Exploring the Changing Diagnosis and Treatments of Neuromyelitis Optica Spectrum Disorder

Kevin Chang, PharmD

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder of the central nervous system (CNS) characterized by severe inflammatory episodes affecting the optic nerves, spinal cord, and brainstem.¹ NMOSD is broadly classified into 2 primary subtypes: aquaporin-4 immunoglobulin G (AQP4-IgG) positive and AQP4-IgG negative.¹ AQP4-IgG–positive NMOSD is defined by the presence of pathogenic antibodies targeting the AQP4 water channel on astrocytes. AQP4-IgG–negative cases include patients who test negative for AQP4-IgG but may have other identifiable autoantibodies, such as myelin oligodendrocyte glycoprotein IgG (MOG-IgG).¹ These patients are further classified as having MOG antibody–associated disease (MOGAD), a condition now recognized as distinct from NMOSD due to its unique pathophysiology and clinical features.² Cases negative for both AQP4-IgG and MOG-IgG are designated as double-negative (DN) NMOSD, representing a heterogeneous and diagnostically challenging subgroup. Each subtype has distinct pathophysiological mechanisms, clinical presentations, and responses to treatment, necessitating a nuanced approach to diagnosis and management.

AQP4-IgG–positive NMOSD is the most common subtype, accounting for about 73% of patients in a cross-sectional study,³ characterized by antibodies targeting AQP4. The diagnosis of AQP4-IgG–positive NMOSD requires the detection of serum AQP4-IgG using a highly specific and sensitive cell-based assay.¹ The binding of AQP4-IgG triggers complement activation, leading to astrocytic injury, inflammation, and subsequent neuronal damage.⁴ Despite this damage, myelin is relatively preserved compared with the astrocytic and neuronal loss, distinguishing AQP4-IgG–positive NMOSD from demyelinating disorders like multiple sclerosis (MS).⁴ Clinically, AQP4-IgG–positive NMOSD often presents with optic neuritis (ON); longitudinally extensive transverse myelitis (LETM); or area postrema syndrome, which includes intractable nausea, vomiting, or hiccups due to medullary involvement.¹

Treatment for AQP4-IgG–positive NMOSD focuses on managing acute attacks and preventing relapses.² Acute episodes are typically treated with high-dose intravenous methylprednisolone.² If symptoms do not respond adequately to steroids, therapeutic plasma exchange is used as an adjunctive therapy.^2,4,5 Long-term immunosuppressive therapy is critical to reduce the frequency of relapses, as the risk of permanent disability from subsequent attacks is high. Commonly used long-term therapies include rituximab, a monoclonal antibody targeting CD20+ B cells, which is favored due to its effectiveness in reducing relapse rates.^5,6 Other options include azathioprine and mycophenolate mofetil, both of which are used to suppress the immune system and minimize relapses.⁶ In recent years, several targeted therapies have been approved by regulatory agencies, including eculizumab (a complement C5 inhibitor), inebilizumab (a B cell–depleting antibody), and satralizumab (an interleukin-6 receptor inhibitor).^4,5 (See FIGURE.) These therapies specifically target immune pathways implicated in AQP4-IgG–positive NMOSD pathogenesis and represent significant advances in preventive treatment.

AQP4, aquaporin-4 protein; BBB, blood-brain barrier; IL-6, interleukin-6.

Satralizumab and tocilizumab inhibit the interleukin-6 (IL-6) receptor, reducing IL-6–driven inflammation, which promotes B-cell activation and aquaporin-4 immunoglobulin G (AQP4-IgG) production. Inebilizumab depletes B cells by targeting CD19, effectively reducing AQP4-IgG levels and associated immune-mediated damage. This broader B-cell depletion strategy interrupts disease progression and is especially effective in seropositive neuromyelitis optica spectrum disorder (NMOSD). Eculizumab, in contrast, blocks complement protein C5. By halting complement activation, it protects the central nervous system from damage. These therapies offer targeted approaches to modulating the immune response, each addressing distinct mechanisms in the pathogenesis of NMOSD, with the greatest efficacy observed in patients with AQP4-IgG antibodies.

MOGAD encompasses a subset of patients with NMOSD-like symptoms who are seronegative for AQP4-IgG but positive for MOG-IgG.¹ In a cross-sectional study, MOGAD accounted for 42% of seronegative patients and 11% of the total cohort observed.³ Clinically, patients with MOG-IgG–positive disease often present with ON, often bilateral; myelitis; acute disseminated encephalomyelitis; or cortical encephalitis, and they demonstrate a better response to corticosteroid therapy than those with AQP4-IgG–positive NMOSD.⁷ Pathogenesis involves oligodendrocytopathy, sparing astrocytes and neurons.^4,8 MRI findings in MOGAD often include multiple spinal cord lesions compared with AQP4-IgG–positive NMOSD, with involvement of the conus medullaris.^1,7 MOGAD can present as either a monophasic or relapsing condition, compared with AQP4-IgG–positive patients, who often have a relapsing course.⁷ Unlike AQP4-IgG, MOG-IgG does not seem to robustly activate complement.⁹ Instead, MOG-IgG acts through complement-independent mechanisms, potentially involving oligodendrocyte injury.⁹

The acute management of MOGAD involves high-dose intravenous corticosteroids to mitigate inflammation. Early tapering of steroids is discouraged, as it can lead to disease relapse.¹⁰ The prognosis for MOGAD tends to be more favorable than for AQP4-IgG–positive NMOSD, and patients typically present a monophasic course. As a result, maintenance therapy is recommended only after a second episode.⁸

DN NMOSD is a heterogeneous group defined by the absence of both AQP4-IgG and MOG-IgG antibodies and accounted for about 16% of patients in a cross-sectional study³. DN NMOSD poses diagnostic challenges, as it can overlap with MS and other conditions affecting the optic nerve, spinal cord, and brainstem.¹¹ LETM is a prerequisite for diagnosing DN NMOSD, with spinal cord lesions typically involving the cervical or thoracic segments or both.^11,12 However, LETM is not exclusive to DN NMOSD, and differential diagnosis is necessary to exclude other possible pathologies. MRI findings typically show longitudinally extensive lesions in the spinal cord spanning 3 or more vertebral segments, as well as optic chiasm lesions in the brain.¹ DN NMOSD patients experience neuronal damage as much as in AQP4-IgG–positive cases and more pronounced than in MOGAD cases.¹¹ Simultaneous ON and LETM are more frequent in DN NMOSD than in AQP4-IgG–positive NMOSD but less common than in MOGAD.¹¹

Although research into NMOSD and its subtypes has advanced significantly, DN NMOSD remains the least understood. Prognosis and therapeutic response in this group are highly variable, and clinical management often relies on strategies developed for antibody-positive NMOSD, as there are no approved therapies for DN NMOSD.¹¹ Unlike with MOGAD, DN NMOSD patients are less responsive to corticosteroids during relapses but have a lower likelihood of relapse following steroid cessation.^1,11 Treatment is recommended after a severe first attack or second attack with rituximab or, alternatively, azathioprine or mycophenolate mofetil.^2,6 Further research is necessary to elucidate the pathophysiology and optimize the treatment of DN cases. By integrating clinical expertise with emerging evidence, clinicians can improve outcomes for all NMOSD subtypes, minimizing relapses and preserving neurological function.

References
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