Academic and professional paths of narcoleptic patients: the Narcowork study.

OBJECTIVE/BACKGROUND: To study educational and professional pathways of narcoleptic patients and examine demographic, disease-related and environmental factors associated with a better academic and professional prognosis. PATIENTS/METHODS: In sum, 69 narcoleptic patients (51 narcolepsy type 1 and 18 narcolepsy type 2, age 42.5 ± 18.2 years) were enrolled in this pilot monocentric cross-sectional study with a comparison group (80 age- and sex-matched controls) between October 2017 and July 2018 in Lyon Center for Sleep Medicine. They completed questionnaires about their academic and professional trajectories and specific scales of quality of life (EuroQol quality of life scale EQ-5D-3L), depression (beck depression inventory, BDI), sleepiness (Epworth Sleepiness Scale, ESS) and narcoleptic symptoms severity (narcolepsy severity scale, NSS). RESULTS: No difference in grade repetition or final obtained diploma was observed between patients and controls, but patients evaluated their academic curricula as more difficult (45.5% vs 16.9%, p = 0.0007), complained for more attentional deficits (75% vs 22.1%, p < 0.0001), and had needed more educational reorientation (28.6% vs 9.9%, p = 0.01). Even if no difference was observed in occupational category and professional status, patients expressed significantly less satisfaction about their work. Patients had more signs of depression [OR severe depression = 4.4 (1.6-12.6), p = 0.02] and their quality of life was significantly decreased (67.3 ± 18.4 vs 80.6 ± 13.2, p = 0.0007) as compared to controls. Multivariate analysis showed that a more favorable professional career was associated with a better quality of life. CONCLUSIONS: Educational and professional pathways do not seem to be significantly impaired in narcoleptic patients, but their experience and quality of life are affected. These findings may allow to reassure patients and should lead to a more comprehensive management of the disease. CLINICAL TRIAL REGISTRATION: Narcowork, https://clinicaltrials.gov/ct2/show/NCT03173378, N° NCT03173378.

Psychological health in central hypersomnias: the French Harmony study.

BACKGROUND: A large observational French study of central hypersomnia, including narcolepsy with cataplexy (C+), without cataplexy (C-) and idiopathic hypersomnia (IH), was conducted to clarify the relationships between the severity of the condition, psychological health and treatment response. METHODS: 601 consecutive patients over 15 years of age suffering from central hypersomnia were recruited on excessive daytime sleepiness, polysomnography and Multiple Sleep Latency Test (MSLT) results. 517 (47.6% men, 52.4% women) were finally included: 82.0% C+, 13.2% C- and 4.8% IH. Face to face standardised clinical interviews plus questionnaires (Epworth Sleepiness Scale (ESS), short version Beck Depression Inventory (S-BDI), Pittsburgh Sleep Quality Index (PSQI) and 36-item Short Form Health Survey (SF-36)) were performed. Patients affected with a different diagnosis and with and without depressive symptoms were compared. RESULTS: Mean ESS and body mass index were higher in C+ compared with C-/IH patients. Half of the patients (44.9%) had no depressive symptoms while 26.3% had mild, 23.2% moderate and 5.6% severe depressive symptoms. C+ patients had higher S-BDI and PSQI and lower SF-36 scores than C-/IH patients. Depressed patients had higher ESS scores than non-depressed patients, with no difference in age, gender, duration of disease or MSLT parameters. Finally, C+ patients treated with anticataplectic drugs (38.7%) had higher S-BDI and lower SF-36 scores than C+ patients treated with stimulants alone. CONCLUSION: Our data confirmed the high frequency of depressive symptoms and the major impact of central hypersomnias on health related quality of life, especially in patients with cataplexy. We recommend a more thorough assessment of mood impairment in central hypersomnias, especially in narcolepsy-cataplexy.

[Misuse of sleep and wakefulness drugs: from undesirable effects to addiction]. / Mésusage des médicaments du sommeil et de la vigilance.

Sleep disorders, mainly insomnia and daytime somnolence, can arise from very different causes. For example insomnia may be related to anxiety-depression or occur in response to a stressful lifestyle or as an element of restless leg syndrome. Subjects with hypersomnia may present episodes of sleep apnea, drug-related depression or narcolepsia. Specific management is required for each etiology. Misuse of sleep drugs generally results from an insufficient etiological diagnosis and a misunderstanding of their proper use. These drugs can be used as necessary expedients but cannot replace correct management or treatment of the cause or causes of the sleep disorder. We present here a review of the undesirable effects, particularly among the elderly population, and of the risk of addiction to the different drugs used to induce sleep in order to propose prescription guidelines.

Nocturnal continuous infusion of growth hormone (GH)-releasing hormone results in a dose-dependent accentuation of episodic GH secretion in normal men.

Fluctuations in plasma GH levels have been found in patients with acromegaly who have continuously elevated levels of ectopically produced GH-releasing hormone (GHRH). Likewise, plasma GH fluctuations have been found in normal subjects receiving continuous GHRH infusions. We report the effects of two doses of GHRH, administered by constant infusion, on nocturnal GH secretion in six normal young men. Each received, in random order, 2.5 ng/kg X min GHRH, 15 ng/kg X min GHRH, and 0.15 M NaCl. During both GHRH doses, a highly significant increase in total nocturnal GH secretion was found (P less than 0.001) as well as an increase in GH secretion during different periods of the night. Nocturnal GH secretion was episodic during the GHRH infusions, with an increase in the number and magnitude of the peaks compared to those during the NaCl infusion. Plasma immunoreactive GHRH concentrations plateaued at 1 h during the high dose and at 3 h during the low dose GHRH infusion. Sleep parameters, including total sleep time, sleep latency, and duration and timing of the different sleep stages, were not affected by GHRH infusions. We conclude that GHRH, continuously infused, increases nocturnal GH secretion according to the dose, while the episodic pattern of GH secretion is maintained.

Changes of middle latency auditory evoked potentials during natural sleep in humans.

During natural nocturnal sleep, Na and Pa middle latency auditory evoked potentials (MLAEPs) underwent significant variations which were related to sleep stages. The deepening of sleep from stage II to stage IV was paralleled by a latency shift and an amplitude decrease of Na and Pa, while MLAEPs were similar in wakefulness and REM sleep. Moreover, Na and Pa components tended to shift over the hemisphere contralateral to the stimulated ear during sleep. These findings demonstrate that the responsiveness of the auditory cortex to acoustic stimuli is modulated during sleep. Vigilance should be monitored during MLAEP recordings in patients.

Sleep ontogenesis revisited: a longitudinal 24-hour home polygraphic study on 15 normal infants during the first two years of life.

The sleep organization of 15 normal infants (seven boys, eight girls) was studied at their homes during six 24-hour periods, i.e. at 3, 6, 9, 12, 18, and 24 months of age, using the Oxford Medical System. Sleep states and stages were scored visually at 30-second intervals, according to Rechtschaffen and Kales' criteria, adapted for children by Guilleminault. All sleep parameters were analyzed for the entire 24-hour period, i.e. during both the nocturnal and the diurnal part of the nycthemere. The results showed a continuous decrease in total sleep time, rapid eye movement (REM) sleep, and indeterminate sleep, and also an increase in waking time, quiet sleep, and stages 1 and 2 sleep. Except for slow-wave sleep, which remained very stable for the different ages, analysis of variance applied to the data showed clear age and day-night effects on sleep ontogenesis. Modifications with age were more precocious and more pronounced for the diurnal part of the nycthemere, especially as regards REM sleep. For the nocturnal part, there was a significant increase in sleep efficiency and in the length of the REM period after 12 months of age, while total sleep duration and number of awakenings decreased. In addition to normative data for clinical use, this study provides three new interesting results related to the maturation of sleep mechanisms and functions: 1) the high stability of the percentage of slow-wave sleep along these 2 years, 2) the presence (from 12 months of age) of a stage 2/REM sleep ratio equal to one, and a sleep change occuring earlier, during the diurnal rather than the nocturnal part of the nycthemere. The first two points could be regarded as indexes of sleep maturation reflecting developmental and neurophysiological changes in central nervous system structures. The third point underlines the importance of the circadian rhythm and the concept of "experience" in the maturation of sleep.

Evoked potentials as a tool for the investigation of human sleep.

This review summarizes studies of evoked potentials (EPs) applied to the investigation of human sleep and of sleep disorders. The first part is devoted to studies dealing with the nature, mechanisms and extent of information processing during sleep. EP studies suggest that the brain's ability to detect salient stimuli persists during even the deepest sleep stages, while discrimination of the stimulus' intrinsic significance and/or semantic content may persist only in stage II and paradoxical sleep (PS). Deviance detection in non-rapid eye movement (NREM) sleep is reflected by amplitude recovery of K-complexes elicited by stimulations that differ from the background. The evoked K-complex appears to be formed by two functionally different modules. The first may be related to the discrimination of relevant information. The second appears more sensitive to stimulus salience than to its intrinsic significance. In PS, the EP signs of stimulus discrimination are similar to those observed during waking. Thus, if the possibilities of information processing are fairly similar during stage II and PS, their respective neural mechanisms are not the same, as judged by their electrophysiological counterparts. The second part of the paper reviews clinical application of EPs to the study of sleep/wake disorders. While early potentials are of little use for diagnosis of sleep disorders, the cognitive P300 may help to quantify cognitive slowing and pathological sleepiness. However, intersubject variability restrains the use of these techniques in individual patients. A promising approach is the utilization of late responses to the study of sleep inertia with the use of "forced awakening" recording paradigms.

Functional dissociation of the early and late portions of human K-complexes.

We analyzed K-complexes (KCs) evoked during sleep stage II by the subject's own name and by other names. KCs were composed either of four consecutive waves (full KCs, N2-P3-N3-P4) or of the two first components only (N2-P3). The amplitude of the late phase of KCs (N3-P4) was identical to all stimuli; conversely, own names enhanced selectively the N2-P3 waves, whether they were or not part of a full KC. Two independent phenomena appear to coexist during a full KC, one being connected to the physical characteristics of the stimulus (N3-P4) and the other to its intrinsic significance. This latter may appear either within a full KC or in isolation, and in this case it is reminiscent of the N200-P300 complex observed in wakefulness.

A differential brain response to the subject's own name persists during sleep.

METHODS: Auditory evoked potentials (AEPs) to the subject's own name and to seven other first names were recorded in ten normal adults during wakefulness, in both passive listening and active detection conditions, and during sleep stage II (SII) and paradoxical sleep (PS). All stimuli were disyllabic, equiprobable and presented in random order. RESULTS: During wakefulness, a parietal positive 'P3' component, peaking at about 500 ms, probably equivalent to the endogenous P300 wave, was enhanced in response to the subject's own name, even in the passive condition. During SII, K-complexes (KCs) were evoked by all first names and were formed by two biphasic consecutive waveforms. While the amplitude of the late complex (N3/P4) was identical for both types of stimuli, the early portion of the KC (N2/P3), and notably the positive wave 'SII-P3' at about 600 ms, was selectively enhanced after the subject's own name. This supports the hypothesis that at least two distinct neuronal systems are activated in parallel in response to auditory stimuli during SII, one reflecting the detection of stimulus' salience and the other the processing of its intrinsic relevance. During PS, the AEP morphology was comparable to that observed in wakefulness. Notably, a posterior 'PS-P3' wave appeared exclusively in response to own names at about 550 ms, and was considered as an equivalent of the waking P300. CONCLUSIONS: These results suggest that the sleeping brain, during SII and PS, elicits a differential cognitive response to the presentation of the subject's own name, comparable to that occurring during wakefulness, and therefore that the sleeping brain is able to detect and categorize some particular aspects of stimulus significance.

Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil.

1. Modafinil, a putative central alpha 1 adrenergic agonist, was tested in idiopathic hypersomnia and narcolepsy. 2. Sleep attacks and drowsiness were significantly decreased in 83% of 18 hypersomniac subjects and 71% of 24 narcoleptics. 3. When cataplectic episodes were not totally suppressed the association of a low dose of Clomipramine was successful in improving them. 4. Modafinil, used for at least 3 years in some patients, produces, in most cases, no peripheric sides effects, does not disturb night sleep and is never responsible of tolerance of drug dependence.

Brain processing of stimulus deviance during slow-wave and paradoxical sleep: a study of human auditory evoked responses using the oddball paradigm.

Auditory evoked potentials (AEPs) to frequent (90%) and deviant (10%) tones were recorded during both wakefulness and all-night sleep in eight drug-free volunteers. During presleep waking (10:00-11:00 p.m.), deviant stimuli elicited, in all subjects, a prominent "P300" wave of parieto-central topography, culminating at 344 ms (average), which was absent in response to frequent tones. This "presleep P300" was delayed and reduced relative to values obtained during full wakefulness (3:00-7:00 p.m.) in a control group. Passage from waking to sleep stage I was characterized by a progressive attenuation and delay of the P300 wave in response to deviant stimuli, without major changes in AEP morphology as compared to the waking state. Thus, in terms of cognitive evoked potentials (EPs), sleep stage I appeared more as a "weak" state of wakefulness than a true phase of sleep. During sleep stages II, III, and IV, both frequent and deviant tones evoked AEPs that closely resembled K-complexes. Responses to rare stimuli were four-to-five times larger than those to frequent tones, this likely being the result of K-complex habituation to monotonous stimuli. During paradoxical sleep (PS), AEP morphology again became comparable to that of wakefulness. Notably, a "P3" wave with similar topography as the waking P300 appeared in response to deviant stimuli exclusively. Thus, even though the brain seems able to detect stimulus deviance during all sleep stages, only during stage I and PS were the electrophysiological counterparts of deviance detection comparable to those of the waking state. Our results support the view that PS is not a state of "sensory isolation"; failure to respond to external stimuli during this stage may depend upon mechanisms occurring only after the sensory input has undergone cognitive analysis.

[Rhythms of falling asleep persisting in adults. Two cases without mental deficiency]. / Rythmies d'endormissement persistant chez l'adulte. Deux cas sans débilité mentale.

Nocturnal rhythmic movements (jactatio capitis nocturnus, JCN) are very frequent in young children but persist only rarely in adults; studies including sleep recordings are exceptional in those cases. We report two new cases of young adults with JCN persisting since the first year of life, associated with restless sleep and diurnal sleepiness. Several episodes of JCN were recorded in each of the two patients; they always occurred after a period of paradoxical sleep, the waking phase preceding the rhythmic movements which are sometimes very short (1 s). The pathophysiology of adult JCN is discussed as a behavioral disorder of sleep onset conditioning or a disorder of sleep maintenance.

[HLA and narcolepsy. Apropos of 28 cases including 2 negative HLA-DR2]. / HLA et narcolepsie. A propos de 28 cas dont deux HLA-DR2 négatifs.

Association between narcolepsy and HLA-DR2 antigen is the strongest so far described between an HLA antigen and a disease. Among 28 narcoleptic patients, we found two HLA-DR2 negative cases: a caucasoid woman also suffering from dystrophia myotonica and a negroid. All of our patients were HLA-DQW1 positive. An hypothetical narcolepsy susceptibility gene could be located in the HLA region, closer to the DQ than to the DR gene. It could be a pathologic allele of a sleep controlling gene in linkage disequilibrium with DQW1. Presence of DQW1 is a quasi-requisite for the expression of narcolepsy. It is not sufficient as it is observed in 70 p. 100 of controls.

[Nocturnus terrors--somnambulism]. / Les terreurs nocturnes--le somnambulisme.

Among disorders of sleep in children, pavor nocturnus ("night terrors") is common and considered harmless. Yet the clinical picture, the child's personality and the polygraphic electroencephalographic recordings suggest that it should be treated sooner and more often than is usually done. Somnambulism ("sleep walking") also is very frequent. It has no consequences in most cases, but it may be the cause of serious events such as falling out of a window which is rare but may result in death or disablement. Some children have repeated attack of somnambulism, and these constitute a true pathology of sleep requiring a specific treatment that will cure or improve. All this must be known to the practitioner who will inform the parents.

Discriminating neurological from psychiatric hypersomnia using the forced awakening test.

INTRODUCTION: Sleep inertia refers to the inability to attain full alertness following awakening from sleep and is a major component of hypersomnia. As event-related potentials (ERPs) are correlated to the degree of consciousness, they allow exploring information processing in transitional states of vigilance. Their modifications during forced awakening (FA) context have been shown to reflect sleep inertia. OBJECTIVES: To assess the diagnostic value of a FA test using an oddball stimulation protocol during a nap in a representative sample of patients with excessive daytime sleepiness (EDS). METHODS: One hundred and seventy three patients [30 narcolepsy, 62 idiopathic hypersomnia, 33 sleep apnoea syndrome, and 48 other (mainly psychiatric) hypersomnia] performed an auditory target detection stimulation task during pre-, post-nap wakefulness, and during two successive intra-nap FA while the EEG was simultaneously recorded. Both the accuracy of target detection and the ERPs were evaluated. ERPs during forced awakening test were considered to reflect sleep inertia if they presented with a P300 delay and/or sleep negativities (N350/N550). RESULTS: Pre-nap behavior and ERPs were normal in all patients. Behavioral results were significantly worse during FA than during wakefulness for all groups of patients. P300 latencies were significantly delayed on FA conditions in each group of patients except the psychiatric group. Sensitivity and specificity for detection of sleep inertia were 64% and 94%, respectively, with predictive values of 96% (positive) and 50% (negative). CONCLUSIONS: Our results suggest that the FA test could be helpful as a diagnostic procedure for discriminating neurological from psychiatric hypersomnia.

Pain and sleep: from reaction to action.

Sleep disruption by painful stimuli is frequently observed both in clinical and experimental conditions. Nociceptive stimuli produce significantly more arousals (30% of stimuli) than non-nociceptive ones. However, even if they do not interrupt sleep, they can trigger a variety of other reactions. Reflex behaviours in response to nociceptive stimuli can be observed during all sleep stages, and are more likely to occur in association with an arousal than alone. Cardiac activation represents a robust sympathetically driven effect preserved whatever the state of vigilance, even if its magnitude can be modulated by a concomitant cortical arousal. Not withstanding these reactions, incorporation of nociceptive stimuli into dream content remains limited. At cortical level, laser-evoked potential studies demonstrate that the processing of nociceptive stimulations is partly conserved during all sleep stages. Furthermore, when nociceptive stimulations interrupt sleep, the cortical response presents a late component suggesting that the stimulation has to be cognitively processed in order to produce a subsequent arousal. More complex reactions to nociceptive stimulations were occasionally reported. In this context, an epileptic patient with intracerebral electrodes implanted for therapeutic purposes allowed us extending these observations. This patient exhibited finger lifts in response to stimulations delivered during paradoxical (REM) sleep. This motor reaction was previously used during wakefulness to indicate that the stimulation had been perceived. When these finger lifts occurred a systematic re-activation of the anterior cingulate preceded each movement. This observation suggests that during PS, not only the processing of sensory inputs but also the capacity for the sleeper to intentionally indicate his perception could be preserved under particular circumstances.

Autonomic pain responses during sleep: a study of heart rate variability.

The autonomic nervous system (ANS) reacts to nociceptive stimulation during sleep, but whether this reaction is contingent to cortical arousal, and whether one of the autonomic arms (sympathetic/parasympathetic) predominates over the other remains unknown. We assessed ANS reactivity to nociceptive stimulation during all sleep stages through heart rate variability, and correlated the results with the presence of cortical arousal measured in concomitant 32-channel EEG. Fourteen healthy volunteers underwent whole-night polysomnography during which nociceptive laser stimuli were applied over the hand. RR intervals (RR) and spectral analysis by wavelet transform were performed to assess parasympathetic (HF(WV)) and sympathetic (LF(WV) and LF(WV)/HF(WV) ratio) reactivity. During all sleep stages, RR significantly decreased in reaction to nociceptive stimulations, reaching a level similar to that of wakefulness, at the 3rd beat post-stimulus and returning to baseline after seven beats. This RR decrease was associated with an increase in sympathetic LF(WV) and LF(WV)/HF(WV) ratio without any parasympathetic HF(WV) change. Albeit RR decrease existed even in the absence of arousals, it was significantly higher when an arousal followed the noxious stimulus. These results suggest that the sympathetic-dependent cardiac activation induced by nociceptive stimuli is modulated by a sleep dependent phenomenon related to cortical activation and not by sleep itself, since it reaches a same intensity whatever the state of vigilance.

Laser evoked responses to painful stimulation persist during sleep and predict subsequent arousals.

We studied behavioural responses and 32-channel brain potentials to nociceptive stimuli during all-night sleep in 12 healthy subjects, using sequences of thermal laser pulses delivered over the dorsum of the hand. Laser stimuli less than 20 dB over perception threshold had clear awakening properties, in accordance with the intrinsic threatening value of nociceptive signals. Even in cases where nociceptive stimulation did not interrupt sleep, it triggered motor responses in 11% of trials. Only four subjects reported dreams, and on morning questionnaires there was no evidence of incorporation to dreams of nociceptive stimuli. Contrary to previous reports suggesting the absence of cortical nociceptive responses during sleep, we were able to record brain-evoked potentials to laser (LEPs) during all sleep stages. Sleep LEPs were in general attenuated, but their morphology was sleep-stage-dependent: in stage 2, the weakened initial response was often followed by a high-amplitude negative wave with typical features of a K-complex. During paradoxical sleep (PS) LEP morphology was similar to that of waking, but frontal components showed strong attenuation, consistent with the reported frontal metabolic deactivation. A late positive component (450-650 ms) was recorded in both stage 2 and PS, the amplitude of which was significantly enhanced in trials that were followed by an arousal. This response appeared functionally related to the P3 wave, which in waking subjects has been associated to conscious perception and memory encoding.