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.

(figure 1)

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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.

(figure 2)

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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 devastating.

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 cognitive deficits.

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 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 disability accrual.

Lesion Structure

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 spinal cord.

MS lesions also vary depending on their age:

•	Early (acute) lesions are characterized by inflammatory mononuclear cells and myelin breakdown. Astrogliosis 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.

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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.

Early Symptoms

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.

•	L'Hermitte's sign. 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.