in severe visual loss at onset, with bilateral involvement, and permanent visual deficits. Classically, NMO included only symptoms of myelitis and ON. However, with the discovery of disease-causing antibodies, a broader spectrum of disease manifestations has been grouped with NMO into the diagnosis of NMOSD. 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. 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