- Neuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune, inflammatory demyelinating disease of the central nervous system (CNS) that predominantly affects the optic nerves, spinal cord, and sometimes the brain.
- Historically considered a variant of multiple sclerosis (MS), NMOSD is now recognized as a distinct entity due to its unique clinical, immunological, and radiological features. The hallmark of NMOSD is the presence of autoantibodies against aquaporin-4 (AQP4-IgG), a water channel protein expressed on astrocytes, in approximately 70-80% of patients.
- NMOSD typically presents with severe attacks of optic neuritis and longitudinally extensive transverse myelitis, leading to significant disability if untreated. The disease affects individuals across all ages but is more common in women and certain ethnic groups, including those of Asian, African, or Hispanic descent.
- The pathogenesis of NMOSD is driven by AQP4-IgG, which binds to aquaporin-4 channels on astrocytic foot processes, triggering complement activation, immune cell infiltration, and inflammation. This cascade damages astrocytes, disrupts the blood-brain barrier (BBB), and secondarily affects oligodendrocytes and neurons, leading to demyelination and axonal loss. Unlike MS, NMOSD lesions are typically more destructive and less likely to resolve fully, contributing to stepwise disability accumulation with each attack. AQP4-negative NMOSD cases may involve antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) or other unidentified mechanisms, but these are often classified separately as MOG-associated disease. Neuroinflammation in NMOSD involves both humoral and cellular immunity, with B-cells, T-cells, and complement playing critical roles. The disease’s relapsing nature underscores the importance of early diagnosis and aggressive treatment to prevent relapses.
- Clinically, NMOSD is characterized by acute, severe attacks that cause visual impairment, motor deficits, sensory loss, and autonomic dysfunction. Optic neuritis in NMOSD often leads to unilateral or bilateral vision loss, pain with eye movement, and poor visual recovery compared to MS. Transverse myelitis manifests as weakness or paralysis, numbness, and bladder or bowel dysfunction, with MRI showing longitudinally extensive lesions spanning three or more vertebral segments. Other manifestations include intractable hiccups, nausea, or vomiting due to area postrema involvement, and, less commonly, brainstem or cerebral lesions causing encephalopathy or seizures. The disease typically follows a relapsing course, with monophasic cases being rare. Disability in NMOSD is attack-related, unlike the progressive neurodegeneration seen in MS, making relapse prevention critical.
- Diagnosis of NMOSD relies on clinical criteria, serological testing, and neuroimaging. The 2015 International Panel for NMO Diagnosis criteria allow diagnosis with or without AQP4-IgG, based on core clinical characteristics (e.g., optic neuritis, myelitis) and exclusion of alternative diagnoses. AQP4-IgG testing, preferably via cell-based assays, is highly specific and aids in distinguishing NMOSD from MS. MRI findings include longitudinally extensive spinal cord lesions, optic nerve enhancement, and characteristic brain lesions in AQP4-rich areas like the hypothalamus or periventricular regions. Cerebrospinal fluid analysis may show pleocytosis but typically lacks oligoclonal bands, unlike MS. Differential diagnosis includes MS, MOG-associated disease, sarcoidosis, and infectious or neoplastic causes of myelitis or optic neuritis.
- The etiology of NMOSD involves genetic and environmental factors, though less is known compared to MS. Associations with HLA-DPB1*05:01 in certain populations suggest genetic predisposition. Environmental triggers, such as infections or vaccinations, may initiate autoimmunity in susceptible individuals, potentially via molecular mimicry. Treatment of NMOSD focuses on acute attack management and relapse prevention. Acute attacks are treated with high-dose intravenous corticosteroids, often followed by plasma exchange or intravenous immunoglobulin for refractory cases. Long-term immunosuppression with agents like azathioprine, mycophenolate mofetil, or rituximab (a B-cell-depleting monoclonal antibody) is standard to prevent relapses. Newer therapies, including eculizumab, satralizumab, and inebilizumab, target complement, IL-6 signaling, and B-cells, respectively, and have shown efficacy in reducing relapse rates. Symptomatic treatments address pain, spasticity, and bladder dysfunction, while rehabilitation supports functional recovery.
- In summary, NMOSD is a debilitating autoimmune CNS disorder driven by AQP4-IgG-mediated inflammation, distinct from MS in its pathophysiology, clinical course, and treatment. Its severe, attack-driven disability highlights the need for prompt diagnosis and aggressive management to preserve neurological function. Advances in understanding NMOSD’s immunological basis have led to targeted therapies, improving outcomes for many patients. However, challenges remain in managing AQP4-negative cases, predicting relapses, and addressing irreversible damage from early attacks. Ongoing research into biomarkers, novel therapies, and repair strategies holds promise for further enhancing care.
