Lesional demyelinations of the central nervous system

Multiple sclerosis and other demyelinating diseases of the central nervous system (CNS) produce lesions (demyelinated areas in the CNS) and glial scars or scleroses. They present different shapes and histological findings according to the underlying condition that produces them. Demyelinating diseases are traditionally classified in two kinds: demyelinating myelinoclastic diseases and demyelinating leukodystrophic diseases. In the first group a normal and healthy myelin is destroyed by a toxic, chemical or autoimmune substance. In the second group, myelin is abnormal and degenerates. The second group was denominated dysmyelinating diseases by Poser Therefore, since Poser demyelinating diseases normally refers to the myelinoclastic part. Demyelinating diseases of the CNS can be classified according to their pathogenesis into five non exclusing categories: demyelination due to inflammatory processes, viral demyelination, demyelination caused by acquired metabolic derangements, hypoxic–ischaemic forms of demyelination and demyelination caused by focal compression.

ADEM can present plaque like lesions which are indistinguishable from MS Nevertheless, ADEM White Matter appears intact under Magnetization Transfer MRI, while MS shows problems (See NAWM). Besides ADEM does not present "black holes" under MRI (zones with axonal damage) and lesions develop strictly around veins instead of the more relaxed rule for MS

Demyelinating lesions whose size is larger than 2 cm. They normally appear together with normal MS lesions, situation described as tumefactive multiple sclerosis. When they appear alone, they are usually named "Solitary sclerosis", being more difficult to diagnose. They look like intracranial neoplasms, and sometimes they get biopsied as suspected tumors. Proton MR spectroscopy can help in their diagnosis.

The hallmark of MS is the lesion, which appears mainly in the white matter and shows macrophage mediated demyelination, BBB breakdown, inflammation and axon transection.

Demyelinating lesions begin with the appearance of some areas named NAWM (normal appearing white matter) which despite its name, is abnormal in several parameters. These areas show axonal transections and stressed oligodendrocytes (the cells responsible for maintaining the myelin), and randomly, they show clusters of activated microglia named pre active lesions. These pre lesions normally resolve themselves, though sometimes they spread towards a capilar vein.

This is followed by the blood–brain barrier (BBB) breakdown. BBB is a tight vascular barrier between the blood and brain that should prevent the passage of antibodies through it, but in MS patients it does not work. For unknown reasons special areas appear in the brain and spine, followed by leaks in the blood–brain barrier where immune cells infiltrate. This leads to the entrance of macrophages into the CNS, triggering the beginning of an immune mediated attack against myelin. Gadolinium cannot cross a normal BBB and, therefore, Gadolinium enhanced MRI is used to show BBB breakdowns.

After the BBB breakdown, the immune mediated attack against myelin happens. T cells, are a kind of lymphocyte that plays an important role in the body's defenses. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called "autoreactive lymphocytes". Demyelination, further inflammation and axonal transection are the result. The attack of myelin starts inflammatory processes, which triggers other immune cells and the release of soluble factors like cytokines and antibodies. Further breakdown of the blood–brain barrier, in turn cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins. Astrocytes can heal partially the lesion leaving a scar. These scars (sclerae) are the known plaques or lesions usually reported in MS. A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell's myelin sheath. Repeated attacks lead to successively less effective remyelinations, until a scar like plaque is built up around the damaged axons. According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17, play a key role in the development of the lesion. 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 central nervous system 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.