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Objective: To obtain insight in the spectrum of narcolepsy symptoms and associated burden in a large cohort of patients., Methods: We used the Narcolepsy Monitor, a mobile app, to easily rate the presence and burden of 20 narcolepsy symptoms. Baseline measures were obtained and analyzed from 746 users aged between 18 and 75 years with a reported diagnosis of narcolepsy., Results: Median age was 33.0 years (IQR 25.0-43.0), median Ullanlinna Narcolepsy Scale 19 (IQR 14.0-26.0), 78% reported using narcolepsy pharmacotherapy. Excessive daytime sleepiness (97.2%) and lack of energy were most often present (95.0%) and most often caused a high burden (79.7% and 76.1% respectively). Cognitive symptoms (concentration 93.0%, memory 91.4%) and psychiatric symptoms (mood 76.8%, anxiety/panic 76.4%) were relatively often reported to be present and burdensome. Conversely, sleep paralysis and cataplexy were least often reported as highly bothersome. Females experienced a higher burden for anxiety/panic, memory, and lack of energy., Conclusions: This study supports the notion of an elaborate narcolepsy symptom spectrum. Each symptom's contribution to the experienced burden varied, but lesser-known symptoms did significantly add to this as well. This emphasizes the need to not only focus treatment on the classical core symptoms of narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®., (© 2023. The Author(s).)

Objective: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy., Methods: In this randomised, double-blind, placebo-controlled, crossover study, driving performance during a 1 h on-road driving test was assessed at 2 and 6 h post-dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post-dose., Results: The study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post-dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, -1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post-dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, -1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (≥5%) included headache, decreased appetite, and somnolence., Conclusions: Solriamfetol 300 mg/day improved on-the-road driving performance, at 2 h post-administration in participants with narcolepsy., (© 2022 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.)

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.)

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.)

Background and Objectives: Recent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers., Methods: We used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups., Results: We included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters., Discussion: Using a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Patients with narcolepsy or idiopathic hypersomnia (IH) are at increased risk of driving accidents. Both excessive daytime sleepiness, i.e. unwanted sleep episodes during the day, and disturbed vigilance are core features of these disorders. We tested on-the-road driving performance of patients with narcolepsy or IH coming in for a routine driving fitness evaluation and examined: (1) correlations between driving performance and the Maintenance of Wakefulness Test (MWT), Sustained Attention to Response Task (SART) and Psychomotor Vigilance Test (PVT) as objective tests; (2) the predictive power of the MWT and SART for increased risk of impaired driving; (3) the best set of objective predictors for increased risk of impaired driving. Participants were 44 patients (aged 18-75 years) with narcolepsy type 1 (NT1), type 2 (NT2) or IH. They completed the MWT, SART, PVT, a subjective sleepiness questionnaire, and a standardised on-the-road driving test. The standard deviation of the lateral position (SDLP) was used as outcome measure of driving performance. The MWT had low correlation with the SDLP (ρ = -0.41 to -0.49, p < 0.01). The SART and PVT had low correlations with SDLP (ρ = 0.30 and ρ = 0.39, respectively, both p < 0.05). The predictive power of MWT for an increased risk of impaired driving was significant, but low (area under the curve = 0.273, p = 0.012), and non-significant for SART. We conclude that in our present group, none of the tests had adequate ability to predict impaired driving, questioning their use for clinical driving fitness evaluation in narcolepsy and IH. Real-time monitoring of sleepiness while driving seems more promising in these patients., (© 2021 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European 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.)

Introduction: The core symptoms of narcolepsy such as excessive daytime sleepiness and cataplexy are well known. However, there is mounting evidence for a much broader symptom spectrum, including psychiatric symptoms. Disordered sleep has previously been linked with dissociative symptoms, which may imply that patients with narcolepsy are more prone to develop such symptoms., Objectives: To investigate the frequency of dissociative symptoms in adult patients with narcolepsy type 1 compared to population controls., Methods: In a retrospective case control study, sixty adult patients fulfilling the criteria for narcolepsy type 1 and 120 matched population control subjects received a structured interview using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) to assess dissociative symptoms and disorders., Results: A majority of narcolepsy patients reported dissociative symptoms, and even fulfilled the DSM-IV-TR criteria of a dissociative disorder (62% vs 1% in controls, p < .001). Most frequently reported symptoms were "dissociative amnesia" (37% vs 1%, p < .001) and "dissociative disorder of voluntary movement" (32% vs 1%, p < .001)., Conclusion: Dissociative symptoms are strikingly prevalent in adult patients with narcolepsy type 1. Although a formal diagnosis of dissociation disorder should not be made as the symptoms can be explained by narcolepsy as an underlying condition, the findings do illustrate the extent and severity of the dissociative symptoms. As for the pathophysiological mechanism, there may be symptom overlap between narcolepsy and dissociation disorder. However, there may also be a more direct link between disrupted sleep and dissociative symptoms. In either case, the high frequency of occurrence of dissociative symptoms should result in an active inquiry by doctors, to improve therapeutic management and guidance.

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.)

Introduction: Excessive Daytime Sleepiness is a core symptom of narcolepsy and idiopathic hypersomnia, which impairs driving performance. Adequate treatment improves daytime alertness, but it is unclear whether driving performance completely normalizes. This study compares driving performance of patients with narcolepsy and idiopathic hypersomnia receiving treatment to that of healthy controls., Methods: Patients diagnosed with narcolepsy type 1 (NT1, n = 33), narcolepsy type 2 (NT2, n = 7), or idiopathic hypersomnia (IH, n = 6) performed a standardized one-hour on-the-road driving test, measuring standard deviation of lateral position (SDLP)., Results: Results showed that mean SDLP in patients did not differ significantly from controls, but the 95%CI of the mean difference (+1.02 cm) was wide (-0.72 to +2.76 cm). Analysis of subgroups, however, showed that mean SDLP in NT1 patients was significantly increased by 1.90 cm as compared to controls, indicating impairment. Moreover, four NT1 patients requested to stop the test prematurely due to self-reported somnolence, and two NT1 patients were stopped by the driving instructor for similar complaints., Conclusion: Driving performance of NT1 patients may still be impaired, despite receiving treatment. No conclusions can be drawn for NT2 and IH patients due to the low sample sizes of these subgroups. In clinical practice, determination of fitness to drive for these patients should be based on an individual assessment in which also coping strategies are taken into account.

As early as the 1920s, pathological studies of encephalitis lethargica allowed Von Economo to correctly identify hypothalamic damage as crucial for the profound associated sleep-related symptoms that helped define the condition. Only over the last 3 decades, however, has the key role of the hypothalamus in sleep-wake regulation become increasingly recognized. As a consequence, a close relation between abnormal sleep symptomatology and hypothalamic pathology is now widely accepted for a variety of medical disorders. Narcolepsy is discussed in some detail as the cardinal primary sleep disorder that is caused directly and specifically by hypothalamic pathology, most notably destruction of hypocretin (orexin)-containing neurons. Thereafter, various conditions are described that most likely result from hypothalamic damage, in part at least, producing a clinical picture resembling (symptomatic) narcolepsy. Kleine-Levin syndrome is a rare primary sleep disorder with intermittent symptoms, highly suggestive of hypothalamic involvement but probably reflecting a wider pathophysiology. ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) and Prader-Willi syndrome are also covered as hypothalamic syndromes with prominent sleep-related symptoms. Finally, sleep issues in several endocrine disorders are briefly discussed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.)

Background: Narcolepsy is a chronic sleep disorder with a broad variety of symptoms. Although narcolepsy is primarily characterized by excessive daytime sleepiness and cataplexy (loss of muscle control triggered by emotions), patients may suffer from hypnagogic hallucinations, sleep paralysis, and fragmented night sleep. However, the spectrum of narcolepsy also includes symptoms not related to sleep, such as cognitive or psychiatric problems. Symptoms vary greatly among patients and day-to-day variance can be considerable. Available narcolepsy questionnaires do not cover the whole symptom spectrum and may not capture symptom variability. Therefore, there is a clinical need for tools to monitor narcolepsy symptoms over time to evaluate their burden and the effect of treatment., Objective: This study aimed to describe the design, development, implementation, and evaluation of the Narcolepsy Monitor, a companion app for long-term symptom monitoring in narcolepsy patients., Methods: After several iterations during which content, interaction design, data management, and security were critically evaluated, a complete version of the app was built. The Narcolepsy Monitor allows patients to report a broad spectrum of experienced symptoms and rate their severity based on the level of burden that each symptom imposes. The app emphasizes the reporting of changes in relative severity of the symptoms. A total of 7 patients with narcolepsy were recruited and asked to use the app for 30 days. Evaluation was done by using in-depth interviews and user experience questionnaire., Results: We designed and developed a final version of the Narcolepsy Monitor after which user evaluation took place. Patients used the app on an average of 45.3 (SD 19.2) days. The app was opened on 35% of those days. Daytime sleepiness was the most dynamic symptom, with a mean number of changes of 5.5 (SD 3.7) per month, in contrast to feelings of anxiety or panic, which was only moved 0.3 (SD 0.7) times per month. Mean symptom scores were highest for daytime sleepiness (1.8 [SD 1.0]), followed by lack of energy (1.6 [SD 1.4]) and often awake at night (1.5 [SD 1.0]). The personal in-depth interviews revealed 3 major themes: (1) reasons to use, (2) usability, and (3) features. Overall, patients appreciated the concept of ranking symptoms on subjective burden and found the app easy to use., Conclusions: The Narcolepsy Monitor appears to be a helpful tool to gain more insight into the individual burden of narcolepsy symptoms over time and may serve as a patient-reported outcome measure for this debilitating disorder., (©Laury Quaedackers, Jan De Wit, Sigrid Pillen, Merel Van Gilst, Nikolaos Batalas, Gert Jan Lammers, Panos Markopoulos, Sebastiaan Overeem. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 07.01.2020.)

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.

Narcolepsy type 1 is a chronic sleep disorder caused by a deficiency of the orexin (hypocretin) neuropeptides. In addition to sleep regulation, orexin is important for motivated control processes. Weight gain and obesity are common in narcolepsy. However, the neurocognitive processes associated with food-related control and overeating in narcolepsy are unknown. We explored the neural correlates of general and food-related attentional control in narcolepsy-type-1 patients (n = 23) and healthy BMI-matched controls (n = 20). We measured attentional bias to food words with a Food Stroop task and general executive control with a Classic Stroop task during fMRI. Moreover, using multiple linear regression, we assessed the relative contribution of neural responses during Food Stroop and Classic Stroop to spontaneous snack intake. Relative to healthy controls, narcolepsy patients showed enhanced ventral medial prefrontal cortex responses and connectivity with motor cortex during the Food Stroop task, but attenuated dorsal medial prefrontal cortex responses during the Classic Stroop task. Moreover, the former activity but not the latter, was a significant predictor of spontaneous snack intake. These findings demonstrate that narcolepsy, characterized by orexin deficiency, is associated with decreased dorsal medial prefrontal cortex responses during general executive control and enhanced ventral medial prefrontal cortex responses during food-driven attention.

Background: In 2010, a safety signal was detected for narcolepsy following vaccination with Pandemrix, an AS03-adjuvanted monovalent pandemic H1N1 influenza (pH1N1) vaccine. To further assess a possible association and inform policy on future use of adjuvants, we conducted a multi-country study of narcolepsy and adjuvanted pH1N1 vaccines., Methods: We used electronic health databases to conduct a dynamic retrospective cohort study to assess narcolepsy incidence rates (IR) before and during pH1N1 virus circulation, and after pH1N1 vaccination campaigns in Canada, Denmark, Spain, Sweden, Taiwan, the Netherlands, and the United Kingdom. Using a case-control study design, we evaluated the risk of narcolepsy following AS03- and MF59-adjuvanted pH1N1 vaccines in Argentina, Canada, Spain, Switzerland, Taiwan, and the Netherlands. In the Netherlands, we also conducted a case-coverage study in children born between 2004 and 2009., Results: No changes in narcolepsy IRs were observed in any periods in single study sites except Sweden and Taiwan; in Taiwan incidence increased after wild-type pH1N1 virus circulation and in Sweden (a previously identified signaling country), incidence increased after the start of pH1N1 vaccination. No association was observed for Arepanrix-AS03 or Focetria-MF59 adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the case-control study nor for children born between 2004 and 2009 in the Netherlands case-coverage study for Pandemrix-AS03., Conclusions: Other than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

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.

Narcolepsy is a chronic sleep disorder that has a typical onset in adolescence and is characterized by excessive daytime sleepiness, which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2), both of which have similar clinical profiles, except for the presence of cataplexy, which occurs only in patients with narcolepsy type 1. The pathogenesis of narcolepsy type 1 is hypothesized to be the autoimmune destruction of the hypocretin-producing neurons in the hypothalamus; this hypothesis is supported by immune-related genetic and environmental factors associated with the disease. However, direct evidence in support of the autoimmune hypothesis is currently unavailable. Diagnosis of narcolepsy encompasses clinical, electrophysiological and biological evaluations, but simpler and faster procedures are needed. Several medications are available for the symptomatic treatment of narcolepsy, all of which have quite good efficacy and safety profiles. However, to date, no treatment hinders or slows disease development. Improved diagnostic tools and increased understanding of the pathogenesis of narcolepsy type 1 are needed and might lead to therapeutic or even preventative interventions.

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.)

This two-centre observational study of vigilance measurements assessed the feasibility of vigilance measurements on multiple days using the Sustained Attention to Response Task and the Psychomotor Vigilance Test with portable task equipment, and subsequently assessed the effect of sodium oxybate treatment on vigilance in patients with narcolepsy. Twenty-six patients with narcolepsy and 15 healthy controls were included. The study comprised two in-laboratory days for the Maintenance of Wakefulness Test and the Oxford Sleep Resistance test, followed by 7-day portable vigilance battery measurements. This procedure was repeated for patients with narcolepsy after at least 3 months of stable treatment with sodium oxybate. Patients with narcolepsy had a higher Sustained Attention to Response Task error count, lower Psychomotor Vigilance Test reciprocal reaction time, higher Oxford Sleep Resistance test omission error count adjusted for test duration (Oxford Sleep Resistance testOMIS / MIN ), and lower Oxford Sleep Resistance test and Maintenance of Wakefulness Test sleep latency compared with controls (all P < 0.01). Treatment with sodium oxybate was associated with a longer Maintenance of Wakefulness Test sleep latency (P < 0.01), lower Oxford Sleep Resistance testOMIS / MIN (P = 0.01) and a lower Sustained Attention to Response Task error count (P = 0.01) in patients with narcolepsy, but not with absolute changes in Oxford Sleep Resistance test sleep latency or Psychomotor Vigilance Test reciprocal reaction time. It was concluded that portable measurements of sustained attention as well as in-laboratory Oxford Sleep Resistance test and Maintenance of Wakefulness Test measurements revealed worse performance for narcoleptic patients compared with controls, and that sodium oxybate was associated with an improvement of sustained attention and a better resistance to sleep., (© 2016 European Sleep Research Society.)

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials., (© 2016 European Sleep Research Society.)

Several studies have identified an association between Pandemrix(TM), an AS03 adjuvanted pandemic influenza A(H1N1) vaccine, and narcolepsy, a rare and under-diagnosed sleep disorder with a median onset-to-diagnosis interval of ten years. This paper reviews potential sources of bias in published studies and aims to provide, through simulation, methodological recommendations for assessment of vaccine safety signals. Our simulation study showed that in the absence of an association between the vaccine and the outcome, presence of detection bias and differential exposure misclassification could account for elevated risk estimates. These may play a major role, particularly in alert situations when observation times are limited and the disease has a long latency period. Estimates from the case-control design were less inflated than those from the cohort design when these biases were present. Overall, these simulations provide useful insights for the design and interpretation of future studies.

Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin-deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 × 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 ± 0.05 °C versus 37.0 ± 0.05 °C, F = 8.31, P = 0.01; proximal: 33.4 ± 0.26 °C versus 34.3 ± 0.26 °C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven., (© 2015 European Sleep Research Society.)

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.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare and complex pediatric syndrome, essentially caused by dysfunction of 3 vital systems regulating endocrine, respiratory, and autonomic nervous system functioning. The clinical spectrum of ROHHAD is broad, but sleep/wake disorders have received relatively little attention so far, although the central hypothalamic dysfunction would make the occurrence of sleep symptoms likely. In this case report, we expand the phenotype of ROHHAD with a number of striking sleep symptoms that together can be classified as a secondary form of narcolepsy. We present a 7-year-old girl with ROHHAD who displayed the classic features of narcolepsy with cataplexy: excessive daytime sleepiness with daytime naps, visual hallucinations, and partial cataplexy reflected in intermittent loss of facial muscle tone. Nocturnal polysomnography revealed sleep fragmentation and a sleep-onset REM period characteristic for narcolepsy. The diagnosis was confirmed by showing an absence of hypocretin-1 in the cerebrospinal fluid. We discuss potential pathophysiological implications as well as symptomatic treatment options.

Study Objectives: Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones., Methods: Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night)., Results: At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones., Conclusions: The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion.

Background: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification., Methods: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom., Results: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time., Conclusions: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease., Competing Interests: The authors have declared that no competing interests exist.

Excessive daytime sleepiness (EDS) is the core symptom of narcolepsy. However, there have been indications that fatigue - which should be separated from EDS--is also a frequent complaint. We determined the prevalence of severe fatigue in a group of narcolepsy patients and its relation with excessive daytime sleepiness, psychological distress, functional impairment and quality of life. We included 80 patients fulfilling the International Classification of Sleep Disorders (ICSD)-2 diagnostic criteria of narcolepsy with cataplexy. Fatigue was measured using the Checklist Individual Strength (CIS). In addition psychological distress, including symptoms of depression, functional impairment and quality of life, were assessed. Comparisons were made between patients with (CIS-fatigue score ≥ 35) and without severe experienced fatigue. Fifty patients (62.5%) reported severe fatigue. There were no sex or age differences between patients with and without severe fatigue. Both fatigued and non-fatigued patients had the same amount of daytime sleepiness (Epworth Sleepiness Score 14.3 ± 4.2 versus 13.1 ± 4.4, P = 0.22), confirming the separation between sleepiness and fatigue. Interestingly, fatigued patients more often used stimulant medication (64% versus 40%, P = 0.02). Severe fatigue was associated with a significantly increased functional impairment, increased depressive symptoms and a lowered general quality of life. In conclusion, a majority of patients with narcolepsy suffer from severe fatigue, which can be distinguished from daytime sleepiness, and results in severe functional impairment., (© 2011 European Sleep Research Society.)

Hypocretin deficiency causes narcolepsy. It is unknown whether melatonin secretion is affected in this sleep disorder. Therefore, in both narcolepsy patients and matched controls, the authors measured plasma melatonin levels hourly for 24 h before and after 5 days of sodium oxybate (SXB) administration. Although mean melatonin concentrations were similar between patients and controls, in narcoleptics the percentage of 24-h melatonin secreted during the daytime was significantly higher, and melatonin secretion exhibited a weaker coupling to sleep. SXB did not affect melatonin secretion. These findings suggest that hypocretin deficiency might disturb both the circadian control of melatonin release and its temporal association with sleep.

Gélineau originally described narcolepsy as a disease with an organic cause. However, the disorder had undeniable emotional triggers and psychiatric-like expressions, and soon a psychiatric etiology of narcolepsy became a seriously considered option. In fact, the psychiatric view dominated scientific thinking for a long time, not necessarily to the benefit of patients. When hypocretin (orexin) defects were proven to be the cause of narcolepsy Gélineau's original disease model was shown to be right. However, the psychiatric symptoms of the disease were not forgotten afterwards, but gained a different significance: as psychiatric expressions of a brain disease. These symptoms, such as anxiety and eating disorders, can be highly debilitating and warrant clinical attention. Here, we describe the role of psychiatry in the history of narcolepsy, showing their evolving association., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Hypocretin deficiency causes narcolepsy and may affect neuroendocrine systems and body composition. Additionally, growth hormone (GH) alterations my influence weight in narcolepsy. Symptoms can be treated effectively with sodium oxybate (SXB; γ-hydroxybutyrate) in many patients. This study compared growth hormone secretion in patients and matched controls and established the effect of SXB administration on GH and sleep in both groups. Eight male hypocretin-deficient patients with narcolepsy and cataplexy and eight controls matched for sex, age, BMI, waist-to-hip ratio, and fat percentage were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken two times 3 g/night for 5 consecutive nights. Both groups underwent 24-h blood sampling at 10-min intervals for measurement of GH concentrations. The GH concentration time series were analyzed with AutoDecon and approximate entropy (ApEn). Basal and pulsatile GH secretion, pulse regularity, and frequency, as well as ApEn values, were similar in patients and controls. Administration of SXB caused a significant increase in total 24-h GH secretion rate in narcolepsy patients, but not in controls. After SXB, slow-wave sleep (SWS) and, importantly, the cross-correlation between GH levels and SWS more than doubled in both groups. In conclusion, SXB leads to a consistent increase in nocturnal GH secretion and strengthens the temporal relation between GH secretion and SWS. These data suggest that SXB may alter somatotropic tone in addition to its consolidating effect on nighttime sleep in narcolepsy. This could explain the suggested nonsleep effects of SXB, including body weight reduction.

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.

Background: Narcolepsy is often not recognized or accurately diagnosed. This may be due to the fact that cataplexy, a core symptom which is virtually 100% specific, can-in practice-only be diagnosed based on the patient's history. However, the current definition of cataplexy is not very precise and the common distinction between "typical" and "atypical" cataplexy is not well codified., Methods: We aimed to provide a detailed description of the phenotypic variability of cataplexy. We included 109 patients with a definite history of cataplexy and a proven hypocretin-1 deficiency. The questionnaire contained 37 items to broadly cover the clinical aspects of cataplexy, including triggers, pattern and duration of muscle weakness, associated aspects such as sensory phenomena, and limitations in daily life due to cataplexy., Results: "Laughing" only listed in place 11th of most frequent triggers. "Laughing excitedly" was much more potent, showing that a certain intensity of the emotion is important for a "cataplectogenic" effect. Anger was the highest ranking "non-humorous" trigger, followed by "unexpectedly meeting someone well known." About 60% of patients also had spontaneous cataplectic attacks. Forty-five percent of patients experienced both partial and complete attacks and 30% only partial cataplexy. Fifteen percent of complete attacks were reported to last longer than 2 min. An abrupt return of muscle function was an important feature. The jaw and the face were most often involved in partial attacks, even more than the knee or the leg., Conclusions: Cataplexy presents with a large phenotypical diversity, so the current "typical" versus "atypical" distinction may be difficult to hold. We propose that grading cataplexy with different levels of diagnostic confidence may be more useful., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

Introduction: Narcolepsy is a primary sleeping disorder with excessive daytime sleepiness and cataplexy as core symptoms. There is increasing interest in the psychiatric phenotype of narcolepsy. Although many authors suggest an overrepresentation of mood disorders, few systematic studies have been performed and conflicting results have been reported. Anxiety disorders in narcolepsy have only received little attention., Methods: We performed a case-control study in 60 narcolepsy patients and 120 age- and sex-matched controls from a previous population study. The Schedules for Clinical Assessment in Neuropsychiatry were used to assess symptoms and diagnostic classifications of mood and anxiety disorders., Results: Symptoms of mood disorders were reported by about one third of patients. However, the prevalence of formal mood disorder diagnoses - including major depression - was not increased. In contrast, more than half of the narcolepsy patients had anxiety or panic attacks. Thirty-five percent of the patients could be diagnosed with anxiety disorder (odds ratio=15.6), with social phobia being the most important diagnosis. There was no influence of age, sex, duration of illness or medication use on the prevalence of mood or anxiety symptoms and disorders., Discussion: Anxiety disorders, especially panic attacks and social phobias, often affect patients with narcolepsy. Although symptoms of mood disorders are present in many patients, the prevalence of major depression is not increased. Anxiety and mood symptoms could be secondary complications of the chronic symptoms of narcolepsy. Recent studies have shown that narcolepsy is caused by defective hypocretin signaling. As hypocretin neurotransmission is also involved in stress regulation and addiction, this raises the possibility that mood and anxiety symptoms are primary disease phenomena in narcolepsy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: Patients with narcolepsy often experience pervasive hypnagogic hallucinations, sometimes even leading to confusion with schizophrenia. We aimed to provide a detailed qualitative description of hypnagogic hallucinations and other "psychotic" symptoms in patients with narcolepsy and contrast these with schizophrenia patients and healthy controls. We also compared the prevalence of formal psychotic disorders between narcolepsy patients and controls., Methods: We used SCAN 2.1 interviews to compare psychotic symptoms between 60 patients with narcolepsy, 102 with schizophrenia and 120 matched population controls. In addition, qualitative data was collected to enable a detailed description of hypnagogic hallucinations in narcolepsy., Results: There were clear differences in the pattern of hallucinatory experiences in narcolepsy vs. schizophrenia patients. Narcoleptics reported multisensory "holistic" hallucinations rather than the predominantly verbal-auditory sensory mode of schizophrenia patients. Psychotic symptoms such as delusions were not more frequent in narcolepsy compared to population controls. In addition, the prevalence of formal psychotic disorders was not increased in patients with narcolepsy. Almost half of narcoleptics reported moderate interference with functioning due to hypnagogic hallucinations, mostly due to related anxiety., Conclusions: Hypnagogic hallucinations in narcolepsy can be differentiated on a phenomenological basis from hallucinations in schizophrenia which is useful in differential diagnostic dilemmas.

Objective: Besides excessive daytime sleepiness, disturbed nocturnal sleep is a major complaint of patients with narcolepsy. Previously, alterations in skin temperature regulation in narcoleptic patients have been shown to be related to increased sleepiness. This study tests the hypothesis that direct control of nocturnal skin temperature might be applied to improve the disturbed sleep of narcoleptic patients., Methods: Participants were eight patients (five males) diagnosed as having narcolepsy with cataplexy according to the ICSD-2 criteria, mean (SD) age 28.6 (6.4) years, range 18-35 years. During two nights, sleep was recorded polysomnographically while proximal and distal skin temperature were manipulated using a comfortable thermosuit that induced skin temperature to cycle slowly with an amplitude of only 0.4 degrees C within the comfortable range normally observed during sleep. Logistic regression was used to evaluate the effect of skin temperature manipulation on the probability of occurrence of different sleep stages and nocturnal wakefulness., Results: Proximal skin warming significantly suppressed wakefulness and enhanced slow wave sleep (SWS). In contrast, distal skin warming enhanced wakefulness and stage 1 sleep at the cost of SWS and REM sleep. The optimal combination of proximal skin warming and distal skin cooling led to a 160% increase in SWS, a 50% increase in REM sleep and a 68% decrease in wakefulness, compared with the least beneficial combination of proximal skin cooling and distal skin warming., Interpretation: Subtle skin temperature manipulations under controlled conditions significantly improved the typical nocturnal sleep problems in narcolepsy.

Study Objectives: We investigated autonomic balance and resting metabolic rate to explore their possible involvement in obesity in hypocretin/orexin-deficient narcoleptic subjects., Methods: Resting metabolic rate (using indirect calorimetry) and variability in heart rate and blood pressure were determined in the fasted resting state. Subjects included 15 untreated, hypocretin-deficient male narcoleptics and 15 male controls matched for age and body mass index., Results: Spectral power analysis revealed greater heart rate and blood pressure variability in hypocretin-deficient male narcoleptic patients (heart rate: p = 0.01; systolic blood pressure: p = 0.02; diastolic: p < 0.01). The low to high frequency ratio of heart rate power did not differ between groups (p = 0.48), nor did resting metabolic rate (controls: 1767 +/- 226 kcal/24 h; patients: 1766 +/- 227 kcal/24h; p = 0.99)., Conclusions: Resting metabolic rate was not reduced in hypocretin-deficient narcoleptic men and therefore does not explain obesity in this group. Whether the increased heart rate and blood pressure variability--suggesting reduced sympathetic tone--is involved in this regard remains to be elucidated.

Narcolepsy with cataplexy is a debilitating sleep disorder with an estimated prevalence of about 0.05%. Narcolepsy is caused by a selective loss of hypocretin (orexin) producing neurons in the perifornical hypothalamus. Based on the very strong association with the HLA subtype DQB1*0602, it is currently hypothesized narcolepsy is caused by an autoimmune-mediated process directed at the hypocretin neurons. So far however, studies focusing on general markers of (auto)immune activation, as well as humoral immunity against the hypocretin system have not yielded consistent results supporting this hypothesis.

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.

Sleep disorders are very prevalent and represent an emerging worldwide epidemic. However, research into the molecular genetics of sleep disorders remains surprisingly one of the least active fields. Nevertheless, rapid progress is being made in several prototypical disorders, leading recently to the identification of the molecular pathways underlying narcolepsy and familial advanced sleep-phase syndrome. Since the first reports of spontaneous and induced loss-of-function mutations leading to hypocretin deficiency in human and animal models of narcolepsy, the role of this novel neurotransmission pathway in sleep and several other behaviors has gained extensive interest. Also, very recent studies using an animal model of familial advanced sleep-phase syndrome shed new light on the regulation of circadian rhythms.