Cerebrospinal Fluid Orexin-A Levels Linked to Sleep Stability in Hypersomnolence

Cerebrospinal fluid orexin (ORX)-A levels are associated with markers of nocturnal sleep stability in patients with hypersomnolence, according to study results published in Neurology.

Previous studies have shown that the ORX/hypocretin system has an important role in sleep-wake regulation, as ORX neurons support the inhibition of sleep-promoting and rapid eye movement sleep-promoting neurons.  Narcolepsy type 1 is associated with wake and sleep instability due to a defect of the orexinergic tone.

The aim of the current study was to explore the association between cerebrospinal fluid ORX-A levels and nocturnal sleep stability in patients with hypersomnolence.

The study included drug-free patients with suspected central hypersomnolence disorders referred to the French National Reference Center for Narcoplepsy and Rare Hypersomnia. All participants completed a standardized clinical evaluation, lumbar puncture to determine cerebrospinal fluid ORX-A levels, a multiple sleep latency test, and video-polysomnography recording to assess markers of nocturnal sleep stability, including wake and sleep bouts and sleep/wake transitions. 

Study researchers collected data on 300 (55% men; 23.67% children; mean age 29.89 years) participants who completed the investigation. The mean cerebrospinal fluid ORX-A level was 155.12 pg/mL, with ORX-A deficiency (<110 pg/mL) in 164 patients, and intermediate (110-200 pg/mL) or normal levels in 136 patients.

The number of wake bouts (43 vs 25, respectively; P <.0001), sleep bouts (43 vs 25.5, respectively; P <.0001), and index of sleep bouts/hour of sleep time were higher in patients with ORX-A deficiency, compared to those with higher levels. The index of wake bouts/hour of wake time was lower in those with ORX-A deficiency than those with intermediate or normal levels (41.4 vs 50.6, respectively; P <.0001).

The percentage of all wake bouts less than 30 seconds was lower in those with ORX-A deficiency than those with higher ORX-A levels (51.3% vs 60.8%, respectively;  P <.001). Wake bouts of at least 1.5 minutes were more frequent in those with ORX-A deficiency than those with higher levels (7.7% vs 6.7%, respectively; P =.02).

 The percentage of sleep bout length no more than 14 minutes was higher in patients with ORX-A deficiency. Conversely, the percentage of sleep bout length greater than 32.5 minutes was higher in those with intermediate or normal ORX-A levels.

Subsequent analyses performed when the population was categorized according to tertiles of cerebrospinal ORX-A concentration confirmed the study findings, with a dose-response effect of ORX-A levels in post-hoc comparisons.

The researchers acknowledged several study limitations, including variability between batches used to quantify ORX-A concentrations, low accuracy, and potential interference due to cross-reactions with matrix constituents.

“Sleep and wake bouts are reliable markers of nocturnal sleep stability that correlate with CSF [cerebrospinal fluid] ORX-A levels in a dose dependent way. These promising PSG [polysomnography] biomarkers could be used in clinical and research settings,” concluded the researchers.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Barateau L, Lopez R, Chenini S, et al. Association of CSF Orexin-A levels and nocturnal sleep stability in patients with hypersomnolence. Neurology. Published online September 1, 2020. doi:10.1212/WNL.0000000000010743