Low hypocretin levels are also observed in a large range of other neurological conditions. In these disorders the alteration of the hcrt level may reflect focal lesions in the hypothalamus or transient or chronic dysfunction of the hypothalamus.
4.1. Kleine-Levin Syndrome (KLS)
KLS is a rare cause of hypersomnia characterized by a recurrent alteration of sleep-wake regulation and frequent abnormal feeding and sexual behaviors. Recent association reported with HLA DQB1*0201 together with the young age of onset, the recurrence of symptoms, and the frequent infectious precipitating factors suggest an autoimmune etiology for KLS.14 Since the role of hypocretin neuropeptides in both feeding behavior and sleep-wake regulation is now well established, an abnormality of the hypocretin neurotransmission has been proposed in KLS patients. CSF hypocretin-1 has been measured in few cases with normal results for most of them (5 out of 6).11,14,28 However, the most striking finding is the two fold decrease in CSF hypocretin-1 level during the symptomatic episode in the only case with CSF available during both asymptomatic and symptomatic period, suggesting a possible intermittent alteration of the hypocretin system.14 We may suggest a focal, transient, and immune-modulated process in the hypothalamic hypocretin system in KLS, resulting in altered hypocretin neurotransmission only during symptomatic episodes.
Prader Willi syndrome is a complex genetic disorder characterized by hypotonia, short stature, hypogonadism, mental retardation, behavioral troubles and hyperphagia, which result in excessive obesity. Intermediate CSF hypocretin levels have been reported in the literature in two cases of Prader-Willi syndrome.11,14 This finding might represent a biological marker of this syndrome that could be also associated with Kleine-Levin syndrome.
Niemann-Pick disease type C is an inherited metabolic disorder in which harmful quantities of a fatty substance accumulate in several tissues including the brain. Subjects with Niemann-Pick disease type C have been reported to display narcolepsy like symptoms, including cataplexy. CSF hypocretin-1 levels were measured in four patients with short mean sleep latencies on the MSLT for three patients and sleep onset REM periods in one patient with cataplexy and HLA DQB1*0602 positive. CSF hypocretin-1 levels were reduced in 2 patients including one patient with cataplexy while, in the 2 other patients, the levels were at the lower range of the normal values. Those findings suggest that lysosomal storage abnormalities that are involved in the physiopathology of the disease may alter the functioning of the hypothalamus and, more specifically, hypocretin-containing cells. The hypocretin system dysfunction observed may explain the sleep abnormalities and cataplexy reported in Niemann-Pick disease type C.29
Myotonic dystrophy type 1 is a multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment caused by a CTG triplet expansion in the 3' untranslated region of the DMPK gene on 19q13. Myotonic dystrophy type 1 is frequently associated with an excessive daytime sleepiness in particular a short sleep latency and the presence of sleep onset REM periods during the MSLT, two characteristics observed in narcolepsy. CSF hypocretin-1 levels were measured in 7 patients in the literature with a mean average of CSF hcrt-1 significantly lower than that in normal controls.14,30 However, the significance of this latter result needs to be confirmed on a larger sample because only one patient had a low level and three had intermediate levels. Hypocretin-1 levels did not correlate clinically with disease severity or duration or with subjective or objective sleepiness reports. We therefore may propose that a dysfunction of the hypothalamic hypocretin system may mediate sleepiness and abnormal regulation of REM in a subgroup of patients with myotonic dystrophy type 1.
A low level of CSF hypocretin-1 has been reported in several cases of alteration of the hypothalamus. For example, a decreased CSF hypocretin level was reported in a hypersomnia case after hypothalamic tumor removal31 as well as in a young man who developed narcolepsy after a large hypothalamic stroke.32 In contrast, a 60-year-old man with acromegaly, who developed narcolepsy with cataplexy two weeks after completing radiotherapy for a pituitary adenoma had normal CSF hypocretin-1 levels,33 indicating that other factors may be important in the development of this condition.
We may therefore hypothesize that a loss of orexin neurons or their relevant targets may underlie the neuropathology of several secondary cases of excessive daytime sleepiness with or without cataplexy. In addition, a common hypothalamic, hypocretin-independent dysfunction may also be present in some of hypersomnia conditions.
Parkinson's disease (PD) is a neurodegenerative disease, mainly of the dopaminergic cells, and is a movement disorder characterized by tremor, rigidity and bradykynesia. Sleep disturbances are frequently observed in PD characterized by difficulties to maintain sleep and excessive daytime sleepiness. Recent attention focused on this latter symptom to report more specifically 'sleep attacks' that can be induced by all dopaminergic drugs. The dopaminergic ventral tegmental area and substantia nigra is one the main target of the hypocretins. Dopamine and hypocretins have both a crucial role in control of arousal34-36 and the projections of these two arousal-related systems, originating in distinct brain areas, jointly target several forebrain regions and brainstem monoaminergic nuclei involved in regulating motivational processes.37 Because an alteration of the hypocretinergic system might major the excessive daytime sleepiness related to dopamine deficiency and because it is not known whether dopamine projections may influence in return the hypocretin tone, several studies examined CSF hcrt-1 levels in PD patients and controls.11'14'38'39 Two of them focused on the relation ship between the disease characteristics and the hcrt levels. Overeem et al.,38 reported normal lumbar CSF hypocretin-1 levels in a few mild PD patients with excessive daytime somnolence whereas, on a larger sample, Drouot et al.,39 showed low levels of ventricular CSF hypocretin-1 in advanced form of the disease as compared to neurological controls. Despite the methodological differences, this discrepancy might be explained by the fact that hcrt levels may be altered only in a restrictive subgroup of PD patients; especially in advanced forms when a highly developed degenerative process may extend to hypocretin neurons. Further studies focusing on hypocretins in different forms of the disease are required in order to determine whether a subgroup of patients40 display low level of hctr and whether these low levels would be related to an hcrt cell degeneration, which would need to be considered for the therapeutic management of these patients.
Restless legs syndrome is a common disorder (5 to 15% of the general population) characterized by dysesthesias in the legs occurring mainly at night and accompanied by a compelling urge to move the legs leading often the patient to walk. Most patients also have periodic leg movements during sleep that are associated with microarousals leading to sleep fragmentation and excessive daytime somnolence in many cases. The cause of the disease still remains unknown except secondary cases due to iron deficiency, side effects of certain drugs, peripheral neuropathies, uremia or others. The efficiency of L-dopa and D2/D3 agonists for the treatment of RLS as well as PLM suggests the involvement of the dopaminergic system in the pathophysiology of the disease. Hypocretins are wakefulness promoting peptides and stimulate the dopaminergic neurons, both systems providing joint innervation to arousal systems. There is no consensus on hcrt levels in RLS. Allen et al., first reported increase CSF levels of hcrt-1 in the early-onset form of the disease that have a high familial aggregation and slow evolution as compared to the late-onset form that is associated with progressive severity and low familial aggregation.41 This result has not been confirmed in two other studies.11,42 They did not find any correlation with the severity of the RLS or PLM or sleep parameters. One possible explanation for the lack of replication of this result might be due to an alteration of the hcrt neurotransmission only in a time-fashion during the symptomatic period of the day, which might explain the differences between the studies since the collection of samples were performed at different time of the day. Further explorations are needed in order to test this hypothesis.
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