Multiple Sclerosis: Hope Through Research, Part II
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.
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
Can MS be Treated?
There is as yet no cure for MS. Many patients do well with no therapy
at all, especially since many medications have serious side effects and
some carry significant risks. Naturally occurring or spontaneous
remissions make it difficult to determine therapeutic effects of
experimental treatments; however, the emerging evidence that MRIs can
chart the development of lesions is already helping scientists evaluate
new therapies.
Until recently, the principal medications physicians used to treat MS
were steroids possessing anti-inflammatory properties; these include
adrenocorticotropic hormone (better known as ACTH), prednisone,
prednisolone, methylprednisolone, betamethasone, and dexamethasone.
Studies suggest that intravenous methylprednisolone may be superior to the
more traditional intravenous ACTH for patients experiencing acute
relapses; no strong evidence exists to support the use of these drugs to
treat progressive forms of MS. Also, there is some indication that
steroids may be more appropriate for people with movement, rather than
sensory, symptoms.
While steroids do not affect the course of MS over time, they can
reduce the duration and severity of attacks in some patients. The
mechanism behind this effect is not known; one study suggests the
medications work by restoring the effectiveness of the blood/brain
barrier. Because steroids can produce numerous adverse side effects (acne,
weight gain, seizures, psychosis), they are not recommended for long-term
use.
One of the most promising MS research areas involves naturally
occurring antiviral proteins known as interferons. Two forms of beta
interferon (Avonex and Betaseron) have now been approved by the Food and
Drug Administration for treatment of relapsing-remitting MS. A third form
(Rebif) is marketed in Europe. Beta interferon has been shown to reduce
the number of exacerbations and may slow the progression of physical
disability. When attacks do occur, they tend to be shorter and less
severe. In addition, MRI scans suggest that beta interferon can decrease
myelin destruction.
Investigators speculate that the effects of beta interferon may be due
to the drug's ability to correct an MS-related deficiency of certain white
blood cells that suppress the immune system and/or its ability to inhibit
gamma interferon, a substance believed to be involved in MS attacks. Alpha
interferon is also being studied as a possible treatment for MS. Common
side effects of interferons include fever, chills, sweating, muscle aches,
fatigue, depression, and injection site reactions.
Scientists continue their extensive efforts to create new and better
therapies for MS. Goals of therapy are threefold: to improve recovery from
attacks, to prevent or lessen the number of relapses, and to halt disease
progression. Some therapies currently under investigation are discussed
below.
Immunotherapy
As evidence of immune system involvement in the development of MS has
grown, trials of various new treatments to alter or suppress immune
response are being conducted. These therapies are, at this time, still
considered experimental.
Results of recent clinical trials have shown that
immunosuppressive agents and techniques can positively (if
temporarily) affect the course of MS; however, toxic side effects often
preclude their widespread use. In addition, generalized immunosuppression
leaves the patient open to a variety of viral, bacterial, and fungal
infections.
Over the years, MS investigators have studied a number of
immunosuppressant treatments. Among the therapies being studied are
cyclosporine (Sandimmune), cyclophosphamide (Cytoxan), methotrexate,
azathioprine (Imuran), and total lymphoid irradiation (a process whereby
the MS patient's lymph nodes are irradiated with x-rays in small doses
over a few weeks to destroy lymphoid tissue, which is actively involved in
tissue destruction in autoimmune diseases). Inconclusive and/or
contradictory results of these trials, combined with the therapies'
potentially dangerous side effects, dictate that further research is
necessary to determine what, if any, role they should play in the
management of MS. Studies are also being conducted with the immune system
modulating drugs linomide (Roquinimex), cladribine (Leustatin), and
mitoxantrone.
Two other experimental treatments -- one involving the use of
monoclonal antibodies and the other involving plasma exchange, or
plasmapheresis -- may have fewer dangerous side effects. Monoclonal
antibodies are identical, laboratory-produced antibodies that are highly
specific for a single antigen. They are injected into the patient in the
hope that they will alter the patient's immune response. Plasmapheresis is
a procedure in which blood is removed from the patient, and the plasma is
separated from other blood substances, which may contain antibodies and
other 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.
Therapy to Improve Nerve Impulse Conduction
Because the transmission of electrochemical messages between the brain
and body is disrupted in MS, medications to improve the conduction of
nerve impulses are being investigated. Since demyelinated nerves show
abnormalities of potassium activity, scientists are studying drugs that
block the channels through which potassium moves, thereby restoring
conduction of the nerve impulse. In several small experimental trials,
derivatives of a drug called aminopyridine temporarily improved vision,
coordination, and strength when given to MS patients who suffered from
both visual symptoms and heightened sensitivity to temperature. Possible
side effects of these therapies include paresthesias (tingling
sensations), dizziness, and seizures.
Therapies Targeting an Antigen
Trials of a synthetic form of myelin basic protein, called copolymer I
(Copaxone), have shown promise in treating people in the early stages of
relapsing-remitting MS. Copolymer I, unlike so many drugs tested for the
treatment of MS, seems to have few side effects. Recent trial data
indicate that copolymer I can reduce the relapse rate by almost one third.
In addition, patients given copolymer I were more likely to show
neurologic improvement than those given a placebo. The Food and Drug
Administration has made the drug available to people with early
relapsing-remitting MS through its "Treatment IND" program and is
currently reviewing data from a large-scale study to determine whether or
not to approve the drug for marketing.
Investigators are also looking at the possibility of developing an MS
vaccine. Myelin-attacking T cells were removed, inactivated, and injected
back into animals with experimental allergic encephalomyelitis (EAE). This
procedure results in destruction of the immune system cells that were
attacking myelin basic protein. In a couple of small trials scientists
have tested a similar vaccine in humans. The product was well-tolerated
and had no side effects, but the studies were too small to establish
efficacy. Patients with progressive forms of MS did not appear to benefit,
although relapsing-remitting patients showed some neurologic improvement
and had fewer relapses and reduced numbers of lesions in one study.
Unfortunately, the benefits did not last beyond two years.
A similar approach, known as peptide therapy, is based on evidence that
the body can mount an immune response against the T cells that destroy
myelin, but this response is not strong enough to overcome the disease. To
induce this response, the investigator scans the myelin-attacking T cells
for the myelin-recognizing receptors on the cells' surface. A fragment, or
peptide, of those receptors is then injected into the body. The immune
system "sees" the injected peptide as a foreign invader and launches an
attack on any myelin-destroying T cells that carry the peptide. The
injection of portions of T cell receptors may heighten the immune system
reaction against the errant T cells much the same way a booster shot
heightens immunity to tetanus. Or, peptide therapy may jam the errant
cells' receptors, preventing the cells from attacking myelin.
Despite these promising early results, there are some major obstacles
to developing vaccine and peptide therapies. Individual patients' T cells
vary so much that it may not be possible to develop a standard vaccine or
peptide therapy beneficial to all, or even most, MS patients. At this
time, each treatment involves extracting cells from each individual
patient, purifying the cells, and then growing them in culture before
inactivating and chemically altering them. This makes the production of
quantities sufficient for therapy extremely time consuming, labor
intensive, and expensive. Further studies are necessary to determine
whether universal inoculations can be developed to induce suppression of
MS patients' overactive immune systems.
Protein antigen feeding is similar to peptide therapy, but is a
potentially simpler means to the same end. Whenever we eat, the digestive
system breaks each food or substance into its primary "non-antigenic"
building blocks, thereby averting a potentially harmful immune attack. So,
strange as it may seem, antigens that trigger an immune response when they
are injected can encourage immune system tolerance when taken orally.
Furthermore, this reaction is directed solely at the specific antigen
being fed; wholesale immunosuppression, which can leave the body open to a
variety of infections, does not occur. Studies have shown that when
rodents with EAE are fed myelin protein antigens, they experience fewer
relapses. Data from a small, preliminary trial of antigen feeding in
humans found limited suggestion of improvement, but the results were not
statistically significant. A multi-center trial is being conducted to
determine whether protein antigen feeding is effective.
Cytokines
As our growing insight into the workings of the immune system gives us
new knowledge about the function of cytokines, the powerful chemicals
produced by T cells, the possibility of using them to manipulate the
immune system becomes more attractive. Scientists are studying a variety
of substances that may block harmful cytokines, such as those involved in
inflammation, or that encourage the production of protective cytokines.
A drug that has been tested as a depression treatment, rolipram, has
been shown to reduce levels of several destructive cytokines in animal
models of MS. Its potential as a therapy for MS is not known at this time,
but side effects seem modest. Protein antigen feeding, discussed above,
may release transforming growth factor beta (TGF), a protective cytokine
that inhibits or regulates the activity of certain immune cells.
Preliminary tests indicate that it may reduce the number of immune cells
commonly found in MS patients' spinal fluid. Side effects include anemia
and altered kidney function.
Interleukin 4 (IL-4) is able to diminish demyelination and improve the
clinical course of mice with EAE, apparently by influencing developing T
cells to become protective rather than harmful. This also appears to be
true of a group of chemicals called retinoids. When fed to rodents with
EAE, retinoids increase levels of TGF and IL-4, which encourage protective
T cells, while decreasing numbers of harmful T cells. This results in
improvement of the animals' clinical symptoms.
Remyelination
Some studies focus on strategies to reverse the damage to myelin and
oligodendrocytes (the cells that make and maintain myelin in the
central nervous system), both of which are destroyed during MS attacks.
Scientists now know that oligodendrocytes may proliferate and form new
myelin after an attack. Therefore, there is a great deal of interest in
agents that may stimulate this reaction. To learn more about the process,
investigators are looking at how drugs used in MS trials affect
remyelination. Studies of animal models indicate that monoclonal
antibodies and two immunosuppressant drugs, cyclophosphamide and
azathioprine, may accelerate remyelination, while steroids may inhibit it.
The ability of intravenous immunoglobulin (IVIg) to restore visual acuity
and/or muscle strength is also being investigated.
Diet
Over the years, many people have tried to implicate diet as a cause of
or treatment for MS. Some physicians have advocated a diet low in
saturated fats; others have suggested increasing the patient's intake of
linoleic acid, a polyunsaturated fat, via supplements of sunflower seed,
safflower, or evening primrose oils. Other proposed dietary "remedies"
include megavitamin therapy, including increased intake of vitamins B12 or
C; various liquid diets; and sucrose-, tobacco-, or gluten-free diets. To
date, clinical studies have not been able to confirm benefits from dietary
changes; in the absence of any evidence that diet therapy is effective,
patients are best advised to eat a balanced, wholesome diet.
Unproven Therapies
MS is a disease with a natural tendency to remit spontaneously, and for
which there is no universally effective treatment and no known cause.
These factors open the door for an array of unsubstantiated claims of
cures. At one time or another, many ineffective and even potentially
dangerous therapies have been promoted as treatments for MS. A partial
list of these "therapies" includes: injections of snake venom, electrical
stimulation of the spinal cord's dorsal column, removal of the thymus
gland, breathing pressurized (hyperbaric) oxygen in a special chamber,
injections of beef heart and hog pancreas extracts, intravenous or oral
calcium orotate (calcium EAP), hysterectomy, removal of dental fillings
containing silver or mercury amalgams, and surgical implantation of pig
brain into the patient's abdomen. None of these treatments is an effective
therapy for MS or any of its symptoms.
Drugs 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)
Are Any MS Symptoms Treatable?
While some scientists look for therapies that will affect the overall
course of the disease, others are searching for new and better medications
to control the symptoms of MS without triggering intolerable side effects.
Many people with MS have problems with spasticity, a condition
that primarily affects the lower limbs. Spasticity can occur either as a
sustained stiffness caused by increased muscle tone or as spasms that come
and go, especially at night. It is usually treated with muscle relaxants
and tranquilizers. Baclofen (Lioresal), the most commonly prescribed
medication for this symptom, may be taken orally or, in severe cases,
injected into the spinal cord. Tizanidine (Zanaflex), used for years in
Europe and now approved in the United States, appears to function
similarly to baclofen. Diazepam (Valium), clonazepam (Klonopin), and
dantrolene (Dantrium) can also reduce spasticity. Although its beneficial
effect is temporary, physical therapy may also be useful and can help
prevent the irreversible shortening of muscles known as contractures.
Surgery to reduce spasticity is rarely appropriate in MS.
Weakness and ataxia (incoordination) are also
characteristic of MS. When weakness is a problem, some spasticity can
actually be beneficial by lending support to weak limbs. In such cases,
medication levels that alleviate spasticity completely may be
inappropriate. Physical therapy and exercise can also help preserve
remaining function, and patients may find that various aids--such as foot
braces, canes, and walkers--can help them remain independent and mobile.
Occasionally, physicians can provide temporary relief from weakness,
spasms, and pain by injecting a drug called phenol into the spinal cord,
muscles, or nerves in the arms or legs. Further research is needed to find
or develop effective treatments for MS-related weakness and ataxia.
Although improvement of optic symptoms usually occurs even
without treatment, a short course of treatment with intravenous
methylprednisolone (Solu-Medrol) followed by treatment with oral steroids
is sometimes used. A trial of oral prednisone in patients with visual
problems suggests that this steroid is not only ineffective in speeding
recovery but may also increase patients' risk for future MS attacks.
Curiously, prednisone injected directly into the veins--at ten
times the oral dose--did seem to produce short-term recovery. Because of
the link between optic neuritis and MS, the study's investigators believe
these findings may hold true for the treatment of MS as well. A follow-up
study of optic neuritis patients will address this and other questions.
Fatigue, especially in the legs, is a common symptom of MS and
may be both physical and psychological. Avoiding excessive activity and
heat are probably the most important measures patients can take to counter
physiological fatigue. If psychological aspects of fatigue such as
depression or apathy are evident, antidepressant medications may help.
Other drugs that may reduce fatigue in some, but not all, patients include
amantadine (Symmetrel), pemoline (Cylert), and the still-experimental drug
aminopyridine.
People with MS may experience several types of pain. Muscle and
back pain can be helped by aspirin or acetaminophen and 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.
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)
Source: National Institute of Neurological Disorders and Stroke, National Institutes of Health, February 2000
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