Multiple sclerosis – causes, symptoms, diagnosis, treatment, pathology

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. Thanks for watching. You can help support us by donating on patreon,
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