Pathophysiology of multiple sclerosis

From Wikipedia, the free encyclopedia
Jump to: navigation, search
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]

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.[5] MS is active even during remission periods.[6] GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS[7]

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.[8] The scars that give the name to the condition are produced by the astrocyte cells healing old lesions.[9]

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,[10] 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.[11] 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.[12][13][14][15][16][17][18][19][20][21][22]

Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS[23] and in the degeneration of the axons.[24] and the oligodendrocytes.[25]

The axons themselves can also be damaged by the attacks.[26] 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[27]

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.[28]

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

Post-mortem autopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord.[34] 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[35] 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.[36] 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.[37]

Due to the distribution of the lesions, since 1916 they are also known as Dawson's fingers.[38] 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.[39] In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues.[40] It has been shown that Fractional anisotropy of cervical spinal cord is lower than normal, showing that there is damage hidden from normal MRI.[41]

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.[42]

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.[43]

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).[44] 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[45]

MS patients show axonal loss in the retina and optic nerve, which can be meassured by Optical coherence tomography[46] or by Scanning laser polarimetry.[47] This measure can be used to predict disease activity[48] and to establish a differential diagnosis from Neuromyelitis optica[49]

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.[50]

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

Proposed procedures for the neurodegeneration are than Narrower arterioles and wider venules have been reported.[53] Also rigidity has been noticed[54]

Neural and axonal damage[edit]

The axons of the neurons are damaged probably by B-Cells,[24] though currently no relationship has been established with the relapses or the attacks.[26] It seems that this damage is a primary target of the immune system, i.e. not secondary damage after attacks against myelin,[55] though this has been disputed[56]

Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.[57]

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[58]

Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy.[59]

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[60]

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.[61] According with the most recent research, an active lesion is composed of different layers:[62]

  • 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[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.[63]

Small lesions are invisible under MRI. Therefore clinically assisted diagnostic criteria are still required for a more accurate MS diagnosis than MRI alone.[64]

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

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

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.[69]

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.[70] 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.[70] 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.[71]

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.[72] 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.[73]

Recently it has been found that BBB damage happens even in non-enhancing lesions.[74] MS has an important vascular component.[75]

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.[76]

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.[77] 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.[78]

BBB can be broken centripetally or centrifugally, the first form being the most normal.[79] 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.[80] The BBB breakdown is responsible for monocyte infiltration and inflammation in the brain.[81] Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase[82]

Using iron nanoparticles, involvement of macrophages in the BBB breakdown can be detected.[83] 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,[73] and are supposed to be related to the mechanism of action of interferons.[84]

Whether BBB dysfunction is the cause or the consequence of MS[85] is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins.[86] Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins.[86] (Adhesion molecules could also play a role in inflammation[87]) 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.[88] Other protein also involved is CXCL12,[89] which is found also in brain biopsies of inflammatory elements,[90] and which could be related to the behavior of CXCL13 under methylprednisolone therapy.[91] Some molecular biochemical models for relapses have been proposed.[92]

Normally, gadolinium enhancement is used to show BBB disruption on MRIs.[93] 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.[94]

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.[95] 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,[96] but not in the grey matter lesions.[97] Besides, uric acid levels are lower during relapses.[98]

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.[99] It has been found that grey matter injury correlates with disability[100] and that there is high oxidative stress in lesions, even in the old ones.[101]

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.[102]

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

Abnormalities in the gray matter (Diffusion tensor MRI alterations) of the brain parenchyma are present early in the course of multiple sclerosis[105]

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.[106] Currently, it is possible to detect lesions before they present demyelination, and they are called pre-active lesions.[67] A fourth area called DAWM (diffusely abnormal white matter) has recently been proposed[107] and can help to differentiate PPMS and SPMS.[108] Abundant extracellular myelin in the meninges of patients with multiple sclerosis has been found[109]

Brain tissues with MRI-hidden problems are usually named Normal Appearing. Exploring the normal-appearing corpus callosum has been found a possible primary hypoperfusion,[110][111] according with other findings in this same direction.[112][113][114][115][116][117] Also iron (in hemosiderin deposits and as well as in ferritin-like structures inside the macrophage) accumulation has been reported[118][119]

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

NAWM in MS has been reported to be similar to NAWM in leukoaraiosis[123]

Normal appearing White Matter[edit]

The white matter with hidden but MRI-visible damage is known as "Normal-appearing white matter" (NAWM)[124] 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.[125]

BBB disruption takes place on NAWM areas.[77] 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.[67][68]

Oligodendrocyte abnormalities appear to be crucially involved.[78][126] 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.[127]

Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls.[128]

Citrullination appears in SPMS.[129] It seems that a defect of sphingolipid metabolism modifies the properties of normal appearing white matter.[130] Related to these, peptidylarginine deiminase 2 is increased in patients with MS, and is related to arginine de-imination.[131]

NAWM shows a decreased perfusion which does not appear to be secondary to axonal loss.[115] 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.[132] 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).[133][134] This MTR parameter is related to axonal density.[135]

It also seems that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at Thr97 than normal individuals.[136]

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.[137] Epstein-Barr virus could be involved,[138] but is not likely.[139] 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.[140]

Iron depositions appear in deep gray matter by magnetic field correlation MRI[141]

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.[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[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.[145] 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,[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]

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.[148] Some other authors like Tracy Putnam[149] pointed to venous obstructions.

Some authors like Franz Schelling proposed a mechanical damage procedure based on violent blood reflux.[150] Later the focus moved to softer hemodynamic abnormalities, which were showing precede changes in sub-cortical gray matter[114] and in substantia nigra.[151] 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.[152] The importance of vascular misbehaviour in MS pathogenesis has also been independently confirmed by seven-tesla MRI.[153] 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.[154]

Some morphologically special medullar lesions (wedge-shaped) have also been linked to venous insufficiency.[155]

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[156]

CCSVI[edit]

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.[157] According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis.[158] Zamboni's results were criticized as some of his studies were not blinded and they need to be verified by further studies.[157][158] As of 2010 the theory is considered at least defensible[159]

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.[160]

Haemodynamic problems have been found in the blood flow of MS patients using Doppler,[161] initially using transcranial color-coded duplex sonography (TCCS), pointing to a relationship with a vascular disease called chronic cerebro-spinal venous insufficiency (CCSVI).[162][163] In 2010 there were conflicting results when evaluating the relationship between MS and CCSVI.[164][165][166][167] 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.[168] This theory could be partially consistent with the previous one[169]

Currently a small trial with 8 participants has been performed[170]

KIR4.1[edit]

It has been reported in 2012 that a subset of MS patients have a seropositive anti-Kir4.1 status,[171] which can represent up to a 47% of the MS cases, and the study has been reproduced by at least other group.[172]

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,[173] researchers expect to find biomarkers able to yield a better diagnosis, and able to predict the response to the different available treatments.[174] As of 2014 no biomarker with perfect correlation has been found,[175] but some of them have shown a special behavior like an autoantibody against the potassium channel Kir4.1.[176] Biomarkers are expected to play an important role in the near future[177]

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.[178]

Creatine and Uric acid levels are lower than normal, at least in women.[179] Ex vivo CD4(+) T cells isolated from the circulation show a wrong TIM-3 (Immunoregulation) behavior,[180] and relapses are associated with CD8(+) T Cells.[181] 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.[182] Platelets are known to have abnormal high levels.[183]

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.[184] 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.[185] 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[186]

Kallikreins are found in serum and are associated with secondary progressive stage.[187] Related to this, it has been found that B1-receptors, part of the kallikrein-kinin-system, are involved in the BBB breakdown[188][189]

There is evidence of Apoptosis-related molecules in blood and they are related to disease activity.[190] B cells in CSF appear, and they correlate with early brain inflammation.[191] 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.[192] Expression of some specific proteins in circulating CD4+ T cells is a risk factor for conversion from CIS to clinically defined multiple sclerosis.[193]

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,[194] 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.[195][196]

Finally, a promising biomarker under study is an antibody against the potassium channel protein KIR4.1.[197] 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.[198]

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.[199] 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[200] and could be used as biomarker via biopsia. Blood circulation is slower in MS patients and can be meassured using contrast[201] or by MRI[202]

In Cerebrospinal Fluid[edit]

It has been known for quite some time that glutamate is present at higher levels in CSF during relapses[203] compared to healthy subjects and to MS patients before relapses. 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.[204] Also Fibroblast growth factor-2 appear higher at CSF.[205]

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.[206] Free kappa chains in CSF are documented and have been proposed as a marker for MS evolution[207]

Varicella-zoster virus particles have been found in CSF of patients during relapses, but this particles are virtually absent during remissions.[208] 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.[209] As of 2011, a recently discovered myelin protein TPPP/p25, has been found in CSF of MS patients[210]

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

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.[212] 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.[68]

Biomarkers by MRI[edit]

Recently SWI adjusted magnetic resonance has given results close to 100% specifity and sensitivity respect McDonalds CDMS status[213]

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.[214] 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.[215]

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.[216]

As previously reported, there is an antibody against the potassium channel protein KIR4.1[197] 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[217]

Demyelination patterns[edit]

Four different damage patterns have been identified by her team in the scars of the brain tissue. 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."

Also known as Lassmann patterns,[218] it is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. This report suggests that there may be several types of MS with different immune-related causes, and that MS may be a family of several diseases. The four identified patterns are:[219]

Pattern I 
The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.[220]
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.[221] This pattern has been considered similar to damage seen in NMO, though AQP4 damage does not appear in pattern II MS lesions[222] Nevertheless, pattern II has been reported to respond to plasmapheresis,[223] 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,[171] 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.[127] For others, it represents ischaemia-like injury with a remarkable availability of a specific biomarker in CSF[224]
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.[225] Anyway, the heterogeneity could be true only for the early stage of the disease.[226] Some lesions present mitochondrial defects that could distinguish types of lesions.[227] Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.[195]

Nevertheless, after some debate among research groups, it seems like the four patterns model is accepted[228][229]

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 [230] and respect the response to the specific potassium channel autoantibody Kir4.1[176]

Proposed correlations[edit]

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[231] and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy).[232] Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions.[233]
  • With MRI and MRS findings: The researchers are attempting this with magnetic resonance images to confirm their initial findings of different patterns of immune pathology and any evidence of possible disease "sub-types" of underlying pathologies. It is possible that such "sub-types" of MS may evolve differently over time and may respond differently to the same therapies. Ultimately investigators could identify which individuals would do best with which treatments. It seems that Pulsed magnetization transfer imaging,[234] diffusion Tensor MRI,[235] and VCAM-1 enhanced MRI[236] are able 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[237]
  • With Optic Coherence Tomography: OCT of the retinal layer yields different results for PPMS and RRMS[238]
  • With CSF findings: Teams in Oxford and Germany,[239] found correlation with CSF and progression in November 2001, and hypotheses have been made suggesting correlation between CSF findings and pathophysiological patterns.[240] In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found,[241] though this is disputed.[242] 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[243]
  • With responses to therapy: It is known that 30% of MS patients are non-responsive to Beta interferon.[244] 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,[245][246] specially IL-17,[247] and interleukins IL12/IL10 ratio has been proposed as marker of clinical course.[248] Besides:
    • Pattern II lesions patients are responsive to plasmapheresis, while others are not.[223][249]
    • 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.[250]
    • People non-responsive to interferons are the most responsive to Copaxone [26][251]
    • In general, people non-responsive to a treatment is more responsive to other,[252] and changing therapy can be effective.[253]
    • There are genetic differences between responders and not responders.[254] 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[255]
  • 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[256]

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)[257] and sodium accumulation is higher[258]

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.[259] 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.,[260] or sometimes Clinically silent MS.[261] 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[262]

Also cases after the CIS but before the confirming second attack (Preclinical MS) can be accepted to study the initial MS pathology[263]

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

See also[edit]

References[edit]

  1. ^ Dutta R, Trapp BD. Pathology and definition of multiple sclerosis, Rev Prat. 2006 Jun 30;56(12):1293-8.
  2. ^ a b Lassmann H (2010). "Acute disseminated encephalomyelitis and multiple sclerosis". Brain 133 (2): 317. doi:10.1093/brain/awp342. 
  3. ^ a b McDonald WI, Compston A, Edan G, et al. (2001). "Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis". Annals of Neurology 50 (1): 121–7. doi:10.1002/ana.1032. PMID 11456302. 
  4. ^ a b c d e Goodkin DE, Rooney WD, Sloan R, et al. (December 1998). "A serial study of new MS lesions and the white matter from which they arise". Neurology 51 (6): 1689–97. doi:10.1212/wnl.51.6.1689. PMID 9855524. 
  5. ^ Lassmann H, Brück W, Lucchinetti CF (April 2007). "The immunopathology of multiple sclerosis: an overview". Brain Pathol. 17 (2): 210–8. doi:10.1111/j.1750-3639.2007.00064.x. PMID 17388952. 
  6. ^ Kirov I, Patil V, Babb J, Rusinek H, Herbert J, Gonen O (June 2009). "MR Spectroscopy Indicates Diffuse Multiple Sclerosis Activity During Remission". J. Neurol. Neurosurg. Psychiatr. 80 (12): 1330–6. doi:10.1136/jnnp.2009.176263. PMC 2900785. PMID 19546105. 
  7. ^ Pirko I, Lucchinetti CF, Sriram S, Bakshi R (February 2007). "Gray matter involvement in multiple sclerosis". Neurology 68 (9): 634–42. doi:10.1212/01.wnl.0000250267.85698.7a. PMID 17325269. 
  8. ^ Meinl E, Krumbholz M, Derfuss T, Dewitt D, (November 2008). "Compartmentalization of inflammation in the CNS: A major mechanism driving progressive multiple sclerosis". J Neurol Sci. 274 (1–2): 42–4. doi:10.1016/j.jns.2008.06.032. PMID 18715571. 
  9. ^ Brosnan, C. F. and Raine, C. S. (2013), The astrocyte in multiple sclerosis revisited. Glia, 61: 453–465. doi:10.1002/glia.22443
  10. ^ Fransson ME, Liljenfeldt LS, Fagius J, Tötterman TH, Loskog AS. (2009). "The T-cell pool is anergized in patients with multiple sclerosis in remission". Immunology 126 (1): 92–101. doi:10.1111/j.1365-2567.2008.02881.x. PMC 2632699. PMID 18624727. 
  11. ^ http://wwwchem.csustan.edu/chem4400/sjbr/corey02.htm
  12. ^ Markovic-Plese S, Cortese I, Wandinger KP, McFarland HF, Martin R (October 2001). "CD4+CD28– costimulation-independent T cells in multiple sclerosis". J. Clin. Invest. 108 (8): 1185–94. doi:10.1172/JCI12516. PMC 209525. PMID 11602626. 
  13. ^ Wulff H, Calabresi PA, Allie R, et al. (June 2003). "The voltage-gated Kv1.3 K+ channel in effector memory T cells as new target for MS". J. Clin. Invest. 111 (11): 1703–13. doi:10.1172/JCI16921. PMC 156104. PMID 12782673. 
  14. ^ Rus H, Pardo CA, Hu L, et al. (August 2005). "The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain". Proc. Natl. Acad. Sci. U.S.A. 102 (31): 11094–9. doi:10.1073/pnas.0501770102. PMC 1182417. PMID 16043714. 
  15. ^ Beeton C, Chandy KG (December 2005). "Potassium channels, memory T cells, and multiple sclerosis". Neuroscientist 11 (6): 550–62. doi:10.1177/1073858405278016. PMID 16282596. 
  16. ^ Okuda Y, Okuda M, Apatoff BR, Posnett DN (August 2005). "The activation of memory CD4(+) T cells and CD8(+) T cells in patients with multiple sclerosis". J. Neurol. Sci. 235 (1–2): 11–7. doi:10.1016/j.jns.2005.02.013. PMID 15972217. 
  17. ^ Krakauer M, Sorensen PS, Sellebjerg F (December 2006). "CD4(+) memory T cells with high CD26 surface expression are enriched for Th1 markers and correlate with clinical severity of multiple sclerosis". J. Neuroimmunol. 181 (1–2): 157–64. doi:10.1016/j.jneuroim.2006.09.006. PMID 17081623. 
  18. ^ Ratts RB, Karandikar NJ, Hussain RZ, et al. (September 2006). "Phenotypic characterization of autoreactive T cells in multiple sclerosis". J. Neuroimmunol. 178 (1–2): 100–10. doi:10.1016/j.jneuroim.2006.06.010. PMID 16901549. 
  19. ^ Haegele KF, Stueckle CA, Malin JP, Sindern E (February 2007). "Increase of CD8+ T-effector memory cells in peripheral blood of patients with relapsing-remitting multiple sclerosis compared to healthy controls". J. Neuroimmunol. 183 (1–2): 168–74. doi:10.1016/j.jneuroim.2006.09.008. PMID 17084910. 
  20. ^ Jilek S, Schluep M, Rossetti AO, et al. (April 2007). "CSF enrichment of highly differentiated CD8+ T cells in early multiple sclerosis". Clin. Immunol. 123 (1): 105–13. doi:10.1016/j.clim.2006.11.004. PMID 17188575. 
  21. ^ Miyazaki Y, Iwabuchi K, Kikuchi S, et al. (September 2008). "Expansion of CD4+CD28- T cells producing high levels of interferon-{gamma} in peripheral blood of patients with multiple sclerosis". Mult. Scler. 14 (8): 1044–55. doi:10.1177/1352458508092809. PMID 18573819. 
  22. ^ Lünemann JD, Jelcić I, Roberts S, et al. (August 2008). "EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2". J. Exp. Med. 205 (8): 1763–73. doi:10.1084/jem.20072397. PMC 2525578. PMID 18663124. 
  23. ^ Hauser SL, Waubant E, Arnold DL, et al. (February 2008). "B-cell depletion with rituximab in relapsing-remitting multiple sclerosis". N Engl J Med. 358 (7): 676–88. doi:10.1056/NEJMoa0706383. PMID 18272891. 
  24. ^ a b Cause of nerve fiber damage in multiple sclerosis identified
  25. ^ Lisak RP, Benjamins JA, Nedelkoska L, Barger JL, Ragheb S, Fan B, Ouamara N, Johnson TA, Rajasekharan S, Bar-Or A. (May 2012). "Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro". J Neuroimmunol. 246 (1–2): 85–95. doi:10.1016/j.jneuroim.2012.02.015. PMID 22458983. 
  26. ^ a b Pascual AM, Martínez-Bisbal MC, Boscá I, et al. (2007). "Axonal loss is progressive and partly dissociated from lesion load in early multiple sclerosis". Neurology 69 (1): 63–7. doi:10.1212/01.wnl.0000265054.08610.12. PMID 17606882. 
  27. ^ Wolswijk G (15 January 1998). "Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells". J Neurosci. 18 (2): 601–9. PMID 9425002. 
  28. ^ Jeroen J. G. Geurtsa, Lars Böc, Petra J. W. Pouwelsd, Jonas A. Castelijnsa, Chris H. Polmanb and Frederik Barkhof, Cortical Lesions in Multiple Sclerosis: Combined Postmortem MR Imaging and Histopathology, American Journal of Neuroradiology 26:572-577, March 2005 [1]
  29. ^ Wattjes MP, Harzheim M, Kuhl CK, et al. (1 September 2006). "Does high-field MR imaging have an influence on the classification of patients with clinically isolated syndromes according to current diagnostic mr imaging criteria for multiple sclerosis?". AJNR Am J Neuroradiol. 27 (8): 1794–8. PMID 16971638. 
  30. ^ Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA (October 2007). "Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging". AJNR Am J Neuroradiol. 28 (9): 1645–9. doi:10.3174/ajnr.A0645. PMID 17885241. 
  31. ^ Roosendaal SD, Moraal B, Vrenken H, et al. (April 2008). "In vivo MR imaging of hippocampal lesions in multiple sclerosis". J Magn Reson Imaging. 27 (4): 726–31. doi:10.1002/jmri.21294. PMID 18302199. 
  32. ^ Geurts JJ, Pouwels PJ, Uitdehaag BM, Polman CH, Barkhof F, Castelijns JA (July 2005). "Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging". Radiology 236 (1): 254–60. doi:10.1148/radiol.2361040450. PMID 15987979. 
  33. ^ Sampat MP, Berger AM, Healy BC, et al. (October 2009). "Regional White Matter Atrophy–Based Classification of Multiple Sclerosis in Cross-Sectional and Longitudinal Data". AJNR Am J Neuroradiol 30 (9): 1731–9. doi:10.3174/ajnr.A1659. PMC 2821733. PMID 19696139. 
  34. ^ Gilmore CP, Donaldson I, Bö L, Owens T, Lowe JS, Evangelou N (October 2008). "Regional variations in the extent and pattern of grey matter demyelination in Multiple Sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord". J Neurol Neurosurg Psychiatry. 80 (2): 182–7. doi:10.1136/jnnp.2008.148767. PMID 18829630. 
  35. ^ Calabrese M, De Stefano N, Atzori M, et al. (2007). "Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis". Arch. Neurol. 64 (10): 1416–22. doi:10.1001/archneur.64.10.1416. PMID 17923625. 
  36. ^ Poonawalla AH, Hasan KM, Gupta RK, et al. (2008). "Diffusion-Tensor MR Imaging of Cortical Lesions in Multiple Sclerosis: Initial Findings". Radiology 246 (3): 880–6. doi:10.1148/radiol.2463070486. PMID 18195384. 
  37. ^ Calabrese M, Filippi M, Rovaris M, Mattisi I, Bernardi V, Atzori M, Favaretto A, Barachino L, Rinaldi L, Romualdi C, Perini P, Gallo P. (2008). "Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study". NeuroImage 42 (4): 1324–8. doi:10.1016/j.neuroimage.2008.06.028. PMID 18652903. 
  38. ^ Dawson fingers, at Radiopedia
  39. ^ Agosta F, Pagani E, Caputo D, Filippi M (2007). "Associations between cervical cord gray matter damage and disability in patients with multiple sclerosis". Arch. Neurol. 64 (9): 1302–5. doi:10.1001/archneur.64.9.1302. PMID 17846269. 
  40. ^ Agosta F, Valsasina P, Rocca MA, Caputo D, Sala S, Judica E, Stroman PW, Filippi M. (2008). "Evidence for enhanced functional activity of cervical cord in relapsing multiple sclerosis". Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine 59 (5): 1035–42. doi:10.1002/mrm.21595. PMID 18429010. 
  41. ^ Cruz LC, Domingues RC, Gasparetto EL (June 2009). "Diffusion tensor imaging of the cervical spinal cord of patients with relapsing-remising multiple sclerosis: a study of 41 cases". Arq Neuropsiquiatr 67 (2B): 391–5. doi:10.1590/S0004-282X2009000300004. PMID 19623432. 
  42. ^ Agosta F, Absinta M, Sormani MP, et al. (August 2007). "In vivo assessment of cervical cord damage in MS patients: a longitudinal diffusion tensor MRI study". Brain 130 (Pt 8): 2211–9. doi:10.1093/brain/awm110. PMID 17535835. 
  43. ^ Gilmore C, Geurts J, Evangelou N, et al. (October 2008). "Spinal cord grey matter lesions in multiple sclerosis detected by post-mortem high field MR imaging". Multiple Sclerosis 15 (2): 180–8. doi:10.1177/1352458508096876. PMID 18845658. 
  44. ^ "eye, human."Encyclopædia Britannica. 2008. Encyclopædia Britannica 2006 Ultimate Reference Suite DVD
  45. ^ Three-Dimensional Geometries Representing the Retinal Nerve Fiber Layer in Multiple Sclerosis, Optic Neuritis, and Healthy Eyes [2]
  46. ^ Pueyo V, Martin J, Fernandez J, Almarcegui C, Ara J, Egea C, Pablo L, Honrubia F. (2008). "Axonal loss in the retinal nerve fiber layer in patients with multiple sclerosis". Multiple sclerosis (Houndmills, Basingstoke, England) 14 (5): 609–14. doi:10.1177/1352458507087326. PMID 18424482. 
  47. ^ Zaveri MS, Conger A, Salter A, Frohman TC, Galetta SL, Markowitz CE, Jacobs DA, Cutter GR, Ying GS, Maguire MG, Calabresi PA, Balcer LJ, Frohman EM. (2008). "Retinal Imaging by Laser Polarimetry and Optical Coherence Tomography Evidence of Axonal Degeneration in Multiple Sclerosis". Archives of neurology 65 (7): 924–8. doi:10.1001/archneur.65.7.924. PMID 18625859. 
  48. ^ Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, García-Layana A, Bejarano B, Villoslada P (May 2007). "Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS". Neurology 68 (18): 1488–94. doi:10.1212/01.wnl.0000260612.51849.ed. PMID 17470751. 
  49. ^ Naismith RT, Tutlam NT, Xu J, et al. (March 2009). "Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis". Neurology 72 (12): 1077–82. doi:10.1212/01.wnl.0000345042.53843.d5. PMC 2677471. PMID 19307541. 
  50. ^ Frohman EM, Fujimoto JG, Frohman TC, Calabresi PA, Cutter G, Balcer LJ (December 2008). "Optical coherence tomography: a window into the mechanisms of multiple sclerosis". Nat Clin Pract Neurol 4 (12): 664–75. doi:10.1038/ncpneuro0950. PMC 2743162. PMID 19043423. 
  51. ^ Lucarelli MJ, Pepose JS, Arnold AC, Foos RY (November 1991). "Immunopathologic features of retinal lesions in multiple sclerosis". Ophthalmology 98 (11): 1652–6. doi:10.1016/s0161-6420(91)32080-3. PMID 1724792. 
  52. ^ Kerrison JB, Flynn T, Green WR (1994). "Retinal pathologic changes in multiple sclerosis". Retina (Philadelphia, Pa.) 14 (5): 445–51. doi:10.1097/00006982-199414050-00010. PMID 7899721. 
  53. ^ Gugleta K, Kochkorov A, Kavroulaki D, et al. (April 2009). "Retinal vessels in patients with multiple sclerosis: baseline diameter and response to flicker light stimulation". Klin Monatsbl Augenheilkd 226 (4): 272–5. doi:10.1055/s-0028-1109289. PMID 19384781. 
  54. ^ Kochkorov A, Gugleta K, Kavroulaki D, et al. (April 2009). "Rigidity of retinal vessels in patients with multiple sclerosis". Klin Monatsbl Augenheilkd 226 (4): 276–9. doi:10.1055/s-0028-1109291. PMID 19384782. 
  55. ^ Huizinga R, Gerritsen W, Heijmans N, Amor S (September 2008). "Axonal loss and gray matter pathology as a direct result of autoimmunity to neurofilaments". Neurobiol Dis. 32 (3): 461–70. doi:10.1016/j.nbd.2008.08.009. PMID 18804534. 
  56. ^ Sobottka B, Harrer MD, Ziegler U, et al. (September 2009). "Collateral Bystander Damage by Myelin-Directed CD8+ T Cells Causes Axonal Loss". Am. J. Pathol. 175 (3): 1160–6. doi:10.2353/ajpath.2009.090340. PMC 2731134. PMID 19700745. 
  57. ^ Filippi M, Bozzali M, Rovaris M, Gonen O, Kesavadas C, Ghezzi A, Martinelli V, Grossman R, Scotti G, Comi G, Falini A (2003). "Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis". Brain 126 (Pt 2): 433–7. doi:10.1093/brain/awg038. PMID 12538409. 
  58. ^ Neuer Diagnose-Ansatz zur Früherkennung von MS
  59. ^ Mostert JP, Blaauw Y, Koch MW, Kuiper AJ, Hoogduin JM, De Keyser J (2008). "Reproducibility over a 1-month period of 1H-MR spectroscopic imaging NAA/Cr ratios in clinically stable multiple sclerosis patients". Eur Radiol 18 (8): 1736–40. doi:10.1007/s00330-008-0925-x. PMC 2469275. PMID 18389250. 
  60. ^ Charles M. Poser, The peripheral nervous system in multiple sclerosis: A review and pathogenetic hypothesis, http://dx.doi.org/10.1016/0022-510X(87)90262-0
  61. ^ Compston A, Coles A (October 2008). "Multiple sclerosis". Lancet 372 (9648): 1502–17. doi:10.1016/S0140-6736(08)61620-7. PMID 18970977. 
  62. ^ Henderson, AP, Barnett, MH, Parratt, JD, Prineas, JW (December 2009). "Multiple sclerosis: distribution of inflammatory cells in newly forming lesions". Annals of Neurology 66 (6): 739–53. doi:10.1002/ana.21800. PMID 20035511. 
  63. ^ van Walderveen MA; Kamphorst W; Scheltens P; van Waesberghe JH; Ravid R; Valk J; Polman CH; Barkhof F, Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. [3]
  64. ^ Antonov SM, Kalinina NI, Kurchavyj GG, Magazanik LG, Shupliakov OV, Vesselkin NP (February 1990). "Identification of two types of excitatory monosynaptic inputs in frog spinal motoneurones". Neuroscience letters 109 (1–2): 82–7. doi:10.1016/0304-3940(90)90541-G. PMID 2156195. 
  65. ^ 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
  66. ^ 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.
  67. ^ a b c van der Valk P, Amor S (June 2009). "Preactive lesions in multiple sclerosis". Current Opinion in Neurology 22 (3): 207–13. doi:10.1097/WCO.0b013e32832b4c76. PMID 19417567. 
  68. ^ a b c 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
  69. ^ Alireza Minagar and J Steven Alexander, Blood–brain barrier disruption in multiple sclerosis [4]
  70. ^ a b Correale, Jorge; Andrés Villa (24 July 2006). "The blood–brain-barrier in multiple sclerosis: Functional roles and therapeutic targeting". Autoimmunity 40 (2): 148. doi:10.1080/08916930601183522. 
  71. ^ Cristante, Enrico; Simon McArthur, Claudio Mauro, Elisa Maggiolo, Ignacio A. Romero, Marzena Wylezinska-Arridge, Pierre O. Couraud, Jordi Lopez-Tremoleda, Helen C. Christian, Babette B. Weksler, Andrea Malaspina, Egle Solito (15 January 2013). "Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications". Proceedings of the National Academy of Sciences of the United States 110 (3): 832. doi:10.1073/pnas.1209362110. 
  72. ^ Prat, Elisabetta; Roland Martin (March–April 2002). "The immunopathogenesis of multiple sclerosis". Journal of Rehabilitation Research and Development 39 (2): 187. 
  73. ^ a b Gray E, Thomas TL, Betmouni S, Scolding N, Love S (September 2008). "Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques". J Neuropathol Exp Neurol. 67 (9): 888–99. doi:10.1097/NEN.0b013e318183d003. PMID 18716555. 
  74. ^ Soon D, Tozer DJ, Altmann DR, Tofts PS, Miller DH (2007). "Quantification of subtle blood–brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes". Multiple Sclerosis 13 (7): 884–94. doi:10.1177/1352458507076970. PMID 17468443. 
  75. ^ Minagar A, Jy W, Jimenez JJ, Alexander JS (2006). "Multiple sclerosis as a vascular disease". Neurol. Res. 28 (3): 230–5. doi:10.1179/016164106X98080. PMID 16687046. 
  76. ^ Washington R, Burton J, Todd RF 3rd, Newman W, Dragovic L, Dore-Duffy P. Expression of immunologically relevant endothelial cell activation antigens on isolated central nervous system microvessels from patients with multiple sclerosis, Ann Neurol. 1994 Jan;35(1):89-97., PMID 7506877
  77. ^ a b Werring DJ, Brassat D, Droogan AG, et al. (August 2000). "The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study". Brain 123 (8): 1667–76. doi:10.1093/brain/123.8.1667. PMID 10908196. 
  78. ^ a b Allen et al.; McQuaid, S; Mirakhur, M; Nevin, G (2001). "Pathological abnormalities in the normal-appearing white matter in multiple sclerosis". Neurol Sci 22 (2): 141–4. doi:10.1007/s100720170012. PMID 11603615. 
  79. ^ Shinohara RT, Crainiceanu CM, Caffo BS, Gaitán MI, Reich DS (May 2011). "Population-Wide Principal Component-Based Quantification of Blood-Brain-Barrier Dynamics in Multiple Sclerosis". NeuroImage 57 (4): 1430–46. doi:10.1016/j.neuroimage.2011.05.038. PMC 3138825. PMID 21635955. 
  80. ^ Pan W, Hsuchou H, Yu C, Kastin AJ (2008). "Permeation of blood-borne IL15 across the blood–brain barrier and the effect of LPS". J. Neurochem. 106 (1): 313–9. doi:10.1111/j.1471-4159.2008.05390.x. PMID 18384647. 
  81. ^ Reijerkerk A, Kooij G, van der Pol SM, Leyen T, van Het Hof B, Couraud PO, Vivien D, Dijkstra CD, de Vries HE. (2008). "Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier". Journal of Immunology (Baltimore, Md. : 1950) 181 (5): 3567–74. doi:10.4049/jimmunol.181.5.3567. PMID 18714030. 
  82. ^ Malik M, Chen YY, Kienzle MF, Tomkowicz BE, Collman RG, Ptasznik A (October 2008). "Monocyte migration and LFA-1 mediated attachment to brain microvascular endothelia is regulated by SDF-1α through Lyn kinase". Journal of Immunology 181 (7): 4632–7. doi:10.4049/jimmunol.181.7.4632. PMC 2721474. PMID 18802065. 
  83. ^ Petry KG, Boiziau C, Dousset V, Brochet B (2007). "Magnetic resonance imaging of human brain macrophage infiltration". Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 4 (3): 434–42. doi:10.1016/j.nurt.2007.05.005. PMID 17599709. 
  84. ^ Boz C, Ozmenoglu M, Velioglu S, et al. (February 2006). "Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta". Clin Neurol Neurosurg. 108 (2): 124–8. doi:10.1016/j.clineuro.2005.01.005. PMID 16412833. 
  85. ^ Waubant E (2006). "Biomarkers indicative of blood–brain barrier disruption in multiple sclerosis". Dis. Markers 22 (4): 235–44. doi:10.1155/2006/709869. PMID 17124345. 
  86. ^ a b Multiple Sclerosis at eMedicine
  87. ^ Elovaara I, Ukkonen M, Leppäkynnäs M, et al. (April 2000). "Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone therapy". Arch. Neurol. 57 (4): 546–51. doi:10.1001/archneur.57.4.546. PMID 10768630. 
  88. ^ Alexandre Prat, Nicole Beaulieu, Sylvain-Jacques Desjardins, New Therapeutic Target For Treatment Of Multiple Sclerosis, Jan. 2008
  89. ^ McCandless EE, Piccio L, Woerner BM, et al. (March 2008). "Pathological Expression of CXCL12 at the Blood-Brain Barrier Correlates with Severity of Multiple Sclerosis". Am J Pathol. 172 (3): 799–808. doi:10.2353/ajpath.2008.070918. PMC 2258272. PMID 18276777. 
  90. ^ Moll NM, Cossoy MB, Fisher E, et al. (January 2009). "Imaging correlates of leukocyte accumulation and CXCR4/CXCR12 in multiple sclerosis". Arch. Neurol. 66 (1): 44–53. doi:10.1001/archneurol.2008.512. PMC 2792736. PMID 19139298. 
  91. ^ Michałowska-Wender G, Losy J, Biernacka-Łukanty J, Wender M (2008). "Impact of methylprednisolone treatment on the expression of macrophage inflammatory protein 3alpha and B lymphocyte chemoattractant in serum of multiple sclerosis patients" (PDF). Pharmacol Rep. 60 (4): 549–54. PMID 18799824. 
  92. ^ Steinman L (May 2009). "A molecular trio in relapse and remission in multiple sclerosis". Nature Reviews Immunology 9 (6): 440–7. doi:10.1038/nri2548. PMID 19444308. 
  93. ^ Waubant E (2006). "Biomarkers indicative of blood–brain barrier disruption in multiple sclerosis". Disease Markers 22 (4): 235–44. doi:10.1155/2006/709869. PMID 17124345. 
  94. ^ Leech S, Kirk J, Plumb J, McQuaid S (2007). "Persistent endothelial abnormalities and blood–brain barrier leak in primary and secondary progressive multiple sclerosis". Neuropathol. Appl. Neurobiol. 33 (1): 86–98. doi:10.1111/j.1365-2990.2006.00781.x. PMID 17239011. 
  95. ^ Kean R, Spitsin S, Mikheeva T, Scott G, Hooper D (2000). "The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity". Journal of Immunology 165 (11): 6511–8. doi:10.4049/jimmunol.165.11.6511. PMID 11086092. 
  96. ^ Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D (2006). "Serum uric acid and multiple sclerosis". Clinical neurology and neurosurgery 108 (6): 527–31. doi:10.1016/j.clineuro.2005.08.004. PMID 16202511. 
  97. ^ van Horssen J, Brink BP, de Vries HE, van der Valk P, Bø L (April 2007). "The blood–brain barrier in cortical multiple sclerosis lesions". J Neuropathol Exp Neurol. 66 (4): 321–8. doi:10.1097/nen.0b013e318040b2de. PMID 17413323. 
  98. ^ Guerrero AL, Martín-Polo J, Laherrán E, et al. (April 2008). "Variation of serum uric acid levels in multiple sclerosis during relapses and immunomodulatory treatment". Eur J Neurol. 15 (4): 394–7. doi:10.1111/j.1468-1331.2008.02087.x. PMID 18312403. 
  99. ^ Laule C, Vavasour IM, Kolind SH, et al. (2007). "Long T(2) water in multiple sclerosis: What else can we learn from multi-echo T(2) relaxation?". J. Neurol. 254 (11): 1579–87. doi:10.1007/s00415-007-0595-7. PMID 17762945. 
  100. ^ Zhang Y, Zabad R, Wei X, Metz LM, Hill MD, Mitchell JR (2007). "Deep grey matter 'black T2' on 3 tesla magnetic resonance imaging correlates with disability in multiple sclerosis". Multiple Sclerosis 13 (7): 880–3. doi:10.1177/1352458507076411. PMID 17468444. 
  101. ^ Holley JE, Newcombe J, Winyard PG, Gutowski NJ (2007). "Peroxiredoxin V in multiple sclerosis lesions: predominant expression by astrocytes". Multiple Sclerosis 13 (8): 955–61. doi:10.1177/1352458507078064. PMID 17623739. 
  102. ^ Otaduy MC, Callegaro D, Bacheschi LA, Leite CC (December 2006). "Correlation of magnetization transfer and diffusion magnetic resonance imaging in multiple sclerosis". Multiple sclerosis 12 (6): 754–9. doi:10.1177/1352458506070824. PMID 17263003. 
  103. ^ Nelson F, Poonawalla A, Hou P, Wolinsky J, Narayana P (November 2008). "3D MPRAGE Improves Classification of Cortical Lesions in Multiple Sclerosis". Multiple Sclerosis 14 (9): 1214–9. doi:10.1177/1352458508094644. PMC 2650249. PMID 18952832. 
  104. ^ Haacke EM, Makki M, Ge Y, et al. (March 2009). "Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging". J Magn Reson Imaging 29 (3): 537–44. doi:10.1002/jmri.21676. PMC 2650739. PMID 19243035. 
  105. ^ Cappellani R1, Bergsland N2, Weinstock-Guttman B3, Kennedy C2, Carl E2, Ramasamy DP2, Hagemeier J2, Dwyer MG2, Patti F4, Zivadinov R Diffusion tensor MRI alterations of subcortical deep gray matter in clinically isolated syndrome, J Neurol Sci. 2013 Dec 31. pii: S0022-510X(13)03102-X. doi: 10.1016/j.jns.2013.12.031. PMID 24423584
  106. ^ Zhang J, Tong L, Wang L, Li N (2008). "Texture analysis of multiple sclerosis: a comparative study". Magnetic resonance imaging 26 (8): 1160–6. doi:10.1016/j.mri.2008.01.016. PMID 18513908. 
  107. ^ Seewann A, Vrenken H, van der Valk P, et al. (May 2009). "Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis". Arch. Neurol. 66 (5): 601–9. doi:10.1001/archneurol.2009.57. PMID 19433660. 
  108. ^ Vrenken, H, Seewann, A, Knol, DL, Polman, CH, Barkhof, F, Geurts, JJ (March 2010). "Diffusely abnormal white matter in progressive multiple sclerosis: in vivo quantitative MR imaging characterization and comparison between disease types". AJNR. American journal of neuroradiology 31 (3): 541–8. doi:10.3174/ajnr.A1839. PMID 19850760. 
  109. ^ Kooi EJ, van Horssen J, Witte ME, et al. (June 2009). "Abundant extracellular myelin in the meninges of patients with multiple sclerosis". Neuropathol. Appl. Neurobiol. 35 (3): 283–95. doi:10.1111/j.1365-2990.2008.00986.x. PMID 19473295. 
  110. ^ A.M. Saindane, M. Law, Y. Ge, G. Johnson, J.S. Babb and R.I. Grossman, Correlation of Diffusion Tensor and Dynamic Perfusion MR Imaging Metrics in Normal-Appearing Corpus Callosum: Support for Primary Hypoperfusion in Multiple Sclerosis, American Journal of Neuroradiology 28:767-772, April 2007 [5]
  111. ^ Juurlink, BH (October 1998). "The multiple sclerosis lesion: initiated by a localized hypoperfusion in a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated?". Medical hypotheses 51 (4): 299–303. doi:10.1016/S0306-9877(98)90052-4. PMID 9824835. 
  112. ^ Matilde Inglese, Sumita Adhya, Glyn Johnson, James S Babb, Laura Miles, Hina Jaggi, Joseph Herbert, and Robert Grossman, Perfusion magnetic resonance imaging correlates of neuropsychological impairment in multiple sclerosis, doi:10.1038/sj.jcbfm.9600504 [6]
  113. ^ Sumita Adhya, MS, Glyn Johnson, PhD, Joseph Herbert, MD,* Hina Jaggi, MS, James S. Babb, PhD, Robert I. Grossman, MD, and Matilde Inglese, MD, PhD, Pattern of Hemodynamic Impairment in Multiple Sclerosis: Dynamic Susceptibility Contrast Perfusion MR Imaging at 3.0 T, doi:10.1016/j.neuroimage.2006.08.008.
  114. ^ a b Varga AW, Johnson G, Babb JS, Herbert J, Grossman RI, Inglese M (July 2009). "White Matter Hemodynamic Abnormalities precede Sub-cortical Gray Matter Changes in Multiple Sclerosis". J. Neurol. Sci. 282 (1–2): 28–33. doi:10.1016/j.jns.2008.12.036. PMC 2737614. PMID 19181347. 
  115. ^ a b De Keyser, J, Steen, C, Mostert, JP, Koch, MW (October 2008). "Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance". Journal of Cerebral Blood Flow and Metabolism 28 (10): 1645–51. doi:10.1038/jcbfm.2008.72. PMID 18594554. 
  116. ^ Matilde Inglese, Sumita Adhya, Glyn Johnson, James S Babb, Laura Miles, Hina Jaggi, Joseph Herbert and Robert I Grossman, Perfusion magnetic resonance imaging correlates of neuropsychological impairment in multiple sclerosis, doi:10.1038/sj.jcbfm.9600504 [7]
  117. ^ Law, M, Saindane, AM, Ge, Y, Babb, JS, Johnson, G, Mannon, LJ, Herbert, J, Grossman, RI (June 2004). "Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter". Radiology 231 (3): 645–52. doi:10.1148/radiol.2313030996. PMID 15163806. 
  118. ^ Adams, CW (February 1988). "Perivascular iron deposition and other vascular damage in multiple sclerosis". Journal of neurology, neurosurgery, and psychiatry 51 (2): 260–5. doi:10.1136/jnnp.51.2.260. PMC 1031540. PMID 3346691. 
  119. ^ Singh, AV, Zamboni, P (December 2009). "Anomalous venous blood flow and iron deposition in multiple sclerosis". Journal of Cerebral Blood Flow and Metabolism 29 (12): 1867–78. doi:10.1038/jcbfm.2009.180. PMID 19724286. 
  120. ^ Bizzozero OA, DeJesus G, Callahan K, Pastuszyn A. (2005). "Elevated protein carbonylation in the brain white matter and gray matter of patients with multiple sclerosis". Journal of neuroscience research 81 (5): 687–95. doi:10.1002/jnr.20587. PMID 16007681. 
  121. ^ Clements RJ, McDonough J, Freeman EJ. (2008). "Distribution of parvalbumin and calretinin immunoreactive interneurons in motor cortex from multiple sclerosis post-mortem tissue". Experimental brain research. Experimentelle Hirnforschung. Experimentation cerebrale 187 (3): 459–65. doi:10.1007/s00221-008-1317-9. PMID 18297277. 
  122. ^ Lukas Haider et al. Oxidative damage in multiple sclerosis lesions, Brain Advance Access published June 7, 2011, doi:10.1093/brain/awr128 [8]
  123. ^ Beggs, Clive B. "Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis." BMC medicine 11.1 (2013): 142. [9]
  124. ^ 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
  125. ^ Werring DJ, Brassat D, Droogan AG, Clark CA, Symms MR, Barker GJ, MacManus DG, Thompson AJ, Miller DH., The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study, NMR Research Unit, Queen Square, London, UK.
  126. ^ Thomas Zeis,Ursula Graumann,Richard Reynolds, Nicole Schaeren-Wiemers (Jan 2008). "Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection". Brain 131 (4): 288–303. doi:10.1093/brain/awm291. PMID 18056737. 
  127. ^ a b Barnett, MH, Prineas, JW (April 2004). "Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion". Annals of Neurology 55 (4): 458–68. doi:10.1002/ana.20016. PMID 15048884. 
  128. ^ Phuttharak W, Galassi W, Laopaiboon V, Laopaiboon M, Hesselink JR (2007). "Abnormal diffusivity of normal appearing brain tissue in multiple sclerosis: a diffusion-weighted MR imaging study". J Med Assoc Thai 90 (12): 2689–94. PMID 18386722. 
  129. ^ Nicholas AP, Sambandam T, Echols JD, Tourtellotte WW. (2004). "Increased citrullinated glial fibrillary acidic protein in secondary progressive multiple sclerosis". The Journal of Comparative Neurology 473 (1): 128–36. doi:10.1002/cne.20102. PMID 15067723. 
  130. ^ Wheeler D, Bandaru VV, Calabresi PA, Nath A, Haughey NJ (November 2008). "A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis". Brain 131 (Pt 11): 3092–102. doi:10.1093/brain/awn190. PMC 2577809. PMID 18772223. 
  131. ^ Too Much Of A Charge-Switching Enzyme Causes Symptoms Of Multiple Sclerosis And Related Disorders In Mouse Models http://www.medicalnewstoday.com/articles/128393.php
  132. ^ De Keyser J, Steen C, Mostert JP, Koch MW. (2008). "Hypoperfusion of the cerebral white matter in multiple sclerosis: possible mechanisms and pathophysiological significance". Journal of Cerebral Blood Flow and Metabolism 28 (10): 1645–51. doi:10.1038/jcbfm.2008.72. PMID 18594554. 
  133. ^ Filippi M, Rocca MA, Martino G, Horsfield MA, Comi G (June 1998). "Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis". Annals of Neurology. 43 (6): 809–14. doi:10.1002/ana.410430616. PMID 9629851. 
  134. ^ Cercignani M, Iannucci G, Rocca MA, Comi G, Horsfield MA, Filippi M (March 2000). "Pathologic damage in MS assessed by diffusion-weighted and magnetization transfer MRI". Neurology 54 (5): 1139–44. doi:10.1212/wnl.54.5.1139. PMID 10720288. 
  135. ^ van Waesberghe JH, Kamphorst W, De Groot CJ, et al. (November 1999). "Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability". Annals of Neurology 46 (5): 747–54. doi:10.1002/1531-8249(199911)46 (inactive 2014-03-24). PMID 10553992. 
  136. ^ Tait AR, Straus SK (August 2008). "Phosphorylation of U24 from Human Herpes Virus type 6 (HHV-6) and its potential role in mimicking myelin basic protein (MBP) in multiple sclerosis". FEBS Letters 582 (18): 2685–8. doi:10.1016/j.febslet.2008.06.050. PMID 18616943. 
  137. ^ Fisher E, Lee JC, Nakamura K, Rudick RA (September 2008). "Gray matter atrophy in multiple sclerosis: a longitudinal study". Annals of Neurology 64 (3): 255–65. doi:10.1002/ana.21436. PMID 18661561. 
  138. ^ Zivadinov R, Zorzon M, Weinstock-Guttman B, et al. (June 2009). "Epstein-Barr virus is associated with grey matter atrophy in multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 80 (6): 620–5. doi:10.1136/jnnp.2008.154906. PMID 19168469. 
  139. ^ Willis SN, Stadelmann C, Rodig SJ, et al. (July 2009). "Epstein–Barr virus infection is not a characteristic feature of multiple sclerosis brain". Brain 132 (Pt 12): 3318–28. doi:10.1093/brain/awp200. PMC 2792367. PMID 19638446. 
  140. ^ Vercellino M, Masera S, Lorenzatti M, et al. (May 2009). "Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter". J. Neuropathol. Exp. Neurol. 68 (5): 489–502. doi:10.1097/NEN.0b013e3181a19a5a. PMID 19525897. 
  141. ^ Ge Y, Jensen JH, Lu H, et al. (October 2007). "Quantitative assessment of iron accumulation in the deep gray matter of multiple sclerosis by magnetic field correlation imaging". AJNR Am J Neuroradiol 28 (9): 1639–44. doi:10.3174/ajnr.A0646. PMID 17893225. 
  142. ^ Laule, C, Vavasour, IM, Leung, E, Li, DK, Kozlowski, P, Traboulsee, AL, Oger, J, MacKay, AL, Moore, GW (October 2010). "Pathological basis of diffusely abnormal white matter: insights from magnetic resonance imaging and histology". Multiple sclerosis (Houndmills, Basingstoke, England) 17 (2): 144–50. doi:10.1177/1352458510384008. PMID 20965961. 
  143. ^ Seewann A, Vrenken H, van der Valk P, et al. (May 2009). "Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis". Arch. Neurol. 66 (5): 601–9. doi:10.1001/archneurol.2009.57. PMID 19433660. 
  144. ^ Vos CM, Geurts JJ, Montagne L, et al. (December 2005). "Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis". Neurobiol. Dis. 20 (3): 953–60. doi:10.1016/j.nbd.2005.06.012. PMID 16039866. 
  145. ^ G. R. W. Moore, C. Laule, A. MacKay, E. Leung, D. K. B. Li, G. Zhao, A. L. Traboulsee, D. W. Paty , Dirty-appearing white matter in multiple sclerosis, Journal of Neurology. 04/2012; 255(11) 1802-1811. doi:10.1007/s00415-008-0002-z
  146. ^ Barnett MH, Parratt JD, Cho ES, Prineas JW. Immunoglobulins and complement in postmortem multiple sclerosis tissue, Ann Neurol. 2009 Jan;65(1) 32-46. doi:10.1002/ana.21524
  147. ^ Singh S, Metz I, Amor S, van der Valk P, Stadelmann C, Brück W. Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons, Acta Neuropathol. 2013 Apr;125(4) 595-608. doi: 10.1007/s00401-013-1082-0. Epub 2013 Jan 26.
  148. ^ Lassmann H (July 2005). "Multiple sclerosis pathology: evolution of pathogenetic concepts". Brain Pathology 15 (3): 217–22. doi:10.1111/j.1750-3639.2005.tb00523.x. PMID 16196388. [verification needed]
  149. ^ Putnam, T.J. (1937) Evidence of vascular occlusion in multiple sclerosis
  150. ^ Schelling, F (October 1986). "Damaging venous reflux into the skull or spine: relevance to multiple sclerosis". Medical hypotheses 21 (2): 141–8. doi:10.1016/0306-9877(86)90003-4. PMID 3641027. 
  151. ^ Walter U, Wagner S, Horowski S, Benecke R, Zettl UK (September 2009). "Transcranial brain sonography findings predict disease progression in multiple sclerosis". Neurology 73 (13): 1010–7. doi:10.1212/WNL.0b013e3181b8a9f8. PMID 19657105. 
  152. ^ Leech S, Kirk J, Plumb J, McQuaid S (February 2007). "Persistent endothelial abnormalities and blood–brain barrier leak in primary and secondary progressive multiple sclerosis". Neuropathol. Appl. Neurobiol. 33 (1): 86–98. doi:10.1111/j.1365-2990.2006.00781.x. PMID 17239011. 
  153. ^ Ge Y, Zohrabian VM, Grossman RI. (2008). "7T MRI: New Vision of Microvascular Abnormalities in Multiple Sclerosis". Archives of neurology 65 (6): 812–6. doi:10.1001/archneur.65.6.812. PMC 2579786. PMID 18541803. 
  154. ^ M. Filippi, G. Comi (2004). "Normal-appearing White and Grey Matter Damage in Multiple Sclerosis. Book review". AJRN 27: 945–946. 
  155. ^ Qiu, W, Raven, S, Wu, JS, Carroll, WM, Mastaglia, FL, Kermode, AG (March 2010). "Wedge-shaped medullary lesions in multiple sclerosis". Journal of the neurological sciences 290 (1–2): 190–3. doi:10.1016/j.jns.2009.12.017. PMID 20056253. 
  156. ^ J. Gutiérrez, J. Linares-Palomino, C. Lopez-Espada, M. Rodríguez, E. Ros, G. Piédrola and M. del C. Maroto, Chlamydia pneumoniae DNA in the Arterial Wall of Patients with Peripheral Vascular Disease, Infection, Volume 29, Number 4 (2001), 196-200, doi:10.1007/s15010-001-1180-0
  157. ^ a b Zamboni P, Galeotti R, Menegatti E, et al. (April 2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024. 
  158. ^ a b Khan O, Filippi M, Freedman MS, et al. (March 2010). "Chronic cerebrospinal venous insufficiency and multiple sclerosis". Annals of Neurology 67 (3): 286–90. doi:10.1002/ana.22001. PMID 20373339. 
  159. ^ Bryce Weir (2010). "MS, A vascular ethiology?". Can. J. Neurol. Sci. 2010; 37: 745-757. 
  160. ^ Bartolomei I. et al (April 2010). "Haemodynamic patterns in chronic cereblrospinal venous insufficiency in multiple sclerosis. Correlation of symptoms at onset and clinical course". Int Angiol 29 (2): 183–8. PMID 20351667. 
  161. ^ Zamboni P, Menegatti E, Bartolomei I, et al. (November 2007). "Intracranial venous haemodynamics in multiple sclerosis". Curr Neurovasc Res. 4 (4): 252–8. doi:10.2174/156720207782446298. PMID 18045150. 
  162. ^ Zamboni P, Galeotti R, Menegatti E, et al. (April 2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". J. Neurol. Neurosurg. Psychiatr. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024. 
  163. ^ Lee AB, Laredo J, Neville R (April 2010). "Embryological background of truncular venous malformation in the extracranial venous pathways as the cause of chronic cerebro spinal venous insufficiency". Int Angiol 29 (2): 95–108. PMID 20351665. 
  164. ^ Al-Omari MH, Rousan LA (April 2010). "Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis". Int Angiol 29 (2): 115–20. PMID 20351667. 
  165. ^ Krogias C, Schröder A, Wiendl H, Hohlfeld R, Gold R (April 2010). "["Chronic cerebrospinal venous insufficiency" and multiple sclerosis : Critical analysis and first observation in an unselected cohort of MS patients.]". Nervenarzt 81 (6): 740–6. doi:10.1007/s00115-010-2972-1. PMID 20386873. 
  166. ^ Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ (August 2010). "No cerebrocervical venous congestion in patients with multiple sclerosis". Annals of Neurology 68 (2): 173–83. doi:10.1002/ana.22085. PMID 20695010. 
  167. ^ Sundström, P.; Wåhlin, A.; Ambarki, K.; Birgander, R.; Eklund, A.; Malm, J. (2010). "Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control study". Annals of Neurology 68 (2): 255–259. doi:10.1002/ana.22132. PMID 20695018.  edit
  168. ^ Damadian RV, Chu D. The possible role of cranio-cervical trauma and abnormal CSF hydrodynamics in the genesis of multiple sclerosis, 2011, [10]
  169. ^ Zamboni et al. CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies, 2010 [11]
  170. ^ Raymond V. Damadian and David Chu, The Possible Role of Cranio-Cervical Trauma and Abnormal CSF Hydrodynamics in the Genesis of Multiple Sclerosis [12][13][14]
  171. ^ a b Srivastava R. et Al, Potassium channel KIR4.1 as an immune target in multiple sclerosis, N Engl J Med. 2012 Jul 12;367(2):115-23. doi: 10.1056/NEJMoa1110740, PMID 22784115
  172. ^ Raphael Schneider, Autoantibodies to Potassium Channel KIR4.1 in Multiple Sclerosis, doi: 10.3389/fneur.2013.00125, PMID 24032025
  173. ^ Wootla B, Eriguchi M, Rodriguez M. Is multiple sclerosis an autoimmune disease? Autoimmune Dis. 2012;2012:969657. doi: 10.1155/2012/969657. Epub 2012 May 16.
  174. ^ Dorothea Buck 1 and Bernhard Hemmer, Biomarkers of treatment response in multiple sclerosis, February 2014, Vol. 14, No. 2 , Pages 165-172 (doi:10.1586/14737175.2014.874289) [15]
  175. ^ Manuel Comabella, Xavier Montalban, Body fluid biomarkers in multiple sclerosis, The Lancet Neurology, Volume 13, Issue 1, Pages 113 - 126, January 2014 doi:10.1016/S1474-4422(13)70233-3
  176. ^ a b Rajneesh Srivastava et al. Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis, New England Journal of Medicine, 2012; 367:115-123July 12, 2012DOI: 10.1056/NEJMoa1110740
  177. ^ Serafeim Katsavos and Maria Anagnostouli, Biomarkers in Multiple Sclerosis: An Up-to-Date Overview, Multiple Sclerosis International Volume 2013 (2013), Article ID 340508, 20 pages [16][17]
  178. ^ Haufschild T, Shaw SG, Kesselring J, Flammer J. Increased endothelin-1 plasma levels in patients with multiple sclerosis. J Neuroophthalmol. 2001 Mar;21(1):37-8.
  179. ^ Kanabrocki EL, Ryan MD, Hermida RC, et al. (2008). "Uric acid and renal function in multiple sclerosis". Clin Ter 159 (1): 35–40. PMID 18399261. 
  180. ^ Yang L, Anderson DE, Kuchroo J, Hafler DA (2008). "Lack of TIM-3 Immunoregulation in Multiple Sclerosis". Journal of Immunology 180 (7): 4409–4414. doi:10.4049/jimmunol.180.7.4409. PMID 18354161. 
  181. ^ Malmeström C, Lycke J, Haghighi S, Andersen O, Carlsson L, Wadenvik H, Olsson B. (2008). "Relapses in multiple sclerosis are associated with increased CD8(+) T-cell mediated cytotoxicity in CSF". J Neuroimmunol. 196 (Apr.5): 35–40. doi:10.1016/j.jneuroim.2008.03.001. PMID 18396337. 
  182. ^ Satoh J. (2008). "Molecular biomarkers for prediction of multiple sclerosis relapse" [Molecular biomarkers for prediction of multiple sclerosis relapse]. Nippon Rinsho (in Japanese) 66 (6): 1103–11. PMID 18540355. 
  183. ^ Sheremata WA, Jy W, Horstman LL, Ahn YS, Alexander JS, Minagar A. (2008). "Evidence of platelet activation in multiple sclerosis". J Neuroinflammation 5: 27. doi:10.1186/1742-2094-5-27. PMC 2474601. PMID 18588683. 
  184. ^ Astier AL (2008). "T-cell regulation by CD46 and its relevance in multiple sclerosis". Immunology 124 (2): 149–54. doi:10.1111/j.1365-2567.2008.02821.x. PMC 2566619. PMID 18384356. 
  185. ^ Kanabrocki EL, Ryan MD, Lathers D, Achille N, Young MR, Cauteren JV, Foley S, Johnson MC, Friedman NC, Siegel G, Nemchausky BA. (2007). "Circadian distribution of serum cytokines in multiple sclerosis". Clin. Ter. 158 (2): 157–62. PMID 17566518. 
  186. ^ Rentzos M, Nikolaou C, Rombos A, Evangelopoulos ME, Kararizou E, Koutsis G, Zoga M, Dimitrakopoulos A, Tsoutsou A, Sfangos C. (2008). "Effect of treatment with methylprednisolone on the serum levels of IL-12, IL-10 and CCL2 chemokine in patients with multiple sclerosis in relapse". Clinical neurology and neurosurgery 110 (10): 992–6. doi:10.1016/j.clineuro.2008.06.005. PMID 18657352. 
  187. ^ Scarisbrick IA, Linbo R, Vandell AG, Keegan M, Blaber SI, Blaber M, Sneve D, Lucchinetti CF, Rodriguez M, Diamandis EP. (2008). "Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration". Biological chemistry 389 (6): 739–45. doi:10.1515/BC.2008.085. PMC 2580060. PMID 18627300. 
  188. ^ New Control System Of The Body Discovered - Important Modulator Of Immune Cell Entry Into The Brain - Perhaps New Target For The Therapy, Dr. Ulf Schulze-Topphoff, Prof. Orhan Aktas, and Professor Frauke Zipp (Cecilie Vogt-Clinic, Charité - Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and NeuroCure Research Center) [18]
  189. ^ Schulze-Topphoff U, Prat A, Prozorovski T, et al. (July 2009). "Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system". Nat. Med. 15 (7): 788–93. doi:10.1038/nm.1980. PMID 19561616. 
  190. ^ Rinta S, Kuusisto H, Raunio M, et al. (October 2008). "Apoptosis-related molecules in blood in multiple sclerosis". J Neuroimmunol. 205 (1–2): 135–41. doi:10.1016/j.jneuroim.2008.09.002. PMID 18963025. 
  191. ^ Kuenz B, Lutterotti A, Ehling R, et al. (2008). "Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple Sclerosis". In Zimmer, Jacques. PLoS ONE 3 (7): e2559. doi:10.1371/journal.pone.0002559. PMC 2438478. PMID 18596942. 
  192. ^ Chiasserini D, Di Filippo M, Candeliere A, Susta F, Orvietani PL, Calabresi P, Binaglia L, Sarchielli P. (2008). "CSF proteome analysis in multiple sclerosis patients by two-dimensional electrophoresis". European Journal of Neurology 15 (9): 998–1001. doi:10.1111/j.1468-1331.2008.02239.x. PMID 18637954. 
  193. ^ Frisullo G, Nociti V, Iorio R, et al. (October 2008). "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". J Neuroimmunol. 205 (1–2): 126–34. doi:10.1016/j.jneuroim.2008.09.003. PMID 18926576. 
  194. ^ Proceedings of the National Academy of sciences, complementary information [19]
  195. ^ a b Quintana FJ, Farez MF, Viglietta V, et al. (December 2008). "Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis". Proc. Natl. Acad. Sci. U.S.A. 105 (48): 18889–94. doi:10.1073/pnas.0806310105. PMC 2596207. PMID 19028871. 
  196. ^ Villar LM, Masterman T, Casanova B, et al. (June 2009). "CSF oligoclonal band patterns reveal disease heterogeneity in multiple sclerosis". J. Neuroimmunol. 211 (1–2): 101–4. doi:10.1016/j.jneuroim.2009.03.003. PMID 19443047. 
  197. ^ a b Rajneesh Srivastava, M.Sc et al. "Potassium Channel KIR4.1 as an Immune Target in Multiple Sclerosis", New England Journal of medicine, N Engl J Med 2012; 367:115-123 July 12, 2012 [20]
  198. ^ Linda Ottoboni, Brendan T. Keenan, Pablo Tamayo, Manik Kuchroo, Jill P. Mesirov, Guy J. Buckle, Samia J. Khoury, David A. Hafler, Howard L. Weiner, and Philip L. De Jager. An RNA Profile Identifies Two Subsets of Multiple Sclerosis Patients Differing in Disease Activity. Sci Transl Med, 26 September 2012 doi:10.1126/scitranslmed.3004186
  199. ^ Grant P .Parnell et al. The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease, http://dx.doi.org/10.1016/j.clim.2014.01.003, [21]
  200. ^ Plumb J, McQuaid S, Mirakhur M, Kirk J (April 2002). "Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis". Brain Pathol. 12 (2): 154–69. doi:10.1111/j.1750-3639.2002.tb00430.x. PMID 11958369. 
  201. ^ Mancini, M, Cerebral circulation time in the evaluation of neurological diseases [22]
  202. ^ Meng Law et al. Microvascular Abnormality in Relapsing-Remitting Multiple Sclerosis: Perfusion MR Imaging Findings in Normal-appearing White Matter [23]
  203. ^ Sarchielli P, Greco L, Floridi A, Floridi A, Gallai V. (2003). "Excitatory amino acids and multiple sclerosis: evidence from cerebrospinal fluid". Arch. Immunol. 60 (8): 1082–8. doi:10.1001/archneur.60.8.1082. PMID 12925363. 
  204. ^ Stoop MP, Dekker LJ, Titulaer MK, et al. (2008). "Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry". Proteomics 8 (8): 1576–85. doi:10.1002/pmic.200700446. PMID 18351689. 
  205. ^ Sarchielli P, Di Filippo M, Ercolani MV, et al. (April 2008). "Fibroblast growth factor-2 levels are elevated in the cerebrospinal fluid of multiple sclerosis patients". Neurosci Lett. 435 (3): 223–8. doi:10.1016/j.neulet.2008.02.040. PMID 18353554. 
  206. ^ Huttner HB, Schellinger PD, Struffert T, et al. (July 2009). "MRI criteria in MS patients with negative and positive oligoclonal bands: equal fulfillment of Barkhof's criteria but different lesion patterns". J. Neurol. 256 (7): 1121–5. doi:10.1007/s00415-009-5081-y. PMID 19252765. 
  207. ^ Villar LM, Espiño M, Costa-Frossard L, Muriel A, Jiménez J, Alvarez-Cermeño JC, High levels of cerebrospinal fluid free kappa chains predict conversion to multiple sclerosis, PMID 22814197
  208. ^ Sotelo J, Martínez-Palomo A, Ordoñez G, Pineda B. (2008). "Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosis". Annals of Neurology 63 (3): 303–11. doi:10.1002/ana.21316. PMID 18306233. 
  209. ^ von Büdingen HC, Harrer MD, Kuenzle S, Meier M, Goebels N (July 2008). "Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies". Eur Journal of Immunology 38 (7): 2014–23. doi:10.1002/eji.200737784. PMID 18521957. 
  210. ^ Vincze O, Oláh J, Zádori D, Klivényi P, Vécsei L, Ovádi J (May 2011). "A new myelin protein, TPPP/p25, reduced in demyelinated lesions is enriched in cerebrospinal fluid of multiple sclerosis". Biochem. Biophys. Res. Commun. 409 (1): 137–41. doi:10.1016/j.bbrc.2011.04.130. PMID 21565174. 
  211. ^ Orbach R, Gurevich M, Achiron A. Interleukin-12p40 in the spinal fluid as a biomarker for clinically isolated syndrome, Mult Scler. 2013 May 30
  212. ^ Cozzone, Zaaraoui and Ranjeva, "Distribution of Brain Sodium Accumulation Correlates with Disability in Multiple Sclerosis–A Cross-Sectional 23Na MR Imaging Study." Radiological Society of North America
  213. ^ Beggs CB, Shepherd SJ, Dwyer MG, Polak P, Magnano C, Carl E, Poloni GU, Weinstock-Guttman B, Zivadinov R. Sensitivity and specificity of SWI venography for detection of cerebral venous alterations in multiple sclerosis, Neurol Res. 2012 Oct;34(8):793-801. doi: 10.1179/1743132812Y.0000000048, PMID 22709857
  214. ^ Satoh J. (2008). "Molecular biomarkers for prediction of multiple sclerosis relapse" [Molecular biomarkers for prediction of multiple sclerosis relapse]. Nippon Rinsho (in Japanese) 66 (6): 1103–11. PMID 18540355. 
  215. ^ García-Barragán N, Villar LM, Espiño M, Sádaba MC, González-Porqué P, Alvarez-Cermeño JC (March 2009). "Multiple sclerosis patients with anti-lipid oligoclonal IgM show early favourable response to immunomodulatory treatment". Eur. J. Neurol. 16 (3): 380–5. doi:10.1111/j.1468-1331.2008.02504.x. PMID 19175382. 
  216. ^ Hagman S, Raunio M, Rossi M, Dastidar P, Elovaara I (May 2011). "Disease-associated inflammatory biomarker profiles in blood in different subtypes of multiple sclerosis: Prospective clinical and MRI follow-up study". Journal of Neuroimmunology 234 (1–2): 141–7. doi:10.1016/j.jneuroim.2011.02.009. PMID 21397339. 
  217. ^ Kuerten S et al. Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood. Clin Immunol. 2014 Mar 5. pii: S1521-6616(14)00051-5. doi: 10.1016/j.clim.2014.02.014, PMID 24607792
  218. ^ Gold R, Linington C (July 2002). "Devic's disease: bridging the gap between laboratory and clinic". Brain 125 (Pt 7): 1425–7. doi:10.1093/brain/awf147. PMID 12076994. 
  219. ^ 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
  220. ^ Holmes, Nick (15 November 2001). "Part 1B Pathology: Lecture 11 - The Complement System". Retrieved 2006-05-10. 
  221. ^ Lucchinetti, Claudia; Wolfgang Brück, Joseph Parisi, Bernd Scheithauer, Moses Rodriguez and Hans Lassmann (December 1999). "A quantitative analysis of oligodendrocytes in multiple sclerosis lesions - A study of 113 cases". Brain 122 (12): 2279–2295. doi:10.1093/brain/122.12.2279. PMID 10581222. Retrieved 2006-05-10. 
  222. ^ Kale N, Pittock SJ, Lennon VA, et al. (October 2009). "Humoral pattern II multiple sclerosis pathology not associated with neuromyelitis Optica IgG". Arch. Neurol. 66 (10): 1298–9. doi:10.1001/archneurol.2009.199. PMC 2767176. PMID 19822791. 
  223. ^ a b Wilner AN, Goodman (March 2000). "Some MS patients have "Dramatic" responses to Plasma Exchange". Neurology Reviews 8 (3). 
  224. ^ Hans Lassmann et al. A new paraclinical CSF marker for hypoxia‐like tissue damage in multiple sclerosis lesions, Oxford Journals Medicine Brain Volume 126, Issue 6 Pp. 1347-1357
  225. ^ Michael H. Barnett, MBBS and John W. Prineas, MBBS (2004). "Relapsing and Remitting Multiple Sclerosis: Pathology of the Newly Forming Lesion". Annals of Neurology 55 (1): 458–468. doi:10.1002/ana.20016. PMID 15048884. 
  226. ^ Breij EC, Brink BP, Veerhuis R, et al. (2008). "Homogeneity of active demyelinating lesions in established multiple sclerosis". Annals of Neurology 63 (1): 16–25. doi:10.1002/ana.21311. PMID 18232012. 
  227. ^ Mahad D, Ziabreva I, Lassmann H, Turnbull D. (2008). "Mitochondrial defects in acute multiple sclerosis lesions". Brain : a journal of neurology 131 (Pt 7): 1722–35. doi:10.1093/brain/awn105. PMC 2442422. PMID 18515320. 
  228. ^ 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
  229. ^ 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
  230. ^ Leussink VI, Lehmann HC, Meyer Zu Hörste G, Hartung HP, Stüve O, Kieseier BC (September 2008). "Rituximab induces clinical stabilization in a patient with fulminant multiple sclerosis not responding to natalizumab : Evidence for disease heterogeneity". J Neurology 255 (9): 1436–8. doi:10.1007/s00415-008-0956-x. PMID 18685916. 
  231. ^ Primary progressive multiple sclerosis
  232. ^ (Article in Spanish) Estudio longitudinal mediante imagen de resonancia magnética (RM) del efecto de la azatioprina [24]
  233. ^ The Mystery of the Multiple Sclerosis Lesion, Frontiers Beyond the Decade of the Brain, Medscape [25]
  234. ^ Smith SA, Farrell JA, Jones CK, Reich DS, Calabresi PA, van Zijl PC (October 2006). "Pulsed magnetization transfer imaging with body coil transmission at 3 Tesla: feasibility and application". Magn Reson Med 56 (4): 866–75. doi:10.1002/mrm.21035. PMID 16964602. 
  235. ^ Goldberg-Zimring D, Mewes AU, Maddah M, Warfield SK (2005). "Diffusion tensor magnetic resonance imaging in multiple sclerosis". J Neuroimaging 15 (4 Suppl): 68S–81S. doi:10.1177/1051228405283363. PMID 16385020. 
  236. ^ New imaging technique allows doctors to ‘see’ molecular activity
  237. ^ 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
  238. ^ Balk L, Tewarie P, Killestein J, Polman C, Uitdehaag B, Petzold A. Disease course heterogeneity and OCT in multiple sclerosis. Mult Scler. 2014 Jan 8
  239. ^ Cepok S, Jacobsen M, Schock S, et al. (November 2001). "Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis". Brain 124 (Pt 11): 2169–76. doi:10.1093/brain/124.11.2169. PMID 11673319. 
  240. ^ Cepok S, Jacobsen M, Schock S, et al. (November 2001). "Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis". Brain 124 (Pt 11): 2169–76. doi:10.1093/brain/124.11.2169. PMID 11673319. 
  241. ^ Pittock SJ, Reindl M, Achenbach S, et al. (January 2007). "Myelin oligodendrocyte glycoprotein antibodies in pathologically proven multiple sclerosis: frequency, stability and clinicopathologic correlations". Multiple Sclerosis 13 (1): 7–16. doi:10.1177/1352458506072189. PMID 17294606. 
  242. ^ Belogurov AA, Kurkova IN, Friboulet A, et al. (January 2008). "Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis". Journal of Immunology 180 (2): 1258–67. doi:10.4049/jimmunol.180.2.1258. PMID 18178866. 
  243. ^ Early research into a treatment for progressive MS
  244. ^ Fernández O, Fernández V, Mayorga C, et al. (December 2005). "HLA class II and response to interferon-beta in multiple sclerosis". Acta Neurol Scand. 112 (6): 391–4. doi:10.1111/j.1600-0404.2005.00415.x. PMID 16281922. 
  245. ^ van Baarsen LG, Vosslamber S, Tijssen M, et al. (2008). "Pharmacogenomics of Interferon-β Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients". In Lassmann, Hans. PLoS ONE 3 (4): e1927. doi:10.1371/journal.pone.0001927. PMC 2271130. PMID 18382694. 
  246. ^ Wiesemann E, Deb M, Hemmer B, Radeke HH, Windhagen A. (2008). "Early identification of interferon-beta responders by ex vivo testing in patients with multiple sclerosis". Clinical immunology (Orlando, Fla.) 128 (3): 306–13. doi:10.1016/j.clim.2008.04.007. PMID 18539537. 
  247. ^ Axtell RC et a. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis, PMID 20348925
  248. ^ Carrieri PB, Ladogana P, Di Spigna G, et al. (2008). "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". Immunopharmacol Immunotoxicol. 30 (4): 1–9. doi:10.1080/08923970802302753. PMID 18686100. 
  249. ^ Patients' Multiple Sclerosis Lesion Type Dictates Effective Treatment
  250. ^ Bitsch A, Brück W (2002). "Differentiation of multiple sclerosis subtypes: implications for treatment". CNS Drugs 16 (6): 405–18. doi:10.2165/00023210-200216060-00004. PMID 12027786. 
  251. ^ Debouverie M, Moreau T, Lebrun C, Heinzlef O, Brudon F, Msihid J (November 2007). "A longitudinal observational study of a cohort of patients with relapsing-remitting multiple sclerosis treated with glatiramer acetate". Eur J Neurol. 14 (11): 1266–74. doi:10.1111/j.1468-1331.2007.01964.x. PMID 17956447. 
  252. ^ Carrá A, Onaha P, Luetic G, et al. (2008). "Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing-remitting multiple sclerosis in Argentina". Eur. J. Neurol. 15 (4): 386–93. doi:10.1111/j.1468-1331.2008.02071.x. PMID 18353125. 
  253. ^ Gajofatto A, Bacchetti P, Grimes B, High A, Waubant E (October 2008). "Switching first-line disease-modifying therapy after failure: impact on the course of relapsing-remitting multiple sclerosis". Multiple sclerosis 15 (1): 50–8. doi:10.1177/1352458508096687. PMID 18922831. 
  254. ^ Byun E, Caillier SJ, Montalban X, et al. (March 2008). "Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis". Arch. Neurol. 65 (3): 337–44. doi:10.1001/archneurol.2008.47. PMID 18195134. 
  255. ^ Vandenbroeck K, Matute C (May 2008). "Pharmacogenomics of the response to IFN-beta in multiple sclerosis: ramifications from the first genome-wide screen". Pharmacogenomics 9 (5): 639–45. doi:10.2217/14622416.9.5.639. PMID 18466107. 
  256. ^ Corlobé A et al. Cavitary lesions in multiple sclerosis: Multicenter study on twenty patients, Rev Neurol (Paris). 2013 Oct 17. pii: S0035-3787(13)00939-9. doi: 10.1016/j.neurol.2013.02.010, PMID 24139243
  257. ^ 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
  258. ^ 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
  259. ^ Frisullo G, Nociti V, Iorio R, et al. (December 2008). "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". J Neuroimmunol. 205 (1–2): 126–34. doi:10.1016/j.jneuroim.2008.09.003. PMID 18926576. 
  260. ^ Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP. (2008). "Subclinical MS: follow-up of four cases". European Journal of Neurology 15 (8): 858–61. doi:10.1111/j.1468-1331.2008.02155.x. PMID 18507677. 
  261. ^ Engell T (May 1989). "A clinical patho-anatomical study of clinically silent multiple sclerosis". Acta Neurol. Scand. 79 (5): 428–30. doi:10.1111/j.1600-0404.1989.tb03811.x. PMID 2741673. 
  262. ^ Mews I, Bergmann M, Bunkowski S, Gullotta F, Brück W (April 1998). "Oligodendrocyte and axon pathology in clinically silent multiple sclerosis lesions". Mult. Scler. 4 (2): 55–62. doi:10.1177/135245859800400203. PMID 9599334. 
  263. ^ Lebrun C, Bensa C, Debouverie M, et al. (2008). "Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile". J Neurol Neurosurg Psychiatry 79 (2): 195–198. doi:10.1136/jnnp.2006.108274. PMID 18202208. 

External links[edit]