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Multiple Sclerosis Cause
What is Multiple Sclerosis – One Disease or Many – MS is a Whole Brain Disease
What is Multiple Sclerosis?
MS is characterized by damage to the myelin sheath of the brain and the spinal cord nerve fibers. Nerve fibers themselves (axons) are relatively preserved.
The damage is caused by the immune system, probably, because some of the brain components are perceived as foreign. Damaged areas in the nervous system tissues are called MS plaques or demyelinating plaques. There are different types of plaques, which possibly suggest that MS is not a single disease entity. Neuromyelitis optica was once believed to be a form of MS. Recent discoveries proved neuromyelitis optica being a distinct disease. It is likely that MS is a cluster of similar disorders with different mechanisms united by similar clinical picture. Finding a precise mechanism of MS will likely help the design of new treatment options.
Multiple sclerosis is a very complex disease. The exact target of the autoimmune attack in MS remains a mystery. It is strongly recommended to review Multiple sclerosis Spectrum Disorders page, where most of the terms, used in this article, are explained. Plaques tend to occur in specific areas of the brain and spinal cord (see Multiple Sclerosis Diagnostic Criteria). MS plaque locations define the individual symptoms in each particular patient.
MS: One Disease or Many?
Tissue damage in multiple sclerosis may be produced by multiple mechanisms.
- Special immune system cells (t-lymphocytes) may attack myelin, or myelin producing cells (olygodendrocytes), or some other brain/spinal cord tissue component.
- The immune system attacks some normal nervous system competent (possibly myelin) by means of producing autoantibodies. Attachment of the antibodies to the intended targets triggers a chain of events that eventually leads to destruction of myelin.
- Bystander effect is an autoimmune attack against some other target and the myelin suffers just because it happens to be in the wrong place at the wrong time.
There are 4 different types of MS plaques. Studies of those plaques support the idea of MS being a set of multiple disorders with similar symptoms. On the other hand, different types of demyelinating plaques may be found in the same patient, which unifies all MS patients under the same diagnosis. There are four patterns described in demyelinating plaque biopsies.
Pattern I (15% of biopsies) is characterized by evidence of inflammation and myelin destruction. There is no evidence of attack by t-cells or autoantibodies. Damage is produced by inflammation caused by macrophages. It is not clear what the target of this attack is. It is obviously a bystander type of damage (#3 above).
Regeneration of myelin (remyelination) is very common. This is because damage to myelin is not associated with destruction of myelin-producing cells (oligodendrocytes). I would speculate that this type of plaque should be associated with significant improvement of symptoms over time.
Pattern II is the most common (58% of biopsies). There is a myelin destruction associated with evidence of autoimmune attack caused by autoantibodies (antibodies against own tissues, #2 above). It is not clear, what component of myelin is targeted. There is a possibility that the attacked is not myelin itself (similar to neuromyelitis optica).
Search for the potential autoantibody targets has not been successful so far. Finding the target in this form of MS lesion might reward us with potential new treatment options in the future. Oligodendrocytes tend to survive and partially restore the myelin.
Pattern III is found in 26% of biopsies. The findings are very different from the two patterns above. This pattern is associated with profound loss of oligodendrocytes.
The death is caused by programmed cell death, called apoptosis. There is no myelin regeneration. This type of damage is typically caused by viruses, poisons, or an attack by T-Cells (#1 above). There is no evidence of autoantibody attack.
Pattern IV is rear, only 1% of biopsies. There is a widespread death of oligodendrocytes, but the cause is not clear.
Almost half of MS plaques remyelinates. It means that myelin may be restored over time. Remyelinated plaques are called shadow plaques. Given substantial amount of time, myelin may be restored close to normal thickness.
The problem is that MS relapses tend to damage the regenerated areas more often than previously normal myelin.
Whole Brain Disease
Damage in MS is not limited to the deep white matter. There is evidence of the brain cortex involvement early in the disease. Cortex is a superficial layer of the brain surface which is rich with nerve cells bodies. Cortex is the essence of the brain information processing power.
Cognitive problems in multiple sclerosis are caused by lesions in the cortex. There is evidence of inflammation in the meninges, which are tissue layers covering the brain surface. Inflammation in the meninges is strongly associated with MS lesions in the cortex.