Original articleThe narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A)
Introduction
Human narcolepsy is a neurological disorder characterized by hypersomnia, cataplexy, sleep paralysis and hypnagogic hallucinations [1]. This full tetrad of symptoms is present in only a minority of narcoleptic patients, and cataplexy is the only pathognomonic symptom of narcolepsy. Biological markers of narcolepsy include sleep-onset REM periods (SOREM) on multiple sleep latency tests (MSLT) and DR2/DQB1*0602 positivity on HLA-typing, which may however be absent in some patients with the disorder [1].
In the absence of a gold standard for the diagnosis of narcolepsy, the definition of its clinical borderland – and in particular the differentiation between such entities as narcolepsy without cataplexy, idiopathic hypersomnia and hypersomnia associated with psychiatric disturbances – remains a matter of controversy [2], [3].
Hypocretins are peptides, synthesized by neurons in the posterior and lateral hypothalamus, which have widespread projections within the brain and have been implicated in sleep-wake functions, feeding and metabolic control [4]. Recent studies suggest a dysfunction of the newly described hypocretin (orexin) neurotransmitter system in narcolepsy. First, positional cloning has identified hypocretin-receptor-2 gene mutations as the cause of narcolepsy in dogs and orexin knockout mice have a narcolepsy-like phenotype [5], [6]. Second, a mutation was found in one of 74 tested human patients and a polymorphism in the prehypocretin gene in six of 178 patients [7], [8]. Third, hypocretin-1 was found to be low or absent in the CSF of >90% of patients with classical narcolepsy (narcolepsy with cataplexy) [9]. In a recent study Ripley et al. confirmed these results, reporting levels of CSF hypocretin-1 <100 pg/ml in 37 of 42 patients with narcolepsy [11]. Fourth, an 85–95% reduction of hypocretin neuronal expression was demonstrated post mortem in the brains of patients with narcolepsy with cataplexy [7], [12]. Finally, an increased body mass index (BMI) and CSF leptin levels were described in narcoleptics, suggesting an altered regulation of food intake and/or metabolism [10], [13].
The aim of the study was twofold. First, we wanted to test the hypothesis that CSF hypocretin-1 is reduced also in narcoleptic patients without cataplexy (so-called monosymptomatic narcolepsy) and in patients with other forms of (mainly) neurological hypersomnia, which belong to the borderland of narcolepsy. Second, we wanted to assess the diagnostic value of a multimodal approach including clinical, electrophysiological, genetic, BMI and CSF leptin data in this same patient group.
Preliminary results of this work have been presented before [14]. A few patients reported here were included in a multicenter study [15].
Section snippets
Subjects and methods
We studied 27 consecutive Caucasian patients (12 women and 15 men; mean age 38 years, range 16–53) with hypersomnia of variable etiology. The main diagnoses (see also Table 1) included narcolepsy with cataplexy (classical narcolepsy, n=3), symptomatic narcolepsy following Bickerstaff's encephalitis (n=1), narcolepsy without cataplexy (n=4), idiopathic hypersomnia (n=5), hypersomnia associated with psychiatric disorders (n=6), HIV-encephalopathy (n=1), brainstem stroke (n=2), periodic
Results
The main results of the study are summarized in Table 1.
Hypocretin-1 (orexin A) levels in the cerebrospinal fluid
Hypocretin-1 levels in the cerebrospinal fluid, and therefore hypocretin transmission, were not deficient in patients with hypersomnia without cataplexy, including monosymptomatic narcolepsy and idiopathic hypersomnia. In other words, the loss of hypocretin neurons in the lateral hypothalamus may be relevant only for narcoleptics with cataplexy, but not necessarily for narcoleptics without cataplexy and patients with other hypersomnolent syndromes of (presumed) neurological origin. Recent
Note
After the submission of this work a paper by Kanbayashi et al. was published reporting normal (n=14) or intermediate (152–198 pg/ml, n=3) levels of CSF hypocretin-1 (orexin A) in a series of Japanese patients with narcolepsy without cataplexy (n=5) and idiopathic hypersomnia (n=12) (J Sleep Res 2002;11:91–3).
Acknowledgements
Dr. M. Okun helped in coordinating the collection and shipping of the CSF samples. Dr. J. Gottselig reviewed the English text of the paper.
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