Double-negative neuromyelitis optica spectrum disorder is a syndrome that differs from aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. It may cause both monophasic and relapsing conditions. However, it does cause severe disability. There is a need for more research to understand the unique treatment requirements of double-negative neuromyelitis optica spectrum disorder patients.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune condition of the CNS particularly affecting the optic nerve and spinal cord. Over the years, understanding of the condition has improved, especially with the discovery of aquaporin 4 (AQP4) antibodies and the ability to detect serum myelin oligodendrocyte glycoprotein IgG (MOG-IgG). Over the years, the disease classification has changed, and now those with MOG-IgG antibodies are considered to be living with a separate condition called MOG antibody-associated disease (MOGAD).
Most NMOSD patients are AQP4-positive, but not all. A significant number of those diagnosed with NMOSD are negative for AQP4 and MOG-IgG, and this condition is referred to as double-negative (DN) NMOSD. DN NMOSD may be monophasic or relapsing, and is not a single disease but rather a syndrome, and thus differs from AQP4 NMOSD or MOGAD. A review published in the Multiple Sclerosis Journal explores how DN NMOSD differs from AQP4 NMOSD and MOGAD and its treatment strategies.
Until 2015, NMOSD was referred to simply as NMO. Patients without AQP4 antibodies and with limited anatomical involvement no longer satisfied the 2015 criteria. With improved assays, antibody-negative disease now refers to patients who are negative for both AQP4-IgG and MOG-IgG.
Epidemiology
The median onset of DN NMO/NMOSD ranges between 32 and 43 years of age. Unlike AQP4-positive patients, DN NMO/ NMSOD does not show a substantial female predominance. DN NMO/NMSOD is more likely to have a monophasic course. However, DN NMSOD patients often exhibit severe neurological symptoms comparable to those seen in antibody-positive NMOSD patients. Immunological studies suggest increased inflammation in DN NMOSD, although the exact mechanisms remain unclear.
Clinical and Laboratory Characteristics
Clinically, DN NMOSD patients typically present with longitudinally extensive optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), or brain/brainstem attacks. Despite some similarities with antibody-positive NMOSD, DN NMOSD patients tend to have similar or more severe residual disability after attacks. Differential diagnosis from MS is crucial, particularly in cases of isolated ON or LETM, which may mimic MS. Laboratory characteristics and imaging biomarkers aid in the diagnosis of DN NMOSD, but no specific biomarker exists. Combined clinical, imaging, and metabolic methods may provide more insights into the heterogeneity of DN NMOSD and help differentiate it from other conditions.
Treatment
Treatment of DN NMOSD remains challenging due to the lack of approved therapies specifically targeting this subgroup. Conventional immunosuppressants are often used empirically, with varying success rates. Emerging therapies, such as tocilizumab and inebilizumab, show promise but require further investigation.
The Bottom Line
To sum up, the definition of DN NMOSD has changed over time. It is a syndrome and not a single disease condition. Doctors must use sensitive assays for MOG-IgG and AQP4-IgG to avoid false diagnoses of DN NMOSD. Although it may be monophasic or relapsing, it can cause as severe a disability as AQP4-NMOSD. Although DN NMOSD patients benefit from immunosuppressants, more research is needed to understand the condition.
Reference:
Wu, Y., Geraldes, R., Juryńczyk, M., & Palace, J. (2023). Double-negative neuromyelitis optica spectrum disorder. Multiple Sclerosis Journal, 29(11–12), 1353–1362. https://doi.org/10.1177/13524585231199819
