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From the Stanford University Center for Narcolepsy (Drs. Fujiki, Hungs, Mignot, and Nishino, and B. Ripley), Palo Alto, CA; Department of Neurology and Clinical Neurophysiology (Dr. Lammers, S. Overeem, and F.W.C. Roelandse), Leiden University Medical Center, Leiden, the Netherlands; Department of Neurology (Dr. Nevsimalova), 1st Medical Faculty, Charles University, Prague, Czech Republic; Department of Neurology (Drs. Uchino and Nishida), Kumamoto University, School of Medicine, Kumamoto, Japan; Department of Veterans Affairs Medical Center (Dr. Yesavage), Palo Alto, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA; The Parkinson’s Institute (Dr. Monte), Sunnyvale, CA; Department of Neurosurgery and Anatomy (Dr. Dohi), Showa University, School of Medicine, Shinagawa, Japan; and Department of Neuroscience (Dr. Melberg), Neurology, University Hospital, Uppsala, Sweden.
Address correspondence and reprint requests to Dr. Seiji Nishino, Stanford University, Center for Narcolepsy, 701B Welch Road, Rm 142, Palo Alto, CA 94304; e-mail: nishino{at}stanford.edu
Objective: To examine the specificity of low CSF hypocretin-1 levels in narcolepsy and explore the potential role of hypocretins in other neurologic disorders.
Methods: A method to measure hypocretin-1 in 100 µL of crude CSF sample was established and validated. CSF hypocretin-1 was measured in 42 narcolepsy patients (ages 16–70 years), 48 healthy controls (ages 22–77 years,) and 235 patients with various other neurologic conditions (ages 0–85 years).
Results: As previously reported, CSF hypocretin-1 levels were undetectably low (<100 pg/mL) in 37 of 42 narcolepsy subjects. Hypocretin-1 levels were detectable in all controls (224–653 pg/mL) and all neurologic patients (117–720 pg/mL), with the exception of three patients with Guillain–Barré syndrome (GBS). Hypocretin-1 was within the control range in most neurologic patients tested, including patients with AD, PD, and MS. Low but detectable levels (100–194 pg/mL) were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, CNS infections, and GBS.
Conclusions: Undetectable CSF hypocretin-1 levels are highly specific to narcolepsy and rare cases of GBS. Measuring hypocretin-1 levels in the CSF of patients suspected of narcolepsy is a useful diagnostic procedure. Low hypocretin levels are also observed in a large range of neurologic conditions, most strikingly in subjects with head trauma. These alterations may reflect focal lesions in the hypothalamus, destruction of the blood brain barrier, or transient or chronic hypofunction of the hypothalamus. Future research in this area is needed to establish functional significance.
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