Making sense of multiple sclerosis

Although a once-promising MS drug has been pulled off the market, other therapies are under investigation.

Every week, about 200 Americans, most of them women, discover that they have multiple sclerosis (MS), a chronic, incurable neurological disease. For many, the bad news begins with a bout of subtle but scary symptoms, which can include tingling sensations, muscle weakness, and blurred or double vision. These symptoms usually wax and wane, reappearing unpredictably after months or even years. Some MS patients are only mildly affected; others eventually need a cane, wheelchair, or human assistance to get around. Aside from the physical challenges of the disease, uncertainty about its course often fosters depression and stress.

Early in 2005, the hopes of many MS patients (and their friends and families) were dashed when Tysabri — a drug shown to prevent relapses better than other currently available therapies — was linked to a very rare, often fatal brain disease. As a result, the manufacturers, Biogen Idec and Elan, suspended marketing. Now, researchers are trying to understand why Tysabri, which blocks certain immune cells from entering the brain, is so helpful to some and so dangerous to others. (Some experts believe it will eventually return to the market, with expanded warnings and restrictions.) Progress is also being made in understanding what causes the disease, predicting its course, and developing new therapies.

What is MS?
MS affects the central nervous system: the brain and spinal cord. For reasons that aren’t fully understood, myelin, the fatty tissue that coats and protects nerves, erodes in some places, leaving scar tissue (sclerosis) and disrupting communication between the central nervous system and the rest of the body. Problems with sensation, movement, vision, and sometimes thinking result. Scarring can occur anywhere in the brain or spinal cord, which explains the wide-ranging symptoms. These may include colorblindness, blindness in one eye, fatigue, balance problems, loss of bladder control, muscle spasms, paralysis, extreme sensitivity to heat, numbness, and mild attention deficits or memory loss.

Usually, MS first appears between ages 20 and 40. It’s two to three times more common in women and also more common among people of Northern European descent. The disease typically takes one of four forms (see box, “Forms of multiple sclerosis,” below), each of which can be mild, moderate, or severe.

What causes MS?
MS is widely regarded as an autoimmune disease, meaning one in which the immune system mistakenly attacks the body’s own cells, tissues, and organs. This hypothesis remains unproven, though. In the areas where myelin is lost, immune cells are found, along with high levels of substances made by immune cells. But no one knows for certain whether immune cells cause the damage or simply have turned up in response to some other process that injures the myelin. Experts agree that both heredity and environment influence the likelihood of developing MS.

Genes. Although MS is not considered a hereditary disease, a person who has an affected first-degree relative (child, sibling, or parent) has a higher-than-average risk for it. At least two different genes (and probably more) are involved. The identical twin of a person with MS has a 30% chance of developing the disease; the risk in non-identical twins, non-twin siblings, and parents is 3%–5%. In the general population, the lifetime risk is less than 0.5%.

Environmental agents. Some research has suggested environmental triggers such as toxins, vaccinations, and surgery, but none have been proven. Many believe a virus or other infection is the culprit. Studies of the blood and spinal fluid of people with MS have found high levels of certain infectious agents, including the viruses that cause measles, mumps, influenza, and mononucleosis (the Epstein-Barr virus), as well as some bacteria. So far the evidence isn’t conclusive.

Location. Where you live also affects MS risk. The disease is more common farther from the equator, even among people with similar genetic backgrounds. The reason may be lack of sunlight. In the northern United States and other areas far from the equator, people get less ultraviolet radiation, which is needed by the body to manufacture vitamin D.

Results from the Nurses’ Health Study published in Neurology in 2004 showed an association between MS and a lack of vitamin D. Women with the highest vitamin D intake from supplements (400 IU or more daily) were 40% less likely to develop MS than women who took no supplements. Although some doctors now recommend vitamin D supplements for people susceptible to MS, there’s no proof that this will prevent the illness or influence its course.

Stress. Emotional stress is another potential player. A 2004 analysis in the British Medical Journal that pooled results from 14 studies found a link between stressful life events and higher risk for MS relapses. Other research has shown a higher risk of developing MS after a life-threatening event or a tragedy like the death of a child. The mechanism isn’t fully understood, but one study found that reducing stress in people with MS lowered levels of gamma-interferon, a molecule that may contribute to relapses.

How is MS diagnosed?
MS may look like other disorders, including chronic fatigue syndrome and brain tumors, so it can be difficult to diagnose. In fact, there’s no single test that either confirms or rules it out. To check for MS, a neurologist examines the patient for areas of numbness and tests her reflexes, balance, coordination, and vision.

The most important diagnostic tool is magnetic resonance imaging (MRI), which uses magnetic fields to create detailed images of the body. Before getting an MRI scan, patients are usually injected with gadolinium, a substance that normally can’t cross the blood-brain barrier. But the loss of myelin creates a gap in the barrier, allowing gadolinium to flow into the central nervous system and reveal areas of scarring (lesions) as opaque spots on the MRI image.

Additional tests are usually needed when a person has symptoms but no lesions. The neurologist may take a sample of spinal fluid (via a spinal tap) or order a set of evoked potential tests, which measure the speed of the nervous system’s response to light flashes, sounds, and small shocks to the skin.

In general, a diagnosis of MS means that a person has met two basic criteria. First, she must have signs of the disease in more than one part of her nervous system. Second, she must have had at least two episodes involving symptoms characteristic of the disease. People who don’t meet both criteria but have experienced classic MS symptoms can remain in limbo for years with a diagnosis of “possible MS.”

Researchers are still looking for a simple test to identify MS and predict its course, and they have produced promising preliminary results. For example, a 2003 study in the New England Journal of Medicine found that people with possible MS tend to have relapses sooner and more often if their blood contains antibodies against certain myelin-related proteins.

Slowing the course of MS
A major focus is medications that target the immune system and slow the progression of the disease.

Medications. Four drugs — Avonex, Betaseron, Copaxone, and Rebif (often referred to as the ABCR drugs) — cut the likelihood of relapses and reduce the development of new MRI lesions. All are given by self-injection. Avonex, Betaseron, and Rebif are forms of beta-interferon, a molecule made by the body to damp down the immune system after an infection has been eradicated. Side effects include flulike symptoms, such as muscle aches, fever, and chills, which tend to lessen over time. Copaxone is a synthetic copy of a myelin protein that helps prevent immune cells from attacking the body’s own myelin. Side effects include redness, swelling, and bruising at the injection site.

Novantrone, originally developed to treat cancer patients, is an immune suppressant used in people with severe, progressive forms of MS. It’s given intravenously in a medical setting. Novantrone carries a boxed warning because it can cause heart damage and it slightly increases the risk for secondary acute myelogenous leukemia. Only people with normal heart function should be allowed to take the drug, and cardiac function should be tested before each dose.

Nondrug approaches. Research shows that exercise can ease some common symptoms of MS, making day-to-day living easier and improving mood and quality of life. Yoga has been shown to reduce fatigue, while certain strength-training exercises can help boost mobility and muscle strength. The National Multiple Sclerosis Society also recommends tai chi (a gentle exercise consisting of slow, rhythmic body movements) and aquatic exercises. MS varies widely in its physical effects, so it’s a good idea to work with a physical therapist or exercise specialist to individualize an exercise regimen. Relaxation and stress-reducing strategies can also help.

Research from the Harvard School of Public Health suggests that quitting smoking may help limit or delay the progression of MS. In a study of 179 patients initially diagnosed with an early form of MS, investigators found that those who were current or past smokers were almost four times as likely as those who had never smoked to develop a more progressive form of the disease (Brain, March 9, 2005).

On the horizon
Investigators are pursuing several treatment approaches. Oral medications similar to Tysabri are in development, although trials of such drugs are on hold as of mid-2005, pending further study of the risks. Other possible therapies include:

Statins. These cholesterol-lowering medications, which also have anti-inflammatory effects, have shown promise in several small trials; larger studies are under way.

Estrogen-based drugs. MS symptoms often abate during pregnancy, an observation that has spurred research into estrogen-based treatments.

Autologous stem-cell transplant. In this risky, expensive procedure, stem cells are removed from the patient’s own bone marrow. This is followed by total body irradiation and chemotherapy to destroy the immune system. Selected immune cells are then injected back into the body to replenish the immune system. Originally a treatment for leukemia and other cancers, autologous stem-cell transplant is reserved for people whose MS continues to worsen despite treatment.