CurrentBlue Cross Blue Shield - TennesseePolicy N/A

Serum Biomarker Testing for Multiple Sclerosis and Related Neurologic Diseases

Defines when serum and CSF biomarker tests (including AQP4-IgG and MOG-IgG assays and oligoclonal band analysis) are covered or not covered for diagnosis of MS, NMOSD, and MOG-EM for BlueCross BlueShield of Tennessee members.

Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicySerum Biomarker Testing for Multiple Sclerosis and Related Neurologic Diseases

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization and include clinical documentation demonstrating that testing meets the specific coverage criteria (e.g., atypical presentation for OCB testing or qualifying features for AQP4/MOG CBA/FACS assays).

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

OCB coveredOCB testing covered

AQP4/MOG coveredAQP4/MOG CBA/FACS covered

Not coveredOther serum biomarker tests not covered

Not coveredELISA/Western blot not covered

>=0.7

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0443UProprietary NfL code

Coverage Criteria for Biomarker Testing

CSF Oligoclonal Band Testing

CSF oligoclonal band analysis MEETS COVERAGE CRITERIA for diagnosis of MS when ANY of the following are present:

CSF OCB coverage: a) Atypical clinical, laboratory, or imaging features.

Paired CSF/serum sampling required to demonstrate CSF-specific OCBs; OCBs may substitute for dissemination-in-time per 2017 McDonald criteria.

CSF OCB coverage: b) Atypical clinically isolated syndrome, including primary progressive or relapsing-remitting course.

CSF examination is strongly recommended in some circumstances when clinical/MRI evidence is insufficient (Thompson et al., 2018).

CSF OCB coverage: c) Belongs to a population in which MS is less common (e.g., children, older individuals).

Lower pre-test probability populations warrant CSF testing to aid diagnosis.

CSF OCB coverage: d) Insufficient clinical or imaging evidence for diagnosis.

OCB demonstration can allow a diagnosis of MS when dissemination-in-space criteria are met but dissemination-in-time is lacking.

Serum AQP4-IgG and MOG-IgG Assays

Serum indirect fluorescence assay or FACS (cell-based) assays for AQP4-IgG and MOG-IgG MEET COVERAGE CRITERIA when ALL of the following are met:

AQP4/MOG serum assay coverage: a) The individual has monophasic or relapsing acute optic neuritis, myelitis, brainstem encephalitis, encephalitis, or any combination thereof;

Clinical presentations compatible with NMOSD/MOG-EM per guidance.

AQP4/MOG serum assay coverage: b) Radiological or electrophysiological findings compatible with central nervous system demyelination;

Imaging/electrophysiology supportive of CNS demyelination required.

AQP4/MOG serum assay coverage: c) The individual has at least one high-risk feature from the list (e.g., pediatric; abnormal MRI with extensive optic nerve or spinal cord lesion or large confluent T2 brain lesions; prominent papilledema/papillitis; neutrophilic CSF pleocytosis; histopathology with intralesional complement and IgG deposits or prior pattern II MS; simultaneous bilateral acute optic neuritis; severe visual deficit or blindness during/after optic neuritis; severe or frequent episodes of acute myelitis or brainstem encephalitis; permanent sphincter or erectile dysfunction after myelitis; prior ADEM).

Not Medically Necessary / Not Covered Tests

Tests that DO NOT MEET COVERAGE CRITERIA:

Not covered tests: 1) In all other situations, serum biomarker tests for multiple sclerosis do not meet coverage criteria.

Requests outside the specified clinical indications will be denied due to lack of published evidence of clinical benefit.

Not covered tests: 2) ELISA, Western blot, immunohistochemistry, or any other serum assays to test for NMOSD or MOG-EM do not meet coverage criteria.

Peptide-based ELISA and Western blot are not recommended for MOG; immunohistochemistry is not recommended due to lower sensitivity/specificity.

Not covered tests: 3) For diagnosis of MS, NMOSD, or MOG-EM, all other CSF biomarker tests, including AQP4-IgG or MOG-IgG in CSF, do not meet coverage criteria.

CSF AQP4-IgG or MOG-IgG testing is not covered per policy.

Clinical indications summarized

Clinical indications and supporting evidence summarized from guideline and studies:

Diagnosis support: CSF-specific oligoclonal bands (paired CSF/serum) can support a diagnosis of MS when clinical or MRI criteria are insufficient; demonstration of CSF OCBs may substitute for dissemination-in-time in appropriate cases.IgG index > 0.7 has high positive predictive value for OCBs

International Panel on Diagnosis of Multiple Sclerosis (2018) supports CSF OCBs for diagnosis; Simonsen et al. found IgG index >0.7 PPV >99%.

Differential diagnosis: Cell-based AQP4 and MOG antibody testing is recommended for patients with features suggesting NMOSD or MOG-EM; use serum CBA (microscopy) or FACS for optimal sensitivity and specificity.

Thompson et al., IPND, and NMOSD panel recommendations emphasize cell-based assays and serum specimen preference for MOG-IgG.

Prognosis and monitoring: Serum neurofilament light chain (sNfL) levels correlate with disease activity, progression risk, brain atrophy, and treatment response; sNfL percentiles/Z-scores adjusted for age and BMI can help identify individuals at higher risk and monitor therapy effects.

ELISA, Western blot, immunohistochemistry, and other non–cell-based serum assays for NMOSD or MOG‑EM are explicitly listed as tests that do not meet coverage criteria. Requests for these assay types should be treated as non‑covered per the policy statement and may be denied when submitted for evaluation of AQP4‑IgG or MOG‑IgG.

The policy references IPND guidance noting that for MOG‑IgG the recommended methods are indirect fluorescence/CBA or FACS targeting full‑length human MOG. It also states that general (non‑selective) MOG‑IgG testing is discouraged in patients with a progressive disease course because of a very low pre‑test probability; therefore routine, non‑targeted MOG screening in progressive presentations is not supported.

There are no explicit procedural exclusions listed in the cited sections beyond the assay‑type exclusions; the document excerpts focus on evidence, guidance citations, and reimbursement context rather than listing additional procedural or specimen‑handling exclusions.

The policy states that serum biomarker tests for multiple sclerosis performed in clinical situations other than those specifically described in the coverage criteria are considered not medically necessary. In practice, this means serum biomarker testing for MS without meeting the listed clinical indications or assay requirements is not supported by the policy.

Consistent with IPND recommendations cited in the policy, routine, non‑selective MOG‑IgG testing in patients with a progressive disease course is not recommended due to very low pre‑test probability and lower expected diagnostic yield.

Systematic reviews and policy assessments cited in the document emphasize diagnostic test performance and specificity. The policy therefore implies that assays or testing strategies without demonstrated diagnostic accuracy and clinical utility (for example, non‑recommended ELISA/Western blot methods) are not recommended and may be excluded from coverage.

Applicable Procedure and Reference Codes

Listed procedure codesCPT | HCPCS

83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
83916	Oligoclonal immune (oligoclonal bands)
84182	Western Blot, with interpretation and report, blood or other body fluid, immunological probe for band identification, each
86051	Aquaporin-4 (neuromyelitis optica [NMO]) antibody; enzyme-linked immunosorbent immunoassay (ELISA)
86052	Aquaporin-4 (neuromyelitis optica [NMO]) antibody; cell-based immunofluorescence assay (CBA), each
86053	Aquaporin-4 (neuromyelitis optica [NMO]) antibody; flow cytometry (ie, fluorescence-activated cell sorting [FACS]), each
86362	Myelin oligodendrocyte glycoprotein (MOG-IgG1) antibody; cell-based immunofluorescence assay (CBA), each
86363	Myelin oligodendrocyte glycoprotein (MOG-IgG1) antibody; flow cytometry (ie, fluorescence-activated cell sorting [FACS]), each
88341	Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)
88342	Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure

1–10 of 11

1/2

Regulatory / FDA referencesmixed

K161951 (510k referenced)

FDA 510(k) decision document cited

Key numeric threshold — IgG index

IgG index threshold>= 0.7 (positive predictive value >99% for OCBs)

Supporting evidenceSimonsen et al. retrospective study of 1295 MS patients found IgG index >0.7 PPV 99.4% for OCBs

Clinical implicationAn elevated IgG index (>=0.7) strongly predicts presence of CSF OCBs and can support MS diagnostic evaluation when paired with clinical/MRI data

Provider Requirements, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for testing when the requested service must be demonstrated to meet the specific clinical coverage criteria described in this policy (for example, CSF oligoclonal band analysis and specialty antibody assays such as AQP4-IgG and MOG-IgG). Requests should include sufficient clinical information to allow review against the coverage criteria.

Prior authorization required when medical necessity is not clearly documented
Include paired CSF and serum sample information for OCB testing when applicable

Documentation Required

Coding and Documentation Requirement

Providers must submit appropriate coding and complete clinical documentation to support the use of the CPT/HCPCS codes listed in the policy (see Applicable CPT/HCPCS Procedure Codes). Documentation should link the submitted code(s) to the indication, relevant clinical findings, imaging or electrophysiology results, and any prior testing or treatments.

Background and Context

Multiple sclerosis is an immune‑mediated inflammatory demyelinating disorder with a variable clinical course. Magnetic resonance imaging (MRI) is the primary diagnostic tool to demonstrate dissemination in space and time; cerebrospinal fluid oligoclonal IgG bands (OCBs) can supplement MRI and clinical findings and, in some situations, substitute for dissemination in time under diagnostic criteria. The policy cites guideline and systematic review literature to place biomarker testing in the context of diagnostic pathways, differential diagnosis (including NMOSD and MOG‑EM), and prognostic assessment.

Key Definitions and Biomarker Terms

Aquaporin-4-immunoglobulin G (AQP4-IgG)

DefinitionAquaporin-4-immunoglobulin G (AQP4-IgG) — autoantibody associated with neuromyelitis optica spectrum disorder (NMOSD)

Recommended assayCell-based serum assays (microscopy or flow cytometry/FACS) are recommended for optimal sensitivity and specificity

Clinical useTest when features suggest NMOSD (eg, optic neuritis, longitudinally extensive transverse myelitis, area postrema syndrome)

Myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)

DefinitionMyelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG)

Recommended assayIndirect fluorescence/CBA or FACS targeting full-length human MOG (IgG-specific) are gold standard; serum is the preferred specimen

Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicySerum Biomarker Testing for Multiple Sclerosis and Related Neurologic Diseases

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateN/A

Next Review DateN/A

SourceLink

On This Page

At least one listed high-risk feature must be present to meet coverage criteria.

AQP4/MOG serum assay coverage: d) Specimen and assay methodology: testing performed on serum using indirect fluorescence assay or cell-based assay/flow cytometry (FACS) techniques.

Cell-based assays (microscopy or FACS) are recommended as gold standard due to superior sensitivity/specificity; serum is the preferred specimen for MOG-IgG.

Cantó et al., Benkert et al., and Martin et al. provide evidence for sNfL and CSF NfL as markers of disease activity and prognosis.

Document clinical indication and link to specific code(s) (eg, 83916 for oligoclonal bands, 86362/86363 for MOG assays, 86052/86053 for AQP4 assays, 0443U for NfL)

Include specimen type (serum vs CSF), timing relative to symptoms/treatment, and paired serum when required for CSF OCB interpretation

Prior Authorization

Prior Authorization May Be Required for Specialty Biomarker Assays

Prior authorization may be required for specialty biomarker assays (for example, AQP4-IgG, MOG-IgG, and ultra-sensitive NfL assays). When submitting requests, include assay methodology and laboratory performing the test because assay performance and methodology (cell-based assay, FACS, ELISA, immunohistochemistry, etc.) affect clinical interpretation and coverage determination.

Cell-based assays (CBA) and FACS for MOG/AQP4 are preferred methods; ELISA/Western blot/immunohistochemistry are not recommended for MOG and may not meet coverage
Specify whether testing is serum or CSF and timing relative to acute attack or immunosuppression

Note

Government Policy Precedence

Government policies (Local Coverage Determinations, National Coverage Determinations, and applicable state Medicaid rules) take precedence over this policy. If there is a conflict for a particular member, the applicable government policy will be used for the coverage determination.

Consult current LCD/NCD and state Medicaid guidance when evaluating coverage for Medicare or Medicaid members

Denial Risk

Potential Reimbursement Risk

Assays with poor or uncertain diagnostic performance may present a reimbursement risk. Requests for tests using non-recommended methodologies or for indications not supported by published literature may be denied or subject to payment denial.

Denial risk for serum biomarker tests for MS outside listed indications
Denial risk for ELISA, Western blot, immunohistochemistry, or other non-recommended serum/CSF assays for NMOSD or MOG-EM

Documentation Required

Required Clinical Documentation

Required clinical documentation must demonstrate that the indication meets covered criteria. For OCB testing, document atypical clinical, laboratory, or imaging features, insufficient MRI/clinical evidence, or membership in a population where MS is less common (eg, pediatric, older adults). For NMOSD/MOG testing, document compatible clinical syndrome and supporting radiologic/electrophysiologic findings or other listed risk features.

For OCBs: paired CSF and serum results, description of atypical features, and how results will impact management
For AQP4/MOG: clinical syndrome (optic neuritis, myelitis, brainstem encephalitis), MRI/electrophysiology findings, and any high-risk features (eg, bilateral optic neuritis, longitudinally extensive spinal cord lesion, severe visual loss)

Documentation Required

Clinical Justification and Timing for Testing

Clinical justification and timing for testing should be clearly stated. Indicate whether MRI or clinical evidence is insufficient, whether presentation is atypical, and the timing of specimen collection relative to symptom onset or immunosuppressive therapy (eg, MOG-IgG is highest during acute attack and when not receiving immunosuppression).

If testing is to support initiation of long-term disease-modifying therapy, state this explicitly
Note prior treatments and their dates (eg, monoclonal antibodies, platform therapies) when interpreting sNfL or antibody levels

Documentation Required

Supporting Diagnostic Evidence

Supporting diagnostic evidence should be provided when available. Cite comparative performance (eg, IgG index vs OCBs) and relevant guideline statements that support the requested test, and include imaging, electrophysiology, histopathology, or CSF findings that corroborate the clinical impression.

Provide MRI findings (DIS/DIT status), CSF cell counts, protein, and other biomarkers as applicable
Reference guideline-based rationale when the test substitutes for dissemination in time (eg, CSF OCBs per McDonald criteria guidance)

Note

Therapy Response Context for sNfL

Therapy-response context for serum neurofilament light chain (sNfL): include prior and current therapies in documentation because sNfL levels change with treatment. High-potency monoclonal therapies may reduce sNfL Z scores to control levels, whereas platform therapies (interferons, glatiramer acetate) may not; this can inform risk stratification and therapy decisions.

Report recent therapies and timing relative to specimen collection
Include age and BMI adjustments or reference percentile/Z-score methodology if available

Timing noteSerum MOG-IgG titers are highest during acute attacks and when not receiving immunosuppressive therapy

Oligoclonal immunoglobulin G bands in CSF (OCBs)

DefinitionOligoclonal immunoglobulin G bands (OCBs) — qualitative CSF IgG bands often detected by isoelectric focusing

Diagnostic roleUp to 95% of clinically definite MS cases have CSF OCBs; presence supports intrathecal IgG synthesis

Testing requirementCSF must be paired with serum to demonstrate CSF-specific OCBs (bands not present in serum)

CSF-specific oligoclonal bands — predictor of second attack and diagnostic support

DefinitionCSF-specific oligoclonal bands — immunoglobulin bands present in CSF but not in paired serum; indicate intrathecal IgG synthesis

Prognostic valueIndependent predictor of risk of a second attack when controlling for demographic, clinical, treatment, and MRI variables

Diagnostic useDemonstration of CSF-specific OCBs can substitute for dissemination in time in McDonald criteria under specified circumstances

Cell-based assay (CBA)

DefinitionCell-based assay (CBA) — laboratory method (microscopy or flow cytometry) that detects AQP4-IgG and MOG-IgG with superior sensitivity/specificity

RecommendationInternational panels recommend CBA (microscopy or FACS) whenever possible and referral to specialized labs if needed

Assay cautionELISA, immunohistochemistry, and peptide-based assays are less sensitive/specific and are not recommended for NMOSD/MOG-EM testing

Serum neurofilament light chain (sNfL)

DefinitionSerum neurofilament light chain (sNfL) — blood biomarker reflecting neuroaxonal damage correlated with MS disease activity and progression risk

Clinical correlationssNfL levels associate with EDSS, MS subtype, treatment status, and longitudinal disability/brain atrophy measures (Cantó et al., 2019)

Use for monitoringsNfL percentiles/Z-scores adjusted for age/BMI may identify individuals at higher risk and track therapy response (Benkert et al., 2022)

Neuromyelitis optica spectrum disorder (NMOSD)

DefinitionNeuromyelitis optica spectrum disorder (NMOSD) — inflammatory demyelinating disorder with distinct international consensus diagnostic criteria referenced for antibody testing

Associated antibodyAQP4-IgG is the serological marker most strongly associated with NMOSD

Testing guidanceInternational NMOSD panel recommends cell-based serum assays (microscopy or FACS) for AQP4-IgG detection for best diagnostic accuracy

Neurofilament light chain (NfL)

DefinitionNeurofilament light chain (NfL) — biomarker measurable in serum or CSF studied for prognostication and disease activity monitoring in MS

Evidence baseMultiple studies and systematic reviews report associations between NfL levels and relapse, progression, and brain atrophy (Martin et al., Cantó et al., Benkert et al.)

Coding noteA proprietary CPT code (0443U) is listed for an ultra-sensitive NfL assay in the policy coding table