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Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and complex pediatric syndrome, essentially caused by dysfunction of 3 vital systems regulating endocrine, respiratory, and autonomic nervous system functioning. The clinical spectrum of ROHHAD is broad, but sleep/wake disorders have received relatively little attention so far, although the central hypothalamic dysfunction would make the occurrence of sleep symptoms likely. In this case report, we expand the phenotype of ROHHAD with a number of striking sleep symptoms that together can be classified as a secondary form of narcolepsy. We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone. Nocturnal polysomnography revealed sleep fragmentation and a sleep-onset REM period characteristic for narcolepsy. The diagnosis was confirmed by showing an absence of hypocretin-1 in the cerebrospinal fluid. We discuss potential pathophysiological implications as well as symptomatic treatment options.

AD, sleep and circadian rhythm physiology display an intricate relationship. On the one hand, AD pathology leads to sleep and circadian disturbances, with a clear negative influence on quality of life. On the other hand, there is increasing evidence that both sleep and circadian regulating systems exert an influence on AD pathology. In this review we describe the impairments of both sleep regulating systems and circadian rhythms in AD and their link to clinical symptoms, as this may increase knowledge on appropriate diagnosis and adequate treatment of sleep problems in AD. Furthermore we discuss how sleep regulating systems, and especially neurotransmitters such as melatonin and hypocretin, may affect AD pathophysiology, as this may provide a role for lack of sleep and circadian rhythm deterioration in the onset of AD., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Alzheimer's disease is associated with sleep disorders. Recently, animal studies demonstrated a link between hypocretin, a sleep-regulation neurotransmitter, and AD pathology. In this study, we investigated the circadian rhythm of hypocretin-1 in Alzheimer's Disease (AD) patients and controls. Moreover, we assessed the relation between CSF hypocretin-1 and amyloid-β. A continuous CSF sampling study via indwelling intrathecal catheter was performed to collect hourly CSF samples of six patients with AD (59-85 yrs, MMSE 16-26) and six healthy volunteers (64-77 yrs). CSF hypocretin-1 and Aβ42 concentrations were determined at 8 individual time points over 24 hours. A circadian pattern was assessed by fitting a 24 hour sine curve to the hypocretin-1 data using mixed model analysis. Clinical diagnosis and Aβ42 were entered into the model as time invariant covariates to determine differences between AD and controls, and correlate Aβ42 to hypocretin-1 levels. A hypocretin-1 circadian rhythm with an amplitude of 11.5 pg/ml was found in clinical AD patients, which did not differ from the control group (7.15 pg/ml). Lower mean CSF Aβ42 levels were related to lower hypocretin-1 levels; 1.6 pg/ml hypocretin-1 per 10 pg/ml Aβ42 (p=0.03), and a higher amplitude of the hypocretin-1 circadian rhythm (0.4 pg/ml, p=0.03). CSF hypocretin-1 has a circadian rhythm for which we could show no difference between AD and controls. However, the association between mean Aβ42 levels and mean hypocretin-1 levels and amplitude may suggest a relationship between AD pathology and hypocretin disturbance, which could hold possibilities for treatment of AD related sleep disorders.

Sleep disturbances in Alzheimer's disease (AD) patients are associated with the severity of dementia and are often the primary reason for institutionalization. These sleep problems partly resemble core symptoms of narcolepsy, a sleep disorder caused by a general loss of the neurotransmitter hypocretin. AD is a neurodegenerative disorder targeting different brain areas and types of neurons. In this study, we assessed whether the neurodegenerative process of AD also affects hypothalamic hypocretin/orexin neurons. The total number of hypocretin-1 immunoreactive neurons was quantified in postmortem hypothalami of AD patients (n = 10) and matched controls (n = 10). In addition, the hypocretin-1 concentration was measured in postmortem ventricular cerebrospinal fluid of 24 AD patients and 25 controls (including the patients and controls in which the hypothalamic cell counts were performed). The number of hypocretin-1 immunoreactive neurons was significantly decreased by 40% in AD patients (median [25th-75th percentiles]); AD 12,935 neurons (9972-19,051); controls 21,002 neurons (16,439-25,765); p = 0.049). Lower cerebrospinal fluid (CSF) hypocretin-1 levels were found in AD patients compared with controls (AD: 275 pg/mL [197-317]; controls: 320 pg/mL [262-363]; p = 0.038). Two AD patients with documented excessive daytime sleepiness showed the lowest CSF hypocretin-1 concentrations (55 pg/mL and 76 pg/mL). We conclude that the hypocretin system is affected in advanced AD. This is reflected in a 40% decreased cell number, and 14% lower CSF hypocretin-1 levels., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Hypocretin deficiency causes narcolepsy. It is unknown whether melatonin secretion is affected in this sleep disorder. Therefore, in both narcolepsy patients and matched controls, the authors measured plasma melatonin levels hourly for 24 h before and after 5 days of sodium oxybate (SXB) administration. Although mean melatonin concentrations were similar between patients and controls, in narcoleptics the percentage of 24-h melatonin secreted during the daytime was significantly higher, and melatonin secretion exhibited a weaker coupling to sleep. SXB did not affect melatonin secretion. These findings suggest that hypocretin deficiency might disturb both the circadian control of melatonin release and its temporal association with sleep.

Background: Narcolepsy is often not recognized or accurately diagnosed. This may be due to the fact that cataplexy, a core symptom which is virtually 100% specific, can-in practice-only be diagnosed based on the patient's history. However, the current definition of cataplexy is not very precise and the common distinction between "typical" and "atypical" cataplexy is not well codified., Methods: We aimed to provide a detailed description of the phenotypic variability of cataplexy. We included 109 patients with a definite history of cataplexy and a proven hypocretin-1 deficiency. The questionnaire contained 37 items to broadly cover the clinical aspects of cataplexy, including triggers, pattern and duration of muscle weakness, associated aspects such as sensory phenomena, and limitations in daily life due to cataplexy., Results: "Laughing" only listed in place 11th of most frequent triggers. "Laughing excitedly" was much more potent, showing that a certain intensity of the emotion is important for a "cataplectogenic" effect. Anger was the highest ranking "non-humorous" trigger, followed by "unexpectedly meeting someone well known." About 60% of patients also had spontaneous cataplectic attacks. Forty-five percent of patients experienced both partial and complete attacks and 30% only partial cataplexy. Fifteen percent of complete attacks were reported to last longer than 2 min. An abrupt return of muscle function was an important feature. The jaw and the face were most often involved in partial attacks, even more than the knee or the leg., Conclusions: Cataplexy presents with a large phenotypical diversity, so the current "typical" versus "atypical" distinction may be difficult to hold. We propose that grading cataplexy with different levels of diagnostic confidence may be more useful., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Hypocretin (orexin) neurotransmission is not only crucially involved in the regulation of sleep and wake, but serves in multiple autonomic and cognitive functions as well. This is reflected in the widespread connections between the hypothalamic hypocretin neurons and the rest of the brain, such as dense projections to the frontal cortex. Both frontal cognitive impairment and autonomic disturbances have been described in ALS. Furthermore, in some ALS patients there may be sleep disturbances other than sleep related breathing disorders, including REM sleep behaviour disorder. In addition, a role for the hypocretin system in the regulation of motor functions has been suggested. Hypocretin defects have been described in several neurodegenerative disorders. We therefore speculated that the hypocretin system is also involved in ALS and measured hypocretin-1 levels in cerebrospinal fluid samples from 20 patients. All results were well within the normal range (>200 pg/ml) and individual values showed no correlation with age, gender and disease duration. We conclude that it is unlikely that the hypocretin system is involved in the degenerative process of ALS.

The hypothalamic hypocretin (orexin) system plays a crucial role in the regulation of sleep and wakefulness. The strongest evidence for this is the fact that the primary sleep disorder narcolepsy is caused by disrupted hypocretin signaling in humans as well as various animal models. There is a growing interest in the role of hypocretin defects not only in the pathophysiology of other sleep disorders, but also in neurological diseases with associated sleep symptomatology. In this paper we first review the current methods to measure the integrity of the hypocretin system in human patients. The most widely used technique entails the measurement of hypocretin-1 in lumbar cerebrospinal fluid. In addition, hypocretin levels can be measured in ventricular cerebrospinal fluid and brain tissue extract. Finally, in post-mortem hypothalamic material, the number of hypocretin neurons can be precisely quantified. In the second part of this paper we describe the various neurological disorders in which hypocretin defects have been reported. These include neurodegenerative, neuromuscular and immune-mediated diseases, as well as traumatic brain injury. We conclude with a discussion of the functional relevance of partial hypocretin defects, and the various pathophysiological mechanisms that can lead to such defects.

To evaluate whether hypocretin-1 (orexin-A) and melanin-concentrating hormone (MCH) neurotransmission are affected in patients with Huntington disease (HD), we immunohistochemically stained hypocretin and MCH neurons and estimated their total numbers in the lateral hypothalamus of both HD patients and matched controls. In addition, hypocretin-1 levels were determined in prefrontal cortical tissue and post-mortem ventricular cerebrospinal fluid (CSF) using a radioimmunoassay. The total number of hypocretin-1 neurons was significantly reduced by 30% in HD brains (P = 0.015), while the total number of MCH neurons was not significantly altered (P = 0.100). Levels of hypocretin-1 were 33% lower in the prefrontal cortex of the HD patients (P = 0.025), but ventricular CSF levels were similar to the control values (P = 0.306). Neuronal intranuclear and cytoplasmic inclusions of mutant huntingtin were present in all HD hypothalami, although with a variable distribution across different hypothalamic structures. We found a specific reduction in hypocretin signaling in patients with HD as MCH cell number was not significantly affected. It remains to be shown whether the moderate decrease in hypocretin neurotransmission could contribute to clinical symptoms. As the number of MCH-expressing neurons was not affected, alterations in MCH signaling are unlikely to have clinical effects in HD patients.

Study Objectives: We investigated autonomic balance and resting metabolic rate to explore their possible involvement in obesity in hypocretin/orexin-deficient narcoleptic subjects., Methods: Resting metabolic rate (using indirect calorimetry) and variability in heart rate and blood pressure were determined in the fasted resting state. Subjects included 15 untreated, hypocretin-deficient male narcoleptics and 15 male controls matched for age and body mass index., Results: Spectral power analysis revealed greater heart rate and blood pressure variability in hypocretin-deficient male narcoleptic patients (heart rate: p = 0.01; systolic blood pressure: p = 0.02; diastolic: p < 0.01). The low to high frequency ratio of heart rate power did not differ between groups (p = 0.48), nor did resting metabolic rate (controls: 1767 +/- 226 kcal/24 h; patients: 1766 +/- 227 kcal/24h; p = 0.99)., Conclusions: Resting metabolic rate was not reduced in hypocretin-deficient narcoleptic men and therefore does not explain obesity in this group. Whether the increased heart rate and blood pressure variability--suggesting reduced sympathetic tone--is involved in this regard remains to be elucidated.

Sleep disturbances occur in 70% of the patients with multiple system atrophy (MSA). Disturbances of the hypothalamic hypocretin neurotransmission have been suggested as a possible cause. Since a systematic study of CSF hypocretin-1 levels in MSA has not yet been performed, we analysed CSF hypocretin-1 concentrations in 6 MSA-P and 6 MSA-C patients and 11 age-matched controls. We did not observe any differences from control values.

The hypothalamic hypocretin (orexin) system plays a central role in the regulation of various functions, including sleep/wake regulation and metabolism. There is a growing interest in hypocretin function in Parkinson's disease (PD), given the high prevalence of non-motor symptoms such as sleep disturbances in this disorder. However, studies measuring CSF hypocretin levels have yielded contradictory results. In PD patients and matched controls, we (i) estimated the number of hypocretin neurons in post-mortem hypothalami using immunocytochemistry and an image analysis system (ii) quantified hypocretin levels in post-mortem ventricular CSF and (iii) prefrontal cortex using a radioimmunoassay. Furthermore, presence of Lewy bodies was verified in the hypothalamic hypocretin cell area. Data are presented as median (25th-75th percentile). We showed a significant decrease between PD patients and controls in (i) the number of hypocretin neurons (PD: 20 276 (13 821-31 229); controls: 36 842 (32 546-50 938); P = 0.016); (ii) the hypocretin-1 concentration in post-mortem ventricular CSF (PD: 365.5 pg/ml (328.0-448.3); controls: 483.5 (433.5-512.3); P = 0.012) and (iii) the hypocretin-1 concentrations in prefrontal cortex (PD: 389.6 pg/g (249.2-652.2); controls: 676.6 (467.5-883.9); P = 0.043). Hypocretin neurotransmission is affected in PD. The hypocretin-1 concentration in the prefrontal cortex was almost 40% lower in PD patients, while ventricular CSF levels were almost 25% reduced. The total number of hypocretin neurons was almost half compared to controls.

Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin) neurotransmission. Injection of hypocretin-1 acutely suppresses TRH and TSH release in rats. In contrast, subchronic administration does not appear to affect the hypothalamo-pituitary-thyroid ensemble in animals. We explored (in 7 patients and 7 controls) whether hypocretin deficiency impacts circulating TSH levels and circadian timing of TSH release in narcoleptic humans. Plasma TSH concentration profiles (blood samples taken at 10-min intervals during 24 h) and TSH levels in response to TRH injection were analyzed by Cluster, robust regression, approximate entropy (ApEn), and deconvolution. Circulating TSH levels were lower in patients, which was primarily attributable to lower pulse amplitude and nadir concentrations. TSH secretion correlated positively with mean 24-h leptin levels (R2 = 0.46, P = 0.02) and negatively with amount of sleep (R2 = 0.29, P = 0.048). Pattern-synchrony between 24-h leptin and TSH concentrations was demonstrated by significant cross-correlation and cross-ApEn analyses with no differences between controls and patients. Sleep onset was closely associated with a fall in circulating TSH. Features of diurnal rhythmicity of circulating TSH fluctuations were similar in patients and controls, with the acrophase occurring shortly after midnight. Thyroxine and triiodothyronine concentrations were similar in patients and controls and did not display a diurnal rhythm. The response of plasma TSH levels to TRH was also similar in both groups. Sleep patterns in narcoleptics were significantly disorderly compared with controls, as measured by ApEn (P = 0.006). In summary, circulating TSH concentrations are low in hypocretin-deficient narcoleptic men, which could be attributable to their low plasma leptin levels and/or their abnormal sleep-wake cycle.

Hypocretin (orexin) peptides are involved in the regulation of energy balance and pituitary hormone release. Narcolepsy is a sleep disorder characterized by disruption of hypocretin neurotransmission. Pituitary LH secretion is diminished in hypocretin-deficient animal models, and intracerebroventricular administration of hypocretin-1 activates the hypothalamo-pituitary-gonadal axis in rats. We evaluated whether hypocretin deficiency affects gonadotropin release in humans. To this end, we deconvolved 24-h serum concentrations of LH and FSH in seven hypocretin-deficient narcoleptic males (N) and seven controls (C) matched for age, body mass index, and sex. Basal plasma concentrations of testosterone, estradiol, and sex hormone-binding globulin were similar in both groups. Mean 24-h LH concentration was significantly lower in narcolepsy patients [3.0 +/- 0.4 (N) vs. 4.2 +/- 0.3 (C) U/l, P = 0.01], which was primarily due to a reduction of pulsatile LH secretion [23.5 +/- 1.6 (N) vs. 34.3 +/- 4.9 (C) U.l(-1).24 h(-1), P = 0.02]. The orderliness of LH and FSH secretion, quantitated by the approximate entropy statistic, was greater in patients than in controls. In contrast, all other features of FSH release were similar in narcoleptic and control groups. Also, LH and FSH secretions in response to intravenous administration of 100 microg of GnRH were similar in patients and controls. These data indicate that endogenous hypocretins are involved in the regulation of the hypothalamo-pituitary-gonadal axis activity in humans. In particular, reduced LH release in the face of normal pituitary responsivity to GnRH stimulation in narcoleptic men suggests that hypocretins promote endogenous GnRH secretion.

Idiopathic narcolepsy is associated with deficient hypocretin transmission. Narcoleptic symptoms have recently been described in paraneoplastic encephalitis with anti-Ma2 antibodies. The authors measured CSF hypocretin-1 levels in six patients with anti-Ma2 encephalitis, and screened for anti-Ma antibodies in patients with idiopathic narcolepsy. Anti-Ma autoantibodies were not detected in patients with idiopathic narcolepsy. Four patients with anti-Ma2 encephalitis had excessive daytime sleepiness; hypocretin-1 was not detectable in their cerebrospinal fluid, suggesting an immune-mediated hypocretin dysfunction.

Hypocretin is a potential regulator of sleep and wakefulness and its levels fluctuate with the day-night cycle with high levels during the animal's activity period. Whether the daily fluctuations are driven endogenously or by external light cycles is unknown. We investigated the circadian and homeostatic regulation of hypocretin in the absence of environmental light cycles. To this purpose we performed repetitive samplings of cerebrospinal fluid in rats through implanted microcannulas in the cisterna magna and determined hypocretin-1 levels by radioimmunoassay. These experiments were also performed in rats that received a lesion of the suprachiasmatic nucleus (SCN), a major pacemaker for circadian rhythms in mammals. The results showed sustained rhythmicity of hypocretin in constant dim red light in control animals. SCN-lesioned animals showed no circadian rhythms in hypocretin and mean hypocretin levels were remarkably low. The results indicate that the SCN is indispensable for rhythmicity in hypocretin and induces a daily increase in hypocretin levels during the animal's active phase. Additional sleep deprivation experiments were carried out to investigate homeostatic regulation of hypocretin. Hypocretin levels increased in response to sleep deprivation in both control and SCN-lesioned animals, demonstrating that sleep homeostatic control of hypocretin occurs independently from the SCN. Our data indicate that the circadian pacemaker of the SCN and sleep homeostatic mechanisms converge on one single sleep regulatory substance.

CSF hypocretin-1 was measured in 28 Guillain-Barré syndrome (GBS), 12 Miller-Fisher syndrome, 12 chronic inflammatory demyelinating polyneuropathy (CIDP), and 48 control subjects. Seven GBS subjects had undetectably low hypocretin-1 levels (<100 pg/mL). Hypocretin-1 levels were moderately reduced in an additional 11 GBS, 5 Miller-Fisher syndrome, and 1 CIDP subject. Low levels in GBS occurred early in the disease and were associated with upper CNS level abnormalities.

Objective: To determine the prevalence of obesity among patients with narcolepsy, to estimate associated long-term health risks on the basis of waist circumference, and to distinguish the impact of hypocretin deficiency from that of increased daytime sleepiness (i.e., reduced physical activity) on these anthropometric measures., Research Methods and Procedures: A cross-sectional, case-control study was conducted. Patients with narcolepsy (n = 138) or idiopathic hypersomnia (IH) (n = 33) were included. Age-matched, healthy members of the Dutch population (Monitoring Project on Risk Factors for Chronic Diseases and Doetinchem Project; n = 10,526) were used as controls. BMI and waist circumference were determined., Results: Obesity (BMI > or = 30 kg/m(2)) and overweight (BMI 25 to 30 kg/m(2)) occurred more often among narcolepsy patients [prevalence: 33% (narcoleptics) vs. 12.5% (controls) and 43% (narcoleptics) vs. 36% (controls), respectively; both p < 0.05]. Narcoleptics had a larger waist circumference (mean difference 5 +/- 1.4 cm, p < 0.001). The BMI of patients with IH was significantly lower than that of narcolepsy patients (25.6 +/- 3.6 vs. 28.5 +/- 5.4 kg/m(2); p = 0.004)., Discussion: Overweight and obesity occur frequently in patients with narcolepsy. Moreover, these patients have an increased waist circumference, indicating excess fat storage in abdominal depots. The fact that patients with IH had a lower BMI than narcoleptics supports the notion that excessive daytime sleepiness (i.e., inactivity) cannot account for excess body fat in narcoleptic patients.

Narcolepsy is a sleep disorder caused by defective hypocretin (orexin) neurotransmission. It is thought to result from an autoimmune destruction of hypocretin producing neurons. Recently, low hypocretin levels were found in patients with Guillain-Barré syndrome, a post-infectious immune-mediated disorder in which a variety of circulating antibodies against neuronal gangliosides are found. We therefore considered gangliosides to be candidate antigens in narcolepsy as well, and screened for the presence of a panel of serum anti-ganglioside antibodies in a group of 28 well-characterized narcoleptic patients. We did not find a correlation between increased titers of anti-ganglioside antibodies and hypocretin-deficient narcolepsy. This study does not support the hypothesis that an autoimmune response is involved in narcolepsy. However, as an autoimmune attack may be selective and/or transient, future studies are needed to ultimately refute or confirm the autoimmune hypothesis.

Narcolepsy is a sleep disorder caused by impaired hypocretin (orexin) neurotransmission. Growth hormone (GH) secretion may be altered in narcolepsy for various reasons. Slow-wave sleep episodes, which are closely associated with GH-secretory events, are more randomly dispersed over 24 h in narcoleptics. Furthermore, hypocretins may inhibit pituitary GH release. We assessed the function of the somatotropic axis in narcolepsy by deconvolving 24-h (10-min sampling interval) plasma GH concentration profiles in seven hypocretin-deficient narcoleptic patients and in seven healthy controls matched for age, sex, and body weight. Both basal and pulsatile GH secretion rate and secretagogue-induced GH release were similar in patients and controls. However, narcoleptics secreted approximately 50% of their total production during the daytime, whereas controls secreted only 25% during the day. Also, the GH output pattern of narcoleptics was significantly less regular. We propose that hypocretin deficiency disrupts the circadian distribution of hypothalamic GH-releasing hormone release in narcoleptic patients to simultaneously cause daytime GH release and promote their propensity to fall asleep during the day.

Study Objectives: Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy., Design: We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes., Setting: Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London., Participants: Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects., Measurements and Results: We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls., Conclusions: VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.

Purpose of Review: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and cataplexy. The discovery that the majority of human patients lack the hypothalamic neuropeptide hypocretin-1 has initiated a large body of new research., Recent Findings: Several studies on cerebrospinal fluid hypocretin-1 levels in narcolepsy and in various other sleep disorders have shown that hypocretin deficiency is both highly sensitive and specific for narcolepsy/cataplexy. Importantly, 15% of narcoleptic patients show low hypocretin levels, despite a negative multiple sleep latency test. Besides regulating sleep, the hypocretin system is involved in the regulation of energy balance, autonomic function and several neuroendocrine ensembles. Consequently, up to one-third of patients are obese (body mass index > 30). Furthermore, serum leptin levels are decreased in both nonoverweight and obese patients. The new rodent models for narcolepsy may aid in the further characterization of these endocrinological abnormalities. Finally, there is increasing insight into the physiological role of the hypocretin system in the regulation of sleep and wakefulness., Summary: Hypocretin measurements may now be applied as a new diagnostic tool, providing the results are interpreted within the clinical context. In the clinical care of narcoleptic patients, attention should be paid to the obesity that frequently accompanies the disorder. In the future, hypocretin agonists may become available. Further characterization of animal models for narcolepsy will undoubtedly increase our insight into the pathophysiology of the disorder., (Copyright 2002 Lippincott Williams & Wilkins)

Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin) neurotransmission. It has been suggested that anomalous timing by the biological clock contributes to the symptomatology. Hypocretins stimulate the pituitary-adrenal (PA) axis in rodents. We explored whether hypocretin deficiency disrupts circadian timing and blunts PA hormone release. We deconvolved 24-h plasma profiles of ACTH and cortisol, and determined their circadian rhythm by cosinor analysis in seven hypocretin-deficient narcoleptic males and seven matched controls. Basal and total ACTH production were blunted in narcoleptics [310 +/- 86 vs. 760 +/-160 ng/liter.24 h (P = 0.02) and 920 +/- 147 vs. 1460 +/- 220 ng/liter.24 h (P = 0.04), respectively], whereas pulsatile release did not differ between groups. In contrast, basal, pulsatile and total cortisol secretion were similar in both groups. The cross-approximate entropy of the joint ACTH/cortisol time series was higher in narcoleptics (1.26 +/- 0.07 vs. 1.07 +/- 0.04; P = 0.04), reflecting reduced secretory process regularity. The acrophases of both ACTH and cortisol occurred at similar clock times (approximately 0830 h) in patients and controls, which supports the idea that the master pacemaker is intact in narcolepsy. The reduced (basal) ACTH secretion and the diminished secretory process regularity of the ACTH/cortisol ensemble conjointly suggest that hypocretin deficiency induces changes in the interplay between PA hormones.

Context: Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels., Objectives: To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy., Design: Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels., Setting: Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif., Participants: There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders)., Intervention: Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies., Main Outcome Measures: Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features., Results: HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions., Conclusions: Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

Recent observations have implicated hypocretin deficiency in the pathogenesis of narcolepsy. Hypocretin neurotransmission also affects energy balance, and narcoleptic patients tend to become obese. Because hypocretins appear to have important neuroendocrine effects, we hypothesized that the neuroendocrine systems that regulate energy balance might be distinctly set in narcolepsy. As leptin is a pivotal part of these systems, we explored the 24-h plasma leptin (20-min sampling interval) concentration profile in six narcoleptic males and six normal controls, matched for age, sex, body mass index, waist/hip ratio, and fat mass. We thus demonstrated a reduction of the mean 24-h leptin concentration in narcoleptics to 52% of that in controls (5.9 microg/liter in narcolepsy vs. 11.4 microg/liter in controls; P < 0.05). Further, a nocturnal acrophase (clock time of the highest concentration), which is typical of normal leptin secretion, was observed in controls (mean, 2335 h; 95% confidence interval, 2105-0205 h), but not in narcoleptic patients. The mechanisms that potentially disturb the circadian rhythm of leptin levels in hypocretin-deficient narcoleptic humans include anomalies of the sleep-wake cycle and/or disruption of the circadian distribution of autonomic activity. As leptin deficiency clearly leads to morbid obesity in experimental animals and humans, we infer that the observed reduction of plasma leptin levels may predispose narcoleptic humans to weight gain.

Objective: To examine the specificity of low CSF hypocretin-1 levels in narcolepsy and explore the potential role of hypocretins in other neurologic disorders., Methods: A method to measure hypocretin-1 in 100 microL of crude CSF sample was established and validated. CSF hypocretin-1 was measured in 42 narcolepsy patients (ages 16-70 years), 48 healthy controls (ages 22-77 years,) and 235 patients with various other neurologic conditions (ages 0-85 years)., Results: As previously reported, CSF hypocretin-1 levels were undetectably low (<100 pg/mL) in 37 of 42 narcolepsy subjects. Hypocretin-1 levels were detectable in all controls (224-653 pg/mL) and all neurologic patients (117-720 pg/mL), with the exception of three patients with Guillain-Barré syndrome (GBS). Hypocretin-1 was within the control range in most neurologic patients tested, including patients with AD, PD, and MS. Low but detectable levels (100-194 pg/mL) were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, CNS infections, and GBS., Conclusions: Undetectable CSF hypocretin-1 levels are highly specific to narcolepsy and rare cases of GBS. Measuring hypocretin-1 levels in the CSF of patients suspected of narcolepsy is a useful diagnostic procedure. Low hypocretin levels are also observed in a large range of neurologic conditions, most strikingly in subjects with head trauma. These alterations may reflect focal lesions in the hypothalamus, destruction of the blood brain barrier, or transient or chronic hypofunction of the hypothalamus. Future research in this area is needed to establish functional significance.

Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.

Narcolepsy is characterized by excessive daytime sleepiness and abnormal manifestations of rapid eye movement sleep such as cataplexy. The authors review the clinical features of narcolepsy, including epidemiology, symptoms, diagnosis, and treatment, in detail. Recent findings show that a loss of hypocretin-producing neurons lies at the root of the signs and symptoms of narcolepsy. The authors review the current state of knowledge on hypocretin anatomy, physiology, and function with special emphasis on the research regarding the hypocretin deficiency in narcolepsy, which may also explain associated features of the disorder, such as obesity. Lastly, they discuss some future perspectives for research into the pathophysiology of sleep/wake disorders, and the potential impact of the established hypocretin deficiency on the diagnosis and treatment of narcolepsy.

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.

A mutation in the HCRT locus was proved in 18-yrs old male suffering from narcolepsy-cataplexy. He has demonstrated cataplectic attacks (brief spells of head dropping provoked by laughter) as well as imperative sleep in spells of several minutes up to one hour since the age of six months. He has suffered from severe bulimia since five years; later hypnagogic hallucinations, sleep paralysis and unquiet nocturnal sleep accompanied by periodic limb movements appeared. Symptoms are partially controlled with methylphenidate and either imipramine, clomipramine or fluoxetine. Periodic leg movements poorly responded to L-DOPA and clonazepam treatment. He is HLA-DQB1*0602 negative. Repeated MSLT (over 16 years followed-up period) showed extremely short latency with predominant SOREMPs and also nocturnal PSG recordings revealed fragmented sleep with SOREMPs. This case report demonstrates that hypocretin (orexin) mutations in human can produce the full narcolepsy phenotype and validates data recently reported in dog and mouse models suggesting a role for hypocretin (orexin) in the pathophysiology of narcolepsy and the regulation of REM sleep.