Neuromyelitis Optica Spectrum Disorder (NMOSD) is a rare, inflammatory disorder affecting the central nervous system. This condition primarily targets the optic nerves and the spinal cord, leading to episodes of vision loss and paralysis. NMOSD is often associated with specific antibodies that attack the body’s own tissues, the most common being the Aquaporin-4 immunoglobulin G (AQP4-IgG) antibody. These antibodies are normally detectable in the blood. When blood tests for known biomarkers are repeatedly negative, the condition is termed “seronegative” NMOSD. The diagnosis of seronegative NMOSD relies on clinical and imaging evidence rather than a simple blood test.
Defining Seronegative Neuromyelitis Optica Spectrum Disorder
The classification of NMOSD relies heavily on the status of two main antibodies that target components of the central nervous system. The AQP4-IgG antibody is the classic marker, targeting a water channel protein called Aquaporin-4, which is abundant on the surface of astrocytes. This antibody is found in the majority of NMOSD patients.
Another related but distinct inflammatory disorder is associated with antibodies against Myelin Oligodendrocyte Glycoprotein (MOG-IgG). While MOG-IgG disease shares clinical overlap with NMOSD, it is increasingly recognized as a separate entity. The term seronegative NMOSD is reserved for individuals who test negative for both the AQP4-IgG and the MOG-IgG antibodies.
The absence of these circulating antibodies does not suggest a milder disease course. Instead, it indicates that the underlying mechanism causing the inflammation may be different, or perhaps that the antibodies are produced locally within the central nervous system and do not cross into the bloodstream in sufficient quantity. This lack of a clear biological marker necessitates a more rigorous diagnostic process. The clinical presentation and severity of attacks in seronegative cases can be similar to those of seropositive NMOSD.
Diagnostic Criteria When Biomarkers Are Absent
The diagnosis of seronegative NMOSD is achieved by applying the stringent 2015 International Consensus Diagnostic Criteria for NMOSD. When the AQP4-IgG antibody is not detected, the diagnosis requires the patient to have experienced at least two distinct core clinical characteristics. These attacks must involve different areas of the central nervous system, showing a dissemination of the disease in space.
Furthermore, at least one of these clinical events must be a severe attack of optic neuritis, acute myelitis, or a syndrome affecting the brainstem area postrema. The area postrema syndrome is characterized by intractable nausea, vomiting, or hiccups due to inflammation in that specific region of the brainstem. The combination of these specific clinical events points strongly toward an NMOSD diagnosis.
The diagnosis is further supported by characteristic findings on magnetic resonance imaging (MRI). A common radiological feature is longitudinally extensive transverse myelitis (LETM), which appears as a spinal cord lesion extending across three or more adjacent vertebral segments. This specific pattern is highly suggestive of NMOSD and is infrequently seen in other demyelinating conditions.
Brain imaging also plays a crucial role, often revealing lesions in areas of the brain where Aquaporin-4 is highly expressed. The necessity of ruling out Multiple Sclerosis (MS) is paramount, as the treatments for the two conditions differ significantly. MRI features that help distinguish NMOSD from MS include the central location of spinal cord lesions in NMOSD and the absence of the small, ovoid, perivenular lesions typically seen in MS.
Treatment Strategies for Seronegative NMOSD
The management of seronegative NMOSD is divided into two primary strategies: treating acute attacks and implementing long-term therapy to prevent future relapses. Since attacks can cause severe and accumulating disability, timely intervention is a high priority. When a flare-up occurs, the standard immediate treatment is high-dose intravenous corticosteroids, such as methylprednisolone.
This pulse therapy is typically administered for several days to rapidly reduce inflammation. If the patient does not show improvement, or if the attack is particularly severe, plasma exchange (PLEX) is often used. PLEX involves filtering the patient’s blood to remove circulating antibodies and inflammatory proteins, which helps limit damage during a severe attack.
For long-term management, continuous immunosuppression is required because of the high risk of severe relapses. The goal of maintenance therapy is to suppress the immune system’s overactivity to prevent new attacks and the resulting accumulation of disability. Traditional immunosuppressants, such as azathioprine or mycophenolate mofetil, are often used. Newer targeted biologic therapies, including B-cell depleting agents like rituximab, are also frequently employed.