LCD L36551

Coverage Guidance

Title XVIII of the Social Security Act (SSA), §1862(a)(1)(A), states that no Medicare payment shall be made for items or services that “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.”

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes

42 CFR §410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

Indications and Limitations of Coverage

Indications and Limitations of Coverage

Based upon currently available information, HLA-DQB1*06:02 typing (81383) for the diagnosis or management of narcolepsy is considered experimental/investigational/unproven for all populations. Although research suggests a strong association between HLA-DQB1*06:02 and narcolepsy risk, HLA-DQB1*06:02 typing is insufficient to confirm a diagnosis of narcolepsy, rule out a diagnosis of narcolepsy or quantify risk for narcolepsy. Therefore, at this time there is no clinical utility for genetic testing or HLA-DQB1*06:02 typing in the diagnosis or treatment of narcolepsy.

Background

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy (sudden loss of voluntary muscle tone), and uncontrollable sleep episodes. Most cases of narcolepsy are sporadic, with symptoms beginning around the time of adolescence.

According to the International Classification of Sleep Disorders, Third Edition (ICSD-3) and the Diagnostic and Statistical Manual of Mental Disorder, Fifth Edition (DSM-5), narcolepsy is diagnosed by a combination of physical exam, medical history, polysomnogram, multiple sleep latency testing (MSLT), and low CSF hypocretin-1 levels. Current recommended treatment options include stimulants and antidepressants. At this time, treatment is aimed towards the control of symptoms and is not curative.12

Narcolepsy has a multifactorial etiology, likely caused by the interaction between genetic risk factors and environmental exposures. Research efforts to identify the genetic contributors to narcolepsy have focused on an association between certain human leukocyte antigen (HLA) haplotypes and narcolepsy risk. The HLA complex encodes greater than 200 genes responsible for the recognition of foreign antigens. These genes are highly polymorphic, and certain alleles have long been known to confer risk for autoimmune disorders.

A variation of the HLA-DQB1 gene called HLA-DQB1*06:02 has been strongly associated with narcolepsy, particularly in individuals who also have cataplexy and a loss of hypocretins. Several genetic association studies in ethnically diverse populations have found a robust association between narcolepsy and the HLA-DQB1*06:02 allele. However, 15 to 25% of unaffected individuals in the general population also carry this risk haplotype, suggesting that it is necessary but not sufficient for the development of narcolepsy.6 Additionally, persons with narcolepsy and cataplexy have been identified without the HLA-DQB1*06:02 marker.4 More recent studies further suggest that predisposition to narcolepsy may be the result of complex genetic associations between multiple risk alleles.11

Despite multiple studies replicating the association between HLA-DQB1*06:02 and narcolepsy in different ethnic groups, the overall contribution of HLA variation to disease risk is low. Monozygotic twin studies have shown only partial concordance (25-31%), indicating that environmental factors play a large role in the etiology of narcolepsy.8 Recent studies have suggested that exposure to streptococcus, H1N1, and the H1N1 vaccine may also increase the risk for narcolepsy, specifically among individuals with the HLA-DQB1*06:02 allele.3,14,4

Although research suggests a strong association between HLA-DQB1*06:02 and narcolepsy risk, at this time there is no evidence for any diagnostic utility of HLA typing.5

Summary of Evidence

N/A

Analysis of Evidence

N/A

Bibliography

• American Academy of Sleep Medicine. The International Classification of Sleep Disorders. 3rd ed. 2014.

• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

• Aran A, Lin L, Nevsimalova S, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009;32(8):979-983. doi:10.1093/sleep/32.8.979

• Han F, Lin L, Schormair B, et al. HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep. 2014;37(10):1601-1608. doi:10.5665/sleep.4066

• Hong SC, Lin L, Jeong JH, et al. A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness. Sleep. 2006;29(11):1429-1438. doi:10.1093/sleep/29.11.1429

• Hor H, Kutalik Z, Dauvilliers Y, et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nature Genet. 2010;42(9):786-789. doi:10.1038/ng.647

• Lin L, Hungs M, Mignot E. Narcolepsy and the HLA region. J Neuroimmunol. 2001;117(1-2):9-20. doi:10.1016/s0165-5728(01)00333-2

• Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50(2 Suppl 1):S16-S22. doi:10.1212/wnl.50.2_suppl_1.s16

• Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 2001;68:686-699. doi:10.1086/318799

• Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep. 1997;20(11):1012-1020.

• Miyagawa T, Toyoda H, Hirataka A, et al. New susceptibility variants to narcolepsy identified in HLA class II region. Hum Mol Genet. 2015;24(3):891-898. doi:10.1093/hmg/ddu480

• Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30(12):1705-1711. doi:10.1093/sleep/30.12.1705

• Online Mendelian Inheritance in Man (OMIM). #161400 Narcolepsy 1;NRCLP1. https://www.omim.org/entry/161400. Accessed July 5, 2023.

• Singh AK, Mahlios J, Mignot E. Genetic association, seasonal infections and autoimmune basis of narcolepsy. J Autoimmun. 2013;43:26-31. doi:10.1016/j.jaut.2013.02.003

• Tafti M, Hor H, Dauvilliers Y, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep. 2014;37(1):19–25. doi:10.5665/sleep.3300