Multiple Sclerosis

What Is Multiple Sclerosis?

Multiple sclerosis (MS) is a disease of the central nervous system (CNS), the nerves that comprise the brain and spinal cord. Its cause is unknown, it cannot be prevented, and neither a cure nor a safe and effective treatment has been able to halt its progression to date. It is not fatal, however, and much progress is being made in treating symptoms and identifying underlying mechanisms that trigger this disease.

Multiple sclerosis is well named. Sclerosis comes from the Greek word skleros, which means hard. Multiple sclerosis refers to multiple areas of patchy scarring, or plaques, that result from demyelination -- destruction of myelin, a fatty insulation covering the nerve fibers. Myelin is made from layers of cell membranes that are produced in the brain and spinal cord by specialized cells called oligodendrocytes. Myelin coats lie in segments along the axons, the long filaments that carry electric impulses away from a nerve cell. The segments are separated from each other by tiny clusters called nodes of Ranvier, which house channels for sodium ions. These sodium ions are important for boosting the electrical charge required to pass signals from one nerve to another. When the myelin sheath is destroyed during the MS disease process, signals transmitted throughout the CNS are disrupted. In many cases, the body may compensate for the loss of myelin by increasing the density of the sodium channels so that electric charges can continue to be carried, in spite of loss of myelin. The nerves also retain the capacity to remyelinate. Unfortunately, the disease process outpaces these corrective actions. Experts once believed that axons themselves were spared during this disease process. Recent research, however, has shown that many are severed in MS and, in fact, axon destruction, not demyelinationmay be the factor responsible for the irreversibility of the disease.

Multiple sclerosis is defined as an autoimmune disease; that is, the body's immune system is damaged by genetic or environmental factors or both into attacking its own tissues. In the case of MS, these tissues are the myelin covering the nerve fibers in the brain.

The symptoms, severity, and course of MS vary widely depending partly on the sites of the plaques and the extent of the demyelination. Experts generally group multiple sclerosis into four types: relapsing-remitting, primary-progressive, secondary-progressive, and progressive-relapsing MS. The latter three forms generally fall under the category of chronic-progressive MS.

Relapsing-Remitting Multiple Sclerosis

Relapsing-remitting multiple sclerosis generally occurs in younger people and is the most common form of MS. Symptoms flare up for several days and then go into remission over the next four to eight weeks. Symptoms are fairly mild in about half of patients with relapsing-remitting MS. Remission periods, when symptoms improve or disappear, may be spontaneous or induced by immunosuppressive drugs. Spontaneous remission probably occurs when the demyelinated nerve cells compensate by building up a line of sodium clusters that can carry an electric charge. A person with multiple sclerosis in remission may have subtle attacks and not realize it; one hand may be a little numb for a few days, or there may be slight awkwardness in gait or coordination. Remissions are almost always followed by symptom flare-ups or periods of deteriorating ability.

Chronic-Progressive Multiple Sclerosis

The term chronic-progressive multiple sclerosis is used to describe cases in which symptoms continue to worsen slowly without remission. Some experts now believe that the progressive nature of MS is caused by nerve axons that are severed during the disease process. About 20% of multiple sclerosis patients (usually those whose first symptoms occur after age 45) have the chronic-progressive form without first developing relapsing-remitting MS. Chronic-progressive MS may lead to serious speech problems and paralysis, and generally it follows a downhill course. Because this form has a number of variations, however, three variants have been proposed to replace the single category.

Primary-Progressive MS. Primary-progressive MS progresses continuously and gradually without remission. It occasionally levels off, and minor improvement is even possible. This occurs in about 10% of patients, who tend to be older than average at the time of diagnosis.

Secondary-Progressive MS. About half of patients with relapsing-remitting MS develop secondary-progressive MS, which follows a progressive course of nerve and muscle deterioration with occasional acute flare-ups, remissions, and plateaus.

Progressive-Relapsing MS. The disease is progressive from the start with acute symptom flare-ups and continued deterioration between relapses. This is a very rare form of MS.

What Causes Multiple Sclerosis?

The general theory for the development of MS is that a genetically damaged immune system is unable to distinguish between virus proteins and the body's own myelin and produces antibodies that attack. In other words, the body becomes allergic to itself, a condition known as autoimmunity.

Inflammatory Response

When an injury or an infection occurs, the immune system mobilizes white blood cells and other factors to rid the body of any foreign proteins, such as viruses. The masses of blood cells that gather at the injured or infected site cause the area to become inflamed. Under normal conditions, this inflammatory process is controlled and self-limiting, but in people with autoimmune diseases such as multiple sclerosis, the process persists and damages surrounding tissues.

The primary infection-fighting units of the immune system are two types of white blood cells -- lymphocytes and leukocytes. Lymphocytes include two subtypes known as T-cells and B-cells. Normally, when a foreign protein invader, or antigen, infects the body, so-called helper T-cells recognize the antigen as alien and trigger a series of immune responses to destroy it. In multiple sclerosis, the T-cells mistake the body's myelin for a foreign antigen and set off a series of cascading events to rid the body of the perceived threat -- in this case -- its own protein. To fight the invader, the B-cells produce antibodiesmolecules designed for attack on a specific antigen. (When these antibodies attack the body's own tissue, they are called autoantibodies.) Large numbers of activated helper T- and B-cells have been found along with antibodies against myelin in the central nervous systems of people with multiple sclerosis. Of particular interest is a substance called myelin proteolipid protein, which comprises about half the protein in myelin and may be a primary target for T-cell attack. People with chronic-progressive MS appear to have decreased numbers of immune cells known as suppressor T-cells; these act as a check on the immune system and would ordinarily restrict the helper T-cells that attack the myelin. The inflammatory response from the immune response may also be responsible for axon destruction, a phenomenon that may account for the irreversibility of MS. On the other hand, it may develop after the protective myelin is gone and the axon is exposed to injury.

Leukocyte activity is also crucial, because leukocytes produce cytokinessmall proteins that in tiny amounts are indispensable for healing. The abnormal immune response of MS, however, triggers overproduction of certain cytokines that play a major role in the disease process. Important cytokines in the disease process appear to be tumor necrosis factors, interleukin-12, and interferon-gamma. Other cytokines, including interleukin-10 and transforming growth factor beta may play a suppressive role and help block inflammatory activity.

Possible Triggers of the Inflammatory Response

Viruses. The most likely antigens triggering the autoimmune response in MS are viruses. One factor that seems to support this theory is the geographical distribution of the disease; the number of MS cases increases the further one gets from the equator in either direction. Epidemics of multiple sclerosis also seem to occur. For example, four separate MS epidemics happened between 1943 and 1989 in the Faroe Islands, located between Iceland and Scandinavia. During World War II, this region was occupied by British troops; each year for 20 years after the war, the incidence of MS increased, leading some researchers to think that the troops might have brought with them some disease-causing agent.

Some viruses are strikingly similar to the myelin protein and may therefore cause confusion in the immune system, causing the T- cells to continue to attack their own protein rather than the viral antigen. More than one antigen may be involved -- some may trigger the disease, others may keep the process going. Although many viruses have been investigated, no one virus has emerged as a proven trigger. HHV-6, a form of herpesvirus, is a prime suspect. Others that have been investigated include herpesviruses 1 and 2, varicella-zoster virus (the cause of chicken pox), cytomegalovirus, Epstein-Barr virus (the cause of mononucleosis), measles virus, adenovirus, polyomavirus, or any of the retroviruses, including HIV, HTLV-I, and HTLVII.

Genetic Factors

Genetic factors certainly play a role in the development of MS. Children of MS patients have an increased risk that is 30 to 50 times that of the normal population. The odds of an MS sibling having the disease are about 20 times higher than in the normal population. One study found a significant association between siblings with MS and the specific form of the disease -- either relapsing-remitting or chronic progressive -- but found no association with the age of onset or severity of initial symptoms. A number of genes working together are likely to be responsible for the inherited risks.

What Are the Symptoms of Multiple Sclerosis?

In some patients, optic neuritis, the inflammation of the nerves in the eye, is the first symptom of multiple sclerosis. Some experts believe this condition may actually be a form of multiple sclerosis even if the complete syndrome doesn't evolve. Vision, usually in one eye, becomes unclear or doubled, and there may be a shimmering effect. Pain or nystagmus -- involuntary jerking or movement of the eye -- may also occur. In 20% of people with this condition, MS develops within two years; in 45% to 80% it develops within 15 years.

Other early symptoms of multiple sclerosis include fatigue, heaviness or clumsiness in the arms and legs, tingling sensations, and poor coordination. Another indication of MS is a reaction known as Llermitte's sign, whereby bending the neck produces an electrical sensation that runs down the back and into the legs. As the disease develops over months or even years, other symptoms may include spasticity, imbalance, tremors, incontinence, constipation, sexual dysfunction, hearing loss, vertigo, facial pain, memory loss, and difficulty in concentrating and problem solving. (For more detailed descriptions of these complications, see What Are the Treatments for Symptoms of Multiple Sclerosis?, below.)

How Serious Is Multiple Sclerosis?

Multiple sclerosis is not fatal, but an MS patient's life expectancy averages six years shorter than normal. The primary life-threatening dangers are infections, particularly in the lung or kidney. The severity of disability incurred over a lifetime is unpredictable; at 15 years after the onset of the disease, about 50% of patients are able to walk and 30% are still working. In very severe cases of MS, paralysis may occur. The negative emotional impact of this disease and its symptoms is considerable. About half of patients display changes in mental function, although in most cases these are not serious and may be experienced only as mild memory loss. In about 10% of cases, however, mental dysfunction may be severe and resemble dementia. Manifestation of the disease varies widely from patient to patient; MS sometimes remains asymptomatic or becomes only mildly symptomatic even long after initial plaque formation. About 20% to 35% of patients have a very mild form of the disease, with little if any disability, no need for medication, and a normal life expectancy. At the other extreme, between 3% and 12% of patients have a very serious, rapidly progressive form of MS. In pregnant women, relapse rates tend to decline, particularly late in the pregnancy; they tend to worsen in the postpartum period, but gradually return to pre-pregnancy levels. Breast feeding may help decrease the rate of relapses after delivery. Pregnancy itself appears to have no effect on disease progression.

Who Gets Multiple Sclerosis?

About 1.1 million people worldwide have multiple sclerosis, and the incidence appears to be increasing, and between 250,000 and 350,000 Americans have the disease. Onset of symptoms typically occurs between the ages of 15 and 40 years, with a peak incidence in people in their 20s and 30s. Women are affected twice as often as men. Multiple sclerosis occurs worldwide but is most common in Caucasian people of northern European origin, especially those of Scottish descent. It is extremely rare among Asians and Africans. In general, MS is more prevalent in temperate regions of the world than in the tropics. It is unclear whether this pattern is attributable to environmental factors or to genetics. A family history of the disease also puts people at risk, although the risk for someone inheriting all the genetic factors contributing to MS is only about 2% to 4%.

What Tests Are Used to Diagnosis Multiple Sclerosis?

Diagnosis is difficult in the early stages, because symptoms are often mild and transient. The correct diagnosis may not be made for months or years. If a patient has had two attacks of neurologic symptoms (each lasting at least 24 hours and occurring at least one month apart) or slow progression of symptoms over a period of at least six months, a physician will suspect the presence of multiple sclerosis. The symptoms of MS are similar to a number of other diseases, which must also be ruled out; these include stroke, alcoholism, emotional disorders, Lyme disease, chronic fatigue syndrome, AIDS, and certain other autoimmune disorders (e.g., scleroderma and systemic lupus erythematosus). The physician will require a patient history, including any family history of MS and any previous or recent illnesses and medications No reliable single laboratory procedure can establish the diagnosis of multiple sclerosis. Several are necessary before a diagnosis of multiple sclerosis can be made.

Expanded Disability Status Scale

Presently physicians and investigators generally use a test called the Expanded Disability Status Scale (EDSS) to rate the severity of and to score the effectiveness of treatments and status of the disease. The scale ranges from 0 to 10 with higher scores indicating more severe symptoms. These are subjective ratings that require physician observation skills.

Physical Examination and Laboratory Tests

The physician may order a lumbar puncture, or spinal tap, to obtain a spinal fluid samples, which is analyzed for abnormal proteins, tiny fragments of myelin, or certain types of white blood cells. The doctor will also perform tests for standard reflexes and a simple and painless electrical test of nerve function called evoked potential (EP) tests, which assess how long it takes nerve impulses from the eye, ear, or skin to reach the brain.

Brain-Imaging Techniques

Magnetic resonance imaging (MRI) is a significant advance in the diagnosis of multiple sclerosis. It is important to note, however, that the lesions (injured sites) revealed by MRI scans are not specific to MS and can indicate other conditions such as infections, migraines, or clots. A diagnosis must still be made by an experienced neurologist familiar with the symptoms of multiple sclerosis. Once diagnosed, periodic follow-up MRIs can be used to track the disease and effectiveness of treatments by distinguishing new lesions from old ones and revealing increasing or decreasing numbers of lesions within the central nervous system. It should be noted, however, that rate of new or growing lesions does not appear to represent symptom severity or predict MS symptom flare-ups. One study has reported that the severity of MS may be indicated by the presence of so-called "black holes", dark areas indicating structural damage.

What Are the Treatments for Symptoms of Multiple Sclerosis?

Fatigue

In one study, nearly half of all MS patients experienced fatigue at least once a week. It may be mild or completely debilitating. Psychological factors, including feelings of poor control over symptoms and a hypersensitivity to physical sensations, appear to be important components in producing fatigue. Amantadine (Symmetrel) is generally helpful and well-tolerated. Pemoline (Cylert) can also lessen fatigue in people with MS. Its most common side effects are anorexia, irritability, and insomnia; it may also lead to abuse or addiction. As a result, most neurologists reserve pemoline for short-term use when MS patients with disabling fatigue face important tasks. It was hoped that these drugs might help improve attention and mental function, but one study found that they did not.

Spasticity

One of the primary symptoms of MS is spasticity, which is characterized by weakness, loss of dexterity, and the inability to control specific movements. It is usually more severe in the legs and torso. Ironically, mild spasticity actually helps improve muscle tone in the legs, which is important in supporting the patient's weight when walking. This benefit can be lost with drug treatment. Mild spasticity, then, should be treated with exercises several times a day that improve range of motion. Baclofen has long been the drug of choice to alleviate more severe spasticity. It is available both orally and administered using an implanted pump, which seems to have helped dramatically in improving many cases of spasticity. Distressing side effects include confusion, drowsiness, and a rubbery-like sensation in the legs that makes it hard to stand. A newer oral drug, tizanidine (Zanaflex) works after one week. In one study, 75% of patients taking tizanidine reported improvement without the leg-muscle weakness experienced using lioresal. Side effects include dizziness, drowsiness, dry mouth, and fatigue. Diazepam (Valium) is also used for spasticity and is particularly useful for patients who also experience anxiety. Drug dependence is the primary problem with diazepam, as well as dizziness, drowsiness, and confusion. The medication should not be used by people who are seriously depressed. Dantrolene (Dantrium) is an effective alternative for MS patients who cannot tolerate diazepam or baclofen. Because dantrolene causes muscle weakness, however, it is best suited for two opposite types of patients -- either those who are wheel-chair bound but still suffer from spasticity or for those whose muscles are still strong, so that the drug-induced weakness isn't unduly debilitating. It also causes nausea, vomiting, and anorexia, and with high dosages can cause dangerous liver damage. Nabilone, a synthetic form of marijuana, has been found to relieve pain from muscle spasms in some patients. In very severe cases where medication and exercise are not helpful, surgery should be considered.

Bladder Dysfunction

Bladder dysfunction, a particularly distressing problem, occurs in two-thirds of MS patients. Fortunately, drug therapy can often treat this problem effectively. The most common symptoms are a feeling of urgency, frequency of urination, and incontinence; these can nearly always be alleviated with either propantheline bromine (Pro-Banthine) or oxybutynin (Ditropan). Urinary retention is the most serious side effect of these drugs, and patients should discuss this problem with their physician before starting therapy. Others drugs being tried with some success for this problem are desmopressin (DDAVP) ordinarily used for bed wetting in children and maprotiline (Ludiomil), an antidepressant. If medication is ineffective a catheter may be needed, either one used intermittently by the patient or placed in the urinary tract. In addition to medical therapy, patients should not drink fluids before going to places where restrooms are not easily available. When possible, they should urinate every three to four hours. Urination can be stimulated by pressing the bladder area with the fist or hand, by tapping against it, or by straining.

Urinary tract infection is common in MS patients and a urinalysis should be performed with any symptom flare-ups, with any fever, or with any change in bladder symptoms. Treatment uses appropriate antibiotic regimens. To help prevent infections, patients should drink plenty of cranberry juice but avoid orange or other citrus juices.

Bowel Dysfunction

Bowel dysfunction, which can include constipation or fecal incontinence, is a serious problem for many MS patients. Constipation may be caused by the disorder itself or by medications used to treat spasms or other symptoms. Patients should drink two quarts of water a day, while avoiding caffeine-containing beverages, which are actually dehydrating. Their diets should be high in fiber, obtained from whole grains (especially bran, oats, or flax), fresh fruits (particularly prunes), and vegetables. Bulk agents, such as psyllium (Metamucil) with or without a stool softener, may be needed. Going to the bathroom the same time every day particularly after a meal and waiting there, possibly as long as an hour, for a movement reduces the risk of losing control later in the day. (Patients can use this time to read, make calls, or write). Exercise is very important to counter constipation. It is important for patients to avoid becoming dependent on laxatives, enemas, or colonic irrigation, which can eventually slow down the bowel and cause imbalances in electrolytes.

Tremors

Major tremors can be very distressing and are particularly hard to treat. Carbamazepine and glutethimide have some possible benefits, but, in general, drug therapy has been disappointing. Weight applied to the affected limb has been beneficial in about 20% of cases. Surgery is very controversial.

Facial and Other Pain

Facial pain occurs in 1% to 2% of patients. If nonprescription pain killers fail to alleviate facial pain, it can be treated with anticonvulsive medications. Carbamazepine (Tegretol) is currently the drug of choice. Another antiseizure drug, gabapentin (Neurontin), may be particularly effective. Other drugs used for this symptom include phenytoin (Dilantin), diazepam (Valium), or pimozide (Orap), and the antidepressant amitriptyline (Elavil). If severe pain persists and interferes with function, some patients elect to have a section of a nerve surgically removed or blocked. This relieves pain but causes numbness. Before patients commit to such a procedure, they should ask the doctor to temporarily block the nerve with an anesthetic in order to experience the effect of numbness before undergoing irreversible surgery.

Among the other types of pain and spasm-related symptoms that can occur during attacks are burning, itching, aching, speech difficulties, and quivering sensations. They usually occur in the extremities and last seconds to minutes. Some people report itching lasting as long as 30 seconds. All of these symptoms can usually be treated with carbamazepine.

Sexual Dysfunction

Sexual dysfunction is a common problem, occurring in 78% of men and 45% of women. Men are likely to have impotence and women problems with vaginal lubrication. Corticosteroids, which are sometimes used for other MS symptoms, also improve sexual function. Patients should not be shy about discussing sexuality with their physician.

Emotional Disorders

Depression has been reported to occur in 25% to 50% of multiple sclerosis patients and treatment of this condition is important. It is not clear whether depression is a primary symptom or secondary to other stressful conditions of the disease itself. Physicians should assess patients for depression, even though there may be no obvious signs of it. Amitriptyline (Elavil) has been successful in managing severe depression when emotional support measures fail. Elavil may also be remarkably effective in alleviating the extreme mood swings that frequently occur in MS patients. This "emotional incontinence", the inability to control emotions, can distress some patients more than physical symptoms. Desipramine (Norpramin, Pertofrane) is also beneficial, and imipramine (Tofranil) may be particularly helpful in those who also have a problem with bladder dysfunction.

General Lifestyle Recommendations

Health Maintenance and Stress Reduction. People with multiple sclerosis should make every effort to preserve their general health. Proper diet with plenty of fiber, sufficient rest, establishing priorities to conserve energy, and developing emotional support networks can all be very helpful. Relaxation or meditation exercises can be beneficial. Special diets, such as those that are gluten- or yeast-free, have not been shown to have any direct effect on the symptoms or course of MS. Low-fat diets have also been recommended which have not been proven to date to have much effect on MS but are, in any case, generally healthy. Because illnesses, such influenza, which are caused by infection can exacerbate MS, a flu shot in the fall may be beneficial. Of some concern, is the possibility that the flu vaccine itself may exacerbate the disease, but a recent study has indicated that the risk is very small, if it exists at all. Stress can worsen symptoms, and may even be linked to worsening of the disease. Reducing stress is an important part of general health maintenance.

Exercise and Physical and Occupational Therapy. Exercise is an important component in managing the disorder. Stretching and range*of*motion exercises can alleviate some muscle spasticity. Pool exercises are particularly helpful; water supports the body, and cool water dissipates heat. In one study, aerobic exercise (40 minutes three times a week) helped improve bladder and bowel function and increased energy and a sense of well being. A health professional should be consulted to determine the best form of physical activity.

Avoid Overheating. Body overheating causes demyelinated nerve to function less efficiently than usual, but this effect is resolved within a few hours of regaining normal body temperature. Patients should use air conditioners in the summer, keep the home slightly cooler in winter, and avoid swimming in heated pools. People with MS may also notice that their symptoms worsen when they have a cold or the flu, but this is believed to result from increased immune system activity, not from fever itself.

Outside Support. Many MS patients require physical and psychological support from family, friends, and health professionals. A number of good associations are available to provide information and help. One interesting study reported that MS patients who owned trained service dogs showed substantial improvement in self-esteem, sense of self control, and psychological well being within only 6 months of having the dog. Reliance on paid and unpaid assistance dramatically decreased during a 2-year period of dog ownership.

What Are the Treatments for the Underlying Causes of Multiple Sclerosis?

Currently medications cannot repair the nerve defects of multiple sclerosis or change the course of the disease, but many drugs are being developed aimed at reducing the underlying inflammation and the immune system's attack on its own nervous system. Because research now indicates that the inflammatory process or other aspects of the MS disease processes may actually damage the nerve fibers, many experts are urging that patients with active disease be treated as soon as they are diagnosed with MS. About 10% of patients have symptoms that are benign enough so that such treatments may not be needed. As with drugs that are targeted at MS symptoms, the effectiveness of these medications often rests on the subjective judgment of the patient. Further advances in MRI techniques are improving the ability to gauge the direct effectiveness of these therapies on lesions in the brain, but to date objective measures are still limited.

Treatments for Relapsing-Remitting Multiple Sclerosis

Corticosteroids. Corticosteroids reduce inflammation in the central nervous system (CNS) and may help suppress the immune system's attack on myelin and even improve electrical conduction. Such drugs include methylprednisolone (usually given intravenously), prednisone (given orally), and ACTH (which stimulates production of natural steroids). Although they are very useful for improving acute symptoms in the relapsing-remitting patient, steroids and ACTH do not improve the long-term course of the disease and can lose effectiveness if over-used. Physicians generally restrict the use of steroids to severe attacks when the patient's ability to function is severely limited.

For moderate to severe relapses, one recommended regimen includes three to five daily high-dose intravenous infusions of methylprednisolone followed by oral prednisone given for about 12 days with tapering doses. One study indicated that high-dose oral methylprednisolone may be effective. Because of the side effects associated with oral corticosteroids, however, their routine use for an acute relapse is controversial and many physicians use them only occasionally. Studies are underway using pulsed doses of intravenous methylprednisolone every other month to determine if it will slow progression in patients with secondary progressive multiple sclerosis. Side effects of long-term use of steroids include weight gain and facial fullness, hypertension, diabetes, osteoporosis, cataracts, intestinal bleeding, and increased susceptibility to infections. In addition, side effects of steroids on the central nervous system can be particular problems for MS patients; they include sleeplessness, memory loss, anxiety, and depression. It should be noted that oral prednisone can actually exacerbate optic neuritis, the swelling of the nerves of the eye, so experts recommend this drug not be prescribed during flare-ups. Optic neuritis is often an early symptom of multiple sclerosis, and in one study the use of high-dose intravenous methylprednisolone followed by oral prednisone delayed the development of MS. It is extremely important after taking steroids continuously for a prolonged period of time, to taper withdrawal very carefully in order to give the body time to recover its own ability to produce natural steroids. A serious condition known as adrenal insufficiency can otherwise develop.

Interferon Beta. Interferons (so-called because they "interfere" with viral replication) both suppress the immune response and have anti-viral properties. Interferon beta appears to block important immune factors, including those known as class II MHC molecules, which are associated with targeting myelin for attack and contributing to the breach in the blood-brain barrier that allows the myelin-destroying T-cells to pass through. Interferon beta drugs are now available: interferon beta 1b (Betaseron) and interferon beta 1a (Avonex). Another interferon beta 1a (Rebif) is also showing strong promise. Interferon betas are now the treatments of choice for relapsing-remitting MS. Both drugs have been proven to significantly reduce relapse rates and even inhibit new plaque formation in the brain. Experts are urging that they be used early in the course of the disease and continued long term, although the ideal duration is not yet known. Avonex appears to have less severe side effects and to slow progression of disability more effectively than Betaseron, indicating that it may be a better choice for long-term therapy. Both interferon beta 1a drugs may even be effective against secondary progressive MS. None of the interferons cures, however, and long-term risks are not yet known.

Betaseron requires injections every other day while Avonex only requires weekly injections. Many patients taking Betaseron complain of severe pain at the injection site caused by damaged tissue. Black dead tissue may form around the site, and many patients taking Betaseron have reported severe skin eruptions. These skin injuries heal after the drug is withdrawn, but scarring can occur. Some people taking Betaseron also report depression and suicidal fantasies. Patients taking Avonex have not reported either serious depression or severe tissue damage at the injection site. Both drugs cause flu-like symptoms, nausea, vomiting, headaches, dizziness, and numbness. Taking Tylenol or other over-the-counter pain killers right before the injection and going to bed promptly often prevents many of these symptoms. They usually fade after two or three months. Within three years, between 35% and 40% of patients develop antibodies to Betaseron that neutralize some of its effect. This neutralizing effect is somewhat lower in Avonex -- about 22% after two years. The costs of these drugs are very high, between $8,000 to $10,000 a year.

Other Interferons. Other interferons being studied are interferon-alpha drug (Omniferontm) and interferon alpha n-3 (Alferon). These agents appear to cause fewer side effects at the injection site than beta interferon 1b.

Glatiramer Acetate. Glatiramer acetate (Copaxone), formerly called copolymer-1, is a synthetic molecule created to resemble a basic protein found in myelin. It is being used as a decoy to trick white blood cells into attacking it instead of myelin. One major study reported that the relapse rate for patients using COP-1 was reduced by 32% and disability scores were better compared to those taking a placebo. Benefits have persisted for at least three years. The best results were in patients in early stages and the longer patients remained on the drug the greater the improvement. Side effects occurred in about 15% of patients, usually right after the injection. They included pain at the injection site, chest pain, rapid heart beat, flushing, and shortness of breath. The drug did not stop progression of MS, and, so far, it has little effect on chronic-progressive MS.

Azathioprine. Azathioprine (Imuran) is designed to suppress the immune system and reduce the number of cells attacking the CNS myelin. It is used with or without steroids and is recommended as an alternative to patients with relapsing-remitting MS who do not respond to either interferon beta or glatiramer acetate. One study reported that 40% of patients had not experienced a relapse after taking the drug for three years, although others report only modest benefits. The drug has no effect on progression of disability.

Intravenous Immunoglobulin. Intravenous immunoglobulin treatments are monthly infusions of antibodies. They appear to have some modest benefits for relapsing-remitting MS. In one two-year study, 31% of treated relapsing-remitting patients improved, 16% had worse symptoms, and 50% were unaffected. Experts are not yet sure why this treatment works and do not know if it has any effect on progression.

Drugs Used for Chronic Progressive Multiple Sclerosis

Many drugs being investigated for chronic progressive multiple sclerosis are immunosuppressants, which block certain factors in the immune system that contribute to the inflammatory process. Each of these drugs can produce serious side effects, including susceptibility to infection and many others; they are reserved for patients with severe MS.

Methotrexate. Methotrexate is an immunosuppressant used for years to treat cancer and arthritis. Now a study has shown that low doses of this drug may slow the course of chronic-progressive MS, particularly those with secondary progressive MS. To date studies have found beneficial effects only the upper body. Although, this drug -- like all immunosuppressants -- can have toxic side effects, the drug can be taken in low doses and so has fewer severe side effects than other immunosuppressants used for MS.

Cyclophosphamide. Cyclophosphamide (Cytoxan) blocks cell growth and also suppresses the immune system. Some studies, but not all, have reported benefits for patients with chronic progressive MS. Combinations of cyclophosphamide and corticosteroids are showing some promise in significantly blocking immune factors responsible for MS inflammation. Cyclophosphamide has many side effects, including hair loss, nausea, vomiting, infertility, lung scarring, and blood abnormalities and should be used for patients who do not respond to methotrexate.

Cyclosporine. Cyclosporine (Sandimmune) has actions similar to cyclophosphamide. In one study, it showed some reduction in progression of disability, but 84% of those treated experienced some kidney damage and many had high blood pressure because of the drug.

Mitoxantrone. Mitoxantrone (Novantrone) is a powerful immunosuppressant often used for treating different cancers. One study reported that when MS patients with very active disease used it with a corticosteroid over a period of six months, symptoms and disease activity was reduced; the corticosteroid used alone had no effect. Another study indicated that mitoxantrone may slow progression of secondary-progressive MS, as well. The drug requires an intravenous infusion administered every three months. The drug has potentially dangerous side effects, including those on the heart; more work needs to be done on its effectiveness and safety.

Miscellaneous Experimental Treatments

Cladribine. Cladribine (Leustatin or 2-CdA) is an immunosuppressive drug that has been used successfully in leukemias and is currently being studied as an agent against progressive chronic multiple sclerosis. In one two-year study, cladribine halted chronic progressive disease and some patients even showed improvement. Immunosuppressants increase the risk for infection, and in the cladribine study low white blood cell counts were noted, and some patients developed herpes zoster, but no other infections were reported.

Human Transforming Growth Factor. Human transforming growth factor (TGF) beta-2 (BetaKine) is related to interferon beta and is being tested on patients with chronic-progressive MS. TGF beta posses many anti-inflammatory properties. The drug poses some risk for reversible kidney damage.

Vaccinations. Investigators are testing a vaccine against T-cells that destroy myelin. The patient is injected with inactive forms of these auto-immune T-cells, thus triggering the body's immune system to attack the active T-cells. In one small study, six out of 17 vaccinated patients experienced improved symptoms or were stable. It should be noted that symptoms worsened in 8 of the 11 people who did not respond to the vaccine. Because of certain associations between multiple sclerosis and the virus that cause shingles and chicken pox, another interesting trial tested the varicella-zoster (chicken pox) vaccine. Out of 50 patients vaccinated, 14 improved, four were worse, and 29 remained unchanged. The results warrant more work.

CD-4 and Peptides. Researchers are interested in certain peptides, which are a specially shaped enzymes, that they hope will block the actions of T-cells. Of particular interest is a peptide that blocks the signals of a T-cell known as CD-4, which is known to attack myelin.

Monoclonal Antibodies. Monoclonal antibodies are specially designed antibodies directed against a specific substance. They are being developed to target immune factors thought to be response for MS. One, Hu23F2g, has been designed to attach to immune cells and prevent their movement across the blood-brain barrier. It is now in clinical trials.

Aminopyridines. Aminopyridines are potassium-blocking compounds that appear to improve nerve conduction through demyelinated areas. In small, preliminary trials, 4*aminopyridine, or AP, has been associated with mild to marked improvement in vision, strength, and coordination and was well tolerated. Beneficial effects, however, lasted only a few hours. A related compound, 3,4*diaminopyridine, or DAP, has also produced temporary improvements in nerve conduction without harmful side effects, even when taken for several weeks. One study comparing the two drugs, however, found that AP was superior in improving walking, fatigue, and overall function. Side effects of AP are more apt to include dizziness and confusion. DAP may cause abdominal pain, numbness, or tingling. Overdose can occur at relatively low doses in both drugs and cause epileptic seizures.

Drugs that Inhibit Tumor Necrosis Factors. Thalidomide was notorious in the 1950s for causing birth defects. It is now being tested, however, for a number of autoimmune diseases, including multiple sclerosis because it appears to block production of tumor necrosis factor, a powerful inflammatory agent. Rolipram, an antidepressant used in Europe, is also proving to be a powerful inhibitor of tumor necrosis factor.

Electromagnetic Fields. Some experts believe that demyelinization may result in delayed conduction in the brain of certain neurotransmitters (chemical messengers in the brain), such as serotonin, which then causes fatigue and other symptoms common to multiple sclerosis. A few centers have been studying pulses of weak electromagnetic fields applied to the brain to produce a steady release of these neurotransmitters. Very small uncontrolled studies have reported improvement in fatigue, tremors, and other symptoms in patients who were severely affected by MS. They may be helpful for women whose symptoms intensify during the premenstrual period.

Oral Myelin. Oral myelin (Myloral) is being tested for relapsing/remitting MS. The drug, derived from cow's myelin, is eaten. The immune system is more tolerant of foreign proteins that are eaten and digested, and researchers hope that the body will produce T-cells that recognize the cow's myelin as harmless and will then suppress the attack that is occurring on the patient's own -- similar -- myelin in the brain. In April, 1997 disappointing preliminary results from a two-year trial reported no difference in effects between oral myelin and placebo.

Bone Marrow Transplant. Bone marrow transplant, used for cancer and some immune disorders, is being investigated for severe MS cases. This is a very experimental, expensive, and risky procedure, which can lead to dangerous infections and be fatal.

Nontraditional Treatments

Patients with chronic conditions may be tempted to try untested treatments, including herbs and other nontraditional therapies. Patients should always be wary of unproven claims for quick cures. Generally harmless -- and possibly helpful -- nontraditional therapies for MS are relaxation and meditation techniques and Eastern martial exercises. Such techniques include biofeedback, music therapy, yoga, tai chi, and massage therapy. Some patients also report benefit from acupuncture, which does carry a small risk, usually for infection. Linoleic acid, commonly known as evening primrose oil, is a polyunsaturated fatty acid believed by some people to be helpful because myelin is composed of fatty acids. No study has proven that it is beneficial, but supplements sold in health food stores do not appear to be harmful. No vitamins, including B12 injections, have been proven to be beneficial and some vitamins, such as B6 and D are toxic in high doses. Anecdotal reports for years have claimed that bee stings relieve some MS symptoms. A research program has been set up to study the effects of honey bee venom (HBV) on animals. HBV contains many chemicals some of which can cause severe and sometimes deadly allergic reactions in some people. High doses of any so-called natural medicines are usually no safer than traditional drugs, and because of the lack of manufacturing standards and knowledge about toxicity or interactions with other drugs, they may even be more dangerous. No one should undergo such therapies without consulting their physicians to be sure such treatment is not harmful and does not interfere with any standard medications being taken.

Recent Literature

Axonal transection in the lesions of multiple sclerosis. The New England Journal of Medicine, 1/29/98

Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology 1998 Aug;51(2):529-34

Drug therapy: Management of multiple sclerosis. The New England Journal of Medicine, 11/27/9

Dyemyelinating diseases -- new pathological insights, new therapeutic targets. The New England Journal of Medicine, 1/29/98

Effects of pregnancy and delivery on disease activity in multiple sclerosis. The New England Journal of Medicine, 7/30/98

Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. Neurology 1998 Aug;51(2):611-4

Living well with multiple sclerosis. Harvard Health Letter. August, 1997

New approaches to multiple sclerosis. HealthNews, 12/30/97

Well-Connected Board of Editors

Harvey Simon, M.D., Editor-in-Chief
Massachusetts Institute of Technology; Physician, Massachusetts General Hospital

Masha J. Etkin, M.D., Gynecology
Harvard Medical School; Physician, Massachusetts General Hospital

John E. Godine, M.D., Ph.D., Metabolism
Harvard Medical School; Associate Physician, Massachusetts General Hospital

Daniel Heller, M.D., Pediatrics
Harvard Medical School; Associate Pediatrician, Massachusetts General Hospital; Active Staff, Children's Hospital

Irene Kuter, M.D., D. Phil., Oncology
Harvard Medical School; Assistant Physician, Massachusetts General Hospital

Paul C. Shellito, M.D., Surgery
Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital

Theodore A. Stern, M.D., Psychiatry
Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital

Carol Peckham, Editorial Director

Cynthia Chevins, Publisher

Copyright * 1998 Nidus Information Services, Inc. Well-Connected Report: Multiple Sclerosis. December 1998. (Online) www.well-connected.com Well-Connected