Can Neuromyelitis Optica Spectrum Disorder (NMOSD) be triggered by a viral illness?

Can NMOSD Be Preceded by a Viral Illness?

Yes, NMOSD can be preceded by a viral illness, and this is recognized as a supportive diagnostic feature in suspected autoimmune neurological syndromes, though the specific viral triggers and their role in disease onset remain incompletely understood.

Evidence for Viral Prodrome in NMOSD

Recognition in Diagnostic Guidelines

The relationship between viral illness and NMOSD is acknowledged in neuroimmunology guidelines, though primarily in the context of broader autoimmune encephalitis syndromes:

• Preceding infectious illness is listed as a "supportive feature" for suspected neuronal surface antibody-associated syndromes (NSAS), which share pathophysiological mechanisms with NMOSD 1
• The recognition stems from observations that many cases of autoimmune encephalitis are preceded by viral disease-like prodromes, and that CNS disorders with acute/subacute onset following viral disease can be generated by parainfectious autoimmune mechanisms 1

Clinical Context and Limitations

While viral prodromes are documented, the evidence specific to NMOSD has important caveats:

• The association between specific infections and NMOSD onset or relapses requires further investigation, as whether factors like AQP4-antibody production actually initiate NMOSD attacks currently remains unclear 2
• Infectious diseases have been proposed as possible environmental factors associated with NMOSD onset, with some infections being more common in Asia and Latin America—paralleling the higher NMOSD incidence in these geographic locations 2

Distinguishing NMOSD from Other Conditions

Differential Diagnosis Considerations

When evaluating a patient with suspected NMOSD following viral illness, critical distinctions must be made:

• CSF findings in NMOSD may mimic CNS infection with neutrophil pleocytosis, impaired blood-CSF barrier function, and lack of CSF-restricted oligoclonal bands 1
• White cell counts in MOG-EM (a related condition) ranged 6-306 cells/μl (median 33), with WCC ≥100 cells/μl in 28% of patients and neutrophils present in 64% of those with pleocytosis 1
• Clinical or paraclinical findings suggesting CNS infection (neurotuberculosis, neuroborreliosis, neurosyphilis) are "red flags" that should prompt reconsideration of the diagnosis 1

Diagnostic Approach After Viral Prodrome

When NMOSD is suspected following viral illness:

• Acute or subacute onset (<12 weeks) of symptoms is a key criterion for suspected immune-mediated disease 1
• Evidence of CNS inflammation must be present: CSF lymphocytic pleocytosis, oligoclonal bands, elevated IgG index, or characteristic MRI findings 1
• Exclusion of active infection is mandatory before initiating immunotherapy, though basic CSF results (cell count, protein, glucose) are sufficient to rule out infection without waiting for complete antibody confirmation 3

Pathophysiological Considerations

Autoimmune Mechanisms

The relationship between viral illness and NMOSD likely involves complex autoimmune mechanisms:

• NMOSD arises from complex interactions between genetic susceptibility and environmental factors, with infectious diseases proposed as possible triggers 2
• The disease is caused by pathogenic serum IgG antibodies against aquaporin-4 (AQP4) in approximately 75% of patients, which bind to AQP4 channels on astrocytes and trigger complement activation 4, 5

Comparison to Other Autoimmune Conditions

The viral prodrome pattern in NMOSD parallels other autoimmune diseases:

• In Adult-Onset Still's Disease (AOSD), various viral infections (rubella, mumps, echovirus 7, cytomegalovirus, Epstein-Barr virus, and others) have been implicated as potential triggers 1
• This suggests a broader pattern where viral infections may act as disease triggers in genetically predisposed hosts through molecular mimicry or other immune mechanisms 1

Clinical Implications

Practical Management Points

• A history of recent viral illness should not delay diagnostic workup or treatment when NMOSD is suspected based on clinical presentation (longitudinally extensive transverse myelitis, severe optic neuritis, area postrema syndrome) 6
• Testing for AQP4-IgG and MOG-IgG antibodies should proceed regardless of viral prodrome history 6
• Relapses should be treated aggressively with high-dose intravenous corticosteroids as first-line therapy, followed by plasma exchange for steroid-refractory cases 6, 4

Common Pitfalls

• Do not mistake the CSF pleocytosis and neutrophilia of NMOSD for active CNS infection—this can delay appropriate immunotherapy 1
• Do not assume that a viral prodrome excludes NMOSD; rather, recognize it as a potential supportive feature in the diagnostic evaluation 1
• Approximately 50% of untreated NMOSD patients will become wheelchair users and blind, with one-third dying within 5 years of first attack, making prompt diagnosis and treatment critical regardless of preceding illness 4