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Multiple Sclerosis

Introduction
Although multiple sclerosis (MS) was first diagnosed in 1849, the earliest known description of a person with possible MS dates from fourteenth century Holland. An unpredictable disease of the central nervous system, MS can range from relatively benign to somewhat disabling to devastating as communication between the brain and other parts of the body is disrupted.

The vast majority of patients are mildly affected, but in the worst cases MS can render a person unable to write, speak, or walk. A physician can diagnose MS in some patients soon after the onset of the illness. In others, however, physicians may not be able to readily identify the cause of the symptoms, leading to years of uncertainty and multiple diagnoses punctuated by baffling symptoms that mysteriously wax and wane.

Once a diagnosis is made with confidence, patients must consider a profusion of information--and misinformation--associated with this complex disease. This brochure is designed to convey the latest information on the diagnosis, course, and possible treatment of MS, as well as highlights of current research. Although a pamphlet cannot substitute for the advice and expertise of a physician, it can provide patients and their families with information to understand MS better so that they can actively participate in their care and treatment.

What is multiple sclerosis?
During an MS attack, inflammation occurs in areas of the white matter of the central nervous system in random patches called plaques. This process is followed by destruction of myelin, the fatty covering that insulates nerve cell fibers in the brain and spinal cord. Myelin facilitates the smooth, high-speed transmission of electrochemical messages between the brain, the spinal cord, and the rest of the body; when it is damaged, neurological transmission of messages may be slowed or blocked completely, leading to diminished or lost function. The name "multiple sclerosis" signifies both the number (multiple) and condition (sclerosis, from the Greek term for scarring or hardening) of the demyelinated areas in the central nervous system.

How many people have MS?
No one knows exactly how many people have MS. It is believed that, currently, there are approximately 250,000 to 350,000 people in the United States with MS diagnosed by a physician. This estimate suggests that approximately 200 new cases are diagnosed each week.

Who gets MS?
Most people experience their first symptoms of MS between the ages of 20 and 40, but a diagnosis is often delayed. This is due to both the transitory nature of the disease and the lack of a specific diagnostic test--specific symptoms and changes in the brain must develop before the diagnosis is confirmed.

Although scientists have documented cases of MS in young children and elderly adults, symptoms rarely begin before age 15 or after age 60. Whites are more than twice as likely as other races to develop MS. In general, women are affected at almost twice the rate of men; however, among patients who develop the symptoms of MS at a later age, the gender ratio is more balanced.

MS is five times more prevalent in temperate climates--such as those found in the northern United States, Canada, and Europe--than in tropical regions. Furthermore, the age of 15 seems to be significant in terms of risk for developing the disease: some studies indicate that a person moving from a high-risk (temperate) to a low-risk (tropical) area before the age of 15 tends to adopt the risk (in this case, low) of the new area and vice versa. Other studies suggest that people moving after age 15 maintain the risk of the area where they grew up.

These findings indicate a strong role for an environmental factor in the cause of MS. It is possible that, at the time of or immediately following puberty, patients acquire an infection with a long latency period. Or, conversely, people in some areas may come in contact with an unknown protective agent during the time before puberty. Other studies suggest that the unknown geographic or climatic element may actually be simply a matter of genetic predilection and reflect racial and ethnic susceptibility factors.

Periodically, scientists receive reports of MS "clusters." The most famous of these MS "epidemics" took place in the Faeroe Islands north of Scotland in the years following the arrival of British troops during World War II. Despite intense study of this and other clusters, no direct environmental factor has been identified. Nor has any definitive evidence been found to link daily stress to MS attacks, although there is evidence that the risk of worsening is greater after acute viral illnesses.

What causes MS?
Scientists have learned a great deal about MS in recent years; still, its cause remains elusive. Many investigators believe MS to be an autoimmune disease--one in which the body, through its immune system, launches a defensive attack against its own tissues. In the case of MS, it is the nerve-insulating myelin that comes under assault. Such assaults may be linked to an unknown environmental trigger, perhaps a virus.

What is the course of MS?
Each case of MS displays one of several patterns of presentation and subsequent course. Most commonly, MS first manifests itself as a series of attacks followed by complete or partial remissions as symptoms mysteriously lessen, only to return later after a period of stability. This is called relapsing-remitting (RR) MS. Primary-progressive (PP) MS is characterized by a gradual clinical decline with no distinct remissions, although there may be temporary plateaus or minor relief from symptoms. Secondary-progressive (SP) MS begins with a relapsing-remitting course followed by a later primary-progressive course. Rarely, patients may have a progressive-relapsing (PR) course in which the disease takes a progressive path punctuated by acute attacks. PP, SP, and PR are sometimes lumped together and called chronic progressive MS.

In addition, twenty percent of the MS population has a benign form of the disease in which symptoms show little or no progression after the initial attack; these patients remain fully functional. A few patients experience malignant MS, defined as a swift and relentless decline resulting in significant disability or even death shortly after disease onset. However, MS is very rarely fatal and most people with MS have a fairly normal life expectancy.

Studies throughout the world are causing investigators to redefine the natural course of the disease. These studies use a technique called magnetic resonance imaging (MRI) to visualize the evolution of MS lesions in the white matter of the brain. Bright spots on a T2 MRI scan indicate the presence of lesions, but do not provide information about when they developed.

Because investigators speculate that the breakdown of the blood/brain barrier is the first step in the development of MS lesions, it is important to distinguish new lesions from old. To do this, physicians give patients injections of gadolinium, a chemical contrast agent that normally does not cross the blood/brain barrier, before performing a scan. On this type of scan, called T1, the appearance of bright areas indicates periods of recent disease activity (when gadolinium is able to cross the barrier). The ability to estimate the age of lesions through MRI has allowed investigators to show that, in some patients, lesions occur frequently throughout the course of the disease even when no symptoms are present.

Can life events affect the course of MS?
While there is no good evidence that daily stress or trauma affects the course of MS, there is data on the influence of pregnancy. Since MS generally strikes during childbearing years, a common concern among women with the disease is whether or not to have a baby. Studies on the subject have shown that MS has no adverse effects on the course of pregnancy, labor, or delivery; in fact symptoms often stabilize or remit during pregnancy. This temporary improvement is thought to relate to changes in a woman's immune system that allow her body to carry a baby: because every fetus has genetic material from the father as well as the mother, the mother's body should identify the growing fetus as foreign tissue and try to reject it in much the same way the body seeks to reject a transplanted organ. To prevent this from happening, a natural process takes place to suppress the mother's immune system in the uterus during pregnancy.

However, women with MS who are considering pregnancy need to be aware that certain drugs used to treat MS should be avoided during pregnancy and while breast feeding. These drugs can cause birth defects and can be passed to the fetus via blood and to an infant via breast milk. Among them are prednisone, corticotropin, azathioprine, cyclophosphamide, diazepam, phenytoin, carbamazepine, and baclofen.

Unfortunately, between 20 and 40 percent of women with MS do have a relapse in the three months following delivery. However, there is no evidence that pregnancy and childbirth affect the overall course of the disease one way or the other. Also, while MS is not in itself a reason to avoid pregnancy and poses no significant risks to the fetus, physical limitations can make child care more difficult. It is therefore important that MS patients planning families discuss these issues with both their partner and physician.

What are the symptoms of MS?
Symptoms of MS may be mild or severe, of long duration or short, and may appear in various combinations, depending on the area of the nervous system affected. Complete or partial remission of symptoms, especially in the early stages of the disease, occurs in approximately 70 percent of MS patients.

The initial symptom of MS is often blurred or double vision, red-green color distortion, or even blindness in one eye. Inexplicably, visual problems tend to clear up in the later stages of MS. Inflammatory problems of the optic nerve may be diagnosed as retrobulbaror optic neuritis. Fifty-five percent of MS patients will have an attack of optic neuritis at some time or other and it will be the first symptom of MS in approximately 15 percent. This has led to general recognition of optic neuritis as an early sign of MS, especially if tests also reveal abnormalities in the patient's spinal fluid.

Most MS patients experience muscle weakness in their extremities and difficulty with coordination and balance at some time during the course of the disease. These symptoms may be severe enough to impair walking or even standing. In the worst cases, MS can produce partial or complete paralysis. Spasticity--the involuntary increased tone of muscles leading to stiffness and spasms--is common, as is fatigue. Fatigue may be triggered by physical exertion and improve with rest, or it may take the form of a constant and persistent tiredness.

Most people with MS also exhibit paresthesias, transitory abnormal sensory feelings such as numbness, prickling, or "pins and needles" sensations; uncommonly, some may also experience pain. Loss of sensation sometimes occurs. Speech impediments, tremors, and dizziness are other frequent complaints. Occasionally, people with MS have hearing loss.

Approximately half of all people with MS experience cognitive impairments such as difficulties with concentration, attention, memory, and poor judgment, but such symptoms are usually mild and are frequently overlooked. In fact, they are often detectable only through comprehensive testing. Patients themselves may be unaware of their cognitive loss; it is often a family member or friend who first notices a deficit. Such impairments are usually mild, rarely disabling, and intellectual and language abilities are generally spared.

Cognitive symptoms occur when lesions develop in brain areas responsible for information processing. These deficits tend to become more apparent as the information to be processed becomes more complex. Fatigue may also add to processing difficulties. Scientists do not yet know whether altered cognition in MS reflects problems with information acquisition, retrieval, or a combination of both. Types of memory problems may differ depending on the individual's disease course (relapsing-remitting, primary-progressive, etc.), but there does not appear to be any direct correlation between duration of illness and severity of cognitive dysfunction.

Depression, which is unrelated to cognitive problems, is another common feature of MS. In addition, about 10 percent of patients suffer from more severe psychotic disorders such as manic-depression and paranoia. Five percent may experience episodes of inappropriate euphoria and despair--unrelated to the patient's actual emotional state--known as "laughing/weeping syndrome." This syndrome is thought to be due to demyelination in the brainstem, the area of the brain that controls facial expression and emotions, and is usually seen only in severe cases.

As the disease progresses, sexual dysfunction may become a problem. Bowel and bladder control may also be lost.

In about 60 percent of MS patients, heat--whether generated by temperatures outside the body or by exercise--may cause temporary worsening of many MS symptoms. In these cases, eradicating the heat eliminates the problem. Some temperature-sensitive patients find that a cold bath may temporarily relieve their symptoms. For the same reason, swimming is often a good exercise choice for people with MS.

The erratic symptoms of MS can affect the entire family as patients may become unable to work at the same time they are facing high medical bills and additional expenses for housekeeping assistance and modifications to homes and vehicles. The emotional drain on both patient and family is immeasurable. Support groups and counseling may help MS patients, their families, and friends find ways to cope with the many problems the disease can cause.

Possible symptoms of multiple sclerosis
• Muscle weakness
• Spasticity
• Impairment of pain, temperature, touch senses
• Pain (moderate to severe)
• Ataxia
• Tremor
• Speech disturbances
• Vision disturbances
• Vertigo
• Bladder dysfunction
• Bowel dysfunction
• Sexual dysfunction
• Depression
• Euphoria
• Cognitive abnormalities
• Fatigue

How is MS diagnosed?
When faced with a patient whose symptoms, neurological examination, and medical history suggest MS, physicians use a variety of tools to rule out other possible disorders and perform a series of laboratory tests which, if positive, confirm the diagnosis.

Imaging technologies such as MRI--often used in conjunction with the contrast agent gadolinium, which helps distinguish new plaques from old on MRI (see section on "What is the Course of MS?")--can help locate central nervous system lesions resulting from myelin loss. However, since these lesions can also occur in several other neurological disorders, they are not absolute evidence of MS. Magnetic resonance spectroscopy (MRS) is a new tool being used to investigate MS. Unlike MRI, which provides an anatomical picture of lesions, MRS yields information about the biochemistry of the brain in MS.

Evoked potential tests, which measure the speed of the brain's response to visual, auditory, and sensory stimuli, can sometimes detect lesions the scanners miss. Like imaging technologies, evoked potentials are helpful but not conclusive because they cannot identify the cause of lesions.

The physician may also study the patient's cerebrospinal fluid (the colorless liquid that circulates through the brain and spinal cord) for cellular and chemical abnormalities often associated with MS. These abnormalities include increased numbers of white blood cells and higher-than-average amounts of protein, especially myelin basic protein and an antibody called immunoglobulin G. Physicians can use several different laboratory techniques to separate and graph the various proteins in MS patients' cerebrospinal fluid. This process often identifies the presence of a characteristic pattern called oligoclonal bands.

Because there is no single test that unequivocally detects MS, it is often difficult for the physician to differentiate between an MS attack and symptoms that can follow a viral infection or even an immunization. Many doctors will tell their patients they have "possible MS." If, as time goes by, the patient's symptoms show the characteristic relapsing-remitting pattern, or continue in a chronic and progressive fashion, and if laboratory tests rule out other likely causes, or specific tests become positive, the diagnosis may eventually be changed to "probable MS."

A number of other diseases may produce symptoms similar to those seen in MS. Other conditions with an intermittent course and MS-like lesions of the brain's white matter include polyarteritis, lupus erythematosus, syringomyelia, tropical spastic paraparesis, some cancers, and certain tumors that compress the brainstem or spinal cord. Progressive multifocal leukoencephalopathy can mimic the acute stage of an MS attack. The physician will also need to rule out stroke, neurosyphilis, spinocerebellar ataxias, pernicious anemia, diabetes, Sjogren's disease, and vitamin B12 deficiency. Acute transverse myelitis may signal the first attack of MS, or it may indicate other problems such as infection with the Epstein-Barr or herpes simplex B viruses. Recent reports suggest that the neurological problems associated with Lyme disease may present a clinical picture much like MS.

Investigators are continuing their search for a definitive test for MS. Until one is developed, however, evidence of both multiple attacks and central nervous system lesions must be found—a process that can take months or even years—before a physician can make a definitive diagnosis of MS.

Can MS be treated?
There is as yet no cure for MS. Many patients do well with no therapy at all, especially since many medications have serious side effects and some carry significant risks. Naturally occurring or spontaneous remissions make it difficult to determine therapeutic effects of experimental treatments; however, the emerging evidence that MRIs can chart the development of lesions is already helping scientists evaluate new therapies.

Until recently, the principal medications physicians used to treat MS were steroids possessing anti-inflammatory properties; these include adrenocorticotropic hormone (better known as ACTH), prednisone, prednisolone, methylprednisolone, betamethasone, and dexamethasone. Studies suggest that intravenous methylprednisolone may be superior to the more traditional intravenous ACTH for patients experiencing acute relapses; no strong evidence exists to support the use of these drugs to treat progressive forms of MS. Also, there is some indication that steroids may be more appropriate for people with movement, rather than sensory, symptoms.

While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some patients. The mechanism behind this effect is not known; one study suggests the medications work by restoring the effectiveness of the blood/brain barrier. Because steroids can produce numerous adverse side effects (acne, weight gain, seizures, psychosis), they are not recommended for long-term use.

One of the most promising MS research areas involves naturally occurring antiviral proteins known as interferons. Two forms of beta interferon (Avonex and Betaseron) have now been approved by the Food and Drug Administration for treatment of relapsing-remitting MS. A third form (Rebif) is marketed in Europe. Beta interferon has been shown to reduce the number of exacerbations and may slow the progression of physical disability. When attacks do occur, they tend to be shorter and less severe. In addition, MRI scans suggest that beta interferon can decrease myelin destruction.

Investigators speculate that the effects of beta interferon may be due to the drug's ability to correct an MS-related deficiency of certain white blood cells that suppress the immune system and/or its ability to inhibit gamma interferon, a substance believed to be involved in MS attacks. Alpha interferon is also being studied as a possible treatment for MS. Common side effects of interferons include fever, chills, sweating, muscle aches, fatigue, depression, and injection site reactions.

Scientists continue their extensive efforts to create new and better therapies for MS. Goals of therapy are threefold: to improve recovery from attacks, to prevent or lessen the number of relapses, and to halt disease progression. Some therapies currently under investigation are discussed below.

Immunotherapy
As evidence of immune system involvement in the development of MS has grown, trials of various new treatments to alter or suppress immune response are being conducted. These therapies are, at this time, still considered experimental.

Results of recent clinical trials have shown that immunosuppressive agents and techniques can positively (if temporarily) affect the course of MS; however, toxic side effects often preclude their widespread use. In addition, generalized immunosuppression leaves the patient open to a variety of viral, bacterial, and fungal infections.

Over the years, MS investigators have studied a number of immunosuppressant treatments. Among the therapies being studied are cyclosporine (Sandimmune), cyclophosphamide (Cytoxan), methotrexate, azathioprine (Imuran), and total lymphoid irradiation (a process whereby the MS patient's lymph nodes are irradiated with x-rays in small doses over a few weeks to destroy lymphoid tissue, which is actively involved in tissue destruction in autoimmune diseases). Inconclusive and/or contradictory results of these trials, combined with the therapies' potentially dangerous side effects, dictate that further research is necessary to determine what, if any, role they should play in the management of MS. Studies are also being conducted with the immune system modulating drugs linomide (Roquinimex), cladribine (Leustatin), and mitoxantrone.

Two other experimental treatments -- one involving the use of monoclonal antibodies and the other involving plasma exchange, or plasmapheresis-- may have fewer dangerous side effects. Monoclonal antibodies are identical, laboratory-produced antibodies that are highly specific for a single antigen. They are injected into the patient in the hope that they will alter the patient's immune response. Plasmapheresis is a procedure in which blood is removed from the patient, and the plasma is separated from other blood substances, which may contain antibodies and other immunologically active products. These other blood substances are discarded and the plasma is then transfused back into the patient. Because their worth as treatments for MS has not yet been proven, these experimental treatments remain at the stage of clinical testing.

Bone marrow transplantation (a procedure in which bone marrow from a healthy donor is infused into patients who have undergone drug or radiation therapy to suppress their immune system so they will not reject the donated marrow) and injections of venom from honeybees are also being studied. Each of these therapies carries the risk of potentially severe side effects.

Therapy to improve nerve impulse conduction
Because the transmission of electrochemical messages between the brain and body is disrupted in MS, medications to improve the conduction of nerve impulses are being investigated. Since demyelinated nerves show abnormalities of potassium activity, scientists are studying drugs that block the channels through which potassium moves, thereby restoring conduction of the nerve impulse. In several small experimental trials, derivatives of a drug called aminopyridine temporarily improved vision, coordination, and strength when given to MS patients who suffered from both visual symptoms and heightened sensitivity to temperature. Possible side effects of these therapies include paresthesias (tingling sensations), dizziness, and seizures.

Therapies targeting an antigen
Trials of a synthetic form of myelin basic protein, called copolymer I (Copaxone), have shown promise in treating people in the early stages of relapsing-remitting MS. Copolymer I, unlike so many drugs tested for the treatment of MS, seems to have few side effects. Recent trial data indicate that copolymer I can reduce the relapse rate by almost one third. In addition, patients given copolymer I were more likely to show neurologic improvement than those given a placebo. The Food and Drug Administration has made the drug available to people with early relapsing-remitting MS through its "Treatment IND" program and is currently reviewing data from a large-scale study to determine whether or not to approve the drug for marketing.

Investigators are also looking at the possibility of developing an MS vaccine. Myelin-attacking T cells were removed, inactivated, and injected back into animals with experimental allergic encephalomyelitis (EAE). This procedure results in destruction of the immune system cells that were attacking myelin basic protein. In a couple of small trials scientists have tested a similar vaccine in humans. The product was well-tolerated and had no side effects, but the studies were too small to establish efficacy. Patients with progressive forms of MS did not appear to benefit, although relapsing-remitting patients showed some neurologic improvement and had fewer relapses and reduced numbers of lesions in one study. Unfortunately, the benefits did not last beyond two years.

A similar approach, known as peptide therapy, is based on evidence that the body can mount an immune response against the T cells that destroy myelin, but this response is not strong enough to overcome the disease. To induce this response, the investigator scans the myelin-attacking T cells for the myelin-recognizing receptors on the cells' surface. A fragment, or peptide, of those receptors is then injected into the body. The immune system "sees" the injected peptide as a foreign invader and launches an attack on any myelin-destroying T cells that carry the peptide. The injection of portions of T cell receptors may heighten the immune system reaction against the errant T cells much the same way a booster shot heightens immunity to tetanus. Or, peptide therapy may jam the errant cells' receptors, preventing the cells from attacking myelin.

Despite these promising early results, there are some major obstacles to developing vaccine and peptide therapies. Individual patients' T cells vary so much that it may not be possible to develop a standard vaccine or peptide therapy beneficial to all, or even most, MS patients. At this time, each treatment involves extracting cells from each individual patient, purifying the cells, and then growing them in culture before inactivating and chemically altering them. This makes the production of quantities sufficient for therapy extremely time consuming, labor intensive, and expensive. Further studies are necessary to determine whether universal inoculations can be developed to induce suppression of MS patients' overactive immune systems.

Protein antigen feeding is similar to peptide therapy, but is a potentially simpler means to the same end. Whenever we eat, the digestive system breaks each food or substance into its primary "non-antigenic" building blocks, thereby averting a potentially harmful immune attack. So, strange as it may seem, antigens that trigger an immune response when they are injected can encourage immune system tolerance when taken orally. Furthermore, this reaction is directed solely at the specific antigen being fed; wholesale immunosuppression, which can leave the body open to a variety of infections, does not occur. Studies have shown that when rodents with EAE are fed myelin protein antigens, they experience fewer relapses. Data from a small, preliminary trial of antigen feeding in humans found limited suggestion of improvement, but the results were not statistically significant. A multi-center trial is being conducted to determine whether protein antigen feeding is effective.

Cytokines
As our growing insight into the workings of the immune system gives us new knowledge about the function of cytokines, the powerful chemicals produced by T cells, the possibility of using them to manipulate the immune system becomes more attractive. Scientists are studying a variety of substances that may block harmful cytokines, such as those involved in inflammation, or that encourage the production of protective cytokines.

A drug that has been tested as a depression treatment, rolipram, has been shown to reduce levels of several destructive cytokines in animal models of MS. Its potential as a therapy for MS is not known at this time, but side effects seem modest. Protein antigen feeding, discussed above, may release transforming growth factor beta (TGF), a protective cytokine that inhibits or regulates the activity of certain immune cells. Preliminary tests indicate that it may reduce the number of immune cells commonly found in MS patients' spinal fluid. Side effects include anemia and altered kidney function.

Interleukin 4 (IL-4) is able to diminish demyelination and improve the clinical course of mice with EAE, apparently by influencing developing T cells to become protective rather than harmful. This also appears to be true of a group of chemicals called retinoids. When fed to rodents with EAE, retinoids increase levels of TGF and IL-4, which encourage protective T cells, while decreasing numbers of harmful T cells. This results in improvement of the animals' clinical symptoms.

Remyelination
Some studies focus on strategies to reverse the damage to myelin and oligodendrocytes (the cells that make and maintain myelin in the central nervous system), both of which are destroyed during MS attacks. Scientists now know that oligodendrocytes may proliferate and form new myelin after an attack. Therefore, there is a great deal of interest in agents that may stimulate this reaction. To learn more about the process, investigators are looking at how drugs used in MS trials affect remyelination. Studies of animal models indicate that monoclonal antibodies and two immunosuppressant drugs, cyclophosphamide and azathioprine, may accelerate remyelination, while steroids may inhibit it. The ability of intravenous immunoglobulin (IVIg) to restore visual acuity and/or muscle strength is also being investigated.

Diet
Over the years, many people have tried to implicate diet as a cause of or treatment for MS. Some physicians have advocated a diet low in saturated fats; others have suggested increasing the patient's intake of linoleic acid, a polyunsaturated fat, via supplements of sunflower seed, safflower, or evening primrose oils. Other proposed dietary "remedies" include megavitamin therapy, including increased intake of vitamins B12 or C; various liquid diets; and sucrose-, tobacco-, or gluten-free diets. To date, clinical studies have not been able to confirm benefits from dietary changes; in the absence of any evidence that diet therapy is effective, patients are best advised to eat a balanced, wholesome diet.

Unproven therapies
MS is a disease with a natural tendency to remit spontaneously, and for which there is no universally effective treatment and no known cause. These factors open the door for an array of unsubstantiated claims of cures. At one time or another, many ineffective and even potentially dangerous therapies have been promoted as treatments for MS. A partial list of these "therapies" includes: injections of snake venom, electrical stimulation of the spinal cord's dorsal column, removal of the thymus gland, breathing pressurized (hyperbaric) oxygen in a special chamber, injections of beef heart and hog pancreas extracts, intravenous or oral calcium orotate (calcium EAP), hysterectomy, removal of dental fillings containing silver or mercury amalgams, and surgical implantation of pig brain into the patient's abdomen. None of these treatments is an effective therapy for MS or any of its symptoms.

Drugs currently available to patients
Steroids, Adrenocorticotropic hormone (ACTH), Prednisone, Prednisolone, Methylprednisolone, Betamethasone, Dexamethasone, Interferons, Beta interferons (Avonex, Betaseron), Beta interferon (Rebif)--available in Europe only.

Some experimental therapies
Alpha interferon, Cyclosporine (Sandimmune), Cyclophosphamide (Cytoxan), Methotrexate, Azathioprine (Imuran), Linomide (Roquinimex), Cladribine (Leustatin), Mitoxantrone, Aminopyridine, derivatives of Copolymer I (Copaxone), Rolipram, Interleukin 4 (IL-4), Retinoids, Total lymphoid irradiation, Monoclonal antibodies, Plasma exchange or plasmapheresis, Bone marrow transplantation, Peptide therapy, Various MS vaccines, Protein antigen feeding, Transforming growth factor beta (TGF), Intravenous immunoglobulin (IVIg).

Are any MS symptoms treatable?
While some scientists look for therapies that will affect the overall course of the disease, others are searching for new and better medications to control the symptoms of MS without triggering intolerable side effects.

Many people with MS have problems with spasticity, a condition that primarily affects the lower limbs. Spasticity can occur either as a sustained stiffness caused by increased muscle tone or as spasms that come and go, especially at night. It is usually treated with muscle relaxants and tranquilizers. Baclofen (Lioresal), the most commonly prescribed medication for this symptom, may be taken orally or, in severe cases, injected into the spinal cord. Tizanidine (Zanaflex), used for years in Europe and now approved in the United States, appears to function similarly to baclofen. Diazepam (Valium), clonazepam (Klonopin), and dantrolene (Dantrium) can also reduce spasticity. Although its beneficial effect is temporary, physical therapy may also be useful and can help prevent the irreversible shortening of muscles known as contractures. Surgery to reduce spasticity is rarely appropriate in MS.

Weakness and ataxia (incoordination) are also characteristic of MS. When weakness is a problem, some spasticity can actually be beneficial by lending support to weak limbs. In such cases, medication levels that alleviate spasticity completely may be inappropriate. Physical therapy and exercise can also help preserve remaining function, and patients may find that various aids--such as foot braces, canes, and walkers--can help them remain independent and mobile. Occasionally, physicians can provide temporary relief from weakness, spasms, and pain by injecting a drug called phenol into the spinal cord, muscles, or nerves in the arms or legs. Further research is needed to find or develop effective treatments for MS-related weakness and ataxia.

Although improvement of optic symptoms usually occurs even without treatment, a short course of treatment with intravenous methylprednisolone (Solu-Medrol) followed by treatment with oral steroids is sometimes used. A trial of oral prednisone in patients with visual problems suggests that this steroid is not only ineffective in speeding recovery but may also increase patients' risk for future MS attacks. Curiously, prednisone injected directly into the veins--at ten times the oral dose--did seem to produce short-term recovery. Because of the link between optic neuritis and MS, the study's investigators believe these findings may hold true for the treatment of MS as well. A follow-up study of optic neuritis patients will address this and other questions.

Fatigue, especially in the legs, is a common symptom of MS and may be both physical and psychological. Avoiding excessive activity and heat are probably the most important measures patients can take to counter physiological fatigue. If psychological aspects of fatigue such as depression or apathy are evident, antidepressant medications may help. Other drugs that may reduce fatigue in some, but not all, patients include amantadine (Symmetrel), pemoline (Cylert), and the still-experimental drug aminopyridine.

People with MS may experience several types of pain. Muscle and back pain can be helped by aspirin or acetaminophen, and by physical therapy to correct faulty posture and strengthen and stretch muscles. The sharp, stabbing facial pain known as trigeminal neuralgia is commonly treated with carbamazapine or other anticonvulsant drugs, and occasionally with surgery. Intense tingling and burning sensations are harder to treat. Some people get relief with antidepressant drugs; others may respond to electrical stimulation of the nerves in the affected area. In some cases, the physician may recommend codeine.

As the disease progresses, some patients develop bladder malfunctions. Urinary problems are often the result of infections that can be treated with antibiotics. The physician may recommend that patients take vitamin C supplements or drink cranberry juice, as these measures acidify urine and may reduce the risk of further infections. Several medications are also available. The most common bladder problems encountered by MS patients are urinary frequency, urgency, or incontinence. A small number of patients, however, retain large amounts of urine. In these patients, catheterization may be necessary. In this procedure, a catheter or drainage tube is temporarily inserted (by the patient or a caretaker) into the urethra several times a day to drain urine from the bladder. Surgery may be indicated in severe, intractable cases. Scientists have developed a "bladder pacemaker" that has helped people with urinary incontinence in preliminary trials. The pacemaker, which is surgically implanted, is controlled by a hand-held unit that allows the patient to electrically stimulate the nerves that control bladder function.

MS patients with urinary problems may be reluctant to drink enough fluids, leading to constipation. Drinking more water and adding fiber to the diet usually alleviates this condition. Sexual dysfunction may also occur, especially in patients with urinary problems. Men may experience occasional failure to attain an erection. Penile implants, injection of the drug papaverine, and electrostimulation are techniques used to resolve the problem. Women may experience insufficient lubrication or have difficulty reaching orgasm; in these cases, vaginal gels and vibrating devices may be helpful. Counseling is also beneficial, especially in the absence of urinary problems, since psychological factors can also cause these symptoms. For instance, depression can intensify symptoms of fatigue, pain, and sexual dysfunction. In addition to counseling, the physician may prescribe antidepressant or antianxiety medications. Amitriptyline is used to treat laughing/weeping syndrome.

Tremors are often resistant to therapy, but can sometimes be treated with drugs or, in extreme cases, surgery. Investigators are currently examining a number of experimental treatments for tremor.

Drugs used to treat symptoms of multiple sclerosis

Symptom Drug
Spasticity Baclofen (Lioresal)
Tizanidine (Zanaflex)
Diazepam (Valium)
Clonazepam (Klonopin)
Dantrolene (Dantrium)
Optic neuritis Methylprednisolone (Solu-Medrol)
Oral steroids
Fatigue Antidepressants
Amantadine (Symmetrel)
Pemoline (Cylert)
Pain Aspirin or acetaminophen
Antidepressants
Codeine
Trigeminal neuralgia Carbamazapine, other anticonvulsant
Sexual dysfunction Papaverine injections (in men)

What recent advances have been made in MS research?
Many advances, on several fronts, have been made in the war against MS. Each advance interacts with the others, adding greater depth and meaning to each new discovery. Four areas, in particular, stand out.

Over the last decade, our knowledge about how the immune system works has grown at an amazing rate. Major gains have been made in recognizing and defining the role of this system in the development of MS lesions, giving scientists the ability to devise ways to alter the immune response. Such work is expected to yield a variety of new potential therapies that may ameliorate MS without harmful side effects.

New tools such as MRI have redefined the natural history of MS and are proving invaluable in monitoring disease activity. Scientists are now able to visualize and follow the development of MS lesions in the brain and spinal cord using MRI; this ability is a tremendous aid in the assessment of new therapies and can speed the process of evaluating new treatments.

Other tools have been developed that make the painstaking work of teasing out the disease's genetic secrets possible. Such studies have strengthened scientists' conviction that MS is a disease with many genetic components, none of which is dominant. Immune system-related genetic factors that predispose an individual to the development of MS have been identified, and may lead to new ways to treat or prevent the disease.

In fact, a treatment that may actually slow the course of the disease has been found and a growing number of therapies are now available that effectively treat some MS symptoms. In addition, there are a number of treatments under investigation that may curtail attacks or improve function of demyelinated nerve fibers. Over a dozen clinical trials testing potential therapies are under way, and additional new treatments are being devised and tested in animal models.

What research remains to be done?
The role of genetic risk factors, and how they can be modified, must be more clearly defined. Environmental triggers, such as viruses or toxins, need to be investigated further. The specific cellular and subcellular targets of immune attack in the brain and spinal cord, and the subsets of T cells involved in that attack, need to be identified. Knowledge of these aspects of the disease will enable scientists to develop new methods for halting--or reversing and repairing--the destruction of myelin that causes the symptoms of MS.

What is the outlook for people with MS?
The 1990s--proclaimed the "Decade of the Brain" in 1989 by President Bush and Congress--have seen an unparalleled explosion of knowledge about neurological disorders. New technologies are forcing even complex diseases like MS to yield up their secrets. These burgeoning opportunities in the field of neurological research have prompted the National Advisory Neurological Disorders and Stroke Council to suggest that an effective treatment for and the cause of MS may be found during the Decade of the Brain. The former has already been achieved; scientists continue to diligently search for the latter. Their dedication is the best hope for a cure, or, better yet, a way to prevent MS altogether.

Information resources
BRAIN
P.O. Box 5801
Bethesda, Maryland 20824
800-352-9424
www.ninds.nih.gov

In addition, a number of private organizations offer a variety of services and information that can help those affected by MS. They include:
National Multiple Sclerosis Society
733 3rd Avenue, 6th Floor
New York, NY 10017-3288
212-986-3240
800-FIGHTMS (344-4867)
212-986-7981 (fax)
e-mail: nat@nmss.org
www.nationalmssociety.org/

Multiple Sclerosis Association of America
706 Haddonfield Road
Cherry Hill, NJ 08002
856-488-4500
800-532-7667
856-661-9797 (fax)
e-mail: msaa@msaa.com
www.msaa.com

Multiple Sclerosis Foundation
6350 North Andrews Avenue
Fort Lauderdale, FL 33309-2130
954-776-6805
888-MSFocus (673-6287)
954-351-0630 (fax)
e-mail: support@msfocus.org
www.msfocus.org/

American Autoimmune Related Diseases Association
22100 Gratiot Avenue
Eastpointe
East Detroit, MI 48201-2227
586-776-3900
800-598-4668
586-776-3903 (fax)
aarda@aol.com
http://www.aarda.org

Boston Cure Project for MS
300 Fifth Aveenue
Waltham, MA 02451
781-487-0008
781-487-0009 (fax)
e-mail: info@bostoncure.org
www.bostoncure.org

Information update: March 2002
On March 7, 2002, the U.S. Food and Drug Administration announced the approval of Rebif (Interferon beta-1a) for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability.

This information was developed by the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

National Institute of Neurological Disorders and Stroke, National Institutes of Health. Multiple Sclerosis: Hope Through Research. Available at: http://www.ninds.nih.gov/health_and_medical/pubs/multiple_sclerosis.htm. Last accessed June 9, 2004.

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