Age at onset of narcolepsy in two large populations of patients in France and Quebec.

BACKGROUND: Narcolepsy usually starts around adolescence; however, there is great variability in the clinical presentation of narcolepsy. OBJECTIVE: To determine the age at onset in conjunction with severity of narcoleptic symptoms in two large populations of narcoleptic patients with a similar genetic background. METHODS: Information on age at onset and severity of the condition was obtained in 317 patients with well-defined narcolepsy-cataplexy from Montpellier (France) and in 202 from Montreal (Canada). RESULTS: The mean age at onset was 23.4 years in Montpellier and 24.4 in Montreal. The age at onset was bimodal in two independent patient populations: a first peak occurring at 14.7 years, and a second peak occurring at 35. Age at onset clearly differentiates patients with a positive family history of narcolepsy (early onset) from those without a family history. Other clinical and polygraphic findings may indicate that young age at onset is associated with increased severity of the condition (higher frequency of cataplexy and decreased mean sleep latency on the Multiple Sleep Latency Test). CONCLUSION: Bimodal distribution of age at onset of narcolepsy was found in two independent patient populations. Our data suggest that age at onset is genetically determined.

HLA-DR2 and narcolepsy.

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.

Homeostasis and narcolepsy.

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.

Are REM cycles in narcoleptic patients governed by an ultradian rhythm?

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.

Dose-response effects of zopiclone on night sleep and on nighttime and daytime functioning.

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.

Sleep in human narcolepsy revisited with special reference to prior wakefulness duration.

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.

Daytime sleep characteristics and their relationships with night sleep in the narcoleptic patient.

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.

Modafinil: a double-blind multicentric study.

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.

Life events in the year preceding the onset of narcolepsy.

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.

Family studies in narcolepsy.

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.

Sleep onset rapid-eye-movement episodes in narcolepsy: REM sleep pressure or nonREM-REM sleep dysregulation?

Thirty-two narcoleptic subjects with excessive daytime sleepiness and cataplexy were recorded for 33 continuous hours. The continuous polysomnographic recording (CPSG) was followed by a standard MSLT at 2-h intervals. There were 64 sleep onset REM episodes (SOREMs) vs 64 sleep onset nonREM episodes (SONREMs) during the CPSG, and 102 SOREMs vs 50 SONREMS during the MSLT. Both sleep onset types peaked at 13-15 h during the CPSG while sleep onsets were evenly distributed during the MSLT. In the latter procedure, the mean sleep latency was significantly shorter with SOREMs occurrence than with SONREMs occurrence. Two factors were extracted in each procedure by means of a Varimax Rotated Factor Analysis. During the CPSG, SOREMs were related to the preceding nocturnal sleep parameters in the first factor, and to the daytime total sleep time and the total number of sleep onsets in the second factor. During the MSLT, SOREMs were related only to the mean sleep latency and the total number of sleep onsets. It was concluded that the occurrence of SOREMs is primarily due to the residual somnolence in narcoleptic subjects. However, their occurrence during the MSLT is largely independent of the prior history of sleep and waking. Thus, we propose a nonREM-REM sleep dysregulation hypothesis to account for the appearance of SOREMs in narcolepsy.

Sleep architecture, slow wave activity, and sleep spindles in adult patients with sleepwalking and sleep terrors.

OBJECTIVES: A very strong SWS intensity reflected by both an increased level of SWA and an abnormal sleep spindles distribution would be responsible for the major difficulty of parasomniac subjects in waking up from SWS, leading to episodes of parasomnia. METHODS: Eleven adult parasomniac subjects, 6 females and 5 males, with sleepwalking (SW) and/or sleep terrors (ST) and 11 age- and sex-matched control subjects underwent polysomnography (PSG) during 2 consecutive nights. After an habituation and selection night followed by a 16 h period of controlled wakefulness, the sleep EEGs of the parasomniac and control subjects were analyzed on the second night by computer-aided visual scoring (integrated digital filtering analysis, IDFA) and spectral analysis (fast Fourier transform, FFT). Throughout the night subject behaviour was controlled and recorded by means of a video infra-red camera and videotape recorder. RESULTS: Fifteen episodes of parasomnia were recorded during the second night in the 11 subjects. Sleep analysis showed significantly (P<0.05) decreased sleep efficiency and stage 2 sleep (absolute values and percentage of total sleep time) and increased (P<0.05) slow wave sleep (absolute values and percentage of total sleep time). Arousal index and wake-time after sleep onset were significantly higher in parasomniac subjects. Sleep fragmentation was mainly concentrated in stages 3 and 4. The slow wave activity (SWA) absolute values averaged during the 2 min immediately preceding an episode of parasomnia were significantly higher than the SWA averaged during 2 min in the same stage 10 min before an episode of parasomnia. Moreover, SWA was higher in the slow wave sleep (SWS) episodes preceding the episode of parasomnia than in the episodes preceding an awakening without an episode of parasomnia. The temporal course of SWA showed a slower exponential decay in both groups, but the time constant of the curve was larger in parasomniacs than in controls. Finally, in control subjects the sleep spindle index increased from the beginning to the end of the night while it was equally distributed in parasomniacs. CONCLUSIONS: An abnormal deep sleep associated with a high SWS fragmentation might be responsible for the occurrence of SW or ST episodes.

Sleep architecture, slow wave activity and sleep spindles in mild sleep disordered breathing.

OBJECTIVE: A high degree of sleep fragmentation by arousals related to respiratory events would result in an abnormal distribution of slow wave activity (SWA) and a decrease in sleep spindle density in sleep disordered breathing (SDB) patients when compared to controls. METHODS: Eighteen mild SDB subjects (6 females and 12 males), aged 18-56 years with (5

Effects of zopiclone on subjective evaluation of sleep and daytime alertness and on psychomotor and physical performance tests in athletes.

1. In a double-blind cross-over study 8 athletes received during 2 sessions of 2 nights zopiclone (7.5 mg) or placebo. 2. Residual effects on subsequent daytime functions were evaluated both subjectively by visual analogue scales as well as objectively by a test battery measuring psychomotor and physical skills. 3. Zopiclone had some favourable effects on self-estimated sleep quality and daytime sleepiness. 4. Psychomotor and physical performance tests did not show any significant difference between zopiclone and placebo. 5. We conclude that zopiclone has useful hypnotic activity without significant adverse effects on athletic performance.

Hypersomnia associated with mood disorders: a new perspective.

Thirty-six subjects affected with hypersomnia associated with mood disorders, 31 with a diagnosis of dysthymia, 4 with a diagnosis of bipolar disorder and one with a diagnosis of major recurrent depression underwent standardized polysomnographic procedures including night 1, MSLT and night 2 (uninterrupted). 36.1% of these subjects had a reduced or intermediate mean sleep latency on the MSLT and 13.8% slept over 9 hr at night. In addition 17 of these subjects underwent prolonged polysomnography during day 2. In comparison with eight subjects affected with idiopathic hypersomnia, mean sleep latency on the MSLT was significantly longer and total sleep time during night 2 and during night 2 plus day 2 was significantly lower in subjects affected with hypersomnia associated with mood disorders. It is concluded that a positive diagnosis of hypersomnia associated with a mood disorder requires both behavioral observation and polysomnography. Among these subjects there may be subjects with well-documented hypersomnia and subjects with anergia facilitating or mimicking sleep.

Use of modafinil in the treatment of narcolepsy: a long term follow-up study.

One hundred and forty patients (104 male and 36 female) aged 42.26 +/- 19.19 (range = 8 to 79.5 years) with narcolepsy-cataplexy were given modafinil (200 to 400 mg) at the Montpellier sleep disorders center from 1984 onwards. The follow-up focused on the reduction of excessive daytime somnolence (EDS), side effects and duration of treatment. In order to determine if any clinical aspect of narcolepsy could be involved in modafinil discontinuation, patients were divided into two groups according to continued or interrupted treatment. When modafinil effect on EDS was evaluated according to a scale varying from 0 (no effect) to 3 (excellent effect), 64.1% of the subjects, scored good or excellent. The mean duration of treatment was 22.05 months +/- 24.9, ranging from 1 to 114 months. Dependency signs were never observed.

[The effects of modafinil (300mg) on sleep, sleepiness and arousal in narcoleptic patients]. / Effets du modafinil (300 mg) sur le sommeil, la somnolence et la vigilance du narcoleptique.

CNS stimulants are the most widely used drugs to treat narcolepsy which is characterized by the excessive daytime sleepiness and typically associated with cataplexy. However, a number of side effects may often arise with this therapeutic approach. Thus, investigating new drugs which are efficient but well tolerated is of utmost importance in the treatment of narcolepsy. Although modafinil, an alpha-1 adreno-receptor agonist, has been reported to bring substantial awakening properties in animals, the studies performed in man, particularly in narcoleptic subjects, are few. In the present study, we evaluated the effects of a 300 mg daily dose of modafinil on sleepiness and psychomotor performance of 16 narcoleptic subjects. The major effect of modafinil in narcoleptic subjects was a decrease of daytime sleepiness and corresponding improvement of performances involving attentive functions. However, the learning effect in psychomotor tests may mask the drug effect.

[Effects of zopiclone on sleep, daytime somnolence and nocturnal and daytime performance in healthy volunteers]. / Effets de la Zopiclone sur le sommeil, la somnolence diurne et les performances nocturnes et diurnes chez le volontaire sain.

Ten healthy volunteers, aged 20 to 39, underwent 2 adaptation nights and 3 sessions of 2 consecutive experimental nights and days at 1 week intervals. In the 3 sessions, subjects received under double blind conditions either Zopiclone 3.75 mg or 7.5 mg or placebo, according to a latin-square design. On nights 1 and 2 of each session, subjects were continuously polygraphically monitored, except for a 45 min provoked wake episode 135 min after sleep onset on night 2. Sleep continuity and architecture were evaluated during night 1, degree of daytime somnolence during day 1 and residual effects during night 2 (0 h 00) and day 2 (8 h 00 and 12 h 00). Sleep continuity was not modified, except for a reduction of the number of night awakenings. NREM sleep stage 1 was reduced and stage 2 was increased (in duration but not in percentage) with Zopiclone 3.75 and 7.5 mg. NREM sleep stages 3 and 4 were increased with Zopiclone 3.75 mg only. REM sleep was reduced (in percentage only) with Zopiclone 3.75 and 7.5 mg. Daytime somnolence varied according to the time but not with the 3 different conditions. One performance test only (choice reaction time test) showed a significant impairment at 0 h 00 with Zopiclone 7.5 mg. From a subjective point of view, sleep quality was improved and night time awakening was reduced with Zopiclone 7.5 mg.

Ultradian aspects of sleep in narcolepsy.

Following a baseline night recording, 9 narcoleptic subjects and 9 sex and age-matched control subjects were maintained on 16 hours of diurnal sleep deprivation. Thereafter subjects were submitted to a 32 hour bed rest protocol in a sound-light attenuated room. The EEG was recorded and processed using a Fast Fourier Transform. Narcoleptic patients did not differ from control subjects in total sleep time over the whole time-span. An ultradian tendency to sleep seems to be predominant in narcoleptic patients and evidence of a strong basic rest activity cycle is shown. The coupling between the homeostatic process of sleep regulation and an ultradian drive to sleep would explain the peculiar 4 hour distribution pattern of SWA in narcoleptic patients.

Effects of zolpidem on the architecture and cyclical structure of sleep in poor sleepers.

Effects of zolpidem, a short acting non benzodiazepine hypnotic, have been studied in eight female poor sleepers, aged 25 to 54 years, documented during two consecutive adaptation nights. Subjects were recorded according to a 22 day single blind study. Placebo was given orally at bedtime on nights 2-4, zolpidem on nights 5-20 and finally placebo on nights 21-22. Polygraphic recordings (conventional analysis) were performed on nights 1-6; 12, 13; 19-22. Parameters of sleep continuity, sleep architecture and cyclical structure of sleep were studied. Zolpidem 10 mg showed a hypnotic effect on poor sleepers. It reduced sleep latency, increased total sleep time and decreased the number of awakenings during all recorded nights. During the first post-drug night a rebound insomnia was observed in two subjects only. Zolpidem did not increase specifically stage 2 to the detriment of stages 3 and 4 but it restored them during the first nights of administration. Study of the rapid eye movements-non rapid eye movements (REM-NREM) sleep cycles structure showed that the increase of stages 3 and 4 occurred only during the first part of the night. Finally, zolpidem had no effect on REM sleep temporal distribution.