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Get Web page suited for printing Although multiple sclerosis (MS) was first diagnosed in 1849, the earliest known
description of a person with possible MS dates from fourteenth century Holland. An
unpredictable disease of the central nervous system, MS can range from relatively benign
to somewhat disabling to devastating as communication between the brain and other parts of
the body is disrupted. The vast majority of patients are mildly affected, but in the worst cases MS can render
a person unable to write, speak, or walk. A physician can diagnose MS in some patients
soon after the onset of the illness. In others, however, physicians may not be able to
readily identify the cause of the symptoms, leading to years of uncertainty and multiple
diagnoses punctuated by baffling symptoms that mysteriously wax and wane. Once a diagnosis is made with confidence, patients must consider a profusion of
information-and misinformation-associated with this complex disease. This brochure is
designed to convey the latest information on the diagnosis, course, and possible treatment
of MS, as well as highlights of current research. Although a pamphlet cannot substitute
for the advice and expertise of a physician, it can provide patients and their families
with information to understand MS better so that they can actively participate in their
care and treatment. Return to Index During an MS attack, inflammation occurs in areas of the white matter* of the
central nervous system in random patches called plaques. This process is followed
by destruction of myelin, the fatty covering that insulates nerve cell fibers in
the brain and spinal cord. Myelin facilitates the smooth, high-speed transmission of
electrochemical messages between the brain, the spinal cord, and the rest of the body;
when it is damaged, neurological transmission of messages may be slowed or blocked
completely, leading to diminished or lost function. The name "multiple
sclerosis" signifies both the number (multiple) and condition (sclerosis, from the
Greek term for scarring or hardening) of the demyelinated areas in the central
nervous system. No one knows exactly how many people have MS. It is believed that, currently, there are
approximately 250,000 to 350,000 people in the United States with MS diagnosed by a
physician. This estimate suggests that approximately 200 new cases are diagnosed each
week. Return to Index
Most people experience their first symptoms of MS between the ages of 20 and 40, but a
diagnosis is often delayed. This is due to both the transitory nature of the disease and
the lack of a specific diagnostic test-specific symptoms and changes in the brain must
develop before the diagnosis is confirmed. Although scientists have documented cases of MS in young children and elderly adults,
symptoms rarely begin before age 15 or after age 60. Whites are more than twice as likely
as other races to develop MS. In general, women are affected at almost twice the rate of
men; however, among patients who develop the symptoms of MS at a later age, the gender
ratio is more balanced. MS is five times more prevalent in temperate climates-such as those found in the
northern United States, Canada, and Europe-than in tropical regions. Furthermore, the age
of 15 seems to be significant in terms of risk for developing the disease: some studies
indicate that a person moving from a high-risk (temperate) to a low-risk (tropical) area
before the age of 15 tends to adopt the risk (in this case, low) of the new area and vice
versa. Other studies suggest that people moving after age 15 maintain the risk of the area
where they grew up. These findings indicate a strong role for an environmental factor in the cause of MS.
It is possible that, at the time of or immediately following puberty, patients acquire an
infection with a long latency period. Or, conversely, people in some areas may come in
contact with an unknown protective agent during the time before puberty. Other studies
suggest that the unknown geographic or climatic element may actually be simply a matter of
genetic predilection and reflect racial and ethnic susceptibility factors. Periodically, scientists receive reports of MS "clusters." The most famous of
these MS "epidemics" took place in the Faeroe Islands north of Scotland in the
years following the arrival of British troops during World War II. Despite intense study
of this and other clusters, no direct environmental factor has been identified. Nor has
any definitive evidence been found to link daily stress to MS attacks, although there is
evidence that the risk of worsening is greater after acute viral illnesses. Return to Index MS is a life-long chronic disease diagnosed primarily in young adults who have a
virtually normal life expectancy. Consequently, the economic, social, and medical costs
associated with the disease are significant. Estimates place the annual costs of MS in the
United States in excess of $2.5 billion. Scientists have learned a great deal about MS in recent years; still, its cause remains
elusive. Many investigators believe MS to be an autoimmune disease-one in which
the body, through its immune system, launches a defensive attack against its own tissues.
In the case of MS, it is the nerve-insulating myelin that comes under assault. Such
assaults may be linked to an unknown environmental trigger, perhaps a virus. Return to Index To understand what is happening when a person has MS, it is first necessary to know a
little about how the healthy immune system works. The immune system - a complex network
of specialized cells and organs - defends the body against attacks by "foreign"
invaders such as bacteria, viruses, fungi, and parasites. It does this by seeking out and
destroying the interlopers as they enter the body. Substances capable of triggering an
immune response are called antigens. The immune system displays both enormous diversity and extraordinary specificity. It
can recognize millions of distinctive foreign molecules and produce its own molecules and
cells to match up with and counteract each of them. In order to have room for enough cells
to match the millions of possible foreign invaders, the immune system stores just a few
cells for each specific antigen. When an antigen appears, those few specifically matched
cells are stimulated to multiply into a full-scale army. Later, to prevent this army from
overexpanding, powerful mechanisms to suppress the immune response come into play. T cells, so named because they are processed in the thymus, appear to play a
particularly important role in MS. They travel widely and continuously throughout the body
patrolling for foreign invaders. In order to recognize and respond to each specific
antigen, each T cell's surface carries special receptor molecules for particular
antigens. T cells contribute to the body's defenses in two major ways. Regulatory T cells help
orchestrate the elaborate immune system. For instance, they assist other cells to make antibodies,
proteins programmed to match one specific antigen much as a key matches a lock. Antibodies
typically interact with circulating antigens, such as bacteria, but are unable to
penetrate living cells. Chief among the regulatory T cells are those known as helper (or
inducer) cells. Helper T cells are essential for activating the body's defenses against
foreign substances. Yet another subset of regulatory T cells acts to turn off, or
suppress, various immune system cells when their job is done. Killer T cells, on the other hand, directly attack diseased or damaged body cells by
binding to them and bombarding them with lethal chemicals called cytokines. Since T
cells can attack cells directly, they must be able to discriminate between
"self" cells (those of the body) and "nonself" cells (foreign
invaders). To enable the immune system to distinguish the self, each body cell carries
identifying molecules on its surface. T cells likely to react against the self are usually
eliminated before leaving the thymus; the remaining T cells recognize the molecular
markers and coexist peaceably with body tissues in a state of self-tolerance. In autoimmune diseases such as MS, the detente between the immune system and the body
is disrupted when the immune system seems to wrongly identify self as nonself and declares
war on the part of the body (myelin) it no longer recognizes. Through intensive research
efforts, scientists are unraveling the complex secrets of the malfunctioning immune system
of patients with MS. Components of myelin such as myelin basic protein have been the focus of much
research because, when injected into laboratory animals, they can precipitate experimental
allergic encephalomyelitis (EAE), a chronic relapsing brain and spinal cord disease
that resembles MS. The injected myelin probably stimulates the immune system to produce
anti-myelin T cells that attack the animal's own myelin. Investigators are also looking for abnormalities or malfunctions in the blood/brain
barrier, a protective membrane that controls the passage of substances from the blood
into the central nervous system. It is possible that, in MS, components of the immune
system get through the barrier and cause nervous system damage. Scientists have studied a number of infectious agents (such as viruses) that have been
suspected of causing MS, but have been unable to implicate any one particular agent. Viral
infections are usually accompanied by inflammation and the production of gamma interferon,
a naturally occurring body chemical that has been shown to worsen the clinical course of
MS. It is possible that the immune response to viral infections may themselves precipitate
an MS attack. There seems to be little doubt that something in the environment is involved
in triggering MS. Return to Index
In addition, increasing scientific evidence suggests that genetics may play a role in
determining a person's susceptibility to MS. Some populations, such as Gypsies, Eskimos,
and Bantus, never get MS. Native Indians of North and South America, the Japanese, and
other Asian peoples have very low incidence rates. It is unclear whether this is due
mostly to genetic or environmental factors. In the population at large, the chance of developing MS is less than a tenth of one
percent. However, if one person in a family has MS, that person's first-degree
relatives-parents, children, and siblings-have a one to three percent chance of getting
the disease. For identical twins, the likelihood that the second twin may develop MS if the first
twin does is about 30 percent; for fraternal twins (who do not inherit identical gene
pools), the likelihood is closer to that for non-twin siblings, or about 4 percent. The
fact that the rate for identical twins both developing MS is significantly less than 100
percent suggests that the disease is not entirely genetically controlled. Some (but
definitely not all) of this effect may be due to shared exposure to something in the
environment, or to the fact that some people with MS lesions remain essentially
asymptomatic throughout their lives. Further indications that more than one gene is involved in MS susceptibility comes from
studies of families in which more than one member has MS. Several research teams found
that people with MS inherit certain regions on individual genes more frequently than
people without MS. Of particular interest is the human leukocyte antigen (HLA) or major
histocompatibility complex region on chromosome 6. HLAs are genetically determined
proteins that influence the immune system. The HLA patterns of MS patients tend to be different from those of people without the
disease. Investigations in northern Europe and America have detected three HLAs that are
more prevalent in people with MS than in the general population. Studies of American MS
patients have shown that people with MS also tend to exhibit these HLAs in
combination-that is, they have more than one of the three HLAs-more frequently than the
rest of the population. Furthermore, there is evidence that different combinations of the
HLAs may correspond to variations in disease severity and progression. Studies of families with multiple cases of MS and research comparing genetic regions of
humans to those of mice with EAE suggest that another area related to MS susceptibility
may be located on chromosome 5. Other regions on chromosomes 2, 3, 7, 11, 17, 19, and X
have also been identified as possibly containing genes involved in the development of MS. These studies strengthen the theory that MS is the result of a number of factors rather
than a single gene or other agent. Development of MS is likely to be influenced by the
interactions of a number of genes, each of which (individually) has only a modest effect.
Additional studies are needed to specifically pinpoint which genes are involved, determine
their function, and learn how each gene's interactions with other genes and with the
environment make an individual susceptible to MS. In addition to leading to better ways to
diagnose MS, such studies should yield clues to the underlying causes of MS and,
eventually, to better treatments or a way to prevent the disease. Return to Index Each case of MS displays one of several patterns of presentation and subsequent course.
Most commonly, MS first manifests itself as a series of attacks followed by complete or
partial remissions as symptoms mysteriously lessen, only to return later after a period of
stability. This is called relapsing-remitting (RR) MS. Primary-progressive (PP) MS is
characterized by a gradual clinical decline with no distinct remissions, although there
may be temporary plateaus or minor relief from symptoms. Secondary-progressive (SP) MS
begins with a relapsing-remitting course followed by a later primary-progressive course.
Rarely, patients may have a progressive-relapsing (PR) course in which the disease takes a
progressive path punctuated by acute attacks. PP, SP, and PR are sometimes lumped together
and called chronic progressive MS. In addition, twenty percent of the MS population has a benign form of the disease in
which symptoms show little or no progression after the initial attack; these patients
remain fully functional. A few patients experience malignant MS, defined as a swift and
relentless decline resulting in significant disability or even death shortly after disease
onset. However, MS is very rarely fatal and most people with MS have a fairly normal life
expectancy. Studies throughout the world are causing investigators to redefine the natural course
of the disease. These studies use a technique called magnetic resonance imaging (MRI)
to visualize the evolution of MS lesions in the white matter of the brain. Bright spots on
a T2 MRI scan indicate the presence of lesions, but do not provide information about when
they developed. Because investigators speculate that the breakdown of the blood/brain barrier is the
first step in the development of MS lesions, it is important to distinguish new lesions
from old. To do this, physicians give patients injections of gadolinium, a chemical
contrast agent that normally does not cross the blood/brain barrier, before performing a
scan. On this type of scan, called T1, the appearance of bright areas indicates periods of
recent disease activity (when gadolinium is able to cross the barrier). The ability to
estimate the age of lesions through MRI has allowed investigators to show that, in some
patients, lesions occur frequently throughout the course of the disease even when no
symptoms are present. Return to Index While there is no good evidence that daily stress or trauma affects the course of MS,
there is data on the influence of pregnancy. Since MS generally strikes during
childbearing years, a common concern among women with the disease is whether or not to
have a baby. Studies on the subject have shown that MS has no adverse effects on the
course of pregnancy, labor, or delivery; in fact symptoms often stabilize or remit during
pregnancy. This temporary improvement is thought to relate to changes in a woman's immune
system that allow her body to carry a baby: because every fetus has genetic material from
the father as well as the mother, the mother's body should identify the growing fetus as
foreign tissue and try to reject it in much the same way the body seeks to reject a
transplanted organ. To prevent this from happening, a natural process takes place to
suppress the mother's immune system in the uterus during pregnancy. However, women with MS who are considering pregnancy need to be aware that certain
drugs used to treat MS should be avoided during pregnancy and while breast feeding. These
drugs can cause birth defects and can be passed to the fetus via blood and to an infant
via breast milk. Among them are prednisone, corticotropin, azathioprine, cyclophosphamide,
diazepam, phenytoin, carbamazepine, and baclofen. Unfortunately, between 20 and 40 percent of women with MS do have a relapse in the
three months following delivery. However, there is no evidence that pregnancy and
childbirth affect the overall course of the disease one way or the other. Also, while MS
is not in itself a reason to avoid pregnancy and poses no significant risks to the fetus,
physical limitations can make child care more difficult. It is therefore important that MS
patients planning families discuss these issues with both their partner and physician. Return to Index Symptoms of MS may be mild or severe, of long duration or short, and may appear in
various combinations, depending on the area of the nervous system affected. Complete or
partial remission of symptoms, especially in the early stages of the disease, occurs in
approximately 70 percent of MS patients. The initial symptom of MS is often blurred or double vision, red-green color
distortion, or even blindness in one eye. Inexplicably, visual problems tend to clear up
in the later stages of MS. Inflammatory problems of the optic nerve may be diagnosed as retrobulbaror optic neuritis. Fifty-five percent of MS patients will have an attack of
optic neuritis at some time or other and it will be the first symptom of MS in
approximately 15 percent. This has led to general recognition of optic neuritis as an
early sign of MS, especially if tests also reveal abnormalities in the patient's spinal
fluid. Most MS patients experience muscle weakness in their extremities and difficulty with
coordination and balance at some time during the course of the disease. These symptoms may
be severe enough to impair walking or even standing. In the worst cases, MS can produce
partial or complete paralysis. Spasticity-the involuntary increased tone of
muscles leading to stiffness and spasms-is common, as is fatigue. Fatigue may be
triggered by physical exertion and improve with rest, or it may take the form of a
constant and persistent tiredness. Most people with MS also exhibit paresthesias, transitory abnormal sensory
feelings such as numbness, prickling, or "pins and needles" sensations;
uncommonly, some may also experience pain. Loss of sensation sometimes occurs. Speech
impediments, tremors, and dizziness are other frequent complaints. Occasionally, people
with MS have hearing loss. Approximately half of all people with MS experience cognitive impairments such as
difficulties with concentration, attention, memory, and poor judgment, but such symptoms
are usually mild and are frequently overlooked. In fact, they are often detectable only
through comprehensive testing. Patients themselves may be unaware of their cognitive loss;
it is often a family member or friend who first notices a deficit. Such impairments are
usually mild, rarely disabling, and intellectual and language abilities are generally
spared. Cognitive symptoms occur when lesions develop in brain areas responsible for
information processing. These deficits tend to become more apparent as the information to
be processed becomes more complex. Fatigue may also add to processing difficulties.
Scientists do not yet know whether altered cognition in MS reflects problems with
information acquisition, retrieval, or a combination of both. Types of memory problems may
differ depending on the individual's disease course (relapsing-remitting,
primary-progressive, etc.), but there does not appear to be any direct correlation between
duration of illness and severity of cognitive dysfunction. . Return to Index Depression, which is unrelated to cognitive problems, is another common feature of MS.
In addition, about 10 percent of patients suffer from more severe psychotic disorders such
as manic-depression and paranoia. Five percent may experience episodes of inappropriate
euphoria and despair-unrelated to the patient's actual emotional state-known as
"laughing/weeping syndrome." This syndrome is thought to be due to demyelination
in the brainstem, the area of the brain that controls facial expression and emotions, and
is usually seen only in severe cases. As the disease progresses, sexual dysfunction may become a problem. Bowel and bladder
control may also be lost. In about 60 percent of MS patients, heat-whether generated by temperatures outside the
body or by exercise-may cause temporary worsening of many MS symptoms. In these cases,
eradicating the heat eliminates the problem. Some temperature-sensitive patients find that
a cold bath may temporarily relieve their symptoms. For the same reason, swimming is often
a good exercise choice for people with MS. The erratic symptoms of MS can affect the entire family as patients may become unable
to work at the same time they are facing high medical bills and additional expenses for
housekeeping assistance and modifications to homes and vehicles. The emotional drain on
both patient and family is immeasurable. Support groups (listed on a card in the pocket at
the back of this pamphlet) and counseling may help MS patients, their families, and
friends find ways to cope with the many problems the disease can cause. Muscle weakness Spasticity Impairment of pain, temperature, touch senses Pain (moderate to severe) Ataxia Tremor Speech disturbances Vision disturbances Vertigo Bladder dysfunction Bowel dysfunction Sexual dysfunction Depression Euphoria Cognitive abnormalities Fatigue
When faced with a patient whose symptoms, neurological examination, and medical history
suggest MS, physicians use a variety of tools to rule out other possible disorders and
perform a series of laboratory tests which, if positive, confirm the diagnosis. Imaging technologies such as MRI-often used in conjunction with the contrast agent
gadolinium, which helps distinguish new plaques from old on MRI (see section on "What
is the Course of MS?")-can help locate central nervous system lesions resulting from
myelin loss. However, since these lesions can also occur in several other neurological
disorders, they are not absolute evidence of MS. Magnetic resonance spectroscopy (MRS) is
a new tool being used to investigate MS. Unlike MRI, which provides an anatomical picture
of lesions, MRS yields information about the biochemistry of the brain in MS. Evoked potential tests, which measure the speed of the brain's response to visual,
auditory, and sensory stimuli, can sometimes detect lesions the scanners miss. Like
imaging technologies, evoked potentials are helpful but not conclusive because they cannot
identify the cause of lesions. The physician may also study the patient's cerebrospinal fluid (the colorless
liquid that circulates through the brain and spinal cord) for cellular and chemical
abnormalities often associated with MS. These abnormalities include increased numbers of
white blood cells and higher-than-average amounts of protein, especially myelin basic
protein and an antibody called immunoglobulin G. Physicians can use several
different laboratory techniques to separate and graph the various proteins in MS patients'
cerebrospinal fluid. This process often identifies the presence of a characteristic
pattern called oligoclonal bands. Because there is no single test that unequivocally detects MS, it is often difficult
for the physician to differentiate between an MS attack and symptoms that can follow a
viral infection or even an immunization. Many doctors will tell their patients they have
"possible MS." If, as time goes by, the patient's symptoms show the
characteristic relapsing-remitting pattern, or continue in a chronic and progressive
fashion, and if laboratory tests rule out other likely causes, or specific tests become
positive, the diagnosis may eventually be changed to "probable MS." A number of other diseases may produce symptoms similar to those seen in MS. Other
conditions with an intermittent course and MS-like lesions of the brain's white matter
include polyarteritis, lupus erythematosus, syringomyelia, tropical spastic paraparesis,
some cancers, and certain tumors that compress the brainstem or spinal cord. Progressive
multifocal leukoencephalopathy can mimic the acute stage of an MS attack. The physician
will also need to rule out stroke, neurosyphilis, spinocerebellar ataxias, pernicious
anemia, diabetes, Sjogren's disease, and vitamin B12 deficiency. Acute transverse
myelitis may signal the first attack of MS, or it may indicate other problems such as
infection with the Epstein-Barr or herpes simplex B viruses. Recent reports suggest that
the neurological problems associated with Lyme disease may present a clinical picture much
like MS. Investigators are continuing their search for a definitive test for MS. Until one is
developed, however, evidence of both multiple attacks and central nervous system lesions
must be found-a process that can take months or even years-before a physician can make a
definitive diagnosis of MS. Return to Index There is as yet no cure for MS. Many patients do well with no therapy at all,
especially since many medications have serious side effects and some carry significant
risks. Naturally occurring or spontaneous remissions make it difficult to determine
therapeutic effects of experimental treatments; however, the emerging evidence that MRIs
can chart the development of lesions is already helping scientists evaluate new therapies. Until recently, the principal medications physicians used to treat MS were steroids
possessing anti-inflammatory properties; these include adrenocorticotropic hormone (better
known as ACTH), prednisone, prednisolone, methylprednisolone, betamethasone, and
dexamethasone. Studies suggest that intravenous methylprednisolone may be superior to the
more traditional intravenous ACTH for patients experiencing acute relapses; no strong
evidence exists to support the use of these drugs to treat progressive forms of MS. Also,
there is some indication that steroids may be more appropriate for people with movement,
rather than sensory, symptoms. While steroids do not affect the course of MS over time, they can reduce the duration
and severity of attacks in some patients. The mechanism behind this effect is not known;
one study suggests the medications work by restoring the effectiveness of the blood/brain
barrier. Because steroids can produce numerous adverse side effects (acne, weight gain,
seizures, psychosis), they are not recommended for long-term use. One of the most promising MS research areas involves naturally occurring antiviral
proteins known as interferons. Two forms of beta interferon (Avonex and Betaseron) have
now been approved by the Food and Drug Administration for treatment of relapsing-remitting
MS. A third form (Rebif) is marketed in Europe. Beta interferon has been shown to reduce
the number of exacerbations and may slow the progression of physical disability. When
attacks do occur, they tend to be shorter and less severe. In addition, MRI scans suggest
that beta interferon can decrease myelin destruction. Investigators speculate that the effects of beta interferon may be due to the drug's
ability to correct an MS-related deficiency of certain white blood cells that suppress the
immune system and/or its ability to inhibit gamma interferon, a substance believed to be
involved in MS attacks. Alpha interferon is also being studied as a possible treatment for
MS. Common side effects of interferons include fever, chills, sweating, muscle aches,
fatigue, depression, and injection site reactions. Scientists continue their extensive efforts to create new and better therapies for MS.
Goals of therapy are threefold: to improve recovery from attacks, to prevent or lessen the
number of relapses, and to halt disease progression. Some therapies currently under
investigation are discussed below. Return to Index As evidence of immune system involvement in the development of MS has grown, trials of
various new treatments to alter or suppress immune response are being conducted. These
therapies are, at this time, still considered experimental. Results of recent clinical trials have shown that immunosuppressive agents and
techniques can positively (if temporarily) affect the course of MS; however, toxic side
effects often preclude their widespread use. In addition, generalized immunosuppression
leaves the patient open to a variety of viral, bacterial, and fungal infections. Over the years, MS investigators have studied a number of immunosuppressant treatments.
Among the therapies being studied are cyclosporine (Sandimmune), cyclophosphamide
(Cytoxan), methotrexate, azathioprine (Imuran), and total lymphoid irradiation (a process
whereby the MS patient's lymph nodes are irradiated with x-rays in small doses over a few
weeks to destroy lymphoid tissue, which is actively involved in tissue destruction in
autoimmune diseases). Inconclusive and/or contradictory results of these trials, combined
with the therapies' potentially dangerous side effects, dictate that further research is
necessary to determine what, if any, role they should play in the management of MS.
Studies are also being conducted with the immune system modulating drugs linomide
(Roquinimex), cladribine (Leustatin), and mitoxantrone. Two other experimental treatments - one involving the use of monoclonal antibodies and
the other involving plasma exchange, or plasmapheresis - may have fewer dangerous side
effects. Monoclonal antibodies are identical, laboratory-produced antibodies that are
highly specific for a single antigen. They are injected into the patient in the hope that
they will alter the patient's immune response. Plasmapheresis is a procedure in which
blood is removed from the patient, and the plasma is separated from other blood
substances, which may contain antibodies and other immmunologically active products. These
other blood substances are discarded and the plasma is then transfused back into the
patient. Because their worth as treatments for MS has not yet been proven, these
experimental treatments remain at the stage of clinical testing. Bone marrow transplantation (a procedure in which bone marrow from a healthy donor is
infused into patients who have undergone drug or radiation therapy to suppress their
immune system so they will not reject the donated marrow) and injections of venom from
honey bees are also being studied. Each of these therapies carries the risk of potentially
severe side effects. Return to Index Because the transmission of electrochemical messages between the brain and body is
disrupted in MS, medications to improve the conduction of nerve impulses are being
investigated. Since demyelinated nerves show abnormalities of potassium activity,
scientists are studying drugs that block the channels through which potassium moves,
thereby restoring conduction of the nerve impulse. In several small experimental trials,
derivatives of a drug called aminopyridine temporarily improved vision, coordination, and
strength when given to MS patients who suffered from both visual symptoms and heightened
sensitivity to temperature. Possible side effects of these therapies include paresthesias
(tingling sensations), dizziness, and seizures. Return to Index Trials of a synthetic form of myelin basic protein, called copolymer I (Copaxone), have
shown promise in treating people in the early stages of relapsing-remitting MS. Copolymer
I, unlike so many drugs tested for the treatment of MS, seems to have few side effects.
Recent trial data indicate that copolymer I can reduce the relapse rate by almost one
third. In addition, patients given copolymer I were more likely to show neurologic
improvement than those given a placebo. The Food and Drug Administration has made the drug
available to people with early relapsing-remitting MS through its "Treatment
IND" program and is currently reviewing data from a large-scale study to determine
whether or not to approve the drug for marketing. Investigators are also looking at the possibility of developing an MS vaccine.
Myelin-attacking T cells were removed, inactivated, and injected back into animals with
experimental allergic encephalomyelitis (EAE). This procedure results in destruction of
the immune system cells that were attacking myelin basic protein. In a couple of small
trials scientists have tested a similar vaccine in humans. The product was well-tolerated
and had no side effects, but the studies were too small to establish efficacy. Patients
with progressive forms of MS did not appear to benefit, although relapsing-remitting
patients showed some neurologic improvement and had fewer relapses and reduced numbers of
lesions in one study. Unfortunately, the benefits did not last beyond two years. A similar approach, known as peptide therapy, is based on evidence that the body can
mount an immune response against the T cells that destroy myelin, but this response is not
strong enough to overcome the disease. To induce this response, the investigator scans the
myelin-attacking T cells for the myelin-recognizing receptors on the cells' surface. A
fragment, or peptide, of those receptors is then injected into the body. The immune system
"sees" the injected peptide as a foreign invader and launches an attack on any
myelin-destroying T cells that carry the peptide. The injection of portions of T cell
receptors may heighten the immune system reaction against the errant T cells much the same
way a booster shot heightens immunity to tetanus. Or, peptide therapy may jam the errant
cells' receptors, preventing the cells from attacking myelin. Despite these promising early results, there are some major obstacles to developing
vaccine and peptide therapies. Individual patients' T cells vary so much that it may not
be possible to develop a standard vaccine or peptide therapy beneficial to all, or even
most, MS patients. At this time, each treatment involves extracting cells from each
individual patient, purifying the cells, and then growing them in culture before
inactivating and chemically altering them. This makes the production of quantities
sufficient for therapy extremely time consuming, labor intensive, and expensive. Further
studies are necessary to determine whether universal inoculations can be developed to
induce suppression of MS patients' overactive immune systems. Protein antigen feeding is similar to peptide therapy, but is a potentially simpler
means to the same end. Whenever we eat, the digestive system breaks each food or substance
into its primary "non-antigenic" building blocks, thereby averting a potentially
harmful immune attack. So, strange as it may seem, antigens that trigger an immune
response when they are injected can encourage immune system tolerance when taken orally.
Furthermore, this reaction is directed solely at the specific antigen being fed; wholesale
immunosuppression, which can leave the body open to a variety of infections, does not
occur. Studies have shown that when rodents with EAE are fed myelin protein antigens, they
experience fewer relapses. Data from a small, preliminary trial of antigen feeding in
humans found limited suggestion of improvement, but the results were not statistically
significant. A multi-center trial is being conducted to determine whether protein antigen
feeding is effective. Return to Index As our growing insight into the workings of the immune system gives us new knowledge
about the function of cytokines, the powerful chemicals produced by T cells, the
possibility of using them to manipulate the immune system becomes more attractive.
Scientists are studying a variety of substances that may block harmful cytokines, such as
those involved in inflammation, or that encourage the production of protective cytokines. A drug that has been tested as a depression treatment, rolipram, has been shown to
reduce levels of several destructive cytokines in animal models of MS. Its potential as a
therapy for MS is not known at this time, but side effects seem modest. Protein antigen
feeding, discussed above, may release transforming growth factor beta (TGF), a protective
cytokine that inhibits or regulates the activity of certain immune cells. Preliminary
tests indicate that it may reduce the number of immune cells commonly found in MS
patients' spinal fluid. Side effects include anemia and altered kidney function. Interleukin 4 (IL-4) is able to diminish demyelination and improve the clinical course
of mice with EAE, apparently by influencing developing T cells to become protective rather
than harmful. This also appears to be true of a group of chemicals called retinoids. When
fed to rodents with EAE, retinoids increase levels of TGF and IL-4, which encourage
protective T cells, while decreasing numbers of harmful T cells. This results in
improvement of the animals' clinical symptoms. Return to Index Some studies focus on strategies to reverse the damage to myelin and oligodendrocytes
(the cells that make and maintain myelin in the central nervous system), both of which are
destroyed during MS attacks. Scientists now know that oligodendrocytes may proliferate and
form new myelin after an attack. Therefore, there is a great deal of interest in agents
that may stimulate this reaction. To learn more about the process, investigators are
looking at how drugs used in MS trials affect remyelination. Studies of animal models
indicate that monoclonal antibodies and two immunosuppressant drugs, cyclophosphamide and
azathioprine, may accelerate remyelination, while steroids may inhibit it. The ability of
intravenous immunoglobulin (IVIg) to restore visual acuity and/or muscle strength is also
being investigated. Diet Over the years, many people have tried to implicate diet as a cause of or treatment for
MS. Some physicians have advocated a diet low in saturated fats; others have suggested
increasing the patient's intake of linoleic acid, a polyunsaturated fat, via supplements
of sunflower seed, safflower, or evening primrose oils. Other proposed dietary
"remedies" include megavitamin therapy, including increased intake of vitamins
B12 or C; various liquid diets; and sucrose-, tobacco-, or gluten-free diets. To date,
clinical studies have not been able to confirm benefits from dietary changes; in the
absence of any evidence that diet therapy is effective, patients are best advised to eat a
balanced, wholesome diet. Return to Index MS is a disease with a natural tendency to remit spontaneously, and for which there is
no universally effective treatment and no known cause. These factors open the door for an
array of unsubstantiated claims of cures. At one time or another, many ineffective and
even potentially dangerous therapies have been promoted as treatments for MS. A partial
list of these "therapies" includes: injections of snake venom, electrical
stimulation of the spinal cord's dorsal column, removal of the thymus gland, breathing
pressurized (hyperbaric) oxygen in a special chamber, injections of beef heart and hog
pancreas extracts, intravenous or oral calcium orotate (calcium EAP), hysterectomy,
removal of dental fillings containing silver or mercury amalgams, and surgical
implantation of pig brain into the patient's abdomen. None of these treatments is an
effective therapy for MS or any of its symptoms. While some scientists look for therapies that will affect the overall course of the
disease, others are searching for new and better medications to control the symptoms of MS
without triggering intolerable side effects. Many people with MS have problems with spasticity, a condition that primarily
affects the lower limbs. Spasticity can occur either as a sustained stiffness caused by
increased muscle tone or as spasms that come and go, especially at night. It is usually
treated with muscle relaxants and tranquilizers. Baclofen (Lioresal), the most commonly
prescribed medication for this symptom, may be taken orally or, in severe cases, injected
into the spinal cord. Tizanidine (Zanaflex), used for years in Europe and now approved in
the United States, appears to function similarly to baclofen. Diazepam (Valium),
clonazepam (Klonopin), and dantrolene (Dantrium) can also reduce spasticity. Although its
beneficial effect is temporary, physical therapy may also be useful and can help prevent
the irreversible shortening of muscles known as contractures. Surgery to reduce spasticity
is rarely appropriate in MS. Weakness and ataxia (incoordination) are also characteristic of
MS. When weakness is a problem, some spasticity can actually be beneficial by lending
support to weak limbs. In such cases, medication levels that alleviate spasticity
completely may be inappropriate. Physical therapy and exercise can also help preserve
remaining function, and patients may find that various aids-such as foot braces, canes,
and walkers-can help them remain independent and mobile. Occasionally, physicians can
provide temporary relief from weakness, spasms, and pain by injecting a drug called phenol
into the spinal cord, muscles, or nerves in the arms or legs. Further research is needed
to find or develop effective treatments for MS-related weakness and ataxia.
Although improvement of optic symptoms usually occurs even without treatment, a
short course of treatment with intravenous methylprednisolone (Solu-Medrol) followed by
treatment with oral steroids is sometimes used. A trial of oral prednisone in patients
with visual problems suggests that this steroid is not only ineffective in speeding
recovery but may also increase patients' risk for future MS attacks. Curiously, prednisone
injected directly into the veins-at ten times the oral dose-did seem to produce
short-term recovery. Because of the link between optic neuritis and MS, the study's
investigators believe these findings may hold true for the treatment of MS as well. A
follow-up study of optic neuritis patients will address this and other questions. Return to Index Fatigue, especially in the legs, is a common symptom of MS and may be both
physical and psychological. Avoiding excessive activity and heat are probably the most
important measures patients can take to counter physiological fatigue. If psychological
aspects of fatigue such as depression or apathy are evident, antidepressant medications
may help. Other drugs that may reduce fatigue in some, but not all, patients include
amantadine (Symmetrel), pemoline (Cylert), and the still-experimental drug aminopyridine. People with MS may experience several types of pain. Muscle and back pain can be
helped by aspirin or acetaminophen and physical therapy to correct faulty posture and
strengthen and stretch muscles. The sharp, stabbing facial pain known as trigeminal
neuralgia is commonly treated with carbamazapine or other anticonvulsant drugs or,
occasionally, surgery. Intense tingling and burning sensations are harder to treat. Some
people get relief with antidepressant drugs; others may respond to electrical stimulation
of the nerves in the affected area. In some cases, the physician may recommend codeine. As the disease progresses, some patients develop bladder malfunctions. Urinary
problems are often the result of infections that can be treated with antibiotics. The
physician may recommend that patients take vitamin C supplements or drink cranberry juice,
as these measures acidify urine and may reduce the risk of further infections. Several
medications are also available. The most common bladder problems encountered by MS
patients are urinary frequency, urgency, or incontinence. A small number of patients,
however, retain large amounts of urine. In these patients, catheterization may be
necessary. In this procedure, a catheter or drainage tube is temporarily inserted (by the
patient or a caretaker) into the urethra several times a day to drain urine from the
bladder. Surgery may be indicated in severe, intractable cases. Scientists have developed
a "bladder pacemaker" that has helped people with urinary incontinence in
preliminary trials. The pacemaker, which is surgically implanted, is controlled by a
hand-held unit that allows the patient to electrically stimulate the nerves that control bladder function. MS patients with urinary problems may be reluctant to drink enough fluids, leading to constipation.
Drinking more water and adding fiber to the diet usually alleviates this condition. Sexual
dysfunction may also occur, especially in patients with urinary problems. Men may
experience occasional failure to attain an erection. Penile implants, injection of the
drug papaverine, and electrostimulation are techniques used to resolve the problem. Women
may experience insufficient lubrication or have difficulty reaching orgasm; in these
cases, vaginal gels and vibrating devices may be helpful. Counseling is also beneficial,
especially in the absence of urinary problems, since psychological factors can also cause
these symptoms. For instance, depression can intensify symptoms of fatigue, pain,
and sexual dysfunction. In addition to counseling, the physician may prescribe
antidepressant or antianxiety medications. Amitriptyline is used to treat laughing/weeping
syndrome. Tremors are often resistant to therapy, but can sometimes be treated with drugs
or, in extreme cases, surgery. Investigators are currently examining a number of
experimental treatments for tremor. Return to Index Symptom Drug Spasticity Baclofen (Lioresal) Tizanidine (Zanaflex) Diazepam (Valium) Clonazepam (Klonopin) Dantrolene (Dantrium) Optic neuritis Methylprednisolone (Solu-Medrol) Oral steroids Fatigue Antidepressants Amantadine (Symmetrel) Pemoline (Cylert) Pain Aspirin or acetaminophen Antidepressants Codeine Trigeminal neuralgia Carbamazapine, other anticonvulsant Sexual dysfunction Papaverine injections(in men) Many advances, on several fronts, have been made in the war against MS. Each advance
interacts with the others, adding greater depth and meaning to each new discovery. Four
areas, in particular, stand out. Over the last decade, our knowledge about how the immune system works has grown at an
amazing rate. Major gains have been made in recognizing and defining the role of this
system in the development of MS lesions, giving scientists the ability to devise ways to
alter the immune response. Such work is expected to yield a variety of new potential
therapies that may ameliorate MS without harmful side effects. New tools such as MRI have redefined the natural history of MS and are proving
invaluable in monitoring disease activity. Scientists are now able to visualize and follow
the development of MS lesions in the brain and spinal cord using MRI; this ability is a
tremendous aid in the assessment of new therapies and can speed the process of evaluating
new treatments. Other tools have been developed that make the painstaking work of teasing out the
disease's genetic secrets possible. Such studies have strengthened scientists' conviction
that MS is a disease with many genetic components, none of which is dominant. Immune
system-related genetic factors that predispose an individual to the development of MS have
been identified, and may lead to new ways to treat or prevent the disease. In fact, a treatment that may actually slow the course of the disease has been found
and a growing number of therapies are now available that effectively treat some MS
symptoms. In addition, there are a number of treatments under investigation that may
curtail attacks or improve function of demyelinated nerve fibers. Over a dozen clinical
trials testing potential therapies are under way, and additional new treatments are being
devised and tested in animal models. Return to Index The role of genetic risk factors, and how they can be modified, must be more clearly
defined. Environmental triggers, such as viruses or toxins, need to be investigated
further. The specific cellular and subcellular targets of immune attack in the brain and
spinal cord, and the subsets of T cells involved in that attack, need to be identified.
Knowledge of these aspects of the disease will enable scientists to develop new methods
for halting-or reversing and repairing-the destruction of myelin that causes the
symptoms of MS. The 1990s-proclaimed the "Decade of the Brain" in 1989 by President Bush and
Congress-have seen an unparalleled explosion of knowledge about neurological disorders.
New technologies are forcing even complex diseases like MS to yield up their secrets.
These burgeoning opportunities in the field of neurological research have prompted the
National Advisory Neurological Disorders and Stroke Council to suggest that an effective
treatment for and the cause of MS may be found during the Decade of the Brain. The former
has already been achieved; scientists continue to diligently search for the latter. Their
dedication is the best hope for a cure, or, better yet, a way to prevent MS altogether. Return to Index The National Institute of Neurological Disorders and Stroke (NINDS) is the Federal
Government's leading supporter of biomedical research on nervous system disorders,
including MS. The NINDS conducts research on MS in its own laboratories at the National
Institutes of Health in Bethesda, MD, and supports research at institutions worldwide. The
Institute also sponsors an active public information program. Information on the NINDS and
its research programs is also available on the World Wide Web at:
http://www.ninds.nih.gov. antibodies - proteins made by the immune system that bind to structures
(antigens) they recognize as foreign to the body. antigen - a structure foreign to the body, such as a virus. The body
usually responds to antigens by producing antibodies. ataxia - a condition in which the muscles fail to function in a
coordinated manner. autoimmune disease - a disease in which the body's defense system
malfunctions and attacks a part of the body itself rather than foreign matter. blood/brain barrier - a membrane that controls the passage of substances
from the blood into the central nervous system. cerebrospinal fluid - the colorless liquid, consisting partially of
substances filtered from blood and partially by secretions released by brain cells, that
circulates around and through the cavities of the brain and spinal cord. Physicians use a
variety of tests-electrophoresis, isoelectric focusing, capillary isotachophoresis, and
radioimmunoassay-to study cerebrospinal fluid for abnormalities often associated with MS. cytokines - powerful chemical substances secreted by T cells. Cytokines
are an important factor in the production of inflammation and show promise as treatments
for MS. demyelination - damage caused to myelin by recurrent attacks of
inflammation. Demyelination ultimately results in nervous system scars, called plaques,
which interrupt communications between the nerves and the rest of the body. experimental allergic encephalomyelitis (EAE) - a chronic brain and
spinal cord disease similar to MS which is induced by injecting myelin basic protein into
laboratory animals. fatigue - tiredness that may accompany activity or may persist even
without exertion. gadolinium - a chemical compound given during MRI scans that helps
distinguish new lesions from old. human leukocyte antigens (HLAs) - antigens, tolerated by the body, that
correspond to genes that govern immune responses. Also known as immunoglobulin G (IgG) - an antibody-containing substance produced by
human plasma cells in diseased central nervous system plaques. Levels of IgG are increased
in the cerebrospinal fluid of most MS patients. immunosuppression - suppression of immune system functions. Many
medications under investigation for the treatment of MS are immunosuppressants. interferons - cytokines belonging to a family of antiviral proteins that
occur naturally in the body. Gamma interferon is produced by immune system cells, enhances
T-cell recognition of antigens, and causes worsening of MS symptoms. Alpha and beta
interferon probably exert a suppressive effect on the immune system and may be beneficial
in the treatment of MS. lesion - an abnormal change in the structure of an organ due to disease
or injury. magnetic resonance imaging (MRI) - a non-invasive scanning technique
that enables investigators to see and track MS lesions as they evolve. myelin - a fatty covering insulating nerve cell fibers in the brain and
spinal cord, myelin facilitates the smooth, high-speed transmission of electrochemical
messages between these components of the central nervous system and the rest of the body.
In MS, myelin is damaged through a process known as demyelination, which results in
distorted or blocked signals. myelin basic protein (MBP) - a major component of myelin. When myelin
breakdown occurs (as in MS), MBP can often be found in abnormally high levels in the
patient's cerebrospinal fluid. When injected into laboratory animals, MBP induces
experimental allergic encephalomyelitis, a chronic brain and spinal cord disease similar
to MS. oligodendrocytes - cells that make and maintain myelin. optic neuritis - an inflammatory disorder of the optic nerve that
usually occurs in only one eye and causes visual loss and sometimes blindness. It is
generally temporary. paresthesias - abnormal sensations such as numbness, prickling, or
"pins and needles." plaques - patchy areas of inflammation and demyelination typical of MS,
plaques disrupt or block nerve signals that would normally pass through the regions
affected by the plaques. receptor - a protein on a cell's surface that allows the cell to
identify antigens. retrobulbar neuritis - an inflammatory disorder of the optic nerve that
is usually temporary. It causes rapid loss of vision and may cause pain upon moving the
eye. spasticity - involuntary muscle contractions leading to spasms and
stiffness or rigidity. In MS, this condition primarily affects the lower limbs. T cells - immune system cells that develop in the thymus gland. Findings
suggest that T cells are implicated in myelin destruction. transverse myelitis - an acute spinal cord disorder causing sudden low
back pain and muscle weakness and abnormal sensory sensations in the lower extremities.
Transverse myelitis often remits spontaneously; however, severe or long-lasting cases may
lead to permanent disability. white matter - nerve fibers that are the site of MS lesions and underlie
the gray matter of the brain and spinal cord. For information on other neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at: In addition, a number of private organizations offer a variety of services and
information that can help those affected by MS. They include: National Multiple Sclerosis Society
Return to Index Multiple Sclerosis Association of America
Multiple Sclerosis Foundation
Other voluntary health agencies that can provide general information on MS or symptoms
associated with MS include: National Ataxia Foundation (NAF)
International Essential Tremor Foundation
Well Spouse Foundation
American Autoimmune Related Diseases Association
Paralyzed Veterans of America (PVA)
Boston Cure Project for MS
National Organization for Rare Disorders (NORD)
In addition to the NINDS, there are several other Federal Government agencies that may
be able to provide information on MS. They are the: Food and Drug Administration (FDA)
National Rehabilitation
Information Center (NARIC)
Return to Index To find better ways to prevent and treat multiple
sclerosis, the NINDS research program supports a broad spectrum of studies by
investigators at leading biomedical research institutions across the country. Information
on research activities at these centers may be obtained by contacting the principal
investigators listed below. The centers that conduct clinical research are indicated with
an asterisk (*): Robert Lazzarini, Ph.D. *Robert P. Lisak, M.D. Stephen Miller, Ph.D. Cedric Raine, M.D. *A. M. Rostami, M.D., Ph.D. Stephen Stohlman, Ph.D. *John N. Whitaker, M.D. On December 23, 1996, the United States Food and Drug Administration approved Copaxone (Copolymer 1) for the treatment of relapsing-remitting MS.
On April 4, 1997, the Pharmacia & Upjohn company announced the halt of three large clinical trials of its experimental drug Linomide (roquinimex) based on reports of unexpected toxicity. On October 13, 2000, the United States Food and Drug Administration announced the approval of Novantrone (mitoxantrone), an approved cancer drug, for the treatment of advanced or chronic MS. On March 7, 2002, the U.S. Food and Drug Administration announced the approval of Rebif (Interferon beta-1a) for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Prepared by: NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke
or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history. All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
