Multiple sclerosis

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A condition that is both common and enigmatic, multiple sclerosis (MS) affects approximately 1 million people worldwide, most of whom are women. Although unpredictable in course and extent, MS is no longer considered untreatable. The last decade has witnessed an explosion of information about the disorder, which has given rise to advances in diagnosis and therapy. In the last few years three new drugs have been approved and several other promising approaches are under study. Optimism has replaced resignation among physicians who treat patients with MS.

What is MS?
A descriptive term, multiple sclerosis refers to the quantity and the state (sclerotic, or scarred) of affected areas of the brain, spinal cord, and peripheral nerves. These "scarred" regions have been stripped of their myelin, the fatty covering that insulates nerve fibers and facilitates the transmission of messages between the nervous system and the rest of the body.

The agents of destruction are thought to be the body's own T lymphocytes -- immune cells that are charged with ridding the body of foreign agents. Why these cells turn on the body's own tissue remains a mystery.

The most widely accepted theory is that MS is the result of an earlier viral infection. Recent reports implicate HHV-6, a strain of herpes virus that is responsible for the childhood illness roseola and which remains dormant in nerve trunks. In this scenario, the T cells that have been roused against the virus (lower right) turn their focus to the myelin, and continue to make sporadic attacks on it long after the virus has receded (page 5).

Symptoms of MS
Multiple sclerosis usually begins between the ages of 10 and 50 years. It is difficult to diagnose because of the wide variation in symptoms. They may be mild or severe, last briefly or for extended periods, and may occur in various combinations. The most common symptoms include:

Changes in vision. Optic neuritis--an inflammation of the optic nerve that is often an early manifestation of MS--can produce red-green colorblindness or even loss of sight in one eye. Double vision, vertigo, and hearing losses can occur less commonly.
Muscle weakness. Most people with MS lose strength and coordination in their extremities, a change that may be experienced as fatigue, loss of balance, spasms, or paralysis. If the mouth and tongue are affected, it becomes difficult to speak clearly. In severe cases, sexual function and bowel and bladder control may be impaired.
Abnormal sensation. Numbness, prickling and tingling, and extreme sensitivity to heat are common with MS. Pain occurs less frequently.
Cognitive impairments. Attention deficits and memory losses are common in MS but are usually mild.
Psychological changes. People with MS often become depressed, and a small percentage develop other psychiatric disorders, such as paranoia. Spells of laughing and/or crying, unrelated to one's emotional state, can also occur when the brain stem is affected.
Diagnosing MS
Because the manifestations of MS are similar to those of various other disorders, ranging from brain tumors to chronic fatigue syndrome, it is impossible to make a diagnosis based on symptoms alone. Moreover, no single test can detect MS conclusively. As a result, it may take months or even years for a physician to determine that a patient has the disease. The process may involve the following.

Imaging tests. Magnetic resonance imaging (MRI) can help to locate areas in which myelin has been lost. Before undergoing MRI, patients may be injected with gadolinium, an opaque substance that cannot cross the blood/brain barrier. The loss of myelin creates a gap in the barrier, allowing gadolinium to flow into the central nervous system. Its presence on the MRI image marks the site of lesions.
Evoked potential tests. Patients look at a range of images and listen to a variety of sounds while monitored by an electroencephalograph, a device that registers electrical impulses from the brain and translates them into a graphic display. Aberrations in an electroencephalogram can indicate lesions missed by MRI but cannot identify their cause.
Lumbar puncture. In this procedure, also known as a spinal tap, fluid is removed from the spinal column and examined for certain abnormalities--increased numbers of white blood cells and higher-than-average amounts of protein, including myelin basic protein and immunoglobulin G (antibodies).
Diagnosis is made by evaluating the results of these tests, ruling out other possibilities, and observing the course of symptoms over time. In most patients, the disorder is classified as one of three types: relapsing/remitting MS, characterized by flares of the disease followed by recovery; progressive MS, in which the condition slowly and steadily worsens; or progressive relapsing/remitting MS, in which each exacerbation of the disease leaves the patient in worse condition than before. In very rare instances, the disorder appears, follows a rapid downward course, and is fatal within a few months.

Treatment
In the absence of a cure for MS, treatment has been directed at alleviating symptoms and trying to arrest or slow its course. The last few years have seen considerable progress, with the approval of two new treatments--glatrimer acetate and beta-interferon--that are associated with greater benefits and fewer side effects than previous approaches.

Glatrimer acetate (Copaxone) is a synthetic copy of myelin basic protein that binds to T cells, diverting them from attacking the body's myelin. In clinical trials, Copaxone not only reduced the number of flares in patients with relapsing/remitting MS, but also improved neurologic symptoms. It was not effective, however, in patients with progressive MS. Copaxone was approved by the Food and Drug Administration in 1996.

Two forms of beta-interferon--Betaseron and Avonex--were approved in 1993 and 1995, respectively. A native human protein, beta-interferon plays a role in damping down the immune system once an infection has been eradicated. It has been shown to reduce the number of MS episodes, and MRI scans indicate that it may decrease myelin destruction. Side effects are usually limited to flulike symptoms, including fever, chills, muscle aches, and fatigue. Beta-interferon is not recommended for people with depression because it can exacerbate that condition.

Prednisone and other corticosteroids have also reduced the duration and severity of MS flares in some patients. However, they are linked to more unpleasant side effects than is beta-interferon. These include acne, diabetes, hypertension, and, occasionally, severe mood swings and even psychotic episodes.

Certain drugs that depress the entire immune system are usually reserved for use when others aren't effective. Azathioprine may reduce the rate of recurrent episodes in patients with relapsing/remitting MS, and low-dose methotrexate has slowed the rate of decline in patients with the progressive form of the disease. Two other immunosuppressants--cyclophosphamide and cyclosporine, which are associated with serious side effects-- are reserved for patients with rapidly advancing disease who haven't been helped by less toxic drugs. There is also a spectrum of experimental treatments under study:

Immune modulation. Scientists are exploring a host of different treatments aimed at wiping out or restraining the particular T cells that have mounted the attack on myelin. Approaches under study are vaccines; natural proteins, such as monoclonal antibodies, interleukin-4, and tumor necrosis factor; and oral tolerization--the ingestion of myelin to familiarize T cells with it in the digestive system so that it is recognized as "friend," not "enemy," in the future.
Bee venom. Anecdotal reports of MS remissions following bee stings have led to trials of injections of honeybee venom.
Plasmapheresis. Researchers are testing a technique in which the patient's blood is circulated through a device that separates plasma and filters out antibodies and other proteins that participate in the immune response. It is under evaluation to determine whether periodically "cleansing" the blood of MS patients has any effect on the course of the disease.
Bone marrow transplantation. This procedure involves infusing marrow from a healthy donor into a patient whose immune system has been suppressed and thus will not reject the transplanted cells. It is designed to offer a permanent cure by essentially replacing the patient's immune system with one that won't attack myelin, but the risks of developing and dying from an infection before the donor's marrow cells become established is comparatively high.
Restoration. Scientists are considering the use of nervous-system cell transplants and nerve growth factors to stimulate nerve regeneration, although such approaches are still untested in humans.
Living With MS
One of the keys to life with MS is to remain as healthy as possible otherwise, preserve strength, and minimize stress. Many women with MS are able to go on with their lives--pursuing careers and having families. MS usually doesn't interfere with pregnancy; in fact, the condition often goes into remission during those months. For many women however, symptoms become worse in the months immediately after delivery.

Pursuing a healthful lifestyle is essential. Maintaining a well-balanced diet is important, particularly since there is no evidence that any of the highly selective diets that have been touted as "cures" for MS are successful. If bladder and bowel functions are declining, a daily intake of 25-30 gm of fiber and 64 oz. of fluid may help to prevent constipation; cranberry juice may ward off urinary-tract infections.

It may help to establish a routine that incorporates physical therapy and exercise to combat muscle weakness. Spasticity can be treated with a variety of drugs, including muscle relaxants and tranquilizers. Injections of prednisone often relieve blurred vision and other optic symptoms. Analgesics like aspirin or acetaminophen may relieve pain but they do not affect other sensory symptoms, such burning or tingling.

Living with the uncertainties of MS is bound to take an emotional toll. Psychotherapy can help one to cope not only with the psychological aspects of MS, but also with the unpredictability of the illness, changes in self-image, the stress of undergoing repeated diagnostic tests, and, for some, the frustration of pursuing one treatment after another.

ILLUSTRATIONS

FOR FURTHER READING
The National Institute if Neurological Disorders and Strke offers a 20-page guide to MS. Call (301) 496-5751 or visit the institute's Web site at http://.www.ninds.nih.gov.

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