12, 13 A mean sleep latency (MSL) of less than or equal to 8 min and the observation of at least 2 sleep onset rapid eye movement periods (SOREMPs) during MSLT were established as diagnostic criteria for narcolepsy using patient groups containing a large majority of patient with cataplexy. 10, 11 After the discovery that many patients enter rapid eye movement (REM) sleep rapidly upon falling asleep, a rare occurrence in control patients, the Multiple Sleep Latency Test (MSLT) was developed as a diagnostic tool for the condition. Patients suffering from narcolepsy-cataplexy also demonstrate disturbed nocturnal sleep with frequent awakenings, although total sleep time over the 24-hr period is generally within the normal range. The classic tetrad for narcolepsy includes excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. 5 Prevalence for narcolepsy-cataplexy is established at 0.02-0.05% in the United States, Western Europe, and Korea. 3, 4 Hypocretin deficiency can be tested by measuring cerebrospinal fluid (CSF) concentrations of hypocretin-1, one third of normal values or 110 pg/ml being the most optimal cutoff based on receiver operating characteristics curve analysis. 1, 2 Until recently, most narcolepsy studies have focused on narcolepsy with cataplexy, an etiologically homogenous disorder tightly associated with hypocretin deficiency and HLA-DQB1*06:02 positivity. Narcolepsy without cataplexy is a complex, heterogeneous disorder. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status. 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. Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. 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). 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. ![]() 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. Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (≤ 110 pg/ml) of CSF hypocretin-1. 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%).
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