pathophysiology of multiple sclerosis pathophysiology of multiple sclerosis multiple sclerosis is an inflammatory demyelinating disease of the cns in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration, and tissue damage. the underlying cause is currently unknown. current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology, provide support for the notion that ms is not a single disease but rather a spectrum. structure of a typical neuron myelin sheath of a healthy neuron dendrite soma axon nucleus node ofranvier axon terminal schwann cell myelin sheath there are three clinical phenotypes: relapsing-remitting ms (rrms), characterized by periods of neurological worsening following by remissions; secondary-progressive ms (spms), in which there is gradual progression of neurological dysfunction with fewer or no relapses; and primary-progressive ms (ms), in which neurological deterioration is observed from onset. pathophysiology is a convergence of pathology with physiology. pathology is the medical discipline that describes conditions typically observed during a disease state; whereas physiology is the biological discipline that describes processes or mechanisms operating within an organism. referring to ms, the physiology refers to the different processes that lead to the development of the lesions and the pathology refers to the condition associated with the lesions. pathology main article: pathology of multiple sclerosis multiple sclerosis can be pathologically defined as the presence of distributed glial scars (or sclerosis) in the central nervous system disseminated in time (dit) and space (dis). the gold standard for ms diagnosis is pathological correlation, though given its limited availability, other diagnosis methods are normally used. the scleroses that define the disease are the remainders of previous demyelinating lesions in the cns white matter of a patient (encephalomyelitis) showing special characteristics, such as confluent instead of perivenous demyelination. there are three phases for how an unknown underlying condition may cause damage in ms: an unknown soluble factor (produced by cd8+ t-cells or cd20+ b-cells), creates a toxic environment that activates microglia. mri-abnormal areas with hidden damage appear in the brain and spine (nawm, nagm, dawm). some clusters of activated microglia, axonal transection and myelin degeneration are present. leaks in the blood–brain barrier appear and immune cells infiltrate, causing demyelination. and axon destruction. multiple sclerosis differs from other idiopathic inflammatory demyelinating diseases in its confluent subpial cortical lesions. these types of lesions are the most specific finding for ms, being exclusively present in ms patients, though currently they can only be detected at autopsy. most ms findings take place inside the white matter, and lesions appear mainly in a periventricular distribution (clustered around the ventricles of the brain). apart from white matter demyelination, the cortex and deep gray matter (gm) nuclei can be affected, together with diffuse injury of the nawm. gm atrophy is independent of classical 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, intrathecal ig production with oligoclonal bands, an environment fostering immune cell persistence, and a disruption of the blood–brain barrier outside of active lesions. the scars that give the name to the condition are produced by astrocytes healing old lesions. ms is active even during remission periods. meningeal tertiary lymphoid-like structures follicle-like aggregates in the meninges are formed only in secondary progressive ms. and correlate with the degree of subpial cortical demyelination and brain atrophy, suggesting that they might contribute to cortical pathology in spms these ectopic lymphoid follicles are composed mainly of ebv infected b-cells. demyelination patterns four different damage patterns have been identified in patient's brain tissues. the original report suggests that there may be several types of ms with different immune causes, and that ms may be a family of several diseases. though originally a biopsy was required 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 cholesterol crystals are believed to both impair myelin repair and aggravate inflammation. 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 effective treatment decisions. according to one of the researchers involved in the original research, "two patterns (i and ii) showed close similarities to t-cell-mediated or t-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. the other patterns (iii and iv) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity." the four identified patterns are: pattern ithe scar presents t-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation. pattern iithe 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. the complement system infiltration in these cases convert this pattern into a candidate for research into autoimmune connections like anti-kir4.1, anti-anoctamin-2 or anti-mog mediated ms about the last possibility, research has found antimog antibodies in some pattern-ii ms patients. pattern ii pathogenic t cells has been shown to be different from others the functional characterization shows that t cells releasing th2 cytokines and helping b cells dominate the t-cell infiltrate in pattern ii brain lesions. pattern iiithe scars are diffuse with inflammation, distal oligodendrogliopathy, microglial activation and loss of myelin-associated glycoprotein (mag). it is considered atypical and an overlap between ms and balo concentric sclerosis. the scars do not surround the blood vessels, and a rim of preserved myelin appears around the vessels. there is evidence of partial remyelinization and oligodendrocyte apoptosis. at first, some researchers thought it was an early stage of the evolution of the other patterns. recently, it is thought that it represents ischaemia-like injury with absence of oligoclonal bands in the csf, related to the pathogenesis of balo concentric sclerosis. pattern ivthe 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. these differences are noticeable only in early lesions and the heterogeneity was controversial for some time because some research groups thought that these four patterns could be a consequence of the age of the lesions. nevertheless, after some debate among research groups, the four patterns model is accepted and the exceptional case found by prineas has been classified as nmo for some investigation teams this means that ms is an immunopathogenetically heterogeneous disease. the latter hypothesis is further corroborated by a recent study that demonstrated significant differences in routine cerebrospinal fluid findings between patients with pattern i lesions and patients with non-pattern i lesions, including a lack of csf-restricted oligoclonal bands, in most pattern ii and iii patients. finally, some previously diagnosed with pattern ii ms were later found to have in fact mog-igg-related encephalomyelitis, suggesting that both the current clinicoradiological diagnostic criteria for ms and the histopathological criteria for ms may be insufficiently specific. this was already indicated by previous studies that found a relatively high rate of false diagnoses of ms among patients with aqp4-igg-positive neuromyelitis optica spectrum disorders or mog encephalomyelitis. currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy. another development in this area is the finding that some lesions present mitochondrial defects that could distinguish types of lesions. physiology of ms in multiple sclerosis, inflammation, demyelination, and neurodegeneration are observed together. some clinical trials have shown that the inflammation produces both the relapses and the demyelination, and that neurodegeneration (axonal transection) is independent from inflammation, produces the accumulative disability, and advances even when inflammation and demyelination are delayed. it seems that neurodegeneration is produced by damaged mitochondria, which in turn comes from activated microglia. currently it is unknown what the primary cause of ms is; if ms is a heterogeneous disease, the lesion development process would not be unique. in particular, some ppms patients having a special clinical course named rapidly progressive multiple sclerosis could have a special genetic cause and a different development process. several types of damage appear in the brain: normal appearing white matter (nawm) and characteristic lesions. changes in nawm include axonal injury without demyelination, low-grade inflammation, and microglial and astrocytic activation ms lesion development illustration of the four different types of glial cells found in the central nervous system: ependymal cells, astrocytes, microglial cells, and oligodendrocytes ms lesions develop inside nawm areas. their shape is influenced by their activity the most accepted sequence of events is first nawm appearance, then the so-called pre-active lesions, with activated microglia, and finally the bbb breakdown, which enables the entry of t-cells to the cns. this marks the beginning of an autoimmune attack which destroys myelin in active lesions. when the attack is resolved, a characteristic glial scar is formed by astrocytes. current models can be divided into two categories: inside-out and outside-in. in the former, it is hypothesized that a problem in cns cells produces an immune response that destroys myelin and subsequently breaks the bbb. in latter, an external factor produces bbb leaks, enters the cns, and destroys myelin and axons. whatever the underlying condition for ms is, it appears that damage is triggered by an unknown soluble factor in the csf, potentially produced in meningeal areas; this factor can diffuse into the cortical parenchyma and destroy myelin either directly or indirectly through microglia activation. the evolution of a preactive lesion is related to microglia reactivity. increased expression of pro-inflammatory cell surface markers have been observed in nawm and "initial" lesions, corresponding to a so-called loss of homeostatic microglial equilibrium. some authors report active lesion formation before bbb breakdown; others point to adipsin as a factor of the breakdown. ms lesions are driven mainly by t-cells. it has been found recently that b-cells are also involved. 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