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Background: Few studies to date have attempted to measure serum anti-Müllerian hormone (AMH) levels in adult men, and solid references ranges have not yet been defined in a large cohort., Objective: In this study, we aimed, first, to establish the reference ranges for serum AMH and AMH-to-total testosterone ratio (AMH/tT) in adult males. Second, we investigated the relationship between serum AMH and both reproductive hormones and semen parameters., Methods: This single-center retrospective study included 578 normozoospermic adult men. Serum AMH concentrations were determined with an automated sandwich chemiluminescent immunoassay., Results: The median serum AMH was 43.5 pmol/L. The 2.5th and 97.5th percentile values for serum AMH and AMH/tT were 16.4 and 90.3 pmol/L and 0.45 and 3.43, respectively. AMH was positively correlated with inhibin B and sperm concentration and negatively correlated with age, follicle-stimulating hormone (FSH), and progressive sperm motility. Interestingly, using immunofluorescence, we documented for the first time that AMH type II receptor (AMH-R2) is expressed in ejaculated human spermatozoa and gonadotrophic cells in the postmortem pituitary gland., Conclusions: We establish a new age-specific reference range for serum AMH and AMH/tT. Moreover, AMH-R2 expression in human spermatozoa and gonadotrophic cells, together with the relationship between serum AMH levels and sperm motility or mean FSH levels, highlight new potential functions of AMH in regulating sperm motility or FSH secretion in adult men., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Study Objective: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects., Design: Retrospective case-control study., Setting: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication., Patients and Participants: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included., Measurements and Results: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified., Conclusion: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Study Objectives: A loss of hypocretin neurons has been observed in human narcolepsy; however, the cause of this disorder is still unknown. While family history and genetic factors are important individual risk factors for narcolepsy, environmental factors also contribute to the pathogenesis of the disease. The aim of the study was to find out whether there is a seasonality of month of birth in narcoleptic patients., Design: Diagnosis of narcolepsy with cataplexy was based on International Classification of Sleep Disorders criteria with clinical, standard polysomnographic, and Multiple Sleep Latency Test features., Patients and Setting: The birth dates of 886 patients with a clear-cut diagnosis of narcolepsy with cataplexy from 3 large narcolepsy databases (352 from Montpellier-France, 157 from Montreal-Canada, and 377 from Stanford-United States of America) were compared with those of 35,160,522 subjects from the general population., Measurements and Results: Patients with narcolepsy had a significantly different seasonality of month of birth compared to that of the general population. The monthly distribution of birth yielded a peak in March with a maximal odds ratio at 1.45 and a trough in September with a minimal odds ratio at 0.63. No gender or country of origin differences were observed., Conclusions: A birth seasonality in the development of narcolepsy suggests the presence of environmental factors acting in combination with genetic factors during the fetal or perinatal period, in terms of an autoimmune process targeting the hypocretin system.

Study Objectives: The aim of the study was to determine the role of respiratory events, assessed by means of esophageal pressure monitoring, during arousals from slow wave sleep in adult patients with parasomnias., Design: N/A., Setting: N/A., Patients: Ten patients with parasomnias (sleepwalking, night terrors, or both) and 10 control subjects matched for gender and age underwent 3 consecutive nights of polysomnography., Interventions: N/A., Measurements and Results: By increasing sleep fragmentation, esophageal pressure monitoring has a deleterious effect on sleep architecture in patients with parasomnias and in control subjects. Respiratory events occur more frequently in parasomniacs than in controls. Respiratory effort seems to be responsible for the occurrence of a great number of arousal reactions in parasomniacs and is involved in triggering the parasomnia episodes., Conclusion: Sleep-disordered breathing seems to be frequently associated with parasomnias during slow wave sleep, emphasizing the utility of performing esophageal pressure monitoring in cases of sleep walking or night terrors.

Study Objectives: The aim of the study was to describe the clinical and polygraphical characteristics of narcoleptics, with and without cataplexy and to assess HLA predisposition across two different ethnic populations., Design and Setting: Patients were 126 men and 58 women referred to the Montpellier Sleep Disorders Center (Mtp) and 12 men and 8 women referred to the Fort-de-France Sleep Disorders Center (FdF) (Martinique, a French West Indy island) with symptoms of narcolepsy., Participants: Narcoleptics were included if they had both excessive daytime sleepiness and clear-cut cataplexy (for the group with cataplexy), a mean sleep latency of less than 8 minutes and at least two sleep onset REM periods., Interventions: N/A., Measurements and Results: Narcolepsy without clear-cut cataplexy was rare (12/172) in the Mtp population whereas it was as frequent as full-blown narcolepsy (10/10) in the FdF population. Comparison between narcoleptics with cataplexy from the Mtp and FdF populations revealed a younger age of onset, a trend towards more severe sleepiness and lower frequency of cataplexy in Martinicans. Comparison between narcoleptics without cataplexy from the Mtp and FdF population revealed a higher frequency of hypnagogic hallucinations and sleep paralysis and a trend towards more severe sleepiness in Martinicans. 4.2% of the Mtp and 15% of the FdF patients were negative for HLA DR2. However all of them were positive for HLA DQ1. Moreover, a tight association with HLA DRB1*1503 was observed in Martinicans in contrast with DRB1*1501 in the Mtp population. Association with HLA DQB1*0602 was observed in 99.4% of narcoleptics with cataplexy and in 89.5% of those without cataplexy., Conclusions: Narcolepsy is a heterogeneous clinical syndrome, the more so as ethnic origins are considered. A modulating effect of HLA and non-HLA genes on symptoms disease may explain these differences.

Modafinil is a central putative alpha-1 postsynaptic agonist with vigilance-promoting properties. Fifty narcoleptics (33 male and 17 female) participated in a multicentric study aimed at assessing the effects of the compound on night sleep, feeling on awakening, excessive daytime sleepiness and cataplexy. Modafinil was administered in a double-blind cross-over design at a daily dosage of 300 mg versus placebo. The duration of the study was 12 weeks, including a 2-week "run in" period with placebo, a first 4-week treatment period with either modafinil or placebo, a 2-week wash-out period with placebo and a second 4-week treatment period with either placebo or modafinil. Daily evaluation was based on a sleep log, visual analog scales, a sleep questionnaire and a clinical global index. Sleep laboratory evaluation took place on nights 1, 28, 42 and 70. It included 1 night of polysomnography preceded by a questionnaire on therapeutic and side effects, and a maintenance of wakefulness test (MWT). Sleep logs did not show any modification of night sleep, but a reduction of daytime sleepiness and sleep. Feeling on awakening was not modified. An overall benefit was noted by physicians as well as by patients. MWT disclosed a positive effect of modafinil on excessive daytime sleepiness. Cataplexy was not modified.

Narcolepsy is characterized by irresistible daytime sleep episodes and cataplectic attacks. Because of the finding of an ultradian rhythmicity of slow-wave sleep in narcolepsy, an alteration of nonrapid eye movement sleep homeostatic regulation has been hypothesized to explain the impairment of the sleep-wakefulness cycle. This hypothesis was tested by two different methods: 1) a sleep-deprivation method (16 or 24 hours) increasing the prior sleep wakefulness and 2) a bed-rest method shortening the prior sleep wakefulness. In both studies normal subjects, sex- and age-matched to narcoleptic subjects, served as controls. Although some differences could be evidenced between the two groups, it was clearly shown that the homeostatic process was functional in narcolepsy and that narcoleptics seemed to be more sensitive to homeostatic regulation of sleep than normal subjects.

A multifactorial etiology for narcolepsy has been postulated, stressing the importance of environmental factors in the clinical onset of the condition. Our study evaluated the occurrence of stressful life events in the year preceding the onset of narcolepsy. Fifty narcoleptic and 50 control subjects completed a life event questionnaire (the Schedule of Recent Experiences). The proportion of narcoleptic subjects reporting the presence of life events in the year preceding the onset of narcolepsy was significantly greater than the proportion of control subjects reporting life events in the corresponding year. Moreover the weight of life events was increased in narcoleptic subjects in comparison with controls. In conclusion life events seem to be increased in narcoleptic subjects in the year preceding the onset of their condition. However a number of other factors could not be taken into consideration, which limits the full significance of these data.

Out of a population of 188 unrelated narcoleptic probands, we identified 14 probands (7.44%) with a family history of narcolepsy, 23 (12.23%) with a family history of isolated repeated episodes of naps and/or lapses into sleep and 151 (80.31%) without a family history of either condition. Clinical, polysomnographic or zygotic differences could not be evidenced in the three groups. Empirical risk for narcolepsy was 40.7 times greater among first-degree relatives of narcoleptics than in the general population. Narcolepsy and the condition characterized by isolated repeated episodes of naps and/or lapses into sleep have a common genetic component. This finding has important implications. Indeed, when the latter condition is included in the spectrum of narcolepsy, the empirical risk figure is relatively close to that expected in cases of simple mode of inheritance. A trend in favor of a more frequent transmission through mothers than fathers is emphasized.

The upper airway cross-sectional areas were studied with pharyngeal computed tomography (CT) at the nasopharyngeal, velopharyngeal, tongue base and hyoid bone levels in 119 consecutively investigated patients with a snoring complaint. According to their findings in an all-night static charge sensitive bed (SCSB) recording, the subjects were divided into four equally sized groups with increasing severity of nocturnal breathing disturbance. The body mass index (BMI) increased and the minimal cross-sectional area at the velopharyngeal level decreased consistently as a function of the severity of nocturnal breathing disturbance. The minimal cross-sectional area at the hyoid bone level showed a biphasic trend, with an initial decrease but a final increase, as the degree of nocturnal breathing disturbance aggravated. The results contradict the idea of gradually increasing anatomical narrowing of the upper airways in general as the nocturnal breathing disturbance exacerbates and support the concept of two anatomically determined entities of partial and complete upper airway obstruction during sleep.

Uvulopalatopharyngoplasty (UPPP) is the surgery most often performed for sleep apnea syndrome (SAS). However, good results with UPPP, demonstrated by polysomnography, have been reported in only 50% of cases. Failure of UPPP may be caused by: 1) bad management of the SAS, which is better treated in some patients with nasal CPAP than with surgery; and 2) an airway obstruction located not only at the palatopharynx (PP) level. Other surgical procedures to enlarge other sites of obstruction are described. Retro-tongue-base-pharynx (RTBP) surgery is emphasized, including mandibular advancement, hyoid bone suspension, and tongue base reduction. Maxillomandibular advancement is the most efficient technique but also the most complicated.

Human narcolepsy is a genetically determined disorder of sleep strongly associated with the human leucocyte antigens (HLA) DR2 and DQw1. In black narcoleptic patients, susceptibility for narcolepsy is more closely related to a specific gene subtype of DQw1, DQB1-0602, than to DR2. About 30% of black narcoleptic patients are nonDR2, but all carry the HLA DQB1-0602 gene. In the present study, we have tested caucasian nonDR2 cataplectic patients (6 sporadic cases and 7 familial cases from 3 multiplex families) for the presence of the HLA DQB1-0602 and DQA1-0102 (DQw1) using a specific polymerase chain reaction (PCR)-oligotyping technique. None of the patients was DQB1-0602 or DQA1-0102 positive, thus proving that, in caucasians, DQB1-0602 and DQA1-0102 (DQw1) are not prerequisites for the diagnosis of narcolepsy. Further studies with more patients are warranted to exclude the possibility that a few caucasian patients carry rare haplotypes with DQB1-0602 independently of DR2.

Sleep of 11 narcoleptic subjects was recorded on baseline and after 16 and 24 hours of prior wakefulness (16 and 24 hours sleep deprivation). Eleven sex- and age-matched control subjects were recorded for comparisons. All recordings in narcoleptic subjects were characterized by frequent sleep onset rapid eye movement (REM) episodes, increased amounts of wake time after sleep onset and low sleep efficiencies. Mean total sleep time (TST) was significantly decreased in narcoleptic subjects after sleep deprivation (SD). Recovery sleep after 24 hours SD showed reduced nonREM (NREM) sleep stage 2 percentage, whereas percentages of stage 4 and slow-wave sleep (SWS = stages 3 + 4) were significantly increased. The values of REM sleep percentage of TST were remarkably constant throughout and did not differ significantly as a function of experimental conditions, indicating a normal REM sleep pressure in narcolepsy. Sleep stage analysis per sleep cycles revealed significant differences between the two groups. Percentages of stage 4 and SWS were increased during the first cycle of recovery sleep in narcoleptic subjects. Stage 2 was decreased during the third cycle, and SWS decreased rapidly from cycle 1 to cycle 2 and slightly increased thereafter. These results indicate that sleep need is increased in narcolepsy, whereas its decrease over the first NREM-REM cycle is accelerated. We hypothesize that this could reflect an alteration of the homeostatic process of sleep regulation in narcolepsy.

Twelve narcoleptic subjects experiencing at least five daytime REM sleep episodes were monitored for 34 consecutive hours in the laboratory starting at 2200 h one evening and ending at 0800 h a day and a half later. There was no significant difference between the length of the daytime and nighttime REM cycles. To test the hypothesis that an underlying rhythm governs REM episodes, a grid was constructed on the basis of the mean and the SD of the daytime cycles (starting at 0800 h the first morning) was projected on the following nighttime and its correspondence with actual night cycles was evaluated. Overall, it was observed that the number of night cycles falling within the projected grid was significantly higher than chance (p less than 0.01), indicating that nighttime REM episodes tended to fall within the same periodicity as their preceding daytime episodes. This observation supports the hypothesis that an underlying basic rest-activity cycle governs REM sleep episodes in narcoleptic subjects.

A positive association between HLA-DR2, DQw1, and narcolepsy was documented in 23 French caucasoid narcoleptic patients, 18 who were heterozygous for DR2 and 5 who were possibly homozygous. An autoimmune mechanism of narcolepsy is proposed with three successive stages, as well as relevant methodology for further investigation. A dominant mode of inheritance of narcolepsy, with an incomplete penetrance, is suggested although not yet evidenced.

Thirty-six narcoleptic patients with overwhelming sleep episodes, cataplexy, and sleep onset REM (SOREM) episodes were recorded for 34 continuous hours in the laboratory starting at 2200 h and ending at 0800 h a day and a half later. There were 94 SOREM and 60 sleep onset NREM (SONREM) episodes. While SONREM episodes were evenly distributed across daytime, SOREM episodes peaked between 0800 and 1000, 1200 and 1400, and 1600 and 1800 h. The ratio of SOREM to SONREM episodes was at its highest level between 1200 and 1400 h. Correlation coefficients between night 1 and night 2 for total sleep time (TST) and percentages of sleep stages were all positive and significant, whereas between daytime and each night, they were significant for percentages of stages 1, 2, and REM. Sleep-stage distribution across the last 24 h of continuous recording indicated that although TST levels were higher than that typical of normal subjects, REM sleep and slow wave sleep followed the same circadian distribution as that observed in normal subjects. The results are interpreted as evidence that the daytime sleep of narcoleptic patients is modified, similar to their night sleep, and that SOREM episodes are influenced by a time-of-day effect which culminates between 1200 and 1400 h.

To investigate the prevalence of excessive daytime somnolence and contributing factors, 58,162 draftees between 17 and 22 years of age, registered in two selection centers of the French army, were screened by means of a 17-item questionnaire. In response, 8,201 subjects (14.1%) reported occasional daytime sleep episodes, 2,210 (3.8%) one or two daily episodes, and 640 (1.1%) more than two daily episodes. Of the total sample, five percent or 2,933 considered these sleep episodes to affect their lives. Different possible factors of daytime sleep episodes were investigated, including hours of nocturnal sleep, sleep-wake schedule, sleep difficulties, use of hypnotics, snoring, and occurrence of cataplexy. A strong association was found between these factors and excessive daytime somnolence. A stepwise multivariate analysis was performed on five of these factors: hours of nocturnal sleep, sleep-wake schedule, sleep difficulties, use of hypnotics, and snoring. All five factors were shown to be independently related to excessive daytime somnolence and were ranked in the following descending order: use of hypnotics, sleep difficulties, irregular sleep-wake schedule, snoring, and hours of sleep.

Six normal volunteers, aged 20 to 39 years, underwent 2 adaptation nights and three sessions of 2 consecutive experimental nights and days at 1-week intervals, according to a latin-square design. In the three sessions, subjects received either zopiclone, 3.75 mg or 7.5 mg, or placebo at 2215 h in a double-blind protocol. On nights 1 and 2 of each session, subjects were continuously monitored polygraphically, except for a 45-min provoked wake episode 135 min after sleep onset on night 2. Degree of daytime somnolence was assessed during day 1 by means of a multiple sleep latency test (MSLT) and performance evaluation was carried out during night 2 (0000 h) and day 2 (800 h and 1200 h) by means of a battery of four tests. NREM sleep stages 3 and 4 increased significantly after 3.75 mg and 7.5 mg zopiclone (p less than 0.05). No significant differences between placebo and 3.75 mg and 7.5 mg zopiclone were found at any time in the MSLT. Two performance tests (eye-hand coordination test and choice reaction time test) showed a highly significant impairment (p less than 0.01) at 0000 h with 7.5 mg zopiclone; one test (eye-hand coordination test) showed a significant impairment (p less than 0.05) at 0800 h also with 7.5 mg zopiclone and none at 1200 h. From a subjective point of view, depth and quality of sleep were improved, whereas number of awakenings and feeling on awakening were not modified. Side effects (bitter taste, jitteriness, difficulty to concentrate) were reported only with 7.5 mg zopiclone.