Subject:
Serum Biomarker Tests for Multiple Sclerosis
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Serum antibodies to polysaccharide-containing molecules, called glycans, and other serum biomarkers are potential biomarker tests for the diagnosis and prognosis of multiple sclerosis (MS). MS is diagnosed according to criteria that incorporate clinical symptoms and magnetic resonance imaging and cerebrospinal fluid findings. Currently, there is no biomarker available to inform diagnosis or prognosis. A serum biomarker is particularly desirable because of ease of repeat measurements.
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| Outcomes |
Individuals:
· With signs and/or symptoms of multiple sclerosis | Interventions of interest are:
· Serum biomarker tests for multiple sclerosis | Comparators of interest are:
· Standard clinical workup without serum biomarkers | Relevant outcomes include:
· Test accuracy
· Test validity
· Other test performance measures
· Symptoms
· Functional outcomes
· Health status measures
· Quality of life |
Background
Disease Description Estimated prevalence of multiple sclerosis (MS) in North America varies regionally and ranges from 240 of 100,000 in Canada to 191 of 100,000 in Minnesota and 40 of 100,000 in Texas.1 Women are affected twice as often as men, and median age of onset is 24 years. Most (85%) patients have relapsing-remitting MS (RRMS), and of these, 60% to 70% will progress to secondary progressive MS, usually 10 to 30 years after disease onset.2 Rarer forms are primary progressive MS and progressive relapsing MS.
MS is characterized by destruction of myelin in the central nervous system. Progressive focal demyelination eventually leads to axonal degeneration and cumulative physical and cognitive disabilities. Because any area of the brain, optic nerve, or spinal cord can be affected, symptoms are diverse and may include cognitive, speech, or vision deficits; numbness; pain; weakness or dyscoordination; and bowel or bladder dysfunction. Diagnosis is made by clinical symptoms, typical magnetic resonance imaging findings, and oligoclonal antibodies in the cerebrospinal fluid assessed using current McDonald criteria.3 Diagnosis requires 2 clinical episodes occurring at 2 discreet points in time, or 1 clinical episode (clinically isolated syndrome; defined next) with lesions detected by magnetic resonance imaging indicating development at 2 discreet points in time (ie, simultaneous appearance of old and new lesions). Disability progression is quantified in practice and in clinical trials using the Kurtzke Expanded Disability Status Scale.4 Patients with scores less than 5 are fully ambulatory; scores of 5 to 10 are defined by incrementally decreasing ability to walk.
The term clinically isolated syndrome (CIS) describes patients who have suffered a first episode suggestive of MS but do not meet diagnostic criteria for definite MS. Studies have indicated that early treatment with interferon beta-1b (IFN-β1b) may delay relapse (ie, a second episode), but not long-term disability outcomes.5,6
In addition to IFN-β1b, 8 other disease-modifying drugs are currently approved by the U.S. Food and Drug Administration for first- or second-line treatment of MS, with varying degrees of efficacy for reducing relapses and preventing neurologic deterioration. First-line treatments include self-injectable drugs (interferon, glatiramer acetate) and newer oral agents (eg, fingolimod, teriflunomide, dimethyl fumarate). Choice of first-line agent depends on severity of initial presentation, patient preference, and adverse effect profile. Patients with more active or refractory disease are more likely to tolerate greater risk for greater efficacy, eg, with second- or third-line agents (eg, natalizumab, alemtuzumab).2,7,8
Biomarkers
Glycominds, based in Israel, markets the diagnostic test gMS Dx, for patients with a first episode or CIS, and the multimarker prognostic test gMS Pro EDSS, for predicting deterioration in patients diagnosed with MS. Both tests detect serum antibodies to glycans, which are polysaccharide- or carbohydrate-containing molecules on the surface of immune and other cells. The gMS Dx test detects immunoglobulin M (IgM) antibodies to the disaccharide glycan, glucose(α1,4)glucose(α) (GAGA4), and gMS Pro EDSS detects IgM antibodies to GAGA2, -3, -4, and -6. These anti-glycan antibodies are thought to interfere with normal function of the immune system.9 Temperature controls are implemented during assay runs to prevent IgM precipitation.
Several other serum biomarkers for MS have been investigated, but no other commercially available tests were identified.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Glycominds (Lod, Israel) offered gMS® Dx and gMS® Pro EDSS as laboratory-developed (in-house) tests at its CLIA-certified laboratory in Simi Valley, California. The current status of the tests is unknown because links to the company’s website are inactive, and ordering information is not readily available through the parent company, Coronis Partners. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Related Policies
Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
Serum biomarker tests for multiple sclerosis are considered investigational in all situations.
Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.
Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.
FIDE SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
[RATIONALE: This policy was created in 2014 and has been updated with a literature review of the MEDLINE database through April 29, 2016.
gMS Dx Test In 2006, Schwarz et al screened sera from 107 patients in Israel diagnosed with relapsing-remitting multiple sclerosis (RRMS) for antibodies to 76 glycan molecules.9 Sera were analyzed by immunofluorescence assay using the GlycoChip® (Glycominds) glycan array. Antibody levels in patients with RRMS were compared to levels in patients with primary progressive MS (PPMS; n=16); patients with other neurologic diseases, including inflammatory (eg, Guillain-Barré syndrome, myasthenia gravis) and noninflammatory (eg, Parkinson disease, Huntington disease,) neurologic diseases (n=50); and patients with other autoimmune diseases (eg, rheumatoid arthritis, Crohn disease; n=27). No differences between groups were observed for immunoglobulin G (IgG) and IgA antibodies. IgM binding to glycans containing free glucose residues (eg, disaccharide glycan, glucose[α1,4]glucose[α] [GAGA4]) best discriminated RRMS patients from other groups; anti-GAGA4 antibody levels were significantly higher in patients with RRMS than in patients with other neurologic disease (p<0.001) and patients with other autoimmune diseases (p=0.02). No differences between patients with RRMS and PPMS was observed. Coefficients of variation for repeated anti-GAGA4 IgM measurements were approximately 8% for quadruple intraplate measurements and 22% for interplate measurements. Area under the receiver operating characteristic (ROC) curve for discriminating patients with MS (RRMS or PPMS) from patients with other neurologic diseases was 0.765 (95% confidence interval [CI], 0.673 to 0.865). Using a cutoff value for anti-GAGA4 IgM positivity (normalized for total IgM) of 2.1´103 relative fluorescence units (RFU)/(μg total IgM/mL serum)0.5 , sensitivity was 57%, and specificity was 85%.
In 2009, Brettschneider et al retrospectively analyzed sera from 2 cohorts of patients: cohort 1 (n=778) comprised 648 U.S. patients with MS (77% RRMS), 30 patients in Germany who had other neurologic disease (suspected neuropsychiatric lupus), and 100 healthy controls from the United States; cohort 2 (n=126) comprised 91 U.S. patients with MS (91% RRMS) and 35 U.S. patients with other inflammatory (eg, Guillain-Barré syndrome) and noninflammatory (eg, amyotrophic lateral sclerosis) neurologic diseases.10 Anti-GAGA4 IgM levels were assessed in all patients by enzyme immunoassay and were higher in MS patients than in controls, although differences were only statistically significant in cohort 1. Area under the curve (AUC) for discriminating MS patients from patients with other neurologic diseases was 0.903 in cohort 1 and 0.812 in cohort 2. For discriminating MS patients from healthy controls (cohort 1), AUC was 0.651. Sensitivity and specificity were determined for the combined cohort of 739 patients with MS and 65 patients with other neurologic diseases using a cutoff determined by anti-GAGA4 IgM levels in the upper 15 percentile of healthy controls (50 enzyme immunoassay units [EU]/[mg total IgM/mL serum]0.5). Sensitivity was 34%; specificity was 99%; positive likelihood ratio was 21.9; and negative likelihood ratio was 0.67.
Freedman et al (2009) retrospectively assessed sera drawn at the time of presentation with a first episode suggestive of MS in 3 cohorts in Canada and Belgium.11 Cohort 1 (n=88) comprised 44 patients later diagnosed with RRMS and 44 age- and sex-matched patients who had other neurologic diseases; cohort 2 (n=252) comprised 167 patients later diagnosed with RRMS and 85 patients with other neurologic diseases; cohort 3 is discussed next. Enzyme-linked immunosorbent assay was used to measure anti- GAGA4 IgM, and values were normalized to total IgM, although 2 different normalizing algorithms were used. In cohort 1, the cutoff value was determined by mean optical density (OD) plus 2 SD in the control group (0.53 OD/[total IgM RFU´106]0.5); in cohort 2, the cutoff value was determined by ROC analysis to achieve 90% specificity for RRMS (42 EU/[mg total IgM/mL serum]0.5). Coefficients of variation for intra- and interplate measurements were 11% and 15%, respectively. In cohorts 1 and 2, respectively, sensitivity was 27% and 26%; specificity was 98% and 91%; positive predictive value (PPV) was 92% and 85%; and negative predictive value (NPV) was 52% and 39%. In cohort 1, 16 (80%) of 20 patients with antibody titers above the median had a second clinical attack within 2 years, compared with 10 (47%) of 21 patients with antibody titers at or below the median (odds ratio, 4.4; 95% CI, 1.1 to 17.7; p=0.05).
Section Summary: gMS Dx Test
Three studies indicated that anti-GAGA4 IgM antibody levels may be higher in patients with RRMS compared with patients with a various other neurologic diseases and healthy controls. Although the test demonstrated high specificity (estimated range, 85%-99%), suggesting that it may be useful to confirm a diagnosis of MS, different assay methodologies were used (fluorescence immunoassay and enzyme immunoassay) and cutoffs were data-driven. Further, prospective studies demonstrating improved health outcomes in patients who may have MS (eg, presenting with a first episode [clinically isolated syndrome (CIS)]) and who are treated according to test results are lacking. The anti-GAGA4 IgM test (gMS Dx) therefore is considered in an early stage of development and investigational for all uses.
gMS Pro EDSS Test Freedman et al conducted 2 exploratory analyses of an IgM antibody panel to GAGA2, -3, -4, and -6 for predicting disease progression in patients presenting with a first episode. The first study (2009)11 comprised cohort 3 of the study previously reviewed. Sera drawn at the time of first presentation in 100 patients were analyzed by immunofluorescence assay. Coefficients of variation were 8% to 12% for intraslide measurements and 15% to 22% for interslide measurements. Cutoffs for each antigen were calculated as mean values plus 1, 1.5, or 2 SD to optimize performance (4.0 RFU [sample/reference sample], 4.5 RFU, 4.5 RFU, and 4.3 RFU for anti-GAGA2, -GAGA3, -GAGA4, and -GAGA6 IgM,
respectively). Samples were considered positive if at least 1 result exceeded the cutoff for 1 of the 4 antibodies. Results in 58 patients who had early relapse (≤24 months) were compared with results in 42 patients who had late relapse (>24 months). For detecting early relapse, sensitivity was 38%; specificity was 88%; PPV was 82%; and NPV was 51%.
The second study (2012)12 prospectively assessed sera from patients presenting with a first episode suggestive of MS who were enrolled in an international trial (BENEFIT) assessing early versus delayed initiation of interferon beta-1b (IFN-β1b).5 IgM antibodies to GAGA2, -3, -4, and -6 were measured by enzyme immunoassay in 286 patients (61% of enrolled patients) who had at least 2 mL of serum available. A total of 177 (62%) patients were randomized to IFN-β1b for 2 years and 109 (38%) patients were randomized to placebo; 255 (89%) of 286 patients enrolled in a follow-up phase with open-label IFN-β1b and were followed for up to 5 years. The primary outcome was the ability of the test to predict early (<24 months) relapse. Cutoffs for each antigen were calculated as mean values plus 1.4 SD, 1.8 SD, 0.8 SD, and 1.7 SD, for anti-GAGA2, -3, -4, and -6, respectively (148.8 EU, 164.6 EU, 133.6 EU, and 168.1 EU for anti-GAGA2, -3, -4, and -6, respectively). Samples were considered positive if at least 1 result exceeded the cutoff for 1 of the 4 antibodies. Sensitivity was 21%, specificity was 83%, PPV was 38%, and NPV was 68%. For secondary outcomes, the risk of confirmed disability progression, defined as a 1-point increase on the Expanded Disability Status Scale (EDSS) score confirmed over 6 months or more, was significantly greater for patients classified as positive than for patients classified as negative (hazard ratio, 2.05; 95% CI, 1.2 to 3.5; p=0.009). However, the results were not statistically significant when testing controlled for baseline EDSS score or examined only in the group who received IFN-β1b from the start of the trial. The assay panel also had no significant predictive value for conversion to MS satisfying McDonald criteria, 2005 version,13 for annualized relapse rates, or for magnetic resonance imaging (MRI) findings. The authors concluded that baseline EDSS score, presence of oligoclonal bands, and MRI findings remain the best predictors of disease progression and stated: “All current first-line, disease-modifying medications reduce the risk for subsequent attacks and lower MRI activity, and have shown benefit in patients at CIS [clinically isolated syndrome], so it is unlikely that CIS patients would not be treated with one of these agents, obviating the need for a baseline biomarker predicting early relapse.”
Section Summary: gMS Pro EDSS Test
Two studies in patients presenting with a first episode suggestive of MS indicated that a panel of anti- GAGA IgM antibodies was not useful for predicting relapse or clinical course. Because different assay methods were used and cutoffs were data-driven, the gMS Pro EDSS test is considered in an early stage of development.
Investigational Serum Biomarkers Several other serum biomarkers for MS have been investigated. These have been reviewed recently elsewhere14,15 and include the factors listed in Table 1. Serum levels of several factors have been shown to change (increase or decrease) during relapses. None have been shown conclusively to alter disease management.
Table 1. Investigational Serum Biomarkers for Multiple Sclerosis
Biomarker | Significance | Citation |
| Anti-KIR4 antibodies | Associated with disease activity | Brill (2015)16 |
| Anti-myelin antibodies | Limited prognostic value in patients with CIS | Findling (2014)17 |
| Antiphospholipid antibody | Associated with disease activity | Koudriavtseva (2014)18 |
| Anti-transferrin antibodies | Associated with disease vs healthy controls | Colomba (2014)19 |
| Apoptosis-related moleculesa | Inconsistent evidence for association with disease activity | Moreno (2013)20 |
| Chemokine (C-X-C motif) ligand 16 (CXCL16) | Associated with disease activity | Holmoy (2013)21 |
| Complement regulator factor H | Associated with disease activity | Ingram (2010)22 |
| Epstein-Barr virus antibodiesb | Associated with disease activity and treatment response | Kvistad (2014)23 |
| Endogenous secretory RAGE | Associated with disease activity | Sternberg (2014)24 |
| Growth hormone | May be involved in myelin repair | Gironi (2013)25 |
| Human herpesvirus 6A/B | Associated with disease activity | Ortega-Madueño (2014)26 |
| Inflammatory mediators/cytokinesc | Inconsistent evidence for associations with disease activity and treatment response | Dimisianos (2014)27
Fissolo (2014)28
Polachini (2014)29
Uysal (2014)30
Trenova (2014)31 |
| Intercellular adhesion molecules | Associated with endothelial cell activation; useful for defining active disease | Hartung (1995)32
Trojano (1996)33 |
| Ischemia-modified albumin | Associated with disease vs healthy controls | Aydin (2014)34 |
| Lactic acid | Associated with disease progression | Amorini (2014)35 |
| Macrophage-derived chemokinesd | Associated with disease in women | Jafarzadeh (2014)36
Stilund (2014)37 |
| Metabolic profilee | May distinguish RRMS from progressive MS | Dickens (2014)38 |
| Metalloproteinases | Associated with breakdown of blood-brain barrier; useful for defining active disease | Waubant (1999)39
Trentini (2015)40 |
| MicroRNA | Associated with disease activity | Kacperska (2015)41 |
| Myelin peptidesf | Inconsistent evidence for predicting early relapse after first episode | Berger (2003)42
Kuhle (2007)43 |
| Neuron-specific enolase | Inconclusive evidence for an association with MS | Koch (2015)44 |
| Osteopontin | Serum levels not associated with disease activity | Kivisakk (2014)45
Shimizu (2013)46 |
| Phospholipase A2 | No association with disease course | Siroos (2013)47 |
| Uric acid | Associated with disease activity | Moccia (2015)48 |
CIS: clinically isolated syndrome; EBV: Epstein-Barr virus; IFN: interferon; Ig: immunoglobulin; IL: interleukin; MS: multiple sclerosis; RAGE: receptor for advanced glycation end products; RRMS: relapse-remitting multiple sclerosis; TNF: tumor necrosis factor.
a Soluble Fas, Fas-ligand, and soluble TNF-related apoptosis-inducing ligand.
b Anti-EBV nuclear antigen 1 IgG, anti-EBV viral capsid antigen IgM.
c IFN-γ, TNF-α, IL-1, IL-6, IL-10, IL-17, C-reactive protein, and soluble TNF receptor 2
d CCL22, CD163.
e Serum fatty acids, phosphocholine, N-acetyl glycoproteins, glucose, and b-hydroxybutyrate.
f Myelin oligodendrocyte glycoprotein, myelin basic protein.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in October 2018 did not identify any ongoing or unpublished trials that would likely influence this review.
Summary of Evidence For individuals who have signs and/or symptoms of multiple sclerosis (MS) who receive serum biomarker tests for MS, the evidence includes cross-sectional studies of diagnostic accuracy and cohort studies. Relevant outcomes are test accuracy and validity, other test performance measures, symptoms, functional outcomes, health status measures, and quality of life. Antibodies to glycan molecules are thought to impair immune function. They include antibodies to 1 (glucose[α1,4]glucose[α] [GAGA4]) or several (GAGA2, -3, -4, and -6) glycan molecules. The gMS Dx and gMS Pro EDSS tests may aid in the diagnosis and prognosis in MS, respectively. Tests for serum levels of other potential MS biomarkers, including but not limited to apoptosis-related molecules, intercellular adhesion molecules, and myelin peptides, have also been described. Current evidence for these other biomarkers makes it difficult to assess their utility in diagnosis and prognosis. The evidence is insufficient to determine the effects of the technology on health outcomes.
Supplemental Information
Practice Guidelines and Position Statements
Multiple Sclerosis Think Tank
In 2013, the Multiple Sclerosis Think Tank, a group of approximately 40 hospital neurologists in France, published consensus recommendations for serum tests useful to diagnose MS.15 Recommendations were developed by systematic review of the literature and a Delphi consensus process. Panelists concurred that “there is currently no useful biological blood test for the positive diagnosis of MS.”
International Advisory Committee on Clinical Trials in Multiple Sclerosis
In 2014, the International Advisory Committee on Clinical Trials in Multiple Sclerosis, jointly sponsored by the U.S. National Multiple Sclerosis Society, the European Committee for Treatment and Research in Multiple Sclerosis, and the MS Phenotype Group, published results of its deliberations on the MS clinical course descriptions in light of current evidence for improved descriptive terminology (eg, incorporating evidence for serum and other biomarkers).49 The Committee concluded: “To date, there are no clear clinical, imaging, immunologic, or pathologic criteria to determine the transition point when RRMS [relapse-remitting MS] converts to SPMS [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.”
U.S. Preventive Services Task Force Recommendations
Not applicable.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Serum Biomarker Tests for Multiple Sclerosis
gMS® Dx
gMS® Pro EDSS
References:
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5. Kappos L, Freedman MS, Polman CH, et al. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. Aug 4 2007;370(9585):389-397. PMID 17679016
6. Kappos L, Freedman MS, Polman CH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. Nov 2009;8(11):987-997. PMID 19748319
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10. Brettschneider J, Jaskowski TD, Tumani H, et al. Serum anti-GAGA4 IgM antibodies differentiate relapsing remitting and secondary progressive multiple sclerosis from primary progressive multiple sclerosis and other neurological diseases. J Neuroimmunol. Dec 10 2009;217(1-2):95-101. PMID 19879655
11. Freedman MS, Laks J, Dotan N, et al. Anti-alpha-glucose-based glycan IgM antibodies predict relapse activity in multiple sclerosis after the first neurological event. Mult Scler. Apr 2009;15(4):422-430. PMID 19324980
12. Freedman MS, Metzig C, Kappos L, et al. Predictive nature of IgM anti-alpha-glucose serum biomarker for relapse activity and EDSS progression in CIS patients: a BENEFIT study analysis. Mult Scler. Jul 2012;18(7):966-973. PMID 22183938
13. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. Dec 2005;58(6):840-846. PMID 16283615
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17. Findling O, Durot I, Weck A, et al. Antimyelin antibodies as predictors of disability after clinically isolated syndrome. Int J Neurosci. Aug 2014;124(8):567-572. PMID 24274327
18. Koudriavtseva T, D'Agosto G, Mandoj C, et al. High frequency of antiphospholipid antibodies in relapse of multiple sclerosis: a possible indicator of inflammatory-thrombotic processes. Neurol Sci. Nov 2014;35(11):1737- 1741. PMID 24847961
19. Colomba P, Fontana S, Salemi G, et al. Identification of biomarkers in cerebrospinal fluid and serum of multiple sclerosis patients by immunoproteomics approach. Int J Mol Sci. 2014;15(12):23269-23282. PMID 25517032
20. 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. Dec 15 2013;191(12):6136-6146. PMID 24249731
21. Holmoy T, Loken-Amsrud KI, Bakke SJ, et al. Inflammation markers in multiple sclerosis: CXCL16 reflects and may also predict disease activity. PLoS One. 2013;8(9):e75021. PMID 24069377
22. Ingram G, Hakobyan S, Hirst CL, et al. Complement regulator factor H as a serum biomarker of multiple sclerosis disease state. Brain. Jun 2010;133(Pt 6):1602-1611. PMID 20421219
23. Kvistad S, Myhr KM, Holmoy T, et al. Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis. Mult Scler. Dec 2014;20(14):1833-1840. PMID 24842958
24. Sternberg Z, Sternberg D, Drake A, et al. Disease modifying drugs modulate endogenous secretory receptor for advanced glycation end-products, a new biomarker of clinical relapse in multiple sclerosis. J Neuroimmunol. Sep 15 2014;274(1-2):197-201. PMID 25064498
25. Gironi M, Solaro C, Meazza C, et al. Growth hormone and disease severity in early stage of multiple sclerosis. Mult Scler Int. 2013;2013:836486. PMID 24260717
26. Ortega-Madueño I, Garcia-Montojo M, Dominguez-Mozo MI, et al. Anti-human herpesvirus 6A/B IgG correlates with relapses and progression in multiple sclerosis. PLoS One. 2014;9(8):e104836. PMID 25110949
27. Dimisianos N, Rodi M, Kalavrizioti D, et al. Cytokines as biomarkers of treatment response to IFN beta in relapsing-remitting multiple sclerosis. Mult Scler Int. 2014;2014:436764. PMID 25152817
28. Fissolo N, Canto E, Vidal-Jordana A, et al. Levels of soluble TNF-RII are increased in serum of patients with primary progressive multiple sclerosis. J Neuroimmunol. Jun 15 2014;271(1-2):56-59. PMID 24794503
29. 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. PMID 24508813
30. Uysal S, Meric Yilmaz F, Bogdaycioglu N, et al. Increased serum levels of some inflammatory markers in patients with multiple sclerosis. Minerva Med. Jun 2014;105(3):229-235. PMID 24988088
31. Trenova AG, Slavov GS, Manova MG, et al. Cytokines and disability in interferon-beta-1b treated and untreated women with multiple sclerosis. Arch Med Res. Aug 2014;45(6):495-500. PMID 25130430
32. Hartung HP, Reiners K, Archelos JJ, et al. Circulating adhesion molecules and tumor necrosis factor receptor in multiple sclerosis: correlation with magnetic resonance imaging. Ann Neurol. Aug 1995;38(2):186-193. PMID 7544573
33. Trojano M, Avolio C, Simone IL, et al. Soluble intercellular adhesion molecule-1 in serum and cerebrospinal fluid of clinically active relapsing-remitting multiple sclerosis: correlation with Gd-DTPA magnetic resonance imaging- enhancement and cerebrospinal fluid findings. Neurology. Dec 1996;47(6):1535-1541. PMID 8960741
34. Aydin O, Ellidag HY, Eren E, et al. Ischemia modified albumin is an indicator of oxidative stress in multiple sclerosis. Biochem Med (Zagreb). 2014;24(3):383-389. PMID 25351357
35. Amorini AM, Nociti V, Petzold A, et al. Serum lactate as a novel potential biomarker in multiple sclerosis. Biochim Biophys Acta. Jul 2014;1842(7):1137-1143. PMID 24726946
36. Jafarzadeh A, Ebrahimi HA, Bagherzadeh S, et al. Lower serum levels of Th2-related chemokine CCL22 in women patients with multiple sclerosis: a comparison between patients and healthy women. Inflammation. Apr 2014;37(2):604-610. PMID 24254331
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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
* CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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