90% of ms patients. recently, the presence of aqp4 has been found to distinguish standard ms from nmo; but as ms is a heterogeneous condition, and some ms cases are reported to be kir4.1 channelopathies (autoimmunity against the potassium channels), it is still possible to consider nmo as part of the ms spectrum. besides, some nmo-aqp4(−) variants are not astrocytopathic, but demyelinating. tumefactive demyelinating lesions in nmo are not usual, but they have been reported to appear in several cases mistakenly treated with interferon beta. also, an overlap with sjögren syndrome has been reported. evolution of diagnostic criteria since the discovery of the aqp4 autoantibody, it has been found that it appears also in patients with nmo-like symptoms that do not fulfill the clinical requirements to be diagnosed with nmo (recurrent and simultaneous optic nerve and spinal cord inflammation). the term neuromyelitis optica spectrum disorders (nmosd) has been designed to allow incorporation of cases associated with non-aqp4 biomarkers. therefore, it includes all the clinical variants due to anti-aqp4, plus other non-related but clinically similar syndromes such as anti-mog associated encephalomyelitis. some cases with mog+ and aqp4+ antibodies have been found. these variants are expected to respond to the same treatments as standard nmo. some authors propose to use the name "autoimmune aquaporin-4 channelopathy" for these diseases, while others prefer a more generic term "aqp4-astrocytopathy", which also includes deficiencies of aqp4 with a non-autoimmune origin. treatment chemical structure of methylprednisolone, which is used to treat attacks there is no cure for nmo, but it is treatable. some patients recover, but many are left with impairment of vision and limbs, which can be severe in some cases. attacks long term neurologic deficits are the cumulative effects of acute attacks, emphasizing the importance of acute treatment. traditionally, attacks have been treated with short courses (3–5 days) of high dosage intravenous corticosteroids, such as methylprednisolone iv (solu-medrol). early initiation of treatment with steroids has been shown to improve vision-related outcomes after acute attacks. however, there is no high-level evidence for steroids affecting long-term outcomes; this treatment strategy was borrowed from that for similar diseases (idiopathic optic neuritis and multiple sclerosis). plasmapheresis can be an effective treatment when attacks progress after the administration of corticosteroids. this treatment involves the patient's own blood being pumped out, blood cells being removed from the plasma and mixed with a solution, then the new blood mixture being pumped back in. secondary prevention prophylactic treatment, to prevent relapses of nmo, is generally employed; but the exact duration of such treatment is debatable. fda-approved pharmaceuticals fda-approved pharmaceuticals against aqp4-igg-positive nmosd, shown to be effective in phase iii clinical trials, first became available in 2019. as of 2020, they are among the most expensive drugs worldwide. they are not available in pill form, which, along with their high price, limits their accessibility. these new drugs' effectiveness against aqp4-igg-negative nmosd is unknown. drug (brand)branddate of fda approvalmechanism of actionnote eculizumabsoliris2019monoclonal antibody against complement protein c5approved for aqp4-igg-positive nmosd inebilizumabuplizna2020 junemonoclonal antibody against cd19+ b cells satralizumabenspryng2020 augustmonoclonal antibody against il-6approved foraqp4-igg-positive nmosd off-label treatments many treatments are used despite the lack of phase iii clinical trials testing their efficacy. neither inferiority nor superiority to the newer, fda approved drugs has been clearly demonstrated; and, considering their being relatively inexpensive and being availability in pill format, these drugs are the current standard treatment. most of these medications affect the immune system in various ways. drug (brand)mechanism of actionnote azathioprine (imuran, azasan)inhibits purine metabolismfirst reported effective in 1998 and was mainstay of treatment 10+ years thereafter. sometimes combined with steroids due to months-long onset of action. mycophenolate mofetil (cellcept)inhibits purine metabolismhas partially replaced azathioprine due to proposed better efficacy and tolerability. sometimes combined with steroids due to months-long onset of action. corticosteroid mitoxantronedna synthesis/repair inhibitor methotrexateinhibits folate metabolism cyclophosphamidedna crosslinker rituximab (rituxan)antibody against cd20 – b cell depletionthe most commonly used treatment for nmosd today. intravenous immunoglobulin (ivig) hematopoietic stem cell transplantation (hsct)can be used in severe cases of nmo. available data suggests that this procedure can reduce inflammatory activity in the short term, but a clear majority of the patients will relapse within 5 years. it is important to note that certain immunosuppressants used to treat ms—such as interferon-β, fingolimod, natalizumab, and alemtuzumab—worsen nmo disease progression and should not be used to treat nmo. prognosis normally, some improvement appears in a few weeks, but severe residual symptoms and even disability may persist. the disease can be monophasic, i.e. a single episode with permanent remission afterwards. however, at least 85% of patients have a relapsing form of the disease with repeated attacks of transverse myelitis and/or optic neuritis. in patients with the monophasic form, the transverse myelitis and optic neuritis occur simultaneously or within days of each other. on the other hand, patients with the relapsing form are more likely to have weeks or months between the initial attacks, and to have better motor recovery after the initial transverse myelitis event. relapses usually occur early, with about 55% of patients having a relapse in the first year and 90% in the first five years. it is possible that the relapsing form is related to the anti-aqp4+ seropositive status and the monophasic form related to its absence. unlike ms, nmo rarely has a secondary progressive phase in which patients have increasing neurologic decline between attacks without remission. instead, disabilities arise from the acute attacks. approximately 20% of patients with monophasic nmo have permanent visual loss, and 30% have permanent paralysis in one or both legs. among patients with relapsing nmo, 50% have blindness or paralysis within five years. in some patients (33% in one study), transverse myelitis in the cervical spinal cord resulted in respiratory failure and subsequent death. however, the spectrum of nmo has widened, due to improved diagnostic criteria; and the options for treatment have improved. as a result, researchers believe these estimates will be lowered. epidemiology prevalence varies by region, ranging from 0.5 to 10 cases per 100,000 people. unlike ms, prevalence has not been found to be related to latitude. nmo is more common in women than men, with women comprising over two-thirds of patients and more than 80% of those with the relapsing form of the disease. a retrospective study found that prevalence of neuromyelitis optica spectrum disorders was 1.5% among a random sample of neurological patients, with a ms:nmosd ratio of 42:7. among 13 nmosd patients, 77% had long spinal cord lesions, 38% had severe optic neuritis, and 23% had brain or brainstem lesions. only 56% had clinically definite nmo at follow-up. nmo is more common in asians than caucasians. in fact, asian optic-spinal multiple sclerosis (osms) (which constitutes 30% of the cases of ms in japan) has been suggested to be identical to nmo (differences between osms and classic ms in japanese patients). in the indigenous populations of tropical and subtropical regions, ms is rare; but when it appears, it often takes the form of osms. the majority of nmo patients have no affected relatives, and it is generally regarded as a nonfamilial condition. history sir thomas clifford allbutt first reports on an association of spinal cord with optic nerve disorders date back to the late 18th and early 19th century. however, only an 1870 report by sir thomas clifford allbutt created sustained interest on the part of neurologists and ophthalmologists in this rare syndrome. in 1894, eugène devic and his phd student fernand gault described 16 patients who had lost vision in one or both eyes and within weeks developed severe spastic weakness of the limbs, loss of sensation, and often of bladder control. they recognized these symptoms were the result of inflammation of the optic nerve and spinal cord, respectively. in 2002, mayo clinic researchers identified a humoral mechanism, targeting a perivascular protein, as the culprit of nmo, and in 2004 an unknown specific autoantibody was found. in 2005 they identified the aquaporin 4 protein as the target of the disease, and developed the first in-house test to aid in the diagnosis of nmo by detection of an antibody, aqp4-igg, in the blood. the first quantitative elisa (enzyme-linked immunosorbent assay) kits were soon developed, however, serum aqp4-igg titer only moderately reflects disease activity, severity, or neurological prognosis. later, some other autoantibodies were found in nmo aqp4-negative cases, such as anti-mog igg, but some nmo anti-aqp4-negative cases still remain idiopathic. research directions since the discovery of aqp4 involvement, some research studies have focused on targeted treatment aimed at anti-aquaporin 4 antibodies. the most established method for antibody removal is plasmapheresis. a number of drugs are being studied: aquaporumab (non-pathogenic antibody blocker of aqp4-igg binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). there is little research into the primary causes of the anti-aqp4 auto-antibodies. it has been noticed that some cases could be paraneoplastic. in addition, several nmo variants have been discovered with antibodies other than those against aqp4, turning nmo into a heterogeneous disease. six different patterns of damage have been reported in nmo, raising the possibility of six different types of auto-antibodies. as of 2019, only three of them are known. research into new autoantibodies an autoantibody—glial fibrillary acidic protein (gfap)—was found in 2016, in transverse myelitis (letm) and atypical nmo, leading to the concept of autoimmune gfap astrocytopathy. other autoantibody being researched is flotillin. it has been found in seronegative nmo and some ms patients. finally, other proteins under study are connexin 43 and anti-aqp1, although, as of 2015, there are only initial reports about the involvement of these proteins. the group aqp4+/mog+ is very small and it can be considered a coincidence of two completely separate diseases in the same person. assuming these cases can be verified, five different kinds of nmo are being considered: nmo derived from an autoimmune channelopathy (aqp4-ab+) – around 80% of total nmo cases nmo derived from an anti-mog associated encephalomyelitis – around 10% of total cases connexin-43 nmo aquaporin-1 associated nmo which could be related to pattern iii ms idiopathic nmo, defined by the absence of all previous antibodies antibody negative neuromyelitis optica some cases of nmo are not due to autoantibodies. they constitute an overlap between nmo and ms. as of 2019 some statistical studies showed that antibody-negative nmo can be classified into three groups, and that this classification has a pathogenic meaning. later studies have increased the number of groups up to four. notable patients christine hà (chef and author) cassie mitchell (paralympian and biomedical engineering professor)