In most cases, the exact cause of neuromyelitis optica is unknown. However, studies of affected nerves have improved our understanding of the disease process. In neuromyelitis optica, certain immune proteins (autoantibodies) attach themselves to specialized proteins in the spinal cord and optical nerve called "water channel proteins." The autoantibodies signal immune cells to attack, resulting in damage to myelin and the breakdown of healthy nerves and tissues.

There is a strong link between neuromyelitis optica and a personal or family history of other autoimmune conditions. In fact, 50% of people with neuromyelitis optica are also affected by other autoimmune conditions and/or have family members with an autoimmune condition.

There have been a few cases of neuromyelitis optica occurring in association with certain infectious conditions (e.g., syphilis, HIV, chlamydia, varicella, cytomegalovirus, and Epstein Barr virus). The nature of this link isn't clear. It is possible that certain infections may trigger neuromyelitis optica in people who are predisposed to the condition.