Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system

Center for Narcolepsy, Stanford University, Palo Alto, CA 94304, USA.
Sleep Medicine Reviews (Impact Factor: 8.51). 09/2005; 9(4):269-310. DOI: 10.1016/j.smrv.2005.03.004
Source: PubMed


Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.

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    • "Genuine multiplex families (with several generations affected) are very rare (Hor et al., 2011). Some neurological diseases, such as multiple sclerosis (MS) and acute disseminated encephalomyelitis can cause focal lesions in the hypothalamus and, thus, symptomatic narcolepsy demonstrating that an autoimmune mechanism can damage the hypocretin system (Kanbayashi et al., 2001; Nishino and Kambayashi, 2005). Early 1980s studies on the genetics of narcolepsy found an association with two HLA class II antigens, DR2 and DQ1. "
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    ABSTRACT: Evidence suggests that autoimmune diseases tend to co-occur so that patients with an autoimmune disorder are at higher risk of a second autoimmune disease. The association between allergic and autoimmune diseases is also of considerable interest. There are no reports on the association between sporadic or familial narcolepsy with cataplexy and other non-neurological immune-mediated diseases. This study reported on the comorbid immunopathological diseases associated with narcolepsy. One-hundred and fifty six narcoleptic patients with a mean age at diagnosis of 39.1 ± 17.8 years (range, 6–70 years) were assessed using the clinical history, physical and neurological examinations, sleep questionnaires, neuroimaging and human leucocyte antigen typing. Diagnosis was confirmed by polysomnography followed by a multiple sleep latency test or by measuring hypocretin-1 levels. Patients with immunopathological diseases were matched for gender and age at the onset of narcoleptic symptoms with narcoleptic patients without immunopathological diseases. Twenty-six patients (16.6%; 50% women; one familial, 25 sporadic) had one or more immunopathological diseases associated: autoimmune diseases, such as idiopathic thrombocytopenic purpura, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, ulcerative colitis, autoimmune thyroid disease, Peyronie's disease and idiopathic recurrent facial palsy; other immunopathological diseases, like atopic dermatitis, allergic asthma and allergic rhinitis. Although not significant, the age at diagnosis of narcolepsy was 9.3 years earlier in patients with narcolepsy + immunopathological diseases. The results demonstrate that the prevalence of comorbid immunopathological diseases is high in narcolepsy, and cataplexy is significantly more severe in patients with narcolepsy + immunopathological diseases.
    Journal of Sleep Research 03/2014; 23(4). DOI:10.1111/jsr.12143 · 3.35 Impact Factor
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    • "Direct sequencing found no mutation in the myelin oligodendrocyte glycoprotein gene, MOG, in our patient [5]. In the literature, none of the recently reported cases of neuromyelitis optica with bilateral hypothalamic lesions and hypocretin deficiency exhibited cataplexy [6], contrary to the seven previously reported sporadic narcoleptic MS cases; however, most of these cases lacked clinical details [7]. Familial cases have been reported by Ekbom [8] in four families in which three family members had narcolepsy and MS. "
    Sleep Medicine 05/2013; 14(7). DOI:10.1016/j.sleep.2013.03.015 · 3.15 Impact Factor
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    • "secondary narcolepsy may occur as a consequence of focal central nervous system lesions, which almost always involve posterior hypothalamus [19]. It is difficult to compare the absolute levels of hypocretin-1 measured in our patients with other studies as the assay is known to give quite large inter-assay variability between different laboratories and cannot be used for standard diagnostics [21]. Thus, we assessed the control values and calculated a cut-off level taken as mean minus 2 standard deviations, which is moderately lower compared to previously reported level by other group [24]. "
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    ABSTRACT: Considering the multiplicity of symptoms associated with multiple sclerosis (MS), there is possibility that hypocretin system function might be involved in the pathogenesis of the disease. The current study aimed to investigate the hypocretin-1 levels in cerebrospinal fluid (CSF) of MS patients in relation to different neurological deficit measures including: Ambulation Index (AI), Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS), and Epworth Sleepiness Scale (ESS) in relapse-onset MS patients. 53 subjects were included into the study: 38 patients with a diagnosis of MS and 15 healthy controls. Among MS patients, 25 had relapsing-remitting and 13 secondary progressive MS. CSF hypocretin-1 levels did not differ between MS patients and healthy controls (p>0.05). A positive correlation between hypocretin-1 level and fatigue level was found in MS patients (p<0.05) and this effect was even stronger in the MS subgroup suffering from fatigue (p=0.01). Hypocretin system seems to be generally unchanged in MS but a positive correlation between hypocretin-1 level and fatigue may indicate involvement of some compensatory mechanisms stimulating the production of the neuropeptide in MS patients.
    Neuroscience Letters 02/2010; 474(1):9-12. DOI:10.1016/j.neulet.2010.02.062 · 2.03 Impact Factor
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