Can a patient with a negative anti-NMO (Neuromyelitis Optica) antibody test still be diagnosed with transverse myelitis?

Yes, Transverse Myelitis Can Absolutely Occur with Negative Anti-NMO (AQP4) Antibodies

A negative AQP4 antibody test does NOT exclude transverse myelitis—in fact, most cases of transverse myelitis are AQP4-negative. Transverse myelitis is a broad clinical syndrome with multiple etiologies, and AQP4-positive neuromyelitis optica spectrum disorder (NMOSD) represents only one specific subset of causes 1, 2.

Understanding the Relationship Between AQP4 Antibodies and Transverse Myelitis

AQP4-Negative Transverse Myelitis is Common

• AQP4 antibodies are highly specific for NMOSD but are NOT required for a diagnosis of transverse myelitis 1, 2
• The majority of transverse myelitis cases are actually AQP4-negative and fall into other diagnostic categories 2, 3
• AQP4 antibodies should be considered useful for determining the specific cause of transverse myelitis when present, but their absence simply means the myelitis has a different etiology 2

Key Diagnostic Algorithm When AQP4 is Negative

When evaluating a patient with transverse myelitis and negative AQP4 antibodies, immediately pursue this structured approach:

1. Test for MOG-IgG antibodies using cell-based assays

• MOG-antibody associated disease accounts for 44-52% of longitudinally extensive transverse myelitis (LETM) cases 4
• If cost permits, test AQP4 and MOG antibodies in parallel; if cost is limiting and disease is stable, test AQP4 first, then MOG 1, 4
• Critical pitfall: Only cell-based assays are acceptable for MOG testing—ELISA has poor specificity 5

2. Distinguish between acute complete vs. acute partial transverse myelitis

• This distinction is useful for determining etiology and relapse risk, with acute partial transverse myelitis more commonly associated with multiple sclerosis 2

3. Assess MRI characteristics of the spinal cord lesion

• Longitudinally extensive (≥3 vertebral segments): Consider MOG-EM, idiopathic LETM, or seronegative NMOSD 6, 4, 2
• Short lesions (<2 segments): More consistent with MS or other causes 1, 2
• Conus medullaris involvement particularly suggests MOG-EM 4

4. Obtain brain MRI to assess for MS-typical lesions

• Perivenular lesions, Dawson's fingers, ovoid periventricular lesions, and juxtacortical U-fiber lesions suggest MS 1
• Normal brain MRI or non-MS-typical lesions increase probability of MOG-EM or seronegative NMOSD 1, 5

5. Analyze CSF findings

• Absence of oligoclonal bands: Seen in 87-88% of MOG-EM patients, distinguishes from MS 4
• Neutrophilic pleocytosis or WCC >50/μl: Suggests MOG-EM or NMOSD rather than MS 4
• Positive oligoclonal bands favor MS but do NOT exclude MOG-EM 6

Specific Etiologies of AQP4-Negative Transverse Myelitis

MOG-Antibody Associated Disease

• Represents a distinct disease entity from AQP4-positive NMOSD 6, 1
• Commonly presents with LETM (80% at onset in pediatric cases) 4
• Characterized by steroid-responsive disease with tendency to flare after steroid taper 6
• May present with both longitudinally extensive and non-longitudinally extensive myelitis 6

Idiopathic Transverse Myelitis

• Diagnosis of exclusion after ruling out AQP4-NMOSD, MOG-EM, MS, and other causes 2, 3
• Can present with variable lesion lengths 3

Multiple Sclerosis

• Typically presents with short spinal cord lesions (<2 segments) peripherally located 1, 2
• Brain MRI usually shows characteristic MS lesions 1, 2
• Important caveat: MS rarely if ever causes LETM; when LETM is present, strongly consider alternative diagnoses 4, 2

Other Causes

• Acute disseminated encephalomyelitis (ADEM), particularly in pediatric populations 4
• Infectious, vascular, or other inflammatory etiologies 2, 3

Treatment Implications Based on Serostatus

For Acute Episodes (Regardless of Antibody Status)

• High-dose intravenous corticosteroids are first-line treatment 7, 8, 2, 9
• Plasma exchange should be considered for patients who fail to improve after corticosteroid treatment 7, 2, 9

For Long-Term Management

• If MOG-IgG positive: Oral prednisone taper over weeks-to-months (rapid taper causes relapses), consider rituximab for severe or refractory disease 6, 5
• If both AQP4 and MOG negative (seronegative): Treatment approach depends on clinical phenotype and relapse risk; may still require immunosuppression if recurrent 2, 3

Critical Clinical Pitfalls to Avoid

• Never assume negative AQP4 antibodies exclude inflammatory myelitis—this is a common diagnostic error 1, 2
• Do not stop the diagnostic workup at negative AQP4—immediately pursue MOG-IgG testing 1, 4
• Beware of "double-positive" AQP4/MOG results—these are extremely rare and should prompt retesting with alternative methodologies as they likely represent false positives 1
• Age and gender provide diagnostic clues: Spinal infarcts are more common in older patients, while MS-related transverse myelitis is more common in females 2
• Do not use MS-directed therapies empirically in AQP4-negative LETM—some MS treatments can worsen NMOSD and may not be appropriate for MOG-EM 7, 9