Original ArticleMelanin concentrating hormone in central hypersomnia
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.
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.
References (32)
- et al.
Narcolepsy with cataplexy
Lancet
(2007) - et al.
Reduced number of hypocretin neurons in human narcolepsy
Neuron
(2000) - et al.
Role of the melanin-concentrating hormone neuropeptide in sleep regulation
Peptides
(2009) - et al.
Behavioral correlates of activity in identified hypocretin/orexin neurons
Neuron
(2005) - et al.
Opposite effects of noradrenaline and acetylcholine upon hypocretin/orexin versus melanin concentrating hormone neurons in rat hypothalamic slices
Neuroscience
(2005) - et al.
Physiological properties of hypothalamic MCH neurons identified with selective expression of reporter gene after recombinant virus infection
Neuron
(2004) - et al.
Pharmacological aspects of human and canine narcolepsy
Prog Neurobiol
(1997) - et al.
Relationship between CSF hypocretin levels and hypocretin neuronal loss
Exp Neurol
(2003) - et al.
Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy
Neurology
(2005) - et al.
Concomitant loss of dynorphin, NARP, and orexin in narcolepsy
Neurology
(2005)