Validation of the ICSD-2 criteria for CSF hypocretin-1 measurements in the diagnosis of narcolepsy in the Danish population.
OBJECTIVE
The International Classification of Sleep Disorders (ICSD-2) criteria for low CSF hypocretin-1 levels (CSF hcrt-1) still need validation as a diagnostic tool for narcolepsy in different populations because inter-assay variability and different definitions of hypocretin deficiency complicate direct comparisons of study results.


METHODS
Interviews, polysomnography, multiple sleep latency test, HLA-typing, and CSF hcrt-1 measurements in Danish patients with narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwC), CSF hcrt-1 measurements in other hypersomnias, neurological and normal controls. Comparisons of hypocretin deficiency and frequency of HLA-DQB1*0602-positivity in the Danish and eligible NC and NwC populations (included via MEDLINE search), by (re)calculation of study results using the ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean).


RESULTS
In Danes, low CSF hcrt-1 was present in 40/46 NC, 3/14 NwC and 0/106 controls (P < 0.0001). Thirty-nine of 41 NC and 4/13 NwC patients were HLA-DQB1*0602-positive (P < 0.01). Hypocretin-deficient NC patients had higher frequency of cataplexy, shorter mean sleep latency, more sleep onset REM periods (P < 0.05) and more awakenings (NS) than did NC patients with normal CSF hcrt-1. Across populations, low CSF hcrt-1 and HLA-DQB1*0602-positivity characterized the majority of NC (80% to 100%, P = 0.53; 80% to 100%, P = 0.11) but a minority of NwC patients (11% to 29%, P = 0.75; 29% to 89%, P = 0.043).


CONCLUSIONS
The study provides evidence that hypocretin deficiency causes a more severe NC phenotype. The ICSD-2 criterion for low CSF hcrt-1 (< 30% of normal mean) is valid for diagnosing NC, but not NwC. HLA-typing should precede CSF hcrt-1 measurements because hypocretin deficiency is rare in HLA-DQB1*0602-negative patients.
Knudsen
Stine
S
Danish Center for Sleep Medicine, University of Copenhagen, Glostrup Hospital, Glostrup, Denmark. stine.knudsen@dadlnet.dk
Jennum
Poul J
PJ
Alving
Jørgen
J
Sheikh
Søren Paludan
SP
Gammeltoft
Steen
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D002385:Cataplexy / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D003718:Denmark; D006970:Disorders of Excessive Somnolence / Q000134:cerebrospinal fluid / Q000175:diagnosis; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006801:Humans; D002534:Hypoxia, Brain / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics; D038801:International Classification of Diseases; D047908:Intracellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid*; D017593:Kleine-Levin Syndrome / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009290:Narcolepsy / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000235:genetics; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000235:genetics; D009479:Neuropeptides / Q000134:cerebrospinal fluid*; D000068797:Orexins; D010641:Phenotype; D017286:Polysomnography; D012016:Reference Values; D055815:Young Adult
C000596229:HCRT protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D000068797:Orexins