Neuromyelitis optica spectrum disorder

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). 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). Fatigue has been found to correlate with quality of life in people with NMOSD. 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. ==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. 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. The discovery of NMO-IgG (anti-AQP4) has opened a new avenue of research into the causes. ==Pathophysiology==

Anti-AQP4+ variants 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. AQP4 monomers form tetramers, and the tetramers aggregate. Thus, NMOSD involving AQP4-IgG can be considered an astrocytopathy or autoimmune astrocytic channelopathy, since the astrocytes are semi-selectively destroyed. 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. 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). In any case, anti-AQP4 is produced mainly intrathecally. Within astrocytes, AQP4 is primarily found in astrocytic foot processes that abut blood vessels and the linings of the brain (meninges). 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. Anti-MOG+ variants 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. Therefore, it can be said that anti-MOG diseases are grouped within AQP4-IgG-negative NMOSD. 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. ==Diagnosis==

NMOSD is diagnosed using consensus clinical criteria, which have undergone multiple revisions, most recently in 2015. 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. Rarely, it has been reported that some courses of anti-NMDAR are consistent with NMO. Preliminary reports suggest that other autoantibodies may play a role in rare cases of NMO. NMOSD with MOG-IgG is considered a manifestation of anti-MOG associated encephalomyelitis. 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, 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 • NMO-IgG negative NMO: AQP4 antibody-seronegative NMO poses a diagnostic challenge. Some cases could be related to anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies. 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. It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS. 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. 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. 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. Some authors propose to use the name "autoimmune aquaporin-4 channelopathy" for these diseases, ==Treatment==

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. 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). 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. 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. 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. 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. 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). ==History==

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. 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. • 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) == See also ==