Near-miss sleepy driving accidents-Powell et al Disclosure Statement This is not an industry supported study. The study was supported in part by the Sleep Education and Research Foundation a registered public nonprofit foundation. Drs. Powell, Schechtman, Riley, Guilleminault, Chiang, and Weaver have indicated no conflicts of interest.

Although attention problems are presumably responsible for a wide variety of difficulties patients with narcolepsy experience in everyday life, empirical investigation of this issue is scarce. Therefore, we conducted a systematic investigation of different aspects of attention and verbal memory in patients with narcolepsy. Control-group design with comparison of performance in four attention tests--measuring phasic alertness, focused attention, divided attention, and flexible attention--and one verbal memory test. 19 patients with narcolepsy (NG) and 20 healthy controls (CG) MEASUREMENTS AND RESULTS: The NG showed no deficits in phasic alertness, focused attention, and verbal memory. However, specific deficits occurred in divided and flexible attention. Furthermore, the NG had generally slower and more variable reaction times in all attention tasks. Our results contradict the hypothesis that attentional impairments in narcolepsy are merely a result of a temporal disturbance of infor...

Recent studies have implicated the orexin system as a critical regulator of sleep/wake states, feeding behavior, and reward processes. Orexin deficiency results in narcolepsy-cataplexy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. Orexin agonists and antagonists are thought to be promising avenues toward the treatment of sleep disorders, eating disorders, and drug addiction. In this chapter, we discuss the current understanding of the physiological roles of orexins in regulation of arousal, sleep/wake states, energy homeostasis, and reward systems.

Objective: Sleepiness and fatigue are conceptually distinct but pervasively confounded in research, measurement instruments, clinical settings, and everyday spoken language. The purpose of the present study was to construct two scales that represent unconfounded measures of sleepiness and fatigue, using widely used questionnaires. Method: Four questionnaires purporting to measure sleepiness [Stanford Sleepiness Scale (SSS); Epworth Sleepiness Scale (ESS)] or fatigue [Fatigue Severity Scale (FSS); Chalder Fatigue Scale (CFS)] were administered, as well as a battery measuring sleep, psychological, and health functioning variables, to three samples: 19 individuals with chronic fatigue syndrome, 14 with narcolepsy, and 11 normal control subjects. Results: Analyses revealed two distinct sets of items (six sleepiness and three fatigue items) that were combined into two scales. These newly formed scales are only minimally correlated and represent separate constructs that have reasonably distinctive patterns of association. Findings were replicated and validated in a sample of 128 older individuals complaining of daytime sleepiness and/or fatigue. Conclusions: We conclude that (a) it is possible to derive empirically distinct sleepiness and fatigue scales from existing, commonly used self-report instruments, (b) the Empirical Sleepiness Scale is limited to the experience of daytime sleep tendency, while (c) the Empirical Fatigue Scale is associated more broadly with insomnia, psychological maladjustment, and poorer perceived health function. The important clinical implication of the new Empirical Sleepiness and Fatigue Scales is in the ability to identify bsleepiness which is not fatigue,Q a construct closely related to primary sleep disorders, such as sleep apnea/hypopnea syndrome, for which there is both available and effective treatment. D

Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic orexin-producing neurons. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies.Here,wedemonstraterescueofthenarcolepsycataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means. Ectopic expression of a prepro-orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous orexin neurons. Central administration of orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. These results indicate that orexin neuronablated mice retain the ability to respond to orexin neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms. Orexin receptor agonists would be of potential value for treating human narcolepsy.

Bright white light ( 500 lx) for 4 h/day was applied to seven narcoleptic patients (age 47-65 years, mean 55 years) The effects of the light on the disturbed sleep-wake cycle in narcoleptics were investigated by the measurement of the following parameters: ( 1) excessive daytime sleepiness and sustained attention (multiple sleep latency test); ( 2) rest-activity cycles;

Genetic and developmental factors were investigated in 101 cases of canine narcolepsy-cataplexy syndrome. An experimental breeding program documented a probable autosomal recessive mode of inheritance in two dog breeds, Doberman pinschers and Labrador retrievers, and in crosses between those breeds. Age of onset of cataplexy and severity of symptoms were remarkably similar in 73 subjects with the genetically transmitted form of narcolepsy. Efforts to demonstrate genetic factors by breeding affected poodles and beagles were unsuccessful. Furthermore, a positive family history could not be documented in these animals or in narcoleptic dogs of 13 other breeds. Both age of onset and severity of symptoms were highly variable within this population. We suggest there may be multiple etiologies in canine narcolepsy syndrome: (i) inheritance via a single autosomal recessive gene, which appears to be identical in at least two unrelated dog breeds (ii) nongenetic mechanisms which may include developmental or traumatic accidents. Preliminary findings of parallel neurochemical studies in narcoleptic dogs indicate distinct abnormalities in central neurotransmitter concentration and turnover. We theorize that these neurochemical abnormalities may result from inherited disorders of synthesis and/or metabolism which are present from birth or from nongenetic neurochemical abnormalities appearing later in life. The observation that symptom characteristics are identical in all affected dogs suggests that a common neurochemical disorder may underlie both genetic and nongenetic variations of the disease.

Previous research has shown that night driving performance may be seriously affected by sleepiness. The present study compared daytime and night-time performance of professional drivers on a simulated truck driving task. A secondary purpose was whether a nap or a rest pause would affect performance. Nine professional drivers participated in a counterbalanced design. The conditions were day driving (DAYDRIVE), night driving (NIGHTDRIVE), night driving with a 30 minute rest (NIGHTREST), and night driving with a 30 minute nap (NIGHTNAP). Each condition consisted of three consecutive 30-min periods. For the DAYDRIVE and NIGHTDRIVE all periods were spent driving while the second period was either a rest pause or a nap for the other two conditions. Mean speed, standard deviation of speed and, standard deviation for lane position were recorded. Self ratings of sleepiness were obtained before and after each 30-min period. Reaction time tests and 10 minute standardized EEG/EOG recordings were obtained before and after each condition. EEG/EOG were also recorded continuously during driving. The effects on driving were small but significant: night driving was slower, with a higher variability of speed, and had higher variability of lane position. Subjective and EEG/EOG sleepiness were clearly higher during the night conditions. Reaction time performance was not significantly affected by conditions. Neither the nap nor the rest pause had any effect.

AbstractÐAnalyses of scalp-recorded sleep spindles have demonstrated topographically distinct slow and fast spindle waves. In the present paper, the electrical activity in the brain corresponding to different types of sleep spindles was estimated by means of low-resolution electromagnetic tomography. In its new implementation, this method is based on realistic head geometry and solution space is restricted to the cortical gray matter and hippocampus. In multichannel allnight electroencephalographic recordings, 10±20 artifact-free 1.25-s epochs with frontally, parietally and approximately equally distributed spindles were marked visually in 10 normal healthy subjects aged 20±35 years. As a control condition, artifact-free non-spindle epochs 1±3 s before or after the corresponding spindle episodes were marked. Low-resolution electromagnetic tomography demonstrated, independent of the scalp distribution, a distributed spindle source in the prefrontal cortex (Brodmann areas 9 and 10), oscillating with a frequency below 13 Hz, and in the precuneus (Brodmann area 7), oscillating with a frequency above 13 Hz. In extremely rare cases only the prefrontal or the parietal source was active. Brodmann areas 9 and 10 have principal connections to the dorsomedial thalamic nucleus; Brodmann area 7 is connected to the lateroposterior, laterodorsal and rostral intralaminar centrolateral thalamic nuclei. Thus, the localized cortical brain regions are directly connected with adjacent parts of the dorsal thalamus, where sleep spindles are generated.

To evaluate the reliability of nocturnal sleep dynamics in the differential diagnosis of central disorders of hypersomnolence. Cross-sectional. Sleep laboratory. One hundred seventy-five patients with hypocretin-deficient narcolepsy type 1 (NT1, n = 79), narcolepsy type 2 (NT2, n = 22), idiopathic hypersomnia (IH, n = 22), and "subjective" hypersomnolence (sHS, n = 52). None. Polysomnographic (PSG) work-up included 48 h of continuous PSG recording. From nocturnal PSG conventional sleep macrostructure, occurrence of sleep onset rapid eye movement period (SOREMP), sleep stages distribution, and sleep stage transitions were calculated. Patient groups were compared, and receiver operating characteristic (ROC) curve analysis was used to test the diagnostic utility of nocturnal PSG data to identify NT1. Sleep macrostructure was substantially stable in the 2 nights of each diagnostic group. NT1 and NT2 patients had lower latency to rapid eye movement (REM) sleep, and NT1 patients...

The studies examined in this review indicate that the MSL is sensitive to conditions expected to increase sleepiness. MSL are generally lower following sleep loss, following use of sedating medications, during wakefulness in the late night or early morning hours, and among patients with sleep disorders associated with excessive sleepiness such as narcolepsy or obstructive sleep apnea. However, the wide range in MSL makes it difficult to establish a specific threshold value for excessive sleepiness or to discriminate patients with sleep disorders from non-patients. Some of this variation may be attributable to methodological differences and some may be attributable to individual differences in sleep tendency (e.g., related to age). The studies analyzed in this review indicate that the MSL on both the MSLT and MWT does not discriminate well between patients with sleep disorders and normal populations. This is due to large SD as well as floor or ceiling effects in the tests. However, t...

Fatalities resulting from popular use of gamma hydroxybutyrate (GHB) have previously been reported. We report three deaths associated with use of Xyrem Ò (sodium oxybate), a pharmaceutical preparation of GHB initially approved for treatment of narcolepsy with cataplexy. One death appears associated with Xyrem Ò abuse, with extremely high postmortem blood GHB levels documented. Although postmortem blood GHB levels in two other deaths are consistent with therapeutic levels, cause and effect cannot be established. We discuss these cases and factors which may have exerted contributory respiratory depressant effects, singly or in combination, including concurrent use of sedative hypnotics, obstructive sleep apnea, and obesity.

REM behaviour disorder RBD Narcolepsy Overlap parasomnia disorder Rem loss atonia Idiopathic RBD Secondary RBD a b s t r a c t Study objectives: To retrospectively examine the characteristics of a population of patients <50 years of age with clinical and polysomnographic features diagnostic for RBD. Methods: Review of our sleep centre's database for patients with RBD diagnosed over the last 7 years. Ninety-one patients were separated into two groups according to their age at the time of diagnosis (<50 y and P50 y). Clinical and polysomnographic data were reviewed. Results: Sixty-two were male; mean age was 52 ± 19 y. Thirty-nine were <50 y. In the group <50 y there was a male predominance but in a smaller proportion (M:F = 1.4:1) compared with the group P50 (M:F = 3:1). Seventy-six patients complained of abnormal behaviour (AB) during sleep, 12 with narcolepsy complained of excessive daytime sleepiness (EDS) with the AB being elicited only during consultation, and three complained of both EDS and AB. All patients, except one in the group P50, described AB related to vivid dreams with violent content. The majority of the patients had the idiopathic form of RBD in both groups (51.2% group <50, 63.4% group P50). The secondary form was associated with narcolepsy in 38.4% of patients in the group <50 y and with a synucleinopathy in 28.8% of patients in the group P50. A strong association was noted between RBD and non-REM parasomnias. Conclusions: In a population of patients with RBD presenting to a regional sleep laboratory, more than one-third of patients were <50 y at time of diagnosis. The commonest associated disorder was narcolepsy in patients <50 y, and synucleinopathy in those P50 y. The coexistence of RBD with a NREM parasomnia was not uncommon in cases of idiopathic RBD affecting patients <50 y.

Excessive sleepiness is defined as sleepiness that occurs in a situation when an individual would usually be expected to be awake and alert. Hypersomnia is characterized by recurrent episodes of excessive daytime sleepiness (EDS) or prolonged nighttime sleep, which affects the everyday life of the patient. Clinical surveys have reported that EDS is a complaint observed in up to 68% of normal high school children, with a negative impact in academic achievement and extracurricular activity. Clues toward recognizing childhood daytime sleepiness may be sleeping longer hours than expected for age, daytime naps beyond normal for age, being sleepy when other children of the same age are active and alert, and sleeping more than previously. Causes of EDS are arbitrarily divided into 3 categories: insufficient nighttime sleep, fragmented nighttime sleep, and increased drive of sleep. A list of various causes of EDS in children has been discussed. A detailed history along with examination of the upper airway is crucial in evaluating patients with EDS. Appropriate screening tools such as sleep logs, sleepiness scales, and sleep questionnaires further help in identifying and quantifying the degree of sleepiness. Confirmatory tests such as polysomnography, multiple sleep latency test, and actigraphy along with referral to a sleep physician may be necessary in appropriate cases. Details of other ancillary testing such use of cerebrospinal fluid orexin levels, HLA subtyping, and so on have also been provided. Semin Pediatr Neurol 15:61-69

Purpose of Review
The complex nature of narcolepsy symptoms, along with the use of stimulants and anticataplectic medications, poses diagnostic difficulties in terms of underlying neuropsychiatric comorbidities. This study reviews recent evidence for the association between narcolepsy and neuropsychiatric disorders. We also critically analyze studies that have addressed the neuropsychiatric correlates of patients with narcolepsy, with a discussion of the possible pathophysiological mechanisms linking narcolepsy and neuropsychiatric disorders.
Recent Findings
Neuropsychiatric manifestations are common among patients with narcolepsy as narcolepsy and some neuropsychiatric disorders share common clinical features. This may create challenges in making the correct diagnosis, and hence result in a delay in starting appropriate treatment. Comorbid neuropsychiatric manifestations in patients with narcolepsy include depression, anxiety, psychosis, rapid eye movement (REM) sleep behavior disorder, and cognitive impairment. Although hypocretin deficiency has been proposed as a pathophysiological mechanism underlying both narcolepsy and neuropsychiatric disorders, further research is necessary to identify the exact mechanisms.
Summary
Narcolepsy patients often manifest comorbid neuropsychiatric symptoms, which makes the diagnosis difficult. Therefore, it is essential to address neuropsychiatric symptoms in the clinical care of patients with narcolepsy.

Narcolepsy is a life-long central nervous system (CNS) syndrome characterised by excessive sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed night-time sleep. Unsuccessfully treated narcolepsy confers increased risks on patients and on society due to the patient&amp;amp;amp;amp;amp;amp;amp;#39;s increased chance of becoming involved in vehicle crashes and workplace mishaps. The syndrome may be diagnosed by a clinical history positive for cataplexy and excessive daytime sleepiness and negative for other more common sleep disorders such as sleep apnoea and sleep deprivation. Night-time polysomnography and multiple sleep latency testing are helpful in differentiating narcolepsy from other sleep problems. Recent data from canine, murine, and human forms of narcolepsy indicate that genetically or developmentally mediated deficits in the hypocretin neurotransmitter system may cause some, but not all, forms of narcolepsy. Pharmacotherapy for narcolepsy is required to control symptoms and involves the use of CNS stimulants or modafinil to control sleepiness and antidepressant medications or sodium oxybate to control cataplexy. Modafinil and sodium oxybate have been developed and approved specifically for the indication of narcolepsy based on large, double-blind, placebo-controlled, parallel group efficacy and safety studies. The efficacy of drugs in the treatment of narcolepsy is variable from patient to patient and usually associated with adverse effects that can limit patient compliance and, therefore, symptom control. Nevertheless, the benefits of pharmacotherapy are judged to outweigh the risks to the patient. The favourable benefit-risk ratio of pharmacotherapy is greater if one considers the reduced risk to society of vehicle crashes and workplace mishaps that might be precipitated by attentional lapses or sleep attacks in the untreated or under-treated patient with narcolepsy.

MicroRNAs (miRNAs) are involved in the pathogenesis of many human diseases, including some neurological disorders. Recently, we have reported dysregulated miRNAs in plasma from patients with central hypersomnias including type 1 and type 2 narcolepsy, and idiopathic hypersomnia. This study addressed whether miRNA levels are altered in the cerebrospinal fluid (CSF) of patients with central hypersomnias. We conducted highthroughput analyses of miRNAs in CSF from patients using quantitative real-time polymerase chain reaction panels. We identified 13, 9, and 11 miRNAs with a more than two-fold change in concentration in CSF from patients with type 1 and type 2 narcolepsy and idiopathic hypersomnia, respectively, compared with matched healthy controls. Most miRNAs differed in more than one of the sleep disorders. However, all miRNAs were detected at low levels in CSF and varied between individuals. None of them showed significant differences in concentrations between groups after correcting for multiple testing, and none could be validated in an independent cohort. Nevertheless, approximately 60% of the most abundant miRNAs in the profile reported here have previously been identified in the CSF of healthy individuals, showing consistency with previous miRNA profiles found in CSF. In conclusion, we were not able to demonstrate distinct levels or patterns of miRNAs in CSF from central hypersomnia patients.

Objective: Despite the fact that narcolepsy is a chronic disorder affecting younger people, there is insufficient information about its societal burden, time course, and familiar effect. We aimed to estimate the factual direct and indirect costs of narcolepsy patients and their families in a national sample using a controlled study design. Patients/Methods: Using records from the Danish National Patient Registry (1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009), all 816 narcolepsy patients and their partners were identified and compared with 3254 randomly chosen controls matched for age, gender, geographic area, and civil status. Direct and indirect costs, including frequencies of primary and secondary sector contacts' and procedures, medication, labor supply, and social transfer payments were extracted from the national databases. Results: Fewer patients (46.7%) than controls (51.4%) were married or cohabiting. Patients with narcolepsy had significantly higher rates of health-related contact, medication use, and a higher socioeconomic cost. Furthermore, they had lower employment rates, and those in employment had a lower income level than control subjects. Partners presented higher public health insurance and public transfers and lower income from employment. In all, the annual mean excess health-related cost, including social transfers, was €9572 for patients with narcolepsy and €3606 for their partners (both p < 0.001). Patient consequences could be identified up to 11 years before first diagnosis and became more pronounced as the disease advanced. Conclusion: Narcolepsy causes socioeconomic consequences, not only for patients, but also for their partners, which is present years prior to disease diagnosis, confirming a diagnostic delay.

Dear Editor: Use of sodium oxybate (SO) in patients with obstructive sleep apnea (OSA) and narcolepsy is controversial. SO is the firstline treatment for cataplexy in patients with narcolepsy . SO is a derivate of Gamma-hydroxybutyrate (GHB), a natural metabolite of the brainstem. GHB is a short-chain fatty acid, with action as an inhibitory neurotransmitter or neuromodulator. Mamelak [2] observed a decrease in apneahypopnea index (AHI) after treatment with gamma-OH in a patient with central apnea and narcolepsy. Another study performed in patients with OSA did not find differences between AHI before and after gamma-OH treatment .

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 d...

Background and purpose: Narcolepsy is a sleep disorder with clinical symptoms attributed to a reduced activation of the arousal system. Cyclic alternating pattern (CAP) is the expression of rhythmic arousability during non-rapid eye movement (NREM) sleep. CAP parameters, arousals and conventional sleep measures were studied in narcoleptic patients with cataplexy. Patients and methods: Data were collected from all-night polysomnographic (PSG) recordings and the multiple sleep latency test (MSLT) on the intervening day of 25 drug-naive patients (10 males and 15 females; mean age: 34±16 years) after adaptation and exclusion of other sleep disorders. A group of 25 age-and gender-matched normal sleepers were selected as controls. Each PSG recording was subdivided into sleep cycles. Analysis of CAP included classification of A phases into subtypes A1, A2, and A3. Results: There was an increase in sleep period time mainly due to an increased wake time after sleep onset. REM latency was sharply reduced. The percentage of NREM sleep was slightly reduced and the balance between light sleep (S1 + S2) and deep sleep (S3 + S4) showed a curtailment of the former, while deep sleep was slightly increased. Excluding sleep cycles with sleep onset REM periods (SOREMPs), the duration of ordered sleep cycles was not different between narcoleptics and controls. The two groups showed similar values of arousal index, while CAP time, CAP rate, number of CAP cycles and of phase A subtypes (in particular subtypes A1) were significantly reduced in narcoleptic patients. Conclusions: The reduced periods of CAP in narcoleptic NREM sleep could be the electroencephalographic (EEG) expression of a generally reduced arousability or an increased strength of sleep-promoting forces in the balance between sleep and arousal systems. This can explain some of the clinical correlates of the disorder, i.e. excessive sleepiness, short sleep latency and impaired attentive performances, even without any sign of arousal-induced sleep fragmentation.

Purpose This study aims to report on catathrenia occurring in narcolepsy with cataplexy (NC) patients under sodium oxybate (SO) treatment. Catathrenia is a parasomnia characterized by groaning and an abnormal respiratory pattern during sleep. Methods Fifty-one patients with NC and starting SO therapy underwent a baseline overnight polysomnography (PSG) to detect any sleep-related breathing disorders (SRBD). To avoid risks due to a possible central respiratory control depression by SO, all patients with concomitant obstructive sleep apnea (OSA) were treated with a nasal continuous positive airway pressure (nCPAP) device. After 2 months of treatment with SO, all patients underwent a follow-up overnight PSG to investigate possible newly occurring SRBD. They also underwent a semi-structured clinical interview to monitor other potential SO side effects. Results At baseline, four out of 51 patients showed simple snoring, and eight, mild to severe OSA. After a titration PSG night, patients with OSA received a nCPAP device. After 2 months of SO treatment, 28 patients (54.9%) showed SO-related side effects, including SRBD in 11 (21.6%). The follow-up PSG showed a respiratory pattern characteristic of catathrenia in seven patients (13.7%) as a newly observed and possibly benign SO side effect, and ruled out a worsening of OSA. Conclusions Catathrenia should be considered a possible side effect in NC patients under SO treatment and should be accurately identified to prevent unnecessary SO withdrawal.

Since the mid-1990s, Americans have been made more aware of chronic sleep deprivation and sleep disorders exacerbated by dominant temporal regimes of work, school and family life, primarily through increased medical and media attention; concomitantly, Americans have turned to medical treatments and pharmaceutical cocktails to achieve “normalcy” rather than attending to the social and cultural causes of sleep sickness. This turn toward pharmaceuticalization is aided in part by the proliferation of medical “disorders” and the pharmaceuticals marketed to treat them (e.g. “excessive daytime sleepiness” requires treatment once reserved for narcoleptics). These cocktails have explicit and implicit components: The former consist of pharmaceuticals, the latter of capital dependencies, including ties to medical insurance companies, stable employment, and familial networks. In this paper, I examine the proliferation of pharmaceutical cocktails through the concept of the pharmakon – something simultaneously remedy and cause – to illuminate the causes and effects of such pharmaceutical regimens in contemporary American society, specifically those relating to sleepiness. Specific cases of this struggle between chemical dependence and normalcy are offered from my ethnographic work with patients who suffer from sleep disorders.

Following studies of patients with postinfluenza encephalitis, the neuropathologist von Economo reported that inflammatory lesions of the preoptic area (POA) were often associated with insomnia and therefore proposed that the POA was critical for the production of normal sleep [1]. Then, Ranson in monkeys, Nauta in rats, and McGinty in cats showed that POA lesions induce a profound and persistent insomnia . It was later shown in cats that POA electrical stimulation induces EEG slow-wave activity and sleep (SWS) . Finally, putative sleep-promoting neurons displaying an elevated discharge rate during SWS compared to waking (W), diffusely distributed within a large region encompassing the horizontal limb of the diagonal bands of Broca and the lateral preoptic area-substantia innominata were recorded in freely moving cats . Altogether, these studies indicate that the POA is a unique brain structure containing neurons that directly promote sleep.

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/liter⅐24 h (P ‫؍‬ 0.02) and 920 ؎ 147 vs. 1460 ؎ 220 ng/liter⅐24 h (P ‫؍‬ 0.04), respectively], whereas pulsatile release did not differ between

Narcolepsy-cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals1 , 2. Narcolepsy was first shown to be tightly associated with HLA-DR23, and later sublocalized to DQB1*06024. Following studies in dogs5 and mice6, a 95% loss of hypocretin-producing cells in human postmortem hypothalami was reported7 , 8, Using Genome Wide Association (GWA) in Caucasians with replication in three ethnic groups, we found association with polymorphisms in the T-Cell receptor alpha (TCRA) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotype odds ratios 1.94 and 2.55, p<10 −21 , 1830 cases, 2164 controls). This is the first documented genetic involvement of the TCRA locus, the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders9, thus narcolepsy will provide new insights on how HLA-TCR interactions contribute to organ specific autoimmune targeting.

The epidemiological study of hypersomnia symptoms is still in its infancy; most epidemiological surveys on this topic were published in the last decade. More than two dozen representative community studies can be found. These studies assessed two aspects of hypersomnia: excessive quantity of sleep and sleep propensity during wakefulness (excessive daytime sleepiness). The prevalence of excessive quantity of sleep when referring to the subjective evaluation of sleep duration is around 4% of the population. Excessive daytime sleepiness (EDS) has been mostly investigated in terms of frequency or severity; duration of the symptom has rarely been investigated. EDS occurring at least 3 days per week has been reported in between 4% and 20.6% of the population, while severe EDS was reported at 5%. In most studies men and women are equally affected. In the International Classification of Sleep Disorders, hypersomnia symptoms are the essential feature of 3 disorders: insufficient sleep syndrome, hypersomnia (idiopathic, recurrent or posttraumatic) and narcolepsy. Insufficient sleep syndrome and hypersomnia diagnoses are poorly documented. The cooccurrence of insufficient sleep and EDS has been explored in some studies and prevalence has been found in around 8% of the general population. However, these subjects often have other conditions such as insomnia, depression or sleep apnea. Therefore, the prevalence of insufficient sleep syndrome is more likely to be between 1% and 4% of the population. Idiopathic hypersomnia would be rare in the general population with prevalence, around 0.3%. Narcolepsy has been more extensively studied, with a prevalence around 0.045% in the general population. Genetic epidemiological studies of narcolepsy have shown that between 1.5% and 20.8% of narcoleptic individuals have at least one family member with the disease. The large variation is mostly due to the method used to collect the information on the family members; systematic investigation of all family members provided higher results. There is still a lot to be done in the epidemiological field of hypersomnia. Inconsistencies in its definition and measurement limit the generalization of the results. The use of a single question fails to capture the complexity of the symptom. The natural evolution of hypersomnia remains to be documented.

Background: Narcolepsy-cataplexy is characterized by excessive daytime sleepiness with recurrent episodes of irresistible sleep, cataplexy, hallucinations and sleep paralysis. Its aetiology is unknown, but it is positively associated with the human leukocyte antigens (HLA) in all studied populations. The purpose of the present study was to investigate the association of HLA class II DRB1/DQB1 alleles with narcolepsy-cataplexy in Mexican Mestizo patients.

Rapid eye movement (REM) sleep behavior disorder (RBD) has been described predominantly in elderly men and in association with neurodegenerative disease. But an increasing proportion of cases in recent reports and in clinical practice do not fit this description; thus we sought to describe a current RBD population and possibly identify new subgroups with RBD.Records of 115 consecutive patients with polysomnogram-confirmed RBD at an academic sleep center were retrospectively reviewed.Male to female ratio was 2:1, and 1.25:1 for early-onset (age <50) cases. Mean age at diagnosis was 53.7 ± 16.4 years. Most (60%) cases were idiopathic, and neurodegenerative disease was coincident primarily in older men. Autoimmune disease was unexpectedly common in women (20%) particularly in the 30–49 age groups (40%). Antidepressant use was frequent (46.1%), especially in early-onset cases (57.8%).RBD is diagnosed more equally between men and women and in younger individuals than previously reported. While neurodegenerative disease is frequently co-incident with RBD in older men, most women and early-onset cases have “idiopathic” RBD. High prevalence of autoimmune disease among women with RBD suggests an intriguing link between immune dysfunction and RBD. A high rate of antidepressant use provides support for a potentially causal role for antidepressants in RBD.

Astute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with cataplexy, a disease resulting from the loss of orexin/hypocretin neurotransmitter signalling in the brain. Narcolepsy with cataplexy is characterized by irresistible bouts of sleep during the day, sleep fragmentation during the night and episodes of cataplexy, a sudden loss of muscle tone while awake and experiencing emotions. The neural mechanisms underlying cataplexy are unknown, but commonly thought to involve those of rapid eye movement-sleep atonia, and cataplexy typically is considered as a rapid eye movement sleep disorder. Here we reassess cataplexy in hypocretin (Hcrt, also known as orexin) gene knockout mice. Using a novel video/electroencephalogram doubleblind scoring method, we show that cataplexy is not a state per se, as believed previously, but a dynamic, multi-phased process involving a reproducible progression of states. A knockout-specific state and a stereotypical paroxysmal event were introduced to account for signals and electroencephalogram spectral characteristics not seen in wild-type littermates. Cataplexy almost invariably started with a brief phase of wake-like electroencephalogram, followed by a phase featuring high-amplitude irregular theta oscillations, defining an activity profile distinct from paradoxical sleep, referred to as cataplexy-associated state and in the course of which 1.5-2 s high-amplitude, highly regular, hypersynchronous paroxysmal theta bursts ($7 Hz) occurred. In contrast to cataplexy onset, exit from cataplexy did not show a predictable sequence of activities. Altogether, these data contradict the hypothesis that cataplexy is a state similar to paradoxical sleep, even if long cataplexies may evolve into paradoxical sleep. Although not exclusive to overt cataplexy, cataplexy-associated state and hypersynchronous paroxysmal theta activities are highly enriched during cataplexy in hypocretin/orexin knockout mice. Their occurrence in an independent narcolepsy mouse model, the orexin/ataxin 3 transgenic mouse, undergoing loss of orexin neurons, was confirmed. Importantly, we document for the first time similar paroxysmal theta hypersynchronies ($4 Hz) during cataplexy in narcoleptic children. Lastly, we show by deep recordings in mice that the cataplexy-associated state and hypersynchronous paroxysmal theta activities are independent of hippocampal theta and involve the frontal cortex. Cataplexy hypersynchronous paroxysmal theta bursts may represent medial prefrontal activity, associated in humans and rodents with reward-driven motor impulse, planning and conflict monitoring.

Narcolepsy with cataplexy (NC) is caused by the early loss of hypocretin-producing neurons in the hypothalamus. 1 Hypocretin activity is strongly associated with the maintenance of waking, but is also implicated in reward processing and addiction through direct and indirect projections to dopaminergic regions, i.e., the ventral tegmental area, the nucleus accumbens, and the amygdala. 2-4 Recently, we reported selective reduced performance by drug-free patients with NC on a decision-making task under ambiguity (the Iowa Gambling Task [IGT]), a typical behavioral assessment of reward processing in experimental psychology. 5 Patients with NC opted more often than controls for high immediate reward regardless of higher future punishment. 5 Our result was further confirmed in a modest-sized sample of 21 patients (drug-naïve and medicated) with NC without statistical power to compare patients taking stimulants with those who were not. Management of NC includes wake-promoting substances for excessive daytime sleepiness and sleep attacks, and

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.

This study determined the test-retest reliability of the polysomnographic findings in narcolepsy. The diagnosis of narcolepsy was based on clinical symptoms and polysomnographic signs. Control subjects were screened before participation and were split based on their screening multiple sleep latency test (MSLT) into high-and low-MSLT groups. Subjects completed two polysomnographic evaluations with at least 5 days between laboratory tests. Narcoleptics had lower sleep efficiencies and high stage 1% when compared to the low MSLT control group. They had more awakenings and less stage 2% than the control groups. Narcoleptics had a shorter latency to 1 when compared to the high-MSLT group but comparable to that of the low-MSLT group. Narcoleptics had a higher number of sleep-onset rapid eye movement periods (SOREMPs) than both control groups. The MSLT scores were stable across the two evaluations and showed a statistically significant correlation. Twentyeight of the 30 narcoleptic subjects had two or more SOREMPs on reevaluation. None of the controls had multiple SOREMPs. Thus, multiple SOREMPs were shown to be a reliable finding in patients with narcolepsy.

Episodic brain disorders (EBD) form an intriguing group of neurological diseases in which at least some of the symptoms occur in attacks. The hypothalamus integrates many brain functions, including endocrine and autonomic control, and governs various body rhythms. It seems a likely site in which the initiation of attacks of EBD can be modulated. Indeed, the hypothalamus has a crucial role in EBD such as narcolepsy and cluster headache. The same may be true for migraine and depression. Here we summarise the evidence supporting an important role for the hypothalamus in the initiation of disease episodes in various EBD. Study of the various pathophysiological concepts of EBD within the context of the hypothalamus may prove a fruitful example of cross-fertilisation between various research areas.

The aim of the study is to compare the course and severity of narcolepsy in relation to different ages at the disease onset. Clinical interviews with the completion of the Stanford questionnaire, Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency Test (MSLT) were evaluated in 105 patients (44 males, 61 females, mean age 45.4+/-19.2, BMI 29.2+/-5.8) suffering from narcolepsy. The severity of the disease was judged by clinical complaints, ESS value and MSLT results. No relations with the age at onset and clinical tetrad were found, however, smoking may be associated with an increased risk of hypnagogic hallucinations. There was no correlation between the number of sleep and cataplectic attacks and the age at onset, nor did subjective ESS show any significant dependence. However, earlier onset of the disease correlated with shorter MSLT mean latency. A correlation was found between the BMI and narcolepsy sleepiness rating in the elderly and between degree of education attained and subjective complaints. The clinical severity of narcolepsy does not depend on the age at onset.