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.

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.

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.

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.

[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.

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.

Sleep/wake abnormalities in patients with periodic leg movements during sleep: factor analysis on data from 24-h ambulatory polygraphy.

Periodic Leg Movements (PLM) in sleep occur in a wide variety of sleep/wake disorders but their relationship with sleep disturbance, and notably with the concomitant existence of a 'restless legs' syndrome (RLS) remains unclear. We performed 24-h ambulatory polygraphy in a population of 54 consecutive, unselected patients with PLMs (Coleman's index greater than 5/h) who complained of different sleep disorders. A Principal Component Analysis (PCA) was conducted on seven variables from the sample, namely PLM index, patient's age, sleep stage changes per hour, sleep depth index (SWS+PS/TST), diurnal sleep time, number of awakenings exceeding 2 min and presence of a RLS. PCA yielded four independent factors. The PLM index and the changes of sleep stage clustered in a single factor, linking therefore sleep fragmentation to the frequency of PLMs. The second factor appeared to reflect a circadian sleep/wake disorder, combining diurnal sleep time with the number of long night awakenings. The third factor was mainly loaded by the patients' age and the sleep depth index, thus reflecting a well known relationship. Finally, the variable reflecting the existence of a RLS appeared isolated in a single factor, independent from the three previously described. These results confirm and extend the link between PLMs and sleep fragmentation, as well as the recently described dissociation between PLMs and diurnal somnolence. On the other hand, our analysis suggests that in PLM patients the concomitant existence of a RLS is not related to the frequency of occurrence of PLMs, at least when these latter are quantified independently of their arousal index.

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.

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.

Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation.

Modafinil is an alerting substance which has been used successfully to treat narcolepsy. Nothing is known about its effect on hormone secretions. For this purpose, eight healthy young men were enrolled in a double blind trial to test the effects of modafinil on daily plasma melatonin, cortisol and growth hormone (GH) rhythms. Blood was sampled for hormone assays, every hour during the daytime and every 30 min during the nighttime. In addition, rectal temperature and mental performances were determined during the study which comprised 3 sessions, two weeks apart: a 24 h control session including a night with sleep (S1) and two 48 h sessions S2 and S3 with a sleep-deprived night (N1) followed by a recovery night (N2). Modafinil (300 mg x 2) or placebo were randomly attributed during N1 at 22 h and 8 h. As expected, performance was improved after modafinil administration and body temperature was maintained or increased. Plasma melatonin and cortisol profiles were similar after modafinil and placebo administration. The levels observed during the recovery and the control nights (N2) displayed no difference. For GH, during both sleep deprived nights, secretion was dramatically reduced compared with the control one, although the number of secretory episodes was unchanged. These data show that the alerting property of modafinil is not related to an alteration of hormone profiles and suggest that the acute modafinil administration is devoid of short-term side-effects.

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.

Actimetry in sleep medicine.

Actigraphy is more and more used in the longterm record of sleep of patients with insomnia. The correlation with data from polysomnography is reasonable for parameters like total sleep period (TSP) with r = 0,95-0,97 in healthy controls and r = 0,77-0,91 in patients. However for parameters, which inform about sleep fragmentation like wake after sleep onset (WASO) the correlation is not satisfieing with r = 0,87 in healthy controls and r = 0,49-0,63 in patients with fragmented sleep. The question is therefore, if actigraphs are really more useful in the record of sleep in patients with insomnia and fragmented sleep than sleep calenders.

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.

Unmasking of cortical SEP components by changes in stimulus rate: a topographic study.

We performed topographic mapping of somatosensory responses to median nerve stimulation delivered at 2, 5 and 10 Hz. Parietal N20 was significantly attenuated in 10 Hz somatosensory evoked potentials (SEPs), while central P22 diminished between 2 and 5 Hz, remaining stable thereafter. The single component most affected by increasing stimulus rate was N30, which abated by more than 50% in 10 Hz SEPs, as compared with basal responses. N30 attenuation disclosed the existence of an earlier negative component, N24, which appeared as a notch on the N30 ascending slope in 2 Hz SEPs, but became a well-defined peak at higher stimulus rates. The N24 negativity was not significantly modified by stimulus rate; it had a parietal counterpart (P24) with the same peak latency and identical behavior during the experimental procedure. Both P24 and N24 could be differentiated from central P22 on the basis of topographical distribution and response to stimulus frequency. P22 topography could be the result of a radially oriented generator, while P24/N24 appeared as the two poles of a neural source tangential to the scalp. P27 was seen in 40% of the subjects only; it is suggested that P27 is itself a composite potential to which the generator of N30 could contribute in part. We conclude that there is no single "optimal" stimulation rate for SEP recording. On the contrary, combination of different frequencies of stimulation should enhance the diagnostic utility of this technique by allowing a more selective assessment of overlapping activities.

Mapping study of somatosensory evoked potentials during selective spatial attention.

We have investigated the effects of selective spatial attention on early and middle-latency SEPs. Baseline control responses to electrical stimulation of 2 digits of the hand were recorded first in conditions of mental relaxation, in the absence of any cognitive task, to obtain truly 'neutral' responses uncontaminated by cognitive components. Then, during a 'task condition,' identical stimuli were applied to the same two fingers, but the subject's attention was driven towards the stimulated territory by the bias of mechanical taps delivered to the same digits. The earliest effect of directing attention towards the territory stimulated was a positive shift on contralateral somatosensory responses, with onset at 27.4 +/- 4 msec post stimulus. This SEP modification: (a) did not entail any change in the scalp distribution of components, as assessed by topographic mapping, and (b) was not present when attention was directed towards the hand contralateral to that receiving electrical stimuli. A second effect was represented by a parieto-central negativity in the 60-80 msec latency range; this feature could also be observed during contralaterally driven attention and was associated with topographical changes in SEP scalp distribution. Finally, a late centro-frontal negativity beginning at 90-100 msec (N140) appeared during ipsilateral attention, while P100 was not enhanced. Subcortical P14 and primary cortical N20 were not significantly affected by the tasks. We conclude that the 'early positive shift' is linked to the spatial aspects of selective attention and represents in part modulation of obligatory components (P25 through P45) existing in control SEPs; it probably corresponds with the deflections with similar polarity and time-course that have been described by others in response to somatosensory target stimuli. Conversely, 60-80 msec negative enhancement is less spatially selective and may represent non-specific arousal effects. The late negative component (N140) shares several features with the 'processing negativity' described in auditory paradigms and could represent the equivalent of this effect in the somatosensory system.

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.