OBJECTIVE: Besides excessive daytime sleepiness, disturbed nocturnal sleep is a major complaint of patients with narcolepsy. Previously, we showed alterations in skin temperature regulation in narcoleptic patients that were related to increased sleepiness. We here tested the hypothesis that direct control of nocturnal skin temperature might be applied to improve the disturbed sleep of narcoleptic patients. METHODS: Participants were eight patients (5 males) diagnosed with narcolepsy with cataplexy according to the ICSD-2 criteria, age 28.6+/-6.4 years (mean +/- standard deviation), range 18-35 years. During two nights sleep was recorded polysomnographically while proximal and distal skin temperature were manipulated using a comfortable thermosuit that induced skin temperature to slowly cycle with an amplitude of only 0.4 degrees C within the comfortable range normally observed during sleep. Logistic regression was used to evaluate the effect of skin temperature manipulation on the probability of occurrence of different sleep stages and nocturnal wakefulness. RESULTS: Proximal skin warming significantly suppressed wakefulness and enhanced slow wave sleep (SWS). In contrast, distal skin warming enhanced wakefulness and stage 1 sleep at the cost of SWS and REM sleep. The optimal combination of proximal skin warming and distal skin cooling led to a 160% increase in SWS, a 50% increase in REM-sleep and a 68% decrease in wakefulness, compared to the least beneficial combination of proximal skin cooling and distal skin warming. Interpretation: Subtle skin temperature manipulations under controlled conditions significantly improved the typical nocturnal sleep problems in narcolepsy.

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.

CONTEXT: Impaired vigilance and sleepiness are two majordaily complaints of patients with narcolepsy. We previously showed their sleepiness to be correlated to an abnormally regulated skin temperature, i.e., increased distal skin temperature compared with proximal skin temperature. OBJECTIVE: Our goal was to investigate a possible causal contribution of skin temperature disturbances to impairments in the ability to maintain vigilance and wakefulness in narcolepsy. DESIGN: In a modified constant routine protocol, the Psychomotor Vigilance Task (PVT) and the Maintenance of Wakefulness Test (MWT) were repeatedly assessed. Meanwhile, skin and core body temperatures were mildly manipulated within the thermoneutral range of the normal diurnal rhythm using a thermosuit and hot or cold food and drinks. SETTING: Tertiary narcolepsy referral center in a university hospital PATIENTS OR OTHER PARTICIPANTS: Eight patients (5 males) diagnosed with narcolepsy with cataplexy according to the ICSD-2 criteria (mean age +/- SD: 28.6 +/- 6.4, range 18-35 years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): MWT sleep latency and PVT response speed. RESULTS: Compared to core cooling, core warming attenuated the typical decline in PVT response speed with increasing time-on-task by 25%(P = 0.02). Compared to distal skin warming, distal skin cooling increased the time that the patients were able to maintain wakefulness by 24%(distal warming: 1.88 min. vs. distal warming: 2.34 min.; P < 0.01). CONCLUSIONS: Core body and skin temperatures causally affect vigilance and sleepiness in narcolepsy. This could lead to future practical applications.

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

Cataplexy is usually seen as rapid eye movement (REM) sleep atonia occurring at an inopportune moment. REM sleep atonia is the result of postsynaptic inhibition, i.e. inhibition of alpha motor neurones. Although this may explain the suppression of H-reflexes during REM sleep, cataplexy and laughter, it is not the only explanation. Presynaptic inhibition, in which afferent impulses are prevented from reaching motor neurones, is an alternative. Testing H-reflexes and magnetic-evoked potentials (MEPs) helps to tell them apart: in postsynaptic inhibition MEPs and H-reflexes change in tandem, while H-reflexes may decrease independent of MEPs with other inhibition modes. We studied motor inhibition during laughter, the strongest trigger for cataplexy. H-reflexes were evoked every 2 s in the soleus muscle in 10 healthy subjects watching comical video fragments. MEPs were evoked when H-reflexes decreased during laughter, and, as a control, when subjects did not laugh. Pairs of MEPs and the immediately preceding H-reflexes were studied. Compared with the control condition, laughter caused mean MEP area to increase by 60%(P=0.006) and mean H-reflex amplitude to decrease by 33%(P=0.008). This pattern proves that postsynaptic inhibition cannot have been the sole influence. The findings do not prove which mechanisms are involved; one possibility is that the decrease in H-reflex amplitude was the result of presynaptic inhibition, and that cortical and/or spinal facilitation accounted for increased MEPs. Regardless, the pattern differs fundamentally from the reported mechanism of REM sleep atonia. Existing scanty data on cataplexy suggest a pattern of H-reflexes and MEPs similar to that during laughter, but this needs further study.

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

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.

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

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.

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 (>200pg/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.

Objectives: While there are a number of observations/quantifications indicating a greater proportion of REM sleep without atonia (RWA) in narcolepsy, the intra-night distribution of this parameter has not been evaluated. Material and methods: Thirty-four patients (15 men and 19 women; mean age 44.9 +/- 18.9) with narcolepsy-cataplexy were included in this retrospective study. The clinical diagnosis was confirmed by MSLT, video-polysomnography and HLA typing. Polysomnographic recordings were scored with particular regard to REM sleep without atonia (RWA) across all the nocturnal REM periods. RWA scoring was done according to a standard method. Results: The analysis showed a significant increase in the proportion of REM sleep without atonia during successive nocturnal REM periods in narcoleptic patiens (p<0.01). No correlation was found between the percentage of RWA and the severity or duration of the disease, no age effect was documented. Conclusion: The study demonstrates for the first time an increasing amount of RWA during the night suggesting enhanced nocturnal REM sleep motor disturbance.

OBJECTIVES: To investigate the behavioural and neurophysiological pattern of cataplexy. METHODS: Seven narcolepsy with cataplexy patients underwent daytime videopolygraphy using humorous movies or/and jokes to trigger cataplectic attacks. RESULTS: During segmental cataplectic attacks, EMG showed brief and irregular periods of silencing focally involving facial, neck, axial or limb muscles, sometimes coinciding with bursts of rapid eye movements. All patients enacted intentional movements in response to these segmental postural lapses. During global cataplectic attacks, EMG showed suppression of activity alternated with patterned enhancement, enhanced EMG activity in neck muscles preceding that of other cranial, axial and lower limb muscles. This waxing and waning EMG pattern ended with a complete body collapse and persistent muscle atonia. Breathing irregularities, heart rate (HR) instability and EEG desynchronization were observed during global cataplectic attacks without any appreciable blood pressure changes, but with HR deceleration and silencing of sympathetic skin response while in complete atonia. Patients subjectively perceived the involuntary postural lapses as startling and alarming. CONCLUSIONS: Cataplexy in our patients showed many of the features of tonic REM sleep. SIGNIFICANCE: Cataplexy can be construed as a "freezing-like" perturbation of the orienting response with transient impairment of posture and movements resulting in a "patchwork-compromise-behaviour".

This study describes the clinical features, natural history and treatment of 100 patients with narcolepsy. Over half had one or more affected relatives. Symptoms commenced in adolescence or early adult life in most patients, and remissions were uncommon. Narcolepsy occurred several times each day, often in unusual circumstances and sometimes with little warning. The mean total sleep time of narco-leptics was a little over 9 hours in each 24 hour period, as compared with under 8 in normal subjects. Cataplexy occurred in 93 patients, most commonly when subjects were tired. Attacks were similar in nature to physiological weakness with laughter, although other sudden sensory or emotional stimuli did not cause paralysis of voluntary movement nor loss of muscle tone in normal subjects. Half these patients had frequent dreams before the onset of proper sleep, and 62 had sleep paralysis. This was often frightening, with feelings of suffocation, accompanied by dreams, and of uncertain length. A minority of patients with narcolepsy had muscle aches and jerks before sleep, double vision or loss of focus during cataplexy, went sleep-walking by day, and had daytime hallucinations. Amphetamines had been given to 71 patients for periods of up to 33 years with adequate, but rarely complete, control of narcolepsy. Side effects were common and almost half these patients became tolerant, needing higher dosage to control symptoms. Three patients had a cerebrovascular accident whilst taking amphetamines. Imipramine or clomipramine had ben given in combination with amphetamines to 33 patients for periods of up to 6 years with considerable improvement in both cataplexy and sleep paralysis, and few side effects. Sustained or paroxysmal hypertension as a result of amphetamines or combined treatment did not occur.

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

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

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

INTRODUCTION: Narcolepsy is a disabling sleep disorder that is characterised by excessive daytime sleepiness and abnormal manifestations in REM (rapid eye movement) sleep that include, among other symptoms, cataplexy (the sudden loss of muscle tone triggered by strong emotions). Studies on the prevalence of narcolepsy-cataplexy in Europe and the United States have yielded a figure of 0.013-0.067% in the general population. Although its prevalence is low, it is probably under-diagnosed for a number of different reasons, the most important perhaps being the difficulties involved in its diagnosis. DEVELOPMENT: Because its diagnosis is essentially clinical, complementary tests can often be very helpful. Today, it is one of the most extensively studied sleep disorders at the molecular level. Human narcolepsy is associated with diminished hypocretin/orexin concentrations, unlike the case of canine narcolepsy, where mutations in the Hcrt receptor have been found. The treatment of narcolepsy must be tailored to meet the needs of each patient after an individual analysis of his or her symptoms. Daytime sleepiness can be controlled by drugs that stimulate the central nervous system, the most common being methylphenidate and modafinil. Cataplexy is usually treated with tricyclic antidepressants and selective serotonin reuptake inhibitors. The appearance of new drugs like sodium oxybate sheds a ray of light on the dark horizon of patients with narcolepsy-cataplexy syndrome. CONCLUSION: Early identification of excessive daytime sleepiness by primary care physicians and specialists is essential for a better management and follow-up of these patients.

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