Neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis).<ref name=":0">Template:Cite journal</ref><ref name="ncbi.nlm.nih.gov">Banerjee S, Butcher R. Rituximab for the Treatment of Neuromyelitis Optica Spectrum Disorder [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021 Feb. Available from: https://www.ncbi.nlm.nih.gov/books/NBK571350/</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Episodes of ON and myelitis can be simultaneous or successive. A relapsing disease course is common, especially in untreated patients.<ref name=":0" /><ref name=":1" />

• 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 is immunoglobulin G autoantibodies to aquaporin 4 (anti-AQP4), the most abundant water channel protein in the central nervous system.<ref>A subset of anti-AQP4-negative cases is associated with antibodies against myelin oligodendrocyte glycoprotein (anti-MOG).</ref><ref name=":0" /><ref name=":1">Template:Cite journal</ref>
• Less common diseases with other manifestations are also part of the NMOSD spectrum.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref name=":1" />

Signs and symptoms

The signs and symptoms of NMOSD depend on the neurologic structures the disease affects, and, to some extent, the antibodies involved.

Spinal cord effects

The most common initial manifestation of the disease is inflammation of the spinal cord (myelitis).<ref name=":1" /> Myelitis causes spinal cord dysfunction, which can result in muscle weakness, paralysis in the limbs, lost or reduced sensation, spasms, loss of bladder and bowel control, or erectile dysfunction.<ref name=":0" /><ref name=":1" /><ref name="ncbi.nlm.nih.gov"/><ref>Levin MC. Neuromyelitis optica spectrum disorder. Kenilworth (NJ): Merck Manuals; 2020: https://www.merckmanuals.com/en-ca/home/brain,-spinal-cord,-and-nerve-disorders/multiple-sclerosis-ms-and-related-disorders/neuromyelitis-optica-spectrum-disorder-nmosd. Accessed 2020 Nov 23</ref><ref>Huang W, Wang L, Zhang B, Zhou L, Zhang T, Quan C. Effectiveness and tolerability of immunosuppressants and monoclonal antibodies in preventive treatment of neuromyelitis optica spectrum disorders: a systematic review and network meta-analysis. Mult Scler Relat Disord. 2019;35:246-252</ref><ref>Mayo Clinic. Neuromyelitis optica 2020; https://www.mayoclinic.org/diseases-conditions/neuromyelitis-optica/symptoms-causes/syc-20375652. Accessed 2020 Nov 23</ref> The myelitis can be transverse, affecting an entire cross-section of the spinal cord, and showing bilateral symptoms.

Optic effects

The second most common initial manifestation of the disease is inflammation of the optic nerve and/or optic chiasm (optic neuritis, ON).<ref name=":1" /> ON may lead to varying degrees of visual impairment with decreased visual acuity, although visual field defects, or loss of color 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.<ref name=":1" />

Brain effects

Less commonly than the spinal cord and optic nerve, NMOSD can affect the brain stem.<ref name=":1" /> Lesions in the brain stem or upper cervical spinal cord can cause respiratory insufficiency. Lesions in the area postrema of the medulla oblongata can cause vomiting or hiccups, as well as pain and tonic spasms.<ref name=":0" /><ref name=":1" /> Additional brain lesions are common but often asymptomatic (though cognitive deficits, as well as depression, may be underdiagnosed sequalae). Lesions may also affect the diencephalon, mostly in Aquaporin-4–Immunoglobulin-G (AQP4-IgG) NMOSD.<ref name=":0" /><ref name=":1" />

Disease course

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.Template:Citation needed

Fatigue

Fatigue is a common symptom, with studies showing that as many as 77% of people with NMOSD have fatigue.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> Fatigue has been found to correlate with quality of life in people with NMOSD.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Comparison with MS

NMO and multiple sclerosis (MS) can be similar in clinical and radiological presentation, and MS may very rarely present with an NMO-like phenotype (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 of pathogenesis, clinical presentation, magnetic resonance imaging, cerebrospinal fluid findings, disease course, and prognosis.<ref name=":0" />

Causes

NMOSD is caused by an autoimmune attack on the nervous system. In more than 80% of cases, IgG autoantibodies against aquaporin-4 (anti-AQP4+) are the cause, and in 10–40% of the remaining cases, IgG antibodies against MOG are the cause.<ref name=":0" /> The cause of the remaining cases is still unknown, and it is likely heterogeneous.<ref>Template:Cite journal</ref><ref name=Pittock2015>Template:Cite journal</ref>

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.<ref name=":0" /> Multiple human leukocyte antigen (HLA) alleles are associated with NMOSD.<ref name=":0" />

NMO was associated in the past with many systemic diseases. Some researchers have pointed out that some other cases could be paraneoplastic.<ref name="Iorio"/> It appears that lupus can produce NMO-IgG autoantibodies, leading to cases of lupus-derived NMO.<ref>Template:Cite journal</ref>

The discovery of NMO-IgG (anti-AQP4) has opened a new avenue of research into the causes.Template:Citation needed

Pathophysiology

File:Glial Cell Types.png

Illustration of the four different types of glial cells found in the central nervous system: ependymal cells, astrocytes, microglial cells, and oligodendrocytes

Anti-AQP4+ variants

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NMOSD is usually caused by autoantibodies targeting aquaporin 4 (AQP4), a channel protein in the cell membrane that allows water to pass through the membrane.<ref name="Wingerchuk">Template:Cite journal</ref> AQP4 monomers form tetramers, and the tetramers aggregate.<ref name=":1" /> AQP4 is found in astrocytes, which are the basis for the glymphatic system.<ref name=pmid16087714>Template:Cite journal</ref> Thus, NMOSD involving AQP4-IgG can be considered an astrocytopathy<ref>Template:Cite journal</ref> or autoimmune astrocytic channelopathy, since the astrocytes are semi-selectively destroyed.<ref name=Pittock>Template:Cite journal</ref>

The astrocytes surround the blood–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 the metalloproteinase-2 and interleukin-6 as culprits responsible for the BBB failure.<ref>Template:Cite journal</ref> There is broad consensus that AQP4/NMO-IgG initially enters the brain via BBB-deficient sites such as the area postrema, where there is access to cerebrospinal fluid (CSF).<ref>Template:Cite journal</ref> In any case, anti-AQP4 is produced mainly intrathecally.<ref name=pmid25626447>Template:Cite journal</ref>

Within astrocytes, AQP4 is primarily found in astrocytic foot processes that abut blood vessels and the linings of the brain (meninges).<ref name=":0" /> NMOSD brain lesions, as seen under a microscope, show IgG, Immunoglobulin M (IgM), inflammatory cells, and complement deposits around blood vessels.<ref name=":0" /> AQP4-IgG is a member of the IgG1 immunoglobulin family, which is an activator of the complement system, which seems to play an integral part in the autoimmune response.<ref name=":0" /> There is a loss of astrocytes, and sometimes also a loss of neurons and oligodendrocytes. Loss of cells other than astrocytes is a consequence of collateral inflammatory damage or astrocyte dysfunction.<ref name=":0" />

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.<ref name=":0" /> The increased BBB permeability at the area postrema helps explain involvement there.<ref name=":0" /> 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.<ref name=":0" />

In NMOSD, areas of brain tissue that appear normal in conventional magnetic resonance imaging (MRI) can show damage in diffusion tensor imaging (DTI), although less so compared to multiple sclerosis (MS).<ref>Template:Cite journal</ref>

Most research into the pathology of NMO has focused on the spinal cord. The damage can range from inflammatory demyelination to necrotic damage of the white and grey matters. The inflammatory lesions in NMO have been classified as type II lesions (complement-mediated demyelination), but they differ from MS pattern II lesions in their prominent perivascular distribution. Therefore, the pattern of inflammation is often quite distinct from that seen in MS.<ref name=Wingerchuk/><ref name="pmid12076996"/>

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.<ref name=":0" />

NMO-IgG-negative cases are less understood. It seems that astrocytes are spared in these cases.<ref>Template:Cite journal</ref>

Anti-MOG+ variants

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The second most frequent autoantibody in NMO is MOG-IgG, which targets myelin oligodendrocyte glycoprotein (MOG). MOG is an integral membrane glycoprotein found on the surface of oligodendrocytes and the outermost surface of myelin sheaths.<ref name=":0" /> Its function is not entirely known.<ref name=":0" /> 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.<ref name=":0" />

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.<ref name=":0" /> 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.<ref name=":0" />

Antibodies against MOG are considered mostly absent in similar diseases, such as MS.<ref>Template:Cite journal</ref> Therefore, it can be said that anti-MOG diseases are grouped within AQP4-IgG-negative NMOSD.<ref name=pmid25889963/>

Together with anti-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 main auto-antibodies.<ref name="kezuka">Template:Cite journal</ref>

The clinical course and the response to therapy is different for various diseases classed within these groups, showing a better prognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis for those in the NMO-Ab(+)/MOG-Ab(+) group.<ref name="kezuka"/> The MOG-related NMO can be radiologically identified by the conus involvement. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging.<ref>Template:Cite journal</ref>

Diagnosis

File:Transverse myelitis MRI.jpg

MRI image of a patient with transverse myelitis, one of the diagnostic criteria for NMOSD

NMOSD is diagnosed using consensus clinical criteria, which have undergone multiple revisions, most recently in 2015.<ref>Template:Cite journal</ref><ref name="pmid26587556">Template:Cite journal</ref>

Diagnostic criteria are more relaxed for seropositive AQP4–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 alternative diagnoses, is sufficient for NMOSD diagnosis.<ref name="Wingerchuk 177–189"/>

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.<ref name="Barkhof 2020">Template:Cite book</ref>

NMOSD diagnostic criteria<ref name="Wingerchuk 177–189">Template:Cite journal</ref>

Core criteria	Additional MRI findings for absent/unknown AQP4-IgG
Optic neuritis	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
Acute myelitis	intramedullary lesion > 3 contiguous segments, or spinal atrophy ≥ 3 contiguous segments
Area Postrema Syndrome (prolonged episodes of hiccuping or vomiting/nausea)	dorsal medulla/area postrema lesions
Acute brainstem syndrome	periependymal brainstem lesions
Symptomatic narcolepsy/acute diencephalic clinical syndrome with an MRI showing diencephalon lesion(s)	None additional
Symptomatic cerebral syndrome with NMOSD-typical brain lesion(s)	None additional

Rarely, it has been reported that some courses of anti-NMDAR are consistent with NMO.<ref>Template:Cite journal</ref> Preliminary reports suggest that other autoantibodies may play a role in rare cases of NMO.<ref name=":2" /><ref>Template:Cite journal</ref>

NMOSD with MOG-IgG is considered a manifestation of anti-MOG associated encephalomyelitis.<ref name="Melania Spadaro pages 295">Template:Cite journal</ref>

Spectrum constituents

After the development of the NMO-IgG test, the spectrum of disorders comprising NMO was expanded. The spectrum is now believed to consist of:

• Standard NMO, according to the diagnostic criteria described above
• Limited forms of NMO, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis
• Asian optic-spinal multiple sclerosis (OSMS), or AQP4+ OSMS. This variant can present brain lesions like MS does,<ref>Template:Cite journal</ref> but it should not be confused with an AQP4-negative form of inflammatory demyelinating diseases of the central nervous system spectrum, sometimes called optic-spinal MS
• Longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease
• Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem<ref name=Symposium>Template:Cite conference</ref>
• NMO-IgG negative NMO: AQP4 antibody-seronegative NMO poses a diagnostic challenge.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Some cases could be related to anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies.<ref name=pmid25889963>Template:Cite journal</ref>

Differential diagnosis

AQP4-Ab-negative NMO presents problems for differential diagnosis. The behavior of the oligoclonal 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.<ref>Template:Cite journal</ref> It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS.<ref name=pmid28465080>Template:Cite journal</ref>

Another problem for diagnosis is that AQP4-ab in MOG-ab levels can be too low to be detected. Some additional biomarkers have been proposed.<ref name="pmid29204291">Template:Cite journal</ref><ref name="pmid29208041">Template:Cite journal</ref>

NMO differs from MS in that it usually has more severe sequelae after an acute episode than standard MS, which infrequently presents as transverse myelitis. In addition oligoclonal bands in the CSF as well as white matter lesions on brain MRIs are uncommon in NMO, but occur in over 90% of MS patients.<ref name=pmid15968305>Template:Cite journal</ref>

Recently, the presence of AQP4 has been found to distinguish standard MS from NMO; but as MS is a heterogeneous condition,<ref>Template:Cite journal</ref> and some MS cases are reported to be Kir4.1 channelopathies<ref name=pmid24032025>Template:Cite journal</ref> (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.<ref>Template:Cite journal</ref>

Tumefactive demyelinating lesions in NMO are not usual, but they have been reported to appear in several cases mistakenly treated with interferon beta.<ref name=pmid25516429>Template:Cite journal</ref>

Also, an overlap with Sjögren syndrome has been reported.<ref>Template:Cite journal</ref>

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).<ref name=pmid23991165>Template:Cite journal</ref>

The term neuromyelitis optica spectrum disorders (NMOSD) has been designed to allow incorporation of cases associated with non-AQP4 biomarkers.<ref name=pmid26587556/> 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.<ref name=pmid26587556/>

These variants are expected to respond to the same treatments as standard NMO.<ref>Template:Cite journal</ref> Some authors propose to use the name "autoimmune aquaporin-4 channelopathy" for these diseases,<ref name=Pittock2015/> while others prefer a more generic term "AQP4-astrocytopathy", which also includes deficiencies of AQP4 with a non-autoimmune origin.<ref name="ReferenceA">Template:Cite journal</ref>

Treatment

File:Methylprednisolone.svg

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.<ref name="mayoclinic.org">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Attacks

Long term neurologic deficits are the cumulative effects of acute attacks, emphasizing the importance of acute treatment.<ref name=":0" /> Traditionally, attacks have been treated with short courses (3–5 days) of high dosage intravenous corticosteroids, such as methylprednisolone IV (Solu-Medrol).<ref name="Kowarik 70–82">Template:Cite journal</ref> Early initiation of treatment with steroids has been shown to improve vision-related outcomes after acute attacks.<ref name=":0" /><ref name="Wallach2021Treatment">Template:Cite journal</ref> 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).<ref name="Wallach2021Treatment" /><ref name="Kowarik 70–82" />

Plasmapheresis can be an effective treatment when attacks progress after the administration of corticosteroids.<ref name=Symposium/> 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.<ref name="mayoclinic.org"/>

Secondary prevention

Prophylactic treatment, to prevent relapses of NMO, is generally employed; but the exact duration of such treatment is debatable.<ref name="Kimbrough et al">Template:Cite journal</ref>

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.<ref name=":0" /> As of 2020, they are among the most expensive drugs worldwide.<ref name=":0" /> They are not available in pill form, which, along with their high price, limits their accessibility.<ref name=":0" /> These new drugs' effectiveness against AQP4-IgG-negative NMOSD is unknown.<ref name=":0" />

Drug (brand)	Brand	Date of FDA approval	Mechanism of action	Note
Eculizumab	Soliris	2019	Monoclonal antibody against complement protein C5	Approved for AQP4-IgG-positive NMOSD<ref name="FDA eculiz">Template:Cite press release</ref>
Inebilizumab	Uplizna	2020 June	Monoclonal antibody against CD19+ B cells	<ref>Template:Cite press release</ref>
Satralizumab	Enspryng	2020 August	Monoclonal antibody against IL-6	citation	CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>

Off-label treatments

Many treatments are used despite the lack of phase III clinical trials testing their efficacy.<ref name=":0" /> 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.<ref name=":0" /> Most of these medications affect the immune system in various ways.<ref name="Kowarik 70–82"/><ref name="Symposium" /><ref>Template:Cite journal</ref>

Drug (brand)	Mechanism of action	Note
azathioprine (Imuran, Azasan)	Inhibits purine metabolism	First reported effective in 1998 and was mainstay of treatment 10+ years thereafter. Sometimes combined with steroids due to months-long onset of action.<ref name=":0" />
mycophenolate mofetil (CellCept)	Inhibits purine metabolism	Has partially replaced azathioprine due to proposed better efficacy and tolerability. Sometimes combined with steroids due to months-long onset of action.<ref name=":0" />
corticosteroid		<ref>Template:Cite journal</ref>
mitoxantrone	DNA synthesis/repair inhibitor
methotrexate	Inhibits folate metabolism
cyclophosphamide	DNA crosslinker
rituximab (Rituxan)	antibody against CD20 – B cell depletion<ref>Template:Cite journal</ref>	The most commonly used treatment for NMOSD today.<ref name="pmid28017256">Template:Cite journal</ref>
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.<ref name=pmid28866625>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Prognosis

Normally, some improvement appears in a few weeks, but severe residual symptoms and even disability may persist.Template:Citation needed

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.<ref name=Wingerchuk/>

It is possible that the relapsing form is related to the anti-AQP4+ seropositive status and the monophasic form related to its absence.<ref name="Ketelslegers">Template:Cite journal</ref> 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.<ref name=Wingerchuk/>

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.<ref name=Wingerchuk/>

Epidemiology

Prevalence varies by region, ranging from 0.5 to 10 cases per 100,000 people.<ref name=":0" /> Unlike MS, prevalence has not been found to be related to latitude.<ref name=":0" /> 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.<ref name=Wingerchuk/>

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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

The majority of NMO patients have no affected relatives, and it is generally regarded as a nonfamilial condition.<ref name=Wingerchuk/>

Rarely, NMO may occur in the context of other autoimmune diseases (e.g. connective tissue disorders, paraneoplastic syndromes) or infectious diseases. In some cases, the etiology remains unknown (idiopathic NMO).Template:Citation needed

History

File:Thomas Clifford Allbutt.jpg

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.<ref name="HistoryOfNMO">Template:Cite journal</ref><ref name="HistoryOfNMOPart2">Template:Cite journal</ref> However, only an 1870 report by Sir Thomas Clifford Allbutt created sustained interest on the part of neurologists and ophthalmologists in this rare syndrome.<ref>Template:Cite journal</ref> 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.<ref name=HistoryOfNMO /><ref name=Devic1894>Template:Cite journal</ref><ref>Template:Cite book</ref>

In 2002, Mayo Clinic researchers identified a humoral mechanism, targeting a perivascular protein, as the culprit of NMO,<ref name="pmid12076996">Template:Cite journal</ref> and in 2004 an unknown specific autoantibody was found.<ref name=Lancet2004>Template:Cite journal</ref> 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.<ref name=pmid16087714/> The first quantitative ELISA (enzyme-linked immunosorbent assay) kits were soon developed,<ref>Template:Cite journal</ref> However, serum AQP4-IgG titer only moderately reflects disease activity, severity, or neurological prognosis.<ref>Template:Cite journal</ref> 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).<ref name="pmid22608667">Template:Cite journal</ref>

There is little research into the primary causes of the anti-AQP4 auto-antibodies. It has been noticed that some cases could be paraneoplastic.<ref name=Iorio>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

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.<ref name=":2">Template:Cite journal</ref>

Other autoantibody being researched is flotillin. It has been found in seronegative NMO and some MS patients.<ref>Template:Cite journal</ref>

Finally, other proteins under study are connexin 43 and anti-AQP1,<ref name="Tzartos">Template:Cite journal</ref> although, as of 2015, there are only initial reports about the involvement of these proteins.<ref name=pmid23991165/><ref name="ReferenceA"/>

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<ref name="Melania Spadaro pages 295"/> – around 10% of total cases
• Connexin-43 NMO
• Aquaporin-1 associated NMO<ref name="Tzartos"/> which could be related to pattern III MS<ref>Template:Cite journal</ref>
• 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.<ref>Template:Cite journal</ref>

Later studies have increased the number of groups up to four.<ref>Template:Cite journal</ref>

Notable patients

• Christine Hà (chef and author)
• Cassie Mitchell (paralympian and biomedical engineering professor)

See also

• Anti-AQP4 disease
• Demyelinating disease
• Idiopathic inflammatory demyelinating diseases
• Multiple sclerosis
• Tocilizumab