Multiple sclerosis is a demyelinating disease of the central nervous system, which includes
the brain and the spinal cord.
Myelin is the protective sheath that surrounds the axons of neurons, allowing them to quickly
send electrical impulses.
This myelin is produced by oligodendrocytes, which are a group of cells that support neurons.
In multiple sclerosis, demyelination happens when the immune system inappropriately attacks
and destroys the myelin, which makes communication between neurons break down, ultimately leading
to all sorts of sensory, motor, and cognitive problems.
Now, the brain, including the neurons in the brain, is protected by things in the blood
by the blood brain barrier, which only lets certain molecules and cells through from the
blood.
For immune cells like T and B cells that means having the right ligand or surface molecule
to get through the blood brain barrier, this is kind of like having the a VIP pass to get
into an exclusive club.
Once a T cell makes its way in it can get activated by something it encounters - in
the case of multiple sclerosis, it’s activated by myelin.
Once the T-cell gets activated, it changes the blood brain barrier cells to express more
receptors, and this allows immune cells to more easily bind and get in, it’s kind of
like bribing the bouncer to let in a lot of people.
Now, multiple sclerosis is a type IV hypersensitivity reaction, or cell-mediated hypersensitivity.
And this means that those myelin specific T-cells release cytokines like IL-1, IL-6,
TNF-alpha, and interferon-gamma, and together dilate the blood vessels which allows more
immune cells to get in, as well as directly cause damage to the oligodendrocytes.
They cytokines also attract B-cells and macrophages as part of the inflammatory reaction.
Those B-cells begin to make antibodies that mark the myelin sheath proteins, and then
the macrophages use those antibody markers to engulf and destroy the oligodendrocytes.
Without oligodendrocytes, there’s no myelin to cover the neurons, and this leaves behind
areas of scar tissue, also called plaques or sclera.
In multiple sclerosis, these immune attacks typically happen in bouts.
In other words, an autoimmune attack on the oligodendrocytes might happen, and then regulatory
T cells will come in to inhibit or calm down the other immune cells, leading to a reduction
in the inflammation.
Early on in multiple sclerosis, the oligodendrocytes will heal and extend out new myelin to cover
the neurons, which is a process called remyelination.
Unfortunately, though, over time as the oligodendrocytes die off the remyelination stops and the damage
becomes irreversible with the loss of axons.
Just like other autoimmune diseases, the exact cause of multiple sclerosis is unknown, but
is linked to both genetic and environmental factors.
Genetic risk factors include being a woman and having genes that encode a specific type
of immune molecule called HLA-DR2 which is used to identify and bind to foreign molecules.
Environmental risk factors might include infections as well as vitamin D deficiency, which is
an interesting one because it might help explain why the rates of multiple sclerosis are higher
at the northern and southern poles compared to the equator where there’s a lot more
sunlight.
Together these genetic and environmental influences might lead to the body not killing off immune
cells that target myelin.
So it turns out that there are four main types of multiple sclerosis based on the pattern
of symptoms over time.
To break this down, we can use this graph with time on the x-axis, where time refers
to the lifespan of the individual, and disability on the y-axis.
The first, and by far the most common pattern of multiple sclerosis, is called relapsing-remitting
multiple sclerosis or RRMS.
This condition is what we just described, bouts of autoimmune attacks happening months,
or even years, apart, and causing an increase in the level of disability.
For example, during a bout a person may lose some vision, but then it may be followed by
improvement if there’s remyelination.
Unfortunately, though, more often than not, the remyelination process is not complete
so there is often some residual disability that remains, and that means that with each
attack, more and more of the central nervous system gets irreversibly damaged.
In the relapsing-remitting multiple sclerosis type there’s typically no increase in disability
between bouts, so the line stays flat during that time.
Now, the second type is called secondary progressive multiple sclerosis or SPMS which initially
is pretty similar to the relapse-remitting type, but over time the immune attack becomes
constant which causes a steady progression of disability.
The third type is primary-progressive multiple sclerosis or PPMS, which is basically one
constant attack on myelin which causes a steady progression of disability over a person’s
lifetime.
The final type is progressive relapsing multiple sclerosis or PRMS, which is also one constant
attack but this time there are bouts superimposed during which the disability increases even
faster.
Specific symptoms varying a lot from person to person, and largely depend on the location
of the plaques.
And multiple sclerosis typically affects individuals between the ages of 20 and 40.
Symptoms related to bouts can typically worsen over weeks and can linger for months without
treatment.
One common trio of multiple sclerosis symptoms is called Charcot’s neurologic triad and
it includes dysarthria, which is difficulty or unclear speech, nystagmus, which is involuntary
rapid eye movements, and an intention tremor.
Dysarthria is due to plaques in the brainstem that affect nerve fibers that control muscles
of the mouth and throat, and this can interfere with conscious movements, like eating and
talking and can lead to things like a new stutter, as well as unconscious movements,
like swallowing.
Nystagmus is due to plaques around the nerves controlling eye movements.
Plaques around the optic nerve causes loss of vision in one or both of the eyes because
of damage to the optic nerve, which is called optic neuritis.
Sometimes there’s blurring or graying of the vision, or alternatively there might be
a dark point in the center of vision.
Additionally, if there’s damage to the nerves controlling eye movement, then eye movements
can be painful and there can even be double vision, if the eyes can no longer move in
a coordinated way.
Finally, intention tremors can be caused by plaques along the motor pathways in the spinal
cord which can affect outbound signals like skeletal muscle control.
Motor symptoms can include muscle weakness, muscle spasms, tremors, and ataxia, which
is a loss of balance and coordination.
In serious cases, this can lead to paralysis.
In addition, plaques in the sensory pathways can affect inbound signals like sensations
from the skin which causes symptoms like numbness, pins-and-needles, and paresthesias which are
often a tingling feeling but may also be a painful itching or burning sensation.
Occasionally there can be very specific sensory symptoms like Lhermitte’s sign, which is
when an electric shock runs down the back and radiates to the limbs when a person bends
their neck forward.
Plaques can also involve the autonomic nervous system which can lead to bowel and bladder
symptoms like constipation and urinary incontinence, as well as sexual symptoms like sexual dysfunction.
Finally, multiple sclerosis can also affect higher order activities of the brain, causing
poor concentration and critical thinking, as well as depression and anxiety.
Multiple sclerosis is typically suspected when there are multiple neurologic symptoms
separated in space, which is attributable to damage in different locations in the nervous
system, as well as time, meaning separate bouts or flare-ups as well as remission.
The diagnosis of multiple sclerosis is supported by an MRI which shows multiple central nervous
system lesions, called white matter plaques, since these regions tend to have lots of myelin.
Also, in the cerebrospinal fluid there might be high levels of antibodies, which indicates
an autoimmune process.
Finally a visual evoked potential can be helpful as well, which measures the nervous system’s
response to visual stimuli.
For treatment, there is no cure for multiple sclerosis, but there are medications which
are particularly effective for the relapsing-remitting type because they lessen the severity of relapses
and make them happen less frequently.
Medications like corticosteroids, cyclophosphamide which is a cell cycle inhibitor, and intravenous
immunoglobulin can all be used to help blunt the autoimmune process.
In addition, plasmapheresis can be effective as well, which is when the plasma is filtered
to remove disease-causing autoantibodies.
Chronic treatment for multiple sclerosis includes immunosuppressants like recombinant beta-IFN
which decreases the level of inflammatory cytokines in the brain and increases the function
of T regulatory cells.
Other immunosuppressants actually block T cells from getting into the brain by interfering
with their cell surface molecules they use to gain passage through the blood brain barrier.
Unfortunately, though, there are fewer treatment options available for the progressive MS.
Instead, treatments are often targeted at managing specific symptoms—everything ranging
from depression to bladder dysfunction.
Physical therapy and cognitive rehabilitation therapy can be particularly helpful with sensory,
motor, and cognitive symptoms.
Finally, there’s also an increasing interest in the role of vitamin D as an effective treatment.
All right, as a quick recap, multiple sclerosis is a chronic and progressive autoimmune disorder,
and the most common pattern is the relapsing-remitting type, where individuals have flares that come
and go, with each one slightly worsening their overall condition.
During a flare, T-cells cause inflammation and damage to oligodendrocytes in the central
nervous system, which leaves behind scarred areas of demyelinated neurons called plaques,
which causes a variety of symptoms depending on the location.
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