Clinical Neuroinflammatory Mimics of Multiple Sclerosis

Although multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) are distinct central nervous system (CNS) demyelinating diseases, their clinical presentations may overlap.¹ The 2024 revisions of the McDonald MS diagnostic criteria included the addition of a fifth anatomic location (the optic nerve) within the CNS, incorporating novel MRI features (the central vein sign and paramagnetic rim lesions) and adding an additional cerebrospinal fluid biomarker (kappa free light chain index) to expedite the diagnosis of MS, allowing for earlier treatment initiation with the ultimate goal of improved clinical outcomes.²

MS is the most common inflammatory CNS disease associated with optic neuritis and myelitis and often manifests with these clinical presentations. However, optic neuritis and myelitis also commonly present during the disease course of NMOSD or MOGAD, each of which has its own distinct diagnostic criteria.^3,4 The Table provides a comparison of key characteristics of NMOSD, MOGAD, and MS.

Both NMOSD and MOGAD have specific immune mechanisms that contribute to the disease. Approximately 80% of individuals with NMOSD are positive for antibodies directed against the aquaporin-4 (AQP4) water channel found on astrocytes.⁵ AQP4 autoantibodies are known to be directly pathogenic in NMOSD, and growing evidence suggests that myelin oligodendrocyte glycoprotein (MOG) autoantibodies may be directly pathogenic in MOGAD.⁶ As such, serum AQP4 and MOG antibody testing is a key component in the diagnosis of these rare CNS demyelinating diseases. Avoiding a misdiagnosis of MS is essential, as crucial differences in response to immune therapy and clinical outcomes exist among individuals with MS, NMOSD, and MOGAD.

This review article summarizes the current understanding of both NMOSD and MOGAD (often using MS as a comparator disease), including a discussion of the clinical and paraclinical (MRI and disease-specific autoantibodies) features of each disorder, as well as a review of their most recent diagnostic criteria. 

Neuromyelitis Optica Spectrum Disorder
The clinical and pathologic understanding of NMOSD has undergone substantial refinement over the past 2 decades. Similar to the 2024 McDonald criteria updates, an international panel of NMOSD experts is actively working to further refine diagnostic criteria.⁷ Given that these updates are not yet finalized and published, our review article focuses on our current understanding of NMOSD using the 2015 international consensus diagnostic criteria for NMOSD.

NMOSD gained clear distinction from other CNS demyelinating diseases following the identification of AQP4 antibodies in 2004, which clarified its primary feature of astrocytopathic injury and its clinical separation from MS. AQP4 is the water channel that is most preferentially expressed on astrocytic foot processes, regulating water homeostasis in the brain.⁸ Antibodies directed against AQP4 lead to complement activation with membrane attack complexes and inflammatory cell recruitment, resulting in direct cytotoxicity of surrounding brain tissue.⁹ This leads to further astrocytic dysregulation resulting in large necrotic CNS lesions that can be observed in individuals with NMOSD.¹

NMOSD is a rare disorder in the United States and Europe, accounting for ~1% to 2% of all CNS demyelinating disorders. In Asian and other populations of non-European ancestry, NMOSD accounts for one-third or more of CNS inflammatory disease diagnoses.⁵ The disease has a higher prevalence in women compared with men, with a median age at onset of ~40 years. However, it is estimated that up to 20% of cases occur in children or adults age >65 years. About 85% of individuals with NMOSD will first present with optic neuritis or myelitis, which are 2 of the 6 core clinical characteristics associated with NMOSD.⁵

Optic neuritis in NMOSD can be unilateral or bilateral. Individuals typically have posterior optic nerve involvement, less frequently leading to orbital pain compared with MS or MOGAD.¹ Optic nerve involvement may not be visible on funduscopic examination, reinforcing the importance of obtaining MRI scans, as T2-hyperintense lesions can be visualized involving the posterior optic nerves, including the optic chiasm.¹⁰ Compared with MS, NMOSD is more likely to cause permanent visual deficits.

Myelitis related to NMOSD is generally characterized by longitudinally extensive transverse myelitis (LETM) lesions, which can lead to paraplegia or tetraplegia at nadir.¹ On MRI scans, spinal cord lesions typically appear as a single, longitudinal, T2-hyperintense lesion, which can range from the cervical spinal cord to the upper thoracic spinal cord, affecting the entire cross-section of the cord. Short-segment spinal cord lesions may be seen, especially if MRI scans are performed at the onset of clinical symptoms, which may lead to initial imaging characteristics similar to those of MS lesions.¹¹

The third core clinical characteristic of NMOSD is area postrema syndrome (APS). Approximately 10% of individuals with NMOSD will first develop APS (localized in the dorsal medulla), which is characterized by intractable nausea, vomiting, or hiccups.^5,12 The other 3 NMOSD core clinical characteristics—acute brainstem syndrome, acute diencephalic syndrome with NMOSD-typical diencephalic MRI lesions (or symptomatic narcolepsy), and symptomatic cerebral syndrome with NMOSD-typical brain lesions—occur less frequently.⁵

The diagnosis of NMOSD is based on clinical features and AQP4 antibody testing. For antibody testing, diagnostic guidelines strongly recommend using cell-based assays to assess for the presence of antibodies against AQP4. For people with AQP4+ NMOSD, only 1 of the 6 core clinical characteristics is required for a diagnosis of NMOSD. If AQP4 antibody testing has negative results, at least 2 core clinical characteristics are required for diagnosis (with one of these core clinical characteristics being optic neuritis, acute myelitis with LETM, or APS), along with further typical MRI findings associated with NMOSD.³

Four new Food and Drug Administration–approved disease-modifying therapies (DMTs) are available for treatment of AQP4+ NMOSD. Each of these therapies have unique mechanisms of action that target immune pathways that contribute to NMOSD pathophysiology, including complement activation, activated B cells, and interleukin-6. These therapies have the ability to prevent relapses and thus future disability for people with AQP4+ NMOSD. However, given the specific targets of these immunotherapies, accuracy of NMOSD diagnosis is imperative, because there is evidence that some of the MS DMTs can be ineffective in people with NMOSD or may even exacerbate NMOSD disease activity.⁶

Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease
The identification of MOG antibodies has led to the recognition of MOGAD as a distinct, antibody-mediated CNS demyelinating condition, characterized by its own clinical presentation, imaging findings, and treatment response. Literature reviews highlight that, prior to the availability of current diagnostic tools, cases of MOGAD were often misclassified as atypical MS, which delayed accurate diagnosis and appropriate treatment—contributing to worse outcomes in some patients.^6,13

Approximately half of individuals with MOGAD follow a relapsing disease course; the remainder experience a monophasic course.⁶ MOGAD typically presents with optic neuritis, myelitis, or acute disseminated encephalomyelitis–like encephalopathy in children, although the diagnostic criteria continue to evolve as other clinical syndromes have been reported.⁴ Optic neuritis is often bilateral, associated with marked optic disc edema, and accompanied by severe pain. Despite the dramatic presentation, visual recovery is frequently favorable, particularly when corticosteroid therapy is initiated promptly. Myelitis often involves long segments of the spinal cord, frequently affects central gray matter, and may extend to the conus medullaris. This pattern results in prominent sensory symptoms, sphincter dysfunction, and flaccid paraparesis. Brain involvement may include cortical and cortical-subcortical lesions, which represent an important distinction from MS and differ from the periependymal or dorsal medullary lesions more typical of AQP4+ NMOSD.^14,15

Advances in neuroimaging have improved the precision of MOGAD diagnosis. MRI lesions associated with MOGAD are commonly poorly marginated and “fluffy,” sometimes with involvement of the deep or juxtacortical white matter, but not in the characteristic ovoid or periventricular distribution seen in MS. LETM is common in individuals with MOGAD but typically shows more prominent central gray matter involvement than in people with AQP4+ NMOSD. Optic nerve imaging often demonstrates long segments of involvement, sometimes including the sheath. These radiologic characteristics support the diagnosis but require cautious interpretation, as significant overlap among these disorders can occur.¹⁶

Diagnostic challenges remain, particularly in distinguishing MOGAD from both MS and AQP4+ NMOSD at first presentation. Isolated optic neuritis or a single episode of myelitis can resemble MS, and early neuroimaging may not yet show classic features associated with each disease. CSF tests can provide additional diagnostic clues. CSF restricted oligoclonal bands are frequently present in cases of MS, but are usually absent in MOGAD. CSF pleocytosis may be more pronounced in MOGAD than in MS, particularly in cases with acute disseminated encephalomyelitis–like presentations. However, these differences are not absolute, and antibody testing remains central to diagnosis.^6,10

The International MOGAD Panel proposed structured criteria that require positivity on a live cell-based assay, recognition of clinical syndromes strongly associated with MOG immunoglobulin G, and systematic exclusion of alternative diagnoses. These criteria also address important nuances, including interpretation of low titers, temporal variation in antibody levels, and the limited diagnostic value of fixed-cell assays. Careful clinical and radiologic correlation remains essential, particularly when results are low-positive or when seroreversion occurs after treatment.^4,17

Accurate disease classification has major therapeutic implications. Similar to what has been seen with their use in NMOSD, many MS DMTs do not provide meaningful benefit in MOGAD and may worsen disease activity. Early recognition of MOGAD therefore guides clinicians toward high-dose corticosteroids for acute attacks and allows a tailored approach to long-term immunotherapy to prevent relapsing disease activity. 

Summary
Over the past 2 decades, the clinical understanding of NMOSD and MOGAD has evolved, with these related yet distinct disorders now clearly separable from each other and from MS. Diagnostic criteria have been developed to support accurate differentiation. Antibody testing, along with MRI and other paraclinical testing, plays a central role in identifying and distinguishing NMOSD and MOGAD.

Therapeutic options for both acute management and relapse prevention are rapidly advancing. Early diagnosis using serum, CSF, and imaging biomarkers paired with prompt treatment of acute attacks improves long-term patient outcomes. Targeted biologic therapies have significantly reduced relapses and subsequent disability in people with AQP4+ NMOSD. Many individuals with MOGAD can achieve recovery and a monophasic course, although relapses are possible. Targeted DMTs for relapse prevention remain an unmet need in this population.

As research advances, the distinctions between NMOSD and MOGAD, and their roles within the wider group of inflammatory demyelinating CNS disorders, are becoming more clearly defined. Ongoing refinement of diagnostic frameworks, improved assay standardization, and increasing familiarity with characteristic imaging and clinical patterns continue to enhance diagnostic accuracy and support more individualized patient management.