Test Catalog

Test ID: ORXNA    
Orexin-A/Hypocretin-1, Spinal Fluid

Useful For Suggests clinical disorders or settings where the test may be helpful

Aiding in the diagnosis and differentiation of type 1 narcolepsy from other causes of hypersomnolence


This assay is not intended for use as a screening test.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Narcolepsy affects 0.02% to 0.05% of the population and the onset of symptoms often occurs in adolescence. Orexin (also known as orexin-A or hypocretin-1) is a neuropeptide produced in the hypothalamus and is involved in the sleep/wake cycle in humans. Impairment of orexin production and orexin-modulated neurotransmission is associated with narcolepsy with cataplexy (episodes of muscle weakness in response to emotional stimuli). An abnormally low concentration of orexin-A/hypocretin-1 in cerebrospinal fluid (CSF) is indicative of what is termed type 1 narcolepsy.


Survey of the literature reveals that approximately 85% to 95% of randomly selected individuals with type 1 narcolepsy and typical cataplexy, exhibit low (<110 pg/mL) CSF orexin (hypocretin-1) concentrations.(1) In one large study, the sensitivity of this cutoff was found to be 87% with a specificity of 99%.(2) Orexin deficiency and type 1 narcolepsy are closely associated with HLA complex DQB1 *0602. It is estimated that only 1 in 500 HLA DQB1*0602-negative individuals exhibit low CSF orexin concentrations. CSF concentrations have been found to almost always be above 200 pg/mL in healthy individuals and those with non-type 1-narcoleptic sleep disorders such as narcolepsy type 2 and idiopathic hypersomnia.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Normal individuals should be >200 pg/mL


Previous literature has defined CSF orexin-A/hypocretin-1 concentrations of < or =110 pg/mL as being consistent with narcolepsy type 1-(Mignot E: Arch Neurol 2002:59;1553-1562). Concentrations between 111 to 200 pg/mL are considered intermediate and have limited diagnostic utility for narcolepsy, as they may be representative of other neurological disorders. Concentrations of >200 pg/mL are considered normal.

Interpretation Provides information to assist in interpretation of the test results

The diagnostic criteria for type 1 narcolepsy in the International Classification of Sleep Disorders (3) include the presence of hypersomnia, cataplexy (episodes of muscle weakness in response to emotional stimuli) and/or measured cerebrospinal fluid (CSF) orexin (hypocretin-1) concentrations less than or equal to 110 pg/mL.


Orexin (hypocretin-1) CSF concentrations have been classified into 3 categories in the literature. They include low (< or =110 pg/mL), which is indicative of type 1 narcolepsy; intermediate (ranges between 111-200 pg/mL); and normal (>200 pg/mL). Previous studies have shown that 106 of 113 patients with clinically defined type 1 narcolepsy exhibited low (<110 pg/mL) orexin concentrations. In another study, all 48 healthy individuals exhibited orexin (hypocretin-1) CSF concentrations above 200 pg/mL.


In the periodic hypersomnia disorder of Kleine-Levin syndrome, the CSF orexin levels may be low during the sleepy periods, with return to normal when individuals are not sleepy.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Several factors contribute in the decision to measure orexin in cerebrospinal fluid (CSF). Orexin deficiency in HLA DQB1*0602-negative patients is rare. This test may be considered for the diagnosis of narcolepsy type 1, after HLA positivity is shown, if a clinical multiple sleep latency test is negative and/or unavailable due to potential confounding circumstances. It may also be considered if there is suspicion that cataplexy is of psychogenic origin.


Orexin (hypocretin-1) concentrations between 111 to 200 pg/mL are considered intermediate and have limited diagnostic utility for type 1 narcolepsy, as they may be representative of other neurological disorders.


This test should not be requested in patients who have recently received radioisotopes, therapeutically or diagnostically, because of potential assay interference. A recommended time period before collection cannot be made because it will depend on the isotope administered, the dose given, and the clearance rate in the individual patient.


Some patients who have been exposed to animal antigens, either in the environment or as part of treatment or imaging procedures, may have circulating anti-animal antibodies present. These antibodies may interfere with the assay reagents to produce unreliable results.

Supportive Data

In an in-house Mayo Clinic study utilizing this assay on cerebrospinal fluid (CSF) from 100 individuals without type 1 narcolepsy, all samples (100%) exhibited orexin (hypocretin-1) concentrations higher than the 200 pg/mL normal threshold (mean value of 531pg/mL + or - 89). Additionally, all 6 out of 6 patients with confirmed type 1 narcolepsy had measured CSF concentrations below 110 ng/mL in this assay (mean value of <50 pg/mL).

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Bourgin P, Zeitzer JM, Mignot E: CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol. 2008 Jul;7(7):649-62.doi:10.1016/S1474-4422(08)70140-6

2. Mignot E, Lammers GJ, Ripley B, Okun M, et al: The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002 Oct;59(10):155-162

3. Sateia MJ: International classification of sleep disorders-third edition: highlights and modifications. Chest. 2014 Nov;146(5):1387-1394. doi: 10.1378/chest.14-0970

4. Dauvilliers Y, Arnulf I, Mignot E: Narcolepsy with cataplexy. Lancet. 2007;369:499-5112

5. Ripley B, Overeem S, Fujiki N, Nevsimalova S, et al: CSF hypocretin/orexin levels in narcolepsy and other neurological conditions. Neurology. 2001 Dec 26;57(12):2253-2258