<unk>  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.<unk>  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 I : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation. ; Pattern II : The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found. 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 III : The 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 IV : The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal-appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss. 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.
Pathophysiology of multiple sclerosis
Pathology of multiple sclerosis
CNS demyelinating autoimmune diseases
Inflammatory demyelinating diseases of the central nervous system
Multiple sclerosis biomarkers
Management of multiple sclerosis
Charcot–Marie–Tooth disease classifications
Genetics of amyotrophic lateral sclerosis