What is Multiple Sclerosis?
Multiple sclerosis (MS) is an autoimmune disease that affects the central
nervous system (CNS) which consists of the brain, spinal cord, and optic nerves.
Somehow the autoimmune system sees the myelin, which is the fatty insulation
around the nerves, as a foreign body or enemy and begins to attack it. The
myelin serves an important purpose in that it not only surrounds and protects
the nerves; it also assists with the smooth conduction of electrical impulses to
and from the brain. Just below in (figure 1) is a drawing of a normal healthy
nerve from its beginning at the nucleus along to the end at the axon terminal.
Over the majority of its length is a long strand covered with myelin, and this
is where the typical damage will take place.|
Enlarge by passing over or clicking
Lesions are formed when the myelin is destroyed, it will cause scarring or
sclerosis around the nerves and will occur
usually in many or multiple places, hence
the name "Multiple Sclerosis". Just like in an electrical wire with plastic
insulation surrounding it, if a small piece of insulation is cut off it should
be somewhat easy to repair the damage. If the insulation is removed in a larger
amount or even part of the wire is cut into, then the repairs are much more
difficult and usually involve replacing the electrical wire. If a damaged wire
isn't repaired or replaced, then it won't work properly. The nerves in the body,
unfortunately, can't be replaced, so what the body does is to form the scarring
which is like a patch or bandage over the nerve. The underlying damage remains
since a scar, or bandage, only covers it and nothing else. The scarring,
however, can't take the place of myelin just like a piece of chewing gum can't
fix an exposed wire.
Enlarge by passing over or clicking
Myelin under normal conditions is covering the actual nerve fibers as seen in
(figure 1) above and functions with a "lightning fast" speed. But when the
myelin is exposed or scarred over as in the damaged area in (figure 2) above,
the nerve fiber will short out and the electrical impulse that travels along so
nice and fast will be slowed, chopped up, or stopped all together. The exactly
location of an attack is also not known until it shows up on an MRI, but all it
takes is one attack on that one special nerve, and the result can be
The Demyelination Process
Demyelination begins with the blood-brain barrier breakdown. It's a tight
vascular barrier between the blood and brain that should prevent the passage of
antibodies through it, but in MS patients it doesn't work. For unknown reasons
special areas appear in the brain and spine, followed by leaks in the
blood-brain barrier where immune cells infiltrate.|
Many researchers feel that a special subset of lymphocytes,
called T helper cells, specifically Th1 and Th17, play a key role in the
development of the lesion. A protein called Interleukin 12 is responsible for
the differentiation of naive T cells into inflammatory T cells. An over
production of this protein is what causes the increased inflammation in MS
patients. Under normal circumstances, these lymphocytes can distinguish between
self and non-self. However, in a person with MS, these cells recognize healthy
parts of the CNS as foreign and attack them as if they were
an invading virus, triggering inflammatory processes and stimulating other
immune cells and soluble factors like cytokines and antibodies. Many of the
myelin-recognizing T cells belong to a terminally differentiated subset called
co-stimulation-independent effector-memory T cells. Recently other type of
immune cells, B Cells, have been also implicated in the pathogenesis of MS and
in the degeneration of the axons.
The axons themselves can also be damaged by the attacks. Often, the brain is
able to compensate for some of this damage, due to an ability called
neuroplasticity. MS symptoms develop as the cumulative result of multiple
lesions in the brain and spinal cord. This is why symptoms can vary greatly
between different individuals, depending on where their lesions occur.
The repair processes, called remyelination, also play an important role in MS.
Remyelination is one of the reasons why, especially in early phases of the
disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve
damage and irreversible loss of neurons occur early in MS.
The oligodendrocytes that originally formed a myelin sheath can't completely
rebuild a destroyed myelin sheath. However, the CNS can
recruit oligodendrocyte stem cells capable of proliferation and migration and
differentiation into mature myelinating oligodendrocytes. The newly-formed
myelin sheaths are thinner and often not as effective as the original ones.
Repeated attacks lead to successively fewer effective remyelinations, until a
scar-like plaque is built up around the damaged axons. Under laboratory
conditions, stem cells are quite capable of proliferating and differentiating
into remyelinating oligodendrocytes; it's therefore suspected that inflammatory
conditions or axonal damage somehow inhibit stem cell proliferation and
differentiation in affected areas.
Brain Lesion Distribution
MS is considered a disease of the white matter because normally lesions appear
in this area, but it's also possible to find some of them into the gray matter.
Post-mortem autopsy has revealed that gray matter demyelination occurs in the motor
cortex, cingulate gyrus, cerebellum, thalamus and spinal cord. Cortical lesions
have been observed specially in those with secondary-progressive MS (SPMS) but
they also appear in relapsing-remitting MS (RRMS) and clinically isolated
syndrome (CIS). They are more frequent in men than in women and they can partly explain
It's known that two parameters of the cortical lesions, fractional anisotropy
and mean diffusivity, are higher in patients than in controls. They are larger
in SPMS than in RRMS and most of them remain unchanged for short follow-up
periods. They don't spread into the subcortical white matter and never show
gadolinium enhancement. Over a one-year period, cortical lesions can increase
their number and size in a relevant proportion of MS patients, without spreading
into the subcortical white matter or showing inflammatory features similar to
those of white matter lesions.
Due to the distribution pattern of the lesions, since 1916 they are also known as
Dawson's fingers and appear around the blood vessels of the brain.
Spinal Cord Damage
The spinal cord has been found to be affected by MS even without attacks,
and damage correlates with disability. In RRMS, cervical spinal cord activity is
enhanced, to compensate for the damage of other tissues. It has been shown that
This is a measure of directional coherence of white matter tracts given a value
between 0 and 1. A value of 0 means that diffusion is isotropic (unrestricted or
equally restricted) in all directions. A value of 1 means that diffusion occurs
only along one axis and is fully restricted along all other directions.
of spinal cord is lower than normal, showing that there is damage hidden from normal MRI.
Progressive tissue loss can occur in the spinal cord of MS patients and spinal
cord pathology is independent of the brain. Damage to the spinal cord can develop
at different rates according to disease phenotype, and is associated to medium-term
MS is a condition defined by the presence of a special kind of lesions in the
brain and spinal cord. Therefore, it's very important to establish what
"MS lesions" are. They mainly consist in demyelination
and scarring in the fatty myelin sheaths around the axons of the brain and
MS lesions also vary depending on their age:
||Early (acute) lesions are characterized by
inflammatory mononuclear cells and myelin breakdown.
Astrogliosis or Astrocytosis is an abnormal increase in the number of
astrocytes due to the destruction of nearby neurons.
and axons are relatively preserved.
||As the lesion progresses, there are fewer inflammatory
cells and more astrogliosis.
Lesions Under MRI
Most MS lesions are isointense to white matter and will appear bright on T1-weighted
MRI. Other MS lesions are called "black holes," which are areas of permanent
axonal damage. These are also called hypointense lesions, meaning that they display as
dark areas on the MRI image. T1-weighted lesions can also be areas of edema (swelling),
which are not permanent and disappear on subsequent scans.
Typically when "black holes" appear, about half of them will go away or revert
within a month providing a sign of remyelination a decrease in edema. But when they
remain, it's regarded as a sign of permanent scarring or demyelination and axonal loss.
Enlarge by passing over or clicking
The two MRI's above show lesions on the brain and on the spinal cord. There are
three distinct lesions on the (left or top) image of the brain and three distinct
lesions on the (right or bottom) image of the spinal cord around the 2nd and 3rd
cervical vertebra. There is a great significance to the lesions on the spinal cord
in that the location is prior to any branching off. Lesions at this location can
have a profound impact on multiple locations and possibly with greater severity.
This could be compared to damage on a high voltage electrical wire and when it
has problems, all of the smaller wires have problems.
Some of the possible early symptoms of MS could be one or more of the following:|
||Optic neuritis and other
problems in the eye. Optic neuritis affects over 50% of patients
and is the first symptom in about 16% of them. Symptoms include
unclear or doubled vision, usually in one eye. Some people see a
shimmering effect. Patients may also experience pain or involuntary
jerking or movement of the eye (nystagmus).
||Fatigue is typically worse in the afternoon and may be
accompanied by an increase in body temperature. At the
onset, this occurs in about 20% of patients, but as the
disease progresses, this is a significant symptom in
nearly all patients.
||Changes in sensations,
heaviness, weakness, or clumsiness in the arms and legs. Tingling
or loss of sensations can also occur, most commonly in the legs.
The first symptoms for patients with primary progressive MS often
develop slowly in the upper legs.
||Muscle weakness in the legs and poor coordination.
This is an electrical sensation that runs down the back and into
the legs, which is produced by bending the neck forward.
||Spasticity is the inability to control muscle tone and leads
to spasms and stiffness and is very common in MS.
||Disturbances in the bladder.
Of the early symptoms listed above, it's very common for someone with MS to have
a combination of them. The combination of symptoms is directly linked to the
location of the damaged nerves. Everyday that someone with MS wakes up, most
will wonder which symptoms will be today's challenge, or which will be their
biggest obstacle. All of these symptoms can be heightened by spending too much
time in the heat, pushing yourself too hard, and even stress, but over time you
will recognize when you need to slow down. You will also be able to distinguish
between having your symptoms as a constant reminder or when an exacerbation is
paying you a visit.