Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy

Abstract

Study objectives: 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.

Setting: University-based sleep clinics and laboratories.

Patients: 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.

Conclusion: 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.

Keywords: Hypocretin; MSLT; REM latency; low CSF-hypocretin-1; narcolepsy without cataplexy; polysomnography.

Figure 1

Receiver operating characteristic curve for cerebrospinal fluid (CSF) hypocretin-1 levels as a predictor of narcolepsy without cataplexy (171 narcolepsy without cataplexy patients versus 170 control patients). The circle highlights the best CSF-hypocretin-1 (≤ 202 pg/ml) cutoff point.

Figure 2

Survival (Kaplan-Meier) curve of patients by cerebrospinal fluid (CSF) hypocretin-1 concentration according to their cataplexy status. Hcrt: CSF hypocretin-1.