Pathology of multiple sclerosis: Difference between revisions

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Drawing of some sclerotic lesions from Babinski's thesis "Etude anatomique et clinique de la sclérose en plaques", 1885

Multiple sclerosis can be pathologically defined as the presence of distributed glial scars (or sclerosis) in the central nervous system.^[1] These glial scars are the remainings of previous demyelinating inflammatory lesions (encephalomyelitis disseminata) in the CNS white matter of a person, showing special characteristics, like for example confluent instead of perivenous demyelination.^[2]

Currently the term "multiple sclerosis" is ambiguous and refers not only to the presence of the scars, but also to the unknown underlying conditions that produce these scars. Besides clinical diagnosis uses the term for the related clinical courses. Specially important in the lesion development are some white matter areas, which are abnormal under MRI, named NAWM (normal appearing white matter) because its where the lesions appear. Also important are NAGM (gray matter areas) and grey matter lesions. Confluent subpial cortical lesions are the most specific finding for MS, being exclusively present in MS patients.^[3] and maybe the initial trigger.^[4] Though this feature can only be detected during an autopsy^[5] there are some subrogate markers under study^[6]

Demyelination process and specific areas of damage

Damage occurs in two phases. First some MRI-abnormal areas with hidden damage appear in the brain and spine (NAWM, NAGM, DAWM), followed later by leaks in the blood–brain barrier where immune cells infiltrate causing the known demyelination.^[7]

According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17,^[8] 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.^[9] 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.^[10]^[11]^[12]^[13]^[14]^[15]^[16]^[17]^[18]^[19]^[20]

Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS^[21] and in the degeneration of the axons.^[22] and the oligodendrocytes.^[23]

The axons themselves can also be damaged by the attacks.^[24] 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. These scars are the so-called "scleroses" that define the condition. They are named glial scars because they are produced by glial cells, mainly astrocytes, and their presence prevents remyelination. Therefore, there is research ongoing to prevent their formation.

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^[25]

Brain lesions distribution

Main: Lesional demyelinations of the CNS

Dawson's Fingers appearing on an MRI scan

Multiple sclerosis is considered a disease of the white matter because normally lesions appear in this area, but it is also possible to find some of them in the grey matter.^[26]

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.^[27] Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical.^[28] Others classify them as hippocampal, cortical, and WM lesions,^[29] 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.^[30] The distribution of the lesions could be linked to the clinical evolution^[31]

Post-mortem autopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord.^[32] 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^[33] and they can partly explain cognitive deficits.

Regarding two parameters of the cortical lesions, fractional anisotropy (FA) is lower and mean diffusivity (MD) is higher in patients than in controls.^[34] The differences are larger in SPMS (secondary progressive multiple sclerosis) than in RRMS (relapsing-remitting multiple sclerosis) 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.^[35]

Due to the distribution of the lesions, since 1916 they are also known as Dawson's fingers.^[36] They appear around the brain blood vessels.

Spinal cord damage

Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability.^[37] In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues.^[38] It has been shown that Fractional anisotropy of cervical spinal cord is lower than normal, showing that there is damage hidden from normal MRI.^[39]

Progressive tissue loss and injury occur in the cervical cord of MS patients. These two components of cord damage are not interrelated, suggesting that a multiparametric MRI approach is needed to get estimates of such a damage. MS cord pathology is independent of brain changes, develops at different rates according to disease phenotype, and is associated to medium-term disability accrual.^[40]

Spinal cord presents grey matter lesions, that can be confirmed post-mortem and by high field MR imaging. Spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the grey matter demyelination.^[41]

Cerebellum and Thalamus

Cerebellar ataxia appears mainly in PPMS and it is related to the pathological changes in the cerebellum. Some special cells present only in the cerebellum, Purkinje cells, have been reported to be part of this problems. Increasing of neurofilament phosphorylation has been reported^[42]

Cerebellum is specially affected in progressive variants. Grey matter damage in the cerebellum is linked to inflammation in the subarachnoid space^[43] Though most of the cerebellum damage occurs in late stages, it can be seen that there are abnormalities since early disease stages^[44] mostly of the "Normal Appearing" kind^[45]

Thalamus degeneration in MS presents several features, such as trans-neuronal or Wallerian degeneration.^[46]

Cortex

Around 26% of MS lesions appear inside or adjacent to the cortex.^[47] It seems that in RRMS patients, both deep and cortical GM atrophy are associated with pathology in connected white matter.^[48] Cortical lesions are inflammatory (immune mediated) and can present relapses^[49]

Cortex lesions are disposed around the principal cortical veins and the majority enter the terrain of the white matter, and have been classified into seven types^[47]

Some research groups have proposed that cortical lesions are the origin of the NAWM areas in the white matter^[50] and 7 Tesla scanners seem to confirm this hypothesis, showing that cortical pathology starts in the pial surface (external layer of the brain), which is in contact with the CSF, and extends later into the brain inner layers^[51]

Lesions in the cortex have been classified by the area they affect into four groups: type I (leukocortical), type II (intracortical), type III (subpial), and type IV (subpial extending through the whole cortical width but not to subcortical WM). This classification is not related to the white matter lesions classification.^[52]^[53]

Olfactory bulb

The olfactory nerve, similar to the optic nerve, is part of the Central Nervous System. This nerve terminates in the olfactory bulb, which also belongs to the central nervous system. Both develop from the CNS embrion, and recently it has been shown, by autopsies, that they are affected by the same diseases than the rest of the CNS.^[54] In particular, they are damaged during the multiple sclerosis course.

Related to this, the CSF of patients with disease activity show high levels of "Lateral Olfactory Tract Usher Substance" (LOTUS)^[55]

Retina and optic nerve damage

The Retina and the optic nerve originate as outgrowths of the brain during embryonic development, so the retina is considered part of the central nervous system (CNS).^[56] It is the only part of the CNS that can be imaged non-invasively in the living organism. The retina nerve fiber layer (RNFL) is thinner than normal in MS patients^[57]

MS patients show axonal loss in the retina and optic nerve, which can be measured by Optical coherence tomography^[58] or by Scanning laser polarimetry.^[59] This measure can be used to predict disease activity^[60] and to establish a differential diagnosis from Neuromyelitis optica^[61]

The procedure by which MS attacks the retina is currently unknown. Nevertheless, given that retina cells have no myelin, it must be different from the autoimmune attack of the brain. The procedure in the retina is pure neurodegeneration.^[62]

About antibodies in the retina, tissue-bound IgG was demonstrated on retinal ganglion cells in six of seven multiple sclerosis cases but not in controls.^[63] Two eye problems, Uveitis and retinal phlebitis are manifestations of MS.^[64]

Proposed procedures for the neurodegeneration are than Narrower arterioles and wider venules have been reported.^[65] Also rigidity has been noticed^[66]

Degenerative process in the optic nerve and retina

Some results suggest the presence of trans-synaptic degeneration as a contributor to chronic axon damage in the optic nerve and retina^[67] Nevertheless, the authors of the paper were unable to identify whether the degeneration condition spreads from the anterior part or from the rear.

The optic radiation (OR), which is a set of axons that lead to the visual cortex, is more similar to the rest of the brain because it contains myelin. It is also damaged. In this area NAWM areas (see below) appear. The optic radiation damage is composed by two factors: trans-synaptic degeneration, and wallerian degeneration ^[68]

Neural and axonal damage

Two different mechanisms of axon destruction are acting in MS. First of all, there is a diffuse axon degeneration, probably related to the NAWM appearance. Later, there is a second axonal damage mechanism localized in old demyelinating lesions, probably produced by B-Cells. This second damage is related to the T1-Hypointense lesions (MRI black holes) which appear when a demyelinating lesion is not remyelinated.^[69]

The axons of the neurons are damaged probably by B-Cells,^[22] though currently no relationship has been established with the relapses or the attacks.^[24] It seems that this damage is a primary target of the immune system, i.e. not secondary damage after attacks against myelin,^[70] though this has been disputed^[71]

Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.^[72]

A relationship between neural damage and N-Acetyl-Aspartate concentration has been established, and this could lead to new methods for early MS diagnostic through magnetic resonance spectroscopy^[73]

Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy.^[74]

Peripheral nervous system involvement

Though MS is defined as a CNS condition, some reports link problems in the peripheral nervous system with the presence of MS plaques in the CNS^[75]

Lesion structure and evolution

MS lesions mainly consist in demyelination and scarring in the fatty myelin sheaths around the axons of the brain and spinal cord.^[76]

Lesions evolve from the Normal Appearing White Matter. In MTR-MRI, the apparent diffusion coefficient (ADCav) is a measure of water molecule motion. It can be seen that before the BBB breakdown, this coeficient increases until, at some point, the blood-brain barrier breaks down and immune cells enter the brain producing the lesion.^[77]

According with the most recent research, an active lesion is composed of different layers:^[78]

NAWM border with the lesion: These areas contained activated microglia, antibodies binding to astrocytes, axons, oligodendrocytes and dendritic cells along blood vessels. No T or B cells are present.
Lesion external layer: Number of oligodendrocyte cell bodies decreases. Remaining oligodendrocytes are sometimes swollen or dying. Myelin sheaths are still intact but swollen. Small increase in microglia and T cells.
Active layer: Phagocytic demyelinating areas: There is myelin debris taken up by local microglia and phagocytes entering from the bloodstream. More T cells in these areas, and in the space adjacent to blood vessels.
Recently demyelinated tissue: Tissues were full of myelin-containing phagocytes. Signs of early remyelination together with small numbers of oligodendrocytes. Large numbers of T cells, B cells, and other immune cells concentrated around blood vessels.
Inactive layer: Again activated microglia and dendritic cells were also found around blood vessels.

Lesions under MRI

Most MS lesions are isointense to white matter (they appear bright) on T1-weighted MRI, but some are "hypointense" (lower intensity). These are called "black holes" (BH). They appear specially in the supratentorial region of the brain.

When BH's appear, around half of them revert in a month. This is considered a sign of remyelination. When they remain, this is regarded as a sign of permanent demyelination and axonal loss. This has been shown on post-mortem autopsies.^[79]

Small lesions are invisible under MRI. Therefore, clinically assisted diagnostic criteria are still required for a more accurate MS diagnosis than MRI alone.^[80]

The lesion evolution under MRI has been reported to begin as a pattern of central hyperintensity. This was seen in the majority of new lesions, both on proton density and contrast-enhanced T1-weighted images.^[81] When gadolinium is used, the lesion expansion can be classified as nodular or ringlike^[82]

Whatever the demyelination process is, currently it is possible to detect lesions before demyelination, and they show clusters of activated microglia and leukocyte infiltration, together with oligodendrocytes abnormalities.^[83] Some research groups consider some areas of the NAWM with clusters of microglial nodules as "preactive MS lesions".^[84]

Lesion evolution can be followed via MRI^[85]

Damage before BBB disruption

Special MRI methods

Main Magnetic resonance imaging

The classic MRI methods are named T1-relaxation and T2-relaxation. They create the images based in the "relaxation time", i.e., the time it takes for a molecule to realign its magnetic with its environment after an electromagnetic pulse has taken it out of the equilibrium.

A third type of MRI is based in the water diffusivity. It is called "Diffusion MRI" or "Diffusion Tensor MRI". and the images produced are normally named Diffusion Tensor Images (DTI). A modification of the image post-processing is to account for the water density in each area. These are called "Diffusion Weighted Images" (DWI) or Difussion Tensor MRI, DT-MRI. The diffusion measures the water response and the tensor structure takes account of the orientation of the tissue fibers. It is important because NAWM and NAGM show abnormal DT-MRI^[86]

A fourth important MRI technique is the Magnetization Transfer technique, MT-MRI. It measures differences in the Magnetization Transfer Ration (MTR). The idea is that the nucleus of any atom that has a net nuclear spin and that is bonded to a hydrogen atom could potentially be imaged via "heteronuclear magnetization transfer MRI". This would image the high-gyromagnetic-ratio hydrogen nucleus instead of the low-gyromagnetic-ratio nucleus that is bonded to the hydrogen atom.^[87] In principle, hetereonuclear magnetization transfer MRI could be used to detect the presence or absence of specific chemical bonds.^[88]^[89] NAWM and Diffusely abnormal areas (DAWM) appear under MT-MRI.

Finally, the fifth more important MRI technique is the Proton Magnetic resonance spectroscopy. Based in the different response to the electromagetic pulses that different substances present, a MRS scanner is able to identify chemical substances in the brain. This is important because N‐acetylaspartate is a marker of axonal damage that can be now identified in-vivo.^[90]

Lesions under the special MRI methods

Normally two different kind of lesions appear on a normal MRI: T2-hypertense lesions and T1-hypointense. The first one are demyelinating lesions and appear brighter than the surroundings in T2-MRI.

The T1-hypointense are areas less dense than the surrounding NAW, and appear black on T1-MRI. They are mainly axonal degeneration areas. Because their black appearance they are sometimes known as black holes. They seem to appear as a sequel after a strong demyelinating lesion.

BBB disruption is normally shown using gadolinium. It is a contrast that cannot cross the BBB except when it is dysfunctional. Therefore, in active lesions with BBB implication the contrast enters the brain and appears in the MRI.

Before BBB disruption, some brain tissues which present normal aspect under T1 and T2 MRI (Normal appearing white matter, NAWM and normal appearing grey matter, NAGM), can show several abnormalities under special MRI technologies:

Magnetization transfer multi-echo T(2) relaxation. Subjects with Long-T(2) lesions had a significantly longer disease duration than subjects without this lesion subtype.^[91] It has been found that grey matter injury correlates with disability^[92] and that there is high oxidative stress in lesions, even in the old ones.^[93]

Diffusion tensor MRI or Magnetic Transfer MRI are two options to enhance MRI-hidden abnormalities discovery. This is currently an active field of research with no definitive results, but it seems that these two technologies are complementary.^[94]

Other methods of MRI allow us to get a better insight of the lesions structure. Recently MP-RAGE MRI has shown better results than PSIR and DIR for gray matter lesions.^[95] Susceptibility weighted imaging (SWI-MRI) has shown iron (hemosiderin) deposition in lesions, and helps to detect otherwise invisible lesions.^[96]

Abnormalities in the gray matter (Diffusion tensor MRI alterations) of the brain parenchyma are present early in the course of multiple sclerosis^[97]

Normal appearing brain tissues

Using several texture analysis technologies, it is possible to classify white matter areas into three categories: normal, normal-appearing and lesions.^[98] Currently, it is possible to detect lesions before they present demyelination, and they are called pre-active lesions.^[83] A fourth area called DAWM (diffusely abnormal white matter) has recently been proposed^[99] and can help to differentiate PPMS and SPMS.^[100] Abundant extracellular myelin in the meninges of patients with multiple sclerosis has been found^[101]

Brain tissues with MRI-hidden problems are usually named Normal Appearing. Exploring the normal-appearing corpus callosum has been found a possible primary hypoperfusion,^[102]^[103] according with other findings in this same direction.^[104]^[105]^[106]^[107]^[108]^[109] Also iron (in hemosiderin deposits and as well as in ferritin-like structures inside the macrophage) accumulation has been reported^[110]^[111]

Several findings in these areas have been shown. Post-mortem studies over NAWM and NAGM areas (Normal appearing White and Gray Matters) show several biochemical alterations, like increased protein carbonylation and high levels of Glial fibrillary acidic protein (GFAP), which in NAGM areas comes together with higher than normal concentration of protein carbonyls, suggesting reduced levels of antioxidants and the presence of small lesions.^[112] The amount of interneuronal Parvalbumin is lower than normal in brain's motor cortex areas,^[113] and oxidative injury of oligodendrocytes and neurons could be associated with active demyelination and axonal injury.^[114]

NAWM in MS has been reported to be similar to NAWM in leukoaraiosis,^[115] though NAWM damage in MS is inflammatory and special microscopic techniques like CARS microscopy show that the CNS of MS patients may be globally altered, and both lesions and NAWM are just manifestations of another underlying problem.^[116] The NAWM is specially abnormal close to the ventricles, which may indicate a pathogenic mechanism mediated via the CSF or ependyma.^[117]

Non-lesional White Matter

Most of the brain in MS is unafected. Though obviously normal white matter appears normal under MRI, so does the NAWM white matter described in the next section. To establish a difference, normal white matter is named Non-lesional white matter (NLWM)^[118]

This normal white matter is reported to be around 56% of the total WM of the patients.^[119]

Normal appearing White Matter

The white matter with hidden but MRI-visible damage is known as "Normal-appearing white matter" (NAWM)^[120] and is where lesions appear.^[7]

The pathology of the NAWM differs from areas near the lesions or near the cortex. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.^[121]

The NAWM precedes the lesions. It has been shown that the apparent diffusion coefficient (ADC) precedes the development of new plaques. Later increases during BBB breakdown (gadolinium enhancement) and finally decays after the enhancement.^[122]

BBB disruption takes place on NAWM areas.^[123] This can be read in different ways. Maybe some hidden changes in White Matter structure trigger the BBB disruption, or maybe the same process that creates the NAWM areas disrupts the BBB after some time.

Pre-active lesions are lesions in an early stage of development. They resolve sometimes without further damage, and not always develop into demyelinating lesions. They present clusters of activated microglia in otherwise normal-appearing white matter.^[83]^[84]

Oligodendrocyte abnormalities appear to be crucially involved.^[124]^[125] The earliest change reported in the lesions examined is widespread oligodendrocyte apoptosis in which T cells, macrophages, activated microglia, reactive astrocytes, and neurons appear normal. This observation points to some change in the local environment (NAWM) to which oligodendrocytes are especially susceptible and which triggers a form of apoptosis.^[126]

Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls.^[127]

Citrullination appears in SPMS.^[128] It seems that a defect of sphingolipid metabolism modifies the properties of normal appearing white matter.^[129] Related to these, peptidylarginine deiminase 2 is increased in patients with MS, and is related to arginine de-imination.^[130]

NAWM shows a decreased perfusion which does not appear to be secondary to axonal loss.^[107] The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K(+) at the nodes of Ranvier and a reduced release of K(+) in the perivascular spaces.^[131] This would be consistent again with cases of Chronic cerebrospinal venous insufficiency.

White matter lesions appear in NAWM areas,^[7] and their behavior can be predicted by MRI parameters as MTR (magnetization transfer ratio).^[132]^[133] This MTR parameter is related to axonal density.^[134]

It also seems that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at Thr97 than normal individuals.^[135]

Gray matter damage. Normal Appearing Gray Matter

Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disability. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS.^[136] Epstein-Barr virus could be involved,^[137] but is not likely.^[138] Involvement of the deep gray matter (DGM), suggested by magnetic resonance imaging, is confirmed, and most DGM lesions involve both GM and white matter. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions.^[139]

Iron depositions appear in deep gray matter by magnetic field correlation MRI^[140] Differently from NAWM, NAGM areas are not related to the development of lesions^[141]

Diffusely abnormal white matter

Other active area of study is the Diffusely abnormal white matter (DAWM). It seems to be a reduction of myelin phospholipids that correlates with a reduction of the myelin water fraction.^[142] The DAWM consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing WM and significantly different from focal WM lesion pathology.^[143] Changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI^[144]

Dirty appearing white matter

Dirty-appearing white matter (referred to as DAWM like the former case) is defined as a region with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (NAWM) and that of plaque on T2-weighted and proton density imaging.^[145] It is probably created by loss of myelin phospholipids, detected by the short T2 component, and axonal reduction.

Microglial nodules

Originally proposed as a biomarker,^[146] the presence of these nodules has a possible pathogenetic significance. Though their role in the lesion evolution is still unclear, their presence in normal-appearing white matter have been suggested to be an early stage of lesion formation ^[147]

Heterogeneity of the disease

Multiple sclerosis has been reported to be heterogeneus in its behavior, in its underlying mechanisms, in its response to medication ^[148] and remarkably, also respect the response to the specific potassium channel autoantibody Kir4.1.^[149]

For some authors, what we call MS in reality is a heterogeneous group of diseases^[150] Some independent reports take also PPMS apart^[151]

Demyelination patterns

Four different damage patterns have been identified in patient's brain tissues. The original report suggests that there may be several types of MS with different immune causes, and that MS may be a family of several diseases. Though originally was required a biopsy to classify the lesions of a patient, since 2012 it is possible to classify them by a blood test^[152] looking for antibodies against 7 lipids, three of which are cholesterol derivatives^[153]

It is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. In any case, understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions

According to one of the researchers involved in the original research "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."

The four identified patterns are:^[154]

Pattern I: The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.^[155]
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.^[156] This pattern has been considered similar to damage seen in NMO, though AQP4 damage does not appear in pattern II MS lesions^[157] Nevertheless, pattern II has been reported to respond to plasmapheresis,^[158] which points to something pathogenic into the blood serum, and the percentaje reported of pattern II is very close to the 47% reported in Kir4.1 MS cases,^[159] making it a candidate for research into the Kir4.1 connection. This patter has also been found in anti-MOG mediated NMO^[160] and it has been reported to present cells clones in the CSF^[161]
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.^[126] For others, it represents ischaemia-like injury with a remarkable availability of a specific biomarker in CSF^[162]^[163]
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 type III to the others and this could be a marker of the disease evolution.^[164] Anyway, the heterogeneity could be true only for the early stage of the disease.^[165] Some lesions present mitochondrial defects that could distinguish types of lesions.^[166] Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.^[167] Nevertheless, after some debate among research groups, it seems like the four patterns model is accepted^[168]^[169]

MRI Phenotypes

Several studies trying to stablish a relationship between the pathological findings and MRI findings have been performed.

For example, pulsed magnetization transfer imaging,^[170] diffusion Tensor MRI,^[171] and VCAM-1 enhanced MRI^[172] have been reported to show the pathological differences of these patterns. Together with MRI, magnetic resonance spectroscopy allows to see the biochemical composition of the lesions, which shows at least two different patterns^[173]

Currently as of 2014, the MRI studies have led to the proposal of four MRI phenotypes,^[174] though both the classification and the relationship with the pathology remains controversial.

Other proposed correlations

Several correlations have been studied trying to stablish a pathological classification:

With clinical courses: No definitive relationship between these patterns and the clinical subtypes has been established by now, but some relations have been established. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study^[175] and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy).^[176] Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions.^[177]
With Optic Coherence Tomography: OCT of the retinal layer yields different results for PPMS and RRMS^[178]
With CSF findings: Teams in Oxford and Germany,^[179] found correlation with CSF and progression in November 2001, and hypotheses have been made suggesting correlation between CSF findings and pathophysiological patterns.^[180] In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found,^[181] though this is disputed.^[182] High levels of anti-nuclear antibodies are found normally in patients with MS^{[citation needed]}. Antibodies against Neurofascin–186 could be involved in a subtype of MS^[183] Recently, it has been shown that the CSF from PPMS patients can transport the disease^[151]

With responses to therapy: It is known that 30% of MS patients are non-responsive to Beta interferon.^[184] The heterogeneous response to therapy can support the idea of hetherogeneous aetiology. It has also been shown that IFN receptors and interleukins in blood serum predicts response to IFN therapy,^[185]^[186] specially IL-17,^[187] and interleukins IL12/IL10 ratio has been proposed as marker of clinical course.^[188] Besides:
- Pattern II lesions patients are responsive to plasmapheresis, while others are not.^[158]^[189]
- The subtype associated with macrophage activation, T cell infiltration and expression of inflammatory mediator molecules may be most likely responsive to immunomodulation with interferon-beta or glatiramer acetate.^[190]
- People non-responsive to interferons are the most responsive to Copaxone [16]^[191]
- In general, people non-responsive to a treatment is more responsive to other,^[192] and changing therapy can be effective.^[193]
- There are genetic differences between responders and not responders.^[194] Though the article points to heterogeneous metabolic reactions to interferons instead of disease heterogeneity, it has been shown that most genetic differences are not related to interferon behavior^[195]

With response to NMO-IgG:: NMO-IgG is the immunoglobulin that attacks Aquaporin-4 in Devic's disease. Multiple sclerosis patients do not have it in blood, but it has been shown that 13% of tested patients reacted with the epitope AQPaa252-275. It is not known if these antibodies define distinct MS subsets, or are simply markers of astrocytic damage
With lesion structure: Cavitary lesions appear only in a subset of patients with a worse clinical course than normal^[196]
Response to intravenous immunoglobin: The response to IVIG is strongly dependent from the genetic profile of each person in a predictive way^[197]
Comorbidity with diabetes: Diabetes mellitus type 1 (T1D) is produced by special leukocyte antigen haplotypes, which seem to be involved also in some cases of MS^[198]

Primary progressive MS

It is currently discussed whether Primary Progressive MS (PPMS) is a different pathological entity or a different degree of the same pathology. No agreement has been established but there are some pathological features that are specific to PPMS. For example, meningeal inflammation is different respect standard cases of Recurrent-Recidivant MS (RRMS)^[199] and sodium accumulation is higher.^[200] Diffusely Abnormal White Matter (DAWM) is different than in RRMS/SPMS patients^[201] and it has been shown that CSF from PPMS patients can transport the disease^[151]

From a pathological point of view, PPMS characteristics are slow expansion of pre-existing white matter lesions, massive cortical demyelination, and extensive diffuse injury of the normal appearing white matter. As in relapsing MS also in progressive MS active tissue injury is invariably associated with inflammation, but inflammation seems to be trapped behind a closed blood brain barrier^[202]

Pathology of early MS and silent MS

Current McDonald criteria usually do not allow to establish a diagnosis for definite MS before two clinical attacks have appeared. This means that for clinical definite cases, MS condition has been present for a long time, difficulting the study of the initial stages.^[203] To study the initial stages of MS, a pathological definition of MS must be used instead of the clinical ones.^[204]

Sometimes patients with their first isolated attack (Clinically Isolated syndrome, or CIS) but before the confirming second attack (Preclinical MS) can be accepted to study the initial MS pathology^[205] but there is a study suggesting that any MS case begins as a silent pathology that can remain unnoticed even for five years.^[206] Therefore, even the CIS can appear too late in MS evolution.

Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS.,^[207] or sometimes Clinically silent MS.^[208] The previous reference states that clinically silent MS plaques were located in the periventricular areas. This reference also reports an estimate of the prevalence of silent MS as high as about 25%. Oligodendrocytes evolution is similar to normal MS clinical courses^[209]

Sometimes patients that undergo a MRI examination for an unrelated cause can show lesions in their brains. These cases of isolated MRI findings have been recently baptised as RIS (Radiologically Isolated Syndrome) and are the most common inspections in which suggestions of silent MS have appeared.^[210]

In respect to the pathology of the RIS cases, we can point out that they show cortical lesions, mainly in patients with oligoclonal bands.^[211] Macroscopic damage is similar to RRMS cases but milder.^[212] Cervical cord lesions are an important predictor of progression^[213] and the quotient N-acetylaspartate to creatine suggest axonal damage^[214]

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@@ Line 48: / Line 48: @@
 Cerebellar [[ataxia]] appears mainly in PPMS and it is related to the pathological changes in the cerebellum. Some special cells present only in the cerebellum, [[Purkinje cell]]s, have been reported to be part of this problems. Increasing of neurofilament phosphorylation has been reported<ref>Redondo J1, Kemp K, Hares K, Rice C, Scolding N, Wilkins A. Purkinje cell pathology and loss in multiple sclerosis cerebellum. Brain Pathol. 2014 Nov 20. doi: 10.1111/bpa.12230. PMID 25411024</ref>
-Cerebellum is specially affected in progressive variants. Grey matter damage in the cerebellum is linked to inflammation in the subarachnoid space<ref>Howell et al. Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space, Neuropathol Appl Neurobiol. 2014 Nov 24. doi: 10.1111/nan.12199. PMID 25421634</ref> Though most of the cerebellum damage occurs in late stages, it can be seen that there are abnormalities since early disease stages<ref>Romascano et al. Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis, Hum Brain Mapp. 2014 Nov 24. doi: 10.1002/hbm.22698, PMID 25421928</ref> mostly of the "Normal Appearing" kind<ref>Deppe M et al. Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration. Mult Scler. 2015 Apr 28. pii: 1352458515579439. PMID 25921041</ref>
+Cerebellum is specially affected in progressive variants. Grey matter damage in the cerebellum is linked to inflammation in the subarachnoid space<ref>Howell et al. Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space, Neuropathol Appl Neurobiol. 2014 Nov 24. doi: 10.1111/nan.12199. PMID 25421634</ref> Though most of the cerebellum damage occurs in late stages, it can be seen that there are abnormalities since early disease stages<ref>Romascano et al. Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis, Hum Brain Mapp. 2014 Nov 24. doi: 10.1002/hbm.22698, PMID 25421928</ref> mostly of the "Normal Appearing" kind<ref>Deppe M et al. Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration. Mult Scler. 2015 Apr 28. pii: 1352458515579439. {{DOI|10.1177/1352458515579439}} PMID 25921041</ref>
-Thalamus degeneration in MS presents several features, such as trans-neuronal or [[Wallerian degeneration]].<ref>Kipp M1, Wagenknecht N, Beyer C, Samer S, Wuerfel J, Nikoubashman O. Thalamus pathology in multiple sclerosis: from biology to clinical application. Cell Mol Life Sci. 2014 Nov 23. PMID 25417212</ref>
+Thalamus degeneration in MS presents several features, such as trans-neuronal or [[Wallerian degeneration]].<ref>Kipp M1, Wagenknecht N, Beyer C, Samer S, Wuerfel J, Nikoubashman O. Thalamus pathology in multiple sclerosis: from biology to clinical application. Cell Mol Life Sci. 2014 Nov 23. {{DOI|10.1007/s00018-014-1787-9}} PMID 25417212</ref>
 ===Cortex===
-Around 26% of MS lesions appear inside or adjacent to the cortex.<ref name="D.Kidd">D. Kidd, F. Barkhof, R. McConnell, P. R. Algra, I. V. Allen, T. Revesz. Cortical lesions in multiple sclerosis. January 1999. DOI: http://dx.doi.org/10.1093/brain/122.1.17 17-26</ref> It seems that in RRMS patients, both deep and cortical GM atrophy are associated with pathology in connected white matter.<ref>Steenwijk MD et al. Unraveling the relationship between regional gray matter atrophy and pathology in connected white matter tracts in long-standing multiple sclerosis. Hum Brain Mapp. 2015 Jan 27. doi: 10.1002/hbm.22738</ref> Cortical lesions are inflammatory (immune mediated) and can present relapses<ref>Puthenparampil M et al. Cortical relapses in multiple sclerosis. Mult Scler. 2015 Mar 19. pii: 1352458514564483 PMID     25791367</ref>
+Around 26% of MS lesions appear inside or adjacent to the cortex.<ref name="D.Kidd">D. Kidd, F. Barkhof, R. McConnell, P. R. Algra, I. V. Allen, T. Revesz. Cortical lesions in multiple sclerosis. January 1999. DOI:10.1093/brain/122.1.17 17-26</ref> It seems that in RRMS patients, both deep and cortical GM atrophy are associated with pathology in connected white matter.<ref>Steenwijk MD et al. Unraveling the relationship between regional gray matter atrophy and pathology in connected white matter tracts in long-standing multiple sclerosis. Hum Brain Mapp. 2015 Jan 27. {{DOI|10.1002/hbm.22738}}</ref> Cortical lesions are inflammatory (immune mediated) and can present relapses<ref>Puthenparampil M et al. Cortical relapses in multiple sclerosis. Mult Scler. 2015 Mar 19. pii: 1352458514564483 {{DOI|10.1177/1352458514564483}} PMID     25791367</ref>
 Cortex lesions are disposed around the principal cortical veins and the majority enter the terrain of the white matter, and have been classified into seven types<ref name="D.Kidd"/>
-Some research groups have proposed that cortical lesions are the origin of the NAWM areas in the white matter<ref>Niraj Mistry, Rasha Abdel-Fahim, Penny Gowland, A CORTICOCENTRIC MODEL FOR MS PATHOGENESIS, J Neurol Neurosurg Psychiatry 2014;85:e4 doi:10.1136/jnnp-2014-309236.135</ref> and 7 Tesla scanners seem to confirm this hypothesis, showing that cortical pathology starts in the [[Cerebral cortex#Layered structure|pial surface]] (external layer of the brain), which is in contact with the CSF, and extends later into the brain inner layers<ref>Mainero C et al. A gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging. Brain. 2015 Feb 12. PMID 25681411</ref>
+Some research groups have proposed that cortical lesions are the origin of the NAWM areas in the white matter<ref>Niraj Mistry, Rasha Abdel-Fahim, Penny Gowland, A CORTICOCENTRIC MODEL FOR MS PATHOGENESIS, J Neurol Neurosurg Psychiatry 2014;85:e4 {{DOI|10.1136/jnnp-2014-309236.135}}</ref> and 7 Tesla scanners seem to confirm this hypothesis, showing that cortical pathology starts in the [[Cerebral cortex#Layered structure|pial surface]] (external layer of the brain), which is in contact with the CSF, and extends later into the brain inner layers<ref>Mainero C et al. A gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging. Brain. 2015 Feb 12. {{DOI|10.1093/brain/awv011}} PMID 25681411</ref>
-Lesions in the cortex have been classified by the area they affect into four groups:  type I (leukocortical), type II (intracortical), type III (subpial), and type IV (subpial extending through the whole cortical width but not to subcortical WM). This classification is not related to the white matter lesions classification.<ref>C. Mainero et al. Contribution of subpial pathology to cortical thinning in multiple sclerosis: a combined 7T - 3T MRI study, Proc. Intl. Soc. Mag. Reson. Med. 18 (2010)</ref><ref>Klaver R. et al. Neuronal and Axonal Loss in Normal-Appearing Gray Matter and Subpial Lesions in Multiple Sclerosis. J Neuropathol Exp Neurol. 2015 Apr 7. PMID 25853695</ref>
+Lesions in the cortex have been classified by the area they affect into four groups:  type I (leukocortical), type II (intracortical), type III (subpial), and type IV (subpial extending through the whole cortical width but not to subcortical WM). This classification is not related to the white matter lesions classification.<ref>C. Mainero et al. Contribution of subpial pathology to cortical thinning in multiple sclerosis: a combined 7T - 3T MRI study, Proc. Intl. Soc. Mag. Reson. Med. 18 (2010)</ref><ref>Klaver R. et al. Neuronal and Axonal Loss in Normal-Appearing Gray Matter and Subpial Lesions in Multiple Sclerosis. J Neuropathol Exp Neurol. 2015 Apr 7. {{DOI|10.1097/NEN.0000000000000189}} PMID 25853695</ref>
 ===Olfactory bulb===
@@ Line 119: / Line 119: @@
 }}</ref>
-Lesions evolve from the Normal Appearing White Matter. In MTR-MRI, the apparent diffusion coefficient (ADCav) is a measure of water molecule motion. It can be seen that before the BBB breakdown, this coeficient increases until, at some point, the blood-brain barrier breaks down and immune cells enter the brain producing the lesion.<ref name="Werring">D. J. Werring, The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosisA serial diffusion MRI study, Brain, 2000, DOI:10.1093/brain/123.8.1667</ref>
+Lesions evolve from the Normal Appearing White Matter. In MTR-MRI, the apparent diffusion coefficient (ADCav) is a measure of water molecule motion. It can be seen that before the BBB breakdown, this coeficient increases until, at some point, the blood-brain barrier breaks down and immune cells enter the brain producing the lesion.<ref name="Werring">D. J. Werring, The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosisA serial diffusion MRI study, Brain, 2000, {{DOI|10.1093/brain/123.8.1667}}</ref>
 According with the most recent research, an active lesion is composed of different layers:<ref>{{cite journal | pmid = 20035511  |name-list-format=vanc | last1 = Henderson | first1 = AP| doi=10.1002/ana.21800 | last2 = Barnett | first2 = MH | last3 = Parratt | first3 = JD | last4 = Prineas | first4 = JW | title = Multiple sclerosis: distribution of inflammatory cells in newly forming lesions | journal = Annals of Neurology | volume=66 | issue=6 |date=December 2009 | pages=739–53}}</ref>
@@ Line 139: / Line 139: @@
 The '''lesion evolution under MRI''' has been reported to begin as a pattern of central hyperintensity. This was seen in the majority of new lesions, both on proton density and contrast-enhanced T1-weighted images.<ref>Charles R. G. Guttmann, Sungkee S. Ahn, Liangge Hsu, Ron Kikinis, and Ferenc A. Jolesz, The Evolution of Multiple Sclerosis Lesions on Serial MR, AJNR Am J Neuroradiol 16:1481–1491, August 1995</ref> When gadolinium is used, the lesion expansion can be classified as nodular or ringlike<ref>María I Gaitán et al. Evolution of the Blood-Brain Barrier in Newly Forming Multiple Sclerosis Lesions, Ann Neurol. 2011 July; 70(1): 22–29.</ref>
-Whatever the demyelination process is, currently it is possible to detect lesions before demyelination, and they show clusters of activated microglia and leukocyte infiltration, together with oligodendrocytes abnormalities.<ref name=vanderValk09/> Some research groups consider some areas of the NAWM with clusters of microglial nodules as "preactive MS lesions".<ref name=Bsibsi>Bsibsi M, Holtman IR, Gerritsen WH, Eggen BJ, Boddeke E, van der Valk P, van Noort JM, Amor S. Alpha-B-Crystallin Induces an Immune-Regulatory and Antiviral Microglial Response in Preactive Multiple Sclerosis Lesions, J Neuropathol Exp Neurol. 2013 Sep 13, PMID 24042199</ref>
+Whatever the demyelination process is, currently it is possible to detect lesions before demyelination, and they show clusters of activated microglia and leukocyte infiltration, together with oligodendrocytes abnormalities.<ref name=vanderValk09/> Some research groups consider some areas of the NAWM with clusters of microglial nodules as "preactive MS lesions".<ref name=Bsibsi>Bsibsi M, Holtman IR, Gerritsen WH, Eggen BJ, Boddeke E, van der Valk P, van Noort JM, Amor S. Alpha-B-Crystallin Induces an Immune-Regulatory and Antiviral Microglial Response in Preactive Multiple Sclerosis Lesions, J Neuropathol Exp Neurol. 2013 Sep 13, {{DOI|10.1097/NEN.0b013e3182a776bf}} PMID 24042199</ref>
 Lesion evolution can be followed via MRI<ref>Laura E. Jonkman et al. Can MS lesion stages be distinguished with MRI? A postmortem MRI and histopathology study, Journal of Neurology, Volume 262, Issue 4 , pp 1074-1080,  {{DOI|10.1007/s00415-015-7689-4}}</ref>
@@ Line 193: / Line 193: @@
 ===Normal appearing White Matter===
-The white matter with hidden but MRI-visible damage is known as "Normal-appearing white matter" (NAWM)<ref>Mangia S, Carpenter AF, Tyan AE, Eberly LE, Garwood M, Michaeli S. Magnetization transfer and adiabatic T1ρ MRI reveal abnormalities in normal-appearing white matter of subjects with multiple sclerosis, Mult Scler. 2013 Dec 12, PMID 24336350</ref> and is where lesions appear.<ref name="Goodkin DE, Rooney WD, Sloan R, et al. 1998 1689–97"/>
+The white matter with hidden but MRI-visible damage is known as "Normal-appearing white matter" (NAWM)<ref>Mangia S, Carpenter AF, Tyan AE, Eberly LE, Garwood M, Michaeli S. Magnetization transfer and adiabatic T1ρ MRI reveal abnormalities in normal-appearing white matter of subjects with multiple sclerosis, Mult Scler. 2013 Dec 12, {{DOI|10.1177/1352458513515084}} PMID 24336350</ref> and is where lesions appear.<ref name="Goodkin DE, Rooney WD, Sloan R, et al. 1998 1689–97"/>
 The pathology of the NAWM differs from areas near the lesions or near the cortex. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.<ref>{{cite journal | author = Moll N. M., Rietsch A. M., Thomas S., Ransohoff A. J., Lee J.-C., Fox R., Chang A., Ransohoff R. M., Fisher E. | year = 2011 | title = Multiple sclerosis normal-appearing white matter: Pathology–imaging correlations | url = | journal = Ann Neurol | volume = 70 | issue = 5| pages = 764–773 | doi = 10.1002/ana.22521 }}</ref>
@@ Line 259: / Line 259: @@
 According to one of the researchers involved in the original research "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."
-The four identified patterns are:<ref name=brainpat96>Lucchinetti CF1, Brück W, Rodriguez M, Lassmann H. Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis, Brain Pathol. 1996 Jul;6(3):259-74. PMID 8864283</ref>
+The four identified patterns are:<ref name=brainpat96>Lucchinetti CF1, Brück W, Rodriguez M, Lassmann H. "Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis, ''Brain Pathol.'' 1996 Jul;6(3):259-74. PMID 8864283</ref>
 ; Pattern I : The scar presents [[T-cells]] and [[macrophages]] around blood vessels, with preservation of [[oligodendrocyte]]s, but no signs of [[complement system]] activation.<ref>{{cite web| url=http://immserv1.path.cam.ac.uk/~immuno/part1/lec10/lec10_97.html| title=Part 1B Pathology: Lecture 11 - The Complement System| accessdate=2006-05-10| first=Nick| last=Holmes| date=15 November 2001}}</ref>
@@ Line 266: / Line 266: @@
 ; 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 type III to the others and this could be a marker of the disease evolution.<ref>{{cite journal |author=Michael H. Barnett, MBBS and John W. Prineas, MBBS |title=Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion |journal=Annals of Neurology |volume=55 |issue=1 |pages=458–468 |year=2004 |pmid=15048884 |doi=10.1002/ana.20016|url=http://www.cpnhelp.org/files/Ref1_Annals04.pdf}}</ref> Anyway, the heterogeneity could be true only for the early stage of the disease.<ref>{{cite journal |author=Breij EC, Brink BP, Veerhuis R |title=Homogeneity of active demyelinating lesions in established multiple sclerosis |journal=Annals of Neurology |volume=63 |issue=1 |pages=16–25 |year=2008 |pmid=18232012 |doi=10.1002/ana.21311|author2=and others |displayauthors=1 }}</ref> Some lesions present [[Mitochondrion|mitochondrial]] defects that could distinguish types of lesions.<ref>{{cite journal |author=Mahad D, Ziabreva I, Lassmann H, Turnbull D. |title=Mitochondrial defects in acute multiple sclerosis lesions |journal= Brain : a journal of neurology|volume= 131|issue= Pt 7|pages= 1722–35|year=2008 |pmid=18515320 |doi=10.1093/brain/awn105 |pmc=2442422|last2=Ziabreva |last3=Lassmann |last4=Turnbull }}</ref> Currently antibodies to [[lipids]] and [[peptides]] in sera, detected by [[microarrays]], can be used as markers of the pathological subtype given by brain biopsy.<ref name=Quintana08>{{cite journal |author=Quintana FJ, Farez MF, Viglietta V |title=Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=105 |issue=48 |pages=18889–94 |date=December 2008 |pmid=19028871 |pmc=2596207 |doi=10.1073/pnas.0806310105 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=19028871|author2=and others |displayauthors=1 |bibcode=2008PNAS..10518889Q |last3=Viglietta |last4=Iglesias |last5=Merbl |last6=Izquierdo |last7=Lucas |last8=Basso |last9=Khoury |last10=Lucchinetti |last11=Cohen |last12=Weiner }}</ref> Nevertheless, after some debate among research groups, it seems like the four patterns model is accepted<ref>Brück W, Popescu B, Lucchinetti CF, Markovic-Plese S, Gold R, Thal DR, Metz I. Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate, Ann Neurol. 2012 Sep;72(3) 385-94. {{DOI|10.1002/ana.23621}}</ref><ref>Arnold P, Mojumder D, Detoledo J, Lucius R, Wilms H Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid-2-related factor 2 and emerging pathways, Clin Pharmacol. 2014 Feb 24;6:35-42. eCollection 2014. PMID 24591852</ref>
+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 type III to the others and this could be a marker of the disease evolution.<ref>{{cite journal |author=Michael H. Barnett, MBBS and John W. Prineas, MBBS |title=Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion |journal=Annals of Neurology |volume=55 |issue=1 |pages=458–468 |year=2004 |pmid=15048884 |doi=10.1002/ana.20016|url=http://www.cpnhelp.org/files/Ref1_Annals04.pdf}}</ref> Anyway, the heterogeneity could be true only for the early stage of the disease.<ref>{{cite journal |author=Breij EC, Brink BP, Veerhuis R |title=Homogeneity of active demyelinating lesions in established multiple sclerosis |journal=Annals of Neurology |volume=63 |issue=1 |pages=16–25 |year=2008 |pmid=18232012 |doi=10.1002/ana.21311|author2=and others |displayauthors=1 }}</ref> Some lesions present [[Mitochondrion|mitochondrial]] defects that could distinguish types of lesions.<ref>{{cite journal |author=Mahad D, Ziabreva I, Lassmann H, Turnbull D. |title=Mitochondrial defects in acute multiple sclerosis lesions |journal= Brain : a journal of neurology|volume= 131|issue= Pt 7|pages= 1722–35|year=2008 |pmid=18515320 |doi=10.1093/brain/awn105 |pmc=2442422|last2=Ziabreva |last3=Lassmann |last4=Turnbull }}</ref> Currently antibodies to [[lipids]] and [[peptides]] in sera, detected by [[microarrays]], can be used as markers of the pathological subtype given by brain biopsy.<ref name=Quintana08>{{cite journal |author=Quintana FJ, Farez MF, Viglietta V |title=Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=105 |issue=48 |pages=18889–94 |date=December 2008 |pmid=19028871 |pmc=2596207 |doi=10.1073/pnas.0806310105 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=19028871|author2=and others |displayauthors=1 |bibcode=2008PNAS..10518889Q |last3=Viglietta |last4=Iglesias |last5=Merbl |last6=Izquierdo |last7=Lucas |last8=Basso |last9=Khoury |last10=Lucchinetti |last11=Cohen |last12=Weiner }}</ref> Nevertheless, after some debate among research groups, it seems like the four patterns model is accepted<ref>Brück W, Popescu B, Lucchinetti CF, Markovic-Plese S, Gold R, Thal DR, Metz I. Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate, Ann Neurol. 2012 Sep;72(3) 385-94. {{DOI|10.1002/ana.23621}}</ref><ref>Arnold P, Mojumder D, Detoledo J, Lucius R, Wilms H Pathophysiological processes in multiple sclerosis: focus on nuclear factor erythroid-2-related factor 2 and emerging pathways, Clin Pharmacol. 2014 Feb 24;6:35-42. eCollection 2014. {{DOI|10.2147/CPAA.S35033}} PMID 24591852</ref>
 ===MRI Phenotypes===
@@ Line 302: / Line 302: @@
 |last3=Maddah
 |last4=Warfield
-}}</ref> and VCAM-1 enhanced MRI<ref>[http://www.admin.ox.ac.uk/po/news/2006-07/sep/24.shtml New imaging technique allows doctors to ‘see’ molecular activity]</ref> have been reported to show the pathological differences of these patterns. Together with MRI, [[magnetic resonance spectroscopy]] allows to see the [[biochemical]] composition of the lesions, which shows at least two different patterns<ref>West J1, Aalto A2, Tisell A1, Leinhard OD1, Landtblom AM3, Smedby O4, Lundberg P5. Normal Appearing and Diffusely Abnormal White Matter in Patients with Multiple Sclerosis Assessed with Quantitative MR. PMID 24747946</ref>
+}}</ref> and VCAM-1 enhanced MRI<ref>[http://www.admin.ox.ac.uk/po/news/2006-07/sep/24.shtml New imaging technique allows doctors to ‘see’ molecular activity]</ref> have been reported to show the pathological differences of these patterns. Together with MRI, [[magnetic resonance spectroscopy]] allows to see the [[biochemical]] composition of the lesions, which shows at least two different patterns<ref>West J1, Aalto A2, Tisell A1, Leinhard OD1, Landtblom AM3, Smedby O4, Lundberg P5. Normal Appearing and Diffusely Abnormal White Matter in Patients with Multiple Sclerosis Assessed with Quantitative MR. {{DOI|10.1371/journal.pone.0095161}} PMID 24747946</ref>
 Currently as of 2014, the MRI studies have led to the proposal of four MRI phenotypes,<ref>Shahamat Tauhid, Mohit Neema, Brian C. Healy, Howard L. Weiner, Rohit Bakshi, MRI phenotypes based on cerebral lesions and atrophy in patients with multiple sclerosis, Journal of neurological sciences, {{DOI|10.1016/j.jns.2014.08.047}}</ref> though both the classification and the relationship with the pathology remains controversial.
@@ Line 327: / Line 327: @@
 }}</ref> found correlation with CSF and progression in November 2001, and hypotheses have been made suggesting correlation between CSF findings and pathophysiological patterns.<ref>{{cite journal |author=Cepok S, Jacobsen M, Schock S |title=Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis |journal=Brain |volume=124 |issue=Pt 11 |pages=2169–76 |date=November 2001 |pmid=11673319 |url=http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=11673319 |doi=10.1093/brain/124.11.2169|author2=and others |displayauthors=1 }}</ref> In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found,<ref>{{cite journal |author=Pittock SJ, Reindl M, Achenbach S |title=Myelin oligodendrocyte glycoprotein antibodies in pathologically proven multiple sclerosis: frequency, stability and clinicopathologic correlations |journal=Multiple Sclerosis |volume=13 |issue=1 |pages=7–16 |date=January 2007 |pmid=17294606 |url=http://msj.sagepub.com/cgi/pmidlookup?view=long&pmid=17294606 |doi=10.1177/1352458506072189|author2=and others |displayauthors=1 }}</ref> though this is disputed.<ref>{{cite journal |author=Belogurov AA, Kurkova IN, Friboulet A |title=Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis |journal=Journal of Immunology |volume=180 |issue=2 |pages=1258–67 |date=January 2008 |pmid=18178866 |url=http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=18178866 |doi=10.4049/jimmunol.180.2.1258|author2=and others |displayauthors=1 }}</ref> High levels of [[Anti-nuclear antibody|anti-nuclear antibodies]] are found normally in patients with MS{{Citation needed|date=April 2012}}. Antibodies against [[Neurofascin]]–186 could be involved in a subtype of MS<ref>[http://www.mssociety.org.uk/news_events/news/research/linington_resear.html Early research into a treatment for progressive MS]</ref> Recently, it has been shown that the CSF from PPMS patients can transport the disease<ref name="Cristofanilli"/>
-*'''With responses to therapy:''' It is known that 30% of MS patients are non-responsive to Beta interferon.<ref>{{cite journal |author=Fernández O, Fernández V, Mayorga C |title=HLA class II and response to interferon-beta in multiple sclerosis |journal=Acta Neurol Scand. |volume=112 |issue=6 |pages=391–4 |date=December 2005 |pmid=16281922 |doi=10.1111/j.1600-0404.2005.00415.x |author2=and others |displayauthors=1 }}</ref> The heterogeneous response to therapy can support the idea of hetherogeneous [[etiology (medicine)|aetiology]]. It has also been shown that IFN receptors and [[interleukin]]s in blood serum predicts response to IFN therapy,<ref>{{cite journal |author=van Baarsen LG, Vosslamber S, Tijssen M |title=Pharmacogenomics of Interferon-β Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients |journal=PLoS ONE |volume=3 |issue=4 |pages=e1927 |year=2008 |pmid=18382694 |pmc=2271130 |doi=10.1371/journal.pone.0001927 |author7=van der Pouw Kraan TC |editor1-last=Lassmann |editor1-first=Hans |author2=and others |displayauthors=1 |bibcode=2008PLoSO...3.1927V |last3=Tijssen |last4=Baggen |last5=Van Der Voort |last6=Killestein |last8=Polman |last9=Verweij }} {{open access}}</ref><ref>{{cite journal |author=Wiesemann E, Deb M, Hemmer B, Radeke HH, Windhagen A. |title=Early identification of interferon-beta responders by ex vivo testing in patients with multiple sclerosis |journal= Clinical immunology (Orlando, Fla.)|volume= 128|issue= 3|pages= 306–13|year=2008 |pmid=18539537 |doi= 10.1016/j.clim.2008.04.007|url=|last2=Deb |last3=Hemmer |last4=Radeke |last5=Windhagen }}</ref> specially IL-17,<ref>Axtell RC et a. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis, PMID 20348925</ref> and interleukins IL12/IL10 ratio has been proposed as marker of clinical course.<ref>{{cite journal |author=Carrieri PB, Ladogana P, Di Spigna G |title=Interleukin-10 and interleukin-12 modulation in patients with relapsing-remitting multiple sclerosis on therapy with interferon-beta 1a: differences in responders and non responders |journal=Immunopharmacol Immunotoxicol. |volume=30 |issue=4 |pages=1–9 |year=2008 |pmid=18686100 |doi=10.1080/08923970802302753 |url=|author2=and others |displayauthors=1 }}</ref> Besides:
+*'''With responses to therapy:''' It is known that 30% of MS patients are non-responsive to Beta interferon.<ref>{{cite journal |author=Fernández O, Fernández V, Mayorga C |title=HLA class II and response to interferon-beta in multiple sclerosis |journal=Acta Neurol Scand. |volume=112 |issue=6 |pages=391–4 |date=December 2005 |pmid=16281922 |doi=10.1111/j.1600-0404.2005.00415.x |author2=and others |displayauthors=1 }}</ref> The heterogeneous response to therapy can support the idea of hetherogeneous [[etiology (medicine)|aetiology]]. It has also been shown that IFN receptors and [[interleukin]]s in blood serum predicts response to IFN therapy,<ref>{{cite journal |author=van Baarsen LG, Vosslamber S, Tijssen M |title=Pharmacogenomics of Interferon-β Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients |journal=PLoS ONE |volume=3 |issue=4 |pages=e1927 |year=2008 |pmid=18382694 |pmc=2271130 |doi=10.1371/journal.pone.0001927 |author7=van der Pouw Kraan TC |editor1-last=Lassmann |editor1-first=Hans |author2=and others |displayauthors=1 |bibcode=2008PLoSO...3.1927V |last3=Tijssen |last4=Baggen |last5=Van Der Voort |last6=Killestein |last8=Polman |last9=Verweij }} {{open access}}</ref><ref>{{cite journal |author=Wiesemann E, Deb M, Hemmer B, Radeke HH, Windhagen A. |title=Early identification of interferon-beta responders by ex vivo testing in patients with multiple sclerosis |journal= Clinical immunology (Orlando, Fla.)|volume= 128|issue= 3|pages= 306–13|year=2008 |pmid=18539537 |doi= 10.1016/j.clim.2008.04.007|url=|last2=Deb |last3=Hemmer |last4=Radeke |last5=Windhagen }}</ref> specially IL-17,<ref>Axtell RC et a. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis, {{DOI|10.1038/nm.2110}} PMID 20348925</ref> and interleukins IL12/IL10 ratio has been proposed as marker of clinical course.<ref>{{cite journal |author=Carrieri PB, Ladogana P, Di Spigna G |title=Interleukin-10 and interleukin-12 modulation in patients with relapsing-remitting multiple sclerosis on therapy with interferon-beta 1a: differences in responders and non responders |journal=Immunopharmacol Immunotoxicol. |volume=30 |issue=4 |pages=1–9 |year=2008 |pmid=18686100 |doi=10.1080/08923970802302753 |url=|author2=and others |displayauthors=1 }}</ref> Besides:
 ** Pattern II lesions patients are responsive to [[plasmapheresis]], while others are not.<ref name="Wilner AN, Goodman"/><ref>[http://www.medicalnewstoday.com/medicalnews.php?newsid=29100 Patients' Multiple Sclerosis Lesion Type Dictates Effective Treatment]</ref>
 ** The subtype associated with macrophage activation, T cell infiltration and expression of inflammatory mediator molecules may be most likely responsive to immunomodulation with interferon-beta or glatiramer acetate.<ref name=pmid12027786>{{cite journal
@@ Line 365: / Line 365: @@
 ==Primary progressive MS==
-It is currently discussed whether Primary Progressive MS (PPMS) is a different pathological entity or a different degree of the same pathology. No agreement has been established but there are some pathological features that are specific to PPMS. For example, meningeal inflammation is different respect standard cases of Recurrent-Recidivant MS (RRMS)<ref>Choi SR, Howell OW, Carassiti D, Magliozzi R, Gveric D, Muraro PA, Nicholas R, Roncaroli F, Reynolds R., Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis, PMID 22907116</ref> and sodium accumulation is higher.<ref>Paling D, Solanky BS, Riemer F, Tozer DJ, Wheeler-Kingshott CA, Kapoor R, Golay X, Miller DH., Sodium accumulation is associated with disability and a progressive course in multiple sclerosis PMID 23801742</ref> Diffusely Abnormal White Matter (DAWM) is different than in RRMS/SPMS patients<ref>H. Vrenken et al, Diffusely Abnormal White Matter in Progressive Multiple Sclerosis: In Vivo Quantitative MR Imaging Characterization and Comparison between Disease Types, American Society of Neuroradiology, October 22, 2009, doi: 10.3174/ajnr.A1839 AJNR 2010 31: 541-548</ref> and it has been shown that CSF from PPMS patients can transport the disease<ref name="Cristofanilli"/>
+It is currently discussed whether Primary Progressive MS (PPMS) is a different pathological entity or a different degree of the same pathology. No agreement has been established but there are some pathological features that are specific to PPMS. For example, meningeal inflammation is different respect standard cases of Recurrent-Recidivant MS (RRMS)<ref>Choi SR, Howell OW, Carassiti D, Magliozzi R, Gveric D, Muraro PA, Nicholas R, Roncaroli F, Reynolds R., Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis, {{DOI|10.1093/brain/aws189}} PMID 22907116</ref> and sodium accumulation is higher.<ref>Paling D, Solanky BS, Riemer F, Tozer DJ, Wheeler-Kingshott CA, Kapoor R, Golay X, Miller DH., Sodium accumulation is associated with disability and a progressive course in multiple sclerosis {{DOI|10.1093/brain/awt149}} PMID 23801742</ref> Diffusely Abnormal White Matter (DAWM) is different than in RRMS/SPMS patients<ref>H. Vrenken et al, Diffusely Abnormal White Matter in Progressive Multiple Sclerosis: In Vivo Quantitative MR Imaging Characterization and Comparison between Disease Types, American Society of Neuroradiology, October 22, 2009, doi: 10.3174/ajnr.A1839 AJNR 2010 31: 541-548</ref> and it has been shown that CSF from PPMS patients can transport the disease<ref name="Cristofanilli"/>
-From a pathological point of view, PPMS characteristics are slow expansion of pre-existing white matter lesions, massive cortical demyelination, and extensive diffuse injury of the normal appearing white matter. As in relapsing MS also in progressive MS active tissue injury is invariably associated with inflammation, but inflammation seems to be trapped behind a closed blood brain barrier<ref>Lassmann H. Clinical and pathological topics of multiple sclerosis. Rinsho Shinkeigaku. 2009 Nov;49(11):715-8. PMID 20030193</ref>
+From a pathological point of view, PPMS characteristics are slow expansion of pre-existing white matter lesions, massive cortical demyelination, and extensive diffuse injury of the normal appearing white matter. As in relapsing MS also in progressive MS active tissue injury is invariably associated with inflammation, but inflammation seems to be trapped behind a closed blood brain barrier<ref>Lassmann H. "Clinical and pathological topics of multiple sclerosis. ''Rinsho Shinkeigaku.'' 2009 Nov;49(11):715-8. PMID 20030193</ref>
 ==Pathology of early MS and silent MS==
@@ Line 373: / Line 373: @@
 Current [[McDonald criteria]] usually do not allow to establish a diagnosis for definite MS before two clinical attacks have appeared. This means that for clinical definite cases, MS condition has been present for a long time, difficulting the study of the initial stages.<ref>{{cite journal |author=Frisullo G, Nociti V, Iorio R |title=The persistency of high levels of pSTAT3 expression in circulating CD4+ T cells from CIS patients favors the early conversion to clinically defined multiple sclerosis |journal=J Neuroimmunol. |volume=205 |issue=1–2 |pages=126–34 |date=December 2008|pmid=18926576 |doi=10.1016/j.jneuroim.2008.09.003 |author2=and others |displayauthors=1 }}</ref> To study the initial stages of MS, a pathological definition of MS must be used instead of the clinical ones.<ref name="brain.oxfordjournals.org">{{cite journal | doi = 10.1093/brain/awp342 | title = Acute disseminated encephalomyelitis and multiple sclerosis | year = 2010 | author = Lassmann H | journal = Brain | volume = 133 | issue = 2 | pages = 317–319 }}</ref>
-Sometimes patients with their first isolated attack (Clinically Isolated syndrome, or CIS) but before the confirming second attack ('''Preclinical MS''') can  be accepted to study the initial MS pathology<ref>{{cite journal |author=Lebrun C, Bensa C, Debouverie M |title=Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile |journal=J Neurol Neurosurg Psychiatry |volume=79 |issue=2 |pages=195–198 |year=2008 |pmid=18202208 |doi=10.1136/jnnp.2006.108274|author2=and others |displayauthors=1 }}</ref> but there is a study suggesting that any MS case begins as a silent pathology that can remain unnoticed even for five years.<ref>Nakamura M, Morris M, Cerghet M, Schultz L, Elias S. "Longitudinal Follow-up of a Cohort of Patients with Incidental Abnormal Magnetic Resonance Imaging Findings at Presentation and Their Risk of Developing Multiple Sclerosis, ''Int J MS Care.'' 2014 Fall;16(3):111-5. doi: 10.7224/1537-2073.2013-016. PMID 25337052</ref> Therefore, even the CIS can appear too late in MS evolution.
+Sometimes patients with their first isolated attack (Clinically Isolated syndrome, or CIS) but before the confirming second attack ('''Preclinical MS''') can  be accepted to study the initial MS pathology<ref>{{cite journal |author=Lebrun C, Bensa C, Debouverie M |title=Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile |journal=J Neurol Neurosurg Psychiatry |volume=79 |issue=2 |pages=195–198 |year=2008 |pmid=18202208 |doi=10.1136/jnnp.2006.108274|author2=and others |displayauthors=1 }}</ref> but there is a study suggesting that any MS case begins as a silent pathology that can remain unnoticed even for five years.<ref>{{cite journal | author = Nakamura M, Morris M, Cerghet M, Schultz L, Elias S | date = Fall 2014 | title = Longitudinal Follow-up of a Cohort of Patients with Incidental Abnormal Magnetic Resonance Imaging Findings at Presentation and Their Risk of Developing Multiple Sclerosis | url = | journal = Int J MS Care. | volume = 16 | issue = 3| pages = 111–5 | doi = 10.7224/1537-2073.2013-016 | pmid = 25337052 | pmc=4204370}}</ref> Therefore, even the CIS can appear too late in MS evolution.
 Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as '''subclinical MS'''.,<ref>{{cite journal |author=Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP. |title=Subclinical MS: follow-up of four cases |journal= European Journal of Neurology|volume= 15|issue= 8|pages= 858–61|year=2008 |pmid=18507677 |doi=10.1111/j.1468-1331.2008.02155.x|last2=Goretti |last3=Portaccio |last4=Zipoli |last5=Amato }}</ref> or sometimes '''Clinically silent MS'''.<ref>{{cite journal |author=Engell T |title=A clinical patho-anatomical study of clinically silent multiple sclerosis |journal=Acta Neurol. Scand. |volume=79 |issue=5 |pages=428–30 |date=May 1989 |pmid=2741673 |doi= 10.1111/j.1600-0404.1989.tb03811.x }}</ref> The previous reference states that clinically silent MS plaques were located in the periventricular areas. This reference also reports an estimate of the prevalence of silent MS as high as about 25%. Oligodendrocytes evolution is similar to normal MS clinical courses<ref>{{cite journal | pmid = 9599334 | volume=4 | issue=2 | title=Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions |date=April 1998 | author=Mews I, Bergmann M, Bunkowski S, Gullotta F, Brück W | journal=Mult. Scler. | pages=55–62 | doi=10.1177/135245859800400203| last2=Bergmann | last3=Bunkowski | last4=Gullotta | last5=Brück }}</ref>
-Sometimes patients that undergo a MRI examination for an unrelated cause can show lesions in their brains. These cases of isolated MRI findings have been recently baptised as RIS (Radiologically Isolated Syndrome) and are the most common inspections in which suggestions of silent MS have appeared.<ref>Siva A. Asymptomatic MS. Clin Neurol Neurosurg. 2013 Dec;115 Suppl 1:S1-5. doi: 10.1016/j.clineuro.2013.09.012. PMID 24321147</ref>
+Sometimes patients that undergo a MRI examination for an unrelated cause can show lesions in their brains. These cases of isolated MRI findings have been recently baptised as RIS (Radiologically Isolated Syndrome) and are the most common inspections in which suggestions of silent MS have appeared.<ref>Siva A. "Asymptomatic MS. ''Clin Neurol Neurosurg.'' 2013 Dec;115(Suppl 1):S1-5. doi: 10.1016/j.clineuro.2013.09.012. PMID 24321147</ref>
-In respect to the pathology of the RIS cases, we can point out that they show cortical lesions, mainly in patients with oligoclonal bands.<ref>Giorgio A et al. Cortical lesions in radiologically isolated syndrome. Neurology. 2011 Nov 22;77(21):1896-9. doi: 10.1212/WNL.0b013e318238ee9b. Epub 2011 Nov 9. PMID 22076541</ref> Macroscopic damage is similar to RRMS cases but milder.<ref>De Stefano N et al. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS One. 2011 Apr 29;6(4):e19452. doi: 10.1371/journal.pone.0019452. {{open access}}</ref> Cervical cord lesions are an important predictor of progression<ref>Granberg T et al. Radiologically isolated syndrome--incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult Scler. 2013 Mar;19(3):271-80. doi: 10.1177/1352458512451943. Epub 2012 Jul 3.</ref> and the quotient N-acetylaspartate to creatine suggest axonal damage<ref>Stromillo ML et al. Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. Neurology. 2013 Jun 4;80(23):2090-4. doi: 10.1212/WNL.0b013e318295d707. Epub 2013 May 1.</ref>
+In respect to the pathology of the RIS cases, we can point out that they show cortical lesions, mainly in patients with oligoclonal bands.<ref>Giorgio A et al. Cortical lesions in radiologically isolated syndrome. Neurology. 2011 Nov 22;77(21):1896-9. doi: 10.1212/WNL.0b013e318238ee9b. Epub 2011 Nov 9. PMID 22076541</ref> Macroscopic damage is similar to RRMS cases but milder.<ref>De Stefano N et al. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS One. 2011 Apr 29;6(4):e19452. doi: 10.1371/journal.pone.0019452. {{open access}}</ref> Cervical cord lesions are an important predictor of progression<ref>Granberg T et al. Radiologically isolated syndrome--incidental magnetic resonance imaging findings suggestive of multiple sclerosis, a systematic review. Mult Scler. 2013 Mar;19(3):271-80. doi: 10.1177/1352458512451943. Epub 2012 Jul 3.</ref> and the quotient N-acetylaspartate to creatine suggest axonal damage<ref>Stromillo ML et al. Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. ''Neurology.'' 2013 Jun;80(23):2090-4. doi: 10.1212/WNL.0b013e318295d707.</ref>
 ==See also==