Jane, a 51-year-old female, initially presented to her primary care physician with complaints of severe fatigue, left-sided facial weakness, and bilateral blurry vision. Despite no significant medical history, she led a relatively active lifestyle, enjoying gardening and community volunteer work. Initial treatment with intravenous steroids for 5 days resulted in significant symptom improvement, and based on her clinical presentation and MRI findings, she was diagnosed with CLIPPERS and started on ongoing corticosteroid therapy for disease maintenance.

However, despite being on chronic steroid treatment, Jane experienced a relapse one month later, with progressive leg weakness, right-sided appendicular ataxia, and frequent falls. She also developed increasing difficulty speaking, a tingling sensation in her head and neck, and persistent headaches. These new symptoms prompted a hospital visit, where she received another course of intravenous steroids, leading to partial symptom resolution.

Over the following months, Jane continued to experience relapsing episodes, characterized by fluctuating neurological deficits, including recurrent visual disturbances, ataxia, and progressive limb weakness. Each episode followed a pattern of initial response to steroids, followed by symptom recurrence despite ongoing corticosteroid therapy. The persistence of these relapses raised concerns that the initial CLIPPERS diagnosis did not fully explain her condition, prompting further evaluation.

Subsequent investigations, including repeated neuroimaging, cerebrospinal fluid analysis, and serum antibody testing, ultimately led to the diagnosis of MOGAD. Her relapsing course, MRI findings, and positive MOG-IgG antibody confirmed the diagnosis, highlighting the importance of reassessing patients with ongoing disease activity despite treatment.

Key Diagnostic Clues from Her History and Presentation

• Childhood neurological event: her history of a multifocal neurological episode, characterized by fever, dysarthria, bilateral vision loss, and unilateral weakness, followed by resolution with steroids, points to an inflammatory demyelinating process. This relapsing pattern is consistent with MOGAD and not typical of static conditions like CLIPPERS or granulomatous diseases like sarcoidosis.
• Sensorineural hearing loss: the unexplained development of bilateral hearing loss highlights systemic neurological involvement, which can occur in MOGAD, because MOGAD can cause polyfocal demyelinating brain lesions that involve key structures related to auditory processing (Flanagan, et al. 2024).
• Current presentation: Jane’s current symptoms of bilateral blurry vision, facial weakness, progressive leg weakness, appendicular ataxia, dysarthria, and multiple falls. The lack of symptoms confined to the pons or cerebellum (typical of CLIPPERS) helped exclude this alternative diagnosis (Tobin WO, et al. 2017).
• Imaging findings: her brain MRI revealed multifocal supra- and infratentorial demyelinating lesions, including brainstem involvement, without the characteristic symmetric perivascular pontine enhancement seen in CLIPPERS (Tobin WO, et al. 2017). The multifocal nature aligns more closely with MOGAD.
• CSF and serum studies: CSF and serum studies in Jane’s case further support the diagnosis of MOGAD. The absence of oligoclonal bands and a high IgG index in the CSF ruled out multiple sclerosis (MS). Additionally, negative infectious and vasculitis panels excluded alternative inflammatory or infectious causes. Most critically, Jane's MOG-IgG titre of 1:100 was a clear positive, reinforcing the diagnosis. Jane's combination of brainstem involvement, characteristic MRI findings, lesion resolution over time, and negative AQP4-IgG testing strongly supports MOGAD as the correct diagnosis (Flanagan, et al. 2024).
• Relapses despite ongoing corticosteroid therapy: Jane’s relapsing course despite ongoing corticosteroid therapy further suggested that her initial diagnosis of CLIPPERS was incorrect. CLIPPERS is a chronic inflammatory condition that typically remains steroid-responsive with stable disease control on maintenance therapy. However, Jane’s recurrent relapses, with initial steroid responsiveness followed by symptom recurrence, were atypical for CLIPPERS and more consistent with a relapsing demyelinating disorder such as MOGAD. This pattern of steroid-dependent but relapsing disease progression was a critical clue prompting further evaluation, ultimately leading to the correct diagnosis.

MOGAD is a recently recognized inflammatory demyelinating condition of the CNS. Discovered in 2007, its epidemiology remains incompletely understood due to the delayed availability of widespread diagnostic testing (Teru SS, et al. 2024).

Studies suggest an incidence of 1.6-3.4 per million person-years in Europe. Unlike AQP4-IgG NMOSD, MOGAD shows no significant sex disparity, and has a median onset age of 20-30 years, but it can affect persons of all ages (Flanagan, et al. 2024).

Geographic variations are notable, with MOGAD being more frequent than AQP4-IgG NMOSD in some regions, such as the UK and Sri Lanka, but less common in Korea. No high-risk ethnicities have been identified (Flanagan, et al. 2024).

Burden of Disease in MOGAD

MOGAD imposes a significant burden on patients due to its unpredictable course and risk of long-term neurological disability. While some patients experience a monophasic episode, others develop a relapsing disease, with the likelihood of relapse increasing with longer follow-up—affecting up to 70% of patients, including both children and adults with a median onset age of 26 years (Trewin BP, et, al, 2025), recurrent attacks can lead to accumulating disability (Flanagan, et al. 2024).

Beyond physical disability, MOGAD imposes a substantial psychosocial burden. Many patients experience anxiety, depression, and emotional distress. While receiving a definitive diagnosis often alleviates some emotional distress, a subset of patients report worsened mental health outcomes. The long-term consequences of diagnostic delays—reported by patients to include vision impairment, neurological complications, and bladder dysfunction—further exacerbate the disease burden (Santoro, et al. 2023).

Delays in MOGAD diagnosis, often due to symptom overlap with CNS demyelinating diseases and lack of awareness, lead to misdiagnosis, inappropriate treatments, and prolonged disease progression (Santoro, et al. 2023). Some patients delay seeking care, while others face dismissal of symptoms (Santoro, et al. 2023), particularly women, who are more likely to be misdiagnosed with mental health conditions. Limited MOG-Ig testing contributes to these challenges (Santoro, et al. 2023). Improved education for healthcare providers, earlier diagnosis, and targeted treatment strategies are essential to reducing the burden of MOGAD (Santoro, et al. 2023).

Unmet Medical Need

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains a rare and underrecognized demyelinating disorder with significant unmet medical needs. Unlike multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), which have well-established treatment guidelines and FDA-approved therapies, there are currently no FDA-approved treatments for MOGAD. Management relies on off-label use of immunosuppressive agents such as corticosteroids, intravenous immunoglobulin (IVIG), rituximab, and mycophenolate mofetil, none of which are specifically tailored to the disease’s unique pathophysiology.

The lack of approved therapies creates challenges in standardizing treatment strategies, leading to variability in care and potential delays in optimal management. Patients with MOGAD often experience relapses despite initial treatment, requiring ongoing immunosuppression to prevent further neurological disability. However, the long-term safety and efficacy of these therapies in MOGAD remain unclear, as most data are extrapolated from MS or NMOSD studies rather than MOGAD-specific research.

Furthermore, delays in diagnosis contribute to inadequate treatment initiation, increasing the risk of unnecessary disability. The fluctuating disease course, overlapping symptoms with other demyelinating disorders, and the need for specialized antibody testing often lead to misdiagnosis or delayed recognition. Improved awareness, better diagnostic tools, and targeted therapeutic development are essential to addressing this growing unmet need and ensuring MOGAD patients receive appropriate, evidence-based care.

Pathophysiology of MOGAD

MOGAD pathophysiology is not fully understood but is likely driven by autoantibodies targeting MOG, a highly immunogenic protein on the outermost layer of the myelin sheath. These antibodies have been shown to directly induce demyelination and complement deposition in experimental models, although most human MOG antibodies do not recognize rodent MOG, limiting direct application of animal research (Flanagan, et al. 2024).

Pathological features of MOGAD include perivenous and cortical demyelination, CD4-positive T-cell and granulocytic inflammation, and complement activation, distinguishing it from MS, which features CD8-positive inflammation. Unlike NMOSD, AQP4 expression remains intact, and astrocytic damage is minimal. These unique features emphasize MOGAD’s distinct mechanisms of immune-mediated myelin damage, warranting further investigation into its pathogenesis and clinical implications (Flanagan, et al. 2024).

Clinical Presentation of MOGAD

MOGAD commonly presents with optic neuritis in adults and ADEM in children under 11 years old. Transverse myelitis is also frequent, while less common manifestations include cerebral cortical encephalitis with seizures, brainstem or cerebellar demyelinating attacks, tumefactive brain lesions, and progressive white matter damage (Banwell, et al. 2023).

Unlike AQP4-IgG NMOSD and MS, MOGAD lacks significant sex or racial predominance and can present as either a monophasic or relapsing disease. This variability underscores its distinct clinical features and the need for individualized diagnostic and treatment strategies (Banwell, et al. 2023).

Diagnosis in MOGAD

MOGAD has been underdiagnosed due to the recent discovery of MOG-IgG in 2007 and the delayed availability of widespread testing. Early reports likely underestimated its frequency, highlighting the need for improved diagnostic awareness and tools to better understand its true prevalence (Flanagan, et al. 2024).

The method used to detect MOG-IgG antibodies is important for accurate diagnosis, as different assays vary in sensitivity and specificity (Redenbaugh V and Flanagan EP, 2022). Live cell-based assays (CBAs) are considered the gold standard for MOG-IgG detection due to their superior sensitivity and ability to detect pathogenic antibodies more reliably than fixed CBAs (Jarius, et al. 2018; Redenbaugh V and Flanagan EP, 2022). This distinction is especially important in cases where low-positive titers are observed, as fixed CBAs may fail to detect MOG-IgG in some patients who genuinely have MOGAD. Given these limitations, live CBAs should be prioritized whenever possible for MOG-IgG testing to ensure accurate diagnosis and reduce the risk of misclassification (Banwell, et al. 2023).

Diagnostic Criteria for MOGAD

The diagnosis of MOGAD requires the fulfillment of the following 3 criteria (Banwell, et al. 2023):

(1) Core Clinical Demyelinating Event

At least 1 of the following clinical presentations:

• Optic neuritis
• Myelitis
• ADEM
• Cerebral monofocal or polyfocal deficits
• Brainstem or cerebellar deficits
• Cerebral cortical encephalitis, often associated with seizures

Less common presentations include cerebral cortical encephalitis (often with seizures), brainstem and cerebellar demyelinating attacks, tumefactive brain lesions, cerebral monofocal and polyfocal CNS deficits associated with demyelinating lesions, cranial neuropathies, and progressive white matter damage (leukodystrophy-like pattern).

(2) Positive MOG-IgG Test

Detection of MOG-IgG via a cell-based serum assay, with the following interpretations:

• Clear positive: no additional supporting features required.
• Low positive: requires:
• seronegativity for AQP4-IgG, and
• at least one supporting clinical or MRI feature.
• Positive without reported titer: seronegativity for AQP4-IgG, and at least 1 supporting feature needed.
• Negative serum but positive CSF: seronegativity for AQP4-IgG, and at least 1 supporting feature required.

Supporting Clinical or MRI Features

• Optic Neuritis
• Bilateral simultaneous clinical involvement
• Longitudinal optic nerve involvement (>50% length of the nerve)
• Perineural optic sheath enhancement
• Optic disc edema
• Myelitis
• Longitudinally extensive myelitis
• Central cord lesion or H-sign
• Conus lesion
• Brain, Brainstem, or Cerebral Syndrome
• Multiple ill-defined T2 hyperintense lesions in the supratentorial and infratentorial white matter
• Deep gray matter involvement
• Ill-defined T2 hyperintensities in the pons, middle cerebellar peduncle, or medulla
• Cortical lesions, with or without lesional and overlying meningeal enhancement

ADEM=acute disseminated encephalomyelitis. AQP4=aquaporin-4. MOG=myelin oligodendrocyte glycoprotein. MOGAD=MOG antibody-associated disease. Optic neuritis is characterised by unilateral or bilateral reduced visual acuity that develops over hours to days and is often associated with retrobulbar orbital pain that is typically exacerbated with eye movement and accompanied by colour vision and visual field loss. Diagnosis of optic neuritis can be supported by the presence of a T2-hyperintense signal in the optic nerve or chiasm, by enhancement of the optic nerve or chiasm with gadolinium, and by exclusion of clinical or radiographical evidence of an alternative compressive, infiltrative, or vascular process impacting the optic nerve or retina. Myelitis is typically characterised by acute disturbance in motor, sensory, sphincter, or erectile function in various combinations referable to the spinal cord that develops over hours to days. The diagnosis of transverse myelitis is supported by MRI spinal cord T2 hyperintensity with or without gadolinium enhancement, by CSF inflammation, and by exclusion of a compressive or vascular disruption of the spinal cord. Spinal MRI sagittal T2 lesions in patients with MOG-IgG frequently extend three or more vertebral segments and often involve the conus and central grey matter (H-sign). ADEM is defined by acute (worsening over hours to days) polyfocal neurological deficits with encephalopathy (alteration in level of consciousness, profound irritability, not related to postictal state) and by MRI features of multifocal T2 bright lesions often involving cerebral white and grey matter. Cerebral monofocal or polyfocal deficits develop over hours to days and are referable to one or more T2-hyperintense lesions (which might or might not be enhanced by gadolinium). T2-hyperintense lesions are often located in the middle cerebellar peduncle, peri-fourth ventricle, in supratentorial white matter, in juxtacortical or cortical in locations, and in deep grey nuclei. Periventricular lesions are less common than for multiple sclerosis. Brainstem or cerebellar clinical deficits develop over hours to days and are associated with T2-hyperintense lesions in the brainstem or cerebellum, which might or might not enhance with gadolinium. Cerebral cortical encephalitis with seizures is associated with T2-hyperintense signal in the cortex often with enhancement of the overlying meninges in a patient with acute or subacute new onset seizures and evidence of cerebral irritation (encephalopathy, confusion, headache, or focal neurological deficits in addition to seizure). Serum testing is recommended for all patients being investigated for MOGAD. Testing both serum and CSF is not recommended for routine evaluation. CSF testing might be valuable in patients with clinical features suggestive of MOGAD but in whom serum testing was negative, particularly if confounded by apheresis or other therapeutic interventions. A live cell-based assay result by a standardised method that is a clear positive according to the individual assay cutoffs or a fixed cell-based assay result with a titre ≥1:100. A live cell-based assay result by a standardised method that is a low positive according to the individual assay cutoffs or a fixed cell-based assay result with a titre ≥1:10 and <1:100. A positive CSF evaluation with a fixed or live cell-based assay by use of standardised methods. CSF contamination by blood should be viewed cautiously as a positive result in such samples could occur due to serum MOG-IgG. Exclusion of no better explanation requires the expertise of the clinician. As an illustrative example, a patient with optic neuritis, MRI features meeting 2017 criteria for multiple sclerosis,20 positive CSF oligoclonal bands, and low titre MOG-IgG would be more appropriately diagnosed with multiple sclerosis. Conversely, a patient with bilateral optic neuritis associated with optic disc swelling and longitudinally extensive optic nerve involvement, with borderline CSF oligoclonal bands, with MRI lesions that involve the areas included in the dissemination in space criteria for multiple sclerosis but that are ill defined in character, and with clearly positive serum MOG-IgG titre, might technically meet 2017 criteria for multiple sclerosis but would be more appropriately diagnosed with MOGAD. Although most patients with multiple sclerosis will not have positive serum MOG-IgG, and most MOGAD patients do not meet the 2017 McDonald criteria for multiple sclerosis, some patients will meet both diagnostic criteria and the final diagnosis requires expertise and careful observation over time. We have compared features of MOGAD, multiple sclerosis, and AQP4-IgG-seropositive NMOSD and outlined other conditions to consider in the differential diagnosis of MOGAD.

Less common presentations include cerebral cortical encephalitis (often with seizures), brainstem and cerebellar demyelinating attacks, tumefactive brain lesions, cerebral monofocal and polyfocal CNS deficits associated with demyelinating lesions, cranial neuropathies, and progressive white matter damage (leukodystrophy-like pattern).

(3) Exclusion of Alternative Diagnoses

Exclusion of better-fitting diagnoses, such as MS, or other conditions that better explain the clinical and imaging findings.

The Timing of MOG-IgG Testing is Important

The timing of MOG-IgG antibody testing plays a pivotal role in accurate diagnosis. Research has demonstrated that low-positive MOG-IgG results are more commonly associated with a longer time from disease onset to sampling (Forcadela et al, 2023). MOG-IgG titers tend to decline over time, meaning the timing of the assay can significantly impact diagnostic accuracy.

In a cohort of MOG-IgG antibody-positive patients tested within 6 months of onset, antibody titers were shown to decline progressively. By 6 months, approximately 25% of patients returned a low-positive result, and by 12 months, 50% returned a negative result. This finding highlights the potential for missed or unclear diagnoses if testing occurs too long after disease onset (Forcadela et al, 2023).

Early testing during or shortly after a clinical event is critical to maximize diagnostic sensitivity and ensure timely, accurate identification of MOGAD.