injury with a remarkable availability of a specific biomarker in csf some authors have stated that distal oligodendrogliopathy could come from a metabolic process. 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 during some time because some research groups thought that these four patterns could be 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 a 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 patients 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. currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy. other developments in this area is the finding that some lesions present mitochondrial defects that could distinguish types of lesions. mri phenotypes 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 led 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 establish 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 and finally led to the description of a new disease, antimog associated encephalomyelitis. high levels of anti-nuclear antibodies are found normally in patients with ms. recently, it has been shown that the csf from ppms patients can transport the disease. some cases could belong to the anti-neurofascin demyelinating diseases category. cortical lesions: not all ms patients develop cortical lesions. only around 40% of patients do. when they appear, they correlate to meningeal inflammation. 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 heterogeneous 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: pattern ii lesions patients are responsive to plasmapheresis, while others are not. 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 response to intravenous immunoglobin: the response to ivig is strongly dependent from the genetic profile of each person in a predictive way comorbidity with diabetes: diabetes mellitus type 1 (t1d) is produced by special leukocyte antigen haplotypes, which seem to be involved also in some cases of ms progressive ms 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. diffusely abnormal white matter (dawm) is different than in rrms/spms patients and it has been shown that csf from ppms patients can transport the disease from a pathological point of view, ppms characteristics are slow expansion of pre-existing white matter lesions, massive cortical demyelination, and extensive diffuse injury of the normal appearing white matter. as in relapsing ms also in progressive ms active tissue injury is invariably associated with inflammation, but inflammation seems to be trapped behind a closed blood brain barrier a specially remarkable difference between ppms and spms are some follicle-like b-cells structures in the meninges of spms patients, that have never been reported in ppms patients. these follicles appear to be related to cortical demyelination in spms. no disease modifying drug is approved for ppms. currently natalizumab is being studied secondary progressive ms secondary progressive ms shows follicle-like b-cells structures (a.k.a. ectopic follicle-like structures, efs's, or tertiary lynphoid tissues, tlt's) in the meninges that appear associated with underlying subpial cortical damage. these follicles do not appear in primary progressive (ppms) nor in remitant-relapsing ms (rrms). pathology of early ms and silent ms mcdonald criteria rely in detecting the lesions disseminated in time and space that define ms by clinical observations. therefore, normally they do not allow to establish 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. to study the initial stages of ms, some additional paraclinical tests must be used to prove the presence and dissemination of the lesions. sometimes patients with their first isolated attack (clinically isolated syndrome, or cis) but before the confirming second attack (preclinical ms) can be accepted to study the initial ms pathology but there is a study suggesting that any ms case begins as a silent pathology that can remain unnoticed even for five years. therefore, even the cis can appear too late in ms evolution. 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 sometimes patients that undergo an mri examination for an unrelated cause can show lesions in their brains. these cases of isolated mri findings have been recently baptised as ris (radiologically isolated syndrome) and are the most common inspections in which suggestions of silent ms have appeared. in respect to the pathology of the ris cases, we can point out that they show cortical lesions, mainly in patients with oligoclonal bands. macroscopic damage is similar to rrms cases but milder. cervical cord lesions are an important predictor of progression and the quotient n-acetylaspartate to creatine suggest axonal damage