sclerosis occasionally, the term ‘malignant’ ms (mms) has been used to describe aggressive phenotypes of ms, but this is another ambiguous term that—despite wide usage—means different things to different people. in 1996, the us national ms society (nmss) advisory committee on clinical trials in multiple sclerosis, “malignant ms” was also included, namely, “disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease onset.” many authors reserve the term malignant for fulminant forms of ms that deteriorate so rapidly from the outset as to be almost monophasic, and result in death within months to a few years. one such example is the marburg variant of ms, which is classically characterized by extensive necrotic and/or tumefactive lesions with mass effect. despite recent (and increasing) emphasis on early detection of patients with aggressive ms, the original definition of mms was not modified by the nmss advisory committee in its latest publication in 2013 (lublin et al., 2014). aggressive ms common to all definitions is the early, unexpected acquisition of disability followed by frequent relapses and highly active disease seen on mri. one definition can be based on edss score and the time to develop secondary progressive ms (spms) (menon et al., 2013). no consensus exists on the speed of progression or degree of disability sufficient for aggressive ms, but some assume that reaching an edss score of 6 points probably represents an upper limit beyond which the risk-benefit ratio for an aggressive treatment is unfavourable. pragmatically, ams has been defined as any type of ms that is associated with repeated severe attacks and accelerated accrual of disability—put more simply, "rapidly progressive" ms. rapidly progressive multiple sclerosis this kind of ms was previously reported to behave different that the standard progressive course, being linked to connexin 43 autoantibodies with pattern iii lesions (distal oligodendrogliopathy) and being responsive to plasma exchange in very rapidly progressive multiple sclerosis the use of immunosuppressive therapy (mitoxantrone/cyclophosphamide), rituximab, autologous haematopoietic stem cell therapy or combination therapy should be considered carefully. under research some auto-antibodies have been found consistently across different ms cases but there is still no agreement on their relevance: hepacam: a cross-reactivity between hepacam (glialcam) and ebna1 has been reported as of 2022 on 25% of ms cases anti-kir4.1: a kir4.1 multiple sclerosis variant was reported in 2012 and later reported again, which could be considered a different disease (as devic's disease did before), and can represent up to a 47% of the ms cases anoctamin 2: auto-antibodies against anoctamin-2 (ano-2), one of the ion-channel proteins, have been reported consistently since 2013 this finding is not universal. most of the ms patients do not show auto-antibodies against ano-2. therefore, this points toward an ano2 autoimmune sub-phenotype in ms. later reports point towards a mimicry between ano-2 and ebv-ebna-1 protein anti-nmdar autoantibodies: there is an overlap between cases of anti-nmda receptor encephalitis and ms, nmo and adem. it also could be a confusion with anti-nmda receptor encephalitis in the early stages but there are also anti-nmdar reported cases that evolve to mcdonalds ms anti-flotilin spectrum: the proteins flotillin 1 and flotillin 2 have been recently identified as target antigens in some patients with multiple sclerosis. first 14 cases were reported together in the first report, and 3 new cases were reported later inside a cohort of 43 patients. mutations in gjb1 coding for connexin 32, a gap junction protein expressed in schwann cells and oligodendrocytes, that usually produce charcot-marie-tooth disease. in some cases also ms (as defined by mcdonalds criteria) can appear in these patients. also an opa1 variant exists. there exist some reports by drs. aristo vojdani, partha sarathi mukherjee, joshua berookhim, and datis kharrazian of an aquaporin-related multiple sclerosis, related to vegetal aquaporin proteins. auto-antibodies against histones have been reported to be involved. anti-aqp1 could be involved in atypical ms and nmo n-type calcium channel antibodies can produce cognitive relapses mimicking ms related cognitive decline, and may coexist with ms. mlkl-ms: mixed lineage kinase domain like pseudokinase (mlkl) related ms - a preliminary report has pointed out evidence of a novel neurodegenerative spectrum disorder related to it. other auto-antibodies can be used to stablish a differential diagnosis from very different diseases like sjögren syndrome which can be separated by anti–calponin-3 autoantibodies. the correlation between this genetic mutation and ms was challenged but in 2018 has been replicated by an independent team. notice that this results do not refer to general ms. in general, nmo-like spectrum without known auto-antibodies is considered ms. principal component analysis of these cases show 3 different kinds of antibody-negative patients. the metabolite discriminators of rrms and ab-nmosd suggest that these groupings have some pathogenic meaning. as ms is an active field for research, the list of auto-antibodies is not closed nor definitive. for example, some diseases like autoimmune gfap astrocytopathy or variants of cidp that affects the cns (cidp is the chronic counterpart of guillain–barré syndrome) could be included. autoimmune variants peripheral neuropathies or progressive inflammatory neuropathy could be in the list assuming the autoimmune model for ms, together with a rare demyelinating lesional variant of trigeminal neuralgia and some nmdar anti-nmda receptor encephalitis. venous induced demyelination has also been proposed as a hypothetical ms variant produced by ccsvi, susac's syndrome and neuro-behçet's disease (ms has an important vascular component), myalgic encephalomyelitis (aka chronic fatigue syndrome). also leukoaraiosis can produce lesions disseminated in time and space, condition usually sufficient in the ms definition. maybe two sub-conditions of leukodystrophy: adrenoleukodystrophy and adrenomyeloneuropathy could be in the list. specially interesting is x-linked adrenoleukodystrophy (x-ald or cald). genetic types different behaviour has been reported according to the presence of different hla genes. hla drb3*02:02 patients in hla drb3 cases, autoimmune reactions against the enzyme gdp-l-fucose synthase has been reported the same report points that the autoimmune problem could derive from the gut microbiota. hla-drb1*15:01 has the strongest association with ms. hla-drb1*04:05, hla-b*39:01, and hla-b*15:01 are associated with independent ms susceptibility and hla-dqβ1 position 9 with phenylalanine had the strongest effect on ms susceptibility. another possible type is one with auto-antibodies against gdp-l-fucose synthase. in hla-drb3*02:02 patients, autoimmune reactions against the enzyme gdp-l-fucose synthase has been reported the same report points that the autoimmune problem could derive from the gut microbiota. rapidly progressive multiple sclerosis see malignant multiple sclerosis this is a specially aggressive clinical course of progressive ms that has been found to be caused by a special genetic variant. 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. primary progressive variants some researchers propose to separate primary progressive ms from other clinical courses. ppms, after recent findings seem to point that it is pathologically a very different disease. some authors think since long ago that primary progressive ms should be considered a disease different from standard ms, and it was also proposed that ppms could be heterogeneous clinical variants have been described. for example, late onset ms. 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. for the rest of the progressive cases, it has been found that the lesions are diffuse instead of the normal focal ones, and are different under mr spectroscopy. rrms and ppms patients also show differences on the retinal layers yields examined under oct. some authors have proposed a dual classification of ppms, according to the shape of edges of the scars, in ms-like and adem-like proteomic analysis have shown that two proteins, secretogranin ii and protein 7b2, in csf can be used to separate rrms from ppms recently, the hypothesis of ppms being apart from rrms/spms is taken further credibility due that it was shown that csf from ppms patients can carry the disease to other animals, producing neurodegeneration in mice and that normal appearing white matter (nawm) structure is also different the predominant lesions in ppms are slowly expanding lesions with t cells, microglial, and macrophage-associated demyelination in close similar to pattern i demyelination as of 2019 it has been found that the profile of t-cells is different in ppms and spms clinical situations inside standard ms ms can be considered among the acquired demyelinating syndromes with a multiphasic instead of monophasic behaviour. multiple sclerosis has a prodromal stage in which an unknown underlying condition, able to damage the brain, is present, but no lesion has still developed. ms is usually classified in clinical types, though they are unrelated to the underlying pathology. some critical reports say that the current "types" were artificially made up, just to treat rrms as a separate disease. in this way the number of patients was low enough to enter the orphan drugs act, and get the interferon approved by the fda under this schema. recent reviews state that all types are a mixture of inflammation and neurodegeneration, and that all types should be considered the same disease. other possible clinical courses are: preclinical ms: cis and cdms the first manifestation of ms is the so-called clinically isolated syndrome, or cis, which is the first isolated attack. the current diagnosis criteria for ms do not allow doctors to give an ms diagnosis until a second attack takes place. therefore, the concept of "clinical ms", for an ms that can be diagnosed, has been developed. until ms diagnosis has been established, nobody can tell whether the disease one is dealing with is ms. cases of ms before the cis are sometimes found during other neurological inspections and are referred to as subclinical ms. preclinical ms refers to cases after the cis but before the confirming second attack. after the second confirming attack the situation is referred to as cdms (clinically defined multiple sclerosis). cis itself is sometimes considered itself as a disease entity, different from ms. even if they share the same underlying condition cis is not ms given that it lacks the presence of lesions. approximately 84% of the subjects with cis experience a second clinical demyelinating event and are diagnosed with clinically definite ms (cdms) within 20 years. ris, subclinical and silent ms