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Serum Biomarker Tests for Multiple Sclerosis

Policy Number: MP-563

Latest Review Date: September 2024

Category: Laboratory                                                            

POLICY:

Serum biomarker tests for multiple sclerosis are considered investigational in ALL situations.

DESCRIPTION OF PROCEDURE OR SERVICE:

Multiple sclerosis (MS) an immune-mediated inflammatory demyelinating disease of the central nervous system defined by multifocal areas of demyelination with loss of oligodendrocytes and astroglial scarring. The most common presenting symptoms are sensory disturbances, weakness and visual disturbances. The disease has a highly variable pace and many atypical forms. MS is primarily diagnosed clinically. The core requirement for diagnosis is the demonstration of central nervous system lesion dissemination in time and space, based upon either clinical findings alone or a combination of clinical and MRI findings. The history and physical examination are most important for diagnostic purposes. MRI is the test of choice to support the clinical diagnosis of MS. Prognosis is hard to predict, which has prompted interest in identifying biomarkers that are associated with disease progression.

Several biomarkers have been proposed as useful for MS diagnosis, prognosis, and therapy response prediction that need to be validated in further studies.

Commercially available serum biomarker tests have been proposed as useful for the diagnosis, prognosis prediction, and therapy response prediction of MS. Some examples of commercially available tests for this purpose include:

  • gMS® Dx, which is a blood test designed to be used as a companion to magnetic resonance imaging (MRI) in suspected cases of MS at the first neurological event and for individuals with clinically isolated syndrome in order to expedite the diagnosis of relapsing-remitting MS.
  • gMS® Pro EDSS, which is designed to be used as a tool to identify individuals with clinically isolated syndrome and relapsing-remitting MS who are at risk for rapid disability progression.
  • Neurofilament light chain (sNfL), which is a serum marker indicating neuronal injury. It may predict future risk of disability in relation to acute MS. This test is not specific to MS, and additional research is needed to determine clinical utility.

KEY POINTS:

This policy has been updated with the most recent review of literature on September 4, 2024.

Summary of Evidence

It has been hypothesized that the diagnosis and prognosis of MS and the monitoring of treatment response and the assessment of the risk of side effects can be facilitated with the help of established biomarkers. Long-term studies of large cohorts are needed to prove the clinical utility of the application of biomarker testing for the diagnosis and prognosis MS. Biomarkers that enable a reliable prediction of the therapy response in order to facilitate individualized therapy are still lacking. Further research is needed using well-designed scientific evidence to validate that the use of biomarkers for MS results in an improvement in net health outcomes.

Practice Guidelines and Position Statements

International Advisory Committee on Clinical Trials in Multiple Sclerosis

The International Advisory Committee on Clinical Trials in Multiple Sclerosis, jointly sponsored by the US National Multiple Sclerosis Society, the European Committee for Treatment and Research in Multiple Sclerosis, and the Multiple Sclerosis Phenotype Group re-examined multiple sclerosis phenotypes, exploring clinical, imaging, and biomarker advances through working groups and literature searches. They found the following:

The MS Phenotype Group stated that further research is needed to better define the value of imaging and biological markers in assessing, confirming, or revising MS phenotype descriptors. One example of further research needed is as follows: Focused cohort studies in large datasets of clinically well-defined patients of potential fluid-borne (blood, CSF) markers that might allow better definition of clinical phenotypes.

The committee concluded that “To date, there are no clear clinical, imaging, immunologic or pathologic criteria to determine the transition point when relapse remitting MS converts to secondary progressive MS; the transition is usually gradual. This has limited our ability to study the imaging and biomarker characteristics that may distinguish this course.

The International Panel on Diagnosis of Multiple Sclerosis

The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions in 2017. They found the following:

Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

gMS Dx, gMS Pro EDSS, multiple sclerosis, serum biomarkers, Octave Multiple Sclerosis Disease Activity (MSDA) Test, Neurofilament light chain (sNfL)

APPROVED BY GOVERNING BODIES:

FDA-approved tests for serum biomarkers in MS are currently unavailable.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the FDA has chosen not to require any regulatory review of this test.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

81599

Unlisted multianalyte assay with algorithmic analysis
83884 Neurofilament light chain (Effective 01/01/25)

84999             

Unlisted chemistry procedure

0361U

Neurofilament light chain, digital immunoassay, plasma, quantitative

REFERENCES:

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  38. Moreno C, Prieto P, Macias A et al. Modulation of voltage-dependent and inward rectifier potassium channels by 15-epi-lipoxin-A4 in activated murine macrophages: implications in innate immunity. J Immunol 2013; 191(12):6136-46.
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  42. Polachini CR, Spanevello RM, Casali EA, et al. Alterations in the cholinesterase and adenosine deaminase activities and inflammation biomarker levels in patients with multiple sclerosis. Neuroscience. Apr 25 2014; 266:266-274.
  43. Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69(2):292-302.
  44. Schwarz M, Spector L, Gortler M, Weisshaus O, Glass-Marmor L, Karni A, Dotan N, Miller A. Serum anti-Glc(alpha1,4)Glc(alpha) antibodies as a biomarker for relapsing-remitting multiple sclerosis. J Neurol Sci. 2006 May 15; 244(1-2):59-68.
  45. Shimizu Y, Ota K, Ikeguchi R et al. Plasma osteopontin levels are associated with disease activity in the patients with multiple sclerosis and neuromyelitis optica. J Neuroimmunol 2013; 263(1-2):148-51.
  46. Siroos B, Balood M, Zahednasab H et al. Secretory phospholipase A2 activity in serum and cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 2013; 262(1-2):125-7.
  47. Skundric DS. Basic Approaches in Therapy of Multiple Sclerosis (MS) and Related Diseases: Current Achievement and Prospective. Cent Nerv Syst Agents Med Chem. 2018 Jan 26; 18(1):21-31.
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POLICY HISTORY:

Medical Policy Panel, April 2014

Medical Policy Group, September 2014 (1) New policy, previously only listed on the Investigational Listing; remains investigational

Medical Policy Administration Committee, October 2014

Available for comment September 19 through November 2, 2014

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3): 2015 Updates to Key Points & References; no change in policy statement

Medical Policy Panel, July 2016

Medical Policy Group, August 2016 (3): Editing review only; no new literature to add to policy; no changes in policy statement. Effective August 2016: Active Policy but no longer scheduled for regular literature reviews and updates.

Medical Policy Group, October 2019 (9): Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Group, August 2021 (9): Updates to Description, Key Points, References. Policy statement updated to remove “not medically necessary,” no change to policy intent.

Medical Policy Group, October 2021 (9): Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, August 2022 (9): Updates to Description, Key Points. Reviewed by consensus. References added. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, August 2023 (5): Updates to Key Points, Benefit Application, and References. No change to Policy Statement. Reviewed by consensus. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, February 2024 (5): Update to Key Words to include: Octave Multiple Sclerosis Disease Activity (MSDA) Test. Current Coding section updated to include CPT 81599. No change to Policy Statement.

Medical Policy Group, September 2024 (5): Reviewed by consensus. Updates to Description, Key Points, Key Words: Neurofilament light chain (sNfL), Current Coding section: 0361U, and References. No change to Policy Statement. No new published peer-reviewed literature available that would alter the coverage statement in this policy.

Medical Policy Group, November 2024 (5): 2025 Annual Coding Update. Added CPT code 83884 to Current Coding section.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.