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Multiple Sclerosis: Hope Through Research
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Contents:
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* How is MS Diagnosed?
* Can MS be Treated?
Immunotherapy
Therapy to Improve Nerve Impulse Conduction
Therapies Targeting an Antigen
Cytokines
Remyelination
Diet
Unproven Therapies
* Are Any MS Symptoms Treatable?
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Return to Multiple Sclerosis Information Page or Main MS Index
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How is MS Diagnosed?
When faced with a patient whose symptoms, neurological examination, and
medical history suggest MS, physicians use a variety of tools to rule out
other possible disorders and perform a series of laboratory tests which, if
positive, confirm the diagnosis.
Imaging technologies such as MRI--often used in conjunction with the
contrast agent gadolinium, which helps distinguish new plaques from old on
MRI (see section on "What is the Course of MS?")--can help locate central
nervous system lesions resulting from myelin loss. However, since these
lesions can also occur in several other neurological disorders, they are not
absolute evidence of MS. Magnetic resonance spectroscopy (MRS) is a new tool
being used to investigate MS. Unlike MRI, which provides an anatomical
picture of lesions, MRS yields information about the biochemistry of the
brain in MS.
Evoked potential tests, which measure the speed of the brain's response to
visual, auditory, and sensory stimuli, can sometimes detect lesions the
scanners miss. Like imaging technologies, evoked potentials are helpful but
not conclusive because they cannot identify the cause of lesions.
The physician may also study the patient's cerebrospinal fluid (the
colorless liquid that circulates through the brain and spinal cord) for
cellular and chemical abnormalities often associated with MS. These
abnormalities include increased numbers of white blood cells and
higher-than-average amounts of protein, especially myelin basic protein and
an antibody called immunoglobulin G. Physicians can use several different
laboratory techniques to separate and graph the various proteins in MS
patients' cerebrospinal fluid. This process often identifies the presence of
a characteristic pattern called oligoclonal bands.
Because there is no single test that unequivocally detects MS, it is often
difficult for the physician to differentiate between an MS attack and
symptoms that can follow a viral infection or even an immunization. Many
doctors will tell their patients they have "possible MS." If, as time goes
by, the patient's symptoms show the characteristic relapsing-remitting
pattern, or continue in a chronic and progressive fashion, and if laboratory
tests rule out other likely causes, or specific tests become positive, the
diagnosis may eventually be changed to "probable MS."
A number of other diseases may produce symptoms similar to those seen in MS.
Other conditions with an intermittent course and MS-like lesions of the
brain's white matter include polyarteritis, lupus erythematosus,
syringomyelia, tropical spastic paraparesis, some cancers, and certain
tumors that compress the brainstem or spinal cord. Progressive multifocal
leukoencephalopathy can mimic the acute stage of an MS attack. The physician
will also need to rule out stroke, neurosyphilis, spinocerebellar ataxias,
pernicious anemia, diabetes, Sjogren's disease, and vitamin B12 deficiency.
Acute transverse myelitis may signal the first attack of MS, or it may
indicate other problems such as infection with the Epstein-Barr or herpes
simplex B viruses. Recent reports suggest that the neurological problems
associated with Lyme disease may present a clinical picture much like MS.
Investigators are continuing their search for a definitive test for MS.
Until one is developed, however, evidence of both multiple attacks and
central nervous system lesions must be found--a process that can take months
or even years--before a physician can make a definitive diagnosis of MS.
Return to Index
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Diagnostic Categories for Multiple Sclerosis
Definite MS Consistent course (relapsing-remitting course with
at least 2 bouts separated by at least 1 month, or
slow or stepwise progressive course for at least 6
months)
Documented neurologic signs of lesions in more than
one site of brain or spinal cord white matter
Onset of symptoms between 10 and 50 years of age
Absence of other more likely neurologic explanation
Probable MS History of relapsing-remitting symptoms
Signs not documented and only one current sign
commonly associated with MS
Documented single bout of symptoms with signs of
more than one white matter lesion; good recovery,
then variable symptoms and signs
Absence of other more likely neurologic explanation
Possible MS History of relapsing-remitting symptoms
No documentation of signs establishing more than one
white matter lesion
Absence of other more likely neurologic explanation
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Can MS be Treated?
There is as yet no cure for MS. Many patients do well with no therapy at
all, especially since many medications have serious side effects and some
carry significant risks. Naturally occurring or spontaneous remissions make
it difficult to determine therapeutic effects of experimental treatments;
however, the emerging evidence that MRIs can chart the development of
lesions is already helping scientists evaluate new therapies.
Until recently, the principal medications physicians used to treat MS were
steroids possessing anti-inflammatory properties; these include
adrenocorticotropic hormone (better known as ACTH), prednisone,
prednisolone, methylprednisolone, betamethasone, and dexamethasone. Studies
suggest that intravenous methylprednisolone may be superior to the more
traditional intravenous ACTH for patients experiencing acute relapses; no
strong evidence exists to support the use of these drugs to treat
progressive forms of MS. Also, there is some indication that steroids may be
more appropriate for people with movement, rather than sensory, symptoms.
While steroids do not affect the course of MS over time, they can reduce the
duration and severity of attacks in some patients. The mechanism behind this
effect is not known; one study suggests the medications work by restoring
the effectiveness of the blood/brain barrier. Because steroids can produce
numerous adverse side effects (acne, weight gain, seizures, psychosis), they
are not recommended for long-term use.
One of the most promising MS research areas involves naturally occurring
antiviral proteins known as interferons. Two forms of beta interferon
(Avonex and Betaseron) have now been approved by the Food and Drug
Administration for treatment of relapsing-remitting MS. A third form (Rebif)
is marketed in Europe. Beta interferon has been shown to reduce the number
of exacerbations and may slow the progression of physical disability. When
attacks do occur, they tend to be shorter and less severe. In addition, MRI
scans suggest that beta interferon can decrease myelin destruction.
Investigators speculate that the effects of beta interferon may be due to
the drug's ability to correct an MS-related deficiency of certain white
blood cells that suppress the immune system and/or its ability to inhibit
gamma interferon, a substance believed to be involved in MS attacks. Alpha
interferon is also being studied as a possible treatment for MS. Common side
effects of interferons include fever, chills, sweating, muscle aches,
fatigue, depression, and injection site reactions.
Scientists continue their extensive efforts to create new and better
therapies for MS. Goals of therapy are threefold: to improve recovery from
attacks, to prevent or lessen the number of relapses, and to halt disease
progression. Some therapies currently under investigation are discussed
below.
Return to Index
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Immunotherapy
As evidence of immune system involvement in the development of MS has grown,
trials of various new treatments to alter or suppress immune response are
being conducted. These therapies are, at this time, still considered
experimental.
Results of recent clinical trials have shown that immunosuppressive agents
and techniques can positively (if temporarily) affect the course of MS;
however, toxic side effects often preclude their widespread use. In
addition, generalized immunosuppression leaves the patient open to a variety
of viral, bacterial, and fungal infections.
Over the years, MS investigators have studied a number of immunosuppressant
treatments. Among the therapies being studied are cyclosporine (Sandimmune),
cyclophosphamide (Cytoxan), methotrexate, azathioprine (Imuran), and total
lymphoid irradiation (a process whereby the MS patient's lymph nodes are
irradiated with x-rays in small doses over a few weeks to destroy lymphoid
tissue, which is actively involved in tissue destruction in autoimmune
diseases). Inconclusive and/or contradictory results of these trials,
combined with the therapies' potentially dangerous side effects, dictate
that further research is necessary to determine what, if any, role they
should play in the management of MS. Studies are also being conducted with
the immune system modulating drugs linomide (Roquinimex), cladribine
(Leustatin), and mitoxantrone.
Two other experimental treatments -- one involving the use of monoclonal
antibodies and the other involving plasma exchange, or plasmapheresis -- may
have fewer dangerous side effects. Monoclonal antibodies are identical,
laboratory-produced antibodies that are highly specific for a single
antigen. They are injected into the patient in the hope that they will alter
the patient's immune response. Plasmapheresis is a procedure in which blood
is removed from the patient, and the plasma is separated from other blood
substances, which may contain antibodies and other 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
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Therapy to Improve Nerve Impulse Conduction
Because the transmission of electrochemical messages between the brain and
body is disrupted in MS, medications to improve the conduction of nerve
impulses are being investigated. Since demyelinated nerves show
abnormalities of potassium activity, scientists are studying drugs that
block the channels through which potassium moves, thereby restoring
conduction of the nerve impulse. In several small experimental trials,
derivatives of a drug called aminopyridine temporarily improved vision,
coordination, and strength when given to MS patients who suffered from both
visual symptoms and heightened sensitivity to temperature. Possible side
effects of these therapies include paresthesias (tingling sensations),
dizziness, and seizures.
Return to Index
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Therapies Targeting an Antigen
Trials of a synthetic form of myelin basic protein, called copolymer I
(Copaxone), have shown promise in treating people in the early stages of
relapsing-remitting MS. Copolymer I, unlike so many drugs tested for the
treatment of MS, seems to have few side effects. Recent trial data indicate
that copolymer I can reduce the relapse rate by almost one third. In
addition, patients given copolymer I were more likely to show neurologic
improvement than those given a placebo. The Food and Drug Administration has
made the drug available to people with early relapsing-remitting MS through
its "Treatment IND" program and is currently reviewing data from a
large-scale study to determine whether or not to approve the drug for
marketing.
Investigators are also looking at the possibility of developing an MS
vaccine. Myelin-attacking T cells were removed, inactivated, and injected
back into animals with experimental allergic encephalomyelitis (EAE). This
procedure results in destruction of the immune system cells that were
attacking myelin basic protein. In a couple of small trials scientists have
tested a similar vaccine in humans. The product was well-tolerated and had
no side effects, but the studies were too small to establish efficacy.
Patients with progressive forms of MS did not appear to benefit, although
relapsing-remitting patients showed some neurologic improvement and had
fewer relapses and reduced numbers of lesions in one study. Unfortunately,
the benefits did not last beyond two years.
A similar approach, known as peptide therapy, is based on evidence that the
body can mount an immune response against the T cells that destroy myelin,
but this response is not strong enough to overcome the disease. To induce
this response, the investigator scans the myelin-attacking T cells for the
myelin-recognizing receptors on the cells' surface. A fragment, or peptide,
of those receptors is then injected into the body. The immune system "sees"
the injected peptide as a foreign invader and launches an attack on any
myelin-destroying T cells that carry the peptide. The injection of portions
of T cell receptors may heighten the immune system reaction against the
errant T cells much the same way a booster shot heightens immunity to
tetanus. Or, peptide therapy may jam the errant cells' receptors, preventing
the cells from attacking myelin.
Despite these promising early results, there are some major obstacles to
developing vaccine and peptide therapies. Individual patients' T cells vary
so much that it may not be possible to develop a standard vaccine or peptide
therapy beneficial to all, or even most, MS patients. At this time, each
treatment involves extracting cells from each individual patient, purifying
the cells, and then growing them in culture before inactivating and
chemically altering them. This makes the production of quantities sufficient
for therapy extremely time consuming, labor intensive, and expensive.
Further studies are necessary to determine whether universal inoculations
can be developed to induce suppression of MS patients' overactive immune
systems.
Protein antigen feeding is similar to peptide therapy, but is a potentially
simpler means to the same end. Whenever we eat, the digestive system breaks
each food or substance into its primary "non-antigenic" building blocks,
thereby averting a potentially harmful immune attack. So, strange as it may
seem, antigens that trigger an immune response when they are injected can
encourage immune system tolerance when taken orally. Furthermore, this
reaction is directed solely at the specific antigen being fed; wholesale
immunosuppression, which can leave the body open to a variety of infections,
does not occur. Studies have shown that when rodents with EAE are fed myelin
protein antigens, they experience fewer relapses. Data from a small,
preliminary trial of antigen feeding in humans found limited suggestion of
improvement, but the results were not statistically significant. A
multi-center trial is being conducted to determine whether protein antigen
feeding is effective.
Return to Index
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Cytokines
As our growing insight into the workings of the immune system gives us new
knowledge about the function of cytokines, the powerful chemicals produced
by T cells, the possibility of using them to manipulate the immune system
becomes more attractive. Scientists are studying a variety of substances
that may block harmful cytokines, such as those involved in inflammation, or
that encourage the production of protective cytokines.
A drug that has been tested as a depression treatment, rolipram, has been
shown to reduce levels of several destructive cytokines in animal models of
MS. Its potential as a therapy for MS is not known at this time, but side
effects seem modest. Protein antigen feeding, discussed above, may release
transforming growth factor beta (TGF), a protective cytokine that inhibits
or regulates the activity of certain immune cells. Preliminary tests
indicate that it may reduce the number of immune cells commonly found in MS
patients' spinal fluid. Side effects include anemia and altered kidney
function.
Interleukin 4 (IL-4) is able to diminish demyelination and improve the
clinical course of mice with EAE, apparently by influencing developing T
cells to become protective rather than harmful. This also appears to be true
of a group of chemicals called retinoids. When fed to rodents with EAE,
retinoids increase levels of TGF and IL-4, which encourage protective T
cells, while decreasing numbers of harmful T cells. This results in
improvement of the animals' clinical symptoms.
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Remyelination
Some studies focus on strategies to reverse the damage to myelin and
oligodendrocytes (the cells that make and maintain myelin in the central
nervous system), both of which are destroyed during MS attacks. Scientists
now know that oligodendrocytes may proliferate and form new myelin after an
attack. Therefore, there is a great deal of interest in agents that may
stimulate this reaction. To learn more about the process, investigators are
looking at how drugs used in MS trials affect remyelination. Studies of
animal models indicate that monoclonal antibodies and two immunosuppressant
drugs, cyclophosphamide and azathioprine, may accelerate remyelination,
while steroids may inhibit it. The ability of intravenous immunoglobulin
(IVIg) to restore visual acuity and/or muscle strength is also being
investigated.
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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
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Unproven Therapies
MS is a disease with a natural tendency to remit spontaneously, and for
which there is no universally effective treatment and no known cause. These
factors open the door for an array of unsubstantiated claims of cures. At
one time or another, many ineffective and even potentially dangerous
therapies have been promoted as treatments for MS. A partial list of these
"therapies" includes: injections of snake venom, electrical stimulation of
the spinal cord's dorsal column, removal of the thymus gland, breathing
pressurized (hyperbaric) oxygen in a special chamber, injections of beef
heart and hog pancreas extracts, intravenous or oral calcium orotate
(calcium EAP), hysterectomy, removal of dental fillings containing silver or
mercury amalgams, and surgical implantation of pig brain into the patient's
abdomen. None of these treatments is an effective therapy for MS or any of
its symptoms.
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Drugs Used to Treat Multiple Sclerosis
Drugs currently available to patients
Steroids
Adrenocorticotropic hormone (ACTH)
Prednisone
Prednisolone
Methylprednisolone
Betamethasone
Dexamethasone
Interferons
Beta interferons (Avonex, Betaseron)
Beta interferon (Rebif)--available in Europe
only
Some experimental therapies
Alpha interferon
Cyclosporine (Sandimmune)
Cyclophosphamide (Cytoxan)
Methotrexate
Azathioprine (Imuran)
Linomide (Roquinimex)
Cladribine (Leustatin)
Mitoxantrone
Aminopyridine, derivatives of
Copolymer I (Copaxone)
Rolipram
Interleukin 4 (IL-4)
Retinoids
Total lymphoid irradiation
Monoclonal antibodies
Plasma exchange or plasmapheresis
Bone marrow transplantation
Peptide therapy
Various MS vaccines
Protein antigen feeding
Transforming growth factor beta (TGF)
Intravenous immunoglobulin (IVIg)
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Are Any MS Symptoms Treatable?
While some scientists look for therapies that will affect the overall course
of the disease, others are searching for new and better medications to
control the symptoms of MS without triggering intolerable side effects.
Many people with MS have problems with spasticity, a condition that
primarily affects the lower limbs. Spasticity can occur either as a
sustained stiffness caused by increased muscle tone or as spasms that come
and go, especially at night. It is usually treated with muscle relaxants and
tranquilizers. Baclofen (Lioresal), the most commonly prescribed medication
for this symptom, may be taken orally or, in severe cases, injected into the
spinal cord. Tizanidine (Zanaflex), used for years in Europe and now
approved in the United States, appears to function similarly to baclofen.
Diazepam (Valium), clonazepam (Klonopin), and dantrolene (Dantrium) can also
reduce spasticity. Although its beneficial effect is temporary, physical
therapy may also be useful and can help prevent the irreversible shortening
of muscles known as contractures. Surgery to reduce spasticity is rarely
appropriate in MS.
Weakness and ataxia (incoordination) are also characteristic of MS. When
weakness is a problem, some spasticity can actually be beneficial by lending
support to weak limbs. In such cases, medication levels that alleviate
spasticity completely may be inappropriate. Physical therapy and exercise
can also help preserve remaining function, and patients may find that
various aids--such as foot braces, canes, and walkers--can help them remain
independent and mobile. Occasionally, physicians can provide temporary
relief from weakness, spasms, and pain by injecting a drug called phenol
into the spinal cord, muscles, or nerves in the arms or legs. Further
research is needed to find or develop effective treatments for MS-related
weakness and ataxia.
Although improvement of optic symptoms usually occurs even without
treatment, a short course of treatment with intravenous methylprednisolone
(Solu-Medrol) followed by treatment with oral steroids is sometimes used. A
trial of oral prednisone in patients with visual problems suggests that this
steroid is not only ineffective in speeding recovery but may also increase
patients' risk for future MS attacks. Curiously, prednisone injected
directly into the veins--at ten times the oral dose--did seem to produce
short-term recovery. Because of the link between optic neuritis and MS, the
study's investigators believe these findings may hold true for the treatment
of MS as well. A follow-up study of optic neuritis patients will address
this and other questions.
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 relax the nerves used
for urine retention or contract those needed to empty the bladder.
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
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Drugs Used to Treat Symptoms of Multiple Sclerosis
Symptom Drug
Drugs currently available
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 acetaminiphen
Antidepressants
Codeine
Trigeminal neuralgia Carbamazapine, other anticonvulsant
drugs
Sexual dysfunction Papaverine, injections (in men)
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Last Edited: March 12, 1997
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892
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