What is the approach to diagnosing and managing Myelin Oligodendrocyte Glycoprotein (MOG)-associated disorders when serum testing is negative but Cerebrospinal Fluid (CSF) testing may be positive?

Diagnostic Approach to Serum-Negative, CSF-Positive MOG-IgG

CSF MOG-IgG testing has proven diagnostic utility and should be performed in patients with clinical phenotypes highly suggestive of MOGAD when serum testing is negative, as approximately 11% of confirmed MOGAD patients are serum-negative but CSF-positive. 1

Understanding the Clinical Reality

The 10% figure mentioned at ECTRIMS aligns with published data showing that 9 of 83 (11%) MOGAD patients were serum MOG-IgG negative but CSF positive, and all of these patients fulfilled the 2023 MOGAD diagnostic criteria. 1 This is not a trivial subset—these are genuine MOGAD cases that would be missed without CSF testing. 1

Key Distinction from Guidelines

While the 2018 international consensus guidelines state that CSF testing is "not usually required" because MOG-IgG is produced mostly extrathecally, 2 this recommendation predates the robust 2024 Mayo Clinic data demonstrating clear diagnostic utility. 1 The guidelines do acknowledge CSF may be "potentially helpful in rare, selected cases." 2

When to Pursue CSF MOG-IgG Testing

Order CSF MOG-IgG testing in the following scenarios:

1. Serum-Negative with High-Risk Phenotypes

• Bilateral optic neuritis or severe visual deficit/blindness 3
• Longitudinally extensive transverse myelitis (LETM) ≥3 vertebral segments 3
• Acute disseminated encephalomyelitis (ADEM)-like presentation 4
• Brainstem encephalitis with features like bilateral ptosis 3
• Cortical encephalitis with seizures and large cortical/subcortical lesions 2

2. Low-Positive Serum Results with Diagnostic Uncertainty

CSF testing is particularly valuable when serum MOG-IgG is borderline positive (titers 1:160-1:320), as CSF positivity was found in 81% of true MOGAD cases versus only 20% of patients with false-positive serum results and alternative diagnoses. 1 This provides critical diagnostic clarification. 1

3. Clinical-Radiological Dissociation

When the clinical presentation strongly suggests MOGAD but serum is negative, particularly in adults where 22% of CSF-only positive cases occurred (versus only 3% in children). 5

Technical Requirements for CSF Testing

Use a live cell-based assay with full-length human MOG and Fc-specific secondary antibodies, with CSF MOG-IgG positivity defined as an IgG-binding index (IBI) ≥2.5. 1 The pan-IgG Fc-specific secondary antibody yields optimal performance with 90% sensitivity and 98% specificity (Youden's index 0.88). 1

Ship CSF at 4°C or on dry ice if samples will not arrive within 1-2 days. 2

Clinical Significance of CSF Positivity

Prognostic Implications

Patients with both serum and CSF MOG-IgG positivity have more severe disease:

• Higher disability at nadir (median EDSS 4.5 vs 3.0) 5
• More frequent motor symptoms (33.6% vs 19%), sensory symptoms (45.5% vs 24%), and sphincter dysfunction (26.9% vs 7.8%) 5
• Persistent sphincter dysfunction at follow-up (17.3% vs 4.3%) 5

CSF-only positive patients (serum-negative) have the worst outcomes:

• Higher disability at last follow-up (EDSS ≥3.0) 5
• CSF-only positivity independently associated with worse disability 5
• These patients present more commonly with motor (45%) and sensory symptoms (42%) 5

Critical Pitfalls to Avoid

Do not dismiss a negative serum result in patients with classic MOGAD phenotypes—11% of confirmed cases are serum-negative. 1 The guideline statement that CSF testing is "not usually required" should not prevent testing in appropriate clinical contexts. 2

Recognize that CSF-only positivity is NOT a "red flag" for false positivity despite being listed as such in the 2018 guidelines. 2 The 2024 data directly contradicts this, showing that CSF-only positive patients had phenotypes compatible with MOGAD and worse outcomes. 5, 1

Be aware of timing issues: MOG-IgG concentrations fluctuate with disease activity and treatment status. 2 If initial serum testing is negative, retest during acute attacks, during treatment-free intervals, or 1-3 months after plasma exchange or IVIG. 2

Avoid testing CSF in patients with low clinical suspicion—the 1.4% false-positive rate in controls means specificity is excellent but not perfect. 1

Practical Algorithm

1. Serum MOG-IgG negative + high-risk phenotype → Proceed to CSF testing 1
2. Serum MOG-IgG low-positive (1:160-1:320) + diagnostic uncertainty → Proceed to CSF testing 1
3. CSF MOG-IgG positive (IBI ≥2.5) + compatible phenotype → Diagnosis of MOGAD confirmed 1
4. Both serum and CSF negative but high clinical suspicion → Retest during acute attack or after treatment washout 2