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, especially the vascular endothelium, 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 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 (the most normal) or centrifugally. several possible biochemical disrupters were proposed. some hypotheses about how the bbb is compromised revolve around the presence of compounds in the blood that could interact with vessels only in the nawm areas. the permeability of two cytokines, interleukin 15 and lps, may be involved in bbb breakdown. 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 lyn kinase. using iron nanoparticles, involvement of macrophages in bbb breakdown can be detected. a special role is played by matrix metalloproteinases. these increase bbb t-cell permeability, specially in the case of mmp-9 and are supposedly related to the mechanism of action of interferons. whether bbb dysfunction is the cause or the consequence of ms is 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. another protein 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 in gray matter in spms. they persist in inactive lesions, particularly in ppms. a uric acid deficiency was implicated in this process. uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in ms by preventing bbb breakdown through inactivation of peroxynitrite. the low level of uric acid found in people with ms is manifestedly causative rather than a tissue damage consequence in the white matter lesions, but not in the grey matter lesions. uric acid levels are lower during relapses. proposed causes it is not known what causes ms. several problems appear together with the white matter lesions, like cortical lesions and normal-appearing tissues. several theories have been proposed to explain it. some areas that appear normal under normal mri look abnormal under special mri, like magnetisation transfer mtr-mri. these are called normal appearing white matter (nawm) and normal appearing grey matter (nagm). the cause why the normal appearing areas appear in the brain is unknown, but seems clear that they appear mainly in the ventricles and that they predict the course of the disease. given that ms lesions begin inside the nawm areas, these areas are expected to be produced by the same underlying condition that produces the lesions, and therefore the ultimate ms underlying condition, whatever it is. historically, several theories about how these areas appear have been presented: autoimmune theories the search for an auto-antigen has taken a long time, but at least there is one reported. it is the enzyme gdp-l-fucose synthase. this theory in part could also explain why some patients report amelioration under dietary treatment. hervs human endogenous retroviruses (hervs) have been reported in ms for several years. in fact, one of the families, human endogenous retrovirus-w was first discovered while studying ms patients. recent research as of 2019 point to one of the herv-w viruses (phev-w), and specifically one of the proteins of the viral capsid that has been found to activate microglia in vitro. activated microglia in turn produces demyelination. some interactions between the epstein-barr virus and the hervs could be the trigger of the ms microglia reactions. supporting this study, a monoclonal antibody against the viral capside (temelimab) has shown good results in trials in phase iib. blood flow related 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. mechanical flow: 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. endothelium: 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. venous insufficiency: some morphologically special medullar lesions (wedge-shaped) have also been linked to venous insufficiency. bbb infection: 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 ccsvi: 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 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. haemodynamic problems have been found in the blood flow of ms patients using doppler, initially using transcranial color-coded duplex sonography (tccs), pointing to a relationship with a vascular disease called chronic cerebro-spinal venous insufficiency (ccsvi). in 2010 there were conflicting results when evaluating the relationship between ms and ccsvi. but is important to note that positives have appeared among the blinded studies. csf flow: other theories focus in the possible role of cerebrospinal fluid flow impairment. this theory could be partially consistent with the previous one. currently a small trial with 8 participants has been performed csf composition: kir4.1 and anoctamin-2 whatever the underlying primary condition is, it is expected to be a soluble factor in the csf, maybe an unknown cytokine or ceramide, or a combination of them. also b-cells and microglia could be involved. in particular, it is known that b-cells of ms patients secrete an unknown toxin against oligodendrocytes it has been reported several times that csf of some ms patients can damage myelin in culture and mice and ceramides have been recently brought into the stage. whatever the problem is, it produces apoptosis of neurons respecting astrocytes in 2012 it 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 two other groups. in 2016 a similar association was reported for anti-anoctamin-2 if the existence of any of these subsets of ms is confirmed, the situation would be similar to what happened for devic disease and aquaporin-4. ms could be considered a heterogeneous condition or a new medical entity will be defined for these cases. primary neuro-degeneration theories some authors propose a primary neurodegenerative factor. maybe the strongest argument supporting this theory comes from the comparison with nmo. though autoimmune demyelination is strong, axons are preserved, showing that the standard model of a primary demyelination cannot be hold. the theory of the trans-synaptic degeneration, is compatible with other models based in the csf biochemistry. others propose an oligodendrocyte stress as primary dysfunction, which activates microglia creating the nawm areas and others propose a yet-unknown intrinsic cns trigger induces the microglial activation and clustering, which they point out could be again axonal injury or oligodendrocyte stress. finally, other authors point to a cortical pathology which starts in the brain external layer (pial surface) and progresses extending into the brain inner layers genetic causes if as expected ms is an heterogeneous disease and the lesion development process would not be unique. in particular, some ppms patients have been found to have a special genetic variant named rapidly progressive multiple sclerosis which would behave differently from what here is explained. it is due to a mutation inside the gene nr1h3, an arginine to glutamine mutation in the position p.arg415gln, in an area that codifies the protein lxra. biomarkers main:multiple sclerosis biomarkers several biomarkers for diagnosis, disease evolution and response to medication (current or expected) are under research. while most of them are still under research, there are some of them already well stablished: oligoclonal bands: they present proteins that are in the cns or in blood. those that are in cns but not in blood suggest a diagnosis of ms. mrz-reaction: a polyspecific antiviral immune response against the viruses of measles, rubella and zoster found in 1992. in some reports the mrzr showed a lower sensitivity than ocb (70% vs. 100%), but a higher specificity (69% vs. 92%) for ms. free light chains (flc). several authors have reported that they are comparable or even better than oligoclonal bands.