Researchers discovered that double seronegative neuromyelitis optica spectrum disorder (DN-NMOSD) has distinct pathogenesis from aquaporin-4 (AQP4) antibody NMOSD (AQP4-NMOSD), as published in the Journal of Neuroinflammation.

The discovery of AQP4 antibodies has led scientists to classify NMOSD as a disease distinct from multiple sclerosis. Studies demonstrate that most patients with NMOSD (over 90%) are seropositive for AQP4 antibodies.

However, some patients are seronegative for AQP4 antibodies but test positive for the myelin oligodendrocyte glycoprotein (MOG) antibody. Patients who are negative for AQP4 and MOG antibodies are termed double seronegative.

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In what aspects do the pathophysiological routes of AQP4-NMOSD and DN-NMOSD converge, and in what aspects do they diverge? Hyun and colleagues conducted a study to find out. They recruited patients who satisfied the 2015 diagnostic criteria for NMOSD and seronegative for both AQP4 and MOG antibodies.

Read more about NMOSD etiology

The selected patients must also have cerebrospinal fluid (CSF) samples available at the point of clinical attack. A total of 17 CSF samples were obtained. Thirty-eight age-matched patients with AQP4-NMOSD, 17 with MOG antibody-associated disease, and 15 patients with other neurological disorders (OND) were recruited as controls. The concentration of CSF glial fibrillary acidic protein (GFAP) was measured in each participant.

The results demonstrated that the CSF GFAP levels in the DN-NMOSD group were significantly lower than patients in the AQP4-NMOSD group. In addition, the overwhelming majority (90%) of patients in the AQP4-NMOSD group had higher CSF GFAP levels than the highest level observed among patients in the OND group.

“The current evidence of the pathophysiological distinction between DN-NMOSD and AQP4–NMOSD raises an issue whether these two potentially different diseases should be within the same umbrella of NMOSD,” the authors concluded.


Hyun JW, Kim Y, Kim KH, et al. CSF GFAP levels in double seronegative neuromyelitis optica spectrum disorder: no evidence of astrocyte damageJ Neuroinflammation. 2022;19(1):86. doi:10.1186/s12974-022-02450-w