Orexin testing, a diagnostic procedure requiring a lumbar puncture, can detect type 1 narcolepsy in conjunction with sleep studies like MSLT. Mayo Clinic has developed a widely clinically available test.

By Yoona Ha

Researchers report that molecules found only in the cerebrospinal fluid can help identify patients with type 1 narcolepsy (narcolepsy with cataplexy). The lack of two brain chemicals called orexins (orexin-A and orexin-B; also known as hypocretin-1 and hypocretin-2) is a hallmark trait. This discovery two decades ago marked a breakthrough in the understanding of narcolepsy.1

Orexin testing, a diagnostic procedure requiring a lumbar puncture, can detect type 1 narcolepsy in conjunction with sleep studies like multiple sleep latency tests and polysomnography. As outlined by the American Academy of Sleep Medicine, orexin deficiency as measured by cerebrospinal fluid’s orexin-A concentration levels, is a hallmark trait of the diagnostic criteria for type 1 narcolepsy.2

Yet providers and patients seeking orexin testing as an additional resource often faced obstacles in getting the test. Up until January 1, 2017, Stanford Medicine’s Center for Narcolepsy offered services measuring orexin levels. For many patients, this meant having one less resource for getting quicker diagnosis and treatment for their condition. The harmful effects of delayed narcolepsy diagnosis are well documented—left untreated, narcolepsy can wreak havoc on a patient’s social, educational, and professional performance. To make matters worse, researchers suggest that patients ages 0 to 39, on average, wait 6.5 or more years before receiving care.3

The good news for patients today is that Mayo Clinic now offers orexin testing even for patients receiving care outside of its health system. Joshua Bornhorst, PhD, DABCC, FACB, co-director of clinical immunoassay and metals laboratories at Mayo Clinic, explains what this means for people with suspected narcolepsy.

Sleep Review (SR): Would you describe orexin testing and its purpose? While it’s not intended to be used as a screening test for narcolepsy, how can it be useful in differentiating type 1 narcolepsy?

Bornhorst: Orexin (sometimes called orexin-A or hypocretin-1) aids in the diagnosis and differentiation of type 1 narcolepsy from other types of narcolepsy. Orexin-A is a neuropeptide produced in the hypothalamus and is involved in the sleep/wake cycle in humans. An abnormally low concentration of orexin-A in cerebrospinal fluid (CSF) is indicative of what is termed type 1 narcolepsy.

Clinical symptoms that should be established prior to testing include the presence of hypersomnia and/or cataplexy (episodes of muscle weakness in response to emotional stimuli).

Although the diagnostic criteria for type 1 narcolepsy in the 2013 International Classification of Sleep Disorders includes evaluation of orexin CSF concentrations, clinical testing for orexin has not been previously broadly available in the United States.

SR: Previously and to this day, orexin testing has not been widely available. For instance, Stanford University used to offer this testing but discontinued offering this assessment for narcolepsy patients. But recently Mayo Clinic expanded this testing to those who are not being treated at Mayo Clinic facilities: What is the significance of this expansion of service to include non-Mayo Clinic patients and what has facilitated Mayo Clinic to be the leading provider of orexin testing in the United States?

Bornhorst: Clinicians and scientists at Stanford University did a great deal of the initial characterization, and research testing for orexin/hypocretin-1, particularly Dr Emmanuel Mignot. Sleep specialists in the department of neurology at Mayo Clinic helped identify this testing as an unfilled clinical need and collaborated with myself and others in the Mayo Clinic’s department of laboratory medicine and pathology to develop a widely clinically available test.

For the first time in the United States (beginning in April 2019), non-Mayo clinicians from across the country (and world) are able to directly show a deficiency of orexin using a reference laboratory (CLIA [Clinical Laboratory Improvement Amendments]-validated) assay. Thus, clinicians can fully evaluate patients’ CSF orexin concentrations in accordance to the previously mentioned classification of sleep disorders guideline.

SR: What are some common misconceptions that people have about orexin testing and its purpose?

Bornhorst: The name of the protein and test. It can be referred to either as orexin-A or as hypocretin-1.

SR: I also noticed that the Mayo Clinic also offers a narcolepsy blood test. When you compare this test to the orexin test, what are the differences and pros and cons of each test for narcolepsy patients? How can this combined with other sleep assessments help patients?

Bornhorst: This test does not measure orexin concentration in the blood.

The narcolepsy associated antigen blood assay involves human leukocyte antigen (HLA) typing for the HLA complex DQB1 0602. Studies have identified DQB106:02 as being associated with narcolepsy. DQB106:02 is found in ~95% of patients with narcolepsy who also have cataplexy (narcolepsy type 1), but only in ~50% of patients with narcolepsy without cataplexy (narcolepsy type 2). However, 25% of normal people also have this HLA complex so it cannot be used to detect the presence of narcolepsy. In a patient who has cataplexy, the absence of the strongly associated DQB106:02 provides good evidence that the patient does not have type 1 narcolepsy.

SR: Who is orexin testing ideal for and who isn’t it for?

Bornhorst: Several factors contribute in the decision to measure orexin in cerebrospinal fluid. Orexin-A deficiency in certain HLA type-negative patients is rare. The orexin test may be considered if there is suspicion that cataplexy is of psychogenic origin, after potential HLA-type compatibility with the presence of type-1 narcolepsy is shown, and/or if a clinical multiple sleep latency test is negative or unavailable.

The orexin-A assay is not intended for use as a screening test (especially as it is a CSF sample). Clinical symptoms that should be established prior to testing include the presence of hypersomnia and/or cataplexy.

Yoona Ha is a freelance writer and healthcare public relations professional.


  1. Mahoney CE, Cogswell A, Koralnik IJ, Scammell TE. The neurobiological basis of narcolepsy. Nat Rev Neurosci. 2019 Feb; 20(2): 83–93.
  2. Krahn LE, Hershner S, Loeding LD, et al. Quality measures for the care of patients with narcolepsy. J Clin Sleep Med. 2015 Mar 15;11(3):335.
  3. Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the Innsbruck Narcolepsy Cohort. J Clin Sleep Med. 2013 Aug 15;9(8): 805–12.

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