The aim of the present study was to examine gender and age-specific effects on subjective daytime sleepiness (as measured by the Epworth Sleepiness Scale), body weight and eating behaviour in patients with central disorders of hypersomnolence. Based on the European Narcolepsy Network database, we compared 1035 patients with narcolepsy type I and 505 patients with other central disorders of hypersomnolence ("narcoleptic borderland"), including narcolepsy type II (N = 308) and idiopathic hypersomnia (N = 174), using logistic regression and general linear models. In the entire study population, the Epworth Sleepiness Scale was higher in women (N = 735, mean age = 30 years, mean Epworth Sleepiness Scale = 16.6 +/- SD 3.9) than in men (N = 805, mean age = 32 years, mean Epworth Sleepiness Scale = 15.8 +/- SD 4.4). In women with narcolepsy type I (N = 475), both Epworth Sleepiness Scale and body mass index increased in parallel with age. In women of the narcoleptic borderland (N = 260), the Epworth Sleepiness Scale markedly peaked in their early 30s, while body mass index only started to rise at that age. This rise in body mass index following the Epworth Sleepiness Scale peak cannot be explained by sleepiness-induced uncontrolled eating, as self-reported uncontrolled eating was negatively associated with the Epworth Sleepiness Scale in this group. We propose that the narcoleptic borderland harbours a unique cluster of women in their fertile years with an unexplored aetiology requiring further investigation towards tailored interventions.

Brain clearance involves the drainage of waste molecules from the brain, a process that is suggested to be amplified during sleep. Recently proposed MRI-based methods attempt to approximate human brain clearance with surrogate measures. The current study aimed to explore whether two brain clearance surrogates are altered in narcolepsy. We processed diffusion-weighted and functional resting-state images to extract two surrogates: Diffusion Tensor Imaging Along the Perivascular Space (DTI-ALPS index), and dBOLD-CSF coupling. Both measures were analysed in 12 drug-free, awake people with narcolepsy type 1 and 11 age- and sex-matched controls, as well as in relation to clinical features. We also assessed the correlation between the DTI-ALPS index and dBOLD-CSF coupling. The DTI-ALPS index and dBOLD-CSF coupling amplitude did not show significant differences between narcolepsy and controls, nor significant relations with the severity of excessive daytime sleepiness. We found a significant correlation between dBOLD-CSF coupling and sleep efficiency, as well as a significant correlation between the DTI-ALPS index and dBOLD-CSF coupling. The hypothesis of altered brain clearance in narcolepsy type 1 is not supported by evidence from the current study. The two surrogates correlated with each other, suggesting that both offer different perspectives from the same underlying physiology. Yet, the suitability of the surrogates as brain clearance markers remains debatable. Whereas DTI is not exclusively sensitive to perivascular fluid, dBOLD-CSF coupling is reflecting large-scale CSF motion. Future work should explore other surrogate markers, preferably during sleep, to better understand the possible role of altered brain clearance in narcolepsy type 1 symptomatology.

STUDY OBJECTIVES:Hypocretin deficiency causes type 1 narcolepsy, a condition characterized 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 labeled water. METHODS:Ten males with type I narcolepsy and nine matched (for age, sex, and BMI) healthy controls were enrolled. Participants stayed in a respiration chamber for 24 hours. They subsequently received doubly labeled water and wore an accelerometer for 2 weeks to assess energy expenditure and physical activity under daily living conditions. Total daily energy expenditure, resting energy expenditure (REE), overnight metabolic rate, physical activity level, and activity-induced energy expenditure were measured. RESULTS:No significant differences were found in REE, 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. CONCLUSIONS: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 behavior.

Objective: It is hypothesized that narcolepsy type 1 (NT1) develops in genetically susceptible people who encounter environmental triggers leading to immune-mediated hypocretin-1 deficiency. The pathophysiologies of narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) remain unknown. The main aim of this study was to collect all reported immunological events before onset of a central disorder of hypersomnolence. Methods: Medical records of 290 people with NT1, and 115 with NT2 or IH were retrospectively reviewed to extract infection and influenza vaccination history. Prevalence, distribution of immunological events, and time until hypersomnolence onset were compared between NT1 and the combined group of NT2 and IH. Results: Immunological events were frequently reported before hypersomnolence disorder onset across groups. Flu and H1N1 influenza vaccination were more common in NT1, and Epstein-Barr virus and other respiratory and non-respiratory infections in NT2 and IH. Distributions of events were comparable between NT2 and IH. Rapid symptom onset within one month of infection was frequent across groups, especially after flu infection in NT1. Hypersomnolence disorder progression after an immunological event was reported in ten individuals. Conclusions: Our findings suggest a variety of immunological triggers potentially related to NT1, including H1N1 influenza infection or vaccination, infection with other flu types, and other respiratory and non-respiratory infections. Frequent reports of immunological events (other than those reported in NT1) immediately prior to the development of NT2 and IH support the specificity of triggers for NT1, and open important new research avenues into possible underlying immunological mechanisms in NT2 and IH.

Narcolepsy type 1 (NT1) is a sleep-wake disorder in which people typically experience excessive daytime sleepiness, cataplexy and other sleep-wake disturbances impairing daily life activities. NT1 symptoms are due to hypocretin deficiency. The cause for the observed hypocretin deficiency remains unclear, even though the most likely hypothesis is that this is due to an auto-immune process. The search for autoantibodies and autoreactive Tcells has not yet produced conclusive evidence for or against the auto-immune hypothesis. Other mechanisms, such as reduced corticotrophin-releasing hormone production in the paraventricular nucleus have recently been suggested. There is no reversive treatment, and the therapeutic approach is symptomatic. Early diagnosis and appropriate NT1 treatment is essential, especially in children to prevent impaired cognitive, emotional and social development. Hypocretin receptor agonists have been designed to replace the attenuated hypocretin signalling. Pre-clinical and clinical trials have shown encouraging initial results. A better understanding of NT1 pathophysiology may contribute to faster diagnosis or treatments, which may cure or prevent it.

Introduction Increased narcolepsy type 1 (NT1) incidence rates have been reported globally in 2010, and were linked to the type A H1N1 2009-2010 influenza pandemic and Pandemrix vaccination. A European child-specific NT1 incidence peak was additionally observed in 2013 post the H1N1 pandemic. Thus, the relationship between NT1 and influenza infection remains unclear. Whether other influenza viruses may also trigger NT1 or other central disorders of hypersomnolence (CDH), is unknown. This study investigated annual European incidence patterns of all CDH in complete samples from multiple European centers, in relation to the severity of individual flu strains in preceding influenza seasons.Methods Incidence rates of NT1 (N=981) and the combined group of narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) (N=545) from eight European countries were temporally analysed to identify possible incidence peaks from 1995 to 2019. Linear mixed models and spearman correlations were conducted between hypersomnolence disorder incidence rates and the number of influenza infections of preceding influenza season, split for types A H1N1 and H3N2, and in the Netherlands also types B Victoria and Yamagata influenza.Results 2010 and 2013 incidence peaks were present in NT1, and a 2010 children peak was unexpectedly found in the combined group of NT2 and IH. Both hypersomnolence groups exhibited a significantly positive relationship with preceding H1N1 influenza season severity and a negative relationship with H3N2 influenza. NT1 was additionally significantly positively correlated with influenza type B Victoria in the Netherlands and showed highest correlation in children.Conclusions Besides H1N1 influenza, the temporal association and severity correlation suggest that influenza type B Victoria may be a novel potential trigger for NT1 that requires further investigation. We additionally provide insights into possible immune-related pathophysiologies of NT2 and IH associated with the 2009-2010 H1N1 influenza pandemic. Further immunological investigations are warranted to unravel the complexities of these relationships and their implications for CDH.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study did not receive any funding### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All sites are members of EUNN and they provided pseudonymised data with ethical approval from their local ethics committees and institutional review boards (i.e., the Netherlands: the Medical Ethical Committee of the VU Medical Center scrutinized the study as it consisted of an analysis of previously acquired clinical data posing no risk to included individuals [reference number: 2020.109]; Montpellier, France: Comité de Protection des Personnes France [reference number: 018-A00703-52]; Bologna, Italy: Comitato Etico di Area Vasta Emilia Centro [reference number: EM539-2022-17009-EM1-OSS-AUSLBO]; Prague, Czech Republic: Etická komise Všeobecné fakultní nemocnice v Praze [reference number: 115/21 S]; Warsaw, Poland: Instytut Psychiatrii I Neurologii Komisja Bioetyczna [reference number 21/2010]; Košice, Slovak Republic: Etická komisia Univerzitnej nemocnice L. Pasteura Košice [reference number 22.05.2014]; Innsbruck, Austria: Eithikkommission der Medizinischen Universität Innsbruck [reference number: AH3368 269/4.7 389/5.13(4311a)]; Madrid, Spain: Comité Ético de Investigación Clínica del Grupo Hospital de Madrid [reference number: 15.02.748-GHM]). The clinical experiments conformed to the principles outlined by the Declaration of Helsinki.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

Objective: Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. Methods: We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported.Results: The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7).Conclusions: Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy.& COPY; 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

The influenza A virus subtype H1N1 pandemic surfaced in the first month of 2009. Subsequently, a rigorous vaccination campaign began. With this came the first reports of a clearly increased incidence of narcolepsy in Scandinavian children [1]. The H1N1 vaccine named Pandemrix was suggested to be the culprit. Not long after, however, research groups from countries with a low vaccination grade (e.g. China, the United States, Taiwan, and several other European countries) reported a more modest increase in narcolepsy incidence [2–5]. A possible role for the H1N1 virus itself was thus emphasized. Increased incidences were mainly reported in children, and to a lesser extent in adults. More than 10 years later, Wang et al., now consolidate one major piece of this puzzle by collecting the incidence of narcolepsy on a large scale over a 20-year period in mainland China with data from multiple sleep centers [6]. The incidence of both narcolepsy types before the H1N1 pandemic was 0.8 per 100 000 person-years. This increased to 3.1 during the pandemic, remaining somewhat higher (1.0) after the pandemic. This remained true when only considering clearly defined type 1 narcolepsy (88% of the 2869 included cases), and when excluding cases that had received prior vaccination against H1N1. Of note, the vaccine used for this in mainland China was not Pandemrix and was also not adjuvanted. Interestingly, the patients during the pandemic were of younger age (5–9 years old) compared to before and after the pandemic. The efforts of Wang et al. clearly show that the chance for people to develop narcolepsy type 1 increases when the H1N1 flu virus is rampant and activating the immune system. This is independent of vaccination against H1N1. Yet, as is well established and now also again seen in the Chinese data, only occurs in people with the DQB1*06:02 HLA allele. Is the autoimmune hypothesis of narcolepsy thus proven? Hypocretin-deficient narcolepsy type 1 is assumed to be caused by the autoimmune destruction of hypothalamic hypocretin neurons [7]. Because the hypocretin peptides resemble parts of the H1N1 virus, cross-reactivity has been suggested [8]. Note that this theory does not explain narcolepsy type 2, in which hypocretin is not absent. People with this form of narcolepsy are thus mostly left out of studies involving the autoimmune hypothesis. In 2018, hypocretin-specific T-cells were identified in the blood of people with narcolepsy type 1 [9]. This was a fascinating and crucial finding. However, these cells were primarily restricted by HLA-DR and not by HLA DQB1*06:02. Furthermore, there was no cross-reactivity with influenza peptides. Finally, similar T-cells were also found in a low percentage of healthy controls. The question thus remains if these T-cells truly reflect the primary narcolepsy disease mechanism. They might also represent secondary effects of hypocretin neurons damaged by an—as of yet—unknown other processes. Therefore, the exact role of HLADQB1*06:02 and autoreactive T-cells is still a mystery. Is H1N1 still triggering narcolepsy across the globe? Since the 1918 Spanish flu pandemic, there has been almost a century in which the H1N1 virus has hardly been detected. The 2009–2010 pandemic changed this [10]. Yet, hypocretin-deficient narcolepsy also existed in the last century. This implies that (vaccination against) H1N1 is not the sole trigger. Multiple other candidates have been suggested. Most convincingly, streptococcal infections have been proposed [11, 12]. Whether there could be a role for non-H1N1 flu strains and other vaccinations in the development of narcolepsy has not been systematically studied. Yet, persistent circulation of the H1N1 virus most likely still contributes to the development of new narcolepsy cases. A study involving 22 sleep centers across the US reported a 1.6-fold increase in pediatric cases after the 2009 pandemic [4]. Within Europe, a new child-specific narcolepsy type 1 incidence peak was seen in 2013 in the Netherlands, Italy, and France [13]. Of note, the 2010 narcolepsy peak was relatively mild in these countries. This may suggest the existence of a “limited pool” of people susceptible to developing narcolepsy. Wang et al. have also reported varying narcolepsy incidence rates in mainland China after 2010, with other peaks in 2012, and 2014. They have deemed the “limited pool” hypothesis unlikely since Chinese post-pandemic narcolepsy incidence rates did not normalize and generally remained increased. Narcolepsy incidence generally peaked in spring in both mainland China and the United States, 4–8 months after the preceding H1N1 flu season intensity peak [4–6]. In contrast, two American

Purpose Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990–2018) and the factors associated with the delay in Europe. Patients and Methods We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7−13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

The brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment often used to assess an individual's ability to resist sleep. It is frequently used in narcolepsy type 1, a disorder characterized by impaired sleep-wake control and the inability to resist daytime sleep. We investigated the neural correlates of active sleep resistance in 12 drug-free people with narcolepsy type 1 and 12 healthy controls. Simultaneous fMRI-EEG measurements were recorded during five cycles of two alternating conditions of active sleep resistance and waking rest. Cleaned EEG signals were used to verify wakefulness and task adherence. Pooling both subject groups, significantly higher fMRI activation when actively resisting sleep was seen in the brainstem, superior cerebellum, bilateral thalamus and visual cortices. In controls the activation clusters were generally smaller compared to patients and no significant activation was seen in the brainstem. Formal comparison between groups only found a significantly higher left primary visual cortex activation in patients during active sleep resistance. The active sleep resistance paradigm is a feasible fMRI task to study sleep resistance and induces evident arousal- and visual-related activity. Significantly higher left primary visual cortical activation in patients could be caused by an enhanced need of visual focus to resist sleep, or reflecting a more rapid descent in their level of alertness when resting.

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.

The thalamus is a central brain structure crucially involved in cognitive, emotional, sensory, and motor functions and is often reported to be involved in the pathophysiology of neurological and psychiatric disorders. The functional subdivision of the thalamus warrants morphological investigation on the level of individual subnuclei. In addition to volumetric measures, the investigation of other morphological features may give additional insights into thalamic morphology. For instance, shape features offer a higher spatial resolution by revealing small, regional differences that are left undetected in volumetric analyses. In this review, we discuss the benefits and limitations of recent advances in neuroimaging techniques to investigate thalamic morphology in vivo, leading to our proposed methodology. This methodology consists of available pipelines for volume and shape analysis, focussing on the morphological features of volume, thickness, and surface area. We demonstrate this combined approach in a Parkinson's disease cohort to illustrate their complementarity. Considering our findings, we recommend a combined methodology as it allows for more sensitive investigation of thalamic morphology in clinical populations.

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.