[Editor's note: This article is from 2007. Some newer treatments are not listed here. Find more on BrainWeb]
sections include: mechanisms and factors, diagnosis, treatment, prognosis
Multiple sclerosis, often referred to as MS, gets its name from the multiple areas of scarring (sclerosis or gloss) that it causes in the nervous system. MS is a major cause of disability in Western societies because of its frequency, tendency to begin in young adulthood, and chronic course. However, manifestations of MS can range from relatively minor symptoms to major incapacity. Most often the first symptoms of MS appear gradually over hours or days, but they may also begin suddenly. MS symptoms that begin rapidly are referred to as an attack or, if they have happened before, a relapse.
The most common initial symptoms of MS are:
- Weakness. This may cause fatigue, difficulty walking, or trouble using fingers for fine movements or handling objects. Facial weakness may produce a drooping mouth, mimicking a stroke (ischemic, hemorrhagic) or Bell’s palsy. Stiffness, which may be one-sided, and spasms often accompany the weakness.
- Imbalance. MS damage in the cerebellum and its connections can render individuals unable to walk in a straight line (heel to toe) or stand with both feet together without falling. These troubles worsen when the individuals close their eyes. The imbalance can be accompanied by dizziness, sometimes enough to cause vomiting. In severe cases, a person’s speech can become slurred, or “scanned,” as he or she loses some capacity to articulate and coordinate the flow of words.
- Vision problems of two sorts. Optic neuritis manifests itself as a sudden difficulty reading, blurred vision in one eye, dimness, or inability to see red and other colors clearly. Many people feel pain around the affected eye. In this condition, MS has affected an optic nerve and the pathway that transmits images from the retina to the brain; in extreme cases, optic neuritis can produce blindness. The other type of visual disturbance is double vision, indicating damage to the nerve fibers in the brain stem that coordinate eye movements; the eyes cannot move together to focus on one image. The double vision disappears when the person with MS covers either eye.
- Sensory problems. Tingling, pins and needles (paresthesias), pain, or numbness can appear on the limbs, torso, or face. People with MS often describe abnormal sensations of swelling, squeezing, “water running on the skin,” burning or cold, or “being wrapped.” Some suffer trigeminal neuralgia, a recurrent shock-like pain in the temples and cheeks. Lhermitte’s sign is another sensation like an electric shock that runs down the spine when one bends the neck forward; it can occur with several disorders of the spinal cord.
The signs and symptoms of MS, especially the fatigue, tend to be exacerbated by heat, usually during periods of hot weather or after a hot bath or shower. Weakness or other symptoms may appear only during exercise.
When a person first suffers an MS attack, he or she might think the problem is a stroke. Other conditions that can mimic an attack include carpal tunnel syndrome (pain or tingling and numbness of hands), a herniated disk or compression of the spine (numbness or weakness of one side or in a limb), and the aura of a migraine attack. Trigeminal neuralgia may be misinterpreted as dental or eye pain. In addition to the most common symptoms, people with MS may experience problems with their bladder and, less often, bowel functions. Some people of both sexes experience impotence. Memory loss, impaired attention, and changes in mood may accompany MS, and more than half the people with the disorder develop depression.
Following the first attack, MS can follow several clinical patterns, each of which can be mild, moderate, or severe. In more than 80 percent of cases, MS begins with attacks coming and going, often without leaving any permanent deficit between them. This pattern is termed relapsing-remitting MS. Some people experience very few such attacks over their lifetime. Others suffer increasing numbers, leading to a degree of permanent disability. On average, a person with relapsing-remitting MS experiences one new clinical attack every 6 to 12 months; magnetic resonance imaging (MRI) studies have suggested that unnoticed attacks occur much more often. Approximately half of people with relapsing-remitting MS shift to a chronic progressive course by 15 years after onset. This form of disease is termed secondary progressive MS. Another 10 percent to 15 percent of people experience what we call primary progressive MS, in which the disease advances steadily from its onset, without remission.
The initial symptoms of a group of diseases termed acute disseminated encephalomyelitis (ADEM) can resemble an MS attack but may be much more explosive. These frequently start after a viral infection or vaccination. ADEM’s symptoms are similar to those of MS, but it is rare for further attacks to occur.
Mechanisms and Factors
Current evidence indicates that MS results from an abnormal response of the body’s own immune system against parts of the brain. We thus classify MS as an autoimmune disease, along with systemic lupus erythematosus (SLE), myasthenia gravis, rheumatoid arthritis, insulin-dependent diabetes mellitus, and others.
MS is a disease of the central nervous system: it involves the structures in the brain and spinal cord responsible for sending commands to the body and receiving and processing information from sensory organs. This pattern distinguishes MS from peripheral nervous system diseases, in which nerve fibers outside the brain and spinal cord are damaged, such as myasthenia gravis. However, both groups of diseases can cause similar weakness, numbness, and pain.
The symptoms of MS result primarily from damage to myelin, the fatty whitish substance that insulates nerve fibers. The myelin sheath narrows at regular intervals along the fibers; such narrowings are termed nodes of Ranvier. When the myelin sheaths are in normal condition, information travels to and from the brain and spine at very high speeds: electrical impulses “jump” from one node of Ranvier to the next. When MS has destroyed those myelin sheaths, these impulses may be blocked, just as a wire that has lost its insulation may no longer conduct properly.
Failure of conduction is responsible for most of the symptoms of MS. The brain can no longer communicate efficiently with the peripheral nerves, muscles, and other organs. The particular nerves that are involved determine a person’s symptoms. Also, demyelinated nerves may conduct impulses under normal conditions but fail under such stresses as repeated use or elevated temperature. That “conduction block” seems to explain why people with MS find their symptoms become worse with exercise or fever.
Recent research has shown that the immune attack in MS may damage not only myelin, but also nerve fibers and neurons. We do not know whether this is a consequence of the destruction of the myelin sheath or due to actual attacks on the nerves.
In temperate climates, MS affects approximately 1 in 1,000 individuals. In both the northern and southern hemispheres, it becomes increasingly common as one moves from the equator to the poles. Thus, MS is common in Scandinavia and northern Europe but rare in Japan and other countries in Asia.
MS affects women about twice as often as men. In both sexes, the incidence rises from adolescence to age 31, then declines gradually. It is unusual but not unknown for MS to begin as early as age 2, or as late as the eighth decade of life.
MS appears to develop in people who inherit genes that make their immune system likely to respond to certain environmental exposures—possibly viruses—by attacking the myelin insulation of nerve fibers. MS is not a genetic condition in a strict sense, but heredity influences how susceptible people are to the condition. Although most people with MS have no relative who is also affected, some families are particularly prone to MS. The lifetime risk for MS is approximately 5 percent for a brother or sister of an affected individual, 5 percent for a fraternal twin, and 30 percent for an identical twin. Spouses of people with MS and children adopted into MS-prone families show no increase in risk, strongly suggesting that the aggregation of MS in some families is due to genetic and not environmental factors.
It is likely that MS susceptibility is the effect of several genes together. To date, the most important is a gene labeled human leukocyte antigen [(HLA)-DR2], which seems to be responsible for 10 percent to 50 percent of genetic susceptibility. We believe that DR2 binds strongly to a fragment of a myelin substance termed myelin basic protein, triggering an immune response.
Most likely, the immune system misinterprets components of myelin as foreign and therefore seeks to destroy them. It has two basic ways to destroy these invaders: white blood cells called T cells, and antibodies, which are vital mechanisms to fight infections, tumors, and other diseases. In MS both T cells and antibodies may be involved; T cells may initiate the process of inflammation, whereas antibodies appear to act in concert to destroy the myelin. This “joint attack” from the immune system may result from a phenomenon called mimicry. When certain components contained in common microbes look like brain components, the T cells or antibodies mistakenly attack the brain and myelin, and may keep doing so even though the microbes are long gone. This theory could explain the global distribution of MS, which could correspond to the location of certain microbes. However, despite numerous claims, no specific infectious agent has been convincingly linked to MS.
Diagnosis
Currently, no test can identify MS, and since its symptoms can occur in other diseases, one of the first steps in diagnosing it is to rule out several alternate possibilities. These include other autoimmune disorders, such as ADEM, systemic lupus erythematosus, and Sjogren’s syndrome; sarcoidosis; Lyme disease; vitamin B12 deficiency; infections such as HIVHTLV-1, and syphilis; spinal cord compression; and tumors, especially when the symptoms have worsened steadily.
Then, to make a diagnosis of definite MS, doctors must find evidence that scarring has occurred in two or more areas of brain white matter in ways that alter a person’s neurological functions. There must also be two or more attacks at least one month apart, each time with symptoms lasting more than 24 hours.
MRI is the method most often used to detect scarring; 98 percent of people with MS have MRI abnormalities of the brain or spinal cord. MRI typically reveals many more lesions than doctors can detect from a clinical examination alone. Doctors can inject the heavy metal gadolinium to make the lesions appear even more clearly. However, the abnormalities an MRI detects are not absolutely specific for MS. On the other hand, if someone with symptoms has a normal MRI of the brain and spinal cord, physicians should focus first on other possibilities.
Other tests include the evoked response test, which records the changes in electrical activity of the brain following stimulation of a nerve pathway, as recorded by electrodes applied to the scalp. Responses are measured after stimulation with light, sound, or electrical current. If the time between the stimulation and the brain recording is unusually long, the electrical impulses must be blocked. These tests are sensitive to lesions in both the brain and spinal cord.
Cerebrospinal fluid, sampled by spinal tap, can show increased concentrations of antibodies in people with MS. In a minority of individuals, there is also a small increase in the number of inflammatory cells.
Treatment
We do not have therapies to prevent or cure MS, but we have treatments that partially alter its course, and a number of effective treatments for MS-related symptoms, which are listed in the table on page 440. MS attacks that are moderate or severe are treated with high doses of glucocorticoid (steroid) medication, given by intravenous infusion (methylprednisolone) or by mouth (prednisone). These medications can be administered to people who experience attacks despite disease-modifying therapy, and they are usually offered on an outpatient basis. Side effects of glucocorticoids include fluid retention, high blood pressure, excitability and insomnia, and stomach ulcers.
Rehabilitation and related therapies are important complementary treatments that help people with MS maximize their capacities. Occupational counseling and other support services may assist these people and their families in coping with the effects of the disease. Stress reduction, eating a balanced diet, getting adequate rest, and other generally healthy behaviors are very useful. We recommend that people with MS keep vaccinations to a minimum because of the possibility that they may stimulate the immune system and trigger an attack. However, it is reassuring that recent controlled studies of hepatitis B, influenza, and tetanus vaccinations have shown no MS-related adverse effects.
Disease-Modifying Therapies for Relapsing-Remitting MS
In the United States, four therapies are approved for people with relapsing-remitting MS: interferon beta-1b (Betaseron), interferon beta-1a (Avonex and Rebif ), and glatiramer acetate (Copaxone). Currently Avonex is the most commonly prescribed. We do not know how these drugs act with certainty, but they appear to suppress the myelin-reactive T cells, prevent them from entering the brain, and/or counteract the harmful substances that they make.
Clinical trials show that people receiving these drugs on average experience 30 percent fewer attacks and fewer new lesions in MRI scans. The interferons also significantly delay the development of new disability. However, these medications are only partially effective and may not be useful for all people with MS.
Betaseron is given by subcutaneous injection every other day, Avonex by intramuscular injection once weekly, Rebif by subcutaneous injection three times weekly, and Copaxone by subcutaneous injection daily. For all medications, the main side effects include local allergic reactions to the shots. Both interferons produce flulike symptoms that tend to disappear after two or three months of treatment and can usually be managed by over-the-counter medications. For some individuals, Betaseron, Rebif, and, less commonly, Avonex may also give rise to neutralizing antibodies, which impair their efficacy. In 15 percent of people Copaxone produces allergic reactions that may be severe but usually do not recur. Betaseron has been associated with depression.
Disease-Modifying Therapies for Secondary Progressive MS
In 2000 the FDA approved mitoxantrone (Novantrone) for treating secondary progressive MS. The drug is administered every three months by intravenous infusion, which is generally well tolerated. Mitoxantrone reduces the attack rate and MS activity, and delays the onset of new disability. Its use is of concern because of doserelated toxicity to the heart and a potential long-term risk of malignancies. Most physicians do not treat individuals with advanced forms of secondary progressive MS who can no longer walk. Individuals with secondary progressive MS who also have ongoing attacks are candidates for therapy with one of the interferons.
Disease-Modifying Therapies for Primary Progressive MS
There are no effective disease-modifying treatments for primary progressive MS. However, clinical trials with a variety of agents, including interferon, glatiramer acetate, and mitoxantrone, are currently under way.
Other Treatment Options
Some medical centers use a variety of treatments that are not FDA-approved for various forms of MS. The “general immunosuppressive therapies” include azathioprine every day orally; methotrexate every week orally; cyclophosphamide, by monthly infusion; methylprednisolone, by monthly infusion. Recent trials of intravenous immunoglobulin infusions suggest that this treatment may also be useful. Finally, plasma exchange has been shown to be helpful for severe MS attacks that have not responded to glucocorticoid therapy. Unfortunately, there are also many claims for therapies of uncertain value. The National Multiple Sclerosis Society is an excellent source of information on the most effective therapeutic options for MS.
Prognosis
Most people with MS eventually experience progressive disability, although some can remain stable for a very long time. In studies that preceded the current disease-modifying therapies, more than 80 percent of people with MS were found to have some functional limitation 15 years after diagnosis. Half required help to walk, 70 percent were limited or unable to perform daily living activities, and 75 percent were unemployed.
These traits are signs that a person with MS might have a more favorable prognosis than the average:
- optic neuritis as the only initial symptom
- complete recovery from the first attack
- onset before age 40
- being female
- having fewer than two relapses within the first year
The degree of impairment five years after the first attack and the number of MS lesions detected on a brain MRI after the first attack also appear to predict disability 10 to 15 years later.
Pregnancy may affect the course of MS. Although there is no proven effect of pregnancy on the overall course of disability, pregnant patients tend to have fewer attacks during gestation but more in the first three months after delivery. This is probably related to hormonal effects that influence the activity of the immune system. Because pregnant mothers should not undertake disease-modifying and immunosuppressive therapies, women with MS should carefully review their health, goals, and family support before deciding to bear a child.
The MS research community has clarified the underlying biology of the disease and shown great promise for developing improved therapy for it. Areas of research that hold promise in the near future include:
- Developing drugs that block the movement of myelin-attacking T cells from the bloodstream into the brain.
- Engineering drugs that specifically inhibit the damaging T cells or antibodies.
- Finding approaches that promote demyelination (myelin repair), which may allow individuals to regain function.
Studies of MRI, immune, and genetic variables that improve our ability to predict the disease course and tailor or engineer therapy to individuals with MS.
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