Transverse myelitis laboratory findings

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Julinka Auta Fernandes

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Overview

• There is no single laboratory test that independently confirms transverse myelitis. Laboratory evaluation is used to demonstrate inflammation associated with the transverse-myelitis syndrome, determine its cause, and exclude infectious, systemic autoimmune, metabolic, nutritional, neoplastic, and paraneoplastic mimics.
• Cerebrospinal fluid (CSF) pleocytosis and evidence of intrathecal immunoglobulin synthesis support inflammatory transverse myelitis but are not specific for its cause. A normal initial CSF examination does not exclude transverse myelitis.
• Transverse myelitis is a clinical syndrome with several possible causes. Serum disease-specific antibody testing helps determine whether transverse myelitis is associated with aquaporin-4 immunoglobulin G (AQP4-IgG) or myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG). MOG-IgG testing can identify transverse myelitis associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), but testing should be restricted to a compatible clinical and radiologic phenotype.

Core laboratory priorities

• Perform CSF analysis, with paired serum where required, to document inflammation and evaluate important mimics.
• Test serum AQP4-IgG using a validated cell-based assay when an AQP4-IgG-associated cause of transverse myelitis is possible.
• Test serum MOG-IgG using a validated cell-based assay only when the transverse-myelitis phenotype is compatible with MOGAD.
• Select autoimmune, infectious, nutritional, metabolic, and paraneoplastic tests according to the clinical context; indiscriminate testing increases false-positive results.

Laboratory Findings

Specimen timing and handling

• When feasible, obtain serum for AQP4-IgG and MOG-IgG before glucocorticoids, plasma exchange, immunoadsorption, intravenous immunoglobulin (IVIG), or other immunotherapy because treatment can reduce antibody concentrations and occasionally produce false-negative or equivocal results. Clinically necessary treatment should not be delayed solely to obtain a specimen.
• Obtain paired CSF and serum samples when assessing oligoclonal bands, immunoglobulin quotients, or the CSF/serum albumin quotient. Record whether the specimen was obtained during an acute attack or remission and before or after immunotherapy.

Cerebrospinal fluid examination

Recommended core studies

In a patient with suspected transverse myelitis, lumbar puncture should generally include:

• White blood cell count with differential and red blood cell count.
• Total protein.
• CSF glucose interpreted with a contemporaneous serum glucose measurement.
• CSF L-lactate when available.
• CSF-specific immunoglobulin G (IgG) oligoclonal bands, tested by isoelectric focusing with a paired serum sample.
• CSF and serum albumin, IgG, immunoglobulin A (IgA), and immunoglobulin M (IgM), with calculation of appropriate CSF/serum quotients when available.
• Targeted microbiologic studies when infection is plausible; these may include Gram stain, bacterial culture, polymerase chain reaction (PCR), pathogen-specific antibody testing, or an intrathecal antibody index.
• Cytology and flow cytometry when lymphoma, leptomeningeal malignancy, or another neoplastic process is suspected.

Interpretation

• Pleocytosis and protein: A lymphocytic or mixed pleocytosis and a mild-to-moderate increase in protein may occur in acute transverse myelitis. These findings demonstrate or support inflammation but do not establish its cause. Marked neutrophilic pleocytosis, very low glucose, or a disproportionately high protein concentration should prompt urgent evaluation for infection, granulomatous inflammation, malignancy, or another alternative diagnosis.
• Transverse Myelitis Consortium criterion: The foundational consensus definition accepts CSF pleocytosis or an elevated CSF IgG index as laboratory evidence of spinal-cord inflammation. If no inflammatory criterion is demonstrated at presentation but the syndrome remains compatible, repeat CSF evaluation between 2 and 7 days after symptom onset may establish inflammation.
• Modern interpretation of intrathecal immunoglobulin synthesis: Although the foundational transverse-myelitis definition included the IgG index, current cerebrospinal-fluid recommendations favor CSF-specific oligoclonal bands or validated paired CSF/serum quotient methods. An isolated IgG index should not be overinterpreted, especially when the blood–CSF barrier is substantially impaired.
• Oligoclonal bands: CSF-restricted oligoclonal IgG bands may be present in transverse myelitis but are not specific and do not independently establish its cause. Their presence should prompt consideration of an underlying acquired inflammatory demyelinating disorder, while their absence does not exclude transverse myelitis.
• Cell pattern: A CSF white blood cell count of 50 cells/µL or greater, neutrophils, eosinophils, or substantial blood–CSF barrier dysfunction may occur in antibody-associated transverse myelitis. Infection and other inflammatory causes must still be excluded when these findings are present.
• Normal CSF: Normal cell count, protein, and intrathecal immunoglobulin studies do not exclude transverse myelitis.

Etiologic antibody testing in transverse myelitis

Aquaporin-4 immunoglobulin G

• Test serum AQP4-IgG in otherwise unexplained transverse myelitis when the clinical and radiologic phenotype suggests an AQP4-IgG-associated cause. A positive result identifies a likely etiology but must be interpreted with the transverse-myelitis syndrome and exclusion of a better diagnosis.
• Use a validated live or fixed cell-based assay (CBA) that expresses conformationally intact, full-length human AQP4. Enzyme-linked immunosorbent assay, immunoblot, peptide-based assay, and tissue immunohistochemistry are less sensitive and/or less specific and should not be used for routine first-line testing when a CBA is available.
• Serum is the preferred specimen. Cerebrospinal-fluid-only AQP4-IgG positivity is not sufficient under current consensus criteria and requires expert review and confirmatory testing.
• Isolated AQP4 immunoglobulin M or immunoglobulin A reactivity does not satisfy current diagnostic criteria; the diagnostically relevant isotype is AQP4-IgG.
• Confirm an unexpected or low-titer positive result with a second sample or a methodologically different CBA. If suspicion remains high despite a negative result, repeat serum testing in another laboratory and/or with another CBA, preferably a live CBA, during an untreated acute attack or treatment-free interval when feasible.

Myelin oligodendrocyte glycoprotein immunoglobulin G

• Order serum MOG-IgG when transverse myelitis has a clinical or radiologic phenotype compatible with MOGAD. Routine screening when the pretest probability is low increases the risk of a false-positive etiologic diagnosis.
• A live CBA using full-length human myelin oligodendrocyte glycoprotein is preferred. A validated fixed CBA is an acceptable alternative, although live assays may be more sensitive. The report should include the assay type, qualitative result, titer or semiquantitative value, and laboratory cutoff.
• Serum is the preferred specimen. Routine CSF MOG-IgG testing is not recommended; it may be considered after specialist consultation in a strongly compatible phenotype when serum testing is negative. A serum-negative/CSF-positive result has uncertain significance and should be confirmed with repeat serum and CSF testing using a methodologically different validated assay.
• A low-positive result or a positive result without a reported titer requires supportive clinical or magnetic resonance imaging features and careful exclusion of alternative diagnoses. Unexpected or low-titer results should be confirmed in a specialized second laboratory, preferably with a live CBA.
• Routine testing for myelin oligodendrocyte glycoprotein immunoglobulin A (MOG-IgA) is not recommended because its independent diagnostic significance has not been established.

Other blood and urine studies

Clinical selection is essential: The studies below are not a universal panel. Testing should be guided by age, immune status, exposures, geography, systemic symptoms, examination, imaging pattern, and CSF profile.

Basic studies

• Complete blood count (CBC) with differential, serum electrolytes, renal and hepatic chemistry, glucose, coagulation studies, and urinalysis.

Systemic autoimmune causes of transverse myelitis

Depending on the phenotype, targeted evaluation may include:

• Antinuclear antibody (ANA), extractable nuclear antigen antibodies (ENA), including anti-Ro and anti-La antibodies, anti-double-stranded deoxyribonucleic acid antibody (anti-dsDNA), complement component 3 (C3), complement component 4 (C4), and urinalysis when systemic lupus erythematosus, Sjögren syndrome, or another connective-tissue disease is suspected.
• Cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) when systemic vasculitis is suspected.
• Antiphospholipid antibody testing, including anticardiolipin antibodies, when antiphospholipid syndrome is suspected.

Nutritional and metabolic mimics of transverse myelitis

• Measure serum vitamin B12 and, when the result is borderline or clinical suspicion remains, methylmalonic acid with or without homocysteine.
• Consider serum copper and ceruloplasmin, folate, vitamin E, and selected toxic or metabolic studies when the phenotype suggests copper deficiency, another nutritional myelopathy, nitrous-oxide exposure, or a metabolic disorder.

Infectious causes of transverse myelitis

Infectious testing should be directed by epidemiology, exposure, immune status, systemic findings, and CSF profile. Potential studies include:

• Human immunodeficiency virus (HIV) antigen/antibody testing.
• Serum syphilis testing, with CSF Venereal Disease Research Laboratory (VDRL) testing and/or a CSF treponemal assay when neurosyphilis is suspected.
• Two-tier serum testing for Lyme disease when epidemiologically appropriate; if neuroborreliosis is suspected, assess paired CSF and serum for intrathecal antibody production rather than ordering an isolated CSF antibody test.
• Human T-lymphotropic virus type 1 (HTLV-1) serology, with confirmatory testing, in patients with relevant epidemiologic risk or a chronic progressive myelopathy.
• Tuberculosis studies, fungal studies, bacterial cultures, or other pathogen-specific assays when exposure, immune status, or the CSF pattern supports them.
• CSF PCR or intrathecal antibody testing for herpes simplex virus types 1 and 2, varicella zoster virus, enteroviruses, or other neurotropic pathogens when an infectious myelitis is suspected.

Paraneoplastic and other autoimmune causes of transverse myelitis

• In patients with a compatible phenotype, cancer risk, or otherwise unexplained transverse myelitis, consider serum and CSF neural-antibody testing using a phenotype-directed panel. Relevant antibodies may include collapsin response-mediator protein 5 (CRMP5), amphiphysin, anti-Hu, and anti-Ma antibodies.
• A positive neural antibody must be interpreted with its phenotype, specimen type, assay method, and cancer risk. Cytology, flow cytometry, and an appropriate malignancy evaluation may be required when neoplastic or paraneoplastic disease is suspected.

Reporting and clinical interpretation

• Document the specimen type, assay platform, testing laboratory, qualitative result, titer or numeric value, cutoff, attack/remission status, and treatment status for AQP4-IgG and MOG-IgG results.
• Interpret all laboratory findings with the clinical syndrome and magnetic resonance imaging findings. No CSF pattern, serum autoantibody, inflammatory marker, or infectious serology should be used in isolation to label a patient as having transverse myelitis.