REM Sleep Duration Shows Potential as Neurophysiological Biomarker for Diagnosing Hypocretin-Deficient Narcolepsy

In a recently published study in Sleep, findings showed that during the multiple sleep latency test (MSLT), patients with hypocretin-deficiency narcolepsy had shorter mean sleep and REM sleep latencies, longer mean sleep and REM sleep durations, and more direct REM sleep transitions.¹ The results suggest that daytime REM sleep duration is a relevant neurophysiological biomarker of hypocretin-deficiency narcolepsy that can be used for diagnosis in clinical and research settings.

In the study, a mean REM sleep duration of at least 4.1 minutes effectively recognized hypocretin-deficiency in patients with hypersomnolence (areas under the curve [AUC] = 0.932; sensitivity, 0.87; specificity, 0.86) and of at least 5.7 minutes in patients with narcolepsy (AUC = 0.832; sensitivity, 0.77; specificity, 0.82). Using current criteria standards for MSLT/polysomnography (PSG), patients with hypocretin-deficiency were identified with a sensitivity of 0.87 and a specificity of 0.69, and 0.81/0.99 when combined with cataplexy.

Lead author Régis Lopez, MD, PhD, department of neurology, Sleep-Wake Disorders Unit, Gui-de-Chauliac Hospital, CHU Montpellier, Montpellier, France, and colleagues wrote, “Overall, our findings suggest that the mean daytime REM sleep duration is the best MSLT parameter to diagnose hypocretin deficiency in patients with hypersomnolence, with better sensitivity and specificity using the cutoff of at least 4.1 minutes compared to current neurophysiological standard criteria.”¹

In the study, 374 drug-free patients with hypersomnolence were analyzed by MSLT parameters, including the collection of a clinical and PSG assessment and cerebrospinal hypocretin-1 measurement. Conventional measures included sleep latency and number of sleep onset REM-SOREM-periods while alternative measures included sleep duration, REM sleep latency and duration, and sleep stage transitions.

Conventional and alternative MSLT measures were compared as function of hypocretin-1 levels, with 110 pg/mL as the cutoff point. For the secondary end point, researchers performed receiver-operating characteristics analyses to determine the best thresholds of MSLT parameters in recognizing hypocretin-deficiency. The analyses were conducted from the global population of patients and in subgroups of patients with narcolepsy, including patients with typical cataplexy or positive MSLT/ PSG criteria (n = 223).

Lopez et al noted, "The use of alternative MSLT measures may improve the diagnostic accuracy of hypocretin deficiency in patients with hypersomnolence and narcolepsy, which could lead to earlier diagnosis and treatment initiation."¹

Among 150 patients (40.1%) with low hypocretin-1 levels, 52 patients (13.9%) had undetectable levels. In 149 patients with typical cataplexy, 142 of them (95.3%) had low hypocretin-1 levels and 7 (4.7%) had levels greater than 110 pg/mL. Among the 150 patients with hypocretin deficiency, 131 were above the at least 4.1-minute cutoff for mean REM sleep duration and 19 patients were below it. In the 223 patients with narcolepsy, 150 patients had hypocretin deficiency and 73 had hypocretin-1 greater than 110 pg/mL.

Before the study, 55.3% of patients had tapered off their stimulant or antidepressant treatment, which may have influenced the results of the MSLT even though all patients performed the MSLT in a drug-free condition. It was also confirmed that the sleep characteristics during MSLT in patients were influenced by age, as results showed a decreased propensity for REM sleep in older patients. This finding was in line with previous research that showed similar percentages of negative MSLT results in patients with narcolepsy with cataplexy, a proportion that increased with age with longer mean sleep latencies and lower number of sleep onset REMs.²

"Future studies should investigate the diagnostic performances of alternative MSLT measures in larger samples of patients with hypersomnolence and narcolepsy, including those with different subtypes of narcolepsy,” Lopez et al noted.¹

REFERENCES
1. Lopez R, Barateau L, Laura Rassu A, et al. Rapid eye movement sleep duration during the multiple sleep latency test to diagnose hypocretin-deficient narcolepsy. Sleep. 2023;46(1):zsac247. doi:10.1093/sleep/zsac247
2. Dauvilliers Y, Gosselin A, Paquet J, Touchon J, Billiard M, Montplaisir J. Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology. 2004;62(1):46-50. doi:10.1212/01.wnl.0000101725.34089.1e