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Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female predominance, severe morning inertia, continuous drowsiness (rather than sleep attacks), unrefreshing naps, absence of cataplexy, sleep onset in REM periods, and hypocretin deficiency. In IH, the multiple sleep latency test demonstrates low sensitivity, specificity, and reproducibility, compared with prolonged sleep monitoring. In some IH cases, an endogenous hypnotic peptide stimulating GABA receptors during wakefulness is suspected, which are improved by anti-GABA drugs. The benefits of modafinil, sodium oxybate, mazindol, and pitolisant were found in mostly retrospective studies.

Study Objectives To establish whether the recent EEG and behavioral criteria of arousal disorders apply to sexsomnia. Methods EEG and behavioral markers upon N3 sleep interruptions in videopolysomnography were retrospectively compared in 24 participants with sexsomnia, 41 participants with arousals disorders, and 40 healthy controls. The specificity and sensitivity of previously suggested EEG and behavioral cutoffs for supporting arousal disorders diagnosis were measured in the sexsomnia vs. control groups. Results Participants with sexsomnia and arousals disorders showed a higher N3 fragmentation index, slow/mixed N3 arousal index, and number of eye openings during N3 interruptions than healthy controls. Ten (41.7%) participants with sexsomnia (vs. one sleepwalker and no control) displayed an apparently sexual behavior (masturbation, sexual vocalization, pelvic thrusting, and hand within the pajama) during N3 arousal. An N3 sleep fragmentation index ≥6.8/h of N3 sleep and two or more N3 arousals associated with eye opening was 95% specific but poorly (46% and 42%) sensitive for diagnosing sexsomnia. An index of slow/mixed N3 arousals ≥2.5/h of N3 sleep was 73% specific and 67% sensitive. An N3 arousal with trunk raising, sitting, speaking, showing an expression of fear/surprise, shouting, or exhibiting sexual behavior was 100% specific for a diagnosis of sexsomnia. Conclusions In patients with sexsomnia, videopolysomnography based markers of arousal disorders are intermediate between healthy individuals and patients with other arousal disorders, supporting the concept of sexsomnia as a specialized, but less neurophysiologically severe, NREM parasomnia. Previously validated criteria for arousal disorders partially fit in patients with sexsomnia.

Study Objectives To evaluate sleep, sleepiness, and excessive need for sleep in patients with craniopharyngioma (a suprasellar tumor which can affect sleep–wake systems). Methods A retrospective study of all adult patients living with craniopharyngioma referred to the sleep clinic, who received a sleep interview, nocturnal polysomnography, multiple sleep latency tests (MSLT), and 18-h bed rest polysomnography. Their sleep measurements were compared with those of age- and sex-matched healthy controls. Results Of 54 patients screened with craniopharyngioma, 42 were analyzed, 80% of whom complained of excessive daytime sleepiness. Sleep testing revealed that 6 (14.3%) of them had secondary narcolepsy (including one with cataplexy), and 11 (26.2%) had central hypersomnia associated with a medical disorder. Compared with controls, patients were more frequently obese, had a shorter mean sleep latency on MSLT, and slept longer on the first night. There was a nonsignificant trend for patients with (vs. without) narcolepsy and hypersomnia to be younger, to have a higher body mass index, to be more likely to have received radiation therapy, and to have more severe damage to the hypothalamus after surgery. Treatment with stimulants (modafinil, pitolisant, and methylphenidate) was beneficial in 9/10 patients. Conclusions Nearly half of the patients with craniopharyngioma and sleep disorders have a central disorder of hypersomnolence (narcolepsy and hypersomnia), which should be investigated and lead to considerations beyond sleep apnea syndrome in these obese patients.

Resume L’hypersomnie idiopathique (HI) est une maladie neurologique rare du sujet jeune, caracterisee par une somnolence diurne excessive malgre un sommeil de nuit de qualite normale, et de duree normale ou prolongee. Elle se distingue de la narcolepsie par sa predominance feminine, des difficultes a se reveiller le matin (ivresse de sommeil), une somnolence continue (plus proche d’un hypo-eveil que d’attaques de sommeil) et des siestes souvent longues et peu rafraichissantes, et par l’absence de cataplexie, d’endormissements en sommeil paradoxal et de deficit en hypocretine. Le diagnostic elimine les causes plus frequentes de somnolence et retient comme anormal une latence moyenne d’endormissement 11 h en enregistrement de 24 h (ou 19 h de sommeil sur 36 h alite). Le TILE n’est cependant ni sensible, ni specifique et peu reproductible, d’ou l’interet de l’enregistrement prolonge. L’imagerie fonctionnelle cerebrale suggere qu’il existe un sommeil local prefrontal chez ces patients en eveil. Dans de rares cas d’hypersomnie resistante, un peptide hypnotique endogene stimulerait les recepteurs GABA-A pendant l’eveil : ces patients seraient ameliores par des medicaments anti-GABA (flumazepil, clarithromycine). En l’absence d’autorisation de mise sur le marche, le diagnostic et la primo-prescription des stimulants doivent etre valides par un centre de reference ou de competence des hypersomnie rares. Le benefice du modafinil a ete montre dans une etude controlee contre placebo, et celui de l’oxybate de sodium, du mazindol et du pitolisant a ete constate dans des etudes observationnelles retrospectives.

STUDY OBJECTIVES: To assess the frequency, determinants, and clinical impact of clinical rapid eye movement (REM) and non-REM (NREM) parasomnias in adult patients with narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia compared with healthy controls. METHODS: Familial and past and current personal parasomnias were assessed by questionnaire and medical interviews in 710 patients (220 NT1, 199 NT2, and 221 idiopathic hypersomnia) and 595 healthy controls. RESULTS: Except for sleep-related eating disorder, current NREM parasomnias were rare in all patient groups and controls. Sleep-related eating disorder was more frequent in NT1 patients (7.9% vs 1.8% in NT2 patients, 2.1% in patients with idiopathic hypersomnia, and 1% in controls) and associated with disrupted nighttime sleep (odds ratio = 3.9) and nocturnal eating in full awareness (odds ratio = 6.9) but not with sex. Clinical REM sleep behavior disorder was more frequent in NT1 patients (41.4%, half being violent) than in NT2 patients (13.2%) and affected men more often than women (odds ratio = 2.4). It was associated with disrupted nighttime sleep, depressive symptoms, and antidepressant use. Frequent (> 1/week) nightmares were reported by 39% of patients with NT1, 29% with NT2, and 27.8% with idiopathic hypersomnia (vs 8.3% in controls) and were associated with depressive symptoms in narcolepsy. No parasomnia (except sleep-related hallucinations) worsened daytime sleepiness. CONCLUSIONS: In patients with central disorders of hypersomnolence, comorbid NREM parasomnias (except for sleep-related eating disorder) are rare and do not worsen sleepiness. In contrast, REM parasomnias are prevalent (especially in NT1) and are associated with male sex, disrupted nighttime sleep, depressive symptoms, and antidepressant use. CITATION: Leu-Semenescu S, Maranci J-B, Lopez R, et al. Comorbid parasomnias in narcolepsy and idiopathic hypersomnia: more REM than NREM parasomnias. J Clin Sleep Med. 2022;18(5):1355–1364.

International audience; BACKGROUND: Insomnia is a frequent complaint of patients with Parkinson’s disease, and it negatively affects quality of life. Drugs that improve both sleep and parkinsonism would be of major benefit to patients with Parkinson’s disease-related insomnia. We aimed to test the safety and efficacy of subcutaneous night-time only apomorphine infusion in patients with Parkinson’s disease and insomnia. METHODS: We did a randomised, multicentre, double-blind, placebo-controlled, crossover trial in 11 expert centres in Parkinson’s disease and sleep centres in France. Participants aged 35-90 years with fluctuating Parkinson’s disease and moderate to severe insomnia (Insomnia Severity Index score ≥15) were randomly assigned to either first receive night-time subcutaneous apomorphine (up to 5 mg/h) or matching placebo. Randomisation was done using a computer-generated plan in blocks of four, stratified by centre. This first intervention was followed by a 14-night washout period, then crossover to the other intervention. The treatment periods consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. The dose was adjusted during the titration phase on the basis of a daily telephone call assessing sleep quality and treatment tolerability. The primary efficacy endpoint was the difference in Parkinson’s disease sleep scale (PDSS) scores from the beginning to the end of each treatment period. Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT02940912. FINDINGS: Between Jan 31, 2017, and Jan 29, 2021, 46 participants were enrolled. 25 (54%) patients were randomly assigned to receive apomorphine first and 21 (46%) patients to receive placebo first. Mean change in PDSS score was significantly greater with night-time apomorphine infusion (15·18 [SD 24·34]) compared with placebo (5·23 [21·52]; treatment effect 9·95 [95% CI 0·88-19·03]; p=0·041). Adverse events were reported in 25 (54%) participants during the apomorphine period and in 17 (37%) participants during the placebo period (p=0·16). Apomorphine was associated with more frequent dizziness than was placebo (seven [15%] vs 0; p=0·041). INTERPRETATION: Subcutaneous night-time only apomorphine infusion improved sleep disturbances according to difference on PDSS score, with an overall safety profile consistent with previous studies in Parkinson’s disease. This treatment might be useful to manage sleep disturbances in patients with advanced Parkinson’s disease and moderate to severe insomnia. FUNDING: Orkyn and Aguettant Pharma. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson’s disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson’s disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.

STUDY OBJECTIVES: ADCY5 mutations cause early-onset hyperkinetic movement disorders comprising diurnal and nocturnal paroxysmal dyskinesia, and patient-reported sleep fragmentation. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia. METHODS: Using video polysomnography, we evaluated the nocturnal motor events and abnormal movements in 7 patients with ADCY5-related dyskinesia and compared their sleep measures with those of 14 age- and sex-matched healthy controls. RESULTS: We observed an increased occurrence of abnormal movements during wake periods compared to sleep in patients with ADCY5-related dyskinesia. While asleep, abnormal movements occurred more frequently during stage N2 and REM sleep, in contrast with stage N3 sleep. Abnormal movements were also more frequent during morning awakenings compared to wake periods before falling asleep. The pattern of the nocturnal abnormal movements mirrored those observed during waking hours. Compared to controls, patients with ADCY5-related dyskinesia had lower sleep efficiencies due to prolonged awakenings secondary to the abnormal movements, but no other differences in sleep measures. Notably, sleep onset latency was short and devoid of violent abnormal movements. CONCLUSIONS: In this series of patients with ADCY5-related dyskinesia, nocturnal paroxysmal dyskinesia were not associated with drowsiness or delayed sleep onset, but emerged during nighttime awakenings with subsequent delayed sleep, whereas sleep architecture was normal.

International audience; BackgroundHyposmia and isolated REM sleep behavior disorder are well-established features of prodromal Parkinson's disease (PD).ObjectivesThe objective of the present study was to evaluate whether taste loss (reported in PD and possibly suggesting brain stem involvement) is present at the isolated REM sleep behavior disorder stage.MethodsWe assessed taste function using the Taste Strip Test (evaluating 4 concentrations of bitter, sweet, sour, and salty) in 44 participants with isolated REM sleep behavior disorder, 19 with PD, and 29 controls. All participants underwent video-polysomnography, standardized questionnaires, and clinical examination, including olfactory assessment.ResultsParticipants with isolated REM sleep behavior disorder and PD had lower taste scores than controls. There was no difference between isolated REM sleep behavior disorder and PD cohorts, nor was there any correlation between taste and olfaction, age, disease duration, cognition, or autonomic function.ConclusionThis study demonstrates for the first time the presence of taste impairment in isolated REM sleep behavior disorder that is independent of olfactory dysfunction and comparable to participants with PD. © 2021 International Parkinson and Movement Disorder Society

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10(−9)) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R(2) = 0.15; P < 2.0 × 10(−22) at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case.control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2= 0.15; P < 2.0 ∼ 10-22at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

Ortega-Albás JJ, López R, Martínez A, Carratalá S, Echeverria I, Ortega P. Kleine-Levin syndrome, GABA, and glutamate. J Clin Sleep Med. 2021;17(3):609–610.

Kleine–Levin syndrome is a rare disorder characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealization and behavioural disturbances. Between episodes, most patients experience normal sleep, mood and behaviour, but they may have some residual abnormalities in brain functional imaging; however, the frequency, localization and significance of abnormal imaging are unknown, as brain functional imaging have been scarce and heterogenous [including scintigraphy 18F-fluorodeoxyglucose positron emission tomography/computerized tomography (FDG-PET/CT) and functional MRI during resting state and cognitive effort] and based on case reports or on group analysis in small groups. Using visual individual analysis of 18F-fluorodeoxyglucose positron emission tomography/computerized tomography at the time of Kleine–Levin syndrome diagnosis, we examined the frequency, localization and clinical determinants of hypo- and hypermetabolism in a cross-sectional study. Among 179 patients with Kleine–Levin syndrome who underwent 18F-fluorodeoxyglucose positron emission tomography/computerized tomography, the visual analysis was restricted to the 138 untreated patients studied during asymptomatic periods. As many as 70% of patients had hypometabolism, mostly affecting the posterior associative cortex and the hippocampus. Hypometabolism was associated with younger age, recent (, Graphical Abstract Graphical Abstract

Kleine-Levin Syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome wide association study in 673 KLS cases collected over 14 years, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (OR=1.48,rs71947865,p=8.6×10−9) with 20 single nucleotide polymorphisms encompassing a 35kb region located in the 3’ region ofTRANK1gene, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases withTRANK1rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 years, we further stratified our sample by birth years and found that recent cases had a significantly reducedTRANK1rs71947865 association. While theTRANK1rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, the TRANK1 rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR=1.54;p=0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo r2=0.15;p−22at p=0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, behavioral rhythmicity, and bipolar disorder, and indicates that theTRANK1polymorphisms in conjunction with reported birth difficulties may predispose to KLS.Significance StatementGenetic markers inTRANK1gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin Syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment are suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in theTRANK1gene region may predispose to KLS when patients have had a difficult birth, suggesting thatTRANK1gene region modulate newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impact birth and KLS.

STUDY OBJECTIVES: To determine the polysomnography characteristics during sleep paralysis, false awakenings, and lucid dreaming (which are states intermediate to rapid eye movement [REM] sleep and wake but exceptionally observed in sleep laboratory). METHODS: In 5 participants, we captured 5 episodes of sleep paralysis (2 time marked with the ocular left–right–left–right code normally used to signal lucid dreaming, 1 time marked by an external noise, and 2 retrospectively reported) and 2 episodes of false awakening. The sleep coding (using 3-second mini-epochs) and spectral electroencephalography analysis were compared during these episodes and normal REM sleep as well as wakefulness in the same 4 of 5 participants and vs lucid REM sleep in 4 other patients with narcolepsy. RESULTS: During episodes of sleep paralysis, 70.8% of mini-epochs contained theta electroencephalography rhythm (vs 89.7% in REM sleep and 21.2% in wakefulness), 93.8% contained chin muscle atonia (vs 89.7% in REM sleep and 33.3% in wakefulness), and 6.9% contained rapid eye movements (vs 11.9% in REM sleep and 8.1% in wakefulness). The electroencephalography spectrum during sleep paralysis was intermediate between wakefulness and REM sleep in the alpha, theta, and delta frequencies, whereas the beta frequencies were not different between sleep paralysis and normal REM sleep. The power spectrum during false awakening followed the same profile as in sleep paralysis. CONCLUSIONS: The predominant theta electroencephalography rhythm during sleep paralysis and false awakenings (with rare and lower alpha rhythm) suggests that the brain during sleep paralysis is not in an awake but in a dreaming state. CITATION: Mainieri G, Maranci JP, Champetier P, et al. Are sleep paralysis and false awakenings different from REM sleep and from lucid REM sleep? A spectral EEG analysis. J Clin Sleep Med. 2021; 17(4):719–727.

In Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson’s disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson’s disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson’s disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson’s disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content., Using multi-modal imaging (MRI and SPECT) in patients with prodromal and early clinical Parkinson’s disease, Biondetti et al. reveal dopaminergic changes, abnormal iron metabolism and neuromelanin changes first in the sensorimotor, then the associative and finally the limbic regions of the nigrostriatal system.

Prader–Willi syndrome (PWS) is a rare, genetic, multisymptomatic, neurodevelopmental disease commonly associated with sleep alterations, including sleep-disordered breathing and central disorders of hypersomnolence. Excessive daytime sleepiness represents the main manifestation that should be addressed by eliciting the detrimental effects on quality of life and neurocognitive function from the patients’ caregivers. Patients with PWS have impaired ventilatory control and altered pulmonary mechanics caused by hypotonia, respiratory muscle weakness, scoliosis and obesity. Consequently, respiratory abnormalities are frequent and, in most cases, severe, particularly during sleep. Adults with PWS frequently suffer from sleep apnoea syndrome, sleep hypoxemia and sleep hypoventilation. When excessive daytime sleepiness persists after adequate control of sleep-disordered breathing, a sleep study on ventilatory treatment, followed by an objective measurement of excessive daytime sleepiness, is recommended. These tests frequently identify central disorders of hypersomnolence, including narcolepsy, central hypersomnia or a borderline hypersomnolent phenotype. The use of wake-enhancing drugs (modafinil, pitolisant) is discussed in multidisciplinary expert centres for these kinds of cases to ensure the right balance between the benefits on quality of life and the risk of psychological and cardiovascular side effects.

This case-control study aimed to identify and validate behavioral markers supporting the diagnosis of disorders of arousal (DOA) with video polysomnography.All behaviors associated with 1,335 episodes of N3 interruptions were compared in 52 adult patients with DOA versus 52 participants without DOA (healthy control patients and patients with insomnia, hypersomnia, or sleep apnea syndrome).Patients with DOA had more frequent (5.1 ± 2.4 versus 3.4 ± 1.9 interruptions/N3 time) and longer (35.8 ± 33 versus 23.1 ± 21.4 sec) arousals and awakenings from N3 than control patients. In the DOA group, the onset of behaviors was more abrupt, and behaviors including eye opening (69% versus 16%), head raising (41% versus 9%), visually exploring the environment (27% versus 1%), expression of fear/surprise (21% versus zero), speaking (18% versus 0.3%), trunk raising (13% versus 0.3%), and interacting with the environment (13% versus 0.5%), were (unlike quiet, comfort behaviors) more frequent than in control patients. A cutoff of two or more N3 interruptions containing eye opening yielded a sensitivity of 94.2% and a specificity of 76.9% for a DOA diagnosis. This accuracy was confirmed in a second set of data (second night of monitoring). Behaviors including an expression of fear/surprise (67.3%), sitting (32.7%), screaming, and standing up were specific to patients with DOA.A simple, behavioral video marker of behavioral reactions during N3 interruption (ie, opening the eyes at least two times in the same night) was sensitive, specific, and reproducible for discriminating patients with DOA from sleep laboratory control patients.This study is a surrogate study of NCT02648568 and NCT03074578 on ClinicalTrials.gov.

International audience; At the extreme spectrum of consciousness during sleep, some patients with rare hypersomnias reported experiencing a specific night 'blackout' when sleeping, i.e., an absence of experiences or recall of them from sleep onset to offset. Thus, we explored through questionnaires the conscious experiences (dreaming experience, mind, self) during the night in 133 patients with idiopathic hypersomnia, 108 patients with narcolepsy, and 128 healthy controls. The night blackout was more frequent in idiopathic hypersomnia than in narcolepsy and control groups. Patients with idiopathic hypersomnia and frequent night amnesia had lower dream recall frequencies, and felt more often sleep as deep and mind as blank during the night. They had a higher proportion of slow wave sleep on their (retrospectively collected) sleep recordings than those without night blackout. This night blackout provides a new model for studying loss of consciousness during sleep, here as a contentless, selfless and timeless feeling upon awakening.

International audience; In the absence of specific clinical signs, imaging or biomarkers, the differential diagnosis of degenerative parkinsonian syndromes may be difficult at early stages of the disease. To reduce the risk of misdiagnosis or delayed diagnosis and referral to multiple medical centers at disease onset, easier access to expert centers should be available. To improve the initial care of parkinsonian patients, the Parkinson's disease Expert Center (PEC) at Pitié-Salpêtrière Academic Hospital has set up a specific outpatients clinic with short waiting times dedicated to the diagnosis of early Parkinson's disease and related disorders.MethodsThe PEC setup first identifies requests for diagnostic confirmation of parkinsonian syndromes, then specific outpatients clinic visits are scheduled weekly, with examinations carried out by neurologists at the PEC on a rotating schedule. Data from the first year of the new procedure were analyzed retrospectively through self-administered questionnaires sent to patients seen during this period. The main outcomes were to confirm the ability to keep to short delays for patients’ examinations and to assess patients’ satisfaction with the setup.ResultsBoth study outcomes were achieved. The creation of an outpatients clinic dedicated to the early diagnosis of parkinsonian syndromes allowed shorter delays before the first examination of 5 weeks instead of several months. Keeping to the weekly schedule and limited time taken for each visit was also achieved. Following this initial outpatients visit, diagnosis of a parkinsonian syndrome was clinically confirmed or further specified in 80% of cases. A survey of patients’ satisfaction showed a rate of over 91% in terms of the timing and course of clinical examinations at our PEC.Discussion/ConclusionThis study of our quality-improvement program for Parkinson's disease management has shown that specific consultations with shorter waiting times aiming to allow early specialized assessment of parkinsonian syndromes is beneficial for patients and reduces the risk of delayed diagnoses.

STUDY OBJECTIVES: ADCY5 mutations cause early-onset hyperkinetic movement disorders comprising diurnal and nocturnal paroxysmal dyskinesia, and patient-reported sleep fragmentation. We aimed to characterize all movements occurring during sleep and in the transition from sleep to awakening, to ascertain if there is a primary sleep disorder, or if the sleep disturbance is rather a consequence of the dyskinesia. METHODS: Using video polysomnography, we evaluated the nocturnal motor events and abnormal movements in 7 patients with ADCY5-related dyskinesia and compared their sleep measures with those of 14 age- and sex-matched healthy controls. RESULTS: We observed an increased occurrence of abnormal movements during wake periods compared to sleep in patients with ADCY5-related dyskinesia. While asleep, abnormal movements occurred more frequently during stage N2 and REM sleep, in contrast with stage N3 sleep. Abnormal movements were also more frequent during morning awakenings compared to wake periods before falling asleep. The pattern of the nocturnal abnormal movements mirrored those observed during waking hours. Compared to controls, patients with ADCY5-related dyskinesia had lower sleep efficiencies due to prolonged awakenings secondary to the abnormal movements, but no other differences in sleep measures. Notably, sleep onset latency was short and devoid of violent abnormal movements. CONCLUSIONS: In this series of patients with ADCY5-related dyskinesia, nocturnal paroxysmal dyskinesia were not associated with drowsiness or delayed sleep onset, but emerged during nighttime awakenings with subsequent delayed sleep, whereas sleep architecture was normal. CITATION: Méneret A, Roze E, Maranci JB, Dodet P, Doummar D, Riant F, Tranchant C, Fraix V, Anheim M, Ekmen A, McGovern E, Vidailhet M, Arnulf I, Leu-Semenescu S. Sleep in ADCY5-related dyskinesia: prolonged awakenings caused by abnormal movements. J Clin Sleep Med. 2019;15(7):1021–1029.

International audience

Kleine-Levin syndrome (KLS) is a rare, relapsing-remitting disease that affects mostly adolescents. It is characterized by episodes lasting from 1 to several weeks, and comprises neurological (hypersomnia, confusion, slowness, amnesia) and neuropsychiatric symptoms (derealization and apathy). Some psychiatric symptoms (megaphagia, hypersexuality, anxiety, depressed mood, hallucinations, delusions) arise during episodes, albeit less frequently, while patients are normal between episodes. However, sudden severe (>18h/day of sleep) and recurrent hypersomnia helps to differentiate KLS from other psychiatric mimics. Derealization, the striking feeling of unreality or of being in a dream-like environment, is strongly associated with hypoperfusion of the associative temporoparietal junction cortex, whereas apathy is almost complete loss of autoactivation: teenagers stop using their cell phones and their only spontaneous initiative is to sleep. The cause of KLS is not known, but evidence suggests it could be a recurrent inflammatory encephalitis. Up to 5% of cases are familial, although no abnormal gene has yet been found. Hypersomnia episodes tend to become less frequent and to disappear with advancing age. However, 28% of patients have long-lasting episodes (>30 days), and around 15% have no signs of recovery after >20 years of living with the disorder. Patients' cognitive and psychiatric status should be regularly checked during asymptomatic periods, as 20-40% develop long-term mild cognitive impairment or mood disorders. Lithium therapy is beneficial for reducing episode frequency, and intravenous steroids can reduce the duration of long episodes.

Breathing is irregular during rapid eye-movement (REM) sleep, whereas it is stable during non-REM sleep. Why this is so remains a mystery. We propose that irregular breathing has a cortical origin and reflects the mental content of dreams, which often accompany REM sleep. We tested 21 patients with narcolepsy who had the exceptional ability to lucid dream in REM sleep, a condition in which one is conscious of dreaming during the dream and can signal lucidity with an ocular code. Sleep and respiration were monitored during multiple naps. Participants were instructed to modify their dream scenario so that it involved vocalizations or an apnoea, -two behaviours that require a cortical control of ventilation when executed during wakefulness. Most participants (86%) were able to signal lucidity in at least one nap. In 50% of the lucid naps, we found a clear congruence between the dream report (e.g., diving under water) and the observed respiratory behaviour (e.g., central apnoea) and, in several cases, a preparatory breath before the respiratory behaviour. This suggests that the cortico-subcortical networks involved in voluntary respiratory movements are preserved during REM sleep and that breathing irregularities during this stage have a cortical/subcortical origin that reflects dream content.

International audience; Objective:To evaluate the frequency, determinants and sleep characteristics of lucid dreaming in narcolepsyMethods:Participants were interviewed regarding the frequency and determinants of lucid dreaming. Twelve narcolepsy patients and 5 controls who self-identified as frequent lucid dreamers underwent nighttime and daytime sleep monitoring after being given instructions regarding how to give an eye signal when lucid.Results:Compared to 53 healthy controls, the 53 narcolepsy patients reported more frequent dream recall, nightmares and recurrent dreams. Lucid dreaming was achieved by 77.4% of narcoleptic patients and 49.1% of controls (P < 0.05), with an average of 7.6 ± 11 vs. 0.3 ± 0.8 lucid dreams/month (P < 0.0001). The frequency of cataplexy, hallucinations, sleep paralysis, dyssomnia, HLA positivity, and the severity of sleepiness were similar in narcolepsy with and without lucid dreaming. Seven of 12 narcoleptic (and 0 non-narcoleptic) lucid dreamers achieved lucid REM sleep across a total of 33 naps, including 14 episodes with eye signal. The delta power in the electrode average, in delta, theta, and alpha powers in C4, and coherences between frontal electrodes were lower in lucid than non-lucid REM sleep in spectral EEG analysis. The duration of REM sleep was longer, the REM sleep onset latency tended to be shorter, and the percentage of atonia tended to be higher in lucid vs. non-lucid REM sleep; the arousal index and REM density and amplitude were unchanged.Conclusion:Narcoleptics have a high propensity for lucid dreaming without differing in REM sleep characteristics from people without narcolepsy. This suggests narcolepsy patients may provide useful information in future studies on the nature of lucid dreaming.

ObjectiveTo clearly define transthyretin familial amyloid polyneuropathies (TTR-FAPs) fulfilling definite clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy (CIDP).MethodsFrom a cohort of 194 patients with FAP, 13 of 84 patients (15%) of French ancestry had late-onset demyelinating TTR-FAP. We compared clinical presentation and electrophysiology to a cohort with CIDP and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome. We assessed nerve histology and the correlation between motor/sensory amplitudes/velocities. Predictors of demyelinating TTR-FAP were identified from clinical and electrophysiologic data.ResultsPain, dysautonomia, small fiber sensory loss above the wrists, upper limb weakness, and absence of ataxia were predictors of demyelinating TTR-FAP (p < 0.01). The most frequent demyelinating features were prolonged distal motor latency of the median nerve and reduced sensory conduction velocity of the median and ulnar nerves. Motor axonal loss was severe and frequent in the median, ulnar, and tibial nerves (p < 0.05) in demyelinating FAP. Ulnar nerve motor amplitude ConclusionMisleading features of TTR-FAP fulfilling criteria for CIDP are not uncommon in sporadic late-onset TTR-FAP, which highlights the limits of European Federation of Neurological Societies/Peripheral Nerve Society criteria. Specific clinical aspects and marked electrophysiologic axonal loss are red flag symptoms that should alert to this diagnosis and prompt TTR gene sequencing.

Objectives To determine the frequency of sleep breathing disorders in multiple systemic atrophy (MSA, combining Parkinsonism, cerebellar syndrome, and dysautonomia) and evaluate the benefit/tolerance of various modes of ventilation. Methods We retrospectively analyzed 45 patients with MSA having undergone a videopolysomnography. Their sleep characteristics were compared to those of 45 patients with Parkinson's disease and 45 healthy controls, matched for age and sex. Patients with MSA received fixed continuous positive airway pressure (CPAP) when stridor was isolated, auto-adjusting CPAP when it was combined with obstructive sleep apnea, and adaptive servo-ventilation (ASV) when combined with central sleep apnea. Results Higher periodic leg movements index and more frequent REM sleep behavior disorder were observed in MSA patients, compared to patients with Parkinson's disease and healthy controls. In MSA, 28/45 (62.2%) patients had sleep breathing disorders, including (overlapping samples) stridor (n = 17, 38%), obstructive sleep apnea (n = 14, 31%), central sleep apnea (n = 4, 9%), and ataxic breathing (n = 1). Except for three initial refusals and two yet untreated patients, fixed CPAP (n = 9), auto-adjusting CPAP (n = 8) and ASV (n = 2) were well-tolerated (limited leaks and good compliance) and successfully controlled stridor plus sleep apnea. Treated patients had survival times similar to those of patients without any sleep breathing disorder. Conclusion In this small group, tailored management of stridor in MSA as an independent issue or combined with obstructive and central sleep apnea, yields a survival similar to survival in patients without sleep breathing disorders.

Objectif La conscience est normalement attenuee pendant le sommeil mais permet une rapportabilite de la nuit (je sais que j’ai dormi, j’ai reve). Dans l’hypersomnie idiopathique (HI) cette conscience semble variable allant d’une plainte de « trop rever » (hyperonirisme) a celle de n’avoir aucune conscience de la nuit (« je pose la tete sur l’oreiller et me reveille 10 heures apres » : « black out »). Nous avons caracterise ces phenotypes, leurs marqueurs polysomnographiques, et les avons compares a ceux des patients avec narcolepsie et aux sujets normaux. Methodes Un questionnaire de 54 items (habitudes de reves, sommeil, sensation de perte de conscience, etc…) a ete adresse a 132 patients avec HI, 109 avec narcolepsie et 160 sujets sains. Trente autres patients avec HI ont rempli, en plus du questionnaire, des rapports de reves/reveries a chaque reveil pendant leur bilan polysomnographique de 48 h. Resultats Deux phenotypes extremes ont ete identifies chez les patients avec HI et pas chez les sujets sains ni avec narcolepsie : une perte de conscience totale pendant la nuit (Black out) chez 30 % des patients avec HI (0 % des controles, 3 % des narcoleptiques) et l’hyperonirisme (13 % des patients avec HI), consistait en un nombre de reves tres eleve associe a la plainte de trop rever. Aucun marqueur d’architecture du sommeil n’explique ces phenotypes. Conclusion Un tiers des patients avec HI rapportent une perte de conscience totale et recurrente pendant la nuit (un marqueur donc specifique d’un type d’HI) et 13 % un hyperonirisme penible (l’hyperconsience pourrait rendre le sommeil moins recuperateur).

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Objectif Stable en sommeil lent, la respiration devient irreguliere en sommeil paradoxal (SP). L’origine de cette variabilite respiratoire reste mysterieuse. Nous proposons que les irregularites respiratoires du SP ont une origine supra-pontique et refletent le contenu mental des reves qui accompagnent souvent ce stade. Methodes Nous avons recrute 21 narcoleptiques reveurs lucides, capables d’influencer leur contenu mental en SP et de signaler leur lucidite via un code oculaire. Les sujets ont realise de multiples siestes diurnes, au cours desquelles ils devaient modifier leur reve pour que le scenario onirique inclue des vocalisations ou une apnee (e.g. plonger sous l’eau) – deux comportements volontaires qui necessitent, a l’eveil, un controle cortical de la ventilation. Si la variabilite respiratoire du SP est bien le reflet des reves, ces comportements devraient se manifester par des apnees centrales sur l’enregistrement polysomnographique. Resultats Au total, 86 % des narcoleptiques a ete lucide en SP a au moins une sieste. Dans 50 % des siestes lucides, le recit de reve (e.g. apnee lors d’une attaque au gaz sarin), etait coherent avec le comportement respiratoire observe (apnee centrale). Surtout, des apnees etaient encadrees par le code oculaire et precedees de signes de preparation respiratoire, ce qui traduit leur caractere volontaire. Conclusion Le fait que les reveurs lucides soient capables de piloter volontairement leur respiration en SP suggere que le controle cortical de la respiration est preserve lors de ce stade et reflete probablement le contenu mental associe.

Objectif Determiner la frequence des troubles respiratoires du sommeil (TRS) dans l’atrophie multisystematisee (AMS) et evaluer le benefice/tolerance des divers modes de ventilation. Methodes Nous avons analyse retrospectivement les caracteristiques du sommeil chez 45 patients atteints d’AMS ayant eu une videopolysomnographie, et les comparees a celles de 45 patients parkinsoniens et 45 temoins sains. Les patients AMS ont recu une pression positive continue (PPC) fixe lorsque le stridor a ete isole, une PPC autopilotee (autoPPC) s’il a ete associe a un syndrome d’apnees obstructives du sommeil (SAOS) et une ventilation auto-asservie (VAA) ou une PPC fixe s’il est combine a un syndrome d’apnees centrales du sommeil (SACS). Resultats L’augmentation de la latence d’endormissement, du pourcentage du stade N2, de l’index de mouvements periodiques des jambes, du trouble comportemental en sommeil paradoxal et la diminution du temps du sommeil total et du pourcentage de sommeil paradoxal ont ete observes chez les patients AMS par rapport aux autres groupes. Dans l’AMS, 62,2 % des patients avaient des TRS : stridor (n = 16), SAOS (n = 14), SACS (n = 4) et respiration ataxique (n = 1). A l’exception de 5 patients (trois refus initiaux et deux en cours d’appareillage), la PPC fixe (n = 9), l’autoPPC (n = 8) et la VAA (n = 2) etaient bien toleres et le stridor a ete bien controle, ainsi que les apnees. Leur survie a ete comparable a celle des patients sans TRS. Conclusion Les TRS associes a l’AMS sont multiples. Les differents traitements par pression positive sont efficaces et bien toleres par les patients.