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•	Multiple sclerosis

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Multiple sclerosis

Highlights

Natalizumab (Tysabri)

• In June 2006, the FDA allowed natalizumab (Tysabri) to return to the market, but with certain restrictions. Natalizumab is only for patients who have not responded to other multiple sclerosis drugs. Patients who receive natalizumab must enroll in a special program run by the drug’s manufacturer. Natalizumab was withdrawn in 2005 after reports that it caused progressive multifocal leukoencephalopathy (PML), a serious neurological disease.
• The benefits of natalizumab may outweigh the risks, according to several studies published in 2006 in the New England Journal of Medicine. The studies showed that natalizumab helps prevent relapse and disability. In one study, natalizumab slowed the rate of relapses by 68% when the drug was used as a single therapy.
• Another study suggested a very low risk of PML when natalizumab is used for a relatively short period of time. The study found that patients who received natalizumab for an average of 18 months had around a 1 in 1,000 risk of developing PML. The risks for longer-term treatment are unknown.

Interferon Drug Warning

Interferon beta 1-a (Avonex) and interferon beta 1-b (Betaseron) may cause serious liver damage and possible liver failure. Patients who take interferon drugs should have regular liver function tests, especially when they begin drug treatment. They should also avoid drinking alcoholic beverages while taking interferon.

Risk Factors

• Epstein Barr virus (EBV), which causes mononucleosis, may be associated with multiple sclerosis. Some people who develop multiple sclerosis many years after EBV infection have abnormally high levels of antibodies to the virus in their blood.
• Birth control pills may reduce a women’s risk of developing multiple sclerosis, suggests a study in the Archives of Neurology. Researchers think that estrogen has a protective effect.

Introduction

Multiple sclerosis (MS) is a disease of the central nervous system (CNS), the nerves that comprise the brain and spinal cord. It has two major features:

• Destruction of myelin, a fatty insulation covering the nerve fibers, is the main characteristic of MS. The end results of this process, called demyelination, are multiple patches of hard, scarred tissue called plaques. (Multiple sclerosis is well named. Sclerosis comes from the Greek word skleros, which means hard.)
• Destruction of axons, the long filaments that carry electric impulses away from a nerve cell, is also a major factor in the permanent disability that occurs with MS.

Myelin is the layer that forms around nerves. Its purpose is to speed the transmission of impulses along nerve cells.

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 two major symptom categories:

• Relapsing-remitting
• Chronic-progressive

Chronic-progressive MS is often subcategorized as primary-progressive, secondary-progressive, and progressive-relapsing.

Recent evidence suggests that the disease process starts long before symptoms begin. By the time symptoms appear, there are often already signs of brain and spinal cord atrophy. MS' cause is unknown, and it cannot be prevented or cured. It is not fatal, however, and great progress is being made in treating it and identifying underlying mechanisms that trigger this disease.

Relapsing-Remitting Multiple Sclerosis

Relapsing-remitting multiple sclerosis generally occurs in younger people and is the most common form of MS. It generally follows this course:

• Most patients first experience a single attack of symptoms called a clinical isolated syndrome, which typically occurs between the ages of 20 and 40 years. Once a second attack occurs, the patient is considered to have relapsing-remitting multiple sclerosis.
• The characteristic feature of relapsing-remitting MS is the attack (also referred to as relapse, flare-up, or exacerbation), which is a bout of specifically MS symptoms (facial pain, Lhermitte’s sign, or bladder instability) that lasts at least 24 hours and typically several days. Such attacks are fairly mild in about half of patients with this form of MS.
• The disease then goes into remission (when symptoms improve or disappear), usually for about 4 to 8 weeks. To be considered a remission, attacks need to be separated by at least 30 days. Remission periods may be spontaneous or induced by immunosuppressive drugs. A person with multiple sclerosis in remission may have subtle attacks and not realize it. For example, hands 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 relapses, in which symptoms flare-up or the patient experiences a period of deteriorating ability.

About 20% of patients with relapsing-remitting MS experience little or no progression after a first attack for long periods of time, although by 25 years most patients have converted to a progressive phase.

Chronic-Progressive Multiple Sclerosis

The term chronic-progressive multiple sclerosis is used to describe cases in which symptoms continue to worsen slowly without remission. 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 generally follows a downhill course, but its severity varies widely. Three variants are commonly used to define this patient group:

• Secondary-Progressive MS (SPMS). SPMS is the natural evolution of relapsing-remitting MS and develops in about half of patients during the first 10 years and nearly all of them within 25 years. It follows a progressive course of nerve and muscle deterioration with occasional acute flare-ups, remissions, and plateaus.
• Primary-Progressive MS (PPMS). PPMS progresses continuously and gradually from the first onset of symptoms and has no remissions. 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.
• Progressive-Relapsing MS (PRMS). PRMS is progressive from the start with acute symptom flare-ups, but may have some relapses with continued deterioration between them. It occurs in less than 5% of patients.

Because the natural courses of primary-progressive and progressive-relapsing MS are similar, some experts believe this distinction is unnecessary.

Click the icon to see an image depicting multiple sclerosis.

The Autoimmune Disease Process

Multiple sclerosis is referred to as an autoimmune disease. 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 so produces antibodies that attack. In other words, the body becomes allergic to itself, a condition known as autoimmunity.

Autoimmunity may develop when the body's immune system is damaged by genetic or environmental factors or both, causing it to attack its own tissues. In the case of MS, the immune system attacks the tissues that make up myelin:

• Myelin is made from layers of cell membranes that are produced in the brain and spinal cord by specialized cells called oligodendrocytes. The destruction of this myelin sheath during the disease process is the hallmark for multiple sclerosis.
• The myelin coat is distributed 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.
• As the myelin insulation is destroyed, signals transmitted from nerve cell to nerve cell throughout the central nervous system are disrupted.
• Experts once believed that axons themselves were spared during the disease process. Research, however, has shown that many are severed in MS and, in fact, axon destruction appears to start at an early stage in the disease and may be a major cause of its irreversibility.

The body often makes corrective actions to offset the effects of the nerve cell destruction:

• For example, researchers have observed an increase in the density of the sodium channels, which carry electric charges. By increasing their numbers, the nerve cells can continue to communicate, in spite of the loss of myelin.
• The nerves also retain some capacity to remyelinate (to restore the insulating myelin).

Such processes are probably responsible for the remissions that most patients experience. Unfortunately, the disease process nearly always eventually outpaces these corrective actions.

Onset of Multiple Sclerosis: The Autoimmune Process and the Inflammatory Response

The Normal Immune Response.

• The most important critical immune factors in the disease process are white blood cells called lymphocytes, which consist of T cells and B cells. These cells are the warriors in the immune defense system.
• Receptors on T cells acquire the ability to recognize specific molecules called antigens. Antigens are typically proteins from infecting organisms, such as bacteria or viruses, and perceived as a threat to the body.
• Once the antigen is identified, specific T cells, called helper T cells, trigger the B cells to release antibodies. These molecules are designed to attach to and destroy the targeted antigen.

Autoimmunity.

• Multiple sclerosis, and probably all autoimmune diseases, involves an error in the education of T cells, which makes them unable to distinguish self from non-self.
• In multiple sclerosis, the miseducated T cells mistake molecules in the body's own myelin as a foreign antigen. Such targets are referred to as self-antigens.
• In response to detection of these self-antigens, the T cells set off the usual cascading immune events, including the release of B lymphocytes, to rid the body of the perceived threat.
• The B lymphocytes fire off antibodies as usual, but in this case they are referred to as autoantibodies, because they are attacking antigens that belong to the body's own self.
• In MS, the immune system is tricked into targeting self-antigens that are myelin proteins, the fatty insulation covering the nerve fibers. Another autoantibody target may be the oligodendrocytes themselves -- the specialized cells that make up myelin.
• To make matters worse, the process perpetuates through a cascading series of events in which the B cells and T cells continue to interact, creating numerous different self-antigens. The attacks continue and, in the process, the original self-antigen is unrecognizable.

Cytokines and the Inflammatory Response. The inflammatory response is the product of an overactive immune system and is a major destructive force in an autoimmune disease.

• Once the lymphocytes have launched a response to an antigen, they also release masses of other white blood cells to gather at the injured or infected site.
• The major players in this response are white blood cells called leukocytes. Researchers are particularly interested in leukocytes called cytokines. These are small powerful proteins that, in tiny amounts, are indispensable for healing. When they are overproduced, however, which occurs in MS, they play a major role in the destructive process.
• Their intensive convergence on the affected area causes it to be become inflamed and injurious to the very cells they are designed to protect. 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 damage occurs in the surrounding tissues.

Important cytokines in MS appear to be tumor necrosis factors, interleukin-12, and interferon-gamma. Other cytokines, including interleukin-10 and transforming growth factor beta, may play a protective role and help block inflammatory activity.

Axon Destruction and Progression of MS

The inflammatory response may trigger the disease, but afterward a progressive course takes over that does not appear to be related to inflammation. Experts have found that destruction of axons, the long filaments that carry electric impulses away from a nerve cell, is a major feature of multiple sclerosis. In fact, it may be the major cause of permanent disability that occurs with this disease. Microscopic studies reveal that axons are injured early on as "bystanders" while myelin is being peeled off. As the disease progresses, these weakened and exposed axons degenerate further. Most of the damage occurs early in the disease process and decreases over time, although some destruction can still be observed years and decades afterward. Such evidence is having significant effect on approaches to treatment and research.

Symptoms

Most patients first experience multiple sclerosis as a single attack of symptoms called a clinical isolated syndrome, which typically occurs between the ages of 20 and 40 years. Once a second attack occurs, the patient is considered to have relapsing-remitting multiple sclerosis. Much less commonly, the disease is progressive from the start and symptoms are more or less continuous.

Early Symptoms

Early symptoms may include the following:

• Optic neuritis and other problems in the eye. Optic neuritis, which is inflammation of the nerves in the eye, affects over 50% of patients and is the first symptom in about 16% of them. Symptoms include unclear or doubled vision, usually in one eye. Some people see a shimmering effect. Patients may also experience pain or involuntary jerking or movement of the eye (called nystagmus). In 20% of people with this condition, MS develops within 2 years after the onset. In 45 - 80%, MS develops within 15 years. About 17% of people eventually experience impaired eye movement.
• Fatigue. Fatigue is typically worse in the afternoon and may be accompanied by an increase in body temperature. At the onset, this occurs in about 20% of patients, but as the disease progresses, this is a significant symptom in nearly all patients.
• Changes in sensations in the arms and legs. Patients can experience heaviness, weakness, or clumsiness in the limbs. Tingling or loss of sensations can also occur, most commonly in the legs. The first symptoms for patients with primary progressive MS often develop slowly in the upper legs.
• Muscle weakness in the legs and poor coordination.
• Lhermitte’s sign. This is an electrical sensation that runs down the back and into the legs, which is produced by bending the neck forward.
• Spasticity. Spasticity is the inability to control muscle tone and leads to spasms and stiffness. It is very common in MS.
• Disturbances in the bladder.

Additional Symptoms That Occur Over Time

In addition to the persistence of early symptoms, some patients experience the following symptoms as the disease progresses:

• Imbalance and dizziness.
• Tremors.
• Facial pain.
• Spasm-related symptoms. They include burning, itching, aching, quivering sensations. They usually occur in the extremities and last seconds to minutes.
• Speech difficulties.
• Difficulty swallowing.
• Symptoms in the gastrointestinal, urinary, and genital tracts. Possible sexual dysfunction and loss of bowel and bladder control in severe cases.
• Emotional mood swings. Depression is very common. About 10% of patients suffer from psychosis (manic depression and paranoia). About 5% of patients with severe MS experience uncontrolled and extreme mood swings called the laughing/weeping syndrome.
• Problems in concentration and memory.
• Hearing loss.

Possible Symptom Triggers

Viral Infections. Viral infections are known to worsen MS. In a 2003 study, for example, the risk for an exacerbation of symptoms tripled within a month of an infection.

Heat. Heat, whether generated by ambient temperature, infection, or physical activity, worsens MS symptoms in about 60% of patients.

Stress. There is a strong correlation between severe stress and exacerbation of MS symptoms. For example, in one study, 85% of instances of MS exacerbations were associated with stressful events that occurred within an average of 14 days before the episode. Stress is not a cause of MS, however.

Trauma. Some experts believe that injury (trauma) to the head, neck, or upper back may trigger new or recurrent symptoms by disrupting the blood-brain barrier and allowing immunological attacks on the brain. This is a highly controversial theory, however, with very little supporting evidence.

Causes

The cause, or causes, of multiple sclerosis remains a mystery. Genetic factors certainly play a role in MS. No single gene, however, is likely to be responsible for causing MS. Rather, the current theory is that the disease occurs in people with a genetic susceptibility who are exposed to some environmental assault (a virus or a toxin) that disrupts the blood-brain barrier. Immune factors converge in the nerve cells and trigger inflammation and an autoimmune attack (a self-attack) on myelin and axons. Still, a number of disease patterns have been observed in patients, and some experts believe that MS may prove to be not a single disorder, but may represent several diseases with different causes.

Some research suggests that all autoimmune diseases are basically due to the same genetic error. A 2001 study found, for example, that the T-cell immune factors in type 1 diabetes target the same self-antigens as in multiple sclerosis (MS). Many questions are unanswered, however. It is not known why the diseases develop in different locations to cause separate disorders. Nor, why some autoimmune events occur in everyone but not everyone develops an autoimmune disease.

Genetic Factors

Genetic factors probably play some role in making a person susceptible to the disease process leading to multiple sclerosis. In particular, abnormalities in the human leukocyte antigen (HLA) region located on chromosome 6 appear to be more prevalent among people with MS. Researchers theorize, however, that a combination of genes (not a single gene) is implicated in the development of MS, and the risk for someone inheriting all of these genetic factors is less than 5%. Advanced techniques called microarray technologies are now making it possible to scan hundreds of genes and identify those most likely to be contributors to MS. Genetic research may also pave the way for the development of new drugs to treat this disease. For example, researchers have recently identified the Olig1 gene as a key regulator in repairing damaged myelin-producing cells.

Infectious Organisms

Infectious organisms, most likely viruses, are the top suspects for triggering the autoimmune response in people genetically susceptible to MS. There are a number of reasons for this belief:

• The geographical distribution of the disease. The number of MS cases increases the further one gets from the equator in either direction.
• Multiple sclerosis clusters. Four separate clusters of multiple sclerosis outbreaks occurred between 1943 and 1989 in the Faroe Islands, located between Iceland and Scandinavia. During World War II, this region was occupied by British troops. The incidence of MS increased each year for 20 years after the war, leading some researchers to think that the troops might have brought with them some disease-causing organism. In fact, one theory suggests that these findings offer evidence that MS is a sexually transmitted infection that occurs during adolescence. For example, the disease clusters observed in the Faroe Islands could be related to high sexual activity between the troops and local young women. A high incidence of MS is found in countries with a high degree of sexual permissiveness. MS is also very rare in traditional cultures, but increases in people from these regions when they immigrate to industrialized Western nations.
• Viral similarity to myelin. 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, and others may keep the process going.

Infectious Organisms Under Suspicion. Although many infectious microorganisms have been investigated, no one organism has emerged as a proven trigger. It is possible different patients may be affected by different organisms, and that infections cause some, but not all, cases of MS. Organisms that are at the top of the suspect list are those that can affect the central nervous system. The following are three primary suspects:

• HHV-6. Herpesvirus 6 (a form of herpesvirus that causes roseola, a benign disease in children) is also known to cause encephalitis (brain inflammation) in patients with impaired immune systems. A number of studies have reported higher than normal rates of HHV-6 infection in patients, and some experts believe that may be important in MS. Other experts argue, however, that nearly everyone harbors this virus and there is still no evidence of a causal relationship. Other herpes viruses can also infect brain cells. They include herpes simplex 1 and 2 (the causes of oral and genital herpes), varicella-zoster virus (the cause of chicken pox and shingles), and cytomegalovirus.
• Epstein-Barr virus (EBV). Evidence suggests an association between EBV, the cause of mononucleosis, and MS. EBV is an extremely common virus and another member of the herpes virus family. Nearly all people have been exposed to EBV. However, researchers have discovered that people who are especially sensitive to the virus and have unusually high levels of EBV antibodies may have a greater risk of developing MS. Scientists are still uncertain if EBV is a cause of MS. EBV has also been linked to other autoimmune diseases such as lupus.
• Chlamydia Pneumoniae. This atypical bacterium has been associated with persistent inflammation. A few studies have reported significantly higher rates of previous Chlamydia infection in patients with MS than in individuals without MS. An important group of 2000 studies reported no connection at all between Chlamydia and MS, and any experts now believe there is no strong evidence linking the microbe to MS. It is still possible, however, that the infection, which can cause widespread inflammation, plays a role early in the course of the disease in some individuals.

Other viruses that have been investigated include measles virus, adenovirus, and the retroviruses (HIV, HTLV-I, and HTLV-II), but none have emerged as having any importance.

Note on Vaccinations: Concerns about a link between the hepatitis B vaccine and MS led France to halt a major vaccination program in 1998. Subsequent research investigating whether the hepatitis B vaccine is indeed associated with an increased risk of MS has yielded mixed results. It appears that the vaccine would be, at most, a contributing-- but not the sole-- factor in MS development. At present, the evidence has not warranted any change in American immunization policies. Research has ruled out a link between any other vaccinations, such as or influenza or tetanus, and relapses of MS.

Risk Factors

An estimated 400,000 Americans and 2.5 million people worldwide suffer from MS.

General Risk Factors

Age. Onset occurs between the ages of 20 to 40 years in 70% of patients with the average age being 30 and the peak incidence occurring in the mid-twenties. The disease can still occur in both younger and older individuals. It rarely develops before age 15 or after age 60, however.

Gender. Women are affected twice as often as men (although among older individuals there is less of a gender difference). The incidence in women also appears to be increasing, at least in the US. In a 2002 study, prevalence of MS in women in the early 1990s was 50% higher than in the early 1980s. Men may be more disabled by the disease than women.

Ethnicity. 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, Africans, and Native Americans. Specific groups (gypsies, Eskimos, Bantus) have never reported a case. While the risk of MS for African Americans is around half of that for Caucasian Americans, a recent study suggested that African Americans are more likely to develop a more aggressive form of the disease and to suffer impaired mobility.

Geography. The risk for MS is higher in different regions of the world. In general, MS is more prevalent in temperate regions than in the tropics. Specifically, prevalence is highest in northern and central Europe (except northern Scandinavia), Italy, southern Australia, and northern regions of North America. Middle-risk areas include southern Europe (except Italy), southern US, northern Australia, and northern Scandinavia. Low-risk areas include parts of Africa and Asia, the Caribbean, Mexico, and possibly northern South America. It is unclear whether this pattern is attributable to environmental factors, genetics, or both.

Family History. A family history of the disease also puts people at risk for MS, although the risk for someone inheriting all the genetic factors contributing to MS is only about 2 - 4%. Nevertheless, when siblings have the disease, they are more likely to have the same degree of severity. Among identical twins the risk is about 25 - 30%.

Factors Associated with a Higher Risk for Multiple Sclerosis

Cow's Milk During Early Infancy. Breast milk contains factors that may help regulate the immune response, and there is some evidence that infants fed only on cow's milk may have a higher risk for either diabetes type 1 (another type of autoimmune disease) or multiple sclerosis later in life. Studies on national differences in diabetes suggest that the risk may vary with different milk proteins, suggesting that not all cow's milk is the same and some proteins carry higher risks than others.

Factors Associated with Lower Risk for Multiple Sclerosis

The Hygiene Theory: Early Infections as Protection Against Allergies and Autoimmune Diseases. Over the past decades, there has been a dramatic increase in asthma, allergies, and autoimmune diseases, such as multiple sclerosis, Crohn's disease, and type 1 diabetes. One theory blames this rise on the reductions in childhood infections that have occurred with modern hygiene and antibiotic use. Studies supporting this have observed a higher incidence of allergies and autoimmune diseases, including MS, among populations with good hygiene and in animals that have been raised in a germ-free environment. The basic theory rests on the idea that early infections stimulate production of specific immune factors that protect against allergies and autoimmune diseases. The exact mechanisms of these effects are as yet unknown. Of note, there is no evidence indicating either a positive or a negative role of vaccinations in the development of autoimmune or allergic diseases.

Exposure to Sunlight. In a 2003 study, higher exposure to sunlight during childhood and early adolescence was associated with a lower risk for MS, perhaps because UV radiation produces higher levels of vitamin D, which has been associated with protection against MS. The effect of sunlight during winter seemed to be more protective than summer light. Unfortunately, higher exposure to sunlight also coincides with a higher risk for skin cancer, which is far more common than MS.

Estrogen and Oral Contraceptives. Higher estrogen levels may temporarily lower the risk of developing multiple sclerosis. Studies indicate that oral contraceptives (which contain estrogen) and pregnancy delay the onset of multiple sclerosis. The risk for a first clinical attack increases, however, in the 6 months after a woman gives birth.

Complications

Multiple sclerosis is not a fatal disease. Some data suggest that it shortens the average life span by only about 6 or 7 years. Still, in about half of MS cases, patients die of complications of the disease, and the disease has significant negative emotional and physical consequences. Suicide rates among patients with MS are higher than average.

The severity of the disease varies widely from patient to patient and is unpredictable. About 20% of patients remain asymptomatic or become only mildly symptomatic after an initial clinical event. Another 20% experience a rapidly progressive condition. Most patients, however, will experience some degree of progression.

Women tend to have a better outlook than men. Factors the determine a higher risk for a severe condition include:

• Age over 40 years at the time of onset of symptoms
• Initial symptoms that affect motor control, mental functioning, or urinary control, or initial symptoms affect multiple regions
• Attacks in the first years that are frequent or interval between the first two attacks is short
• Incomplete remissions
• Rapid progression to disability
• MS that is progressive from the beginning or becomes progressive shortly after the onset

Doctors and researchers often use a scale called the Kurtzke Disability Status Scale to assess and predict future disability. The system uses a score of 1 to 10 to rate the degree of walking disability. Experts have used the scale to attempt to predict average times for progression from one stage to the next depending on whether patients have relapsing-remitting or chronic progressive MS.

Specific Physical Complications of Multiple Sclerosis

Because the effects of nerve injury are widespread, complications can be very severe and affect all parts of the body. Although not all patients experience all of the following problems, any of them can negatively impair quality of life.

Fatigue. Fatigue is one of the most common and debilitating MS symptoms and affects at least two-thirds of patients with MS. Fatigue specifically attributed to MS and not to other causes is defined as abnormal fatigue that lasts at least half of the time or more than 6 weeks. It causes a general lack of energy that significantly limits daily functioning regardless of any neurologic symptoms or specific muscle weaknesses. Up to 40% of patients describe fatigue as the most disabling MS symptom, which is higher than weakness, spasticity, motor control, or bowel or urinary problems. Many conditions that are common in MS (sleep disorders, depression, hypersensitivity to sensation, hypothyroidism, medications, heat) may contribute to fatigue. None fully explain the consistent presence or severity of this problem in MS. Researchers using imaging techniques have identified possible changes in part of the brain in MS that may play a role in the fatigue of MS.

Loss of Mobility and Spasticity. Nearly every patient loses some mobility, which may take the form of less or impaired motor control, muscle weakness, impaired balance, and, importantly, spasticity. Spasticity is one of the primary symptoms of MS. It 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.) Mobility can be affected by many non-physical factors including mental well-being, social networks, fatigue, and even the weather.

Pain. About two-thirds of patients experience pain at some point during the course of the disease and 40% are never pain free. MS causes many pain syndromes; some are acute while others are chronic. Some worsen with age and disease progression. Pain syndromes associated with MS are trigeminal (facial) pain, powerful spasms and cramps, optic neuritis (pain in the eye), pressure pain, stiffened joints, and a variety of sensations including feelings of itching, burning, and shooting pain.

Bowel Dysfunction. Bowel dysfunction, which can include constipation or fecal incontinence, is a serious problem for many patients. Constipation may be caused by the disorder itself or by medications used to treat spasms or other symptoms.

Sexual Dysfunction. Sexual dysfunction is a common problem, occurring in over 70% of patients. Men are likely to have impotence and women, problems with vaginal lubrication. It appears to be highly associated with urinary dysfunction.

The nerves that branch off the central nervous system (CNS) provide messages to the muscles and organs for normal function. When there is CNS damage, the function of these organs and tissues may be compromised. In multiple sclerosis, the demyelinization of nerve cells may lead to bowel incontinence, bladder problems and/or sexual dysfunction.

Urinary Dysfunction. Urinary problems from bladder dysfunction occur in two-thirds of patients. Some patients have difficulties in urinating at will, called urinary retention. Often it takes the form of urge incontinence (also called hyperactive or irritable bladder). People with urge incontinence need to urinate frequently or are unable to reach the bathroom before leakage. In such cases, the bladder is overactive. Complications in the urinary tract also produce a high rate of urinary tract infections.

Difficulty Swallowing. A third to a half of patients experience difficulty in chewing or swallowing, problems that may be caused or made worse by many MS medications.

Speech and Hearing Problems. Problems in speech may occur because of difficulty in controlling the quality of the voice and articulating words. (Problems with language itself, however, are very rare in MS.) Hearing problems also occur in MS and may affect speech.

Problems in the Lungs. As the muscles that control breathing weaken, the ability to cough is impaired and the patient is at higher risk for pneumonia and other complications in the lungs.

Osteoporosis. Osteoporosis (loss of bone density) and subsequent fractures are common and under-recognized problems among patients. Osteoporosis is caused and worsened by immobility and by some MS medications. Fractures caused by falls can be far more serious in patients than in the normal population, leading to problems including deconditioning or even inability to walk, obstruction of the intestines (from pain-relieving medications), and respiratory complications.

Problems in Thinking and Concentration

Cognitive problems, such as having trouble concentrating and solving problems, affect about half of patients. More people with MS leave work because of such cognitive difficulties than because of physical problems, according to a 2000 study. In about 10% of cases mental dysfunction may be severe and resemble dementia. The severity of such mental changes appears to be associated with the degree of loss of brain tissue. This offers another argument for early treatment as interferon medications may improve these symptoms.

Depression

Between 40 - 60% of patients suffer from depression at some point over the course of the illness, and studies have reported risks for suicide ranging from 3 - 15%. There is some evidence that depression in multiple sclerosis is not only due to the social and psychologic impact of MS but to the disease process itself. Depression may have biologic effects, such as increasing production of inflammatory cytokines, that could exacerbate the disease itself. Doctors should assess patients for depression, even if there are no obvious signs of it. The risk for suicide may be present even in patients who are not obviously depressed. People at highest risk for suicide are those who live alone, those with a history of an emotional disorder (depression, anxiety, alcohol abuse), a family history of mental illness, and people with high social stress.

Diagnosis

Multiple sclerosis is characterized by recurring neurologic episodes that are due to multiple lesions (injured areas) in different locations in the central nervous system. The diagnostic challenges in multiple sclerosis are two-fold:

• Making an initial diagnosis as early as possible in order to slow down the disease progression. Most patients first seek medical help after an initial inflammatory event (known as a clinically isolated syndrome) originating from demyelination in the eye, the spinal cord, or the brain. About 30% of these individuals will develop progressive MS within the year. At this time, however, experts cannot predict who among these patients are at highest risk for rapid progression.
• Predicting the severity of the disease. Once MS has been diagnosed, the pattern of the disease is uncertain. It can be very benign to rapidly progressive and severe. Magnetic resonance imaging (MRI) is able to detect lesions in the brain indicating MS. But, the severity of the disease does not appear related to the number of lesions, the rate of their appearance, or their location. Researchers are hoping to identify some biologic marker, possibly certain antibodies, that will enable doctors to accurately determine the onset and severity of the problem once a diagnosis has been made.

The McDonald Criteria. There is no single test that can accurately diagnose MS and a number of other conditions may mimic its symptoms. Some doctors use a set of factors, called the McDonald criteria, for diagnosing multiple sclerosis in early stages. The criteria include the presence of specific symptoms, spinal fluid evaluation, and magnetic resonance imaging techniques for detecting lesions within the central nervous system and tracking them over time. The criteria show high reliability in identifying MS in patients with a variety of disease stages or states, including having only one episode, having a typical relapsing-remitting course, or having a slow insidious progression without clear attacks or remissions. Depending on the MRI and other findings, the patient is then categorized as having MS, possible MS, or no MS.

Ruling Out Other Disorders

The symptoms of MS are similar to a number of other diseases, which must be ruled out. These include stroke, alcoholism, emotional disorders, Lyme disease, chronic fatigue syndrome, fibromyalgia, AIDS, and certain other autoimmune disorders (hypothyroidism, scleroderma, Sjögrens syndrome, and systemic lupus erythematosus).

Expanded Disability Status Scale

Doctors and investigators generally use a test called the Expanded Disability Status Scale (EDSS) to rate the severity of symptoms. It is also used after a diagnosis to gauge the status of the disease, and score the effectiveness of treatments. The scale ranges from 0 to 10 with higher scores indicating more severe symptoms. These are subjective ratings that require doctor observation skills.

Objections to the use of the EDSS are that it assesses only limp and walking problems and does not assess other important complications, including fatigue, sexual function, and mental function.

Laboratory Tests

No reliable single laboratory procedure or test can establish the diagnosis of multiple sclerosis. Several are necessary before a diagnosis can be made.

Analysis of Cerebrospinal Fluid (CFS). Obtaining a sample of spinal fluid requires a lumbar puncture, or spinal tap. Testing spinal fluid is becoming increasingly important for detecting abnormal proteins, tiny fragments of myelin, or specific white blood cells that can help in making a diagnosis. For example, high levels of the immunoglobulin IgG is useful for making a diagnosis and may be a marker for disease progression. (Immunoglobulins are protein chains that are part of the immune system.)

A lumbar puncture, or spinal tap, is a procedure to collect cerebrospinal fluid to check for the presence of disease or injury. A spinal needle is inserted, usually between the 3rd and 4th lumbar vertebrae in the lower spine. Once the needle is properly positioned in the subarachnoid space (the space between the spinal cord and its covering, the meninges), pressures can be measured and fluid can be collected for testing.

Evoked Potential (EP) Test. This is a simple and painless electrical test of nerve function that assesses how long it takes nerve impulses from the eye, ear, or skin to reach the brain.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) scans are important diagnostic tools in MS and are used for diagnosing multiple sclerosis, tracking changes over time, and helping to determine treatment effectiveness.

Click the icon to see an image of a brain MRI.

Making a Diagnosis and Tracking the Disease. Magnetic resonance imaging (MRI) scans can detect bright patches that indicate injured tissue (lesions) caused by MS. Such lesions may also indicate other conditions such as infections, migraines, or clots. Importantly, a very sensitive MRI technique using enhancement by an contrast material called gadolinium can indicate recent activity by showing if the blood-brain barrier has been broken down (the first step in the development of MS lesions). Detecting lesions and treating MS early in the disease process may help reduce progression. Many experts therefore now advocate performing a brain MRI as soon as symptoms appear.

Once diagnosed, periodic follow-up MRIs can be used to track the disease and effectiveness of treatments in two ways:

• By distinguishing new lesions from old ones
• Revealing increasing or decreasing numbers of lesions within the central nervous system over time

Unfortunately, neither the rate nor the number of new or growing lesions necessarily predicts whether symptoms will worsen or if the patient will develop secondary progressive MS.

Measuring Atrophy in Brain and Spinal Cord. As myelin, axons, oligodendrocytes, and neurons are destroyed, the brain begins to shrink. Processing MRI images to determine brain volume may be a useful way to monitor progression and treatment effects. MRI can also detect shrinkage in the spinal cord, which is proving to be a very strong marker of disease progression. A variation of MRI, magnetic resonance spectroscopy (MRS), provides information on the biochemistry of the brain, and may be particularly helpful in detecting this destructive aspect of MS.

Detecting Black Holes.Severe disease progression can be gauged by the presence of so-called "black holes.” These are lesions in the brain that emit very low signals on an MRI scan. Some evidence suggests that they may represent iron deposits in the brain.

Investigative Laboratory Tests

Researchers are continuously searching for biologic markers that might help make an accurate diagnosis, predict outcome, or both. Promising markers are antibodies that target two key protein components of myelin: Myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP). If future studies confirm the predictive value of these antibodies, scientists may be able to develop a blood test for MOG and MBP.

Treatment

Patients diagnosed with multiple sclerosis face great uncertainty, since the course of the illness varies so widely among patients. Experts recommend a multidisciplinary approach to the disease, which might involve a neurologist, a nurse or social worker expert in MS, and possibly a specialist in mental health (since depression is so common and the suicide rate is higher than average).

Decisions to Treat MS after First Indications (Clinically Isolated Syndromes)

Evidence now strongly suggests that the most destructive changes from multiple sclerosis in the brain occur very early on in the disease process -- and may cause considerable damage even before symptoms begin.

Many experts are now urging treatment after a first episode of relapsing MS (a clinically isolated syndrome) using medication called disease-modifying drugs. They include three interferons -- IFN1b (Betaseron) and IFN1a (Avonex, Rebif)--and glatiramer (Copaxone). These drugs are all effective and may help slow down or even prevent progression in some patients. Definitive studies comparing them are ongoing.

The best current approach is to use specific findings from advanced MRI techniques to help determine which patients are at highest risk for progression and would be likely candidates for early treatment with disease modifying drugs.

Interferons and other disease-modifying drugs can have significant side effects and are expensive. Furthermore, a significant number of patients have a mild course that can be managed with less toxic drugs. Nevertheless, strong evidence suggests that delaying treatment in most patients increases the risk for severe disability.

Treating Acute Relapses

Corticosteroids are the standard drugs for treating an acute relapse and hastening recovery. Typically, intravenous methylprednisolone (IVMP) is given once a day for 3 days. Sometimes this is followed by oral prednisolone for a few days.

Maintenance Treatment for Relapsing-Remitting Multiple Sclerosis (RRMS)

Disease Modifying Drugs. Since the introduction of the disease modifying drugs -- interferons beta (Betaseron) and alpha (Avonex, Rebif) and glatiramer (Copaxone) -- relapsing-remitting multiple sclerosis is now considered a treatable disease. In patients with very active MS, some experts start with Betaseron or Rebif. For patients with possible or probable MS, they begin with Avonex. This drug is slightly less effective than Rebif and Betaseron but has fewer side effects. Copaxone is also be a reasonable choice for early mild MS. It appears to have the fewest side effects, longer relapse-free rates than interferons, and its benefits persist for years.

The newest drug, the monoclonal antibody natalizumab (Tysabri) was approved in November 2004 for treatment of relapsing forms of MS. The FDA withdrew it from the market, however, in February 2005 following reports of serious neurological events. In June 2006, the FDA allowed natalizumab back on the market but with special restrictions (see Drug Treatment section).

Other Approaches. Some research has reported benefits from the use of pulsed administration of intravenous methylprednisolone (IVMP) or intravenous immunoglobulin, although there is not enough evidence for either approach to recommend them as first-line choices. Other drugs showing promise include azathioprine (an immunosuppressant) and laquinimod (an oral immune-modulating drug).

Chronic-Progressive Multiple Sclerosis

Treating Secondary Progressive Multiple Sclerosis (SPMS). Interferons and other standard treatments for relapsing-remitting MS may be helpful for patients with SPMS who are still experiencing relapses. It is not clear if they help those whose condition has become continuously progressive.

Mitoxantrone (Novantrone) was the first drug approved for SPMS. The drug is an immunosuppressant and is proving to delay relapse and progression. Side effects, however, can be serious in some cases. Some experts recommend using mitoxantrone when evidence suggests progression to SPMS, and continuing the interferons Betaseron or Rebif for maintenance.

Other immunosuppressants, such as cyclophosphamide, methotrexate, and cladribine, may help some patients with SPMS. They can have very toxic side effects, however, and there must be clear treatment indications for patients who take these drugs.

Treating Primary Progressive Multiple Sclerosis. No treatments have been proven yet to slow progressive multiple sclerosis. Studies using interferons and glatiramer are under way.

Treating Complications

A number of treatments are available for managing symptoms and complications.

Drug Treatment

Corticosteroids

Corticosteroids (commonly called steroids) are mainstay treatments for acute relapses patients with relapse-remitting MS. High-dose methylprednisolone given intravenously (IVMP) is typically administered for major relapse, often followed by oral prednisone for a few days. Steroids reduce inflammation in the central nervous system and may help suppress the immune system's attack on myelin and even improve electrical conduction.

Steroids, in general, do not improve the long-term course of the disease and can lose effectiveness if overused. They are not generally used for maintenance therapy. Some research, however, is reporting benefits from the use of pulsed administration of intravenous methylprednisolone. Such an approach typically administers the steroid daily for 5 days every 4 months for 3 years, then every 6 months for 2 years. Some research suggests that this approach might reduce destruction in central nervous system, although more evidence is needed before it can be recommended. They can also have considerable adverse effects when used over time.

Side Effects. 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 (sleeplessness, memory loss, anxiety, and depression) can be particular problems for patients. It is extremely important to taper withdrawal very carefully after continuously taking steroids for a prolonged period of time. This gives the body time to recover its own ability to produce natural steroids. A serious condition known as adrenal insufficiency can otherwise develop.

Interferons

Interferons (so-called because they “interfere” with viral replication) both suppress important inflammatory factors in the immune system and have anti-viral properties. Interferons specifically block immune factors known as class II MHC molecules, which are associated with the attack on myelin and the breach in the blood-brain barrier that allows the destructive T cells to pass through.

Specific Interferons Used for MS. Interferon drugs used for MS are IFN1b (Betaseron) and IFN1a (Avonex, Rebif). They are now the treatments of choice for relapsing-remitting MS. Expert organizations urge that they be used early in the course of the disease and continued indefinitely, unless they produce no benefits or have severe side effects.

Successes and Drawbacks.  Interferons can reduce flare-ups overall by 30% and have an even greater effect on reducing major relapses. Disease activity, as measured by MRI scanning, is reduced by over 80%. They appear to be about equal in reducing disability. To date, only Avonex has demonstrated slowing progression of mental impairment. It also appears to be better tolerated than other interferons. Studies on their effects on quality of life are limited. None of the interferons is a cure, in any case, and when the drug is discontinued, disease activity may increase. All of these drugs need to be injected. (Oral forms are under investigation.)

Side Effects and Complications. Side effects include:

• Pain at the injection site. Many patients taking Betaseron complain of severe pain at the injection site caused by damaged tissue. Experts recommend taking acetaminophen (Tylenol) before the injection and then every 6 hours after each injection for 24 hours during the first 6 months of treatment.
• Skin injury at the injection site. 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. This side effect is least severe with Avonex, followed by Rebif.
• Other physical side effects. Both drugs cause flu-like symptoms, nausea, vomiting, headaches, and dizziness. Such side effects usually fade after 2 to 3 months.
• Depression. Early studies associated taking interferon with a higher risk for depression during the first 2 to 6 months following initial therapy. More recent studies, however, have reported no greater risk for depression in patients taking any of these drugs. MS itself, in any case, is highly associated with depression.
• Thyroid abnormalities. Interferon has been associated with autoimmune thyroiditis, a cause of hypothyroidism. Some experts recommend monitoring for thyroid function, particularly in the first year and in those with a history of thyroid problems. If there is no evidence of the condition during that period, the risk for its occurrence appears to be very low.
• Liver damage. Interferon may cause liver damage and, in rare cases, liver failure. Patients should avoid alcohol and have regular liver function tests while taking this drug

Neutralizing Antibodies That Reduce Effectiveness. Over time, people taking the interferons develop antibodies to the drugs, some of which can neutralize their effects. The risk for neutralizing antibodies (NAbs) increases with higher doses and greater frequency of use. Interferons injected under the skin (Betaseron, Rebif) are more likely to produce neutralizing antibodies than Avonex, which is injected into a muscle. Patients who experience this, however, often can be effectively treated with an alternative interferon or with glatiramer, which has an extremely low risk, for NAbs. In many cases, after switching drugs, NAb levels decline and the patient may be able to return to the original interferon.

Glatiramer Acetate

Glatiramer acetate (Copaxone) formerly called Cop-1 or 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. Studies indicate that this drug may be superior to others in reducing relapse rates, with a 2003 comparison study reporting relapse free rates of 83% during a 16-month period. The best results are in patients in early stages, but the longer patients remain on the drug, the greater the improvement. Benefits have persisted for years.

Side Effects. Side effects occur in about 15% of patients, usually right after the injection. They include pain at the injection site, chest pain, rapid heartbeat, flushing, anxiety, and shortness of breath.

Natalizumab and Other Monoclonal Antibodies

Monoclonal antibodies (MAbs) are drugs that target specific antibodies involved with the immune response. In 2004, natalizumab (Tysabri) became the only MAb approved for treatment of MS. Shortly afterwards, reports emerged of progressive multifocal leukoencephalopathy (PML) occurring among patients who took natalizumab for more than 2 years. PML is a rare neurological disease that can affect people with compromised immune systems. Based on these reports, the FDA suspended marketing of natalizumab in February 2005 and recommended that patients discontinue its use.

In June 2006, the FDA allowed natalizumab to return to the market with certain safety restrictions. Doctors can prescribe the drug only to patients who have failed to respond to or who cannot tolerate other MS treatments. Natalizumab can only be taken alone, not in combination with other immune-modifying drugs. Patients who take natalizumab must enroll in a special program called TOUCH, which is run by the drug’s manufacturer. Patients need to get magnetic resonance imaging (MRI) brain scans before they begin taking the drug, and they be evaluated regularly during drug treatment to make sure they are not at risk of developing PML.

Clinical trials indicate that natalizumab’s benefits may outweigh its risks. Several studies published in 2006 in the New England Journal of Medicine showed that natalizumab, alone or in combination with IFN1a (Avonex) can help prevent disability in patients with multiple sclerosis. Another study suggested that the risk of PML is very low if patients use natalizumab for less than 18 months.

Other MAbs under investigation for MS include daclizumab and alemtuzumab. Results from a 2005 phase II trial for alemtuzumab (Campath) indicated that the drug helped prevent relapse but also caused serious side effects. Patients who took the drug had a high risk for developing a serious bleeding disorder caused by a low blood platelet count.

Intravenous Immunoglobulin

Intravenous immunoglobulin treatments are monthly infusions of natural antibodies. They appear to have some modest benefits for relapsing-remitting MS. Studies suggests that intravenous immunoglobulin reduces relapse rates and occurrences of new lesions and slows disease progression in relapsing-remitting MS. It does not appear to reduce disability. It is extremely expensive and does not appear to have any benefits for patients with secondary progressive MS.

Immunosuppressants for Chronic Progressive MS

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. Evidence on benefits is uncertain, mainly because of high toxicity or study limitations. Still, some may help some patients with severe MS. Among immunosuppressant drugs or procedures that have been investigated with little or no obvious benefits or unacceptably high side effects are total lymphoid irradiation, sulfasalazine, cyclosporine, acyclovir, and oral bovine myelin.

Mitoxantrone. Mitoxantrone (Novantrone) was the first drug approved specifically for secondary progressive MS. Two studies suggested that it may be of some help in reducing progression and relapse rates. Cumulative doses can have toxic effects on the heart, however, so the drug is only used for a limited period.

Methotrexate. In some patients, low doses of the immunosuppressant methotrexate may slow the course of chronic-progressive MS, particularly in those with secondary progressive MS. To date, studies have found beneficial effects only on the upper body, however. Although this drug, like all immunosuppressants, can have toxic side effects, it may be taken in low doses for MS and so side effects are generally minimal.

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. Small studies suggest that monthly intravenous administration or a combination with interferon-beta may help some patients with rapidly deteriorating MS. 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.

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 sometimes used 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 3 years, although others report only modest benefits. The drug has no effect on progression of disability.

Cladribine. Cladribine (Leustatin) may be effective in delaying progression in patients with chronic progressive MS. It has no significant effect on relapsing-remitting MS.

Experimental Drugs and Treatments

A number of treatments are under investigation that may prove to be helpful for multiple sclerosis. Those discussed below are only some of them.

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 may cause epileptic seizures.

Cannabinoids. Cannabinoids are compounds in marijuana (cannabis), which may have properties that protect nerve cells. Cannabis has been found to improve pain, mobility, tremor, mood, appetite, fatigue, vision, sexual and urinary function, and memory. In a 2003 study, patients reported less pain and improved mobility (although spasticity itself did not improve). Not all patients respond. The drug may also worsen balance and posture in patients with spasticity. Synthetic versions are being investigated that allow rapid delivery without the unwanted side effects of natural cannabis.

Estrogen. Although estrogen is commonly associated with heightened immune factors, some autoimmune diseases, including multiple sclerosis, improve during pregnancy when levels of estriol, a form of estrogen, are high. (Estriol levels are low at other times.) In one small study, estriol treatment was associated with significantly fewer lesions and less disease activity in patients with relapsing-remitting MS. Long-term use may have adverse effects, however, and further research is needed.

T-Cell Modulators. Teriflunomide is being investigated for treating multiple sclerosis with relapse. Although many multiple sclerosis drugs are injected, teriflunomide is taken by mouth. In 2006, a phase II trial of teriflunomide showed promising results in preventing relapses and reducing the number of brain lesions (damaged tissue). Teriflunomide appears to affect the response of the immune system’s T cells.

Plasmapheresis. Plasmapheresis with plasma exchange is a procedure in which blood is removed from the body. Blood cells are separated from plasma (the liquid portion of blood) and mixed with replacement plasma, which is then returned to the body. The replacement plasma is thought to dilute antibodies and other immunologically active substances that may trigger MS. Small investigative studies suggest this procedure may have significant benefits for some patients with severe MS, particularly if they are younger and have an early response to this treatment. Side effects include risk of infection and blood clotting problems.

Oligodendrocyte Implants. A newly developed, minimally invasive method to transplant modified oligodendrocyte cells directly into the brain is under investigation. Such cells stimulate nerve and axon growth. If feasible, this approach might be helpful in patients whose MS is not caused by an autoimmune response (where the new cells would be attacked, just as the patient's own cells were).

Stem Cell Transplantation. Some investigators are studying the benefits of stem-cell transplantation procedures. Stem cells are produced in the bone marrow and are the early forms for all blood cells in the body (including red, white, and immune cells). Early studies indicate that it may slow progression, although at this point it is not a cure.

Statins. Statins (medically referred to as HMG-CoA reductase inhibitors) are currently the most important drugs for lowering cholesterol. They are also showing possible benefits, including anti-inflammatory and nerve protecting properties, which may help patients with neurologic conditions, including multiple sclerosis. In one 2002 study, the statin atorvastatin (Lipitor) improved MS symptoms in mice. Other statins include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), and fluvastatin (Lescol).

Other Treatments

Nontraditional Treatments

Nearly 60% of patients try some form of nontraditional remedies. Research on any benefits is slim and there may be some danger with many remedies commonly used by patients. The following are a few alternative remedies sometimes used for MS.

Relaxation and Meditation Techniques. Generally harmless, and possibly helpful, nontraditional therapies for MS are relaxation and meditation techniques and Eastern martial art exercises. Such techniques include biofeedback, music therapy, yoga, tai chi, and massage therapy.

Acupuncture. Some patients report benefit from acupuncture, which does carry a very small risk, usually for infection.

Acupuncture, hypnosis and biofeedback are all alternative ways to control pain. Acupuncture involves the insertion of tiny sterile needles, slightly thicker than a human hair, at specific points on the body.

Electromagnetic Stimulation. A few centers have studied pulses of weak electromagnetic fields applied to the brain. Very small studies have reported improvement in fatigue, tremors, depression, and other symptoms in patients who were severely affected by MS. In one controlled study, this approach relieved symptoms more effectively than placebo. The effect was small however and more research is needed.

Linoleic Acid. 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.

Oral Enzymes. Oral drugs containing various natural enzymes, including bromelain, trypsin, papain, and rutin, have been used overseas to treat arthritic pain. They appear to reduce inflammation and are also being studied in patients with MS. Such enzymes have been marketed alone and in combinations (Wobenzym, Phlogenzym). In one small study, Phlogenzym was associated with a decline in complications and longer remission. They are not painkillers; any benefits derived from them may take several weeks. As with any natural remedy, there are few clinical studies on these products and no U.S. regulation of quality, safety, or effectiveness.

Treating the Complications

Fatigue

Fatigue affects at least two-thirds of patients. It is among the most disabling problems in MS and is difficult to treat. Treating any problem (depression, hypothyroidism) that may be causing fatigue is important. Aerobic exercise programs scheduled early in the day have been helpful for patients who can participate. Preventing overheating can improve fatigue.

Modafinil (Provigil, Alertec) is a promising drug that promotes long-lasting wakefulness and is currently used in narcolepsy. Small studies report that it is effective in reducing fatigue and sleepiness, with lower doses (200 mg) being more effective than higher ones. Studies also suggest that the antiviral drug amantadine (Symmetrel) may be helpful.

Spasticity and Lower-Limb Pain

Managing pain and spasticity in the lower limbs can be difficult. Although many drugs are used to reduce spasticity and lower-limb pain, most studies investigating these drugs have been poorly designed and no treatment has emerged as a front-runner.

Exercise. 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.

Drugs Used for Spasticity.

• Baclofen (Lioresal) has long been the drug of choice to alleviate more severe spasticity. It is available both orally and infused through an implanted pump. Distressing side effects include confusion, drowsiness, and a rubbery-like sensation in the legs that makes it hard to stand.
• Antiseizure medications, such as gabapentin (Neurontin) or levetiracetam (Keppra) may help reduce spasticity without increasing fatigue or impairing concentration. Studies on gabapentin also suggest that it also have other specific benefits for patients, including reducing facial pain and improving vision.
• Tizanidine (Zanaflex) is an oral drug that works after one week. In one study, 75% of patients taking tizanidine reported improvement without the leg-muscle weakness experienced using baclofen. The drug does not appear to be any more effective than baclofen, however. Side effects include dizziness, drowsiness, dry mouth, and fatigue. Liver function must be monitored.
• Diazepam (Valium) is also used for spasticity and may be 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.
• Botulinum toxin (Dysport) injections are being investigated for spasticity in specific regions such as the hip.
• Dantrolene (Dantrium) may be an effective alternative for patients who cannot tolerate diazepam or baclofen. Because dantrolene causes muscle weakness, however, it is best suited for either patients who are wheelchair 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 it can cause dangerous liver damage.

Surgery. In very severe cases where medication and exercise are not helpful, surgery may be considered. In such cases, the surgeon cuts the tendons that are involved with spasticity.

Spinal Injections. In very severe cases, administering phenol using spinal injections in the lower back may reduce pain and spasms for some patients with severe conditions. Most patients are not appropriate candidates for this approach.

Bladder Dysfunction

Urge Incontinence. Urge incontinence (the need to urinary frequently) is common in patients. To help reduce social difficulties, patients should not drink fluids before going to places where restrooms are not easily available. When possible, they should urinate every 3 to 4 hours. A number of medications are available for urge incontinence, including anticholinergic drugs, such as propantheline bromine (Pro-Banthine), tolterodine (Detrol), or oxybutynin (Ditropan). Sacral nerve stimulation (InterStim) sends electrical pulses to help retrain nerves in the pelvic area, and is also proving to be helpful. Botulinum toxin injection into the urinary tract muscles is being investigated and may be helpful for incontinence caused by spasticity. [See In-Depth Report #50: Urinary incontinence.]

Urinary Retention. Urinary retention occurs in some patients. Sometimes urination can be stimulated simply by pressing the bladder area with the fist or hand, by tapping against it, or by straining. Drugs being tried with some success for this problem are desmopressin (DDAVP), ordinarily used for bed wetting in children, and maprotiline (Ludiomill), an antidepressant. If medication is ineffective, a catheter may be needed, either one used intermittently by the patient or placed in the urinary tract. Various new surgical procedures that reconstruct the bladder or divert urine flow may be effective in severe cases of bladder dysfunction. Because urinary symptoms usually remain intermittent for years, treatment approaches for bladder dysfunction should be limited to medications and other reversible therapies as long as possible.

Urinary Tract Infections. Urinary tract infection is common in patients and a urinalysis should be performed with any symptom flare-ups, any fever, or any change in bladder symptoms. Treatment uses appropriate antibiotic regimens. Some evidence suggests that cranberry juice may help prevent infections. [See In-Depth Report #36: Urinary tract infection.]

Bowel Dysfunction

In addition to maintaining a high-fiber diet and drinking plenty of fluids, bulk fiber 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 for a movement, reduces the risk of losing control later in the day. Exercise helps patients avoid becoming dependent on laxatives, enemas, or colonic irrigation, which can eventually slow down the bowel and cause imbalances in electrolytes. Biofeedback techniques may be helpful in some patients with limited multiple sclerosis.

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 Pain

Trigeminal neuralgia is severe facial pain, usually on one side, that can be very severe and may be triggered by an event as mild as a breeze or teeth brushing. If nonprescription painkillers fail to alleviate facial pain, it can be treated with anticonvulsive medications. Carbamazepine (Tegretol) is currently the drug of choice. Carbamazepine is also effective on other types of MS pain and spasm-related symptoms, including itching and aching. Another antiseizure drug, gabapentin (Neurontin), however, may be particularly effective for MS. This drug also appears to improve blurred vision associated with MS and may help spasticity in general.

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.

Pseudobulbar Affect

A small percentage of patients suffer from pseudobulbar affect (uncontrollable laughing and/or crying). Neurodex is an investigative drug that is showing promise in controlling these symptoms. The drug combines dextromethorphan (an ingredient contained in many cough suppressants) and the enzyme inhibitor quinidine.

Sexual Dysfunction

Sildenafil (Viagra) may help improve sexual dysfunction in some patients. Corticosteroids, which are sometimes used for other MS symptoms, also improve sexual function. Other treatments are available that might be very beneficial. Patients should not be shy about discussing sexuality with their doctor. [See In-Depth Report # 15: Erectile dysfunction .]

Difficulty Swallowing

Techniques for helping patients with swallowing problems include using specific head and tongue positions to assist swallowing, and preparing pureed food. Patients may need to work with otolaryngologists (doctors specializing in ear, nose, and throat disorders) to address swallowing problems. Left untreated, swallowing problems can increase patients' risks of aspiration pneumonia, malnutrition, dehydration, and other problems.

Osteoporosis

MS is a strong risk factor for osteoporosis. In addition to calcium and vitamin D supplements, a number of drugs are now available to help prevent bone loss and reduce the risk of fractures due to osteoporosis. [See In-Depth Report #18: Osteoporosis.]

Depression and Stress

Treating Depression. Treating depression may not only improve mood but may also have direct benefits for patients.

• Antidepressants known as tricyclics may have specific benefits for MS in addition to managing severe depression. Amitriptyline (Elavil), for example, may be effective in alleviating the extreme mood swings that frequently occur in patients. This “emotional incontinence,” the inability to control emotions, can distress some patients more than physical symptoms. Other tricyclics include desipramine (Norpramin, Pertofrane) and imipramine (Tofranil), which have additional effects that improve bladder symptoms in some patients. These drugs, however, can have severe side effects.
• Newer antidepressant drugs, known as SSRIs (serotonin-reuptake inhibitors), which include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil), may be better tolerated. A study on sertraline suggested that it may also reduce the immune system's inflammatory response.

Stress Reduction and Supportive Measures. Stress can worsen symptoms, and may worsen the disease itself. Reducing stress is an important part of general health maintenance. Studies on methods for reducing stress report improved well-being in patients. A sense of control and connection appears to be extremely important for patients. Relaxation or meditation exercises can be beneficial, although cognitive-behavioral methods may be more effective in these patients. [See In-DepthReport # 31: Stress.]

Support for Caregivers. Many patients require long-term physical, financial, and psychological support from family and friends. Both the physical and mental health of the caregiver are critical. In one study, caregivers reported that among the most distressing aspects were the psychological impact of MS on the patient and the incurability of the disease. Most caregivers identified the best form of support to be practical help, cooking, cleaning, and better availability of medical and financial advice. Therapeutic help for family members may also be helpful.

Improving Mental Functioning

Interferon, used to treat MS, may improve mental function. Other medications and therapies may also be helpful. For example, drugs called cholinesterase inhibitors, such as donepezil (Aricept), which are used for Alzheimer's disease, may help improve mental functioning. Vocational programs for the patient may also be helpful. Therapeutic programs for both patients and their families can help them better understand and cope with cognitive weaknesses such as concentration and problem solving.

Lifestyle Changes

People with multiple sclerosis should make every effort to preserve their general health. A healthy diet, sufficient rest, establishing priorities to conserve energy, and developing emotional support networks can all be very helpful.

Dietary Factors

Some dietary suggestions for patients with MS include:

• Drink two quarts of water a day and avoid caffeine-containing beverages, which are actually dehydrating. This helps avoid constipation (although may cause difficulties in patients who also have urge incontinence).
• Eat a diet rich in fiber, particularly from whole grains (especially bran, oats, or flax), fruits (particularly prunes), and vegetables.
• Low-fat diets have not proven to have much effect on MS but are, in any case, generally healthy.
• Fish and fish oil. Omega-3 fatty acids, which are found in oily fish, have been associated with protection against inflammation and some reduction in symptoms in people with various autoimmune conditions. Such fatty acids are also available in supplements as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. Standards for optimal amounts and forms of omega-3 fatty acids have not yet been established, however. Some experts recommend that people with MS eat three fish meals a week.

Special diets, such as those that are gluten- or yeast-free, have not shown to have any direct effect on the symptoms or course of MS.

Exercise and Physical and Occupational Therapy

Exercise is an important component in managing MS. An active patient with MS is less likely to develop certain complications, such as bladder and bowel dysfunction, osteoporosis, permanent muscle contractions, ulcerations of the skin, or abnormal blood clotting. MS symptoms can temporarily worsen during physical activity, however, so any program must be planned carefully. A health professional should be consulted to determine the best form of physical activity. One study reported that physical rehabilitation for 3 weeks in a hospital setting was significantly more effective in achieving functional independence than home exercise. It is not known if the same benefits can be achieved with a similar program outside the hospital.

Some suggestions include:

• Exercise programs must be designed to stimulate working muscles, but at the same time avoid overload and overheating, which can block nerve conduction.
• Stretching and range-of-motion exercises are important because they can relieve muscle spasticity.
• Pool exercises are particularly helpful. Water supports the body, and cool water dissipates heat.
• Specific exercises that strengthen and increase the endurance of muscles that control breathing functions may be helpful. However, it is unclear if such exercises reduce lung complications over the long-term.
• Gradually, patients may be able to build up to more complex exercise programs.

Cooling Methods

Body overheating causes demyelinated nerves to function less efficiently than usual. Although this effect is resolved within a few hours of regaining normal body temperature, active cooling can help reduce fatigue and improve stability. The following measures may be helpful:

• Use air conditioners in the summer
• Keep the home slightly cool in winter
• Avoid swimming in heated pools
• A portable helmet that uses cold liquid to cool the head and neck and therefore lower core body temperatures may help MS symptoms during daily activities
• Cooling suits are being investigated

Prevention of Influenza

MS symptoms worsen during a cold or the flu, probably because of increased immune system activity. Experts recommend that patients with MS receive a flu shot in the fall. However, experts warn that patients should not take the nasal spray version of the flu vaccine (FluMist Intranasal). Unlike the flu injection vaccine, which uses an inactivated virus, FluMist contains a live virus. Live virus vaccinations may be harmful for people with MS, especially those who take immune-suppressing drugs.

Resources

• www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
• www.aan.com -- American Academy of Neurology
• www.msaa.com -- Multiple Sclerosis Association of America
• www.nmss.org -- National Multiple Sclerosis Society
• www.msfacts.org -- Multiple Sclerosis Foundation
• www.www.fda.gov/cder/drug/infopage/natalizumab -- FDA information on natalizumab (Tysabri)
• www.myelin.org -- The Myelin Project
• www.abledata.com -- National database of assistive devices and rehabilitation equipment

References

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Delorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A. Epstein-Barr virus and multiple sclerosis: Evidence of association from a prospective study with long-term follow-up. Arch Neurol. 2006 Apr 10; [Epub ahead of print]

Lunemann JD, Edwards N, Muraro PA, Hayashi S, Cohen JI, Munz C, et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain. 2006 Mar 28; [Epub ahead of print]

O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, et al. A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006;66(6):894-900.

Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.

Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911-923.

Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354(9):924-933.

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