Elsevier

Sleep Medicine

Volume 12, Issue 8, September 2011, Pages 768-772
Sleep Medicine

Original Article
Melanin concentrating hormone in central hypersomnia

https://doi.org/10.1016/j.sleep.2011.04.002Get rights and content

Abstract

Background

Narcolepsy with cataplexy (NC) is a disabling disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations, due to a deficient hypocretin/orexin neurotransmission. Melanin concentrating hormone (MCH) neurons involved in the homeostatic regulation of REM sleep are intact. We hypothesized that an increased release of MCH in NC would be partly responsible for the abnormal REM sleep manifestations.

Methods

Twenty-two untreated patients affected with central hypersomnia were included: 14 NC, six idiopathic hypersomnia with long sleep time, and two post-traumatic hypersomnia. Fourteen neurological patients without any sleep disorders were included as controls. Using radioimmunoassays, we measured hypocretin-1 and MCH levels in cerebrospinal fluid (CSF).

Results

The MCH level was slightly but significantly lower in patients with hypersomnia (98 ± 32 pg/ml) compared to controls (118 ± 20 pg/ml). After exclusion of patients affected with post-traumatic hypersomnia the difference became non-significant. We also failed to find any association between MCH level and hypocretin level, the severity of daytime sleepiness, the number of SOREMPs, the frequency of cataplexy, and the presence of hypnagogic hallucinations or sleep paralysis.

Conclusion

This study reports the first measurement of MCH in CSF using radioimmunoassay technology. It appears to be a non-informative tool to differentiate etiologies of central hypersomnia with or without REM sleep dysregulation.

Introduction

Narcolepsy-cataplexy (NC) is a disabling disorder characterized by excessive daytime sleepiness (EDS) and abnormal rapid eye movement (REM) sleep manifestations [1]. These include cataplexy (sudden loss of muscle tone triggered by strong emotions), sleep paralysis, hypnagogic hallucinations, and sleep-onset REM periods (SOREMP). Recent pathophysiological insights have demonstrated that NC is caused by the early loss of hypothalamic neurons producing hypocretin/orexin [2], [3], [4], [5]. A striking decrease in cerebrospinal fluid (CSF) hypocretin-1 concentrations has been noted in most of those patients with a high (94%) positive predictive value for the diagnosis of NC [6], [7]. In addition, NC is one of the diseases most tightly associated with a specific HLA allele, DQB1*0602, found in 85–95% of sporadic patients [1].

In contrast, little is known regarding the pathophysiology of other central hypersomnia, especially narcolepsy without cataplexy, and idiopathic hypersomnia (IH) with long or without long sleep time. It remained difficult in many cases to clinically differentiate patients affected with IH without long sleep time and those with narcolepsy without cataplexy [8]. Despite short latencies, the two latter diagnoses differ mainly on the number of SOREMPs observed on the multiple sleep latency tests (MSLT). Another chronic central hypersomnia etiology may be diagnosed in a context of a traumatic brain injury. Indeed, a recent prospective study has reported frequent hypersomnia following traumatic brain injury with the rare occurrence of REM sleep manifestations [9]. In contrast to NC, no biological or genetic tools have helped to understand and differentiate those central hypersomnias.

Melanin concentrating hormone (MCH) neurons localized within the same hypothalamic areas as hypocretin neurons are intact in patients with NC, as shown in post-mortem samples [4], [10]. It is interesting to note that hypocretin and MCH neuropeptides are involved in similar physiological functions but often in an antagonistic way. Hypocretins promote wakefulness [11] while MCH induces REM sleep [12] (for review [13]). In vivo electrophysiological recordings showed that hypocretin neurons are active during waking [14], [15] while MCH neurons are active during REM sleep [16]. Furthermore, neurotransmitters involved in wakefulness such as noradrenalin, serotonin and acetylcholine exert a direct inhibitory action on MCH neurons [17], [18], [19]. As decreased hypocretinergic and monoaminergic tones have been described in NC [20], a lack of inhibition of MCH neurons may occur with an increased release of MCH neuropeptide as a consequence. CSF hypocretin-1 levels represent a major biological tool to diagnose NC. We hypothesize that CSF MCH levels may be an additional interesting biological marker involved in central hypersomnia with high REM sleep pressure.

The aim of the present study was to compare hypocretin and MCH CSF levels between patients with NC, patients affected with central hypersomnia without REM sleep dysregulation, and neurological controls.

Section snippets

Patients

Twenty-two unrelated patients (mean age at 39.4 ± 14.9, range from 12 to 58 years old) were included with a central hypersomnia diagnosis according to revised criteria [21]. All patients underwent one night of polysomnographic recording followed by the MSLT in the sleep laboratory as required in ICSD-2 [21]. Patients also filed a sleep diary with a particular focus on assessing good sleep hygiene the week before the polysomnography recording in order to avoid sleep deprivation and large variation

Results

Table 1 presents demographic, clinical, biological and sleep characteristics of patients with hypersomnia and neurological controls. Between-group comparison revealed a significantly higher severity of objective sleepiness in NC compared to patients with IH and post-traumatic hypersomnia (p < 0.01). CSF hypocretin-1 levels were significantly lower in patients with NC compared to patients with IH and post-traumatic hypersomnia (p < 0.0001).

We found 98 ± 32 pg/ml of MCH-ir in CSF of patients affected

Discussion

The present study reports the first measurement of human CSF level of MCH-ir in patients affected with central hypersomnia compared to neurological controls. We found a slight but significantly lower CSF MCH-ir level in patients with hypersomnia compared to controls, results becoming non-significant after exclusion of patients with post-traumatic hypersomnia from analysis.

We included patients with separate clear-cut central hypersomnia diagnosis only, avoiding narcolepsy without cataplexy and

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.04.002.

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Acknowledgments

The authors would like to thank Rachida Rabilloud for her advice and technical help. This study was financially supported by CNRS, Université Claude Bernard-Lyon1. LH was supported by the French Ministry of Research.

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