Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acuteinflammation of theoptic nerve (optic neuritis, ON) and thespinal cord (myelitis).[1][2][3] Episodes of ON and myelitis can be simultaneous or successive. A relapsing disease course is common, especially in untreated patients.[1][4]
Neuromyelitis optica (NMO) is a particular disease within the NMOSD spectrum. It is characterised by optic neuritis and longitudinally extensive myelitis. In more than 80% of NMO cases, the cause isimmunoglobulin Gautoantibodies toaquaporin 4 (anti-AQP4), the most abundantwater channel protein in the central nervous system.[5][1][4]
Less common diseases with other manifestations are also part of the NMOSD spectrum.[6][4]
The most common initial manifestation of the disease is inflammation of the spinal cord (myelitis).[4] Myelitis causes spinal cord dysfunction, which can result inmuscle weakness, paralysis in the limbs, lost or reduced sensation, spasms, loss ofbladder and bowel control, or erectile dysfunction.[1][4][2][7][8][9] The myelitis can betransverse, affecting an entire cross-section of the spinal cord, and showing bilateral symptoms.
The second most common initial manifestation of the disease is inflammation of the optic nerve and/oroptic chiasm (optic neuritis, ON).[4] ON may lead to varying degrees of visual impairment with decreasedvisual acuity, althoughvisual field defects, or loss ofcolor vision, may occur in isolation or prior to formal loss of visual acuity. Compared to idiopathic ON and ON due to multiple sclerosis (MS), ON due to NMOSD more often results in severe visual loss at onset, with bilateral involvement, and permanent visual deficits.[4]
Signs and symptoms usually follow a relapsing and remitting course, but occasionally can be progressive (monophasic). Deficits can be temporary or permanent, the latter especially in the absence of treatment.[citation needed]
Fatigue is a common symptom, with studies showing that as many as 77% of people with NMOSD have fatigue.[10][11] Fatigue has been found to correlate with quality of life in people with NMOSD.[12][13]
NMO andmultiple sclerosis (MS) can be similar in clinical and radiological presentation, and MS may very rarely present with an NMO-likephenotype (e.g. in patients with long-standing MS resulting in confluent spinal cord lesions mimicking the longitudinally extensive spinal cord lesions typically seen in NMO). In consequence, NMO was in the past wrongly considered a clinical variant of MS. However, NMO is not related to MS in the vast majority of cases and differs from MS substantially in terms ofpathogenesis, clinical presentation,magnetic resonance imaging, cerebrospinal fluid findings, disease course, and prognosis.[1]
NMOSD is caused by anautoimmune attack on the nervous system. In more than 80% of cases,IgGautoantibodies againstaquaporin-4 (anti-AQP4+) are the cause, and in 10–40% of the remaining cases, IgG antibodies againstMOG are the cause.[1] The cause of the remaining cases is still unknown, and it is likely heterogeneous.[14][15]
Why autoimmunity develops is largely unknown. Multiple genetic and environmental factors are known to increase the risk of developing NMOSD. The strongest risk factor is being female, especially in AQP4-IgG-positive NMOSD.[1] Multiplehuman leukocyte antigen (HLA) alleles are associated with NMOSD.[1]
NMO was associated in the past with many systemic diseases. Some researchers have pointed out that some other cases could beparaneoplastic.[16] It appears thatlupus can produce NMO-IgG autoantibodies, leading to cases oflupus-derived NMO.[17]
Illustration of the four different types of glial cells found in the central nervous system: ependymal cells, astrocytes, microglial cells, and oligodendrocytes
The astrocytes surround theblood–brain barrier (BBB), a system responsible for preventing substances in the blood from entering the brain. For antibodies from the blood to reach astrocytes in the central nervous system (CNS), they must cross the BBB, the mechanism of which is not completely known. Some reports point to themetalloproteinase-2 andinterleukin-6 as culprits responsible for the BBB failure.[22] There is broad consensus thatAQP4/NMO-IgG initially enters the brain via BBB-deficient sites such as thearea postrema, where there is access tocerebrospinal fluid (CSF).[23] In any case,anti-AQP4 is produced mainlyintrathecally.[24]
Within astrocytes, AQP4 is primarily found in astrocyticfoot processes that abut blood vessels and the linings of the brain (meninges).[1] NMOSD brain lesions, as seenunder a microscope, show IgG,Immunoglobulin M (IgM), inflammatory cells, and complement deposits around blood vessels.[1] AQP4-IgG is a member of theIgG1 immunoglobulin family, which is an activator of thecomplement system, which seems to play an integral part in the autoimmune response.[1] There is a loss of astrocytes, and sometimes also a loss of neurons andoligodendrocytes. Loss of cells other than astrocytes is a consequence of collateral inflammatory damage or astrocyte dysfunction.[1]
NMOSD selectively affects the optic nerve, spinal cord, and brain stem. This selectivity can be explained by the increased amount of AQP4 in these structures, and, furthermore, by the increased amount of AQP4 aggregates in the optic nerve and spinal cord.[1] The increased BBB permeability at the area postrema helps explain involvement there.[1] AQP4 is present in tissues outside the central nervous system (e.g. the kidneys), but these tissues aren't affected in NMOSD, at least in part because of the presence of autoimmune downregulators outside of the central nervous system.[1]
AQP4-IgG levels are coarsely correlated with NMOSD disease activity, those levels generally increasing before relapse and declining during remission, with higher levels being correlated to more severe disease manifestation.[1]
NMO-IgG-negative cases are less understood. It seems thatastrocytes are spared in these cases.[27]
The second most frequent autoantibody in NMO is MOG-IgG, which targetsmyelin oligodendrocyte glycoprotein (MOG). MOG is anintegral membraneglycoprotein found on the surface of oligodendrocytes and the outermost surface of myelin sheaths.[1] Its function is not entirely known.[1] MOG-IgG is produced outside the central nervous system (CNS) despite MOG existing only in the CNS (with the BBB separating the two), leading to the hypothesis that MOG drained via cerebral spinal fluid into lymph nodes causes autoimmune reaction formation.[1]
MOG-IgG-positive NMOSD brain lesions, as seen under a microscopic, show demyelination with preservation of oligodendrocytes and axons, presence of inflammatory cells, and IgG and complement deposits.[1] MOG-IgG levels coarsely correlate with disease severity, with levels being higher during active disease, and higher levels being associated with more severe disease manifestation.[1]
Antibodies against MOG are considered mostly absent in similar diseases, such as MS.[28] Therefore, it can be said thatanti-MOG diseases are grouped within AQP4-IgG-negative NMOSD.[29]
Together withanti-AQP4 disease, anti-MOG diseases form the wider part of the NMO spectrum. The NMO cases are classified in four classes, according to the presence or absence of any of these two mainauto-antibodies.[30]
The clinical course and the response to therapy is different for various diseases classed within these groups, showing a betterprognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worseprognosis for those in the NMO-Ab(+)/MOG-Ab(+) group.[30] The MOG-related NMO can be radiologically identified by theconus involvement. Myelin-oligodendrocyte glycoproteinantibody–positivepatients were more likely to haveconus involvement onspinalmagnetic resonance imaging.[31]
Diagnostic criteria are more relaxed forseropositiveAQP4–IgG cases than they are for seronegative AQP4-IgG ones. If AQP4-IgG is detected, then one core clinical criterion, along with the ruling out of alternativediagnoses, is sufficient for NMOSD diagnosis.[34]
If AQP4-IgG is undetected, or its status is unknown, two core clinical criteria, each with supportive MRI findings, along with the ruling out of alternative diagnoses, are needed for an NMOSD diagnosis.[35]
Either 1) brain MRI showing normal findings or only nonspecific white matter lesions, or 2) optic nerve MRI showing T2-hyperintensity, or T1 enhancing lesion, greater than 1/2 optic nerve length or involving optic chiasm
Rarely, it has been reported that some courses ofanti-NMDAR are consistent with NMO.[36] Preliminary reports suggest that otherautoantibodies may play a role in rare cases of NMO.[37][38]
AQP4-Ab-negative NMO presents problems fordifferential diagnosis. The behavior of theoligoclonal bands can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after attacks, while in MS they are nearly always present and persistent.[44] It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinallesions in MS.[45]
Another problem for diagnosis is that AQP4-ab inMOG-ab levels can be too low to be detected. Some additionalbiomarkers have been proposed.[46][47]
NMO differs from MS in that it usually has more severesequelae after an acute episode than standard MS, which infrequently presents astransverse myelitis. In addition oligoclonal bands in theCSF as well aswhite matter lesions on brainMRIs are uncommon in NMO, but occur in over 90% of MS patients.[48]
Since the discovery of theAQP4autoantibody, 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 simultaneousoptic nerve andspinal cordinflammation).[54]
The term neuromyelitis optica spectrum disorders (NMOSD) has been designed to allow incorporation of cases associated with non-AQP4biomarkers.[33] Therefore, it includes all the clinical variants due toanti-AQP4, plus other non-related but clinically similar syndromes such asanti-MOG associated encephalomyelitis. Some cases withMOG+ and AQP4+antibodies have been found.[33]
These variants are expected to respond to the same treatments as standard NMO.[55] Some authors propose to use the name "autoimmune aquaporin-4channelopathy" for these diseases,[15] while others prefer a more generic term "AQP4-astrocytopathy", which also includes deficiencies of AQP4 with a non-autoimmune origin.[56]
Chemical structure of methylprednisolone, which is used to treat attacks
There is nocure 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.[57]
Long term neurologic deficits are the cumulative effects of acute attacks, emphasizing the importance of acute treatment.[1] Traditionally, attacks have been treated with short courses (3–5 days) of high dosageintravenouscorticosteroids, such asmethylprednisolone IV (Solu-Medrol).[58] Early initiation of treatment with steroids has been shown to improve vision-related outcomes after acute attacks.[1][59] 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).[59][58]
Plasmapheresis can be an effective treatment when attacks progress after the administration ofcorticosteroids.[41] This treatment involves the patient's ownblood being pumped out,blood cells being removed from theplasma and mixed with a solution, then the new blood mixture being pumped back in.[57]
FDA-approved pharmaceuticals against AQP4-IgG-positive NMOSD, shown to be effective in phase III clinical trials, first became available in 2019.[1] As of 2020, they are among the most expensive drugs worldwide.[1] They are not available in pill form, which, along with their high price, limits their accessibility.[1] These new drugs' effectiveness against AQP4-IgG-negative NMOSD is unknown.[1]
Many treatments are used despite the lack of phase III clinical trials testing their efficacy.[1] 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.[1] Most of these medicationsaffect the immune system in various ways.[58][41][65]
First reported effective in 1998 and was mainstay of treatment 10+ years thereafter. Sometimes combined with steroids due to months-long onset of action.[1]
Has partially replaced azathioprine due to proposed better efficacy and tolerability. Sometimes combined with steroids due to months-long onset of action.[1]
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.[69]
It is important to note that certain immunosuppressants used to treat MS—such asinterferon-β,fingolimod,natalizumab, andalemtuzumab—worsen NMO disease progression and should not be used to treat NMO.[70]
Normally, some improvement appears in a few weeks, but severe residual symptoms and evendisability may persist.[citation needed]
The disease can be monophasic, i.e. a single episode with permanentremission afterwards. However, at least 85% of patients have a relapsing form of the disease with repeated attacks oftransverse myelitis and/oroptic 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% ofpatients having a relapse in the first year and 90% in the first five years.[18]
It is possible that the relapsing form is related to theanti-AQP4+seropositive status and the monophasic form related to its absence.[71] 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.[18]
Approximately 20% of patients with monophasic NMO have permanentvisual loss, and 30% have permanentparalysis in one or both legs. Among patients with relapsing NMO, 50% haveblindness orparalysis within five years. In some patients (33% in one study), transverse myelitis in thecervical spinal cord resulted inrespiratory failure and subsequentdeath. 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.[18]
Prevalence varies by region, ranging from 0.5 to 10 cases per 100,000 people.[1] Unlike MS, prevalence has not been found to be related tolatitude.[1] 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.[18]
A retrospective study found that prevalence of neuromyelitis optica spectrum disorders was 1.5% among a random sample of neurologicalpatients, with a MS:NMOSD ratio of 42:7. Among 13 NMOSD patients, 77% had longspinal cordlesions, 38% had severeoptic neuritis, and 23% hadbrain orbrainstemlesions. Only 56% had clinically definite NMO at follow-up.[72]
NMO is more common inAsians thanCaucasians. In fact, Asian optic-spinal multiple sclerosis (OSMS) (which constitutes 30% of the cases of MS inJapan) has been suggested to be identical to NMO (differences between OSMS and classic MS in Japanese patients). In theindigenous populations oftropical andsubtropical regions, MS is rare; but when it appears, it often takes the form of OSMS.[73]
The majority of NMO patients have no affected relatives, and it is generally regarded as a nonfamilial condition.[18]
First reports on an association ofspinal cord withoptic nerve disorders date back to the late 18th and early 19th century.[74][75] However, only an 1870 report by SirThomas Clifford Allbutt created sustained interest on the part ofneurologists andophthalmologists in this rare syndrome.[76] In 1894,Eugène Devic and hisPhD student Fernand Gault described 16 patients who had lostvision in one or botheyes and within weeks developed severespasticweakness of the limbs, loss of sensation, and often ofbladder control. They recognized these symptoms were the result ofinflammation of the optic nerve and spinal cord, respectively.[74][77][78]
In 2002,Mayo Clinic researchers identified ahumoral mechanism, targeting a perivascular protein, as the culprit of NMO,[26] and in 2004 an unknown specific autoantibody was found.[79] In 2005 they identified theaquaporin 4 protein as the target of the disease, and developed the first in-house test to aid in thediagnosis of NMO by detection of anantibody, AQP4-IgG, in theblood.[19] The first quantitativeELISA (enzyme-linked immunosorbent assay) kits were soon developed,[80] However, serum AQP4-IgGtiter only moderately reflects disease activity, severity, or neurological prognosis.[81] Later, some otherautoantibodies were found in NMO AQP4-negative cases, such asanti-MOG IgG, but some NMOanti-AQP4-negative cases still remain idiopathic.
There is little research into the primary causes of the anti-AQP4 auto-antibodies. It has been noticed that some cases could beparaneoplastic.[16]
In addition, several NMO variants have been discovered with antibodies other than those against AQP4, turning NMO into aheterogeneous disease. Six different patterns of damage have been reported in NMO, raising the possibility of six different types ofauto-antibodies. As of 2019, only three of them are known.[83]
Other autoantibody being researched isflotillin. It has been found in seronegative NMO and some MS patients.[84]
Finally, other proteins under study areconnexin 43 and anti-AQP1,[85] although, as of 2015, there are only initial reports about the involvement of theseproteins.[54][56]
The groupAQP4+/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:
Some cases of NMO are not due toautoantibodies. They constitute an overlap between NMO and MS.
As of 2019 some statistical studies showed thatantibody-negative NMO can be classified into three groups, and that this classification has apathogenic meaning.[87]
Later studies have increased the number of groups up to four.[88]
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