Multiple sclerosis

Introduction
• 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 lecture is designed to convey the latest
information on the diagnosis, course, and possible treatment of MS, as
well as highlights of current research..

• Multiple sclerosis is one of the most common diseases of the central
nervous system (brain and spinal cord). MS is an inflammatory
demyelinating condition. Myelin is a fatty material that insulates
nerves, acting much like the covering of an electric wire and allowing
the nerve to transmit its impulses rapidly. It is the speed and
efficiency with which these impulses are conducted that permits
smooth, rapid and co-ordinated movements to be performed with little
conscious effort.
In MS, the loss of myelin (demyelination) is accompanied by a
disruption in the ability of the nerves to conduct electrical impulses to
and from the brain and this produces the various symptoms of MS.
The sites where myelin is lost (plaques or lesions) appear as hardened
(scar) areas: in MS these scars appear at different times and in
different areas of the brain and spinal cord. The term MS means,
literally, many scars. Demyelination is the root cause of the symptoms
that people with MS experience. When it occurs the speed at which
messages pass along the nerves is slower than normal. Even when the
patches of scarring caused by demyelination have healed and
remyelination has occurred, the response time of the nerve endings
tends to remain slower.

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Quick Facts:
• MS is a progressive disease of the nervous system, for which there is no cure.
• An estimated 2,500,000 people in the world have MS.
• More women than men have MS, with a ratio of 2 men to 3 women affected.
• MS is the most common diseases of the central nervous system in young adults.
• There are four types of MS: benign, relapsing remitting, secondary progressive, primary
progressive.
• Sclerosis means scars, these are the plaques or lesions in the brain and spinal cord.
• In MS, the protective myelin covering of the nerve fibres in the central nervous system is
damaged.
• Inflammation and ultimate loss of myelin causes disruption to nerve transmission and affects
many functions of the body.
• While the exact cause of MS is not known, much is known about its effect on immune system
function which may be the ultimate cause of the disease.
• MS is not directly hereditary, although genetic susceptibility plays a part in its development.
• MS is not contagious.
• Diagnosis of MS is generally between 20 and 40 years of age, although onset may be earlier.
• MS is rarely diagnosed under 12 and over 55 years of age.
• Life span is not significantly affected by MS.
• There are a wide range of symptoms. Fatigue is one of the most common.
• The incidence of MS increases in countries further from the equator.
• There is no drug that can cure MS, but treatments are now available which can modify the
course of the disease.
• Many of the symptoms of MS can be successfully managed and treated.

Causes of MS:
• The cause of multiple sclerosis is not yet known, but thousands of
researchers all over the world are meticulously putting the pieces of
this complicated puzzle together.
The damage to myelin in MS may be due to an abnormal
response of the body's immune system, which normally defends the
body against invading organisms (bacteria and viruses). Many of the
characteristics of MS suggest an 'auto-immune' disease whereby the
body attacks its own cells and tissues, which in the case of MS is
myelin. Researchers do not know what triggers the immune system to
attack myelin, but it is thought to be a combination of several factors.
One theory is that a virus, possibly lying dormant in the body,
may play a major role in the development of the disease and may
disturb the immune system or indirectly instigate the auto-immune
process. A great deal of research has taken place in trying to identify
an MS virus. It is probable that there is no one MS virus, but that a
common virus, such as measles or herpes, may act as a trigger for MS.
This trigger activates white blood cells (lymphocytes) in the blood
stream, which enter the brain by making vulnerable the brain's
defence mechanisms (i.e. the blood/brain barrier). Once inside the
brain these cells activate other elements of the immune system in such
a way that they attack and destroy myelin.

It is impossible to predict accurately the course of MS for any individual, but the first
five years give some indication of how the disease will continue for that person. This is based
upon the course of the disease over that period and the disease type. (i.e relapsing- remitting
or progressive ). The level of disability reached at end points such as five and ten years is
thought to be a reliable predictor of the future course of the disease.
However, there are many variables in this scenario:
• a large percentage of people with MS (approx 45%) are not severely affected by MS and live
normal and productive lives.
• there is a significant group (40%) which become progressive after a period of some years as
relapsing-remitting.
Age at onset and gender may also be indicators of the long-term course of the disease.
Some research has indicated that younger age at onset [under 16 years of age] implies a more
favourable prognosis, but this must be tempered by the knowledge that for a young adult
living with MS for 20 or 30 years may result in substantial disability even if the progress
towards disability is slow and in the first 10 or 15 years he or she is relatively mildly
affected. Other research has indicated that late onset [ie over 55 years of age], particularly in
males, may indicate a progressive course of the disease.
The prospect of therapy for MS should be encouraging to those newly diagnosed with
MS. Drugs such as interferon beta are possible treatments for those who are relapsing-
remitting and ambulatory. The interferon betas may slow the progression of disability as well
as reduce the severity and frequency of exacerbations. At this stage it is not known whether
interferon beta has any impact on primary progressive MS. The breadth of research currently
targeting MS gives hope that therapy which will interfere with the process of MS (even if not
curing the disease) is not an unreasonable expectation in the near future.
It should be remembered that many people with MS go through life with a manageable
disability (e.g. fatigue, a limp, bladder problems). At least 15% of people with MS, however,
will become severely disabled (i.e.having to use a wheelchair on a full-time basis). Life
expectancy for persons with MS is near normal.

Symptoms of MS
MS is a very variable condition and the symptoms depend on which areas of
the central nervous system have been affected. There is no set pattern to MS and
everyone with MS has a different set of symptoms, which vary from time to time
and can change in severity and duration, even in the same person.
There is no typical MS. Most people with MS will experience more than one
symptom, and though there are symptoms common to many people, no person
would have all of them. Common symptoms include:
Visual disturbances
• blurring of vision
• double vision (diplopia)
• optic neuritis
• involuntary rapid eye movement
• (rarely) total loss of sight
Balance & co-ordination problems
• loss of balance
• tremor
• unstable walking (ataxia)
• giddiness (vertigo)
• clumsiness of a limb
• lack of co-ordination
• weakness: this can particularly affect the legs and walking

Spasticity
• altered muscle tone can and muscle stiffness can affect mobility and walking
• spasms
Altered sensation
• tingling
• ‘pins and needles’
• numbness (paraesthesia)
• burning sensations
• pain may be associated with MS, e.g. facial pain, (such as trigeminal neuralgia), and muscle pains
Abnormal speech
• slowing of speech
• slurring of words
• changes in rhythm of speech
difficulty in swallowing (dysphagia)
Fatigue
• a debilitating kind of general fatigue which is unpredictable or out of proportion to the activity. Fatigue is
one of the most common (and one of the most troubling) symptoms of MS
Bladder & bowel problems
• Bladder problems include the need to pass water frequently and/or urgently, incomplete emptying or
emptying at inappropriate times.
• Bowel problems include constipation and, infrequently, loss of bowel control
Sexuality & intimacy
• impotence
• diminished arousal
• loss of sensation
Sensitivity to heat: this symptom very commonly causes a transient worsening of symptoms
Cognitive & emotional disturbances:loss of short term memory, loss of concentration, judgment or
reasoning

Types of MS
Some people are minimally affected by the disease while others have rapid progress to
total disability, with most people fitting between these two extremes. Although every individual
will experience a different combination of MS symptoms there are a number of distinct patterns
relating to the course of the disease.
Relapsing-Remitting MS. In this form of MS there are unpredictable relapses
(exacerbations, attacks) during which new symptoms appear or existing symptoms become
more severe. This can last for varying periods (days or months) and there is partial or total
remission (recovery). The disease may be inactive for months or years. Frequency - approx
85%
Benign MS. After one or two attacks with complete recovery, this form of MS does not
worsen with time and there is no permanent disability. Benign MS can only be identified when
there is minimal disability 10-15 years after onset and initially would have been categorised as
relapsing-remitting MS. Benign MS tends to be associated with less severe symptoms at onset
(e.g. sensory). Frequency - approx 20%
Secondary Progressive MS
For some individuals who initially have relapsing-remitting MS, there is the development of
progressive disability later in the course of the disease often with superimposed relapses.
Frequency - approx 40%
Primary Progressive MS
This form of MS is characterised by a lack of distinct attacks, but with slow onset and steadily
worsening symptoms. There is an accumulation of deficits and disability which may level off at
some point or continue over months and years. Frequency - approx 15%
Progressive-Relapsing MS, which is the least common disease course, shows
progression of disability from onset but with clear acute relapses, with or without full recovery.
Approximately 5% of people with MS appear to have PRMS at diagnosis. Not infrequently a
patient may be initially diagnosed as having PPMS and then will experience an acute attack,
thereby establishing the diagnosis of PRMS.

Relapsing-Remitting MS (RRMS). It is characterized by clearly defined acute
attacks with full recovery (1a) or with residual deficit upon recovery (1b).

Primary Progressive (PPMS) is characterized by progression of disability
from onset, without plateaus or remissions(2a)or with occasional plateaus
and temporary minor improvements (2b).

Secondary-Progressive (SPMS) begins with an initial relapsing-remitting
disease course, followed by progression of disability (3a) that may include
occasional relapses and minor remissions and plateaus (3b).

Progressive-Relapsing (PRMS)
PRMS, which is the least common disease course, shows progression of
disability from onset but with clear acute relapses, with (4a) or without
(4b) full recovery.

The Assessment of Disease Progression
• Physicians evaluate disease progression in three
ways:
• Radiographically—by looking for new lesions,
gadolinium-enhanced lesions, or an increased amount
of disease on MRI
• Electrophysiologically—by measuring changes in the
sensory evoked potentials
• Neurologically—by measuring changes in function
on the neurologic examination
• Functionally—by assessing the person’s physical and
cognitive abilities

• Diagnosing MS
• Unlike many other diseases, there is no straightforward ‘positive or negative’ test for MS and none
of the range of tests available to help doctors with their diagnosis is 100 percent conclusive on its own.
This means that ultimately a doctor will diagnose MS by a combination of observing a person’s
symptoms, and ruling out other possibilities. This is called a ‘clinical diagnosis’.
• Problems with diagnosis
• Unfortunately for a significant minority of people (10–15 percent) a definite diagnosis is still not
possible even after all the available tests have been carried out. However, it is possible to rule out other
very serious causes of MS type symptoms, and over time with periodic examinations and the monitoring
of changes in a person’s condition, diagnosis is possible in the vast majority of cases.
• New MS Diagnostic Criteria
• MSIF’s International Medical and Scientific Board have drawn up new MS diagnostic criteria to
help medical professionals distinguish between MS and other conditions that may present similar
symptoms. The new criteria allow the results of MRI scanning to included so that it may be possible to
diagnose MS when someone has had only one episode of symptoms. When the new criteria are used, a
person may be classified as having MS, possible MS or not MS.
Clinical diagnosis
• Early MS may present itself as a history of vague symptoms, which may occur sporadically over a
prolonged period of time and could often also be attributed to a number of other medical conditions.
Invisible or subjective symptoms are often difficult to communicate to doctors and health professionals
and sadly it has not been uncommon for people with MS to be treated unsympathetically in the very early
stages of diagnosis.
Even when a person shows a ‘classic’ pattern of MS type symptoms, the symptoms must conform
to agreed criteria before a doctor or neurologist can diagnose clinically ‘definite’ MS. These criteria are
that:
‘Two different areas of the central nervous system are affected, and that these effects have been
experienced on at least two separate occasions of at least one month apart and that the person is within the
normal age range for the onset of MS’
So although it is possible to be diagnosed as having ‘definite’ MS on first visit to a neurologist, it is also
quite likely that the diagnosis will be uncertain, and that the person will be referred for further tests.

• Diagnostic tests
• Medical History (anamnesis)
• Neurological Examination
• The neurologist is testing for abnormalities in the nerve pathways that
take messages from the brain to the other parts of body, will look for
changes in eye movements, limb co-ordination, weakness, balance,
sensation, speech, and reflexes.
Testing of Visual, Auditory and Somatosensory Evoked Potentials
• In spite of their complicated sounding name, the point of these tests is
straightforward. They are used to measure the speed at which
messages from the brain pass along the nerves.
The speed of messages passing through the nervous system is
measured by placing small electrodes on the head, which monitor
brain waves in response to visual and auditory (hearing) or sensory
stimuli. The most useful of the three tests is the visual evoked
potential although nowadays, with increased use of MRI, the evoked
potential test are required less often
These tests are not invasive or painful and therefore do not require a
stay in hospital.
The time it takes for nerves to pass on messages from the brain is
an indicator of the condition of the nervous system and is used to help
determine whether demyelination has occurred.

• Magnetic Resonance Imaging (MRI)
• The MRI scanner is a more recent diagnostic test and takes very detailed pictures of
‘slices’ of the brain and spinal cord, showing any existing areas of sclerosis (lesions
or plaques).
During an MRI scan the person being tested lies absolutely still on a table that
moves inside a large tube which is part of the machine that contains the magnet. The
person conducting the test sits in a separate room monitoring the equipment
receiving the images; however they can also see the person being tested, usually
through a large window.
There is no pain involved in MRI, but many people find it quite an unusual
experience, and it can be both claustrophobic and noisy. Any discomfort can be
alleviated by a mild sedative. Sometimes an injection is given in to a vein of a
contrast agent containing gadolinium as this can show up new areas of inflammation
and may help to make the diagnosis.
It is worth remembering that the person conducting the test is not usually able
to give you any direct feedback and the images from the scan will be sent to your
doctor for analysis.
Whilst this is the only test in which the lesions of Multiple Sclerosis can be
seen, it cannot be regarded as conclusive. The scanner may not pick up all lesions,
particularly in the early stages of the disease, and some other conditions can
produce identical changes in the nervous system.
The MRI clearly shows the size, quantity and distribution of lesions and
together with supporting evidence from medical history and neurological
examination, is very significant indicator toward confirming the diagnosis of MS. It
is abnormal in over 95% with a definite clinical diagnosis. The MRI is a very useful
tool in clinical trials in assessing the value of new therapies, due to its ability to
demonstrate changes in the disease’s activity.

The lesions in white substance of brain hemispheres have various sizes
and forms.

Lumbar Puncture
• There are several tests that can be carried out on cerebrospinal fluid (the fluid which
flows around the brain and spinal cord), but usually with MS the patterns formed by
proteins are examined.
The fluid is taken from the spinal cord by inserting a needle into the lower
back. A local anaesthetic is given to numb the skin, and therefore whilst it is
uncomfortable it is not usually painful.
This test requires the person to lay flat for a number of hours after the test, and
headaches due to dehydration are a noted side effect; this can be alleviated by
drinking fluids immediately after the procedure, to help the body rapidly replace the
cerebrospinal fluid it has lost. Some people may require an overnight stay in
hospital and a subsequent short period of recuperation.
The proteins in the spinal fluid of the majority of people (90%) with
established MS form a particular pattern when an electrical current is passed
through them, and so this procedure can potentially confirm an MS diagnosis.
However, the cerebrospinal fluid proteins of people with early or mild MS do not
always show the same pattern, so again may not be conclusive. It is often used when
MRI results have been inconclusive.
• Examination of cerebrospinal fluid can show 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.

• While it can still be difficult for the physician to differentiate between an MS
attack and symptoms that can follow a viral infection or even an
immunization, our growing understanding of disease mechanisms and the
expanded use of MRI is enabling physicians to diagnose MS with far more
confidence than ever before. Today, most patients who undergo a
diagnostic evaluation for MS will be classified as either having MS or not
having MS, although there are still cases where a person may have the
clinical symptoms of MS but not meet all the criteria to confirm a diagnosis
of MS. In these cases, a diagnosis of "possible MS" is used.
• 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.
Physicians 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 before a diagnosis of MS is given.

TREATMENTS
• Currently there is no cure for MS. However, there are treatments available that may
slow its progression and alleviate associated symptoms.
• Drug therapies—Medications that target the body's immune system may decrease
the frequency and duration of attacks. These medications can be used on a long-
term basis and also to treat specific attacks. Additional medications may be
prescribed for other symptoms, such as pain or depression.
• Additional therapies—Because MS may affect the patient's ability to perform self-
care and other activities of daily living, treatment may also include referral to
specialists for physical and occupational therapy.
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.
• In the past, 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. Three forms of beta interferon
(Avonex, Betaseron, and Rebif) have now been approved by the Food and
Drug Administration for treatment of relapsing-remitting MS. 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. Most of 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. One such treatment, Novantrone
(mitoxantrone), was approved by the FDA for the treatment of advanced or
chronic MS. Other 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 drug cladribine (Leustatin).

• Another potential treatment for MS is monoclonal antibodies, which 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. One monoclonal antibody, natalizumab
(Tysabri), was shown in clinical trials to significantly reduce the frequency of
attacks in people with relapsing forms of MS and was approved for
marketing by the U.S. Food and Drug Administration (FDA) in 2004.
However, in 2005 the drug’s manufacturer voluntarily suspended marketing
of the drug after several reports of significant adverse events. In 2006, the
FDA again approved sale of the drug for MS but under strict treatment
guidelines involving infusion centers where patients can be monitored by
specially trained physicians.
• Another experimental treatment for MS is plasma exchange, or
plasmapheresis. Plasmapheresis is a procedure in which blood is removed
from the patient and the blood plasma is separated from other blood
substances that may contain antibodies and other immunologically active
products. These other blood substances are discarded and the plasma is
then transfused back into the patient. Because its worth as a treatment for
MS has not yet been proven, this experimental treatment remains 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
• Вecause 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),
were successful, leading the FDA to approve the agent for the treatmernt of
relapsing-remitting MS. Copolymer I, unlike so many drugs tested for the treatment of
MS, has few side effects, and studies indicate that the agent can reduce the relapse
rate by almost one third. In addition, patients given copolymer I are more likely to
show neurologic improvement than those given a placebo.
• 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
canmount 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.

• Exercise
• Physiotherapy and regular exercise can be helpful in keeping as fit as
possible. You and your doctor will probably want to discuss what
therapy or exercise programme would be of benefit. It might involve
having physiotherapy on a fairly regular basis or doing specific
exercises at home. Others have found activities such as swimming,
yoga and horseback riding to be helpful. Any exercise that you enjoy
and are able to do comfortably will be beneficial. Besides maintaining
good muscle tone, exercise can be a great way to release tension and
to relax. Your local or national MS society may offer recreation or
exercise programmes that would be helpful, or recommend facilities
or health personnel to provide these activities.
• Diet
• Over the years, a number of diets for MS have been proposed, which
is probably only natural for a disease with no known cause or cure.
Whilst some of the suggested diets contradict each other, it does make
sense to have a nutritionally balanced diet that will ensure you have
all the required vitamins and minerals. Some people find that a diet
low in animal fats and high in polyunsaturated fats is helpful to them.
Please see the section on Alternative Therapies Used by People with
MS from "MS The Guide to Treatment and Management" as well. It
would be wise to discuss any changes in your own diet with your

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.

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 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.

Drugs Used to Treat Symptoms of
Multiple Sclerosis
Symptom Drug
Spasticity
Optic neuritis
Fatigue
Pain
Trigeminal neuralgia
Sexual dysfunction
Baclofen (Lioresal)
Tizanidine (Zanaflex)
Diazepam (Valium)
Clonazepam (Klonopin)
Dantrolene (Dantrium)
Methylprednisolone (Solu-Medrol)
Oral steroids
Antidepressants
Amantadine (Symmetrel)
Pemoline (Cylert)
Aspirin or acetaminophen
Antidepressants
Codeine
Carbamazepine, other anticonvulsant
Papaverine injections(in men

Multiple sclerosis

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