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).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/ Episodes of ON and myelitis can be simultaneous or successive. A relapsing disease course is common, especially in untreated patients.

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.A subset of anti-AQP4-negative cases is associated with antibodies against myelin oligodendrocyte glycoprotein (anti-MOG). Less common diseases with other manifestations are also part of the NMOSD spectrum.

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). 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.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 23Huang 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;35:246-252Mayo Clinic. Neuromyelitis optica 2020; https://www.mayoclinic.org/diseases-conditions/neuromyelitis-optica/symptoms-causes/syc-20375652. Accessed 2020 Nov 23 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). 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.

Brain effects Less commonly than the spinal cord and optic nerve, NMOSD can affect the brain stem. 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. 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.

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.

Fatigue Fatigue is a common symptom, with studies showing that as many as 77% of people with NMOSD have fatigue. 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. The cause of the remaining cases is still unknown, and it is likely heterogeneous.

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. Multiple human leukocyte antigen (HLA) alleles are associated with NMOSD.

NMO was associated in the past with many systemic diseases. Some researchers have pointed out that some other cases could be paraneoplastic. It appears that lupus can produce NMO-IgG autoantibodies, leading to cases of lupus-derived NMO.

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. AQP4 is found in astrocytes, which are the basis for the glymphatic system. 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). NMOSD brain lesions, as seen under a microscope, show IgG, Immunoglobulin M (IgM), inflammatory cells, and complement deposits around blood vessels. 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. 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.

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. The increased BBB permeability at the area postrema helps explain involvement there. 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.

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).

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.

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.

NMO-IgG-negative cases are less understood. It seems that astrocytes are spared in these cases.

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. Its function is not entirely known. 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.

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. 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.

Antibodies against MOG are considered mostly absent in similar diseases, such as MS. Therefore, it can be said that anti-MOG diseases are grouped within AQP4-IgG-negative NMOSD.

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.

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. 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.

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.

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.