Altered Sleep Stage Transitions of REM Sleep: A Novel and Stable Biomarker of Narcolepsy

Abstract

EDS, such as obstructive sleep apnea syndrome (OSAS), 5,6 behaviorally induced insuffi cient sleep syndrome (BIISS), 7 and sleep interruption, 8 can also show similar diagnostic features of narcolepsy on MSLT. It was found that 3.9% to 17% of the general population had multiple SOREMPs, 9,10 and 3.6% could meet the MSLT diagnostic criteria of narcolepsy.11 In other words, the MSLT criteria of ICSD-3 would likely give rise to a high false positive rate in diagnosing narcolepsy. BRIEF SUMMARYCurrent Knowledge/Study Rationale: Recent data suggested that altered sleep stage transition of REM sleep might be able to differentiate narcolepsy from other hypersomnias, but its longitudinal stability and association with HLA typing are unclear. Study Impact: Altered sleep stage transition from stage non-N2/N3 to stage R has good sensitivity and specifi city in diagnosing narcolepsy especially with the help of additional sleep variables in the decision tree analysis, which suggests its clinical utility in the differential diagnosis of hypersomnias. The longitudinal stability and association with HLA DBQ1*0602 further demonstrates that altered sleep stage transition is a trait marker of the instability of NREM-REM sleep regulation in narcolepsy.Objectives: To determine the diagnostic values, longitudinal stability, and HLA association of the sleep stage transitions in narcolepsy. Methods: To compare the baseline differences in the sleep stage transition to REM sleep among 35 patients with type 1 narcolepsy, 39 patients with type 2 narcolepsy, 26 unaffected relatives, and 159 non-narcoleptic sleep patient controls, followed by a reassessment at a mean duration of 37.4 months. Results:The highest prevalence of altered transition from stage non-N2/N3 to stage R in multiple sleep latency test (MSLT) and nocturnal polysomnography (NPSG) was found in patients with type 1 narcolepsy (92.0% and 57.1%), followed by patients with type 2 narcolepsy (69.4% and 12.8%), unaffected relatives (46.2% and 0%), and controls (39.3% and 1.3%). Individual sleep variables had varied sensitivity and specifi city in diagnosing narcolepsy. By incorporating a combination of sleep variables, the decision tree analysis improved the sensitivity to 94.3% and 82.1% and enhanced specifi city to 82.4% and 83% for the diagnosis of type 1 and type 2 narcolepsy, respectively. There was a signifi cant association of DBQ1*0602 with the altered sleep stage transition (OR = 16.0, 95% CI: 1.7-149.8, p = 0.015).

Sleep-stage transitions during polysomnographic recordings as diagnostic features of type 1 narcolepsy

“…A decreased N2 to REM sleep transition feature was also found to be specific for narcolepsy (data not shown), but as it inversely correlated with the SOREMPs at night transition feature and was less predictive, it was not pursued. This is in accordance with the findings of Liu et al [23] who found altered transition from N2/N3 sleep to REM sleep in narcolepsy types 1 and 2 compared with unaffected relatives and controls. By combining sleep variables in a decision tree, they enhanced the sensitivity and specificity of diagnosing narcolepsy types 1 and 2, but they found that the transition measures computed from MSLT were more indicative than those computed from nocturnal PSGs [23].…”

“…This is in accordance with the findings of Liu et al [23] who found altered transition from N2/N3 sleep to REM sleep in narcolepsy types 1 and 2 compared with unaffected relatives and controls. By combining sleep variables in a decision tree, they enhanced the sensitivity and specificity of diagnosing narcolepsy types 1 and 2, but they found that the transition measures computed from MSLT were more indicative than those computed from nocturnal PSGs [23]. However, they did not include a confirmation sample, and it is therefore unclear how their decision tree would perform in a clinical setting.…”

“…Prior studies have shown abnormal sleep-wake transitions during nocturnal sleep in narcoleptics [1,[19][20][21][22][23]. Specifically, Liu et al [23] investigated the diagnostic value of transitions to REM sleep in nocturnal PSGs as well as in MSLT for narcolepsy types 1 and 2. This study not only investigates transitions to REM sleep but also performs an extensive search in various sleep transitions between all sleep stages and thresholds on the total number hereof to identify specific features, which can identify narcolepsy in a clinical setting.…”

Comparison of the macro and microstructure of sleep in a sample of sleep clinic hypersomnia cases

“…Consequently, patients with N-1 often complain of (in addition to cataplexy) disrupted sleep/wake continuity and often display abnormal sleep architecture upon laboratory study. For example, several studies have shown that, compared to controls, N-1 is associated with reduced sleep efficiency, increased wake after sleep onset (WASO), high arousal indices, frequent sleep stage transitions, increased time in “light” sleep (Sorensen et al, 2013, Pizza et al, 2015, Mukai et al, 2003, Khatami et al, 2008, Jiménez-Correa et al, 2009, Frauscher et al, 2011; Roth et al, 2013) and abnormal REM sequencing (Liu et al, 2015, Drakatos et al, 2016). It is also well-documented that N-1 patients have a shortened latency to nocturnal REM, now known to be statistically specific for low or absent hypocretin (Andlauer et al, 2013, Reiter et al, 2015; Cairns and Bogan, 2015).…”

“…Quantitative analyses elucidate high-resolution temporal changes in electroencephalogram (EEG) frequency population that are not adequately reflected using traditional scoring methods (Achermann, 2009). Existing literature on narcolepsy using quantitative analyses suggests impairments in both slow wave activity (SWA) and REM sleep processes including altered REM sequencing (Liu et al, 2015, Drakatos et al, 2016), attenuated circadian organization of REM (Mukai et al, 2003), and potentially hyper-sensitive homeostatic regulation of SWA (Khatami et al, 2008, Khatami et al, 2007, Yun et al, 2017). However, the majority of research has been conducted on narcolepsy with confirmed low or absent hypocretin, and very little is known about the regulation of nocturnal sleep in other hypersomnias, including N-2 and IH.…”