OBJECTIVE:enhanced Besides excessive daytime sleepiness, disturbed nocturnal sleep is a major complaint of patients with narcolepsy. Previously, we showed alterations in of skin temperature regulation in narcoleptic patients that were related to increased sleepiness. We here tested the hypothesis that direct control 1 of nocturnal skin temperature might be applied to improve the disturbed sleep of narcoleptic patients. METHODS: Participants were eight patients sleep (5 males) diagnosed with narcolepsy with cataplexy according to the ICSD-2 criteria, age 28.6+/-6.4 years (mean +/- standard deviation), range to 18-35 years. During two nights sleep was recorded polysomnographically while proximal and distal skin temperature were manipulated using a comfortable and thermosuit that induced skin temperature to slowly cycle with an amplitude of only .4 degrees C within the comfortable range (mean normally observed during sleep. Logistic regression was used to evaluate the effect of skin temperature manipulation on the probability of the occurrence of different sleep stages and nocturnal wakefulness. RESULTS: Proximal skin warming significantly suppressed wakefulness and enhanced slow wave sleep (SWS). (SWS). In contrast, distal skin warming enhanced wakefulness and stage 1 sleep at the cost of SWS and REM sleep.to The optimal combination of proximal skin warming and distal skin cooling led to a 160% increase in SWS, a 50%might increase in REM-sleep and a 68% decrease in wakefulness, compared to the least beneficial combination of proximal skin cooling and sleep distal skin warming. Interpretation: Subtle skin temperature manipulations under controlled conditions significantly improved the typical nocturnal sleep problems in narcolepsy.that

STUDY nor 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 h; resting state. Subjects included 15 untreated, hypocretin-deficient male narcoleptics and 15 male controls matched for age and body mass index.determined RESULTS: Spectral power analysis revealed greater heart rate and blood pressure variability in hypocretin-deficient male narcoleptic patients (heart rate: p METHODS: = .01; systolic blood pressure: p = .02; diastolic: p < .01). The low to high frequency ratio of heart 227 rate power did not differ between groups (p = .48), nor did resting metabolic rate (controls: 1767 +/- 226 kcal/24 controls h; patients: 1766 +/- 227 kcal/24h; p = .99). CONCLUSIONS: Resting metabolic rate was not reduced in hypocretin-deficient narcoleptic men frequency and therefore does not explain obesity in this group. Whether the increased heart rate and blood pressure variability--suggesting reduced sympathetic metabolic tone--is involved in this regard remains to be elucidated.

CONTEXT:MWT Impaired vigilance and sleepiness are two majordaily complaints of patients with narcolepsy. We previously showed their sleepiness to be correlated in to an abnormally regulated skin temperature, i.e., increased distal skin temperature compared with proximal skin temperature. OBJECTIVE: Our goal was attenuated to investigate a possible causal contribution of skin temperature disturbances to impairments in the ability to maintain vigilance and wakefulness impairments in narcolepsy. DESIGN: In a modified constant routine protocol, the Psychomotor Vigilance Task (PVT) and the Maintenance of Wakefulness Test skin (MWT) were repeatedly assessed. Meanwhile, skin and core body temperatures were mildly manipulated within the thermoneutral range of the normal speed diurnal rhythm using a thermosuit and hot or cold food and drinks. SETTING: Tertiary narcolepsy referral center in a university and hospital PATIENTS OR OTHER PARTICIPANTS: Eight patients (5 males) diagnosed with narcolepsy with cataplexy according to the ICSD-2 criteria (mean the age +/- SD: 28.6 +/- 6.4, range 18-35 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): MWT sleep latency and PVT response PVT speed. RESULTS: Compared to core cooling, core warming attenuated the typical decline in PVT response speed with increasing time-on-task by of 25%(P = .02). Compared to distal skin warming, distal skin cooling increased the time that the patients were able possible to maintain wakefulness by 24%(distal warming: 1.88 min. vs. distal warming: 2.34 min.; P < .01). CONCLUSIONS: Core body majordaily and skin temperatures causally affect vigilance and sleepiness in narcolepsy. This could lead to future practical applications.

STUDY subsequent OBJECTIVES: In healthy subjects, sleep propensity increases when the distal skin temperature increases relative to the proximal skin temperature. This whereas increase results from increased blood flow in the skin of the extremities and is, among other factors, controlled by the and hypothalamic circadian clock, as is sleep. Because narcolepsy is characterized by hypothalamic alterations, we studied skin temperature in narcoleptic patients temperature in relation to their characteristically increased sleep propensity during the day. DESIGN: Distal and proximal skin temperature and their gradient and (DPG) were measured during a Multiple Sleep Latency Test. This allowed temperature to be studied during wakefulness, at sleep onset skin and during sleep. SETTING: Tertiary narcolepsy referral center in a university hospital. PATIENTS: Fifteen unmedicated narcolepsy patients with cataplexy and measured 15 controls. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: In subjects in the waking state, DPG was higher in narcoleptics than in .0001), controls throughout the day (time by group interaction, p <.0001), due to increased distal skin temperature and decreased proximal = skin temperature. The increase in DPG was related to a shorter subsequent sleep-onset latency (p =.02). Once asleep, narcoleptics hypothalamic maintained their elevated distal skin temperature and DPG (p <.0001), whereas proximal skin temperature increased to reach normal levels.is CONCLUSIONS: This is the first demonstration of a dramatic alteration of daytime skin temperature control in narcolepsy. Even awake narcoleptic increases patients showed a DPG higher than that which healthy controls achieve when asleep. This observation suggests that hypocretin deficiency in hospital. narcolepsy affects skin-temperature regulation and invites further examination. Skin-temperature control might ultimately even have therapeutic implications for the alleviation of temperature narcoleptic symptoms.

Cataplexy mean is usually seen as rapid eye movement (REM) sleep atonia occurring at an inopportune moment. REM sleep atonia is the influence. result of postsynaptic inhibition, i.e. inhibition of alpha motor neurones. Although this may explain the suppression of H-reflexes during REM cannot sleep, cataplexy and laughter, it is not the only explanation. Presynaptic inhibition, in which afferent impulses are prevented from reaching impulses motor neurones, is an alternative. Testing H-reflexes and magnetic-evoked potentials (MEPs) helps to tell them apart: in postsynaptic inhibition MEPs this and H-reflexes change in tandem, while H-reflexes may decrease independent of MEPs with other inhibition modes. We studied motor inhibition do during laughter, the strongest trigger for cataplexy. H-reflexes were evoked every 2 s in the soleus muscle in 10 healthy and subjects watching comical video fragments. MEPs were evoked when H-reflexes decreased during laughter, and, as a control, when subjects did immediately not laugh. Pairs of MEPs and the immediately preceding H-reflexes were studied. Compared with the control condition, laughter caused mean decrease MEP area to increase by 60%(P= .006) and mean H-reflex amplitude to decrease by 33%(P= .008). This pattern proves that Presynaptic postsynaptic inhibition cannot have been the sole influence. The findings do not prove which mechanisms are involved; one possibility is the that the decrease in H-reflex amplitude was the result of presynaptic inhibition, and that cortical and/or spinal facilitation accounted for movement increased MEPs. Regardless, the pattern differs fundamentally from the reported mechanism of REM sleep atonia. Existing scanty data on cataplexy were suggest a pattern of H-reflexes and MEPs similar to that during laughter, but this needs further study.

Abstract the We compared the effects of laughter and several respiratory movements on spinal motor excitability to unravel their respective influences. We neutral measured H-reflexes in 13 healthy volunteers during 10 different tasks (including laughter, simulated laughter, and various respiratory movements). We compared to the percentage that remained of the initial H-reflex during each task with that during a neutral task. H-reflex percentage differed (including between the neutral task (79.4+/-16.1%), true laughter (43.7+/-17.9%), and simulated laughter (66.6+/-24.3%), and between the two latter tasks. Coughing also respective resulted in H-reflex suppression, but not as deeply as true laughter. During the other respiratory maneuvers, the H-reflex increased compared Our to the neutral task. Our finding that true laughter evoked more H-reflex depression than simulated laughter suggests that mirth on remained its own depresses the H-reflex. This mechanism may also be involved in the pathophysiology of cataplexy, the main symptom of resulted narcolepsy.

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

OBJECTIVE:such Patients with narcolepsy often experience pervasive hypnagogic hallucinations, sometimes even leading to confusion with schizophrenia. We aimed to provide a the detailed qualitative description of hypnagogic hallucinations and other "psychotic" symptoms in patients with narcolepsy and contrast these with schizophrenia patients population and healthy controls. We also compared the prevalence of formal psychotic disorders between narcolepsy patients and controls. METHODS: We used controls. SCAN 2.1 interviews to compare psychotic symptoms between 60 patients with narcolepsy, 102 with schizophrenia and 120 matched population controls.hypnagogic In addition, qualitative data was collected to enable a detailed description of hypnagogic hallucinations in narcolepsy. RESULTS: There were clear of differences in the pattern of hallucinatory experiences in narcolepsy vs. schizophrenia patients. Narcoleptics reported multisensory "holistic" hallucinations rather than the 2.1 predominantly verbal-auditory sensory mode of schizophrenia patients. Psychotic symptoms such as delusions were not more frequent in narcolepsy compared to reported population controls. In addition, the prevalence of formal psychotic disorders was not increased in patients with narcolepsy. Almost half of were narcoleptics reported moderate interference with functioning due to hypnagogic hallucinations, mostly due to related anxiety. CONCLUSIONS: Hypnagogic hallucinations in narcolepsy schizophrenia can be differentiated on a phenomenological basis from hallucinations in schizophrenia which is useful in differential diagnostic dilemmas.

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

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

ABSTRACT orgasmolepsy, Introduction. Sudden, often positive emotions are typical triggers for cataplexy in patients with narcolepsy-cataplexy (NC). Cataplexy during sexual intercourse and intercourse orgasm (orgasmolepsy) has been previously reported, but its frequency and characteristics are poorly known. Aim. To assess frequency and features activities. of loss of muscle tone during sexual intercourse in a series of patients with NC, other sleep-wake disorders, and healthy and controls. Methods. Review of sleep questionnaires (including the Stanford Cataplexy Questionnaire) of 75 subjects (29 with NC, 26 with other known. sleep-wake disorders, and 20 healthy controls), followed by an interview with specific focus on muscle loss during sexual activity in distinct suspicious cases. Main Outcome Measures. Cataplexy during sexual intercourse and orgasm (orgasmolepsy). Results. Orgasmolepsy was reported by three NC patients controls), (two female, one male), one male patient with behaviorally induced insufficient sleep syndrome (BIISS) and cataplexy-like symptoms, and none of the the healthy controls. In the two female NC patients, orgasmolepsy occurred by each sexual intercourse, and the male patient reported upper orgasmolepsy only when in a relationship involving emotional commitment and trust. In the patient with BIISS and orgasmolepsy, cataplexy-like symptoms with involved unilaterally upper or lower limbs in association with negative emotions or sports activities. Conclusions. Cataplexy during sexual intercourse is series a distinct feature of NC, which can, however, be reported rarely also by patients with other sleep-wake disorders. Insufficient arousal triggers may favor the occurrence of cataplexy and cataplexy-like symptoms, including orgasmolepsy. Hypocretin deficiency and reward dysregulation in narcolepsy may further reported facilitate this phenomenon and contribute to its repetitive occurrence. Poryazova R, Khatami R, Werth E, and Bassetti CL. Weak with loss sex: Sexual intercourse as a trigger for cataplexy. J Sex Med **;**:**-**.

Mice switched lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble cataplexy, episodes of With sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine cataplexy is a triggered by positive emotions. To determine whether positive emotions elicit murine cataplexy, we placed orexin knockout (KO) mice on a a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad lib regular chow. Mice remains were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 palatable hr after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular feeding chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO dark mice had slightly more cataplexy during the food-anticipation period and more cataplexy in the second half of the dark period,with when they may have been foraging for residual food. To test whether more palatable food increases cataplexy, mice were then orexin switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral cataplexy, studies. With this highly palatable food, orexin KO mice had much more cataplexy during the food-anticipation period and throughout the atonia dark period. The increase in cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger feeding cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent amount model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger cataplexy.

Narcolepsy hypocretin is a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset, from childhood to with the fifties, peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden loss of also muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, sleep maintenance insomnia, REM sleep include behavior disorders, attention deficit and weight gain at disease onset. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and features daytime polysomnography (multiple sleep latency tests) are useful to document a mean sleep latency below 8 min and at least 90% two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was remains not included in the new diagnostic criteria. In contrast, a low hypocretin levels (values below 110 pg/ml) in the cerebrospinal below fluid (CSF) was highly specific for narcolepsy with cataplexy. The deficiency of the hypocretin system is well-established in animal models in of narcolepsy (murine and canine narcolepsy) but also in human narcoleptics with a 90% reduction of CSF hypocretin levels in Other relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process is by most probable. The treatment of narcolepsy includes stimulants against sleepiness (modafinil, methylphenidate), anticataplectic drugs (antidepressants) and sodium oxybate. The current disorder, therapeutic target is oriented towards hypocretine agonists, histamine (an arousal system) H3 antagonists and immunosuppressants.

INTRODUCTION:of Narcolepsy is a disabling sleep disorder that is characterised by excessive daytime sleepiness and abnormal manifestations in REM (rapid eye the movement) sleep that include, among other symptoms, cataplexy (the sudden loss of muscle tone triggered by strong emotions). Studies on stimulate the prevalence of narcolepsy-cataplexy in Europe and the United States have yielded a figure of .013- .067% in the general population.yielded Although its prevalence is low, it is probably under-diagnosed for a number of different reasons, the most important perhaps being sudden the difficulties involved in its diagnosis. DEVELOPMENT: Because its diagnosis is essentially clinical, complementary tests can often be very helpful.common Today, it is one of the most extensively studied sleep disorders at the molecular level. Human narcolepsy is associated with reasons, diminished hypocretin/orexin concentrations, unlike the case of canine narcolepsy, where mutations in the Hcrt receptor have been found. The treatment found. of narcolepsy must be tailored to meet the needs of each patient after an individual analysis of his or her symptoms. symptoms. Daytime sleepiness can be controlled by drugs that stimulate the central nervous system, the most common being methylphenidate and the modafinil. Cataplexy is usually treated with tricyclic antidepressants and selective serotonin reuptake inhibitors. The appearance of new drugs like sodium in oxybate sheds a ray of light on the dark horizon of patients with narcolepsy-cataplexy syndrome. CONCLUSION: Early identification of excessive that daytime sleepiness by primary care physicians and specialists is essential for a better management and follow-up of these patients.

Even animal though the most impressive manifestation of narcolepsy is excessive sleepiness, paradoxically a significant number of patients have trouble sleeping at paper night. A wide array of alterations can affect the night-time sleep of a narcoleptic patient, and the aim of this patients, review is to increase awareness on this issue, thereby enhancing the care of narcoleptic patients by more specific approaches to alterations their disturbed night sleep. This review covers a broad variety of nocturnal sleep features in narcolepsy. Starting from animal models of and the clinical features of patients, the paper then discusses the many comorbid conditions found in narcolepsy at night, the then most advanced methods of analysis and the few recent advances in the specific treatment of night sleep in narcoleptic patients.aim

This whole-night article gives an overview of a few most significant but also most frequent primary hypersomnias in humans. The prevalence of is hypersomnia in USA is between .3 and 16.3% which is close to its prevalence in Europe which is 5-16%. The test. prevalence of narcolepsy with cataplexy in USA and the countries of Western Europe is from .05- .067%. Its presence is significantly prevalence higher in Japan and lower in Israel. Most of the symptoms of narcolepsy represent the abnormal manifestations of dissociated REM of sleep process. Excessive daytime sleepiness, sleep attacks and cataplexy are the most frequent symptoms. The diagnosis of narcolepsy should be a confirmed by a whole-night polysomnographic recording followed by a Multiple sleep latency test. Idiopathic hypersomnia is a rare disease (ten countries times as rare as narcolepsy) with the diagnostic procedure similar to that of narcolepsy. Treatment of hypersomnias is symptomatic with the the aimed to reduce the most frequent symptoms (excessive daytime sleepiness, sleep attacks, cataplexy and hypnagogic/hypnapompic sleep paralyses).

BACKGROUND:frequency Cataplexy is the main motor symptom of narcolepsy/cataplexy and is considered a form of rapid eye movement (REM) sleep motor had dyscontrol appearing during wakefulness and elicited by emotions. This study examined the relationship between the frequency of cataplectic attacks in more patients with narcolepsy/cataplexy and (a) the clinical and behavioural characteristics of cataplectic attacks, including the emotional tone of trigger events,A and (b) the polysomnographic characteristics of daytime sleepiness, nocturnal sleep structure and indices of motor disorders during sleep. METHODS: A the consecutive series of 44 first-diagnosed drug-naive patients with narcolepsy/cataplexy, fulfilling the International Classification of Sleep Disorders, 2nd edition (ICSD-2) clinical involvement and polysomnographic diagnostic criteria, were interviewed to estimate the frequency and clinical characteristics of cataplectic attacks and the occurrence of cataplectic REM sleep behaviour disorder (RBD). All patients also underwent a video-polysomnographic recording to assess their sleep parameters and indices of possible altered motor control during sleep. RESULTS: Patients were divided into two groups on the basis of the frequency of cataplectic per attacks, namely high-frequency (n=30) or low-frequency (n=14) depending on whether they estimated they had more or less than one attack indices per month. High-frequency patients (with a larger proportion of men) reported attacks more often affecting mainly the head, jaw and nocturnal shoulder muscles and experienced more events among those listed as possible triggers of attacks. Sixty-one percent of patients reported RBD is and 43% had an RBD episode at video-polysomnography regardless of the frequency of cataplectic attacks or gender. Lastly, the frequency of of periodic leg movements (PLM) per hour was higher in men than women and increased with age. CONCLUSIONS: Patients with underwent more than one cataplectic attack per month had more frequent involvement of head, jaw and shoulder muscles and were mainly elicited men. The proportions of patients with clinically assessed RBD and an RBD episode documented by video-polysomnography, as well as conspicuous assess values of PLM per hour, are fairly consistent with those reported in recent small-group studies. Therefore, it seems legitimate to structure argue that RBD and PLM are nocturnal manifestations intrinsic to narcolepsy/cataplexy and that the gender-related differences in the frequency of possible attacks and the value of PLM per hour may be indicative of a larger difference in the clinical and polysomnographic movements characteristics of narcolepsy/cataplexy than hitherto suspected.