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Original Investigation |

Nocturnal Rapid Eye Movement Sleep Latency for Identifying Patients With Narcolepsy/Hypocretin Deficiency

Olivier Andlauer, MD1,3,4; Hyatt Moore, IV, MSc1; Laura Jouhier, MD5; Christopher Drake, PhD6; Paul E. Peppard, PhD7; Fang Han, MD8; Seung-Chul Hong, MD, PhD9; Francesca Poli, MD10; Giuseppe Plazzi, MD10; Ruth O’Hara, PhD1,2; Emmanuel Haffen, MD, PhD3,4; Thomas Roth, PhD6; Terry Young, PhD7; Emmanuel Mignot, MD, PhD1
[+] Author Affiliations
1Center for Sleep Sciences and Medicine and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California
2Department of Veterans Affairs Health Care System, Palo Alto, California
3Department of Clinical Psychiatry, University Hospital of Besancon, and Technological Innovation Clinical Investigation Center (INSERM CIC-IT 808), Besancon, France
4EA 481 Laboratoire de Neurosciences, University of Franche-Comte, Besancon, France
5Universite Paris Descartes, Faculte de medecine, Paris, France
6Henry Ford Sleep Disorders Center, Detroit, Michigan
7Department of Population Health Sciences, University of Wisconsin–Madison, Madison
8Department of Pulmonary Medicine, Beijing University People’s Hospital, Beijing, China
9Department of Neuropsychiatry, St Vincent’s Hospital, Catholic University of Korea, Suwon, Korea
10Sleep Disorders Center, Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy
JAMA Neurol. 2013;70(7):891-902. doi:10.1001/jamaneurol.2013.1589.
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Importance  Narcolepsy, a disorder associated with HLA-DQB1*06:02 and caused by hypocretin (orexin) deficiency, is diagnosed using the Multiple Sleep Latency Test (MSLT) following nocturnal polysomnography (NPSG). In many patients, a short rapid eye movement sleep latency (REML) during the NPSG is also observed but not used diagnostically.

Objective  To determine diagnostic accuracy and clinical utility of nocturnal REML measures in narcolepsy/hypocretin deficiency.

Design, Setting, and Participants  Observational study using receiver operating characteristic curves for NPSG REML and MSLT findings (sleep studies performed between May 1976 and September 2011 at university medical centers in the United States, China, Korea, and Europe) to determine optimal diagnostic cutoffs for narcolepsy/hypocretin deficiency compared with different samples: controls, patients with other sleep disorders, patients with other hypersomnias, and patients with narcolepsy with normal hypocretin levels. Increasingly stringent comparisons were made. In a first comparison, 516 age- and sex-matched patients with narcolepsy/hypocretin deficiency were selected from 1749 patients and compared with 516 controls. In a second comparison, 749 successive patients undergoing sleep evaluation for any sleep disorders (low pretest probability for narcolepsy) were compared within groups by final diagnosis of narcolepsy/hypocretin deficiency. In the third comparison, 254 patients with a high pretest probability of having narcolepsy were compared within group by their final diagnosis. Finally, 118 patients with narcolepsy/hypocretin deficiency were compared with 118 age- and sex-matched patients with a diagnosis of narcolepsy but with normal hypocretin levels.

Main Outcome and Measures  Sensitivity and specificity of NPSG REML and MSLT as diagnostic tests for narcolepsy/hypocretin deficiency. This diagnosis was defined as narcolepsy associated with cataplexy plus HLA-DQB1*06:02 positivity (no cerebrospinal fluid hypocretin-1 results available) or narcolepsy with documented low (≤ 110 pg/mL) cerebrospinal fluid hypocretin-1 level.

Results  Short REML (≤15 minutes) during NPSG was highly specific (99.2% [95% CI, 98.5%-100.0%] of 516 and 99.6% [95% CI, 99.1%-100.0%] of 735) but not sensitive (50.6% [95% CI, 46.3%-54.9%] of 516 and 35.7% [95% CI, 10.6%-60.8%] of 14) for patients with narcolepsy/hypocretin deficiency vs population-based controls or all patients with sleep disorders undergoing a nocturnal sleep study (area under the curve, 0.799 [95% CI, 0.771-0.826] and 0.704 [95% CI, 0.524-0.907], respectively). In patients with central hypersomnia and thus a high pretest probability for narcolepsy, short REML remained highly specific (95.4% [95% CI, 90.4%-98.3%] of 132) and similarly sensitive (57.4% [95% CI, 48.1%-66.3%] of 122) for narcolepsy/hypocretin deficiency (area under the curve, 0.765 [95% CI, 0.707-0.831]). Positive predictive value in this high pretest probability sample was 92.1% (95% CI, 83.6%-97.0%).

Conclusions and Relevance  Among patients being evaluated for possible narcolepsy, short REML (≤15 minutes) at NPSG had high specificity and positive predictive value and may be considered diagnostic without the use of an MSLT; absence of short REML, however, requires a subsequent MSLT.

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Figures

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Figure 1.
Overlaid Histograms of Rapid Eye Movement Sleep Latency (REML) Distributions for Narcoleptic Cases and Controls

A, Distribution of REML of 15 minutes or less. B, Distribution of REML more than 15 minutes (y-axis has been scaled up). Each bar represents the frequency for a 5-minute REML range.

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Figure 2.
Receiver Operating Characteristic Curves of Comparisons 1a, 1b, 1, 2, 3, and 4

A, Receiver operating characteristic curves in 89 patients with narcolepsy with low cerebrospinal fluid (CSF) hypocretin-1 levels vs 89 controls (comparison 1a), 427 patients with narcolepsy with cataplexy and HLA-DQB1*06:02 positivity vs 427 controls (comparison 1b), and 516 patients with narcolepsy with either low CSF hypocretin-1 levels or cataplexy and HLA-DQB1*06:02 positivity vs 516 controls (comparison 1). In patients with low CSF hypocretin-1 levels (comparison 1a), the optimal cutoff was a rapid eye movement sleep latency (REML) of 17 minutes or less (specificity, 97.8% [95% CI, 92.1-99.7]; sensitivity, 44.9% [95% CI, 34.4-55.9]; area under the curve [AUC], 0.704 [95% CI, 0.625-0.786]); in patients with cataplexy and HLA-DQB1*06:02 positivity (comparison 1b), the optimal cutoff was an REML of 21 minutes or less (specificity, 99.5% [95% CI, 98.3-99.9]; sensitivity, 53.9% [95% CI, 49.0-58.7]; AUC, 0.820 [95% CI, 0.789-0.850]). An REML of 18 minutes or less (specificity, 99.2% [95% CI, 98.5-100.0]; sensitivity, 51.6% [95% CI, 47.2-55.9]) was the best cutoff for optimal specificity in comparison 1 (AUC, 0.799 [95% CI, 0.771-0.826]). These results were virtually identical. B, Receiver operating characteristic curves in 14 patients with narcolepsy/hypocretin deficiency vs 735 patients with other sleep disorders (comparison 2), 122 patients with narcolepsy/hypocretin deficiency vs 132 patients with narcolepsy without hypocretin deficiency, idiopathic hypersomnia, and Kleine-Levin syndrome (high pretest probability sample, comparison 3), and 118 patients with narcolepsy with low CSF hypocretin-1 levels vs 118 patients with narcolepsy with normal CSF hypocretin-1 levels (comparison 4). In comparison 2, an REML of 16 minutes or less (specificity, 99.6% [95% CI, 99.1-100.0]; sensitivity, 42.9% [95% CI, 16.9-68.8]) was the best cutoff for the diagnosis of narcolepsy/hypocretin deficiency vs other sleep disorders (AUC, 0.704 [95% CI, 0.524-0.907]). In comparison 3, an REML of 17 minutes or less (specificity, 95.5% [95% CI, 90.4-98.3]; sensitivity, 58.2% [95% CI, 48.9-67.1]) was the best cutoff for the diagnosis of narcolepsy with low CSF hypocretin-1 levels vs narcolepsy with normal hypocretin-1 levels, idiopathic hypersomnia, and Kleine-Levin syndrome (AUC, 0.765 [95% CI, 0.707-0.831]). In comparison 4, an REML of 8 minutes or less (specificity, 87.3% [95% CI, 81.3-93.3]; sensitivity, 44.1% [95% CI, 35.1-53.0]) was the best cutoff for the diagnosis of narcolepsy with low CSF hypocretin-1 levels vs narcolepsy with normal CSF hypocretin-1 levels (AUC, 0.628 [95% CI, 0.558-0.702]).

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