Contemporary Clinical Neuroscience
The Orexin/Hypocretin System
Physiology and Pathophysiology
10.1385/1-59259-950-8:71
Seiji Nishino and Takeshi Sakurai
6. Hypocretin Measurements in the CSF, and Blood and Brain Tissue
Basic and Clinical Applications
Seiji Nishino4
(4) Center for Narcolepsy, Stanford University School of Medicine, Palo Alto, CA
After the discovery of narcolepsy genes in dogs (hypocretin receptor 2) and mice (prepro-orexin) establishing functional assays for hypocretin/oresin status in human cases became a high priority. It is unlikely that these high-penetrant hypocretin-related genes found in animals are involved in most human narcoleptic cases (this was later confirmed by mutation screenings in human narcoleptic subjects including high-risk cases; but functional loss/impairment of hypocretin neurotransmission might be involved.
We therefore initiated hypocretin measures in the blood and cerebrospinal fluid (CSF) using commercially available "125 I radioimmunoassay (RIA)" kits and foudn that hypocretin-1 can be reliably measured in human CSF but not in blood. ... Using these RIA kits, we subsequently found that most human narcolepsy-cataplexy subjects had undetectably low CSF hypocretin levels.
This finding in human CSF was immediately confirmed by several other investigators; undetectably low CSF hypocretin levels were observed in 90-95% of narcolepsy-cataplexy subjects in several ethnic groups. Because of the specificity of low CSF hypocretin levels in neurologic and sleep disorders is high, CSF hypocretin measures will be included in the diagnostic criteria for narcolepsy in the second version of International Classification of Sleep Disorders (ICSD). Narcolepsy is currently diagnosed mostly by clinialc observation and polysomnographic findings (shorter sleep latencies and sleep onset REM periods during multiple sleep latency tests) with the aid of human leukocyte antigen (HLA) typing (HLA DQb1*0602 positive). However, the sensitivity and specificity of these findings for narcolepsy are not high, and the final diagnosis is often delayed for several years after the disease onset. With this new discovery, many patients are likely to receive immediate benefit from this new diagnostic test. The results of CSF hypocretin measures also addressed nosological issues regarding classification of narcolepsy/excessive daytime sleepiness.
Hypocretin Measurements in the CSF, and Blood and Brain Tissue
Basic and Clinical Applications
Book Series Contemporary Clinical Neuroscience
Book The Orexin/Hypocretin System
Publisher Humana Press
DOI 10.1385/1592599508
Copyright 2005
ISBN 978-1-58829-444-9 (Print) 978-1-59259-950-9 (Online)
Part Part III
DOI 10.1385/1-59259-950-8:71
Pages 73-82
Subject Collection Biomedical and Life Sciences
SpringerLink Date Thursday, November 22, 2007
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and the National Institutes of Health