Multiple sclerosis (MS) is a
demyelinating disease, a non-contagious chronic autoimmune disorder of
the central nervous system which can present with a variety of
neurological symptoms occurring in attacks or slowly progressing over
The prevalence of multiple sclerosis
(MS) is approximately 350,000 cases in the United States and more
than 2.5 million worldwide. There are at least 10,000 newly
diagnosed cases of MS annually.
In northern Europe, continental North
America, and Australasia, about one of every 1000 citizens suffers
from multiple sclerosis, whereas in the Arabian peninsula, Asia, and
continental South America, the frequency is much lower. In Sub-Saharan
Africa, MS is extremely rare. With important exceptions, there is a
North-South gradient in the Northern hemisphere and a South-North
gradient in the Southern hemisphere, with very low frequencies near
the equator (between latitudes 40 degrees North and 40 degrees South. Climate, diet, geomagnetism, toxins, sunlight, genetic
factors, and infectious diseases have been discussed as possible
reasons for these regional differences. It has been postulated that an
environmental factor during childhood might play an important role for
the development of MS later in life. This was based on several studies
in migrants demonstrating that if migration occurs before the age of
15, the migrant acquires his new region's susceptibility to MS. If
migration takes place after 15, the migrant keeps the susceptibility
of his home country.
MS occurs mainly in the Caucasian race.
It is 20-fold lower in the Inuits of Canada than in other Canadians
living in the same region. It is also rare in the Native American
tribes of North America, the Australian Aborigine and the Maoris of
New Zealand. These few examples point out that the genetic background
plays an important role in the development of MS (see below).
As observed in many autoimmune
disorders, MS is more common in females than males; the mean sex ratio
is about two females for every male. In children, who rarely develop
MS, the sex ratio may reach three females for each male, whereas MS
occurring in the fifth decade more commonly affects males. Onset of
symptoms usually occurs between 20 to 40 years of age, rarely below 15
or above 60, although both is possible.
MS is not strictly a hereditary
disease. However, MS is a disease influenced by a variety of factors,
one of which is the genetic background of an individual. There is no
single gene known to be responsible for MS, though a few genes have
been demonstrated to increase the risk of development. Although these
genes are of scientific interest and continue to play a part in
research, they are not enough to diagnose an individual with MS.
Overall, an average one of every 25
siblings of an individual with MS will also be afflicted. Up to every
second identical twin of a MS-affected person will develop MS, but
only one of 20 fraternal twins. If one parent is affected by MS, only
about 1 of 40 of his children will develop MS later in life. There
also seems to be an association with specific HLA antigens
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Etiology and Pathogenesis
The ultimate cause of MS is unknown. It
is hypothesised that a viral infection or other environmental factor
in childhood might prime the immune system for an abnormal reaction
later in life. On a molecular level, there might be a structural
similarity between an unidentified infectious agent and components of
the central nervous system, causing confusion in the immune system
later in life (a process called "molecular mimicry"). However, so far
there is no known "MS virus". Certainly MS is not an infectious
disease and not contagious. The importance of genetic factors has been
It is widely accepted that a special
subset of white blood cells, called T cells, play a key role in the
development of MS. Under normal circumstances, these lymphocytes can
distinguish between self and non-self. In a person with MS, however,
these cells recognize healthy parts of the central nervous system as
foreign, and attack them as they would a virus. In MS, the part of the
nervous system primarily attacked is myelin. Myelin is a fatty
substance that covers the axons of nerve cells, and which is important
for proper nerve conduction. Normally, there is a tight barrier
between blood and brain, called the blood-brain barrier (BBB), built
up of endothelial cells lining the blood vessel walls.
Lymphocytes (blue) surrounding blood
vessel (center) within MS lesionIn MS, the BBB breaks down;
autoreactive T cells cross the BBB and trigger an inflammatory
process, also mediated by other immune cells, such as cytokines and
antibodies. Due to this abnormal behavior of the immune system, MS is
considered to be an autoimmune disorder. The inflammatory process
finally leads to a destruction of myelin called demyelination. Repair
processes, called remyelination, also play an important role. This is
one of the reasons why, especially in early phases of the disease,
symptoms tend to decrease or disappear temporarily after days to
months. Nevertheless, axonal damage and irreversible loss of neurons
occur early during the course of the disease. However, due to its
plasticity the brain can often compensate for some portion of the
damage. MS symptoms develop as a result of multiple lesions in the
brain and spinal cord, and can vary greatly between different
individuals, depending on where the lesions occur.
Factors triggering a relapse
In general, relapses tend to occur more
frequently during spring and summer than during autumn and winter.
Infections like the common cold, influenza or unspecific diarrhea
increase the risk for a relapse. In contrast, influenza vaccination is
safe and does not trigger relapses as demonstrated in several recent
studies. It can therefore be recommended for MS patients, especially
for those at risk for influenza (e.g. healthcare workers). Tetanus
vaccination is considered to be safe as well, although so far it has
not been studied in that respect. In general, vaccinations with
living, attenuated viruses increase the risk of relapses.
Pregnancy can directly effect the
susceptibility for relapse. The last three months of pregnancy offers
a natural protection against relapses, whereas during the first few
months after pregnancy, especially during the first six weeks, the
risk for a relapse is increased 20-40%. According to current
knowledge, pregnancy doesn't seem to influence long term disability.
MS does not increase the risk of bearing a handicapped child.
Statistically, there is no good
evidence for triggering of relapses through trauma or operations. In
principle, surgical procedures require no special precautions if not
dictated by existing disability. Participation in sports is possible,
although extremes, such as marathon running, should probably be
avoided. Emotional stress may cause a relapse, although study data has
Heat can transiently increase symptoms,
in something known as Uhthoff's phenomenon. This is why some patients
avoid saunas or even hot showers. However, heat is not an established
trigger of relapses. Extensive exposure to the sun should be avoided,
since ultraviolet radiation is a strong stimulus for the immune
Currently there are no clinically
established laboratory investigations available to predict prognosis
or therapeutic response, although promising approaches have been
undertaken that need further confirmation, such as treatments based on
the two antibodies anti-MOG and anti-MBP, and TRAIL, a TNF-Related
Apoptosis Inducing Ligand.
Disease course and clinical subtypes
In most cases MS starts with an acute
flare-up of symptoms within hours to days, called a relapse,
exacerbation, bout, episode, or attack. Inflammation of an optic nerve
(optic neuritis), causing painfulness of eye movement and visual
deterioration frequently is the first symptom. However, not all
patients with optic neuritis develop MS. Sensory disturbances such as
numbness or tingling sensations are other frequent initial symptoms.
In principle, MS can start with any of the symptoms mentioned in the
Especially in early phases of the
disease, symptoms frequently decrease or resolve spontaneously within
days to months. Therefore, this disease course is called relapsing
remitting. New relapses can occur within weeks to many years and can
include formerly experienced and/or new symptoms. However, MRI studies
have shown that nerve damage can continue in relapsing remitting
patients even if symptoms subside. It has long been known that "MS
never sleeps". This highlights the importance of preventive treatment
if and when it is available.
In many cases, the disease course
changes after several years and symptoms start to deteriorate slowly
with or without superimposed relapses. This course is called secondary
chronic-progressive, or just secondary progressive. However, some
patients stay in a relapsing remitting course for the rest of their
About 10% of all MS-affected
individuals experience chronic progression without relapses from onset
of symptoms. This course is called primary progressive and frequently
comes along with weakness of the legs, gait and bladder disturbances.
Degenerative processes and not inflammation are thought to play the
most important role in this clinical disease course.
Chronic progression from onset of
symptoms with superimposed relapses is referred to as relapsing
Signs and symptoms
MS is suspected in a female, between 15
and 60 years old and usually of Northern European, Northern US or
Affected individuals may experience a
wide variety of symptoms, such as vision loss, double vision,
nystagmus, difficulty with speech, various kinds of tremor, clumsiness
of the hands, unsteady gait, weakness, spasticity, numbness, and
bladder (urgency, hesitancy), bowel, as well as sexual dysfunction. Various cognitive
impairments are also common, such as difficulty performing multiple
tasks at once, difficulty following detailed instructions, loss of
short term memory, depression, and fatigue.
Symptoms and signs may partially
disappear after a few days or weeks.
MS plaques appear hyperintense on T2
weighted studies. They usually are oval in shape, and appear in the
periventricular region or corpus callosum. Detection of gadolinium
enhancement can help differentiate active from chronic lesions and
could help in establishing the temporal dissemination of the disease
on follow up.
A lumbar puncture, which is a procedure
done to collect a sample of cerebrospinal fluid, is useful for
providing evidence of chronic inflammation of the central nervous
system, often indicated by oligoclonal banding. Nerve conduction
studies of optic, sensory and motor nerves can provide further
evidence for MS, as the process of demyelination results in reduced
nerve conduction velocities. The diagnostic process is completed by
several laboratory tests to exclude other diseases that can mimic
MS, such as Sarcoidosis, Vasculitis, and Lyme disease).
A definite diagnosis of MS requires
evidence for dissemination of lesions within the central nervous
system both in space and in time. This means that not only must there
exist evidence of at least two distinct lesions, verifiable by
clinical symptoms or by Magnetic Resonance Imaging (MRI), there must
also be evidence of an occurrence of new symptoms or lesions within a
time interval of at least 30 days.
Diagnosis of multiple sclerosis is made
using the 2005 revised McDonald diagnostic criteria :
Generally speaking, three parameters
are used to assess the diagnosis.
An attack refers to an episode of
neurological disturbance that has lasted for at least 24 hours.
This is usually a subjective report by the patient and should be
backed by objective findings.
A clinical lesion refers to a
neurological lesion detected by history and physical
A paraclinical lesion refers to a
lesion that is detected by MRI, evoked response testing or
In addition to the assessment of the
three parameters discussed above, the criteria require that evidence
for dissemination of lesions in both space (spatial dissemination)
and time (temporal dissemination).
2005 revised McDonald Diagnostic
Criteria for Multiple Sclerosis
For relapsing-remitting disease
For monosymptomatic / clinically
For primary progressive disease
One year of disease progression + two
of the following
Positive brain MRI
Positive spinal cord MRI
There is no known definitive cure for
multiple sclerosis. However, several drugs have proven to be effective
in its treatment. Intensive research is underway to study a variety of
promising new drugs. Treatment is aimed at maintaining a maximum
quality of life. Physiotherapy plays an important role.
There are three primary forms of
medication used to treat the symptoms:
During an exacerbation, corticosteroids
(such as prednisone or methylprednisolone) used at high dosages (500
mg - 2 g per day intravenously for a course of 3 to 5 days) can
accelerate regression of symptoms. Subsequent tapering with pills may
be reasonable in certain cases. There is clear evidence that sole
treatment with oral steroids at dosages of 100 mg per day or less and
subsequent tapering is inferior to intravenous high dose treatment. In
principle, steroid treatment during pregnancy is possible. There is no
good evidence that corticosteroids influence longterm outcome.
Long-term treatment can influence the
course of the disease:
Interferon-beta1a or beta1b (Avonex;
Betaseron [in Europe Betaferon]; Rebif) has been shown to reduce the
relapse rate by about 30%, decrease the number of new MRI lesions and
slow progression of disability. Interferon-beta is a cytokine that
under natural conditions is produced by the body during viral
infections; as a drug it is extracted either from special mammalian
cells or special bacteria. All preparations must be injected into
either muscle or skin every second day to once per week, depending on
the preparation. Attempts to develop pills containing Interferon-beta
have not been successful so far. Some of the interferons have been
proven to be effective not only in relapsing remitting MS, but also in
secondary progressive MS, as long as superimposed relapses occur. Main
side effects include flu-like symptoms which tend to decrease during
ongoing therapy and which can be alleviated, for example, by
paracetamol or ibuprofen. Another frequent side effect is inflammatory
skin reactions at the injection site if Intereferon-beta is injected
into the skin. Regular blood monitoring is required.
Glatiramer acetate (Copaxone) has also
been shown to reduce the relapse rate by about 30%, decrease the
number of new MRI lesions and slow progression of disability.
Concerning its therapeutic effect it is approximately comparable to
Interferon-beta. Glatiramer acetate consists of synthetic peptides
made of four different amino acids, which are basic modules of all
proteins in the human body. Once per day must be injected into the
skin. Attempts to develop pills containing glatiramer acetate have
also been unsuccessful. Copaxone is effective in the treatment of
relapsing remitting MS. So far, beneficial effects in secondary
progressive MS have not been convincingly demonstrated. Main side
effects include inflammatory skin reactions at the injection site, and
a rare but transient and perturbing "post-injection" reaction
manifested by flushing, chest tightness, heart palpitations,
breathlessness, and anxiety. A post-injection reaction does not
require discontinuation of therapy. In general, Copaxone is considered
to cause fewer side effects than Interferon-beta. However, most MS
patients injecting Interferon-beta also tolerate their therapy well.
Regular blood monitoring is required.
Azathioprine is an agent available as a
pill approved for the treatment of relapsing remitting MS in some
countries. However, its effectiveness has not been proven as
stringently as for the interferons and glatiramer acetate, and an
effect in secondary progressive MS has not been demonstrated. In
general, it is well tolerated. After longtime therapy the risk of
cancer increases slightly (after 10 years of therapy about fourfold).
Regular blood monitoring is required.
There is some evidence that
immunoglobulins (antibodies) are effective in the treatment of
relapsing remitting MS, a large clinical trial (PRIVIG) is presently
continuing. Immunoglobulins have not been
proven to be effective in secondary progressive MS.
The currently most effective drug in the preventive treatment of MS is
Mitoxantrone. It has been proven to be effective in relapsing
remitting and in secondary progressive MS. In most cases it is
administered every three months intravenously. Therapy with
Mitoxantrone is generally well tolerated, however, since with ongoing
therapy the risk for damage of the heart muscle increases, at an
average Mitoxantrone can only be administered for 3 to 4 years. This
is why Mitoxantrone is only used in cases of rapid disease
progression. Mitoxantrone treatment requires monitoring of the heart
function during therapy. Regular blood monitoring is required. With
these precautions Mitoxantrone treatment is safe.
A family of cholesterol-lowering drugs,
the statins, have shown anti-inflammatory effects in animal models of
MS. However, so far there has not been provided sufficient evidence
that statins are beneficial in the treatment of human MS patients with
normal cholesterol levels.
Recently, scientists found women who
took vitamin D supplements were 40% less likely to develop multiple
sclerosis than women who did not take supplements. However, this study
does not allow to conclude that vitamin D has a beneficial influence
on ongoing MS. Furthermore it could not distinguish between a
beneficial effect of vitamin D and multivitamin drugs including
vitamin E and various B vitamins which may also exert a protective
Primary progressive MS is very
difficult to treat. High dose corticosteroids every three months can
show some effect. In principle, there is no efficient preventive
treatment for primary progressive MS available. Symptomatic therapy as
described in the next paragraph and physiotherapy play an important
A variety of medications are used to
treat symptoms without influencing the inflammatory nature of the
disease (symptomatic treatment):
Baclofen and tizanidine can be useful
against spasticity. There is no convincing evidence that cannabinoids
(marijuana) can improve spasticity.
The anticonvulsant drugs Gabapentin and
Carbamazepine and the antidepressant amitriptyline can improve pain
and tingling sensations in certain cases.
SSRIs be used for depression, as well
as for fatigue. Fatigue can also be influenced by amantadine and
There is also treatment for bladder
disturbances available which is effective in many cases. Examples are
oxybutynin and trospium chloride.
Treatment with sildenafil (Viagra?) or
similar substances can improve male erectile dysfunction in many
Additional treatment options include
plasmapheresis ("washing the blood", showing similarities to dialysis)
for severe, non-steroidresponsive relapses.
Because of improved treatment for
complications such as lung and bladder infections, the life expectancy
of those diagnosed with MS is only slightly reduced. The earlier in
life disease onset occurs, the slower disability progresses. This is
due to more frequent chronic progressive courses with faster
accumulation of disability when onset occurs at a higher age.
Disability after 5 years correlates well with disability after 15
years: 2/3 of MS patients with low disability after 5 years will not
markedly deteriorate during the next ten years. Further MS cases in
the family do not influence disease progression. 1 of 3 patients will
still be able to work after 15-20 years. Visual loss as the initial
symptom is a marker for a rather good prognosis; gait disturbance,
weakness or numbness for a rather poor prognosis. Rapid regression of
initial symptoms, age at onset below 35, only a single symptom at
onset, rapid development of initial symptoms and short duration of the
last relapse indicate a good prognosis. When the initial disease
course is relapsing remitting, the statistical duration until a
wheelchair is needed, is 20 years. This means that many MS patients
will never need a wheelchair. If the disease course is primary
progressive then a wheelchair at an average will be needed after 6 to
7 years. It has to be noted that most of this longterm data was
acquired before the advent of modern immunomodulatory drugs about 10
years ago, which have been shown to delay disease progression over a
period of several years.