

"When the myelin sheath is destroyed, the axons are broken in two and contract into balls," Weiner says. "But we don't know what causes this damage."

For a time, the brain seems to compensate for this steady nerve destruction, which may explain why sufferers experience periodic attacks but then recover.

"Once this loss reaches a certain threshold, the brain can no longer compensate, and you enter the stage of the disease where the disability is progressive and irreversible," says Bruce D. Trapp, a neuroscientist at the Cleveland Clinic Foundation in Ohio who conducted the axon research. Weiner says he hopes his study will determine what triggers the inflammation and nerve cell damage, what prompts the condition to switch from periodic attacks to progressive debilitation and whether early aggressive treatment will stop brain cell damage.

"We finally have tools to decipher these complexities," he says. Answering these questions could generate more effective therapies, transforming MS into a "relatively mild condition that can be kept in check with the right medicines."



Preventing damage to nerve cells

Treatments for MS include drugs that reduce inflammation, including Avonex, Betaseron, Copaxone and Rebif.

For people with more advanced forms of the disease, chemotherapy is used to kill or suppress immune system cells. A new anti-inflammatory drug, called Antegren, which works by preventing errant immune system cells from entering the brain, is expected to be available within the next year.

Scientists have also had promising results with two nerve-preserving drugs, riluzole and memantine. Small human studies have found that they block the action of glutamate, a naturally occurring brain chemical that can kill cells when levels are too high. In addition, animal studies have shown that another drug, which blocks the sodium channels on the surface of nerve cells, prevented nerve cell damage.

"What we'll probably see in the future is that MS will be like cardiac disease, where we'll have multiple drugs to use," says neuroscientist Bruce D. Trapp of the Cleveland Clinic Foundation.

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