Multiple sclerosis is a condition where the CNS of a person present a special kind of distributed lesions (sclerosis)  whose pathophysiology is complex and still under investigation. It is considered a pathological entity by some authors and a clinical entity by some others.
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. MS is active even during remission periods. GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS
At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, intrathecalIg 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. The scars that give the name to the condition are produced by the astrocyte cells healing old lesions.
According to the view of most researchers, a special subset of lymphocytes, called T helper cells, specifically Th1 and Th17, play a key role in the development of the lesion. 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. Under normal circumstances, these lymphocytes can distinguish between self and non-self. However, in a person with MS, these cells recognize healthy parts of the central nervous system as foreign and attack them as if they were an invading virus, triggering inflammatory processes and stimulating other immune cells and soluble factors like cytokines and antibodies. Many of the myelin-recognizing T cells belong to a terminally differentiated subset called co-stimulation-independent effector-memory T cells.
Recently other type of immune cells, B Cells, have been also implicated in the pathogenesis of MS and in the degeneration of the axons. and the oligodendrocytes.
The axons themselves can also be damaged by the attacks. Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur.
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
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.
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. Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical. Others classify them as hippocampal, cortical, and WM lesions, 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. The distribution of the lesions could be linked to the clinical evolution
Post-mortem autopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord. 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 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. 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.
Due to the distribution of the lesions, since 1916 they are also known as Dawson's fingers. They appear around the brain blood vessels.
Spinal cord damage
Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability. In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues. It has been shown that Fractional anisotropy of cervical spinal cord is lower than normal, showing that there is damage hidden from normal MRI.
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.
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.
Retina and optic nerve damage
The Retina and the optic nerve originate as outgrowths of the brain during embryonic development, so the retina is considered part of the central nervous system (CNS). 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
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.
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. Two eye problems, Uveitis and retinal phlebitis are manifestations of MS.
Proposed procedures for the neurodegeneration are than Narrower arterioles and wider venules have been reported. Also rigidity has been noticed
Neural and axonal damage
The axons of the neurons are damaged probably by B-Cells, though currently no relationship has been established with the relapses or the attacks. It seems that this damage is a primary target of the immune system, i.e. not secondary damage after attacks against myelin, though this has been disputed
Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.
Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy.
Peripheral nervous system involvement
Though MS is defined as a CNS condition, some reports link problems in the peripheral nervous system with the presence of MS plaques in the CNS
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. 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. According with the most recent research, an active lesion is composed of different layers:
Lesion external layer: Number of oligodendrocyte cell bodies decreases. Remaining oligodendrocytes are sometimes swollen or dying. Myelin sheaths are still intact but swollen. Small increase in microglia and T cells.
Active layer:Phagocytic demyelinating areas: There is myelin debris taken up by local microglia and phagocytes entering from the bloodstream. More T cells in these areas, and in the space adjacent to blood vessels.
Recently demyelinated tissue: Tissues were full of myelin-containing phagocytes. Signs of early remyelination together with small numbers of oligodendrocytes. Large numbers of T cells, B cells, and other immune cells concentrated around blood vessels.
Inactive layer: Again activated microglia and dendritic cells were also found around blood vessels.
Lesions under MRI
Most MS lesions are isointense to white matter (they appear bright) on T1-weighted MRI, but some are "hypointense" (lower intensity). These are called "black holes" (BH). They appear specially in the supratentorial region of the brain.
When BH's appear, around half of them revert in a month. This is considered a sign of remyelination. When they remain, this is regarded as a sign of permanent demyelination and axonal loss. This has been shown on post-mortem autopsies.
Small lesions are invisible under MRI. Therefore clinically assisted diagnostic criteria are still required for a more accurate MS diagnosis than MRI alone.
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. When gadolinium is used, the lesion expansion can be classified as nodular or ringlike
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. Some research groups consider some areas of the NAWM with clusters of microglial nodules as "preactive MS lesions".
Blood–brain barrier disruption
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.
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. 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. 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.
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. 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.
Recently it has been found that BBB damage happens even in non-enhancing lesions. MS has an important vascular component.
Postmortem BBB study
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.
In vivo BBB study
As lesions appear (using MRI) in "Normal-appearing white matter" (NAWM), the cause that finally triggers the BBB disruption is supposed to be there. The damaged white matter is known as "Normal-appearing white matter" (NAWM) and is where lesions appear. These lesions form in NAWM before blood–brain barrier breakdown.
BBB can be broken centripetally or centrifugally, the first form being the most normal. 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. The BBB breakdown is responsible for monocyte infiltration and inflammation in the brain. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lynkinase
Using iron nanoparticles, involvement of macrophages in the BBB breakdown can be detected. 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, and are supposed to be related to the mechanism of action of interferons.
Whether BBB dysfunction is the cause or the consequence of MS is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins. Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins. (Adhesion molecules could also play a role in inflammation) 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. Other protein also involved is CXCL12, which is found also in brain biopsies of inflammatory elements, and which could be related to the behavior of CXCL13 under methylprednisolone therapy. Some molecular biochemical models for relapses have been proposed.
Normally, gadolinium enhancement is used to show BBB disruption on MRIs. 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.
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. 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, but not in the grey matter lesions. Besides, uric acid levels are lower during relapses.
Damage before BBB disruption
Special MRI methods
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:
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.
Abnormalities in the gray matter (Diffusion tensor MRI alterations) of the brain parenchyma are present early in the course of multiple sclerosis
Normal appearing brain tissues
Using several texture analysis technologies, it is possible to classify white matter areas into three categories: normal, normal-appearing and lesions. Currently, it is possible to detect lesions before they present demyelination, and they are called pre-active lesions. A fourth area called DAWM (diffusely abnormal white matter) has recently been proposed and can help to differentiate PPMS and SPMS. Abundant extracellular myelin in the meninges of patients with multiple sclerosis has been found
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. The amount of interneuronal Parvalbumin is lower than normal in brain's motor cortex areas, and oxidative injury of oligodendrocytes and neurons could be associated with active demyelination and axonal injury.
Most of the brain in MS is unafected. Though obviously normal white matter appears normal under MRI, so does the NAWM white matter described in the next section. To stablish a difference, normal white matter is named Non-lesional white matter (NLWM)
Normal appearing White Matter
The white matter with hidden but MRI-visible damage is known as "Normal-appearing white matter" (NAWM) and is where lesions appear. 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.
BBB disruption takes place on NAWM areas. 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.
Oligodendrocyte abnormalities appear to be crucially involved. 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.
Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls.
NAWM shows a decreased perfusion which does not appear to be secondary to axonal loss. 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. This would be consistent again with cases of Chronic cerebrospinal venous insufficiency.
White matter lesions appear in NAWM areas, and their behavior can be predicted by MRI parameters as MTR (magnetization transfer ratio). This MTR parameter is related to axonal density.
It also seems that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at Thr97 than normal individuals.
Gray matter damage. Normal Appearing Gray Matter
Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disability. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS.Epstein-Barr virus could be involved, but is not likely. 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.
Iron depositions appear in deep gray matter by magnetic field correlation MRI
Diffusely abnormal white matter
Other active area of study is the Diffusely abnormal white matter (DAWM). It seems to be a reduction of myelin phospholipids that correlates with a reduction of the myelin water fraction. 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. Changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI
Dirty appearing white matter
Dirty-appearing white matter (referred to as DAWM like the former case) is defined as a region with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (NAWM) and that of plaque on T2-weighted and proton density imaging. It is probably created by loss of myelin phospholipids, detected by the short T2 component, and axonal reduction.
Originally proposed as a biomarker, 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 
Origin of the normal-appearing tissues
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
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. Some other authors like Tracy Putnam pointed to venous obstructions.
Some authors like Franz Schelling proposed a mechanical damage procedure based on violent blood reflux. Later the focus moved to softer hemodynamic abnormalities, which were showing precede changes in sub-cortical gray matter and in substantia nigra. 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.
Other theories point to a possible primary endothelial dysfunction. The importance of vascular misbehaviour in MS pathogenesis has also been independently confirmed by seven-tesla MRI. 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.
Some morphologically special medullar lesions (wedge-shaped) have also been linked to venous insufficiency.
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
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. According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis. Zamboni's results were criticized as some of his studies were not blinded and they need to be verified by further studies. As of 2010[update] the theory is considered at least defensible
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.
In 2012 was reported that a subset of MS patients have a seropositive anti-Kir4.1 status, which can represent up to a 47% of the MS cases, and the study has been reproduced by at least other group.
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.
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, researchers expect to find biomarkers able to yield a better diagnosis, and able to predict the response to the different available treatments. As of 2014 no biomarker with perfect correlation has been found, but some of them have shown a special behavior like an autoantibody against the potassium channel Kir4.1. Biomarkers are expected to play an important role in the near future
Molecular biomarkers in blood
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.
Creatine and Uric acid levels are lower than normal, at least in women. Ex vivo CD4(+) T cells isolated from the circulation show a wrong TIM-3 (Immunoregulation) behavior, and relapses are associated with CD8(+) T Cells. 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.Platelets are known to have abnormal high levels.
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. 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. 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
There is evidence of Apoptosis-related molecules in blood and they are related to disease activity.B cells in CSF appear, and they correlate with early brain inflammation. 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. Expression of some specific proteins in circulating CD4+ T cells is a risk factor for conversion from CIS to clinically defined multiple sclerosis.
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, 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.
Finally, a promising biomarker under study is an antibody against the potassium channel protein KIR4.1. 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
By RNA profile
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.
By transcription factor
The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease. 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
Endothelial dysfunction has been reported in MS and could be used as biomarker via biopsia. Blood circulation is slower in MS patients and can be meassured using contrast or by MRI
Interleukin-12p40 has been reported to separate RRMS and CIS from other neurological diseases
In Cerebrospinal Fluid
It has been known for quite some time that glutamate is present at higher levels in CSF during relapses compared to healthy subjects and to MS patients before relapses. This observation has been linked to the activity of the infiltrating leukocytes and activated microglia, and to the damage to the axons
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. Also Fibroblast growth factor-2 appear higher at CSF.
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. Free kappa chains in CSF are documented and have been proposed as a marker for MS evolution
Varicella-zoster virus particles have been found in CSF of patients during relapses, but this particles are virtually absent during remissions. 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. As of 2011, a recently discovered myelin protein TPPP/p25, has been found in CSF of MS patients
A study found that quantification of several immune cell subsets, both in blood and CSF, showed differences between intrathecal (from the spine) and systemic immunity, and between CSF cell subtypes in the inflammatory and noninflammatory groups (basically RRMS/SPMS compared to PPMS). This showed that some patients diagnosed with PPMS shared an inflammatory profile with RRMS and SPMS, while others didn't.
Other study found using a proteomic analysis of the CSF that the peak intensity of the signals corresponding to Secretogranin II and Protein 7B2 were significantly upregulated in RRMS patients compared to PrMS (p<0.05), whereas the signals of Fibrinogen and Fibrinopeptide A were significantly downregulated in CIS compared to PrMS patients
Biomarkers in brain cells and biopsies
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. 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.
Biomarkers by MRI
Recently SWI adjusted magnetic resonance has given results close to 100% specificity and sensitivity respect McDonalds CDMS status
Subgroups by molecular biomarkers
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. 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.
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.
As previously reported, there is an antibody against the potassium channel protein KIR4.1 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
Heterogeneity of the disease
Multiple sclerosis has been reported to be heterogeneus in its behavior, in its underlying mechanisms, in its response to medication  and respect the response to the specific potassium channel autoantibody Kir4.1
Four different damage patterns have been identified in patient's brain tissues. The original report suggests that there may be several types of MS with different immune causes, and that MS may be a family of several diseases. Though originally was required a biopsy to classify the lesions of a patient, since 2012 it is possible to classify them by a blood test looking for antibodies against 7 lipids, three of which are cholesterol derivatives
It is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. In any case, understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions
According to one of the researchers involved in the original research "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."
The 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. This pattern has been considered similar to damage seen in NMO, though AQP4 damage does not appear in pattern II MS lesions Nevertheless, pattern II has been reported to respond to plasmapheresis, 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, making it a candidate for research into the Kir4.1 connection.
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. For others, it represents ischaemia-like injury with a remarkable availability of a specific biomarker in CSF
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. Anyway, the heterogeneity could be true only for the early stage of the disease. Some lesions present mitochondrial defects that could distinguish types of lesions. Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.
Nevertheless, after some debate among research groups, it seems like the four patterns model is accepted
Several studies trying to stablish a relationship between the pathological findings and MRI findings have been performed.
For example, pulsed magnetization transfer imaging, diffusion Tensor MRI, and VCAM-1 enhanced MRI have been reported to show the pathological differences of these patterns. Together with MRI, magnetic resonance spectroscopy allows to see the biochemical composition of the lesions, which shows at least two different patterns
Currently as of 2014, the MRI studies have lead to the proposal of four MRI phenotypes, though both the classification and the relationship with the pathology remains controversial.
Other proposed correlations
Several correlations have been studied trying to stablish a pathological classification:
With clinical courses: No definitive relationship between these patterns and the clinical subtypes has been established by now, but some relations have been established. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy).Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions.
With Optic Coherence Tomography: OCT of the retinal layer yields different results for PPMS and RRMS
With CSF findings: Teams in Oxford and Germany, found correlation with CSF and progression in November 2001, and hypotheses have been made suggesting correlation between CSF findings and pathophysiological patterns. In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found, though this is disputed. High levels of anti-nuclear antibodies are found normally in patients with MS. Antibodies against Neurofascin–186 could be involved in a subtype of MS
With responses to therapy: It is known that 30% of MS patients are non-responsive to Beta interferon. 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, specially IL-17, and interleukins IL12/IL10 ratio has been proposed as marker of clinical course. Besides:
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.
People non-responsive to interferons are the most responsive to Copaxone 
In general, people non-responsive to a treatment is more responsive to other, and changing therapy can be effective.
There are genetic differences between responders and not responders. 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
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
Primary progressive MS
It is currently discussed whether Primary Progressive MS (PPMS) is a different pathological entity or a different degree of the same pathology. No agreement has been established but there are some pathological features that are specific to PPMS. For example, meningeal inflammation is different respect standard cases of Recurrent-Recidivant MS (RRMS) and sodium accumulation is higher
Pathology of early MS and silent MS
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. Therefore for studying this initial stage no clinical CDMS cases and pathological definitions are normally used. 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., or sometimes Clinically silent MS. 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
Also cases after the CIS but before the confirming second attack (Preclinical MS) can be accepted to study the initial MS pathology
These studies are performed for ethiological research purposes and not for improving diagnosis.
^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. PMID18715571.
^Brosnan, C. F. and Raine, C. S. (2013), The astrocyte in multiple sclerosis revisited. Glia, 61: 453–465. doi:10.1002/glia.22443
^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. PMID18272891.
^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. PMID22458983.
^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 
^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. PMID18829630.
^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. PMID17923625.
^Poonawalla AH, Hasan KM, Gupta RK, et al. (2008). "Diffusion-Tensor MR Imaging of Cortical Lesions in Multiple Sclerosis: Initial Findings". Radiology246 (3): 880–6. doi:10.1148/radiol.2463070486. PMID18195384.
^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". NeuroImage42 (4): 1324–8. doi:10.1016/j.neuroimage.2008.06.028. PMID18652903.
^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. PMID17846269.
^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 Medicine59 (5): 1035–42. doi:10.1002/mrm.21595. PMID18429010.
^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". Brain130 (Pt 8): 2211–9. doi:10.1093/brain/awm110. PMID17535835.
^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 Sclerosis15 (2): 180–8. doi:10.1177/1352458508096876. PMID18845658.
^Three-Dimensional Geometries Representing the Retinal Nerve Fiber Layer in Multiple Sclerosis, Optic Neuritis, and Healthy Eyes 
^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. PMID18424482.
^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 neurology65 (7): 924–8. doi:10.1001/archneur.65.7.924. PMID18625859.
^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 Augenheilkd226 (4): 272–5. doi:10.1055/s-0028-1109289. PMID19384781.
^Kochkorov A, Gugleta K, Kavroulaki D, et al. (April 2009). "Rigidity of retinal vessels in patients with multiple sclerosis". Klin Monatsbl Augenheilkd226 (4): 276–9. doi:10.1055/s-0028-1109291. PMID19384782.
^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. PMID18804534.
^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". Brain126 (Pt 2): 433–7. doi:10.1093/brain/awg038. PMID12538409.
^ abcBsibsi 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
^Alireza Minagar and J Steven Alexander, Blood–brain barrier disruption in multiple sclerosis 
^ abCorreale, Jorge; Andrés Villa (24 July 2006). "The blood–brain-barrier in multiple sclerosis: Functional roles and therapeutic targeting". Autoimmunity40 (2): 148. doi:10.1080/08916930601183522.
^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 States110 (3): 832. doi:10.1073/pnas.1209362110.Cite uses deprecated parameters (help)
^Prat, Elisabetta; Roland Martin (March–April 2002). "The immunopathogenesis of multiple sclerosis". Journal of Rehabilitation Research and Development39 (2): 187.
^ abGray 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. PMID18716555.
^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 Sclerosis13 (7): 884–94. doi:10.1177/1352458507076970. PMID17468443.
^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
^ abAllen et al.; McQuaid, S; Mirakhur, M; Nevin, G (2001). "Pathological abnormalities in the normal-appearing white matter in multiple sclerosis". Neurol Sci22 (2): 141–4. doi:10.1007/s100720170012. PMID11603615.
^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. PMID18714030.
^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 NeuroTherapeutics4 (3): 434–42. doi:10.1016/j.nurt.2007.05.005. PMID17599709.
^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. PMID16412833.
^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 neurosurgery108 (6): 527–31. doi:10.1016/j.clineuro.2005.08.004. PMID16202511.
^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. PMID17413323.
^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. PMID18312403.
^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. PMID17762945.
^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 Sclerosis13 (7): 880–3. doi:10.1177/1352458507076411. PMID17468444.
^Holley JE, Newcombe J, Winyard PG, Gutowski NJ (2007). "Peroxiredoxin V in multiple sclerosis lesions: predominant expression by astrocytes". Multiple Sclerosis13 (8): 955–61. doi:10.1177/1352458507078064. PMID17623739.
^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 neuroradiology31 (3): 541–8. doi:10.3174/ajnr.A1839. PMID19850760.
^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 
^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 hypotheses51 (4): 299–303. doi:10.1016/S0306-9877(98)90052-4. PMID9824835.
^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
^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.
^ abDe 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 Metabolism28 (10): 1645–51. doi:10.1038/jcbfm.2008.72. PMID18594554.
^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
^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". Radiology231 (3): 645–52. doi:10.1148/radiol.2313030996. PMID15163806.
^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 research81 (5): 687–95. doi:10.1002/jnr.20587. PMID16007681.
^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 cerebrale187 (3): 459–65. doi:10.1007/s00221-008-1317-9. PMID18297277.
^Lukas Haider et al. Oxidative damage in multiple sclerosis lesions, Brain Advance Access published June 7, 2011, doi:10.1093/brain/awr128
^Beggs, Clive B. "Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis." BMC medicine 11.1 (2013): 142. 
^Petzold A1, Tozer DJ, Schmierer K. Axonal damage in the making: neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter, Exp Neurol. 2011 Dec;232(2):234-9. doi: 10.1016/j.expneurol.2011.09.011. Epub 2011 Sep 17.
^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
^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.
^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 Thai90 (12): 2689–94. PMID18386722.
^Nicholas AP, Sambandam T, Echols JD, Tourtellotte WW. (2004). "Increased citrullinated glial fibrillary acidic protein in secondary progressive multiple sclerosis". The Journal of Comparative Neurology473 (1): 128–36. doi:10.1002/cne.20102. PMID15067723.
^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 Metabolism28 (10): 1645–51. doi:10.1038/jcbfm.2008.72. PMID18594554.
^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. PMID9629851.
^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 Letters582 (18): 2685–8. doi:10.1016/j.febslet.2008.06.050. PMID18616943.
^Fisher E, Lee JC, Nakamura K, Rudick RA (September 2008). "Gray matter atrophy in multiple sclerosis: a longitudinal study". Annals of Neurology64 (3): 255–65. doi:10.1002/ana.21436. PMID18661561.
^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. PMID20965961.
^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. PMID19433660.
^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. PMID16039866.
^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
^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
^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.
^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 sciences290 (1–2): 190–3. doi:10.1016/j.jns.2009.12.017. PMID20056253.
^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
^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 Angiol29 (2): 183–8. PMID20351667.
^Al-Omari MH, Rousan LA (April 2010). "Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis". Int Angiol29 (2): 115–20. PMID20351667.
^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.]". Nervenarzt81 (6): 740–6. doi:10.1007/s00115-010-2972-1. PMID20386873.
^Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ (August 2010). "No cerebrocervical venous congestion in patients with multiple sclerosis". Annals of Neurology68 (2): 173–83. doi:10.1002/ana.22085. PMID20695010.
^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 Neurology68 (2): 255–259. doi:10.1002/ana.22132. PMID20695018.edit
^Damadian RV, Chu D. The possible role of cranio-cervical trauma and abnormal CSF hydrodynamics in the genesis of multiple sclerosis, 2011, 
^Zamboni et al. CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies, 2010 
^Raymond V. Damadian and David Chu, The Possible Role of Cranio-Cervical Trauma and Abnormal CSF Hydrodynamics in the Genesis of Multiple Sclerosis 
^Alcázar A1, Regidor I, Masjuan J, Salinas M, Alvarez-Cermeño JC. Axonal damage induced by cerebrospinal fluid from patients with relapsing-remitting multiple sclerosis, J Neuroimmunol. 2000 Apr 3;104(1):58-67.
^Alvarez-Cermeño JC1, Cid C, Regidor I, Masjuan J, Salinas-Aracil M, Alcázar-González A. The effect of cerebrospinal fluid on neurone culture: implications in the pathogenesis of multiple sclerosis. Rev Neurol. 2002 Nov 16-30;35(10):994-7.
^Cid C1, Alvarez-Cermeño JC, Camafeita E, Salinas M, Alcázar A. Antibodies reactive to heat shock protein 90 induce oligodendrocyte precursor cell death in culture. Implications for demyelination in multiple sclerosis FASEB J. 2004 Feb;18(2):409-11. Epub 2003 Dec 19.
^Tiwari-Woodruff SK1, Myers LW, Bronstein JM. Cerebrospinal fluid immunoglobulin G promotes oligodendrocyte progenitor cell migration. J Neurosci Res. 2004 Aug 1;77(3):363-6.
^Cristofanilli M1, Cymring B, Lu A, Rosenthal H, Sadiq SA. Cerebrospinal fluid derived from progressive multiple sclerosis patients promotes neuronal and oligodendroglial differentiation of human neural precursor cells in vitro, Neuroscience. 2013 Oct 10;250:614-21. doi: 10.1016/j.neuroscience.2013.07.022. Epub 2013 Jul 19.
^Cristofanilli M1, Rosenthal H1, Cymring B1, Gratch D1, Pagano B1, Xie B1, Sadiq SA2, Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice, Exp Neurol. 2014 Aug 8. pii: S0014-4886(14)00248-9. doi: 10.1016/j.expneurol.2014.07.020, PMID 25111532
^ abSrivastava 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
^Raphael Schneider, Autoantibodies to Potassium Channel KIR4.1 in Multiple Sclerosis, doi: 10.3389/fneur.2013.00125, PMID 24032025
^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.
^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) 
^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
^ abRajneesh 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
^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 
^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.
^Kanabrocki EL, Ryan MD, Hermida RC, et al. (2008). "Uric acid and renal function in multiple sclerosis". Clin Ter159 (1): 35–40. PMID18399261.
^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. PMID18396337.
^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. PMID18540355.
^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. PMID17566518.
^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 neurosurgery110 (10): 992–6. doi:10.1016/j.clineuro.2008.06.005. PMID18657352.
^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) 
^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. PMID19561616.
^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 Neurology15 (9): 998–1001. doi:10.1111/j.1468-1331.2008.02239.x. PMID18637954.
^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. PMID18926576.
^Proceedings of the National Academy of sciences, complementary information 
^ abRajneesh 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 
^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
^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. PMID11958369.
^Mancini, M, Cerebral circulation time in the evaluation of neurological diseases 
^Meng Law et al. Microvascular Abnormality in Relapsing-Remitting Multiple Sclerosis: Perfusion MR Imaging Findings in Normal-appearing White Matter 
^Orbach R, Gurevich M, Achiron A. Interleukin-12p40 in the spinal fluid as a biomarker for clinically isolated syndrome, Mult Scler. 2013 May 30
^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. PMID12925363.
^Frigo M1, Cogo MG, Fusco ML, Gardinetti M, Frigeni B., Glutamate and multiple sclerosis, Curr Med Chem. 2012;19(9):1295-9, PMID 22304707
^Stoop MP, Dekker LJ, Titulaer MK, et al. (2008). "Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry". Proteomics8 (8): 1576–85. doi:10.1002/pmic.200700446. PMID18351689.
^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. PMID18353554.
^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. PMID19252765.
^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
^Sotelo J, Martínez-Palomo A, Ordoñez G, Pineda B. (2008). "Varicella-zoster virus in cerebrospinal fluid at relapses of multiple sclerosis". Annals of Neurology63 (3): 303–11. doi:10.1002/ana.21316. PMID18306233.
^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 Immunology38 (7): 2014–23. doi:10.1002/eji.200737784. PMID18521957.
^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. PMID21565174.
^Han S1, Lin YC, Wu T, Salgado AD, Mexhitaj I, Wuest SC, Romm E, Ohayon J, Goldbach-Mansky R, Vanderver A, Marques A, Toro C, Williamson P, Cortese I, Bielekova B. Comprehensive immunophenotyping of cerebrospinal fluid cells in patients with neuroimmunological diseases, J Immunol. 2014 Mar 15;192(6):2551-63. doi: 10.4049/jimmunol.1302884. Epub 2014 Feb 7, PMID 24510966
^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
^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
^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. PMID18540355.
^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 Neuroimmunology234 (1–2): 141–7. doi:10.1016/j.jneuroim.2011.02.009. PMID21397339.
^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
^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 Neurology255 (9): 1436–8. doi:10.1007/s00415-008-0956-x. PMID18685916.
^F. Quintana et al., Specific Serum Antibody Patterns Detected with Antigen Arrays Are Associated to the Development of MS in Pediatric Patients, Neurology, 2012. Freely available at 
^Harnesing the clinical value of biomarkers in MS, International Journal of MS care, June 2012 
^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
^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
^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
^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 Med56 (4): 866–75. doi:10.1002/mrm.21035. PMID16964602.
^Goldberg-Zimring D, Mewes AU, Maddah M, Warfield SK (2005). "Diffusion tensor magnetic resonance imaging in multiple sclerosis". J Neuroimaging15 (4 Suppl): 68S–81S. doi:10.1177/1051228405283363. PMID16385020.
^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
^Shahamat Tauhid, Mohit Neema, Brian C. Healy, Howard L. Weiner, Rohit Bakshi, MRI phenotypes based on cerebral lesions and atrophy in patients with multiple sclerosis, Journal of neurological sciences, DOI: 10.1016/j.jns.2014.08.047
^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. PMID18539537.
^Axtell RC et a. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis, PMID 20348925
^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. PMID18686100.
^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. PMID17956447.
^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. PMID18353125.
^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 sclerosis15 (1): 50–8. doi:10.1177/1352458508096687. PMID18922831.
^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. PMID18195134.
^Vandenbroeck K, Matute C (May 2008). "Pharmacogenomics of the response to IFN-beta in multiple sclerosis: ramifications from the first genome-wide screen". Pharmacogenomics9 (5): 639–45. doi:10.2217/146224126.96.36.1999. PMID18466107.
^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
^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
^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
^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. PMID18926576.