PREDICTORS OF HYPOCRETIN DEFICIENCY IN NARCOLEPSY WITHOUT CATAPLEXY
Predictors of Hypocretin (Orexin) Deficiency in Narcolepsy Without Cataplexy
Olivier Andlauer, MD1,2,3; Hyatt Moore, MSc1; Seung-Chul Hong, MD, PhD4; Yves Dauvilliers, MD5; Takashi Kanbayashi, MD, PhD6; Seiji Nishino, MD, PhD1; Fang Han, MD7; Michael H. Silber, MB, ChB8; Tom Rico, BS1; Mali Einen1; Birgitte R. Kornum, PhD1,9; Poul Jennum, MD9; Stine Knudsen, MD, PhD9; Sona Nevsimalova, MD10; Francesca Poli, MD11; Giuseppe Plazzi, MD11; Emmanuel Mignot, MD, PhD1
1Center for Sleep Sciences and Medicine, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA; 2University Hospital of Besancon, Department of Clinical Psychiatry, F-25000 Besancon, France; 3EA 481 Laboratoire de Neurosciences, University of Franche-Comte, 1 place du maréchal Leclerc, 25030 Besançon Cedex, France; 4Department of Neuropsychiatry, St. Vincent's Hospital, Catholic University of Korea, Suwon, Korea; 5National Reference Network for Narcolepsy, Sleep-Disorders Center, Department of Neurology, Hôpital Gui de Chauliac, Inserm U1061, UM1, Montpellier, France; 6Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan; 7Department of Pulmonary Medicine, Beijing University People's Hospital, Beijing, China; 8Center for Sleep Medicine and the Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN; 9Danish Center for Sleep Medicine, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark; 10Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic; 11Sleep Disorders Center, Department of Neurological Sciences, University of Bologna; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (≤ 110 pg/ml), intermediate (110–200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1.
University-based sleep clinics and laboratories.
Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1.
Design and interventions:
Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis.
Measurements and Results:
The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (≤ 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (≤ 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 ± 0.3 versus 4.4 ± 0.2 min) and more sleep-onset REM periods (3.6 ± 0.1 versus 2.9 ± 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status.
Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF hypocretin-1 in patients with narcolepsy without cataplexy.
Andlauer O; Moore H; Hong SC; Dauvilliers Y; Kanbayashi T; Nishino S; Han F; Silber MH; Rico T; Einen M; Kornum BR; Jennum P; Knudsen S; Nevsimalova S; Poli F; Plazzi G; Mignot E. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. SLEEP 2012;35(9):1247–1255.