The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A).
OBJECTIVE
Biological markers of narcolepsy with cataplexy (classical narcolepsy) include sleep-onset REM periods (SOREM) on multiple sleep latency tests (MSLT), HLA-DQB1*0602 positivity, low levels of cerebrospinal fluid (CSF) hypocretin-1 (orexin A), increased body mass index (BMI), and high levels of CSF leptin. The clinical borderland of narcolepsy and the diagnostic value of different markers of narcolepsy remain controversial and were assessed in a consecutive series of 27 patients with hypersomnia of (mainly) neurological origin.


METHODS
Diagnoses included classical narcolepsy (n=3), symptomatic narcolepsy (n=1), narcolepsy without cataplexy (n=4), idiopathic hypersomnia (n=5), hypersomnia associated with psychiatric disorders (n=5), and hypersomnia secondary to neurological disorders or of undetermined origin (n=9). Clinical assessment included BMI, Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), and history of REM-symptoms (sleep paralysis, hallucinations). HLA-typing, electrophysiological studies (conventional polysomnography, MSLT, 1-week actigraphy), and measurements of CSF levels of hypocretin and leptin were also performed.


RESULTS
Hypocretin-1 was undetectable in three patients with classic narcolepsy and detectable in the remaining 24 patients. Other narcoleptic markers also frequently found in patients without narcolepsy included ESS>14 (78% of 27 patients), UNS>14 (75%), REM symptoms (30%), sleep latencies on MSLT<5 min (41%), >/=2 SOREM (30%), DQB1*0602 positivity (52%), BMI>25 (52%), and increased CSF leptin (48%). Hypersomnia was documented by an increased time 'asleep' in 41% of patients. Overlapping clinical and electrophysiological findings were seen mostly in patients with narcolepsy without cataplexy, idiopathic hypersomnia, and psychiatric hypersomnia.


CONCLUSIONS
(1) Hypocretin dysfunction is not the 'final common pathway' in the pathophysiology of most hypersomnolent syndromes that fall on the borderline for a diagnosis of narcolepsy. (2) The observed overlap among these hypersomnolent syndromes implies that current diagnostic categories are not entirely unambiguous. (3) A common hypothalamic, hypocretin-independent dysfunction may be present in some of these syndromes.
Bassetti
Claudio
C
Department of Neurology, University Hospital, Bern, Switzerland. claudio.bassetti@nos.usz.ch
Gugger
Matthias
M
Bischof
Matthias
M
Mathis
Johannes
J
Sturzenegger
Christian
C
Werth
Esther
E
Radanov
Bogdan
B
Ripley
Beth
B
Nishino
Seiji
S
Mignot
Emmanuel
E
D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002352:Carrier Proteins / Q000134:cerebrospinal fluid*; D003937:Diagnosis, Differential; D006970:Disorders of Excessive Somnolence / Q000175:diagnosis; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D015802:HLA-DR2 Antigen / Q000235:genetics; D006650:Histocompatibility Testing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009290:Narcolepsy / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000503:physiopathology; D009479:Neuropeptides / Q000134:cerebrospinal fluid* / Q000172:deficiency; D000068797:Orexins; D017286:Polysomnography; D012494:Sampling Studies; D012720:Severity of Illness Index
D015415:Biomarkers; D002352:Carrier Proteins; C000596229:HCRT protein, human; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D015802:HLA-DR2 Antigen; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D000068797:Orexins