Pathophysiology of multiple sclerosis

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Structure of a typical neuron
Myelin sheath of a healthy neuron
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Structure of a typical neuron
Myelin sheath of a healthy neuron

Multiple sclerosis is a condition where the CNS of a person present a special kind of distributed lesions (sclerosis) [1] whose pathophysiology is complex and still under investigation. It is considered a pathological entity by some authors[2] and a clinical entity by some others.[3]

The unknown underlying condition causes damage 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[4] and axon destruction.[5]

MS is mainly a white matter disease, and lesions appear mainly in a peri-ventricular distribution (lesions clustered around the ventricles of the brain), but apart from the usually known white matter demyelination, also the cortex and deep gray matter (GM) nuclei are affected, together with diffuse injury of the normal-appearing white matter.[6] MS is active even during remission periods.[7] GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS[8]

At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, intrathecal Ig production with oligoclonal bands, an environment fostering immune cell persistence, Follicle-like aggregates in the meninges and a disruption of the blood–brain barrier also outside of active lesions.[9] The scars that give the name to the condition are produced by the astrocyte cells healing old lesions.[10]

Demyelination process and specific areas of damage[edit]

Demyelinization by MS. The Klüver-Barrera colored tissue show a clear decoloration in the area of the lesion (Original scale 1:100)
Demyelinization by MS. The CD68 colored tissue shows several Macrophages in the area of the lesion. Original scale 1:100

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.[4]

According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17,[11] 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.[12] 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.[13][14][15][16][17][18][19][20][21][22][23]

Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS[24] and in the degeneration of the axons.[25] and the oligodendrocytes.[26]

The axons themselves can also be damaged by the attacks.[27] 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[28]

Brain lesions distribution[edit]

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.[29]

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.[30] Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical.[31] Others classify them as hippocampal, cortical, and WM lesions,[32] 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.[33] The distribution of the lesions could be linked to the clinical evolution[34]

Post-mortem autopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord.[35] 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[36] 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.[37] 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.[38]

Due to the distribution of the lesions, since 1916 they are also known as Dawson's fingers.[39] They appear around the brain blood vessels.

Spinal cord damage[edit]

Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability.[40] In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues.[41] It has been shown that Fractional anisotropy of cervical spinal cord is lower than normal, showing that there is damage hidden from normal MRI.[42]

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.[43]

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.[44]

Retina and optic nerve damage[edit]

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).[45] 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[46]

MS patients show axonal loss in the retina and optic nerve, which can be meassured by Optical coherence tomography[47] or by Scanning laser polarimetry.[48] This measure can be used to predict disease activity[49] and to establish a differential diagnosis from Neuromyelitis optica[50]

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.[51]

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.[52] Two eye problems, Uveitis and retinal phlebitis are manifestations of MS.[53]

Proposed procedures for the neurodegeneration are than Narrower arterioles and wider venules have been reported.[54] Also rigidity has been noticed[55]

Neural and axonal damage[edit]

The axons of the neurons are damaged probably by B-Cells,[25] though currently no relationship has been established with the relapses or the attacks.[27] It seems that this damage is a primary target of the immune system, i.e. not secondary damage after attacks against myelin,[56] though this has been disputed[57]

Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.[58]

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[59]

Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy.[60]

Peripheral nervous system involvement[edit]

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[61]

Lesion structure[edit]

Layers of a lesion

Multiple sclerosis is a condition defined by the presence of a special kind of lesions in the brain and spinal cord.[3] Therefore it is very important to establish what those "lesions typical of MS" are. They mainly consist in demyelination and scarring in the fatty myelin sheaths around the axons of the brain and spinal cord.[62] According with the most recent research, an active lesion is composed of different layers:[63]

Lesions under MRI[edit]

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.[64]

Small lesions are invisible under MRI. Therefore clinically assisted diagnostic criteria are still required for a more accurate MS diagnosis than MRI alone.[65]

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.[66] When gadolinium is used, the lesion expansion can be classified as nodular or ringlike[67]

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.[68] Some research groups consider some areas of the NAWM with clusters of microglial nodules as "preactive MS lesions".[69]

Blood–brain barrier disruption[edit]

The blood–brain barrier (BBB) is a protective barrier that denies the entrance of foreign material into the nervous system. BBB disruption is the moment in which penetration of the barrier by lymphocytes occur and has been considered one of the early problems in MS lesions.[70]

The BBB is composed of endothelial cells which line the blood vessel walls of the central nervous system. Compared to normal endothelial cells, the cells lining the BBB are connected by occludin and claudin which form tight junctions in order to create a barrier to keep out larger molecules such as proteins. In order to pass through, molecules must be taken in by transport proteins or an alteration in the BBB permeability must occur, such as interactions with associated adaptor proteins like ZO-1, ZO-2 and ZO-3.[71] The BBB is compromised due to active recruitment of lymphocytes and monocytes and their migration across the barrier. Release of chemokines allow for the activation of adhesion molecules on the lymphocytes and monocytes, resulting in an interaction with the endothelial cells of the BBB which then activate the expression of matrix metalloproteinases to degrade the barrier.[71] This results in disruption of the BBB, causing an increase in barrier permeability due to the degradation of tight junctions which maintain barrier integrity. Inducing the formation of tight junctions can restore BBB integrity and reduces its permeability, which can be used to reduce the damage caused by lymphocyte and monocyte migration across the barrier as restored integrity would restrict their movement.[72]

After barrier breakdown symptoms may appear, such as swelling. Activation of macrophages and lymphocytes and their migration across the barrier may result in direct attacks on myelin sheaths within the central nervous system, leading to the characteristic demyelination event observed in MS.[73] After demyelination has occurred, the degraded myelin sheath components, such as myelin basic proteins and Myelin oligodendrocyte glycoproteins, are then used as identifying factors to facilitate further immune activity upon myelin sheaths. Further activation of cytokines is also induced by macrophage and lymphocyte activity, promoting inflammatory activity as well continued activation of proteins such as matrix metalloproteinases, which have detrimental effect on BBB integrity.[74]

Recently it has been found that BBB damage happens even in non-enhancing lesions.[75] MS has an important vascular component.[76]

Postmortem BBB study[edit]

Postmortem studies of the BBB, specially the vascular endotelium, show immunological abnormalities. Microvessels in periplaque areas coexpressed HLA-DR and VCAM-1, some others HLA-DR and urokinase plasminogen activator receptor, and others HLA-DR and ICAM-1.[77]

In vivo BBB study[edit]

As lesions appear (using MRI) in "Normal-appearing white matter" (NAWM), the cause that finally triggers the BBB disruption is supposed to be there.[78] The damaged white matter is known as "Normal-appearing white matter" (NAWM) and is where lesions appear.[4] These lesions form in NAWM before blood–brain barrier breakdown.[79]

BBB can be broken centripetally or centrifugally, the first form being the most normal.[80] Several possible biochemical disrupters have been proposed. Some hypothesis about how the BBB is compromised revolve around the presence of different compounds in the blood that could interact with the vascular vessels only in the NAWM areas. The permeability of two cytokines, Interleukin 15 and LPS, could be involved in the BBB breakdown.[81] The BBB breakdown is responsible for monocyte infiltration and inflammation in the brain.[82] Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase[83]

Using iron nanoparticles, involvement of macrophages in the BBB breakdown can be detected.[84] A special role is played by Matrix metalloproteinases. These are a group of proteases that increase T-cells permeability of the blood–brain barrier, specially in the case of MMP-9,[74] and are supposed to be related to the mechanism of action of interferons.[85]

Whether BBB dysfunction is the cause or the consequence of MS[86] is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins.[87] Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins.[87] (Adhesion molecules could also play a role in inflammation[88]) In particular, one of these adhesion proteins involved is ALCAM (Activated Leukocyte Cell Adhesion Molecule, also called CD166), and is under study as therapeutic target.[89] Other protein also involved is CXCL12,[90] which is found also in brain biopsies of inflammatory elements,[91] and which could be related to the behavior of CXCL13 under methylprednisolone therapy.[92] Some molecular biochemical models for relapses have been proposed.[93]

Normally, gadolinium enhancement is used to show BBB disruption on MRIs.[94] Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions, and gray matter in SPMS. They persist in inactive lesions, particularly in PPMS.[95]

A deficiency of uric acid has been implicated in this process. Uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in MS by preventing the breakdown of the blood brain barrier through inactivation of peroxynitrite.[96] The low level of uric acid found in MS victims is manifestedly causative rather than a consequence of tissue damage in the white matter lesions,[97] but not in the grey matter lesions.[98] Besides, uric acid levels are lower during relapses.[99]

Damage before BBB disruption[edit]

Special MRI methods[edit]

Before BBB disruption, brain tissues present normal aspect under normal MRI (Normal appearing white matter, NAWM and normal appearing grey matter, NAGM), but 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.[100] It has been found that grey matter injury correlates with disability[101] and that there is high oxidative stress in lesions, even in the old ones.[102]

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.[103]

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.[104] Susceptibility weighted imaging (SWI-MRI) has shown iron (hemosiderin) deposition in lesions, and helps to detect otherwise invisible lesions.[105]

Abnormalities in the gray matter (Diffusion tensor MRI alterations) of the brain parenchyma are present early in the course of multiple sclerosis[106]

Normal appearing brain tissues[edit]

Using several texture analysis technologies, it is possible to classify white matter areas into three categories: normal, normal-appearing and lesions.[107] Currently, it is possible to detect lesions before they present demyelination, and they are called pre-active lesions.[68] A fourth area called DAWM (diffusely abnormal white matter) has recently been proposed[108] and can help to differentiate PPMS and SPMS.[109] Abundant extracellular myelin in the meninges of patients with multiple sclerosis has been found[110]

Brain tissues with MRI-hidden problems are usually named Normal Appearing. Exploring the normal-appearing corpus callosum has been found a possible primary hypoperfusion,[111][112] according with other findings in this same direction.[113][114][115][116][117][118] Also iron (in hemosiderin deposits and as well as in ferritin-like structures inside the macrophage) accumulation has been reported[119][120]

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.[121] The amount of interneuronal Parvalbumin is lower than normal in brain's motor cortex areas,[122] and oxidative injury of oligodendrocytes and neurons could be associated with active demyelination and axonal injury.[123]

NAWM in MS has been reported to be similar to NAWM in leukoaraiosis[124]

Non-lesional White Matter[edit]

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 stablish a difference, normal white matter is named Non-lesional white matter (NLWM)[125]

Normal appearing White Matter[edit]

The white matter with hidden but MRI-visible damage is known as "Normal-appearing white matter" (NAWM)[126] and is where lesions appear.[4] It has been shown that a steady and moderate increase of apparent diffusion coefficient (ADC) can precede the development of new plaques and be followed by a rapid and marked increase at the time of Gadolinium enhancement and a slower decay after the cessation of enhancement.[127]

BBB disruption takes place on NAWM areas.[78] 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.[68][69]

Oligodendrocyte abnormalities appear to be crucially involved.[79][128] 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.[129]

Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls.[130]

Citrullination appears in SPMS.[131] It seems that a defect of sphingolipid metabolism modifies the properties of normal appearing white matter.[132] Related to these, peptidylarginine deiminase 2 is increased in patients with MS, and is related to arginine de-imination.[133]

NAWM shows a decreased perfusion which does not appear to be secondary to axonal loss.[116] 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.[134] This would be consistent again with cases of Chronic cerebrospinal venous insufficiency.

White matter lesions appear in NAWM areas,[4] and their behavior can be predicted by MRI parameters as MTR (magnetization transfer ratio).[135][136] This MTR parameter is related to axonal density.[137]

It also seems that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at Thr97 than normal individuals.[138]

Gray matter damage. Normal Appearing Gray Matter[edit]

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.[139] Epstein-Barr virus could be involved,[140] but is not likely.[141] 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.[142]

Iron depositions appear in deep gray matter by magnetic field correlation MRI[143]

Diffusely abnormal white matter[edit]

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.[144] 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.[145] Changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI[146]

Dirty appearing white matter[edit]

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.[147] It is probably created by loss of myelin phospholipids, detected by the short T2 component, and axonal reduction.

Microglial nodules[edit]

Originally proposed as a biomarker,[148] 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 [149]

Origin of the normal-appearing tissues[edit]

The cause why the normal appearing areas appear in the brain is unknown. Historically, several theories about how this happens has been presented.

Old blood flow theories[edit]

Venous pathology has been associated with MS for more than a century. Pathologist Georg Eduard Rindfleisch noted in 1863 that the inflammation-associated lesions were distributed around veins.[150] Some other authors like Tracy Putnam[151] pointed to venous obstructions.

Some authors like Franz Schelling proposed a mechanical damage procedure based on violent blood reflux.[152] Later the focus moved to softer hemodynamic abnormalities, which were showing precede changes in sub-cortical gray matter[115] and in substantia nigra.[153] However, such reports of a "hemodynamic cause of MS" are not universal, and possibly not even common. At this time the evidence is largely anecdotal and some MS patients have no blood flow issues. Possibly vascular problems may be an aggravating factor, like many others in MS. Indeed the research, by demonstrating patients with no hemodynamic problems actually prove that this is not the only cause of MS.

Endothelium theories[edit]

Other theories point to a possible primary endothelial dysfunction.[154] The importance of vascular misbehaviour in MS pathogenesis has also been independently confirmed by seven-tesla MRI.[155] It is reported that a number of studies have provided evidence of vascular occlusion in MS, which suggest the possibility of a primary vascular injury in MS lesions or at least that they are occasionally correlated.[156]

Some morphologically special medullar lesions (wedge-shaped) have also been linked to venous insufficiency.[157]

It has also been pointed out that some infectious agents with positive correlation to MS, specially Chlamydia pneumoniae, can cause problems in veins and arteries walls[158]


The term "chronic cerebrospinal venous insufficiency" was coined in 2008 by Paolo Zamboni, who described it in patients with multiple sclerosis. Instead of intracranial venous problems he described extracranial blockages, and he stated that the location of those obstructions seemed to influence the clinical course of the disease.[159] According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis.[160] Zamboni's results were criticized as some of his studies were not blinded and they need to be verified by further studies.[159][160] As of 2010 the theory is considered at least defensible[161]

A more detailed evidence of a correlation between the place and type of venous malformations imaged and the reported symptoms of multiple sclerosis in the same patients was published in 2010.[162]

Haemodynamic problems have been found in the blood flow of MS patients using Doppler,[163] initially using transcranial color-coded duplex sonography (TCCS), pointing to a relationship with a vascular disease called chronic cerebro-spinal venous insufficiency (CCSVI).[164][165] In 2010 there were conflicting results when evaluating the relationship between MS and CCSVI.[166][167][168][169] but is important to note that positives have appeared among the blinded studies.

CSF flow theories[edit]

Other theories focus in the possible role of cerebrospinal fluid flow impairment.[170] This theory could be partially consistent with the previous one[171]

Currently a small trial with 8 participants has been performed[172]

CSF composition and Kir4.1[edit]

It has been reported several times that CSF of some MS patients can damage myelin in culture[173][174][175][176][177] and mice[178]

In 2012 was reported that a subset of MS patients have a seropositive anti-Kir4.1 status,[179] which can represent up to a 47% of the MS cases, and the study has been reproduced by at least other group.[180]

If the existence of this subset of MS is confirmed the situation will be similar to what it happened for Devic Disease and Aquaporine-4. MS could be considered a heterogeneous condition or a new medical entity will be defined for these cases.

MS biomarkers[edit]

Diagnosis of MS has always been made by clinical examination, supported by MRI or CSF tests. According with both the pure autoimmune hypothesis and the immune-mediated hypothesis,[181] researchers expect to find biomarkers able to yield a better diagnosis, and able to predict the response to the different available treatments.[182] As of 2014 no biomarker with perfect correlation has been found,[183] but some of them have shown a special behavior like an autoantibody against the potassium channel Kir4.1.[184] Biomarkers are expected to play an important role in the near future[185]

Molecular biomarkers in blood[edit]

Blood serum of MS patients shows abnormalities. Endothelin-1 shows maybe the most striking discordance between patients and controls, being a 224% higher in patients than controls.[186]

Creatine and Uric acid levels are lower than normal, at least in women.[187] Ex vivo CD4(+) T cells isolated from the circulation show a wrong TIM-3 (Immunoregulation) behavior,[188] and relapses are associated with CD8(+) T Cells.[189] There is a set of differentially expressed genes between MS and healthy subjects in peripheral blood T cells from clinically active MS patients. There are also differences between acute relapses and complete remissions.[190] Platelets are known to have abnormal high levels.[191]

MS patients are also known to be CD46 defective, and this leads to Interleukin-10 (IL-10) deficiency, being this involved in the inflammatory reactions.[192] Levels of IL-2, IL-10, and GM-CSF are lower in MS females than normal. IL6 is higher instead. These findings do not apply to men.[193] This IL-10 interleukin could be related to the mechanism of action of methylprednisolone, together with CCL2. Interleukin IL-12 is also known to be associated with relapses, but this is unlikely to be related to the response to steroids[194]

Kallikreins are found in serum and are associated with secondary progressive stage.[195] Related to this, it has been found that B1-receptors, part of the kallikrein-kinin-system, are involved in the BBB breakdown[196][197]

There is evidence of Apoptosis-related molecules in blood and they are related to disease activity.[198] B cells in CSF appear, and they correlate with early brain inflammation.[199] There is also an overexpression of IgG-free kappa light chain protein in both CIS and RR-MS patients, compared with control subjects, together with an increased expression of an isoforms of apolipoprotein E in RR-MS.[200] Expression of some specific proteins in circulating CD4+ T cells is a risk factor for conversion from CIS to clinically defined multiple sclerosis.[201]

Recently, unique autoantibody patterns that distinguish RRMS, secondary progressive (SPMS), and primary progressive (PPMS) have been found, based on up- and down-regulation of CNS antigens,[202] tested by microarrays. In particular, RRMS is characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. These antibodies patterns can be used to monitor disease progression.[203][204]

Finally, a promising biomarker under study is an antibody against the potassium channel protein KIR4.1.[205] This biomarker has been reported to be present in around a half of MS patients, but in nearly none of the controls.

MS types by genetics[edit]

By RNA profile[edit]

Also in blood serum can be found the RNA type of the MS patient. Two types have been proposed classifying the patients as MSA or MSB, allegedly predicting future inflammatory events.[206]

By transcription factor[edit]

The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease.[207] The importance of this discovery is that the expression of these genes appears in blood and can be measured by a simple blood analysis.

In blood vessels tissue[edit]

Endothelial dysfunction has been reported in MS[208] and could be used as biomarker via biopsia. Blood circulation is slower in MS patients and can be meassured using contrast[209] or by MRI[210]

Interleukin-12p40 has been reported to separate RRMS and CIS from other neurological diseases[211]

In Cerebrospinal Fluid[edit]

It has been known for quite some time that glutamate is present at higher levels in CSF during relapses[212] compared to healthy subjects and to MS patients before relapses. This observation has been linked to the activity of the infiltrating leukocytes and activated microglia, and to the damage to the axons[213]

Also a specific MS protein has been found in CSF, chromogranin A, possibly related to axonal degeneration. It appears together with clusterin and complement C3, markers of complement-mediated inflammatory reactions.[214] Also Fibroblast growth factor-2 appear higher at CSF.[215]

CSF also shows oligoclonal bands (OCB) in the majority (around 95%) of the patients. Several studies have reported differences between patients with and without OCB with regard to clinical parameters such as age, gender, disease duration, clinical severity and several MRI characteristics, together with a varying lesion load.[216] Free kappa chains in CSF are documented and have been proposed as a marker for MS evolution[217]

Varicella-zoster virus particles have been found in CSF of patients during relapses, but this particles are virtually absent during remissions.[218] Plasma Cells in the cerebrospinal fluid of MS patients could also be used for diagnosis, because they have been found to produce myelin-specific antibodies.[219] As of 2011, a recently discovered myelin protein TPPP/p25, has been found in CSF of MS patients[220]

A study found that quantification of several immune cell subsets, both in blood and CSF, showed differences between intrathecal (from the spine) and systemic immunity, and between CSF cell subtypes in the inflammatory and noninflammatory groups (basically RRMS/SPMS compared to PPMS). This showed that some patients diagnosed with PPMS shared an inflammatory profile with RRMS and SPMS, while others didn't.[221]

Other study found using a proteomic analysis of the CSF that the peak intensity of the signals corresponding to Secretogranin II and Protein 7B2 were significantly upregulated in RRMS patients compared to PrMS (p<0.05), whereas the signals of Fibrinogen and Fibrinopeptide A were significantly downregulated in CIS compared to PrMS patients[222]

Biomarkers in brain cells and biopsies[edit]

Abnormal sodium distribution has been reported in living MS brains. In the early-stage RRMS patients, sodium MRI revealed abnormally high concentrations of sodium in brainstem, cerebellum and temporal pole. In the advanced-stage RRMS patients, abnormally high sodium accumulation was widespread throughout the whole brain, including normal appearing brain tissue.[223] It is currently unknown whether post-mortem brains are consistent with this observation.

The pre-active lesions are clusters of microglia driven by the HspB5 protein, thought to be produced by stressed oligodendrocytes. The presence of HspB5 in biopsies can be a marker for lesion development.[69]

Biomarkers by MRI[edit]

Recently SWI adjusted magnetic resonance has given results close to 100% specificity and sensitivity respect McDonalds CDMS status[224]

Subgroups by molecular biomarkers[edit]

Differences have been found between the proteines expressed by patients and healthy subjects, and between attacks and remissions. Using DNA microarray technology groups of molecular biomarkers can be established.[225] For example, it is known that Anti-lipid oligoclonal IgM bands (OCMB) distinguish MS patients with early aggressive course and that these patients show a favourable response to immunomodulatory treatment.[226]

It seems that Fas and MIF are candidate biomarkers of progressive neurodegeneration. Upregulated levels of sFas (soluble form of Fas molecule) were found in MS patients with hypotense lesions with progressive neurodegeneration, and also levels of MIF appeared to be higher in progressive than in non-progressing patients. Serum TNF-α and CCL2 seem to reflect the presence of inflammatory responses in primary progressive MS.[227]

As previously reported, there is an antibody against the potassium channel protein KIR4.1[205] which is present in around a half of MS patients, but in nearly none of the controls, pointing towards an heterogeneous etiology in MS. The same happens with B-Cells[228]

Heterogeneity of the disease[edit]

Multiple sclerosis has been reported to be heterogeneus in its behavior, in its underlying mechanisms, in its response to medication [229] and respect the response to the specific potassium channel autoantibody Kir4.1[184]

Demyelination patterns[edit]

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[230] looking for antibodies against 7 lipids, three of which are cholesterol derivatives[231]

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:[232]

Pattern I 
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.[233]
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.[234] This pattern has been considered similar to damage seen in NMO, though AQP4 damage does not appear in pattern II MS lesions[235] Nevertheless, pattern II has been reported to respond to plasmapheresis,[236] 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,[179] making it a candidate for research into the Kir4.1 connection.
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.[129] For others, it represents ischaemia-like injury with a remarkable availability of a specific biomarker in CSF[237]
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.[238] Anyway, the heterogeneity could be true only for the early stage of the disease.[239] Some lesions present mitochondrial defects that could distinguish types of lesions.[240] Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.[203]

Nevertheless, after some debate among research groups, it seems like the four patterns model is accepted[241][242]

MRI Phenotypes[edit]

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

For example, pulsed magnetization transfer imaging,[243] diffusion Tensor MRI,[244] and VCAM-1 enhanced MRI[245] 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[246]

Currently as of 2014, the MRI studies have lead to the proposal of four MRI phenotypes,[247] though both the classification and the relationship with the pathology remains controversial.

Other proposed correlations[edit]

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

Primary progressive MS[edit]

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)[270] and sodium accumulation is higher[271]

Pathology of early MS and silent MS[edit]

Current McDonald criteria usually do not allow to stablish 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.[272] Therefore for studying this initial stage no clinical CDMS cases and pathological definitions are normally used.[2] Sometimes patients with their first isolated attack (Clinically Isolated syndrome, or CIS) are used instead.

Cases of MS before the CIS are sometimes found during other neurological inspections and are referred to as subclinical MS.,[273] or sometimes Clinically silent MS.[274] 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[275]

Also cases after the CIS but before the confirming second attack (Preclinical MS) can be accepted to study the initial MS pathology[276]

These studies are performed for ethiological research purposes and not for improving diagnosis.

See also[edit]


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