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Study Objectives: Hypocretin deficiency causes type 1 narcolepsy, a condition characterised by excessive daytime sleepiness, cataplexy, and fragmented nocturnal sleep. Two-thirds of people with narcolepsy are also overweight, of which half are obese. The pathophysiology behind weight gain in people with narcolepsy remains unknown. We assessed a possible decrease in energy expenditure as a cause for overweight in narcolepsy using respiration chamber calorimetry and doubly labelled water., Methods: Ten males with type I narcolepsy and nine matched (for age, sex, and BMI) healthy controls were enrolled. Subjects stayed in a respiration chamber for 24 hours. They subsequently received doubly labelled water and wore an accelerometer for two weeks to assess energy expenditure and physical activity under daily living conditions. Total daily energy expenditure, resting energy expenditure, overnight metabolic rate, physical activity level and activity-induced energy expenditure were measured., Results: No significant differences were found in resting energy expenditure, mean 24-hour respiration chamber energy expenditure, overnight metabolic rate and activity-induced energy expenditure when comparing people with narcolepsy type 1 to controls. Physical activity was also comparable between groups., Conclusion: Energy expenditure in narcolepsy type 1 is similar to matched controls, suggesting comparable metabolism and physical activity rates. It remains possible that metabolic changes are most pronounced around disease onset. In addition, patients had to discontinue their medication which may have influenced the results. Still, our findings suggest that other factors may also play a role in weight gain in narcolepsy, such as differences in dietary behaviour., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Study Objectives: Hypnograms contain a wealth of information and play an important role in sleep medicine. However, interpretation of the hypnogram is a difficult task and requires domain knowledge and "clinical intuition." This study aimed to uncover which features of the hypnogram drive interpretation by physicians. In other words, make explicit which features physicians implicitly look for in hypnograms., Methods: Three sleep experts evaluated up to 612 hypnograms, indicating normal or abnormal sleep structure and suspicion of disorders. ElasticNet and convolutional neural network classification models were trained to predict the collected expert evaluations using hypnogram features and stages as input. The models were evaluated using several measures, including accuracy, Cohen's kappa, Matthew's correlation coefficient, and confusion matrices. Finally, model coefficients and visual analytics techniques were used to interpret the models to associate hypnogram features with expert evaluation., Results: Agreement between models and experts (Kappa between 0.47 and 0.52) is similar to agreement between experts (Kappa between 0.38 and 0.50). Sleep fragmentation, measured by transitions between sleep stages per hour, and sleep stage distribution were identified as important predictors for expert interpretation., Conclusions: By comparing hypnograms not solely on an epoch-by-epoch basis, but also on these more specific features that are relevant for the evaluation of experts, performance assessment of (automatic) sleep-staging and surrogate sleep trackers may be improved. In particular, sleep fragmentation is a feature that deserves more attention as it is often not included in the PSG report, and existing (wearable) sleep trackers have shown relatively poor performance in this aspect., (© The Author(s) 2023. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: To review the Maintenance of Wakefulness Test (MWT) as assessment of daytime sleepiness in the evaluation of treatment effects and driving fitness in central disorders of hypersomnolence (CDH)., Methods: We performed a scoping review of studies using the MWT in patients with CDH (i.e. narcolepsy types 1 and 2, and idiopathic hypersomnia). N = 20 articles were included, comprising 683 patients and 129 controls. MWT effect sizes were compared to the Clinical Global Impression (GCI) scale and the Epworth Sleepiness Scale (ESS). MWT sleep latency was correlated to objective driving performances. The role of motivation was evaluated by comparing MWTs of treatment studies (low motivation) to driving fitness studies (high motivation to stay awake). Healthy controls were compared to norm values., Results: MWT and CGI were both impacted by the same treatment; however, the MWT has higher effect sizes and was more sensitive to measure these effects. The MWT correlated fairly to moderately (ρ = -0.26 to -0.56; p ≤ .05) to objective driving performance. Motivation played a major role on MWT sleep latencies (d = 0.76 to 1.43; p ≤ .001). Current norm values may not be valid, as sleep latency may be impacted by age., Conclusions: The MWTs applicability to measure treatment effects in CDH was confirmed, but age-adjusted norm values are needed. For a more complete evaluation of EDS it should be combined with subjective measures. Its reliability for driving fitness evaluation is insufficient, and motivation plays a major role. To predict or monitor driving performance in CDH, valid and easy methods should be developed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Sleep stage classification is an important tool for the diagnosis of sleep disorders. Because sleep staging has such a high impact on clinical outcome, it is important that it is done reliably. However, it is known that uncertainty exists in both expert scorers and automated models. On average, the agreement between human scorers is only 82.6%. In this study, we provide a theoretical framework to facilitate discussion and further analyses of uncertainty in sleep staging. To this end, we introduce two variants of uncertainty, known from statistics and the machine learning community: aleatoric and epistemic uncertainty. We discuss what these types of uncertainties are, why the distinction is useful, where they arise from in sleep staging, and provide recommendations on how this framework can improve sleep staging in the future., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Objectives: The most sensitive and specific investigative method for the diagnosis of narcolepsy type 1 (NT1) is the determination of hypocretin-1 (orexin-A) deficiency (≤110 pg/mL) in cerebrospinal fluid using a radioimmunoassay (RIA). We aimed to assess the reliability of the Phoenix Pharmaceuticals hypocretin-1 RIA, by determining the lower limit of quantification (LLOQ), the variability around the cutoff of 110 pg/mL, and the inter- and intra-assay variability., Methods: Raw data of 80 consecutive hypocretin-1 RIAs were used to estimate the intra- and inter-assay coefficient of variation (CV). The LLOQ was established and defined as the lowest converted concentration with a CV <25%; the conversion is performed using a harmonization sample which is internationally used to minimize variation between RIAs., Results: The mean intra-assay CV was 4.7%, while the unconverted inter-assay CV was 28.3% (18.5% excluding 2 outliers) and 7.5% when converted to international values. The LLOQ was determined as 27.9 pg/mL. The intra-assay CV of RIAs with lower specific radioactive activity showed a median of 5.6% (n = 41, range 1.6%-17.0%), which was significantly higher than in RIAs with higher specific activity (n = 36; median 3.2%, range 0.4%-11.6%, p = .013). The CV around the 110 pg/mL cutoff was <7%., Conclusions: Hypocretin-1 RIAs should always be harmonized using standard reference material. The specific activity of an RIA has a significant impact on its reliability, because of the decay of 125I radioactivity. Values around the hypocretin-1 cut-off can reliably be measured. Hypocretin-1 concentrations below 28 pg/mL should be reported as "undetectable" when measured with the Phoenix Pharmaceuticals RIA., Clinical Trial Information: This study is not registered in a clinical trial register, as it has a retrospective database design., (© Sleep Research Society 2022. Published by Oxford University Press on behalf of the Sleep Research Society.)

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Study Objectives: To ascertain the presence of cognitive and attention problems in treatment naïve children with narcolepsy type 1 (NT1) and to explore whether children recently diagnosed with NT1 improve with respect to cognition and attention problems 1 year after regular treatment for NT1., Methods: A total of 15 treatment naïve children (7-15 years) with recently diagnosed NT1 were recruited from three sleep medicine centers in the Netherlands. The control group consisted of 15 healthy children, being frequency matched on age and gender. Both groups were investigated at baseline to examine intelligence profile (Wechsler Intelligence Scale for Children [WISC] III), attention problems, and processing speed (Bourdon Vos and sustained attention to respond task [SART]). These tests were repeated in children with NT1 1 year after regular (behavioral and medication) treatment for NT1., Results: Children with NT1 scored significantly lower on the verbal scale and processing speed subscale of the WISC III, showed more fluctuations in reaction time of the Bourdon Vos and made more mistakes during the SART than the healthy control group at baseline. Children with NT1 significantly improved on total IQ score, and on the WISC indices processing speed, and perceptual organization 1 year after treatment. At follow-up, test scores of treated children were largely comparable to those of the control group at baseline., Conclusions: Children with NT1 show improvement in several cognitive domains 1 year after start of treatment. Our findings stress the need for early detection and treatment of narcolepsy in childhood., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Study Objectives: To validate a previously developed sleep staging algorithm using heart rate variability (HRV) and body movements in an independent broad cohort of unselected sleep disordered patients., Methods: We applied a previously designed algorithm for automatic sleep staging using long short-term memory recurrent neural networks to model sleep architecture. The classifier uses 132 HRV features computed from electrocardiography and activity counts from accelerometry. We retrained our algorithm using two public datasets containing both healthy sleepers and sleep disordered patients. We then tested the performance of the algorithm on an independent hold-out validation set of sleep recordings from a wide range of sleep disorders collected in a tertiary sleep medicine center., Results: The classifier achieved substantial agreement on four-class sleep staging (wake/N1-N2/N3/rapid eye movement [REM]), with an average κ of 0.60 and accuracy of 75.9%. The performance of the sleep staging algorithm was significantly higher in insomnia patients (κ = 0.62, accuracy = 77.3%). Only in REM parasomnias, the performance was significantly lower (κ = 0.47, accuracy = 70.5%). For two-class wake/sleep classification, the classifier achieved a κ of 0.65, with a sensitivity (to wake) of 72.9% and specificity of 94.0%., Conclusions: This study shows that the combination of HRV, body movements, and a state-of-the-art deep neural network can reach substantial agreement in automatic sleep staging compared with polysomnography, even in patients suffering from a multitude of sleep disorders. The physiological signals required can be obtained in various ways, including non-obtrusive wrist-worn sensors, opening up new avenues for clinical diagnostics., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objectives: To extend and validate a previously suggested model of the influence of uninterrupted sleep bouts on sleep onset misperception in a large independent data set., Methods: Polysomnograms and sleep diaries of 139 insomnia patients and 92 controls were included. We modeled subjective sleep onset as the start of the first uninterrupted sleep fragment longer than Ls minutes, where parameter Ls reflects the minimum length of a sleep fragment required to be perceived as sleep. We compared the so-defined sleep onset latency (SOL) for various values of Ls. Model parameters were compared between groups, and across insomnia subgroups with respect to sleep onset misperception, medication use, age, and sex. Next, we extended the model to incorporate the length of wake fragments. Model performance was assessed by calculating root mean square errors (RMSEs) of the difference between estimated and perceived SOL., Results: Participants with insomnia needed a median of 34 minutes of undisturbed sleep to perceive sleep onset, while healthy controls needed 22 minutes (Mann-Whitney U = 4426, p < 0.001). Similar statistically significant differences were found between sleep onset misperceivers and non-misperceivers (median 40 vs. 20 minutes, Mann-Whitney U = 984.5, p < 0.001). Model outcomes were similar across other subgroups. Extended models including wake bout lengths resulted in only marginal improvements of model outcome., Conclusions: Patients with insomnia, particularly sleep misperceivers, need larger continuous sleep bouts to perceive sleep onset. The modeling approach yields a parameter for which we coin the term Sleep Fragment Perception Index, providing a useful measure to further characterize sleep state misperception., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Study Objectives: To explore impairments in social functioning in children with narcolepsy compared to healthy children., Methods: Parents of 53 pediatric patients with narcolepsy type 1 and 64 matched healthy children completed the Social Responsiveness Scale (SRS) and the Child Behavior Checklist 6-18 (CBCL 6-18)., Results: Patients scored significantly higher on the total score of the SRS (median 56, interquartile range [IQR] 23.5) compared to controls (median 44.5, IQR 8.5, U = 797.0, p < 0.001). Patients also scored higher on the sum of the CBCL 6-18 subscales indicative of social functioning (Withdrawn/Depressed, Social Problems, and Thought Problems; median 183, IQR 30.5) compared to controls (median 155, IQR 13, U = 500.0, p < 0.001). A total of 24 patients (45.3%) reported at least mild-to-moderate difficulties in social functioning compared to seven controls (10.9%, χ2 = 17.165, p < 0.001). Eleven patients (20.8%) and only one control (1.6%) had T scores above 75, which points to severely impaired social functioning (χ2 = 11.602, p = 0.001). Within the patient group, girls reported mild-to-moderate difficulties in social functioning significantly more often compared to boys on the SRS (77.8% versus 28.6%, χ2 = 17.560, p < 0.001)., Conclusions: Impaired social functioning is common in children with narcolepsy type 1, especially in girls. Questionnaires such as the SRS and the CBCL 6-18 may help in early detection of social problems in pediatric narcolepsy. Recognition of these problems could be valuable in the management of young people with narcolepsy.

Study Objectives: To describe the motor pattern of cataplexy and to determine its phenomenological differences from pseudocataplexy in the differential diagnosis of episodic falls., Methods: We selected 30 video-recorded cataplexy and 21 pseudocataplexy attacks in 17 and 10 patients evaluated for suspected narcolepsy and with final diagnosis of narcolepsy type 1 and conversion disorder, respectively, together with self-reported attacks features, and asked expert neurologists to blindly evaluate the motor features of the attacks. Video documented and self-reported attack features of cataplexy and pseudocataplexy were contrasted., Results: Video-recorded cataplexy can be positively differentiated from pseudocataplexy by the occurrence of facial hypotonia (ptosis, mouth opening, tongue protrusion) intermingled by jerks and grimaces abruptly interrupting laughter behavior (i.e. smile, facial expression) and postural control (head drops, trunk fall) under clear emotional trigger. Facial involvement is present in both partial and generalized cataplexy. Conversely, generalized pseudocataplexy is associated with persistence of deep tendon reflexes during the attack. Self-reported features confirmed the important role of positive emotions (laughter, telling a joke) in triggering the attacks, as well as the more frequent occurrence of partial body involvement in cataplexy compared with pseudocataplexy., Conclusions: Cataplexy is characterized by abrupt facial involvement during laughter behavior. Video recording of suspected cataplexy attacks allows the identification of positive clinical signs useful for diagnosis and, possibly in the future, for severity assessment.

Study Objectives: Besides influencing vigilance, orexin neurotransmission serves a variety of functions, including reward, motivation, and appetite regulation. As obesity is an important symptom in orexin-deficient narcolepsy, we explored the effects of satiety on food-related choices and spontaneous snack intake in patients with narcolepsy type 1 (n = 24) compared with healthy matched controls (n = 19). In additional analyses, we also included patients with idiopathic hypersomnia (n = 14) to assess sleepiness-related influences., Methods: Participants were first trained on a choice task to earn salty and sweet snacks. Next, one of the snack outcomes was devalued by having participants consume it until satiation (i.e., sensory-specific satiety). We then measured the selective reduction in choices for the devalued snack outcome. Finally, we assessed the number of calories that participants consumed spontaneously from ad libitum available snacks afterwards., Results: After satiety, all participants reported reduced hunger and less wanting for the devalued snack. However, while controls and idiopathic hypersomnia patients chose the devalued snack less often in the choice task, patients with narcolepsy still chose the devalued snack as often as before satiety. Subsequently, narcolepsy patients spontaneously consumed almost 4 times more calories during ad libitum snack intake., Conclusions: We show that the manipulation of food-specific satiety has reduced effects on food choices and caloric intake in narcolepsy type 1 patients. These mechanisms may contribute to their obesity, and suggest an important functional role for orexin in human eating behavior., Clinical Trials Registration: Study registered at Netherlands Trial Register. URL: www.trialregister.nl. Trial ID: NTR4508., (© 2016 Associated Professional Sleep Societies, LLC.)

Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells., Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles., Results: HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10(-4)), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10(-3)), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10(-3)) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr(9) (OR = 1.32 [1.15-1.52] P = 6.95*10(-5)) and HLA-C-Ser(11) (OR = 1.34 [1.15-1.57] P = 2.43*10(-4))., Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons., (© 2016 Associated Professional Sleep Societies, LLC.)

Study Objectives: Many people with Parkinson disease experience "sleep benefit": temporarily improved mobility upon awakening. Here we used quantitative motor tasks to assess the influence of sleep on motor functioning in Parkinson disease., Design: Eighteen Parkinson patients with and 20 without subjective sleep benefit and 20 healthy controls participated. Before and directly after a regular night sleep and an afternoon nap, subjects performed the timed pegboard dexterity task and quantified finger tapping task. Subjective ratings of motor functioning and mood/vigilange were included. Sleep was monitored using polysomnography., Results: On both tasks, patients were overall slower than healthy controls (night: F2,55 = 16.938, P < 0.001; nap: F2,55 = 15.331, P < 0.001). On the pegboard task, there was a small overall effect of night sleep (F1,55 = 9.695, P = 0.003); both patients and controls were on average slightly slower in the morning. However, in both tasks there was no sleep*group interaction for nighttime sleep nor for afternoon nap. There was a modest correlation between the score on the pegboard task and self-rated motor symptoms among patients (rho = 0.233, P = 0.004). No correlations in task performance and mood/vigilance or sleep time/efficiency were found., Conclusions: A positive effect of sleep on motor function is commonly reported by Parkinson patients. Here we show that the subjective experience of sleep benefit is not paralleled by an actual improvement in motor functioning. Sleep benefit therefore appears to be a subjective phenomenon and not a Parkinson-specific reduction in symptoms., (© 2015 Associated Professional Sleep Societies, LLC.)

Background: Diagnosing narcolepsy without cataplexy is often a challenge as the symptoms are nonspecific, current diagnostic tests are limited, and there are no useful biomarkers. In this report, we review the clinical and physiological aspects of narcolepsy without cataplexy, the limitations of available diagnostic procedures, and the differential diagnoses, and we propose an approach for more accurate diagnosis of narcolepsy without cataplexy., Methods: A group of clinician-scientists experienced in narcolepsy reviewed the literature and convened to discuss current diagnostic tools, and to map out directions for research that should lead to a better understanding and more accurate diagnosis of narcolepsy without cataplexy., Recommendations: To aid in the identification of narcolepsy without cataplexy, we review key indicators of narcolepsy and present a diagnostic algorithm. A detailed clinical history is mainly helpful to rule out other possible causes of chronic sleepiness. The multiple sleep latency test remains the most important measure, and prior sleep deprivation, shift work, or circadian disorders should be excluded by actigraphy or sleep logs. A short REM sleep latency (≤ 15 minutes) on polysomnography can aid in the diagnosis of narcolepsy without cataplexy, although sensitivity is low. Finally, measurement of hypocretin levels can helpful, as levels are low to intermediate in 10% to 30% of narcolepsy without cataplexy patients.

Introduction: Narcolepsy is associated with obesity though it is uncertain whether this is caused by changes in glucose and fat metabolism. Therefore, we performed a detailed analysis of systemic energy homeostasis in narcolepsy patients, and additionally, investigated whether it was affected by three months of sodium oxybate (SXB) treatment., Methods: Nine hypocretin deficient patients with narcolepsy-cataplexy, and nine healthy sex, age, and BMI matched controls were enrolled. A hyperinsulinemic-euglycemic clamp combined with stable isotopes ([6,6-(2)H2]-glucose and [(2)H5]- glycerol) was performed at baseline. In seven patients a second study was performed after three months of SXB treatment., Results: Glucose disposal rate (GDR) per unit serum insulin was significantly higher in narcolepsy patients compared to matched controls (1.6 ± 0.2 vs. 1.1 ± 0.3 μmol/kgFFM/min/mU×L; P = 0.024), whereas β-cell function was similar (P = 0.50). Basal steady state glycerol appearance rate tended to be lower in narcolepsy patients (5.2 ± 0.4 vs. 7.5 ± 1.3 μmol/kgFM/min; P = 0.058), suggesting a lower rate of lipolysis. SXB treatment induced a trend in reduction of the GDR (1.4 ± 0.1 vs. 1.1 ± 0.2 μmol/kgFFM/min/mU×L; P = 0.063) and a reduction in endogenous glucose production (0.24 ± 0.03 vs. 0.16 ± 0.03 μmol/kgFFM/min/mU×L: P = 0.028) per unit serum insulin. After SXB treatment lipolysis increased (4.9 ± 0.4 vs. 6.5 ± 0.6 μmol/kgFM/min; P = 0.018), and body weight decreased in narcolepsy patients (99.2 ± 6.0 vs. 94.0 ± 5.4 kg; P = 0.044)., Conclusion: We show that narcolepsy patients are more insulin sensitive and may have a lower rate of lipolysis than matched controls. SXB stimulated lipolysis in narcolepsy patients, possibly accounting for the weight loss after treatment. While sodium oxybate tended to decrease systemic insulin sensitivity, it increased hepatic insulin sensitivity, suggesting tissue-specific effects.

Study Objective: Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects., Design: Retrospective case-control study., Setting: A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication., Patients and Participants: For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included., Measurements and Results: None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified., Conclusion: An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.

Objective: Hypocretin deficiency causes narcolepsy and may affect neuroendocrine systems, including TSH, ACTH and LH secretion. Symptoms can be treated effectively with sodium oxybate (SXB) in many patients. This study was performed to compare prolactin (PRL) secretion in patients and matched controls and establish the effect of SXB administration on PRL and sleep in both the groups., Design: Open label intervention. Blood was sampled before and after 5 days of SXB treatment. The study was performed at the Leiden University Medical Centre, Leiden, The Netherlands., Methods: Subjects were admitted to the clinical research centre on both occasions., Patients or Participants: Eight male hypocretin-deficient narcolepsy with cataplexy patients and eight controls matched for sex, age, body mass index, waist-to-hip ratio and fat percentage were enrolled., Interventions: SXB two times 3 g per night for five consecutive nights., Results: Patients and controls underwent 24 h blood sampling at 10 min intervals for measurement of PRL concentrations. The PRL concentration time series was analysed with a new deconvolution programme, approximate entropy (ApEn) and Cosinor analysis. Sleep was polygraphically recorded. Basal and pulsatile PRL secretion, as well as pulse regularity and frequency, ApEn and diurnal parameters were similar in patients and controls. SXB treatment caused similar nocturnal increase in PRL secretion, advance of the acrophase and decrease in ApEn in patients and controls. Slow wave sleep was increased to a similar extent in patients and controls., Conclusion: This detailed study did not demonstrate altered PRL secretion in hypocretin-deficient narcolepsy patients during the basal state or during SXB administration. Therefore, hypocretin signalling is unlikely to be a regulator of the lactotrophic system.

Freezing of gait is a common, debilitating feature of Parkinson's disease. We have studied gait planning in patients with freezing of gait, using motor imagery of walking in combination with functional magnetic resonance imaging. This approach exploits the large neural overlap that exists between planning and imagining a movement. In addition, it avoids confounds introduced by brain responses to altered motor performance and somatosensory feedback during actual freezing episodes. We included 24 patients with Parkinson's disease: 12 patients with freezing of gait, 12 matched patients without freezing of gait and 21 matched healthy controls. Subjects performed two previously validated tasks--motor imagery of gait and a visual imagery control task. During functional magnetic resonance imaging scanning, we quantified imagery performance by measuring the time required to imagine walking on paths of different widths and lengths. In addition, we used voxel-based morphometry to test whether between-group differences in imagery-related activity were related to structural differences. Imagery times indicated that patients with freezing of gait, patients without freezing of gait and controls engaged in motor imagery of gait, with matched task performance. During motor imagery of gait, patients with freezing of gait showed more activity than patients without freezing of gait in the mesencephalic locomotor region. Patients with freezing of gait also tended to have decreased responses in mesial frontal and posterior parietal regions. Furthermore, patients with freezing of gait had grey matter atrophy in a small portion of the mesencephalic locomotor region. The gait-related hyperactivity of the mesencephalic locomotor region correlated with clinical parameters (freezing of gait severity and disease duration), but not with the degree of atrophy. These results indicate that patients with Parkinson's disease with freezing of gait have structural and functional alterations in the mesencephalic locomotor region. We suggest that freezing of gait might emerge when altered cortical control of gait is combined with a limited ability of the mesencephalic locomotor region to react to that alteration. These limitations might become particularly evident during challenging events that require precise regulation of step length and gait timing, such as turning or initiating walking, which are known triggers for freezing of gait.

Study Objectives: To study the prevalence of and symptoms of eating disorders in patients with narcolepsy., Design: We performed a case-control study comparing symptoms of eating disorders in patients with narcolepsy versus healthy population controls, using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN 2.1). To study whether an increased body mass index (BMI) could be responsible for symptoms of an eating disorder, we also compared patients with BMI-matched controls, using the SCAN as well as the Eating Disorder Examination-Questionnaire., Setting: University hospital., Patients and Participants: Patients with narcolepsy/cataplexy (n = 60) were recruited from specialized sleep centers. Healthy controls (n = 120) were drawn from a population study previously performed in the Netherlands. Separately, 32 BMI-matched controls were recruited., Interventions: N/A., Measurements and Results: In total, 23.3% of the patients fulfilled the criteria for a clinical eating disorder, as opposed to none of the control subjects. Most of these were classified as Eating Disorder-Not Otherwise Specified, with an incomplete form of binge eating disorder. On the symptom level, half of the patients reported a persistent craving for food, as well as binge eating. Twenty-five percent of patients even reported binging twice a week or more often. When compared with BMI-matched controls, the significant increases persisted in symptoms of eating disorders among patients with narcolepsy. Except for a higher level of interference in daily activities due to eating problems in patients using antidepressants, medication use did not influence our findings., Conclusions: The majority of patients with narcolepsy experience a number of symptoms of eating disorders, with an irresistible craving for food and binge eating as the most prominent features. Eating disorder symptomatology interfered with daily activities. These findings justify more attention for eating disorders in the treatment of patients with narcolepsy.

Context: Impaired vigilance and sleepiness are two majordaily complaints of patients with narcolepsy. We previously showed their sleepiness to be correlated to an abnormally regulated skin temperature, i.e., increased distal skin temperature compared with proximal skin temperature., Objective: Our goal was to investigate a possible causal contribution of skin temperature disturbances to impairments in the ability to maintain vigilance and wakefulness in narcolepsy., Design: In a modified constant routine protocol, the Psychomotor Vigilance Task (PVT) and the Maintenance of Wakefulness Test (MWT) were repeatedly assessed. Meanwhile, skin and core body temperatures were mildly manipulated within the thermoneutral range of the normal diurnal rhythm using a thermosuit and hot or cold food and drinks., Setting: Tertiary narcolepsy referral center in a university hospital, Patients or Other Participants: Eight patients (5 males) diagnosed with narcolepsy with cataplexy according to the ICSD-2 criteria (mean age +/- SD: 28.6 +/- 6.4, range 18-35 years)., Intervention(s): None., Main Outcome Measure(s): MWT sleep latency and PVT response speed., Results: Compared to core cooling, core warming attenuated the typical decline in PVT response speed with increasing time-on-task by 25% (P = 0.02). Compared to distal skin warming, distal skin cooling increased the time that the patients were able to maintain wakefulness by 24% (distal warming: 1.88 min. vs. distal warming: 2.34 min.; P < 0.01)., Conclusions: Core body and skin temperatures causally affect vigilance and sleepiness in narcolepsy. This could lead to future practical applications.

The hypothalamic hypocretin (orexin) system plays a central role in the regulation of various functions, including sleep/wake regulation and metabolism. There is a growing interest in hypocretin function in Parkinson's disease (PD), given the high prevalence of non-motor symptoms such as sleep disturbances in this disorder. However, studies measuring CSF hypocretin levels have yielded contradictory results. In PD patients and matched controls, we (i) estimated the number of hypocretin neurons in post-mortem hypothalami using immunocytochemistry and an image analysis system (ii) quantified hypocretin levels in post-mortem ventricular CSF and (iii) prefrontal cortex using a radioimmunoassay. Furthermore, presence of Lewy bodies was verified in the hypothalamic hypocretin cell area. Data are presented as median (25th-75th percentile). We showed a significant decrease between PD patients and controls in (i) the number of hypocretin neurons (PD: 20 276 (13 821-31 229); controls: 36 842 (32 546-50 938); P = 0.016); (ii) the hypocretin-1 concentration in post-mortem ventricular CSF (PD: 365.5 pg/ml (328.0-448.3); controls: 483.5 (433.5-512.3); P = 0.012) and (iii) the hypocretin-1 concentrations in prefrontal cortex (PD: 389.6 pg/g (249.2-652.2); controls: 676.6 (467.5-883.9); P = 0.043). Hypocretin neurotransmission is affected in PD. The hypocretin-1 concentration in the prefrontal cortex was almost 40% lower in PD patients, while ventricular CSF levels were almost 25% reduced. The total number of hypocretin neurons was almost half compared to controls.

Study Objectives: In healthy subjects, sleep propensity increases when the distal skin temperature increases relative to the proximal skin temperature. This increase results from increased blood flow in the skin of the extremities and is, among other factors, controlled by the hypothalamic circadian clock, as is sleep. Because narcolepsy is characterized by hypothalamic alterations, we studied skin temperature in narcoleptic patients in relation to their characteristically increased sleep propensity during the day., Design: Distal and proximal skin temperature and their gradient (DPG) were measured during a Multiple Sleep Latency Test. This allowed temperature to be studied during wakefulness, at sleep onset and during sleep., Setting: Tertiary narcolepsy referral center in a university hospital., Patients: Fifteen unmedicated narcolepsy patients with cataplexy and 15 controls., Interventions: None., Measurements and Results: In subjects in the waking state, DPG was higher in narcoleptics than in controls throughout the day (time by group interaction, p < .0001), due to increased distal skin temperature and decreased proximal skin temperature. The increase in DPG was related to a shorter subsequent sleep-onset latency (p = .02). Once asleep, narcoleptics maintained their elevated distal skin temperature and DPG (p < .0001), whereas proximal skin temperature increased to reach normal levels., Conclusions: This is the first demonstration of a dramatic alteration of daytime skin temperature control in narcolepsy. Even awake narcoleptic patients showed a DPG higher than that which healthy controls achieve when asleep. This observation suggests that hypocretin deficiency in narcolepsy affects skin-temperature regulation and invites further examination. Skin-temperature control might ultimately even have therapeutic implications for the alleviation of narcoleptic symptoms.

Study Objectives: Recent studies suggest that narcolepsy is caused by degeneration of hypocretin (orexin) producing neurons. To find evidence for this hypothesis, we aimed to detect structural changes in the hypothalamus and/or hypocretin projection areas of patients with narcolepsy., Design: We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes., Setting: Image acquisition was carried out in the department of Radiology at Leiden University Medical Center; image post-processing was performed in the Wellcome Department of Cognitive Neurology, London., Participants: Fifteen narcoleptic patients were studied, all having cataplexy and typical findings on Multiple Sleep Latency Testing. All patients were HLA-DQB1*0602 positive and hypocretin-1 deficient. The control group consisted of 15 age and sex matched healthy subjects., Measurements and Results: We found no differences in global gray or white matter volumes between patients and controls. Furthermore, regional gray or white matter volumes in the hypothalamus and hypocretin projection areas did not differ between patients and controls., Conclusions: VBM failed to show structural changes in the brains of patients with narcolepsy. This suggests that narcolepsy either is associated with microscopic changes undetectable by VBM or that functional abnormalities of hypocretin neurons are not associated with structural correlates.

Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin) neurotransmission. It has been suggested that anomalous timing by the biological clock contributes to the symptomatology. Hypocretins stimulate the pituitary-adrenal (PA) axis in rodents. We explored whether hypocretin deficiency disrupts circadian timing and blunts PA hormone release. We deconvolved 24-h plasma profiles of ACTH and cortisol, and determined their circadian rhythm by cosinor analysis in seven hypocretin-deficient narcoleptic males and seven matched controls. Basal and total ACTH production were blunted in narcoleptics [310 +/- 86 vs. 760 +/-160 ng/liter.24 h (P = 0.02) and 920 +/- 147 vs. 1460 +/- 220 ng/liter.24 h (P = 0.04), respectively], whereas pulsatile release did not differ between groups. In contrast, basal, pulsatile and total cortisol secretion were similar in both groups. The cross-approximate entropy of the joint ACTH/cortisol time series was higher in narcoleptics (1.26 +/- 0.07 vs. 1.07 +/- 0.04; P = 0.04), reflecting reduced secretory process regularity. The acrophases of both ACTH and cortisol occurred at similar clock times (approximately 0830 h) in patients and controls, which supports the idea that the master pacemaker is intact in narcolepsy. The reduced (basal) ACTH secretion and the diminished secretory process regularity of the ACTH/cortisol ensemble conjointly suggest that hypocretin deficiency induces changes in the interplay between PA hormones.

Recent observations have implicated hypocretin deficiency in the pathogenesis of narcolepsy. Hypocretin neurotransmission also affects energy balance, and narcoleptic patients tend to become obese. Because hypocretins appear to have important neuroendocrine effects, we hypothesized that the neuroendocrine systems that regulate energy balance might be distinctly set in narcolepsy. As leptin is a pivotal part of these systems, we explored the 24-h plasma leptin (20-min sampling interval) concentration profile in six narcoleptic males and six normal controls, matched for age, sex, body mass index, waist/hip ratio, and fat mass. We thus demonstrated a reduction of the mean 24-h leptin concentration in narcoleptics to 52% of that in controls (5.9 microg/liter in narcolepsy vs. 11.4 microg/liter in controls; P < 0.05). Further, a nocturnal acrophase (clock time of the highest concentration), which is typical of normal leptin secretion, was observed in controls (mean, 2335 h; 95% confidence interval, 2105-0205 h), but not in narcoleptic patients. The mechanisms that potentially disturb the circadian rhythm of leptin levels in hypocretin-deficient narcoleptic humans include anomalies of the sleep-wake cycle and/or disruption of the circadian distribution of autonomic activity. As leptin deficiency clearly leads to morbid obesity in experimental animals and humans, we infer that the observed reduction of plasma leptin levels may predispose narcoleptic humans to weight gain.