Lesional demyelinations of the central nervous system

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Dawson's Fingers appearing on an MRI scan

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 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.[1]

Demyelinating diseases that produce lesions in the CNS[edit]

The list of the diseases that produce CNS demyelinating lesions is not complete, but it includes:

  • Balo concentric sclerosis, an unusual presentation of plaques forming concentrenic circles, which can sometimes get better spontaneously.
  • Schilder disease or diffuse myelinoclastic sclerosis: is a rare disease that presents clinically as a pseudotumoural demyelinating lesion; and is more common in children.[2][3]

And also some diseases like

Also Leukodystrophy and its sub-conditions, Adrenoleukodystrophy and Adrenomyeloneuropathy could be in the list,

Demyelination patterns in standard MS[edit]

Four different damage patterns, known as Lassmann patterns,[6] have been identified by her team in the scars of the brain tissue in multiple sclerosis, and they are used sometimes as a basis for describing lesions in other demyelinating diseases.

Pattern I 
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.[7]
Pattern II 
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found.[8] Though this pattern could be considered similar to damage seen in NMO, some authors report no AQP4 damage in pattern II lesions[9]
Pattern III 
The scars are diffuse with inflammation, distal oligodendrogliopathy and microglial activation. There is also loss of myelin-associated glycoprotein (MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis. For some researchers this pattern is an early stage of the evolution of the others.[10]
Pattern IV 
The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.

The meaning of this fact is controversial. For some investigation teams it means that MS is a heterogeneous disease. Others maintain that the shape of the scars can change with time from one type to other and this could be a marker of the disease evolution.[11] Anyway, the heterogeneity could be true only for the early stage of the disease.[12] Some lesions present mitochondrial defects that could distinguish types of lesions.[13] Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.[14]

After some debate among research groups, currently the heterogeneity hypothesis looks like accepted[15]

ADEM demyelination[edit]

ADEM can present plaque-like lesions which are indistinguishable from MS[16]

NMO demyelination[edit]

As with MS, several patterns have been described inside NMO, but they are heterogeneus inside the same individual, reflecting stages in the lesion evolution:[17]

  • The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis
  • demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2).
  • Wallerian degeneration in lesion-related tracts (lesion type 3).
  • Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4).
  • Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5).
  • Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6).

Early active demyelinating NMO lesions may show complement within macrophages and oligodendrocyte apoptosis associated with a selective loss of minor myelin proteins, in addition to typical NMO features in a subset of active demyelinating NMO lesions[15]

Dawson's fingers[edit]

"Dawson's fingers" is the name for the lesions around the ventricle-based brain veins[18][19] of patients with multiple sclerosis. The condition is thought to be the result of inflammation or mechanical damage by blood pressure[20] around long axis of medular veins.

Dawson's fingers spread along, and from, large periventricular collecting veins, and are attributed to perivenular inflammation.[21]

Lesions far away from these veins are known as Steiner's splashes.[20]

MS lesions[edit]

Demyelinization by MS. The Klüver-Barrera colored tissue show a clear decoloration in the area of the lesion (Original scale 1:100)

Using high field MRI system, with several variants several areas show lesions, and can be spacially classified in infratentorial, callosal, juxtacortical, periventricular, and other white matter areas.[22] Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical.[23] Others classify them as hippocampal, cortical, and WM lesions,[24] and finally, others give seven areas: intracortical, mixed white matter-gray matter, juxtacortical, deep gray matter, periventricular white matter, deep white matter, and infratentorial lesions.[25] The distribution of the lesions could be linked to the clinical evolution[26]

Post-mortem authopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord.[27] Cortical lesions have been observed specially in people with SPMS but they also appear in RRMS and clinically isolated syndrome. They are more frequent in men than in women[28] and they can partly explain cognitive deficits.

It is known that two parameters of the cortical lesions, fractional anisotropy (FA) and mean diffusivity (MD), are higher in patients than in controls.[29] They are larger in SPMS than in RRMS and most of them remain unchanged for short follow-up periods. They do not spread into the subcortical white matter and never show gadolinium enhancement. Over a one-year period, CLs 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.[30]

The first plausible explanation of their distribution was published by Dr. Schelling. He said:

The specific brain plaques of multiple sclerosis can only be caused by energetic venous back-jets set in motion by intermittent rises in the pressure in the large collecting veins of the neck, but especially of the chest..[20]

But no problems with chest veins was ever found.

Recently, it has been remarked that it can plausibly be accounted for by veno-venous reflux,[31][32] according to the CCSVI theory. This results in a finger-like appearance of the lesions extending mainly off the ventricles within the brain.

This morphologic appearance was named Dawson's fingers by Charles Lumsden, after the Scottish pathologist James Walker Dawson,[33] who first defined the condition in 1916.

Demyelination process[edit]

Demyelinization by MS. The CD68 colored tissue shows several Macrophages in the area of the lesion. Original scale 1:100

Demyelination begins with the blood–brain barrier breakdown. It 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.

According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17,[34] 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.[35][36][37][38][39][40][41][42][43][44][45] Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS[46] and in the degeneration of the axons.[47]

The axons themselves can also be damaged by the attacks.[48] 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.

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 cannot completely rebuild a destroyed myelin sheath. However, the central nervous system 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 is therefore suspected that inflammatory conditions or axonal damage somehow inhibit stem cell proliferation and differentiation in affected areas[49]

See also[edit]

External links[edit]

  • Dawson Fingers in Multiple Sclerosis [5]

Sources[edit]

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