There are long-standing unsolved issues regarding the diagnosis and classification of central disorders of hypersomnolence. These include delineating and identifying phenotypes and unique... Show moreThere are long-standing unsolved issues regarding the diagnosis and classification of central disorders of hypersomnolence. These include delineating and identifying phenotypes and unique conditions (“sui generis”), sleep deprivation’s impact on phenotypes and how to separate sleep deprivation as a trigger from other causes, as well as the association of excessive sleepiness with other disorders. We discuss these issues and present a novel, straightforward classification system with consistent terminology to get out of the impasse and do justice to people with hypersomnolence. Show less
Finger, B.M.; Triller, A.; Bourke, A.M.; Lammers, G.J.; Veauthier, C.; Yildizli, M.; Kallweit, U. 2023
BackgroundManagement of narcolepsy includes behavior strategies and symptomatic pharmacological treatment. In the general population, complementary and alternative medicine (CAM) use is common in... Show moreBackgroundManagement of narcolepsy includes behavior strategies and symptomatic pharmacological treatment. In the general population, complementary and alternative medicine (CAM) use is common in Europe (30%), also in chronic neurological disorders (10–20%). The aim of our study was to evaluate frequency and characteristics of CAM use in German narcolepsy patients.MethodsDemographic, disease-related data frequency and impact of CAM use were assessed in an online survey. Commonly used CAM treatments were predetermined in a questionnaire based on the National Center for Complementary and Alternative Medicine and included the domains: (1) alternative medical systems; (2) biologically based therapies; (3) energy therapies; (4) mind-body interventions, and (5) manipulative and body-based therapies.ResultsWe analyzed data from 254 questionnaires. Fifteen percent of participants were at the time of survey administration using CAM for narcolepsy, and an additional 18% of participants reported past use. Among the 33% of CAM users, vitamins/trace elements (54%), homoeopathy (48%) and meditation (39%) were used most frequently. 54% of the users described CAM as helpful. CAM users more frequently described having side effects from their previous medication (p = 0.001), and stated more frequently not to comply with pharmacological treatment than non-CAM users (21% vs. 8%; p = 0.024).DiscussionThe use of CAM in narcolepsy patients is common. Our results indicate that many patients still feel the need to improve their symptoms, sleepiness and psychological well-being in particular. Frequent medication change, the experience of adverse events and low adherence to physician-recommended medication appears more frequent in CAM users. The impact of CAM however seems to be limited. Show less
The mechanisms involved in the autoimmune hypothesis of narcolepsy are investigated in this thesis. The role of HLA, auto- and cross-reactive T cells is explored and immune cell populations of... Show moreThe mechanisms involved in the autoimmune hypothesis of narcolepsy are investigated in this thesis. The role of HLA, auto- and cross-reactive T cells is explored and immune cell populations of interest are identified by a new technique, called mass cytometry. The second part of the thesis assesses unexplored clinical features of narcolepsy, such as weight gain and sleep state misperception. Show less
This thesis covers several steps in the process of validating the Sustained Attention to Response Task as a measure of vigilance in patients with excessive daytime sleepiness. It comprises a review... Show moreThis thesis covers several steps in the process of validating the Sustained Attention to Response Task as a measure of vigilance in patients with excessive daytime sleepiness. It comprises a review of the currently circulation definitions of vigilance and a proposal for a covering definition; an extension of previous vigilance measurements in narcolepsy and other patient groups with excessive daytime sleepiness; an assessment of factors possibly influencing SART results, such as task repetition, napping, time of day, and test instruction; and the value of the SART as a treatment efficacy measure in narcolepsy and obstructive sleep apnoea. Show less
We reviewed current definitions of vigilance to propose a definition, applicable in sleep medicine. As previous definitions contained terms such as attention, alertness, and arousal, we addressed... Show moreWe reviewed current definitions of vigilance to propose a definition, applicable in sleep medicine. As previous definitions contained terms such as attention, alertness, and arousal, we addressed these concepts too. We defined alertness as a quantitative measure of the mind state governing sensitivity to stimuli. Arousal comprises a stimulus-induced upward change in alertness, irrespective of the subsequent duration of the increased level of alertness. Vigilance is defined as the capability to be sensitive to potential changes in one's environment, ie the capability to reach a level of alertness above a threshold for a certain period of time rather than the state of alertness itself. It has quantitative and temporal dimensions. Attention adds direction towards a stimulus to alertness, requiring cognitive control: it involves being prepared to process stimuli coming from an expected direction. Sustained attention corresponds to a state in which some level of attention is purposefully maintained, adding a time factor to the definition of attention. Vigilance differs from sustained attention in that the latter in addition implies a direction to which attention is cognitively directed as well as a specification of duration. Attempts to measure vigilance, however, are often in fact measurements of sustained attention. (C) 2021 The Authors. Published by Elsevier B.V. Show less
Lindstrom, M.; Schinkelshoek, M.; Tienari, P.J.; Kukkonen, J.P.; Renkonen, R.; Fronczek, R.; ... ; Itkonen, O. 2021
Background: Orexin-A and-B are neuropeptides involved in sleep-wake regulation. In human narcolepsy type 1, this cycle is disrupted due to loss of orexin-producing neurons in the hypothalamus.... Show moreBackground: Orexin-A and-B are neuropeptides involved in sleep-wake regulation. In human narcolepsy type 1, this cycle is disrupted due to loss of orexin-producing neurons in the hypothalamus. Cerebrospinal fluid (CSF) orexin-A measurement is used in the diagnosis of narcolepsy type 1. Currently available immunoassays may lack specificity for accurate orexin quantification. We developed and validated a liquid chromatography mass spectrometry assay (LC-MS/MS) for CSF orexin-A and B.Methods: We used CSF samples from narcolepsy type 1 (n = 22) and type 2 (n = 6) and non-narcoleptic controls (n = 44). Stable isotope-labeled orexin-A and-B internal standards were added to samples before solid-phase extraction and quantification by LC-MS/MS. The samples were also assayed by commercial radioimmunoassay (RIA, n = 42) and enzymatic immunoassay (EIA, n = 72) kits. Stability of orexins in CSF was studied for 12 months.Results: Our assay has a good sensitivity (10 pmol/L = 35 pg/mL) and a wide linear range (35-3500 pg/mL). Added orexin-A and-B were stable in CSF for 12 and 3 months, respectively, when frozen. The median orexin-A concentration in CSF from narcolepsy type 1 patients was < 35 pg/mL (range < 35-131 pg/mL), which was lower than that in CSF from control individuals (98 pg/mL, range < 35-424 pg/mL). Orexin-A concentrations determined using our LC-MS/MS assay were five times lower than those measured with a commercial RIA. Orexin-B concentrations were undetectableConclusions: Orexin-A concentrations measured by our LC-MS/MS assay were lower in narcolepsy type 1 patients as compared to controls. RIA yielded on average higher concentrations than LC-MS/MS. Show less
Purpose of ReviewClinical presentation of central hypersomnolence disorders, including narcolepsy type 1 and 2 and idiopathic hypersomnia, is often similar, and determining the correct diagnosis... Show morePurpose of ReviewClinical presentation of central hypersomnolence disorders, including narcolepsy type 1 and 2 and idiopathic hypersomnia, is often similar, and determining the correct diagnosis remains challenging. Neuroimaging techniques have provided valuable insights into the pathophysiology of narcolepsy and idiopathic hypersomnia. Here, we review current structural and functional brain imaging findings in central hypersomnolence disorders and discuss the future perspectives of neuroimaging in these sleep disorders.Recent FindingsMost studies have focused on narcolepsy type 1 (or narcolepsy with cataplexy), showing inconsistent but extensive structural differences in the hypothalamus and its normally widespread projections. Functional studies have mainly focused on resting-state or emotion regulation in narcolepsy type 1 and have revealed disturbed activity in limbic and mesolimbic structures in relation to cataplexy. Finally, recent studies suggest a disruption of the default-mode network in patients with idiopathic hypersomnia.SummaryMost neuroimaging studies to date have been conducted in small samples, while narcolepsy type 2 (or narcolepsy without cataplexy) and idiopathic hypersomnia remain relatively understudied. Larger studies with consistent clinical phenotyping should be the focus of future investigations. In addition, multi-modal imaging methods will be crucial to resolve previous inconsistencies and identify reliable objective biomarkers that could aid in understanding the pathophysiology and potentially support the diagnostic process. Show less
The aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on... Show moreThe aim of this European initiative is to facilitate a structured discussion to improve the next edition of the International Classification of Sleep Disorders (ICSD), particularly the chapter on central disorders of hypersomnolence.The ultimate goal for a sleep disorders classification is to be based on the underlying neurobiological causes of the disorders with clear implication for treatment or, ideally, prevention and or healing. The current ICSD classification, published in 2014, inevitably has important shortcomings, largely reflecting the lack of knowledge about the precise neurobiological mechanisms underlying the majority of sleep disorders we currently delineate. Despite a clear rationale for the present structure, there remain important limitations that make it difficult to apply in routine clinical practice. Moreover, there are indications that the current structure may even prevent us from gaining relevant new knowledge to better understand certain sleep disorders and their neurobiological causes.We suggest the creation of a new consistent, complaint driven, hierarchical classification for central disorders of hypersomnolence; containing levels of certainty, and giving diagnostic tests, particularly the MSLT, a weighting based on its specificity and sensitivity in the diagnostic context.We propose and define three diagnostic categories (with levels of certainty): 1/"Narcolepsy" 2/"Idiopathic hypersomnia", 3/"Idiopathic excessive sleepiness" (with subtypes). (C) 2020 The Author(s). Published by Elsevier Ltd. Show less
We aimed to compare HLA-DQB1-associations in narcolepsy type 1 (NT1) patients with disease onset before and after the 2009 H1N1 pandemic in a large Dutch cohort 525 NT1 patients and 1272 HLA-DQB1... Show moreWe aimed to compare HLA-DQB1-associations in narcolepsy type 1 (NT1) patients with disease onset before and after the 2009 H1N1 pandemic in a large Dutch cohort 525 NT1 patients and 1272 HLA-DQB1*06:02-positive healthy controls were included. Because of the discussion that has arisen on the existence of sporadic and post-H1N1 NT1, HLA-DQB1-associations in pre- and post-H1N1 NT1 patients were compared. The associations between HLA-DQB1 alleles and NT1 were not significantly different between pre- and post-H1N1 NT1 patients. Both HLA-DQB1-associations with pre- and -post H1N1 NT1 reported in recent smaller studies were replicated. Our findings combine the results of studies in pre- and post-H1N1 NT1 and argue against considering post-H1N1 NT1 as a different entity. Show less
Study objectives: Sleep state misperception is common in various sleep disorders, especially in chronic insomnia with a prevalence ranging between 9-50%. Most prior studies used nocturnal... Show moreStudy objectives: Sleep state misperception is common in various sleep disorders, especially in chronic insomnia with a prevalence ranging between 9-50%. Most prior studies used nocturnal polysomnography (PSG) for the identification of sleep state misperception during nighttime. Our objective was to assess sleep state misperception during daytime in people with sleep disorders with excessive daytime sleepiness (EDS).Methods: In this prospective observational study, we assessed the occurrence of, and factors influencing sleep state misperception in consecutive patients undergoing a routine multiple sleep latency test (MSLT) in a tertiary sleep-wake centre included between 2014 and 2017. Mixed models were applied to assess the influence of patients' clinical data on sleep state perception.Results: People with narcolepsy type 1 (NT1, n = 33) and type 2 (NT2, n = 14), idiopathic hypersomnia (IH, n = 56), obstructive sleep apnea (OSA, n = 31) and insufficient sleep syndrome (ISS, n = 31) were included. The prevalence of both classical and reverse sleep state misperception did not differ between the sleep disorders (mean 25%, range 8-37%) after correction for sleep stage, sleep onset latency and age. Longer sleep onset latency and reaching only non-rapid eye movement (REM) sleep stage 1 were significant predictors for classical sleep state misperception.Conclusions: Sleep state misperception is common in people with NT1 and NT2, IH, OSA, and ISS. Classical sleep state misperception is more frequent in patients with longer sleep onset latencies who only reach non-REM sleep stage 1 during a nap. (C) 2020 Elsevier B.V. All rights reserved. Show less
Objective: Solriamfetol (formerly JZP-110), a dopamine/norepinephrine reuptake inhibitor, is approved in the US to improve wakefulness in adults with excessive daytime sleepiness associated with... Show moreObjective: Solriamfetol (formerly JZP-110), a dopamine/norepinephrine reuptake inhibitor, is approved in the US to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy (75-150 mg/d) or obstructive sleep apnea (37.5-150 mg/d). In a randomized, double-blind, placebocontrolled trial in participants with narcolepsy, effects of solriamfetol on functional status, health-related quality of life (HRQoL), and work productivity were evaluated.Methods: Participants with narcolepsy (N = 239) were randomized to solriamfetol 75, 150, or 300 mg, or placebo for 12 weeks. Outcome measures included the Functional Outcomes of Sleep Questionnaire short version (FOSQ-10), 36-Item Short Form Health Survey version 2 (SF-36v2), and Work Productivity and Activity Impairment questionnaire for Specific Health Problem (WPAI:SHP). A mixed-effects model with repeated measures was used for comparisons vs placebo.Results: At week 12, solriamfetol increased FOSQ-10 total score, with greatest mean difference from placebo (95% CI) at 300 mg (1.45 [0.31, 2.59]). On SF-36v2, improvements vs placebo were observed in physical component summary scores (300 mg: 2.22 [0.04, 4.41]) and subscales of role physical, general health, and vitality. On WPAI:SHP, solriamfetol 150 mg reduced overall work impairment vs placebo (-15.5 [-29.52, -1.47]), and 150 and 300 mg reduced activity impairment vs placebo (-10.05 [-19.48, -0.62] and -13.49 [-23.19, -3.78], respectively). Most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. Common TEAEs were headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety.Conclusions: Solriamfetol improved measures of functional status, HRQoL, and work productivity, particularly at the 150- and 300-mg doses. Most TEAEs were mild to moderate. (C) 2019 Elsevier B.V. All rights reserved. Show less
Gool, J.K.; Fronczek, R.; Leemans, A.; Kies, D.A.; Lammers, G.J.; Werf, Y.D. van der 2019
Following the 2009 H1N1 influenza pandemic, an increased risk of narcolepsy type 1 was observed. Homology between an H1N1 hemagglutinin and two hypocretin sequences has been reported.T cell... Show moreFollowing the 2009 H1N1 influenza pandemic, an increased risk of narcolepsy type 1 was observed. Homology between an H1N1 hemagglutinin and two hypocretin sequences has been reported.T cell reactivity to these peptides was assessed in 81 narcolepsy type 1 patients and 19 HLA-DQ6-matched healthy controls.HLA-DQ6-restricted H1N1 hemagglutinin-specific T cell responses were detected in 28.4% of patients and 15.8% of controls. Despite structural homology between HLA-DQ6-hypocretin and -H1N1 peptide complexes, T cell cross-reactivity was not detected.These results indicate that it is unlikely that cross-reactivity between H1N1 hemagglutinin and hypocretin peptides presented by HLA-DQ6 is involved in the development of narcolepsy. Show less
Schinkelshoek, M.S.; Fronczek, R.; Kooy-Winkelaar, E.M.C.; Petersen, J.; Reid, H.H.; Heide, A. van der; ... ; Koning, F. 2019
This thesis is divided into to two parts. The first part investigates the effects of the pharmaceutical gamma-hydroxybutyrate (GHB), also known as sodium oxybate (Xyrem), in various clinical... Show moreThis thesis is divided into to two parts. The first part investigates the effects of the pharmaceutical gamma-hydroxybutyrate (GHB), also known as sodium oxybate (Xyrem), in various clinical populations, including individuals with Parkinson’s disease. Most of research in part one investigates GHB in those with the condition of narcolepsy. The effects of GHB on sleep parameters, including sleep quality, is a key focus point. Other chapters explore the hormonal phenotype of narcolepsy and the impact GHB has on the hormones leptin and ghrelin in both narcolepsy and health controls. Gamma-hydroxybutyrate has a history of abuse and know abuse liability. Chapter 5 in this thesis explores the how illicit GHB and Xyrem differ in their abuse potential and incidence. Part two of the thesis focuses on how various aspects of lifestyle influence metabolism and indicators of health status. In Chapter 9, eating behavior is evaluated in response to ecologically relevant amounts of sleep loss common experienced by average people in the modern world. In Chapter 10, we explore how health young adults respond to a four-day, Paleolithic theory-themed nature trip in the German countryside. Show less
Gool, J.K.; Fronczek, R.; Leemans, A.; Kies, D.A.; Lammers, G.J.; Werf, Y.D. van der 2019
Narcolepsy type 1 is caused by a selective loss of hypothalamic hypocretin-producing neurons, resulting in severely disturbed sleep-wake control and cataplexy. Hypocretin-producing neurons project... Show moreNarcolepsy type 1 is caused by a selective loss of hypothalamic hypocretin-producing neurons, resulting in severely disturbed sleep-wake control and cataplexy. Hypocretin-producing neurons project widely throughout the brain, influencing different neural networks. We assessed the extent of microstructural white matter organization and brain-wide structural connectivity abnormalities in a homogeneous group of twelve drug-free patients with narcolepsy type 1 and eleven matched healthy controls using diffusion tensor imaging with multimodal analysis techniques. First, tract-based spatial statistics (TBSS) was carried out using fractional anisotropy (FA) and mean, axial and radial diffusivity (MD, AD, RD). Second, quantitative analyses of mean FA, MD, AD and RD were conducted in predefined regions-of-interest, including sleep-wake regulation-related, limbic and reward system areas. Third, we performed hypothalamus-seeded tractography towards the thalamus, amygdala and midbrain. TBSS analyses yielded brain-wide significantly lower FA and higher RD in patients. Localized significantly lower FA and higher RD in the left ventral diencephalon and lower AD in the midbrain, were seen in patients. Lower FA was also found in patients in left hypothalamic fibers connecting with the midbrain. No significant MD and AD differences nor a correlation with disease duration were found. The brain-wide, localized ventral diencephalon (comprising the hypothalamus and different sleep- and motor-related nuclei) and hypothalamic connectivity differences clearly show a heretofore underestimated direct and/or indirect effect of hypocretin deficiency on microstructural white matter composition, presumably resulting from a combination of lower axonal density, lower myelination and/or greater axon diameter. Show less
Weibel, D.; Sturkenboom, M.; Black, S.; Ridder, M. de; Dodd, C.; Bonhoeffer, J.; ... ; Shimabukuro, T.T. 2018
Narcolepsy is a disorder of the regulation of sleep and wakefulness, with as its major features excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and... Show moreNarcolepsy is a disorder of the regulation of sleep and wakefulness, with as its major features excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. The first part of this thesis concernes an overview of the pathophysiology, symptoms and treatment of narcolepsy type 1. The second part elaborates some pathophysiological aspects, focussing on the autoimmune hypothesis of narcolepsy. The third part focuses on alterations of temperature regulation and on measuring treatment effects of symptomatic treatment on sustained attention, i.e. vigilance. Show less
