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    Reduced brain amyloid burden in elderly patients with narcolepsy type 1. Gabelle Audrey,Jaussent Isabelle,Bouallègue Fayçal Ben,Lehmann Sylvain,Lopez Régis,Barateau Lucie,Grasselli Caroline,Pesenti Carole,de Verbizier Delphine,Béziat Séverine,Mariano-Goulart Denis,Carlander Bertrand,Dauvilliers Yves, , Annals of neurology OBJECTIVE:To determine whether brain amyloid burden in elderly patients with narcolepsy type 1 (NT1) is lower than in controls, and to assess in patients with NT1 the relationships between amyloid burden, cerebral spinal fluid (CSF) markers of Alzheimer disease (AD), CSF orexin-A, and cognitive profile. METHODS:Cognitive and F-florbetapir positron emission tomography (PET) data were compared in patients with NT1 aged ≥ 65 years (n = 23) and in age- and sex-matched controls free of clinical dementia selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 69) and the Multi-Domain Intervention Alzheimer's Prevention Trial (MAPT-18F AV45-PET; n = 23) cohorts. The standardized uptake values (SUVs) of the cortical retention index for 6 regions of interest were computed and averaged to create a mean SUV ratio normalized to 3 subcortical reference regions (cerebellum, pons, and a composite region). A cortical/cerebellum SUV ratio ≥ 1.17 defined positive PET amyloid. RESULTS:Lower cortical amyloid burden was observed in the NT1 than in the ADNI and MAPT-AV45 groups (mean cortical/cerebellum SUV ratios = 0.95 ± 0.15, 1.11 ± 0.18 [p < 0.0001], and 1.14 ± 0.17 [p = 0.0005], respectively). Similar results were obtained with all subcortical reference regions and for all cortical regions of interest, except cingulum. Only 1 patient with NT1 (4.4%) had positive PET amyloid compared with 27.5% in the ADNI and 30.4% in the MAPT-AV45 group. In the NT1 group, cortical or regional amyloid load was not associated with CSF orexin-A, CSF AD biomarkers, or neuropsychological profile. INTERPRETATION:Lower brain amyloid burden, assessed by F-florbetapir PET, in patients with NT1 suggests delayed appearance of amyloid plaques. ANN NEUROL 2019;85:74-83. 10.1002/ana.25373
    Association of CSF orexin-A levels and nocturnal sleep stability in patients with hypersomnolence. Barateau Lucie,Lopez Régis,Chenini Sofiene,Rassu Anna-Laura,Scholz Sabine,Lotierzo Manuela,Cristol Jean-Paul,Jaussent Isabelle,Dauvilliers Yves Neurology OBJECTIVE:To evaluate the associations between CSF orexin-A (ORX) levels and markers of nocturnal sleep stability, assessed by polysomnography. METHODS:Nocturnal polysomnography data and ORX levels of 300 drug-free participants (55% men, 29.9±15.5 years, ORX level 155.1±153.7 pg/mL) with hypersomnolence were collected. Several markers of nocturnal sleep stability were analyzed: sleep and wake bouts and sleep/wake transitions. Groups were categorized according to ORX levels, in 2 categories (deficient ≤110; >110), in tertiles (≤26, 26-254, >254), and compared using logistic regression models. Results were adjusted for age, sex, and body mass index. RESULTS:We found higher number of wake bouts (43 vs 25, < 0.0001), sleep bouts (43 vs 25.5, < 0.0001), and index of sleep bouts/hour of sleep time, but lower index of wake bouts/hour of wake time (41.4 vs 50.6, < 0.0001), in patients with ORX deficiency. The percentage of wake bouts <30 seconds was lower (51.3% vs 60.8%, < 0.001) and of wake bouts ≥1 minutes 30 seconds higher (7.7% vs 6.7%, = 0.02) when ORX deficient. The percentage of sleep bouts ≤14 minutes was higher (2-5 minutes: 23.7% vs 16.1%, < 0.0001), and of long sleep bouts lower (>32 minutes 30 seconds: 7.3% vs 18.3%, < 0.0001), when ORX deficient. These findings were confirmed when groups were categorized according to ORX tertiles, with a dose-response effect of ORX levels in post hoc comparisons, and in adjusted models. INTERPRETATION:This study shows an association between ORX levels and nocturnal sleep stabilization in patients with hypersomnolence. Sleep and wake bouts are reliable markers of nighttime sleep stability that correlate with CSF ORX levels in a dose-dependent manner. 10.1212/WNL.0000000000010743
    Sodium oxybate treatment in narcolepsy and its effect on muscle tone. Mayer Geert,Rodenbeck Andrea,Kesper Karl, Sleep medicine AIMS:To estimate the effect of the compound sodium oxybate (SO) on chin muscle tone in sleep, a re-analysis of the results of the international multicenter study SXB-15 was performed, applying a validated semi-automatic analysis of muscle tone. This analysis distinguishes short (<0.5 s) and long (>0.5 s) muscle activity indices per hour (SMI, LMI) in 116 patients with narcolepsy-cataplexy. While stable stimulant medication was permitted, tricyclics and SSRIs were withdrawn. Polysomnographies were performed at baseline (V5), four weeks after titration of SO to 4.5 g, 6 g, or 9 g or placebo (V6) and after another four weeks on stable SO dose (V7). RESULTS:SMI and LMI decreased significantly during light sleep. LMI remained stable in all SO groups during slow wave sleep (SWS), but decreased significantly during REM sleep. SMI decreased non-significantly, but consistently during SWS and REM in the 9 g group only. A subgroup analysis of patients who stayed on stimulants showed that they had higher SMIs and LMIs in all groups. Patients who had been treated with anticataplectic medication prior to study inclusion had lower LMIs in the 9 g group during REM sleep in all visits. CONCLUSION:SO has a differential effect on muscle tone that is dose and sleep stage dependent. Low dosages increase short muscle activity, possibly enabling the occurrence of parasomnias. High doses are especially efficacious in REM sleep, suggesting that SO could be used to treat REM sleep behavior disorder. Comedication with stimulants and prior medication with anticataplectic medication exerts an influence on muscle tone. 10.1016/j.sleep.2017.03.023
    Utility of the sleep stage sequence preceding sleep onset REM periods for the diagnosis of narcolepsy: a study in a Japanese cohort. Kawai Ryoko,Watanabe Akiko,Fujita Shiho,Hirose Marina,Esaki Yuichi,Arakawa Chiaki,Iwata Nakao,Kitajima Tsuyoshi Sleep medicine BACKGROUND:The minimum narcolepsy criteria "mean sleep latency (MSL) ≤8 min and ≥2 sleep onset rapid eye movement (REM) periods (SOREMPs) on polysomnography (PSG) and the multiple sleep latency test (MSLT)," according to The International Classification of Sleep Disorders, Third Edition (ICSD-3), are not specific to narcolepsy. Recently, the characteristic sleep stage sequences preceding SOREMPs in narcolepsy have received attention, but their diagnostic utility remains unclear. METHODS:We retrospectively reviewed PSG/MSLT records and chart data for 102 Japanese patients with hypersomnia and at least one SOREMP. We examined the sporadic rates of two sleep stage sequences preceding the SOREMPs-wakefulness or stage 1 to REM (W/S1→R) and stage 2 to REM (S2→R)-comparing these between patient groups with narcolepsy type 1 (N = 28), narcolepsy type 2 (N = 19), and other hypersomnia (N = 55). We also examined the utility of three simple indices using the occurrence of W/S1→R SOREMPs for distinguishing between narcolepsy and other hypersomnia in patients who satisfied the minimum narcolepsy criteria. RESULTS:W/S1→R SOREMPs were significantly more frequent in narcolepsy than in other hypersomnia, and this tendency was also observed even in the patients who satisfied the minimum narcolepsy criteria. The three indices had moderate sensitivities and specificities for distinguishing between narcolepsy and other hypersomnia in patients satisfying the minimum narcolepsy criteria. CONCLUSIONS:The W/S1→R pattern was observed significantly more frequently in narcolepsy than in other hypersomnia, suggesting it may help with differentiating narcolepsy from other hypersomnia in patients demonstrating the narcolepsy criteria, although its ability to do so may be modest. 10.1016/j.sleep.2019.04.008
    REM Sleep Behavior Disorder in Children With Type 1 Narcolepsy Treated With Sodium Oxybate. Antelmi Elena,Filardi Marco,Pizza Fabio,Vandi Stefano,Moresco Monica,Franceschini Christian,Tinazzi Michele,Ferri Raffaele,Plazzi Giuseppe Neurology OBJECTIVE:To study the effect of stable treatment with sodium oxybate (SO) on nocturnal REM sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) that severely affected children with type 1 narcolepsy (NT1). METHODS:Nineteen children and adolescents with NT1 (9 female, mean age 12.5 ± 2.7 years, mean disease duration 3.4 ± 1.6 years) underwent neurologic investigations and video-polysomnography (v-PSG) at baseline and after 3 months of stable treatment with SO. v-PSG was independently analyzed by 2 sleep experts to rate RBD episodes. RSWA was automatically computed by means of the validated REM sleep atonia index (RAI). RESULTS:Compared to baseline, RAI significantly improved ( < 0.05) and complex movements during REM sleep were remarkably reduced after stable treatment with SO. Compared to baseline, children also reported improvement in clinical complaints and showed a different nighttime sleep-stage architecture. CONCLUSIONS:RBD and RSWA improved after treatment with SO, pointing to a direct role of the drug in modulating motor control during REM sleep. CLASSIFICATION OF EVIDENCE:This study offers Class IV evidence of the positive effect of SO on modulation of muscle atonia during REM sleep in children with NT1 because of the absence of a control group. 10.1212/WNL.0000000000011157
    The diagnostic value of sleep and vigilance tests in central disorders of hypersomnolence. Mathis Johannes,Andres Daniel,Schmitt Wolfgang J,Bassetti Claudio L,Hess Christian W,Schreier David R Sleep STUDY OBJECTIVES:This retrospective cross-sectional observational study explored the diagnostic value of selected sleep and vigilance tests (SVT) beyond the multiple sleep latency test to differentiate between various central disorders of hypersomnolence (CDH) and fatigue syndromes. METHODS:Data from patients who underwent the multiple sleep latency test and at least one additional SVT were extracted from the Bern sleep database (1997-2018). One thousand three hundred fifty-two patients with a CDH (106 narcolepsy type 1, 90 narcolepsy type 2, 119 idiopathic hypersomnia, 192 nonorganic hypersomnia, 205 insufficient sleep syndrome), fatigue syndromes (n = 183), and a subgroup of patients with sleep apnea (n = 457) were analyzed. Classification based on SVT parameters was compared with the final clinical diagnosis serving as a reference. RESULTS:An overall model predicted the final diagnosis in 49.5% of patients. However, for the pairwise differentiation of two clinically suspected diagnoses, many SVT parameters showed a sensitivity and specificity above 70%. While the overall discrimination power of the multiple sleep latency test was slightly better than the one of the maintenance of wakefulness test, the latter differentiated best between narcolepsy and idiopathic hypersomnia with prolonged sleep need. Disproportionally poor results in reaction tests (e.g. steer clear test), despite comparable or lower sleepiness levels (SLAT, WLAT), were valuable for differentiating nonorganic hypersomnia from idiopathic hypersomnia/sleep insufficiency syndrome. CONCLUSION:This study demonstrates how the combination of a careful clinical assessment and a selection of SVTs can improve the differentiation of CDH, whereas it was not possible to establish an overall prediction model based on SVTs alone. 10.1093/sleep/zsac017
    Comparison of the macro and microstructure of sleep in a sample of sleep clinic hypersomnia cases. Cairns Alyssa,Bogan Richard Neurobiology of sleep and circadian rhythms The purpose of this study was to elucidate the differentiating or grouping EEG characteristics in various hypersomnias (type 1 and type 2 narcolepsy (N-1 and N-2) and idiopathic hypersomnia (IH) compared to an age-matched snoring reference group (SR). Polysomnogram sleep EEG was decomposed into a 4-frequency state model. The IH group had higher sleep efficiency (SE; 92.3% vs. 85.8%; sp < 0.05), lower WASO (IH = 35.4 vs. N-1 = 65.5 min; p < 0.01), but similar (i.e. high) arousal indices as N-1 (~33/h). N-1 and N-2 had earlier REM latency than IH and SR (N-1 = 64.8, N-2 = 76.3 vs. IH/SR = 118 min, p < 0.05). N-1 and N-2 showed an increase in MF1 segments (characteristic of stage 1 and REM) across the night as well as distinct oscillations every 2 h, but MF1 segment timing was advanced by 30 min compared to the SR group (p < 0.05). This suggests the presence of circadian organization to sleep that is timed earlier or of increased pressure and/or lability. MF1 demonstrated a mixed phenotype in IH, with an early 1 oscillation (like N-1 and N-2), 2 oscillation that overlapped with the SR group, and a surge prior to wake (higher than all groups). This phenotype may reflect a heterogeneous group of individuals, with some having more narcolepsy-like characteristics (i.e. REM) than others. LF domain (delta surrogate) was enhanced in IH and N-1 and more rapidly dissipated compared to N-2 and SR (p < 0.05). This suggests an intact homeostatic sleep pattern that is of higher need/reduced efficiency whereas rapid dissipation may be an underlying mechanism for sleep disruption. 10.1016/j.nbscr.2019.02.001
    Polysomnographic Measurement of Sleep Duration and Bodily Pain Perception in the Sleep Heart Health Study. Weingarten Jeremy A,Dubrovsky Boris,Basner Robert C,Redline Susan,George Liziamma,Lederer David J Sleep STUDY OBJECTIVES:To determine whether total sleep time (TST) and specific sleep stage duration are associated with bodily pain perception and whether sex, age, or subjective sleepiness modifies this relationship. METHODS:Data from adults ages 39-90 y (n = 5,199) who took part in the Sleep Heart Health Study Exam 1 were analyzed. TST, rapid eye movement (REM) sleep time, and slow wave sleep (SWS) time were measured by unattended, in-home nocturnal polysomnography. Bodily pain perception was measured via the Short Form-36 questionnaire bodily pain component. We used logistic regression to examine associations between total and individual sleep stage durations and bodily pain perception controlling for age, sex, race, body mass index, apnea-hypopnea index, antidepressant use, and important cardiovascular conditions (smoking [pack-years], history of diabetes, and history of percutaneous coronary intervention and/or coronary artery bypass graft). RESULTS:In the fully adjusted model, REM sleep time and SWS time were not associated with "moderate to severe pain," whereas TST was: Each 1-h decrement in TST was associated with a 7% increased odds of "moderate to severe pain" (odds ratio 1.07, 95% confidence interval 1.002, 1.14). Due to modification of the association between SWS time and "moderate to severe pain" by sex (P for interaction = 0.01), we performed analyses stratified by sex: Each 1-h decrement in SWS time was associated with a 20% higher odds of "moderate to severe pain" among men (odds ratio 1.20, 95% confidence interval 1.03-1.42) whereas an association was not observed among women. CONCLUSIONS:Shorter TST among all subjects and shorter SWS time in men was associated with "moderate to severe pain." REM sleep time was not associated with bodily pain perception in this cohort. 10.5665/sleep.6026
    Longitudinal study of narcolepsy symptoms in first, second, and third-degree relatives of simplex and multiplex narcolepsy families. Ohayon Maurice M,Black Jed,Krystal Andrew D,Shapiro Colin M,Swick Todd J,Bogan Richard,Wells Charles C Sleep medicine OBJECTIVE:To assess the evolution of narcolepsy symptoms in first-, second, and third-degree relatives and to compare multiplex and simplex families. METHODS:A total of 4045 family members and 362 narcoleptic individuals were entered in the study; with 3255 family members interviewed twice, five to seven years apart. A control group (n = 178) composed of spouses or housemates was also interviewed twice. Family members were divided according to their blood relationship with the probands and further divided into multiplex (ie, more than one narcolepsy cases) and simplex (only one narcolepsy case) families. Telephone interviews were conducted with the help of the Sleep-EVAL system; narcolepsy probands were evaluated and diagnosed by a Sleep Specialist in a Sleep Clinic Center. RESULTS:A total of 1123 family members from 72 families were identified as members of multiplex families while the rest of the sample were a part of simplex families (n = 2132). Multiplex families had higher incidence and chronicity of hypersomnolence than the simplex family members and the control group. For cataplexy-like symptoms, only prevalence at the time of the first assessment distinguished multiplex (5.5%) and simplex (2.9%) families. Prevalence of sleep paralysis was higher among the first- and second-degree relatives coming from multiplex families, while incidence was the highest among second- and third-degree relatives. Hypnagogic hallucinations had similar prevalence between multiplex and simplex families but the incidence and chronicity were significantly higher among multiplex families. For each symptom, predictive factors were also determined in simplex and multiplex families. CONCLUSIONS:Our results show that individuals coming from multiplex families are at greater risks of a broad range of narcolepsy symptoms compared to simplex families. 10.1016/j.sleep.2018.06.015
    Effect of psychostimulants on blood pressure profile and endothelial function in narcolepsy. Bosco Adriana,Lopez Régis,Barateau Lucie,Chenini Sofiene,Pesenti Carole,Pépin Jean-Louis,Jaussent Isabelle,Dauvilliers Yves Neurology OBJECTIVE:To assess the effect of psychostimulant treatments on the 24-hour blood pressure (BP) profile of patients with narcolepsy type 1 (NT1). METHODS:Heart rate (HR) and BP were monitored for 24 hours and morning endothelial function was evaluated in 160 consecutive patients with NT1: 68 untreated (41 male, median age 34.9 years), 54 treated (32 male, median age 40.9 years), and 38 evaluated twice (21 male, median age 32 years), before and during treatment. RESULTS:Patients treated for NT1 showed higher 24-hour, daytime, and nighttime diastolic BP and HR values compared with the untreated group. Similarly, HR as well as 24-hour and daytime systolic BP were increased during treatment in the group evaluated twice. The combination of stimulant and anticataplectic drugs showed a synergistic effect on BP, without differences among stimulant categories. Based on 24-hour BP monitoring, hypertension was diagnosed in 58% of treated patients and in 40.6% of untreated patients. After adjustments for age, sex, and body mass index, the percentage of REM sleep remained associated with 24-hour hypertension in untreated and treated patients. Endothelial function was comparable in treated and untreated patients. CONCLUSIONS:The finding that patients with NT1 treated with psychostimulants have higher diastolic BP and HR than untreated patients suggests an increased long-term risk of cardiovascular diseases that requires careful follow-up and specific management. 10.1212/WNL.0000000000004911
    Alternative diagnostic criteria for idiopathic hypersomnia: A 32-hour protocol. Evangelista Elisa,Lopez Régis,Barateau Lucie,Chenini Sofiene,Bosco Adriana,Jaussent Isabelle,Dauvilliers Yves Annals of neurology OBJECTIVE:To assess the diagnostic value of extended sleep duration on a controlled 32-hour bed rest protocol in idiopathic hypersomnia (IH). METHODS:One hundred sixteen patients with high suspicion of IH (37 clear-cut IH according to multiple sleep latency test criteria and 79 probable IH), 32 with hypersomnolence associated with a comorbid disorder (non-IH), and 21 controls underwent polysomnography, modified sleep latency tests, and a 32-hour bed rest protocol. Receiver operating characteristic curves were used to find optimal total sleep time (TST) cutoff values on various periods that discriminate patients from controls. RESULTS:TST was longer in patients with clear-cut IH than other groups (probable IH, non-IH, and controls) and in patients with probable IH than non-IH and controls. The TST cutoff best discriminating clear-cut IH and controls was 19 hours for the 32-hour recording (sensitivity = 91.9%, specificity = 85.7%) and 12 hours (100%, 85.7%) for the first 24 hours. The 19-hour cutoff displayed a specificity and sensitivity of 91.9% and 81.2% between IH and non-IH patients. Patients with IH above the 19-hour cutoff were overweight, had more sleep inertia, and had higher TST on all periods compared to patients below 19 hours, whereas no differences were found for the 12-hour cutoff. An inverse correlation was found between the mean sleep latency and TST during 32-hour recording in IH patients. INTERPRETATION:In standardized and controlled stringent conditions, the optimal cutoff best discriminating patients from controls was 19 hours over 32 hours, allowing a clear-cut phenotypical characterization of major interest for research purposes. Sleepier patients on the multiple sleep latency test were also the more severe in terms of extended sleep. Ann Neurol 2018;83:235-247. 10.1002/ana.25141
    Characteristics associated with hypersomnia and excessive daytime sleepiness identified by extended polysomnography recording. Sleep STUDY OBJECTIVES:Hypersomnolence, defined by excessive daytime sleepiness (EDS) or excessive quantity of sleep (EQS), has been associated with increased morbidity. The aim of this study was to determine the clinical and polysomnographic characteristics associated with EQS and EDS assessed objectively during extended polysomnography recording. METHODS:A total of 266 drug-free subjects (201 women; mean age: 26.5 years [16.08; 60.87]) underwent 32-h bed-rest polysomnography recording preceded by polysomnography and modified multiple sleep latency test (mMSLT). Participants were categorized according to their total sleep time (bed-rest TST ≥19 h, hypersomnia), objective EDS (mean sleep latency on MSLT ≤8 min), and self-reported EDS (Epworth sleepiness scale score >10) and EQS (≥9 h/24 h per week). RESULTS:Subjects with hypersomnia were often younger, with normal sleep architecture, high nighttime sleep efficiency, and severe objective EDS. No association with sex, body mass index, Epworth sleepiness scale, EQS, and depressive symptoms was detected. Subjects with objective EDS had less EQS, higher sleep efficiency, and increased hypersomnia. Discrepancies were observed between objective and self-reported measures of sleep duration and EDS. Finally, 71 subjects were identified who had objective hypersomnia and/or EDS, no medical and psychiatric conditions and normal polysomnography parameters, and therefore met the stringent criteria of idiopathic hypersomnia, an orphan disorder. CONCLUSIONS:Sleep duration and EDS should be quantified using self-reported and objective measures in a controlled procedure to differentiate long sleepers, patients with hypersomnia, and patients with idiopathic hypersomnia. This will help to better understand their biology, to identify specific biomarkers, and to assess related health outcomes. 10.1093/sleep/zsaa264
    Linking clinical complaints and objective measures of disrupted nighttime sleep in narcolepsy type 1. Sleep STUDY OBJECTIVES:Despite its high frequency in narcolepsy type 1(NT1), disrupted nocturnal sleep (DNS) remains understudied, and its determinants have been poorly assessed. We aimed to determine the clinical, polysomnographic (PSG), and biological variables associated with DNS in a large sample of patients with NT1, and to evaluate the effect of medication on DNS and its severity. METHODS:Two hundred and forty-eight consecutive adult patients with NT1 (145 untreated, 103 treated) were included at the National Reference Center for Narcolepsy-France; 51 drug-free patients were reevaluated during treatment. DNS, assessed with the Narcolepsy Severity Scale (NSS), was categorized in four levels (absent, mild, moderate, severe). Clinical characteristics, validated questionnaires, PSG parameters (sleep fragmentation markers: sleep (SB) and wake bouts (WB), transitions), objective sleepiness, and orexin-A levels were assessed. RESULTS:In drug-free patients, DNS severity was associated with higher scores on NSS, higher sleepiness, anxiety/depressive symptoms, autonomic dysfunction, worse quality of life (QoL). Patients with moderate/severe DNS (59%) had increased sleep onset REM periods, lower sleep efficiency, longer wake after sleep onset, more N1, SB, WB, sleep instability, transitions. In treated patients, DNS was associated with the same clinical data, and antidepressant use; but only with longer REM sleep latency on PSG. During treatment, sleepiness, NSS scores, depressive symptoms decreased, as well as total sleep time, WB, SB, transitions. DNS improved in 55% of patients, without predictors except more baseline anxiety. CONCLUSION:DNS complaint is frequent in NT1, associated with disease severity based on NSS, several PSG parameters, and objective sleepiness in untreated and treated conditions. DNS improves with treatment. We advocate the systematic assessment of this symptom and its inclusion in NT1 management strategy. 10.1093/sleep/zsac054
    Intermediate hypocretin-1 cerebrospinal fluid levels and typical cataplexy: their significance in the diagnosis of narcolepsy type 1. Sleep STUDY OBJECTIVES:The diagnosis of narcolepsy type 1 (NT1) is based upon the presence of cataplexy and/or a cerebrospinal fluid (CSF) hypocretin-1/orexin-A level ≤ 110 pg/mL. We determined the clinical and diagnostic characteristics of patients with intermediate hypocretin-1 levels (111-200 pg/mL) and the diagnostic value of cataplexy characteristics in individuals with central disorders of hypersomnolence. METHODS:Retrospective cross-sectional study of 355 people with known CSF hypocretin-1 levels who visited specialized Sleep-Wake Centers in the Netherlands. For n = 271, we had full data on cataplexy type ("typical" or "atypical" cataplexy). RESULTS:Compared to those with normal hypocretin-1 levels (>200 pg/mL), a higher percentage of individuals with intermediate hypocretin-1 levels had typical cataplexy (75% or 12/16 vs 9% or 8/88, p < .05), and/or met the diagnostic polysomnographic (PSG) and Multiple Sleep Latency Test (MSLT) criteria for narcolepsy (50 vs 6%, p < .001). Of those with typical cataplexy, 88% had low, 7% intermediate, and 5% normal hypocretin-1 levels (p < .001). Atypical cataplexy was also associated with hypocretin deficiency but to a lesser extent. A hypocretin-1 cutoff of 150 pg/mL best predicted the presence of typical cataplexy and/or positive PSG and MSLT findings. CONCLUSION:Individuals with intermediate hypocretin-1 levels or typical cataplexy more often have outcomes fitting the PSG and MSLT criteria for narcolepsy than those with normal levels or atypical cataplexy. In addition, typical cataplexy has a much stronger association with hypocretin-1 deficiency than atypical cataplexy. We suggest increasing the NT1 diagnostic hypocretin-1 cutoff and adding the presence of clearly defined typical cataplexy to the diagnostic criteria of NT1. Clinical trial information: This study is not registered in a clinical trial register, as it has a retrospective database design. 10.1093/sleep/zsac052
    A standardized test to document cataplexy. Vandi Stefano,Pizza Fabio,Antelmi Elena,Neccia Giulia,Iloti Martina,Mazzoni Alice,Avoni Patrizia,Plazzi Giuseppe Sleep medicine OBJECTIVE/BACKGROUND:Cataplexy is the pathognomonic symptom of narcolepsy type 1 (NT1). Since it is considered difficult to be directly observed or documented by clinicians, its diagnosis relies mainly on history taking. Our study aimed at testing the feasibility of a standardized video recording procedure under emotional stimulation to document cataplexy in the diagnostic work-up of suspected hypersomnia of central origin. PATIENTS/METHODS:Two-hundred-eight consecutive patients underwent the diagnostic work-up and reached the final diagnosis of NT1 (n = 133), idiopathic hypersomnia or narcolepsy type 2 (IH/NT2 group, n = 33), or subjective excessive daytime sleepiness (sEDS group, n = 42). All subjects underwent a standardized video recording procedure while watching funny movies selected according to individual preferences, and a technician blind to clinical features reviewed the recordings to identify hypotonic phenomena that were finally confirmed by patients. RESULTS:The video recording under emotional stimulation captured hypotonic phenomena in 72.2%, 9.1% and 4.8% of NT1, IH/NT2, and sEDS subjects (p < 0.0001), respectively. When tested against CSF hypocretin deficiency, the documentation of a hypotonic episode at the test showed an area under the ROC curve of 0.823 ± 0.033 (p < 0.0001). NT1 patients under anticataplectic medications showed less frequently hypotonic episodes than untreated ones (48.0% vs 77.8%, p = 0.003). CONCLUSIONS:A standardized video recording procedure under emotional stimulation can help in the characterization of suspected hypersomnia of central origin. Further multi-center studies are warranted to extend the present findings and integrate a shared procedure for the laboratory work-up of narcolepsy. 10.1016/j.sleep.2017.08.021
    Remitting narcolepsy? Longitudinal observations in a hypocretin-deficient cohort. Büchele Fabian,Baumann Christian R,Poryazova Rositsa,Werth Esther,Valko Philipp O Sleep Study Objective:Narcolepsy type 1 (NT1) is considered a chronic, incurable disease. Excessive daytime sleepiness (EDS) is typically the most troublesome symptom, and more difficult to control by pharmacologic treatment than cataplexy. Although many NT1 patients are monitored by regular follow-ups, the purported relentless persistence of EDS has rarely been the object of longitudinal studies. Methods:Retrospective analysis of 26 well-defined hypocretin-deficient NT1 patients who underwent longitudinal assessments of Epworth sleepiness scale (ESS) scores under stable pharmacotherapy. We present detailed case reports of four patients with unusual spontaneous improvement. Results:Over a mean observation period of 5 years, changes in ESS scores between first and last examination were ≤4 points in 19 patients (73%). Three patients deteriorated by 5 points, four patients ameliorated by 7-11 points. Among the latter, subjective sleepiness resolved in all four patients, and three of them continued showing ESS scores <11 after cessation of their pharmacotherapy. Without therapy, two patients did not fulfill anymore the ICSD-3 multiple sleep latency test criteria (mean sleep latency >8 minutes), one of whom did not fall asleep during maintenance of wakefulness test. Multiple linear regression analysis identified higher cerebrospinal fluid (CSF) hypocretin level (p < 0.001) and absence of fragmented nighttime sleep (p = 0.001) as independent associates of EDS improvement. Conclusions:The longitudinal course of NT1-related sleepiness is not invariably stable, but included spontaneous deterioration or improvement in 27%. Spontaneous improvement can persist after treatment discontinuation and resemble remission. Milder hypocretin deficiency and good nighttime sleep may predict a more favorable disease course. 10.1093/sleep/zsy118
    Developing mental number line games to improve young children's number knowledge and basic arithmetic skills. Journal of experimental child psychology The learning of number knowledge in childhood may directly influence children's mathematics learning ability in subsequent periods. Previous studies also show that the difficulties in mathematics learning faced by schoolchildren are mainly rooted in the lack of number knowledge in early childhood. Focusing on the development of numerical knowledge and basic arithmetic skills in early childhood, this study designed a linear number line game based on the theory of the mental number line. Accordingly, this study examined the effectiveness of the linear number line game in children's learning of number concepts and arithmetic skills and compared the effectiveness of the linear number line game with that of two other games (a nonlinear number line game and a non-number-line game). This study adopted a quasi-experimental research design. A total of 140 young children from remote areas of eastern Taiwan participated and were divided into three experimental groups and one control group, and a pretest-posttest experiment was conducted. The experimental results showed that the linear number line game could help children to acquire numerical knowledge effectively, especially in number line estimation compared with other experimental groups. In terms of the learning effectiveness of basic arithmetic skills (e.g., addition, subtraction), the two number line games (linear and nonlinear number line games) are significantly superior to the non-number-line game (traditional number decomposition and synthesis game). This study recommends that preschool teachers use linear number line games to improve children's numerical knowledge and arithmetic skills. 10.1016/j.jecp.2022.105479
    Video-polysomnography procedures for diagnosis of rapid eye movement sleep behavior disorder (RBD) and the identification of its prodromal stages: guidelines from the International RBD Study Group. Cesari Matteo,Heidbreder Anna,St Louis Erik K,Sixel-Döring Friederike,Bliwise Donald L,Baldelli Luca,Bes Frederik,Fantini Maria Livia,Iranzo Alex,Knudsen-Heier Stine,Mayer Geert,McCarter Stuart,Nepozitek Jiri,Pavlova Milena,Provini Federica,Santamaria Joan,Sunwoo Jun-Sang,Videnovic Aleksandar,Högl Birgit,Jennum Poul,Christensen Julie A E,Stefani Ambra Sleep Video-polysomnography (v-PSG) is essential for diagnosing rapid eye movement (REM) sleep behavior disorder (RBD). Although there are current American Academy of Sleep Medicine standards to diagnose RBD, several aspects need to be addressed to achieve harmonization across sleep centers. Prodromal RBD is a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria for RBD. However, the boundary between prodromal and definite RBD is still unclear. As a common effort of the Neurophysiology Working Group of the International RBD Study Group, this manuscript addresses the need for comprehensive and unambiguous v-PSG recommendations to diagnose RBD and identify prodromal RBD. These include: (1) standardized v-PSG technical settings; (2) specific considerations for REM sleep scoring; (3) harmonized methods for scoring REM sleep without atonia; (4) consistent methods to analyze video and audio recorded during v-PSGs and to classify movements and vocalizations; (5) clear v-PSG guidelines to diagnose RBD and identify prodromal RBD. Each section follows a common template: The current recommendations and methods are presented, their limitations are outlined, and new recommendations are described. Finally, future directions are presented. These v-PSG recommendations are intended for both practicing clinicians and researchers. Classification and quantification of motor events, RBD episodes, and vocalizations are however intended for research purposes only. These v-PSG guidelines will allow collection of homogeneous data, providing objective v-PSG measures and making future harmonized multicentric studies and clinical trials possible. 10.1093/sleep/zsab257
    REM sleep muscle activity in idiopathic REM sleep behavior disorder predicts phenoconversion. McCarter Stuart J,Sandness David J,McCarter Allison R,Feemster John C,Teigen Luke N,Timm Paul C,Boeve Bradley F,Silber Michael H,St Louis Erik K Neurology OBJECTIVE:To determine whether REM sleep without atonia (RSWA) during polysomnography (PSG) predicts phenoconversion in patients with idiopathic REM sleep behavior disorder (iRBD), a prodromal feature of a neurodegenerative disease. METHODS:We analyzed RSWA in 60 patients with iRBD, including manual phasic, tonic, and any muscle activity in the submentalis and anterior tibialis muscles and the automated REM atonia index in the submentals. We identified patients who developed parkinsonism or mild cognitive impairment (MCI) during at least 3 years of follow-up after PSG. Kaplan-Meier analysis was performed and receiver operator curves were calculated to determine RSWA cutoffs predicting faster phenoconversion. RESULTS:Twenty-six (43%) patients developed parkinsonism (n = 17) or MCI (n = 9). Phenoconverters were older at iRBD diagnosis ( = 0.02). Median time to phenoconversion was 3.9 ± 2.5 years. iRBD phenoconverters had significantly more RSWA at diagnosis. Phenoconversion risk from iRBD diagnosis was 20% and 35% at 3 and 5 years, respectively, with greater risk in patients with iRBD with >46.4% any combined RSWA, which increased further to 30% and 55% at 3 and 5 years for patients >65 years of age at diagnosis. CONCLUSIONS:Patients with iRBD with higher amounts of polysomnographic RSWA had a greater risk of developing Parkinson disease or MCI. Patients with older age and higher RSWA amounts had more rapid phenoconversion than younger patients with RBD. Our study suggests that RSWA is a potential biomarker for risk stratification of iRBD phenoconversion that could facilitate prognostication for patients with iRBD. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with iRBD, increased RSWA correlates with increased risk for developing parkinsonism or MCI. 10.1212/WNL.0000000000008127
    Simultaneous tonic and phasic REM sleep without atonia best predicts early phenoconversion to neurodegenerative disease in idiopathic REM sleep behavior disorder. Nepozitek Jiri,Dostalova Simona,Dusek Petr,Kemlink David,Prihodova Iva,Ibarburu Lorenzo Y Losada Veronika,Friedrich Latica,Bezdicek Ondrej,Nikolai Tomas,Perinova Pavla,Dall'Antonia Irene,Dusek Pavel,Ruml Martin,Ruzicka Evzen,Sonka Karel Sleep STUDY OBJECTIVES:Rapid eye movement (REM) sleep without atonia (RWA) is the main polysomnographic feature of idiopathic REM sleep behavior disorder (iRBD) and is considered to be a promising biomarker predicting conversion to manifested synucleinopathy. Besides conventionally evaluated tonic, phasic and any RWA, we took into consideration also periods, when phasic and tonic RWA appeared simultaneously and we called this activity "mixed RWA." The study aimed to evaluate different types of RWA, to reveal the most relevant biomarker to the conversion. METHODS:A total of 55 patients with confirmed iRBD were recruited with mean follow-up duration 2.3 ± 0.7 years. Scoring of RWA was based on Sleep Innsbruck Barcelona rules. Positive phenocoversion was ascertained according to standard diagnostic criteria during follow-up. Receiver operator characteristic analysis was applied to evaluate predictive performance of different RWA types. RESULTS:A total of nine patients (16%) developed neurodegenerative diseases. Yearly phenoconversion rate was 5.5%. Significantly higher amounts of mixed (p = 0.009), tonic (p = 0.020), and any RWA (p = 0.049) were found in converters. Optimal cutoffs differentiating the prediction were 16.4% (sensitivity 88.9; specificity 69.6) for tonic, 4.4% (sensitivity 88.9; specificity 60.9) for mixed, and 36.8% (sensitivity 77.8; specificity 65.2) for any RWA. With area under the curve (AUC) 0.778, mixed RWA has proven to be the best predictive test followed by tonic (AUC 0.749) and any (AUC 0.710). CONCLUSIONS:Mixed, tonic and any RWA may serve as biomarkers predicting the conversion into neurodegenerative disease in iRBD. The best predictive value lies within mixed RWA, thus it should be considered as standard biomarker. 10.1093/sleep/zsz132
    Evolution of Prodromal REM Sleep Behavior Disorder to Neurodegeneration: A Retrospective, Longitudinal Case-control Study. Neurology BACKGROUND AND OBJECTIVES:Individuals with a history of recurrent dream-enactment behaviors, but with subthreshold REM sleep without atonia levels for REM sleep behavior disorder (RBD) diagnosis, are currently classified to have prodromal RBD (pRBD). However, the REM sleep elevated EMG diagnostic cut-off, progression trajectory, and long-term neurodegenerative outcome of pRBD are not well understood. This study aimed to delineate the evolution of REM sleep EMG levels, determine the EMG cut-off score for diagnosing pRBD, and examine the risk for neurodegenerative diseases of pRBD. METHODS:This retrospective longitudinal case-control study recruited pRBD patients and age, sex, and follow-up duration matched controls who were free of neurodegenerative disease at baseline in the Sleep Assessment Unit, the Chinese University of Hong Kong from 1997 to 2018. Patients and controls underwent clinical and video-polysomnography assessments at baseline and follow-up(s). REM sleep EMG activity level on mentalis and anterior tibialis (AT) muscles on video-polysomnography at each visit was scored. The diagnosis of neurodegenerative diseases was confirmed by a neurologist. RESULTS:44 patients (67.4 ± 8.2 years old, 6 females) and 44 controls were recruited. The combined REM sleep EMG level on mentalis and AT muscles of pRBD patients significantly increased during 8.2 ± 3.3 years of follow-up (from 19.3 ± 9.7% to 47.3 ± 27.4% with estimated annual increase of 3.9%), yielding 29 pRBD patients (66%) meeting the full-blown RBD diagnostic criteria. Baseline REM sleep mentalis and AT muscles EMG activity of patients who developed full-blown RBD could favourably differentiate pRBD from controls (6.3% for mentalis 'any' and 9.1% for combination of mentalis 'any' and bilateral AT muscles phasic EMG with AUC of 0.88 [0.78-0.98] and 0.97 [0.92-1.00] respectively). pRBD patients had a higher risk for neurodegenerative diseases (9 developed Parkinson's disease and 3 developed dementia with Lewy bodies) when compared to controls (5 developed Alzheimer's disease, adjusted hazard ratio = 2.95, 95% CI = 1.02-8.54). CONCLUSIONS:pRBD has a predictive progression in both pathophysiology and neurodegenerative outcome. This finding has significant implications to the nosological status of pRBD, the current REM sleep-related EMG diagnostic criteria, spectrum concept of RBD and future neuroprotective intervention. CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that EMG activity during REM sleep predicts the development of prodromal REM sleep behavior disorder. 10.1212/WNL.0000000000200707
    Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. Maski Kiran,Trotti Lynn Marie,Kotagal Suresh,Robert Auger R,Rowley James A,Hashmi Sarah D,Watson Nathaniel F Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine INTRODUCTION:This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. METHODS:The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS:The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. Adult patients with narcolepsy: 1:We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). 2:We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). 3:We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). 4:We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). 5:We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). 6:We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). 7:We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). Adult patients with idiopathic hypersomnia: 8:We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). 9:We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 10:We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 11:We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 12:We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). Adult patients with Kleine-Levin syndrome: 13:We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). Adult patients with hypersomnia due to medical conditions: Hypersomnia secondary to alpha-synucleinopathies: 14:We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). 15:We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). 16:We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). Posttraumatic hypersomnia: 17:We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). 18:We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). Adult patients with genetic disorders associated with primary central nervous system somnolence: 19:We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). Adult patients with hypersomnia secondary to brain tumors, infections, or other central nervous system lesions: 20:We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). Pediatric patients with narcolepsy: 21:We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). 22:We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). CITATION:Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. . 2021;17(9):1881-1893. 10.5664/jcsm.9328
    Sleep apnea, sleepiness, and driving risk. American Thoracic Society. American journal of respiratory and critical care medicine 10.1164/ajrccm.150.5.7952578
    French consensus. Idiopathic hypersomnia: Investigations and follow-up. Leu-Semenescu S,Quera-Salva M-A,Dauvilliers Y Revue neurologique Idiopathic hypersomnia is a rare, central hypersomnia, recently identified and to date of unknown physiopathology. It is characterised by a more or less permanent, excessive daytime sleepiness, associated with long and unrefreshing naps. Night-time sleep is of good quality, excessive in quantity, associated with sleep inertia in the subtype previously described as "with long sleep time". Diagnosis of idiopathic hypersomnia is complex due to the absence of a quantifiable biomarker, the heterogeneous symptoms, which overlap with the clinical picture of type 2 narcolepsy, and its variable evolution over time. Detailed evaluation enables other frequent causes of somnolence, such as depression or sleep deprivation, to be eliminated. Polysomnography and multiple sleep latency tests (MSLT) are essential to rule out other sleep pathologies and to objectify excessive daytime sleepiness. Sometimes the MSLT do not show excessive sleepiness, hence a continued sleep recording of at least 24hours is necessary to show prolonged sleep (>11h/24h). In this article, we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from idiopathic hypersomnia. 10.1016/j.neurol.2016.09.015
    French consensus. Hypersomnolence: Evaluation and diagnosis. Dauvilliers Y,Lopez R,Lecendreux M Revue neurologique Sleepiness is one of the most frequently reported complaints in adults and children during specialised sleep consultations. It is responsible for an alteration that can be severe in quality of life, a lowering of academic or professional performance, and domestic or work accidents. Hypersomnolence is the first cause of road accidents on the highway, responsible for a third of fatal accidents. Furthermore its presence is associated with an increased risk of morbi-mortality related to cardiovascular and neurodegenerative pathologies. Hence, its represents a real public health issue. Recent revisions in international classifications have clarified confusing terminology, and the complaint of hypersomnia has now been replaced by the terms hypersomnolence or excessive sleepiness. It is clinically defined as an excessive quantity of sleep over 24hours, and/or by an alteration in the quality of arousal defined as incapacity to maintain a satisfactory level of vigilance during the day or in the morning on awakening (defined as sleep inertia). The evaluation of sleepiness requires a rigorous clinical approach, completed by subjective and objective measurements. The Epworth Sleep Scale, Multiple Sleep Latency Tests and the Maintenance of Wakefulness Test are the most studied and used in clinical practice. However, to date, no gold standard measurement of excessive sleepiness exists, and there are no quantifiable biological markers. It is therefore important to optimise our evaluation tools, improve our pathophysiological understanding of sleepiness, and define genetic and environmental risk factors. 10.1016/j.neurol.2016.09.017