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This paper investigates the relationship between the experiences of mass vaccinations against two pandemic viruses: the swine flu in 2009–2010 and COVID-19 in the early 2020s. We show how distressing memories from the swine flu vaccination, which led to the rare but severe adverse effect of narcolepsy in approximately 500 children in Sweden, were triggered by the COVID-19 pandemic. The narcolepsy illness story has rarely been told in academic contexts; therefore, we will provide space for this story. It is presented through a dialogue with the aim of shedding light on the interrelationship between pandemics—and between mass vaccinations—to investigate what could be termed cultural wounds that influence societies because they are characterized by the difficulty of talking about them. The paper explores the multiple shocks of illness in life and what can be learned from them by sharing them. [ABSTRACT FROM AUTHOR]

In order to clarify the difference in clinical characteristics between narcolepsy-like hypersomnia without cataplexy, which is called essential hypersomnia syndrome (EHS), and narcolepsy, we compared background variables, symptoms and treatment outcomes between 19 EHS patients and 20 narcoleptic patients. The results indicated significantly milder rapid eye movement (REM)-related symptoms, longer sleep latencies on multiple sleep latency test and smaller dosages of psycho-stimulants for suppressing daytime sleepiness in EHS than in narcolepsy. Positive findings of HLA-DQB1*0602 were recognized in less than 40% of EHS patients. We speculated that EHS would form a subgroup of hypersomnia in which disease severity is milder, and treatment response is better than typical narcolepsy. [ABSTRACT FROM AUTHOR]

The article presents several research papers related to medicine. One paper discusses how respiratory events in Obstructive Sleep Apnea (OSA) end without Cortical Arousal. Another research is on sleepiness and information processing among individuals with narcolepsy. Another study discusses how chronic insomnia can be treated through light therapy.

Background: Narcolepsy impacts quality of life (QoL) with its symptomatology in hobbies and everyday activities, work and productivity and has social and economic consequences. The aim of this review is to map and synthesize evidence about QoL in narcolepsy patients and to focus on research strategies and publications in the matter. Methods: A scoping review of articles published between 2014–2025. The initial search of WoS resulted in 7748 articles and 2583 in PubMed being screened for eligibility. Intervention, comorbidity, non-narcolepsy, prevalence and medical trials studies were excluded. We extracted data on bibliometric characteristics, research questions, sample and recruitment method, design, concepts and measures, and the main findings. Two independent reviewers did the screening and analyses. The analyzed data were consulted on with stakeholders to settle gaps, possibilities and directions for future research. This study followed the PRISMA-ScR guidelines. Results: Twenty papers were included in this study. There is an increasing trend in publishing studies focused on QoL in narcolepsy patients, but its spread is very limited across various audiences. Most of the studies assess the association of narcolepsy symptoms, treatment, mental health or nutritional status and QoL in narcolepsy patients. Most used was a questionnaire-based cross-sectional design comparing a control group vs narcolepsy patients recruited through regular follow up at a sleep clinic or national reference centers or patients’ organization. Conclusion: There is a need to spread knowledge beyond the neurology audience, to widen the scope of research beyond the burden of the symptoms and to employ explorative qualitative designs. [ABSTRACT FROM AUTHOR]

Narcolepsy is associated with disrupted nighttime sleep (DNS). Sodium oxybate (SXB; Xyrem®), administered twice nightly, is indicated for the treatment of cataplexy and excessive daytime sleepiness in patients 7 years or older with narcolepsy. Recently, low-sodium oxybate (LXB, Xywav®; for people 7 years of age and older), which contains 92% less sodium than SXB and is dosed twice nightly, and sodium oxybate for extended release (SXB-ER; Lumryz™; for adults), which contains equal sodium to SXB and is dosed once nightly, have also been approved to treat cataplexy or excessive daytime sleepiness in narcolepsy. This paper reviews the evidence regarding the overall impact of oxybate administration, and impact of different oxybate dosing regimens (once nightly, SXB-ER; twice nightly, SXB), on DNS in narcolepsy utilizing polysomnographic data from five clinical trials (three assessing SXB in adults [referred to here as SXB trials 1, 2, and 3], one assessing SXB in children [referred to as the pediatric SXB trial], and one assessing SXB-ER in adults [REST-ON]). Both once-nightly and twice-nightly oxybate regimens similarly improved symptoms of DNS. Regardless of dosing regimen, people with narcolepsy treated with oxybate experience roughly 42–53 arousals and 9–38 awakenings each night, with one of these awakenings on twice-nightly oxybate being due to the second dosing requirement in studies of SXB. Additionally, for SXB, but not SXB-ER, polysomnographic data has been analyzed by half of the night, demonstrating a greater positive impact on sleep architecture in the second half of the night, which might be related to its nonlinear pharmacokinetic profile. We conclude that while once-nightly and twice-nightly oxybate dosing regimens differ in their pharmacokinetic profiles, both improve DNS in patients with narcolepsy to a similar degree. Plain Language Summary: Narcolepsy causes daytime sleepiness and difficulty sleeping (commonly called disrupted nighttime sleep). Sodium oxybate (Xyrem®) and low-sodium oxybate (Xywav®, which contains 92% less sodium than sodium oxybate), are taken twice nightly in patients with narcolepsy. Sodium oxybate for extended release (Lumryz™), which contains as much sodium as sodium oxybate, is taken once per night. All three medications improve narcolepsy symptoms and have the same active ingredient. It is important to understand how well they improve nighttime sleep. This review examined results of five clinical studies looking at disrupted nighttime sleep in people with narcolepsy: three of twice-nightly sodium oxybate in adults (called SXB trials 1, 2, and 3 here), one of twice-nightly sodium oxybate in children (called the pediatric SXB trial here), and one of once-nightly sodium oxybate for extended release in adults (called REST-ON here). No studies specifically investigated disrupted nighttime sleep with twice-nightly low-sodium oxybate in people with narcolepsy. Although the trial designs for these studies were different, both twice-nightly and once-nightly oxybate medications improved sleep similarly, and neither eliminated arousals or awakenings. Certain aspects of sleep improved more during the second half of the night in SXB trials 1 and 3 compared with the first half of the night. Both once-nightly and twice-nightly oxybate medications similarly improve nighttime sleep in people with narcolepsy. Twice-nightly oxybate may be particularly helpful in improving sleep in the second half of the night. [ABSTRACT FROM AUTHOR]

Purpose of Review: This paper reviews how sleep is impacted in patients with Prader-Willi syndrome (PWS), focusing on sleep-related breathing disturbances and excessive daytime sleepiness (EDS). Recent Findings: Hypothalamic dysfunction may underlie several aspects of the PWS phenotype. Central sleep apnea (CSA) can persist beyond infancy. Nocturnal hypoventilation is common and may occur without central or obstructive sleep apnea (OSA). Adenotonsillectomy, a mainstay of OSA treatment, may cause velopharyngeal insufficiency. Growth hormone (GH) is considered safe, but close surveillance for OSA remains important. Cardiac autonomic dysfunction occurs during slow wave sleep and may increase the risk of cardiovascular events. EDS and narcolepsy are also common. Modafinil and pitolisant are treatment options currently being studied. Summary: Sleep disorders are prevalent in individuals with PWS. Sleep-related breathing disorders present as CSA in infancy and later in life as OSA and hypoventilation. GH therapy has improved the clinical outcomes of patients with PWS, but close surveillance and treatment for OSA is recommended. EDS can persist even after sleep-related breathing disorders are treated, and some individuals may even develop narcolepsy. Early recognition and treatment of sleep-related disorders may prevent morbidity and result in improved survival of patients with PWS. [ABSTRACT FROM AUTHOR]

Background: Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy. Objective: The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications. Methods: Eligible participants (adults aged 18–70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3–10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study. Results: At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1–2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3–10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics. Conclusions: LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticataplectics. Trial Registration: A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy; https://clinicaltrials.gov/ct2/show/NCT03030599; clinicaltrials.gov identifier: NCT03030599. Plain Language Summary: People with narcolepsy are often sleepy during the day. They may also have sudden muscle weakness (known as cataplexy). Lower-sodium oxybate (LXB) is a narcolepsy medicine that is similar to sodium oxybate (SXB) but has 92% less sodium. A recent study found that treatment with LXB was better at reducing how often people with narcolepsy had sleepiness and cataplexy than no medicine at all (NCT03030599). This paper is about the first 12 weeks of that study, when all the people taking part in the study first tried LXB to check that they were being given the right amount. In people who only took LXB, cataplexy happened less often over time. Some people were already taking other medicines to treat their cataplexy (such as antidepressants), so they were asked to slowly stop those medicines while taking LXB. In those people, cataplexy happened more often at first as they stopped taking antidepressants and then less often later on. The increase in cataplexy when antidepressants were stopped was smaller in people who switched from SXB to LXB. This study shows that many people getting treatment for narcolepsy can switch to LXB without their cataplexy becoming worse. [ABSTRACT FROM AUTHOR]

Background Gamma-hydroxybutyric acid (GHB), well known as a party drug, especially in Europe, is also legally used (sodium oxybate, Xyrem®) to treat a rare sleep disorder, narcolepsy with cataplexy. This exploratory study was set up to measure GHB concentrations in dried blood spots (DBS) collected by narcoleptic patients treated with sodium oxybate. Intra- and inter-individual variation in clinical effects following sodium oxybate administration has been reported. The use of DBS as a sampling technique, which is stated to be easy and convenient, may provide a better insight into GHB concentrations following sodium oxybate intake in a real-life setting. Objective The aim was twofold: evaluation of the applicability of a recently developed DBS-based gas chromatography- mass spectrometry (GC-MS) method, and of the feasibility of the sampling technique in an ambulant setting. Methods Seven narcoleptic patients being treated with sodium oxybate at the Department for Respiratory Diseases of Ghent University Hospital were asked to collect DBS approximately 20 min after the first sodium oxybate (Xyrem ®; UCB Pharma Ltd, Brussels, Belgium) intake on a maximum of 7 consecutive days. Using an automatic lancet, patients pricked their fingertip and, after wiping off the first drop of blood, subsequent drops were collected on a DBS card. The DBS cards were sent to the laboratory by regular mail and, before analysis, were visually inspected to record DBS quality (large enough, symmetrically spread on the filter paper with even colouration on both sides of the filter paper). Results Of the seven patients, three patients succeeded to collect five series of DBS, one patient decided to cease participation because of nausea, one was lost during follow- up and two patients started falling asleep almost immediately after the intake of sodium oxybate. Analysing the DBS in duplicate resulted in acceptable within-DBS card precision. DBS with acceptable quality were obtained by patients without supervision. Conclusion Our results demonstrate the acceptable precision of the complete procedure, from sampling at home to quantitative analysis in the laboratory. Given the intraand inter-individual variability in clinical effects seen with sodium oxybate, the easy adaptation of DBS sampling opens the possibility of following up GHB concentrations in patients in real-life settings in future studies. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

The paper considers recent studies of brain orexinergic system in animals and humans. The considered neurotransmitter system is involved in the regulation of a wide spectrum of brain responses occurring in living organisms during wakefulness. This study reflects the current concept of the triggering role of orexins A and B in initiation of awakening and cites scientific opinions of a number of leading researchers on the studied problem. Orexin-containing neurons located in the hypothalamus play one of the top roles in the regulation of brain aminergic systems during active wakefulness. The summary of scientific data accumulated in the past ten years makes it possible to sufficiently extend the existing concepts of the sleep–wake cycle regulation mechanisms. The progress in revealing relationships and events in the brain that are necessary for normal sleep–wake changeover forms the basis for developing new methods for correction of disorders of these processes. [ABSTRACT FROM AUTHOR]

Introduction: Low-sodium oxybate (LXB) is approved for treatment of narcolepsy in patients aged 7 years and older and treatment of idiopathic hypersomnia in adults. LXB contains the same active moiety with 92% less sodium than sodium oxybate (SXB). As the indication for oxybate treatment in patients with idiopathic hypersomnia is new and allows for individualized dosing optimization, guidance for beginning LXB treatment is needed. In particular, clinicians may benefit from guidance regarding treatment initiation, dosing/regimen options, potential challenges, and treatment expectations. Additionally, pharmacokinetic profiles differ slightly between both treatments, and further guidance on transitioning from SXB to LXB in patients with narcolepsy may aid clinicians. Methods: An expert panel of five sleep specialists was convened to obtain consensus on recommendations for these topics using a modified Delphi process. Results: Across two virtual meetings, the panel agreed on 31 recommendations with a high degree of consensus that fell into four overarching topics: (1) introducing LXB to patients; (2) initiating LXB for adult narcolepsy and idiopathic hypersomnia; (3) addressing challenges in using LXB; and (4) transitioning from SXB to LXB. The panel recommended that clinicians provide a clear overview of how LXB works for treating symptoms in narcolepsy or idiopathic hypersomnia, as appropriate for their patients, explain safety aspects, and set expectations prior to initiating LXB treatment. Strategies for initial dosing and regimen are provided. Strategies for adjusting the dose, regimen, timing, and consideration of individual factors were developed for specific instances in which patients may have trouble staying asleep or waking up, as well as guidance for addressing potential adverse events, such as nausea, dizziness, anxiety, and depression. Discussion points based on existing literature and clinical experience were included as relevant for each statement. Conclusion: Clinicians may use this resource to guide LXB dosing optimization with patients. [ABSTRACT FROM AUTHOR]

Purinergic receptor P2Y11, a G protein-coupled receptor that is stimulated by extracellular ATP, has been demonstrated to be related to the chemotaxis of granulocytes, apoptosis of neutrophils, and secretion of cytokines in vitro. P2Y11 mutations were associated with narcolepsy. However, little is known about the roles of P2RY11 in the occurrence of narcolepsy and inflammatory response in vivo. In this study, we generated a zebrafish P2Y11 mutant using CRISPR/Cas9 genome editing and demonstrated that the P2Y11 mutant replicated the narcolepsy-like features including reduced HCRT expression and excessive daytime sleepiness, suggesting that P2Y11 is essential for HCRT expression. Furthermore, we accessed the cytokine expression in the mutant and revealed that the P2RY11 mutation disrupted the systemic inflammatory balance by reducing il4, il10 and tgfb, and increasing il6, tnfa, and il1b. In addition, the P2RY11-deficient larvae with caudal fin injuries exhibited significantly slower migration and less recruitment of neutrophils and macrophages at damaged site, and lower expression of anti-inflammatory cytokines during tissue damage. All these findings highlight the vital roles of P2RY11 in maintaining HCRT production and secreting anti-inflammatory cytokines in the native environment, and suggested that P2RY11-deficient zebrafish can serve as a reliable and unique model to further explore narcolepsy and inflammatory-related diseases with impaired neutrophil and macrophage responses. [ABSTRACT FROM AUTHOR]

In the 24/7 modern society, sleep disorders and the role of normal amounts and timing of sleep for health are often neglected by both doctors and their patients. Sleep has been said to be 'of the brain, by the brain and for the brain' and the most immediate and obvious consequence of disrupted sleep is impaired brain function. This review will cover some of the recent papers published in both the Journal of Neurology and elsewhere in 2013/2014 that have advanced our knowledge of sleep and circadian rhythm disorders. [ABSTRACT FROM AUTHOR]

This paper reviews recent work investigating the influence of sleep disturbances on maternal hyperglycemia, particularly gestational diabetes mellitus (GDM). The incidence and prevalence of hyperglycemia are increasing worldwide, which is cause for concern because GDM and even mild hyperglycemia are associated with adverse pregnancy outcomes. A better understanding of sleep-related risk factors for maternal hyperglycemia is an important health matter. Evidence demonstrates associations between sleep disturbances, especially sleep-disordered breathing, and hyperglycemia, but causal effects and the underlying mechanisms linking these conditions have not been fully elucidated. Subjective sleep assessments show associations between sleep disturbances and maternal hyperglycemia. There are, however, few studies using objective measures to support these findings. Large prospective studies are required to examine causal relationships between sleep disturbances and maternal hyperglycemia. There is also a need for smaller mechanistic studies to understand the pathophysiology. Furthermore, interventional studies are required to address whether improvement of sleep parameters can prevent/decrease the risk of developing maternal hyperglycemia. Taken together, the data suggests that sleep disturbances during pregnancy are important to identify and manage in order to minimize maternal hyperglycemia and GDM, and improve maternal and fetal well-being. [ABSTRACT FROM AUTHOR]

Dyssomnias are sleep disorders associated with complaints of insomnia or hypersomnia. The daytime sleepiness of narcolepsy is treated by a combination of planned daytime naps, regular exercise medications such as modafinil, or salts of methylphenidate, or amphetamine. Cataplexy that accompanies narcolepsy is treated with anticholinergic agents, selective serotonin reuptake inhibitors, or sodium oxybate. Children with neurodevelopmental disabilities such as autism have sleep initiation and maintenance difficulties on a multifactorial basis, with favorable response to melatonin in some patients. Childhood onset restless legs syndrome is often familial, associated with systemic iron deficiency, and responsive to iron supplementation and gabapentin. Parasomnias are episodic phenomena events which occur at the sleep -- wake transition or by intrusion on to sleep. Arousal parasomnias such as confusional arousals and sleep walking can sometimes be confused with seizures. A scheme for differentiating arousal parasomnias from nocturnal seizures is provided. Since arousal parasomnias are often triggered by sleep apnea, restless legs syndrome, or acid reflux, treatment measures directed specifically at these disorders often helps in resolution. Clonazepam provided in a low dose at bedtime can also alleviate sleep walking and confusional arousals. Obstructive sleep apnea affects about 2 percent of children. Adeno-tonsillar hypertrophy, cranio-facial anomalies, and obesity are common predisposing factors. Mild obstructive sleep apnea can be treated using a combination of nasal corticosteroids and a leukotriene antagonist. Moderate to severe obstructive sleep apnea are treated with adeno-tonsillectomy, positive airway pressure breathing devices, or weight reduction as indicated. This paper provides an overview of the topic, with an emphasis on management steps. Where possible, the level of evidence for treatment recommendations is indicated. [ABSTRACT FROM AUTHOR]

Rationale: Modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy or attention deficit disorders and to enhance vigilance in sleep-deprived military personal. So far, understanding of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete. Objectives: The aim of this study was to investigate the effects of modafinil on working memory processes in humans and how they are related to noradrenergic stimulation of the prefrontal cortex. Methods: Sixteen healthy volunteers (aged 20-29 years) received either modafinil 200 mg or placebo using a double blind crossover design. Two computerized working memory tasks were administered, a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths. The battery was supplemented by standardized paper pencil tasks of attentional functions. Results: Modafinil significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions, but not in the maintenance condition of the numeric task. Analyses of reaction times showed no speed-accuracy trade-off. Attentional control tasks (letter cancellation, trail-making, catch trials) were not affected by modafinil. Conclusions: In healthy volunteers without sleep deprivation modafinil has subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks, especially in lower performing subjects. Overlapping attentional and working memory processes have to be considered when studying the noradrenergic modulation of the prefrontal cortex. [ABSTRACT FROM AUTHOR]

Harriet Tubman, a hero of the abolitionist movement and early civil rights advocate, suffered a head injury in childhood and subsequently developed sleep attacks associated with visions that were extensively documented in historical accounts. Her contemporaries perceived these visions together with unpredictable and unavoidable urges to sleep as manifestations of her deep faith, rather than as symptoms of an illness. While religious perspectives remain crucial to understanding Tubman's sleep-related experiences, some may consider them insufficient in view of modern medical advances. We propose the parallel explanation that her sleep attacks, usually attributed to temporal lobe epilepsy, actually represent a hypersomnia that is most consistent with the modern diagnosis of post-traumatic narcolepsy. Using historical analysis as well as current understandings of sleep medicine, we aim to shed light on this under-recognized aspect of Tubman's life. In addition, this case study allows us to review the potential long-term effects of severe traumatic brain injuries; consider a differential for excessive daytime sleepiness and hypnagogic hallucinations; and familiarize readers with the pathophysiology, diagnosis, and treatment of narcolepsy. Whether her symptoms are viewed through the lens of the past or measured against current biomedical standards, Tubman demonstrated an inspiring ability to persevere despite intrusive sleep episodes and to realize her dreams for the betterment of others. [ABSTRACT FROM AUTHOR]

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®. Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement. [ABSTRACT FROM AUTHOR]

Central hypersomnia (HS) and delayed sleep–wake phase disorder (DSWPD) appear commonly in adolescents, and they severely reduce quality of life and have an enormous impact on academic performance and other aspects of development. Although these disorders are thought to be considerably different in etiology, it is sometimes difficult to distinguish them because of their similar clinical features. This study aimed to compare psychosocial factors and sleep study findings between HS and DSWPD in teenagers. The clinical data of 89 teenagers who visited the psychiatric section of the Sleep Medicine Center of Nihon University Itabashi Hospital from January 2013 to December 2019 were analyzed. Psychosocial factors were evaluated at the first visit, and polysomnography (PSG) and the multiple sleep latency test (MSLT) were performed for patients deemed to require definitive diagnosis. Compared with patients with HS, those with DSWPD had a higher rate of mother's employment, introversion, adjustment problems, events that triggered the disorder, concurrent mental disorders, habitual lateness, and difficulty attending school or work. PSG did not show any differences in sleep parameters between the two disorders, except for sleep latency. On the MSLT, sleep latency was shorter in those with HS on the second, third, and fourth tests. The present results suggest that focusing on psychosocial factors could be useful for differential diagnosis of the two disorders that appear commonly in adolescents. [ABSTRACT FROM AUTHOR]

Introduction: Excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75–150 mg/day) or OSA (37.5–150 mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies. Methods: Data were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150 mg/day (3 days) followed by 300 mg/day (4 days), or placebo (7 days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2 h post-dose; 6 h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores. Results: In participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2 h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points. Conclusion: This study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed). Trial Registration: NCT02806895, EudraCT 2015-003930-28: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Obstructive Sleep Apnea. NCT02806908, EudraCT 2015-003931-36: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Narcolepsy. [ABSTRACT FROM AUTHOR]

Purpose: To review how REM sleep behavior disorder (RBD) is a complex condition with heterogeneous underlying disorders; and to review clinical management issues and prognostic implications. Methods: PubMed literature search and contents from the first textbook of RBD (2018). Results: RBD, with its core objective diagnostic feature of REM-without-atonia (RWA) documented by video-polysomnography, can emerge during the entire lifespan, and can initially present as an idiopathic (isolated) condition (iRBD), or can be associated with a broad spectrum of disorders including narcolepsy, alpha-synuclein neurodegenerative disorders (esp. Parkinson's disease [PD] and dementia with Lewy bodies [DLB]), paraneoplastic neurological syndromes and autoimmune disorders, CNS lesions (e.g., tumors, stroke), other neurological disorders, psychiatric disorders (PTSD, mood disorders), can be triggered by antidepressant/other medications, and can emerge acutely with drug withdrawal states, toxic-metabolic states, etc. Important clinical issues include the evolution of iRBD to PD/DLB in most middle-aged and older patients over a period of years to several decades, with compelling prognostic implications, along with the hope of enrolling these patients in future clinical trials to test promising disease-modifying therapies. Also, the strong link of RBD with narcolepsy needs further investigation. Parasomnia overlap disorder involves RBD and NREM parasomnias that can be idiopathic or linked with a broad range of clinical disorders. RBD usually responds to therapy consisting mainly of melatonin and/or clonazepam at bedtime. The complex associations of RBD with OSA are being increasingly investigated. RBD mimics with dream-enactment need to be recognized for diagnostic and management purposes, including severe OSA, NREM parasomnias, PLMD, nocturnal seizures, and other conditions. Conclusions: The clinical and research RBD fields span across the disciplines of neurology, pulmonary, psychiatry, psychology, and pediatric sleep medicine, along with physical medicine and rehabilitation medicine, other allied disciplines, and the basic and clinical neurosciences. [ABSTRACT FROM AUTHOR]

Background: Sodium oxybate has been recognized as a gold standard for the treatment of disrupted nighttime sleep due to narcolepsy. Its short half-life and immediate-release formulation require patients to awaken 2.5–4 h after their bedtime dose to take a second dose. A novel extended-release, once-nightly sodium oxybate formulation (ON-SXB; FT218) is under US Food and Drug Administration review for the treatment of adults with narcolepsy. Objective: A phase III trial of ON-SXB in individuals with narcolepsy type 1 (NT1) or 2 (NT2) [the REST-ON trial; NCT02720744] has been conducted and the primary results reported elsewhere. Secondary objectives from REST-ON were to assess the efficacy of ON-SXB on disrupted nighttime sleep; the results of this analysis are reported here. Methods: In the double-blind, phase III REST-ON trial, patients aged ≥ 16 years were randomly assigned 1:1 to ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Secondary endpoints included polysomnographic measures of sleep stage shifts and nocturnal arousals and patient-reported assessments of sleep quality and refreshing nature of sleep at 6, 7.5, and 9 g; post hoc analyses included changes in time spent in each sleep stage, delta power, and assessments in stimulant-use subgroups for prespecified endpoints. Results: In total, 190 participants (n = 97, ON-SXB; n = 93, placebo) were included in the efficacy analyses. All three ON-SXB doses demonstrated a clinically meaningful, statistically significant decrease vs placebo in the number of transitions to wake/N1 from N1, N2, and rapid eye movement (REM) stages (all doses p < 0.001) and the number of nocturnal arousals (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g). Sleep quality and refreshing nature of sleep were significantly improved with all three ON-SXB doses vs placebo (p < 0.001). Post hoc analyses revealed a significant reduction in time spent in N1 (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g) and REM (all p < 0.001) and increased time spent in N3 with ON-SXB vs placebo (all p < 0.001), with a significant increase in delta power (p < 0.01 ON-SXB 6 g; p < 0.05 7.5 g; p < 0.001 9 g) and increased REM latency (ON-SXB 7.5 g vs placebo; p < 0.05). Significant improvements in disrupted nighttime sleep were observed regardless of concomitant stimulant use. Conclusions: The clinically beneficial, single nighttime dose of ON-SXB significantly improved disrupted nighttime sleep in patients with narcolepsy. Clinical Trial Registration: ClinicalTrials.gov NCT02720744. [ABSTRACT FROM AUTHOR]

The differential diagnosis of narcolepsy versus schizophrenia is sometimes complicated by similar phenomenology, particularly when hallucinations predominate. REM sleep disturbances seem fundamental in the pathophysiology of narcolepsy, and REM sleep intrusions during periods of wakefulness are often associated with hallucinations also in healthy controls and in patients with other brain disorders including schizophrenia. This study used a semistructured interview to investigate different aspects of hallucinations (frequency, modality, content, and dependence on body posture) in 148 patients with narcolepsy, 21 patients with acute exacerbation of a schizophrenic disorder, and 128 healthy subjects. About 80% of patients with narcolepsy, 81% of schizophrenics, and 37% of healthy subjects reported lifetime occurrence of hallucinations (at least once). Auditory hallucinations were reported by 81% of schizophrenic patients (narcoleptics 45%, healthy controls 9%), whereas 83% of narcoleptic patients reported visual hallucinations (schizophrenics 29%, healthy controls 19%). Kinetic hallucinations were experienced by 71% of patients with narcolepsy and 53% of healthy controls in contrast to only 5% of schizophrenics. Accordingly, the content of hallucinations differed substantially between the groups. Most hallucinations in narcoleptics but not in schizophrenics, were sleep-related and dependent on body posture. Taken together, the qualitative aspects of hallucinations in narcolepsy and schizophrenia were so different that a common underlying mechanism of hallucinations in the two conditions is unlikely. Although the clinical separation of patients with narcolepsy and schizophrenia with predominant hallucinations is sometimes difficult, clinical features including the patient's illness history, and careful psychopathological assessments can help to avoid misdiagnoses and treatment failures. [ABSTRACT FROM AUTHOR]

Narcolepsy is a chronic neurologic disorder associated with the dysregulation of the sleep–wake cycle that often leads to a decreased quality of life and results in a considerable health burden. There is often a delay to diagnosis of narcolepsy, mainly due to the lack of recognition of this disorder. One of the main factors hindering the diagnosis of narcolepsy is the association of comorbidities, which include other sleep disorders, psychiatric disorders, cardiovascular disorders, and metabolic disorders. The signs and symptoms of these comorbidities often overlap with those of narcolepsy, and some of the medications used for their treatment may obscure the symptoms of narcolepsy, leading to a delay in diagnosis. This review is targeted to clinicians unaccustomed to working with sleep disorders and aims to increase recognition and improve the management of narcolepsy. [ABSTRACT FROM AUTHOR]

Background: Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy.Objective: Analyses evaluated the time to onset of clinical response during treatment with pitolisant.Methods: Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo.Results: The analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]).Conclusions: Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy. CLINICALTRIALS.Gov Identifier: NCT01067222 (February 2010), NCT01800045 (February 2013). [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 (NT1) is a chronic neurological disorder having a strong association with HLA-DQB1*0602, thereby suggesting an immunological origin. Increased risk of NT1 has been reported among children or adolescents vaccinated with AS03 adjuvant-supplemented pandemic H1N1 influenza A vaccine, Pandemrix. Here we show that pediatric Pandemrix-associated NT1 patients have enhanced T-cell immunity against the viral epitopes, neuraminidase 175–189 (NA175–189) and nucleoprotein 214–228 (NP214–228), but also respond to a NA175–189-mimic, brain self-epitope, protein-O-mannosyltransferase 1 (POMT1675–689). A pathogenic role of influenza virus-specific T-cells and T-cell cross-reactivity in NT1 are supported by the up-regulation of IFN-γ, perforin 1 and granzyme B, and by the converging selection of T-cell receptor TRAV10/TRAJ17 and TRAV10/TRAJ24 clonotypes, in response to stimulation either with peptide NA175–189 or POMT1675–689. Moreover, anti-POMT1 serum autoantibodies are increased in Pandemrix-vaccinated children or adolescents. These results thus identify POMT1 as a potential autoantigen recognized by T- and B-cells in NT1. Narcolepsy type 1 (NT1) is a severe sleep disorder with strong association to the HLA type DQB1*0602 and increased incidence among children vaccinated with the Influenza A vaccine Pandemrix. Here the authors show that these children develop T and B cell autoimmunity against protein-O-mannosyltransferase 1 via cross-reactivity. [ABSTRACT FROM AUTHOR]

A meta-analysis was conducted to review the prevalence and associated moderators of depression or depressive symptoms in patients with narcolepsy. An extensive search of the literature yielded 1104 articles and abstracts, of which 31 studies were included in the meta-analysis. Meta-analysis revealed that the overall pooled prevalence of depression or depressive symptoms in patients with narcolepsy was 32% (95% Confidence Interval, 28–36%) with high between-study heterogeneity (Q = 249.77, df = 30, p < 0.001, τ2 = 0.0087, I2 = 88%). An analysis of 13 studies with healthy control groups indicated that narcolepsy was associated with a significantly increased risk of depression or depressive symptoms (Odds Ratio 3.48, 95% Confidence Interval 2.73–4.45; Q = 41.23, df = 12, p < 0.001, τ2 = 0.0087, I2 = 70.9%). The prevalence of depression or depressive symptoms in patients with narcolepsy was significantly affected by study design (Q = 5.05, p = 0.02) and recruitment setting (Q = 5.98, p = 0.01), and was marginally affected by age group (Q = 3.44, p = 0.06). The results indicate that narcolepsy patients should be closely monitored for depression and depressive symptoms and that early screening should be considered. However, these conclusions should be tempered because of high variability between studies. The estimates across studies are very inconsistent, indicating the need for larger, multicenter studies, with stringent case definitions. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate cardiovascular and sudomotor function during wakefulness and to assess autonomic symptoms in de novo patients with type 1 narcolepsy compared to healthy controls. Methods: De novo patients with type 1 narcolepsy (NT1) and healthy controls underwent cardiovascular function tests including head-up tilt test, Valsalva maneuver, deep breathing, hand grip, and cold face, and sudomotor function was assessed through Sudoscan. Autonomic symptoms were investigated using the Scales for Outcomes in Parkinson's Disease–Autonomic Dysfunction (SCOPA-AUT) questionnaire. Results: Twelve de novo patients with NT1 and 14 healthy controls were included. In supine rest condition and at 3 min and 10 min head-up tilt test, the systolic blood pressure values were significantly higher in the NT1 group than in controls (p < 0.05). A lower Valsalva ratio (p < 0.01), significantly smaller inspiratory–expiratory difference in deep breathing (p < 0.05), and lower delta heart rate in the cold face test (p < 0.01) were also observed in the NT1 group. The mean hand electrochemical skin conductance values were significantly lower (p < 0.05) and the mean SCOPA-AUT total scores were significantly higher in patients with NT1 than in healthy subjects (p < 0.001), with greater involvement of cardiovascular and thermoregulatory items. Conclusion: De novo patients with NT1 exhibit blunted parasympathetic activity during wakefulness, mild sudomotor dysfunction, and a large variety of autonomic symptoms. [ABSTRACT FROM AUTHOR]

White matter alterations related to hypocretin pathway have been less evaluated in patients who have narcolepsy with cataplexy (NC), as compared to the identified exploration of gray matter and have varied among structural brain magnetic resonance imaging studies. The aim of this study was to investigate the disruption of specific white matter tracts in drug-naïve patients with NC, by using a tract-specific statistical analysis (TSSA). Forty drug-naïve NC patients with cataplexy and 42 heathy controls were enrolled in the study. All participants completed diffusion weighted imaging, polysomnography, and neuropsychological testing. At that time, we automatically identified fourteen major fiber tracts using diffusion tensor imaging techniques and analyzed the group comparison of fractional anisotropy (FA) values for each tract between the NC and controls, controlling for the participant's age and gender. The mean age of the NC patients was 26.9 years and the onset age of daytime sleepiness and cataplexy was 16.7 years and 19.9 years, respectively. Relative to the controls, the NC patients showed that there were identified decreased FA values in the bilateral inferior fronto-occipital fasciculus (IFO). The Epworth sleepiness scale was positively correlated with FA values for the left IFO and right cingulate. The REM sleep latency was positively correlated with FA values for the left IFO, cingulate, and uncinate fasciculus in patients. This TSSA study revealed disintegration of the IFO in the NC patients and suggested that disintegration of WM tracts connected to the frontal cortex contributes to clinical manifestations of narcolepsy. [ABSTRACT FROM AUTHOR]

This case–control study compared the body composition, resting metabolic rate (RMR), and respiratory quotient (RQ) of narcolepsy patients with those of body mass index (BMI)- gender and age-matched controls. This study included 14 male patients with narcolepsy and 14 matched controls. The narcolepsy patients were subdivided into two subgroups (n = 7/each): those with cataplexy (NT1) and those without cataplexy (NT2). Anthropometric measurements, bioelectric impedance analysis, and indirect calorimetry were used in addition to the calculation of common body-composition indices (conicity index, abdominal volume index, and body adiposity index). Our results showed no significant difference in fat percentage, fat mass, fat-free mass, and TBW among NT1, NT2, and controls (p > 0.05). Compared to matched controls, there was a reduction of muscle mass in both NT1 and NT2 subgroups. The RMR was similar in all groups, while patients in the NT1/NT2 subgroups had a lower RQ, used more fat and fewer carbohydrates during the fasting period. These findings give an insight into the distinctive state of altered metabolism in patients with narcolepsy, especially the resting metabolic rate, which was not altered in NT1 vs. NT2 compared to the controls when matched for BMI, age, and gender. [ABSTRACT FROM AUTHOR]

Background: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, improved wakefulness and reduced excessive daytime sleepiness (EDS) in studies of participants with narcolepsy with and without cataplexy.Objective: Prespecified subgroup analyses of data from a 12-week randomized, double-blind, placebo-controlled, phase III trial of solriamfetol for EDS in narcolepsy evaluated the efficacy and safety of solriamfetol by cataplexy status.Methods: Participants with narcolepsy received solriamfetol (75, 150, or 300 mg/day) or placebo and were stratified by cataplexy status. Coprimary endpoints were change from baseline on Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS); Patient Global Impression of Change (PGI-C) was the key secondary endpoint. Change in frequency of cataplexy attacks was evaluated in participants reporting cataplexy at baseline. Safety was evaluated. No adjustments were made for multiple comparisons; therefore p values are nominal.Results: There were 117 participants in the cataplexy subgroup and 114 in the non-cataplexy subgroup. At week 12, least-squares (LS) mean (95% confidence interval [CI]) differences from placebo on change from baseline in MWT for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were 1.6 (- 3.6 to 6.9), 6.1 (0.7-11.4), and 8.9 (3.5-14.2) minutes, respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup were 3.4 (- 1.9 to 8.7), 9.1 (3.8-14.3), and 11.2 (5.8-16.6) minutes, respectively (p < 0.001; 150 and 300 mg). At week 12, LS mean (95% CI) differences from placebo on ESS change from baseline for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup were - 1.3 (- 3.9 to 1.3), - 3.7 (- 6.4 to - 1.1), and - 4.5 (- 7.1 to - 1.9), respectively (p < 0.01; 150 and 300 mg), and in the non-cataplexy subgroup were - 3.0 (- 5.6 to - 0.4), - 3.7 (- 6.3 to - 1.2), and - 4.9 (- 7.6 to - 2.2), respectively (p < 0.05; all doses). For PGI-C at week 12, the mean percentage difference from placebo (95% CI) for solriamfetol 75, 150, and 300 mg in the cataplexy subgroup was 10% (- 15 to 35), 33% (9-57), and 39% (16-61), respectively (p < 0.05; 150 and 300 mg), and in the non-cataplexy subgroup was 48% (25-70), 44% (21-67), and 52% (30-73), respectively (p < 0.001; all doses), with somewhat differential treatment effects for 75 mg by cataplexy status. No changes in the number of cataplexy attacks were observed for solriamfetol compared with placebo (mean ± standard deviation changes: - 3.6 ± 13.3 [combined solriamfetol] and - 3.5 ± 9.8 [placebo]). Common adverse events (headache, nausea, decreased appetite, and nasopharyngitis) were similar between cataplexy subgroups.Conclusions: These data strongly indicate that solriamfetol was effective in treating EDS in participants with narcolepsy with or without cataplexy, as indicated by robust effects on MWT, ESS, and PGI-C. The safety profile was similar regardless of cataplexy status.Trial Registration and Date: ClinicalTrials.gov NCT02348593. 28 January 2015. [ABSTRACT FROM AUTHOR]

Narcolepsy with cataplexy is characterized by excessive daytime sleepiness, cataplexy, and other REM sleep phenomena. Previous MRI studies were cross-sectional in design and could not adequately address if disease progression leads the brain structural abnormalities in narcolepsy. Our analysis in patients using longitudinally collected brain MRIs (n = 17; 2 scans per patient; scan interval: 4.7 ± 1.9 years) revealed widespread progressive cortical thinning in bilateral dorsolateral frontal and fusiform cortices, right anterior cingulate (corrected p < 0.05). Cross-sectional analyses showed faster progressive cortical thinning in patients than controls (n = 83, one scan per subject available), which we confirmed significant in the analysis of a small-set of longitudinal control data (n = 10). The pattern of progressive thinning in patients was overlapped well with those found in structural and functional studies of narcolepsy. We also found a faster progression of cortical thinning and worse disease severity (decreased sleep efficiency, increased sleep latency and arousal index) over time in a subgroup of patients with earlier disease onset (n = 9, onset age: 15.9 ± 2.5 years old) compared to later disease onset (n = 8, 25.3 ± 4.9). The faster progressive cortical thinning and worse disease severity over time in the patients with early-onset suggest compelling evidence of disease progression existing in this phenotype of narcolepsy syndrome. Our result based on a small dataset, however, demands a more careful investigation of the underlying mechanism. [ABSTRACT FROM AUTHOR]

The incorporation of telemedicine and artificial intelligence for early screening and assessment of severity of life-style disorders has a great potential for better assessment in a busy outpatient clinic and thereby curtail down the related morbidities. A computer based algorithm based upon standardized questionnaire (from established assessment tools) is designed to assess the risk of obstructive sleep apnoea syndrome (OSAS). In addition the incorporation of basic screening questions of anamnesis help in suggesting a probable diagnosis of sleep related disorder as well. The overall data at our center has been analyzed to establish the existing pattern of sleep related disorders. Of 850 healthy subjects screened, prevalence of snoring was 20.47% while OSAS was seen in 4.20% (N = 25) in males and 2.64% (N = 8) in females. The parasomnia was most prevalent (14.71%), followed by insomnia (10.24%), periodic leg movement (6.59%), bruxism (1.65%) and narcolepsy (0.59%). Hypertension, laryngopharyngeal reflux and obesity were the common co-morbidities in OSAS while family history of hypertension and diabetes were common in snorers. A significant association with OSA was seen with diabetes mellitus, neck circumference and nasal obstruction, while, obesity and apnoeic episodes were more significantly associated with OSA than snorers. Increased waist to hip ratio was appreciated in both the OSAS and snorers. The algorithm based online assessment is likely to diagnose the occult clinical cases as well as assess the risk of OSAS. In routine outpatient clinic, a clinician may better assess the patient morbidity with a comprehensive availability of symptoms and moreover enhance the post-treatment compliance. In addition a smartphone based computerized assessment for general population may be designed for other lifestyle disorders as well. [ABSTRACT FROM AUTHOR]

The article focuses on Pitolisant which is new drug with a new mechanism of action, inverse agonist at the H3 histamine receptor, marketed in narcolepsy and excessive daytime sleepiness in obstructive sleep apnea syndrome. Topics include examines the clinical trials found that its main adverse events are neuropsychiatric, including headache, insomnia, anxiety, and depression, but also vomiting and weight gain.

Objective: Narcolepsy is a lifelong disease, manifesting with excessive daytime sleepiness and cataplexy, arising between childhood and young adulthood. The diagnosis is typically made after a long delay that burdens the disease severity. The aim of the project, promoted by the "Associazione Italiana Narcolettici e Ipersonni" is to develop Red Flags to detect symptoms for early referral, targeting non-sleep medicine specialists, general practitioners, and pediatricians.Materials and Methods: A multidisciplinary panel, including patients, public institutions, and representatives of national scientific societies of specialties possibly involved in the diagnostic process of suspected narcolepsy, was convened. The project was accomplished in three phases. Phase 1: Sleep experts shaped clinical pictures of narcolepsy in pediatric and adult patients. On the basis of these pictures, Red Flags were drafted. Phase 2: Representatives of the scientific societies and patients filled in a form to identify barriers to the diagnosis of narcolepsy. Phase 3: The panel produced suggestions for the implementation of Red Flags.Results: Red Flags were produced representing three clinical pictures of narcolepsy in pediatric patients ((1) usual sleep symptoms, (2) unusual sleep symptoms, (3) endocrinological signs) and two in adult patients ((1) usual sleep symptoms, (2) unusual sleep symptoms). Inadequate knowledge of symptoms at onset by medical doctors turned out to be the main reported barrier to diagnosis.Conclusions: This report will hopefully enhance knowledge and awareness of narcolepsy among non-specialists in sleep medicine in order to reduce the diagnostic delay that burdens patients in Italy. Similar initiatives could be promoted across Europe. [ABSTRACT FROM AUTHOR]

Purpose: Symptomatic narcolepsy is characterized as low orexin (hypocretin) levels (≤ 110 pg/ml) due to neurological diseases. However, we have experienced the cases that show symptoms similar to narcolepsy, complaining of pathological sleepiness even in cases with intermediate orexin levels (110-200 pg/ml). Therefore, we reevaluated the previously reported cases to make the concept of disease to the group in which the orexin concentration is intermediate.Methods: Although orexin-deficient symptomatic narcolepsy has been reported worldwide, facilities that are capable of measuring orexin are still limited. Currently, our laboratory handles with almost all the CSF samples from Asian countries for determining orexin levels. We measured over 2500 cases including 182 cases suspected of symptomatic narcolepsy/hypersomnolence. Therefore, we subdivided these cases into three groups according to CSF orexin levels, low orexin group (≤ 110 pg/ml), intermediate orexin group (110-200 pg/ml), and normal orexin group (> 200 pg/ml). We defined "symptomatic hypersomnia" for hypersomnolence cases with intermediate CSF orexin levels. MSLT was recommended but not necessary. Short sleep latency (< 8 min) without SOREMPs should be observed on MSLT when performed. We compared symptoms (excessive daytime sleepiness and cataplexy) and objective measures (mean sleep latency and number of SOREMPs in MSLT) among the three groups, attempting to characterize the "symptomatic hypersomnia" group.Result: Among the 182 cases with clinical hypersomnolence, there were 32 cases of symptomatic narcolepsy (16%) and 14 cases of symptomatic hypersomnia (8%). Causative diseases of symptomatic narcolepsy cases consist of immune-mediated demyelinating disorders (34%) and neurodegenerations (19%), whereas those of symptomatic hypersomnia are immune-mediated demyelinating disorders (43%) and encephalopathies (14%). Significant differences were not found between orexin levels and the existence of cataplexy, SOREMPs, and short sleep latency among three hypersomnolence groups. From these results, we found that it is difficult to estimate orexin concentration from subjective symptoms and PSG/MSLT findings.Conclusion: We identified that 32 symptomatic narcolepsy and 14 cases of symptomatic hypersomnolence with intermediate CSF orexin levels. We proposed these latter cases as a novel category of "symptomatic hypersomnia". Currently, symptomatic hypersomnia cases with intermediate orexin levels or short sleep latency (< 8 min) without SOREMPs were not classified as a specific entity. However, symptomatic hypersomnia had similar severity of hypersomnolence symptoms to symptomatic narcolepsy. Therefore, these cases including equivalent pathophysiology are enough to make a comparable category as "symptomatic hypersomnia". Since it is difficult to estimate the orexin concentration from subjective symptoms and physiological findings (PSG/MSLT), further studies for the characterization of "symptomatic hypersomnia" and understanding its pathophysiology are necessary. [ABSTRACT FROM AUTHOR]

Narcolepsy is a rare disease that entails excessive daytime sleepiness, often associated with sudden episodes of muscle weakness known as cataplexy. Narcolepsy with cataplexy (NC) is due to the loss of hypothalamic neurons that release the neuropeptides orexin A and B. Orexin neuron projections prominently target brain structures involved in wake-sleep state switching and the central autonomic network. This review provides an updated summary of the links between NC and autonomic cardiovascular dysfunction from a translational perspective. The available evidence suggests that, compared with control subjects, the heart rate in patients and animal models with NC is variable during wakefulness and normal to high during sleep. Responses of the heart rate to internal stimuli (arousal from sleep, leg movements during sleep, defense response) are blunted. These alterations result from orexin deficiency and, at least during wakefulness before sleep, involve decreased parasympathetic modulation of the heart rate. On the other hand, NC in patients and animal models is associated with a blunted fall in arterial blood pressure from wakefulness to sleep, and particularly to the REM state, coupled to a variable decrease in arterial blood pressure during wakefulness. The former effect is caused, at least in part, by deranged control of the heart, whereas the latter may be due to decreased vasoconstrictor sympathetic activity. Systematic studies are warranted to help clarify whether and how the links between NC and autonomic dysfunction impact on the cardiovascular risk of patients with narcolepsy. [ABSTRACT FROM AUTHOR]

Modafinil, an FDA approved wakefulness drug prescribed to narcolepsy patients, has recently been shown to have anti-inflammatory effects and provides protection against neuroinflammation. It is unknown if modafinil can also protect against atherosclerosis, pathogenesis of which implicates inflammation. Using an apoE-deficient mouse model, we tried to elucidate the effects of modafinil treatment on the development of atherosclerosis. We tested serum levels of cytokines. We isolated mouse bone marrow-derived macrophages (BMDMs), detected effect of modafinil on the viability and proliferation of BMDMs, and on oxidized low-density lipoprotein-induced IL-6 and TNF-α, and supernatant level of IFN-γ as well as NF-κB activity in BMDMs. Modafinil inhibited the development of atherosclerosis in apoE−/− mice. Modafinil suppressed the secretion of pro-inflammatory cytokines IL-6, TNF and IFN-γ, and promoted secretion of anti-inflammatory cytokines IL-4 and IL-10. Modafinil inhibited viability and proliferation of macrophages by negatively regulating levels of pro-inflammatory cytokines, p-Akt, p-IKBα and NF-κB activity in macrophages. Modafinil mitigates inflammation in apoE−/− atherosclerosis mice via inhibiting NF-κB activity in macrophages, and could potentially serve as a therapeutic agent for atherosclerosis. [ABSTRACT FROM AUTHOR]

Patients with attention deficit/hyperactivity disorder (ADHD) suffer from hypersomnia; indeed, we have often encountered ADHD patients that fulfill the diagnostic criteria for narcolepsy type 2 (NA 2). Because not all patients with NA 2 carry the HLA-DQB1*06:02 allele, which is closely associated with narcolepsy type 1 (NA 1), NA 2 is believed to be heterogeneous. To reveal the contribution of ADHD in hypersomnia, we studied the characteristics of hypersomnia patients with ADHD, especially those diagnosed with NA 2. Participants were 77 of 185 consecutive outpatients who were diagnosed with NA 2 or idiopathic hypersomnia. We investigated sleep variables in (a) participants with hypersomnia with/without ADHD and (b) patients with NA 2 with/without ADHD and those with/without the DQB1*06:02 allele. The proportion of those diagnosed with NA 2 was higher in hypersomnia patients with ADHD compared to those without ADHD. None of the NA 2 patients with ADHD carried the narcolepsy-specific DQB1*06:02 allele. These patients with NA 2 with ADHD exhibited short REM latencies on the MSLT (similarly to DQB1*06:02-positive patients with NA 2 without ADHD), but less REMrelated phenomena than patients with NA 2 without ADHD. Hypersomnia patients with ADHD tended to show short REM latencies, and fulfilled NA 2 diagnostic criteria in the absence of the DQB1*06:02 allele, suggesting a different etiology from NA 1. These findings support the hypotheses of noradrenergic dysregulation and delayed brain maturation that have been proposed for the pathophysiology of ADHD. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 (NT1) is a rare sleep disorder caused by the very specific loss of hypothalamic hypocretin (Hcrt)/orexin neurons. The exact underlying process leading to this destruction is yet unknown, but indirect evidence strongly supports an autoimmune origin. The association with immune-related genetic factors, in particular the strongest association ever reported in a disease with an allele of a human leukocyte antigen (HLA) gene, and with environmental factors (i.e., the H1N1 influenza infection and vaccination during the pandemic in 2009) are in favor of such a hypothesis. The loss of Hcrt neurons is irreversible, and NT1 is currently an incurable and disabling condition. Patients are managed with symptomatic medication, targeting the main symptoms (excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep), and they require a lifelong treatment. Improved diagnostic tools, together with an increased understanding of the pathogenesis of NT1, may lead to new therapeutic and even preventive interventions. One future treatment could include Hcrt replacement, but this neuropeptide does not cross the blood-brain barrier. However, Hcrt receptor agonists may be promising candidates to treat NT1. Another option is immune-based therapies, administered at disease onset, with already some initiatives to slow down or stop the dysimmune process. Whether immune-based therapy could be beneficial in NT1 remains, however, to be proven. [ABSTRACT FROM AUTHOR]

Relationships between symptoms of hypersomnolence, psychiatric disorders, and hypersomnia disorders (i.e., narcolepsy and idiopathic hypersomnia) are complex and multidirectional. Hypersomnolence is a common complaint across mood disorders; however, patients suffering from mood disorders and hypersomnolence rarely have objective daytime sleepiness, as assessed by the current gold standard test, the Multiple Sleep Latency Test. An iatrogenic origin of symptoms of hypersomnolence, and sleep apnea syndrome must be considered in a population of psychiatric patients, often overweight and treated with sedative drugs. On the other hand, psychiatric comorbidities, especially depression symptoms, are often reported in patients with hypersomnia disorders, and an endogenous origin cannot be ruled out. A great challenge for sleep specialists and psychiatrists is to differentiate psychiatric hypersomnolence and a central hypersomnia disorder with comorbid psychiatric symptoms. The current diagnostic tools seem to be limited in that condition, and further research in that field is warranted. [ABSTRACT FROM AUTHOR]

Rationale: Orexin knockout (KO) mice exhibit a phenotype that is similar to human narcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds. Objectives: The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice. Results: A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT receptor agonist) and DOI (5-HT receptor agonist), inhibited this hypolocomotion. We also found that 5-HT receptor mRNA levels, but not those for 5-HT or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT. Conclusion: These results suggest that a dysfunction of 5-HT receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexin deficiency-induced sleep disorders. Further, the use of 5-HT receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin. [ABSTRACT FROM AUTHOR]

Discusses the results of a study on the role of orexin neurons in the development of narcolepsy. Proportion of individual who suffer from narcolepsy as of 2001; Observations on the behavior of mice which lack orexin neurons; Significance of the research.

γ-Hydroxybutyric acid (GHB) is a powerful central nervous system depressant, currently used in medicine for the treatment of narcolepsy and alcohol dependence. In recent years, it has gained popularity among illegal club drugs, mainly because of its euphoric effects as well as doping agent and date rape drug. The purpose of the present work was the development of a rapid analytical method for the analysis of GHB in innovative biological matrices, namely dried blood spots (DBSs) and dried urine spots (DUSs). The analytical method is based on capillary zone electrophoresis with indirect UV absorption detection at 210 nm and capillary wall dynamic coating. The background electrolyte is composed of a phosphate buffer containing nicotinic acid (probe for detection) and cetyltrimethylammonium bromide (CTAB, reversal of electroosmosis in wall dynamic coating). The influence of probe and CTAB concentration, together with buffer pH, on migration time and signal response was investigated. Under the optimized conditions, analytical linearity and precision were satisfactory; absolute recovery values were also high (>90 %); the use of dried matrices (DBSs and DUSs) was advantageous as an alternative matrix to classical ones. No interferences were found either from the most common exogenous or from endogenous compounds. This analytical approach can offer a rapid, precise and accurate method for GHB determination in innovative biological samples, which could be important for screening purposes in clinical and forensic toxicology. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Type 1 narcolepsy, an autoimmune disease affecting hypocretin (orexin) neurons, is strongly associated with HLA-DQB1*06:02. Among polymorphisms associated with the disease is single-nucleotide polymorphism rs2305795 (c.*638G>A) located within the P2RY11 gene. P2RY11 is in a region of synteny conserved in mammals and zebrafish containing PPAN, EIF3G and DNMT1 (DNA methyltransferase 1). As mutations in DNMT1 cause a rare dominant form of narcolepsy in association with deafness, cerebellar ataxia and dementia, we questioned whether the association with P2RY11 in sporadic narcolepsy could be secondary to linkage disequilibrium with DNMT1. Based on genome-wide association data from two cohorts of European and Chinese ancestry, we found that the narcolepsy association signal drops sharply between P2RY11/EIF3G and DNMT1, suggesting that the association with narcolepsy does not extend into the DNMT1 gene region. Interestingly, using transethnic mapping, we identified a novel single-nucleotide polymorphism rs3826784 (c.596-260A>G) in the EIF3G gene also associated with narcolepsy. The disease-associated allele increases EIF3G mRNA expression. EIF3G is located in the narcolepsy risk locus and EIF3G expression correlates with PPAN and P2RY11 expression. This suggests shared regulatory mechanisms that might be affected by the polymorphism and are of relevance to narcolepsy. [ABSTRACT FROM AUTHOR]

Use of highly pure antigens to improve vaccine safety has led to reduced vaccine immunogenicity and efficacy. This has led to the need to use adjuvants to improve vaccine immunogenicity. The ideal adjuvant should maximize vaccine immunogenicity without compromising tolerability or safety. Unfortunately, adjuvant research has lagged behind other vaccine areas such as antigen discovery, with the consequence that only a very limited number of adjuvants based on aluminium salts, monophosphoryl lipid A and oil emulsions are currently approved for human use. Recent strategic initiatives to support adjuvant development by the National Institutes of Health should translate into greater adjuvant choices in the future. Mechanistic studies have been valuable for better understanding of adjuvant action, but mechanisms of adjuvant toxicity are less well understood. The inflammatory or danger-signal model of adjuvant action implies that increased vaccine reactogenicity is the inevitable price for improved immunogenicity. Hence, adjuvant reactogenicity may be avoidable only if it is possible to separate inflammation from adjuvant action. The biggest remaining challenge in the adjuvant field is to decipher the potential relationship between adjuvants and rare vaccine adverse reactions, such as narcolepsy, macrophagic myofasciitis or Alzheimer's disease. While existing adjuvants based on aluminium salts have a strong safety record, there are ongoing needs for new adjuvants and more intensive research into adjuvants and their effects. [ABSTRACT FROM AUTHOR]

We studied the relationship of orexin (hypocretin) system and astrocyte activation in hypersomnolence symptom ( HS) in Parkinson's disease ( PD). In a total of 30 subjects, including five PD patients with HS, eight PD patients without HS, eight patients with narcolepsy, and nine control subjects, orexin and glial fibrillary acidic protein ( GFAP) as well as S100B levels in cerebrospinal fluid ( CSF), which are markers of astrocyte activation, were measured and compared. In the comparison of orexin levels among the four groups of subjects, only the narcolepsy group showed significantly lower levels. The levels of CSF orexin in the PD patients with HS tended to be lower compared with those in the control group, although the difference was not statistically significant. The majority of reports have indicated that CSF orexin levels are in the normal range in most PD patients, some PD patients with severe HS showed low orexin levels. Compared with those of the control group, GFAP levels were significantly higher in the group of PD with HS and narcolepsy, but not PD without HS. No groups showed a significant difference in S100B levels. In the whole subjects with PD, narcolepsy, and controls, orexin levels were inversely correlated with GFAP. Therefore, increased GFAP may indicate orexin deficiency both in narcolepsy and PD with HS. [ABSTRACT FROM AUTHOR]

Narcolepsy is a chronic disorder of the sleep-wake cycle with pathological shifts between sleep stages. These abrupt shifts are induced by a sleep-regulating flip-flop mechanism which is destabilized in narcolepsy without obvious alterations in EEG oscillations. Here, we focus on the question whether the pathology of narcolepsy is reflected in EEG microstate patterns. 30 channel awake and NREM sleep EEGs of 12 narcoleptic patients and 32 healthy subjects were analyzed. Fitting back the dominant amplitude topography maps into the EEG led to a temporal sequence of maps. Mean microstate duration, ratio total time (RTT), global explained variance (GEV) and transition probability of each map were compared between both groups. Nine patients reached N1, 5 N2 and only 4 N3. All healthy subjects reached at least N2, 19 also N3. Four dominant maps could be found during wakefulness and all NREM- sleep stages in healthy subjects. During N3, narcolepsy patients showed an additional fifth map. The mean microstate duration was significantly shorter in narcoleptic patients than controls, most prominent in deep sleep. Single maps' GEV and RTT were also altered in narcolepsy. Being aware of the limitation of our low sample size, narcolepsy patients showed wake-like features during sleep as reflected in shorter microstate durations. These microstructural EEG alterations might reflect the intrusion of brain states characteristic of wakefulness into sleep and an instability of the sleep-regulating flip-flop mechanism resulting not only in pathological switches between REM- and NREM-sleep but also within NREM sleep itself, which may lead to a microstructural fragmentation of the EEG. [ABSTRACT FROM AUTHOR]

Sleep disorders are a pervasive problem throughout all patient populations but represent an especially important health problem for the elderly. Alterations in sleep architecture that occur as a part of normal aging will contribute to sleep problems as we grow older. Other contributing factors-including comorbid medical conditions, changes in lifestyle and schedule, altered circadian rhythm, among a host of others-can have detrimental effects on the health of the elderly. Coupled with a number of sleep disorders that either emerge or exacerbate with age, the effects of poor sleep often result in an overall worsening of quality of life. Treatment options can be unique in this population and often more difficult due to the effects of normal aging, as well as polypharmacy and possible medication interactions. The following article will focus on the common sleep disorders that can besiege this population, symptoms to aid in diagnosis, and specific treatment options to help improve quality of life in the elderly. [ABSTRACT FROM AUTHOR]

Narcolepsy is a severe, incurable, neurological disorder that is treated by pharmacological management of its symptoms. The main symptoms are excessive daytime sleepiness (EDS) and cataplexy, although addition symptoms that may require treatment include sleep paralysis, hypnagogic hallucinations, and disturbed nocturnal sleep. Sodium oxybate and modafinil/armodafinil are the first-line treatments for EDS, and sodium oxybate for cataplexy. Sodium oxybate treats all the symptoms of narcolepsy, whereas modafinil is effective for EDS only. Alternative medications for EDS include methylphenidate or amphetamines such as dextroamphetamine, lisdexamfetamine, methamphetamine, or combination amphetamine salts. Non-FDA approved medications for cataplexy include norepinephrine reuptake inhibitors such as venlafaxine or atomoxetine. Combination therapy can be more effective for sleepiness such as sodium oxybate and modafinil/armodafinil. Medication for narcolepsy is generally well tolerated and usually required life-long although does not eliminate all symptoms of narcolepsy. [ABSTRACT FROM AUTHOR]