Validation of the ICSD-2 Criteria for CSF Hypocretin-1 Measurements in the Diagnosis of Narcolepsy in the Danish Population

NARCOLEPSY WITH CATAPLEXY (NC) IS CAUSED BY ALMOST COMPLETE LOSS OF HYPOCRETIN (OREXIN) NEURONS IN THE HYPOTHALAMUS. THESE NEURONS produce the sleep-wake and REM sleep-regulating neuropeptides hypocretin-1 and hypocretin-2 (orexin-A and orexin-B).1, 2 Several studies have detected a low level of hypocretin-1 in the cerebrospinal fluid (CSF hcrt-1) in the majority of NC patients as well as in some patients with narcolepsy without cataplexy (NwC). Thus, determination of CSF hcrt-1 may be of diagnostic value for narcolepsy, and it has been included as a diagnostic tool in the current International Classification of Sleep Disorders (ICSD-2).3 However, the prevalence of low CSF hcrt-1 seems to vary greatly between studied populations: 77%4 to 94%5 in NC patients and 11%6 to 38%7 in NwC patients. This may reflect true between-population differences, but this is difficult to determine mainly because of different study definitions of low and normal CSF hcrt-1 levels and the great inter-assay variability of the CSF hcrt-1 radioimmunoassay. Hypocretin-deficient patients often carry the HLA-DQB1*0602-allele,8 so different HLA-DQB1*0602 frequencies in the study populations might also contribute to the variation observed. Direct extrapolation of study results from different sleep laboratories has therefore not yet been possible. Hence, the ICSD-2 criterion for low CSF hcrt-1 still needs to be validated in different populations. We aimed to (1) characterize the relationship between the clinical profile, the paraclinical profile (sleep investigations, HLA-type), and the ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean) in a Danish population consisting of patients with narcolepsy with or without cataplexy, other hypersomnias, neurological disorders, and normal controls; and (2) recalculate the CSF hcrt-1 results of all eligible NC and NwC populations (identified by MEDLINE search) according to the ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean), and then directly compare all study results.