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Narcolepsy is mainly associated with excessive daytime sleepiness, but the characteristic feature is abnormal rapid eye movement (REM) sleep phenomena. REM sleep disturbances can manifest as cataplexy (in narcolepsy type 1), sleep paralysis, sleep-related hallucinations, REM sleep behavior disorder, abnormal dreams, polysomnographic evidence of REM sleep disruption with sleep-onset REM periods, and fragmented REM sleep. Characterization of REM sleep and related symptoms facilitates the differentiation of narcolepsy from other central hypersomnolence disorders and aids in distinguishing between narcolepsy types 1 and 2. A circuit comprising regions within the brainstem, forebrain, and hypothalamus is involved in generating and regulating REM sleep, which is influenced by changes in monoamines, acetylcholine, and neuropeptides. REM sleep is associated with brainstem functions, including autonomic control, and REM sleep disturbances may be associated with increased cardiovascular risk. Medications used to treat narcolepsy (and REM-related symptoms of narcolepsy) include stimulants/wake-promoting agents, pitolisant, oxybates, and antidepressants; hypocretin agonists are a potential new class of therapeutics. The role of REM sleep disturbances in narcolepsy remains an area of active research in pathophysiology, symptom management, and treatment. This review summarizes the current understanding of the role of REM sleep and its dysfunction in narcolepsy.

Summary Clinicians and people with narcolepsy report varied access to higher‐cost narcolepsy treatments in England associated with variations in national and local commissioning. There are no publicly available data quantifying use of these drugs to support policy decisions. We therefore aimed to describe national, regional and local prescribing trends for higher‐cost narcolepsy drugs using new national databases. We used the English prescribing dataset and secondary care medicines data to quantify volumes of high‐cost narcolepsy drugs issued between 01 January 2019 and 31 December 2022. Volumes were converted to World Health Organisation defined daily doses, to estimate the monthly number of defined daily doses of sodium oxybate, pitolisant and solriamfetol issued by each integrated care board and region. We compared national, integrated care board, and regional level issuance of each drug over time. Analysis of almost 6000 primary care prescriptions and 2000 cumulative months of secondary care pharmacy stock data, issued across 41/42 integrated care boards in England, revealed a 49.1% increase in issuance of high‐cost narcolepsy drugs between 2019 and 2022. In 2022, sodium oxybate accounted for 52.66% of issuance, pitolisant 43.09% and solriamfetol 4.25%, with 22.31% of defined daily doses issued in primary care. Three integrated care boards (NHS Southeast London, NHS Cumbria and North‐East, NHS Cheshire and Merseyside) predominate, issuing 56.33% of all defined daily doses. Variations between integrated care boards and regions differ substantially by drug and route of issuance. Our findings describe substantial variation in the use of specialist narcolepsy drugs in England, and highlight the untapped potential of using large, public domain datasets to publicly review higher‐cost drug prescribing. [ABSTRACT FROM AUTHOR]

Summary Excessive daytime sleepiness is a possible symptom of post‐COVID syndrome and is also the cardinal symptom of narcolepsy, a rare life‐long sleep disorder with a possible autoimmune background. Recent reports indicate that COVID‐19 infection may trigger narcolepsy. However, it remains unclear how best to identify and treat such cases. A 25‐year‐old male developed daytime sleepiness after COVID‐19 infection. A diagnosis of narcolepsy type II was made based on pathologically shortened sleep latencies in polysomnography and multiple sleep latency tests (MSLT) together with several sleep‐onset REM‐sleep periods (SOREMs). Pupillography and neuropsychological testing revealed reduced alertness levels. Hypocretin levels in the cerebrospinal fluid were borderline. Based on the postulated autoimmune background of narcolepsy, we performed an intravenous high‐dose corticosteroid pulse therapy with methylprednisolone. Narcoleptic symptoms immediately and consistently remitted after the corticosteroid pulse. Follow‐up after 4 months revealed normalisation of sleep latencies, no further SOREMs in the MSLT, and increased alertness in pupillography and neurocognitive testing. No further wakefulness promoting drug therapy was required. Narcolepsy should be considered in the differential diagnosis of post‐COVID syndrome with leading symptoms of daytime sleepiness. Furthermore, immunosuppressive therapy may offer a treatment option in managing an otherwise lifelong disorder in select cases. [ABSTRACT FROM AUTHOR]

This study employs the Mendelian Randomization (MR) approach to explore the potential causal relationship between schizophrenia and the risk of developing narcolepsy. Genome-Wide Association Studies (GWAS) data from European populations were used to identify independent genetic variants associated with schizophrenia and narcolepsy, which were then used as instrumental variables in the analysis. The inverse variance weighting (IVW) method was performed to validate the findings. Effect sizes were presented as odds ratios (OR) and beta coefficients (β). The IVW analysis showed no significant causal relationship between schizophrenia and narcolepsy (OR: 1.002, 95 % CI: 0.996–1.007, P = 0.531). Likewise, the reverse analysis did not find any significant causal association (OR: 1.059, 95 % CI: 0.717–1.567, P = 0.421). Sensitivity analyses further confirmed the robustness of these findings. The MR analysis does not provide evidence for a bidirectional causal relationship between schizophrenia and narcolepsy. Further research is needed to elucidate the underlying mechanisms and to identify potential targets for intervention. [ABSTRACT FROM AUTHOR]

Summary: The differential diagnosis of narcolepsy type 1, a rare, chronic, central disorder of hypersomnolence, is challenging due to overlapping symptoms with other hypersomnolence disorders. While recent years have seen significant growth in our understanding of nocturnal polysomnography narcolepsy type 1 features, there remains a need for improving methods to differentiate narcolepsy type 1 nighttime sleep features from those of individuals without narcolepsy type 1. We aimed to develop a machine learning framework for identifying sleep features to discriminate narcolepsy type 1 from clinical controls, narcolepsy type 2 and idiopathic hypersomnia. The population included polysomnography data from 350 drug‐free individuals (114 narcolepsy type 1, 90 narcolepsy type 2, 105 idiopathic hypersomnia, and 41 clinical controls) collected at the National Reference Centers for Narcolepsy in Montpelier, France. Several sets of nocturnal sleep features were explored, as well as the value of time‐resolving sleep architecture by analysing sleep per quarter‐night. Several patterns of nighttime sleep evolution emerged that differed between narcolepsy type 1, clinical controls, narcolepsy type 2 and idiopathic hypersomnia, with increased nighttime instability observed in patients with narcolepsy type 1. Using machine learning models, we identified rapid eye movement sleep onset as the best single polysomnography feature to distinguish narcolepsy type 1 from controls, narcolepsy type 2 and idiopathic hypersomnia. By combining multiple feature sets capturing different aspects of sleep across quarter‐night periods, we were able to further improve between‐group discrimination and could identify the most discriminative sleep features. Our results highlight salient polysomnography features and the relevance of assessing their time‐dependent changes during sleep that could aid diagnosis and measure the impact of novel therapeutics in future clinical trials. [ABSTRACT FROM AUTHOR]

The incidence of early puberty in children has been increasing. It has been suspected that both genetic and various environmental factors such as nutrition and hormonal exposure could influence the mechanisms underlying the earlier onset of puberty. Interestingly, several previous studies have reported a strong connection between sleep and puberty. Specifically, it was discovered that luteinizing hormone (LH), a potential marker for the onset of puberty, was increased during the deep sleep period. Furthermore, a high prevalence of early puberty was observed in patients with sleep disorders, especially in those experiencing narcolepsy. In this review article, findings related to the association between sleep disturbance and early puberty have been comprehensively summarized. Any contrary findings are also included and discussed. Advances in the knowledge surrounding sleep disturbance have led to a greater understanding of a correlation between early puberty and sleep disorder and provide alternative therapeutic options for the treatment of central precocious puberty in the future. [ABSTRACT FROM AUTHOR]

Summary EEG spectral analysis provides a more sensitive measure of sleep disruption than conventional sleep macro‐architecture. We aimed to examine the use of this technique applied to overnight polysomnography in distinguishing children with narcolepsy and idiopathic hypersomnia (IH) from subjectively sleepy children with a non‐diagnostic multiple sleep latency test. The relative power was calculated for delta (0.5–3.9 Hz), theta (4–7.9 Hz), alpha (8–11.9 Hz), sigma (12–13.9 Hz), and beta power (14–30 Hz). A mean value for each frequency was calculated for each 30 s epoch then averaged for each sleep stage within each child. Data are presented as median and interquartile range. Twenty‐eight children with narcolepsy, 11 with IH, and 26 with subjective sleepiness were included and individually matched for age and sex with a control child. In N2, the F4 beta power was lower in the narcolepsy compared with the IH group (p < 0.05). The F4 theta power was higher in the narcolepsy compared with the subjectively sleepy group during wake (p < 0.001), N2 (p < 0.01), N3 (p < 0.05), and total sleep (p < 0.01). During total sleep the F4 delta power was lower in both the narcolepsy and IH groups compared with the subjectively sleepy group (p < 0.05 for both). Our study identified specific EEG frequencies which differed between groups of children referred for assessment of EDS. In particular, differences in theta and delta power in children with narcolepsy and IH compared with others with subjective sleepiness may provide insights into the pathophysiology associated these conditions. [ABSTRACT FROM AUTHOR]

Objective: Narcolepsy, a rare neurological disorder believed to have an autoimmune etiology, necessitates lifelong management. This study aimed to provide evidence supporting the safety of pharmacological treatment for narcolepsy. Methods: Five-year data on pitolisant, sodium oxybate, solriamfetol, and modafinil were extracted from the FDA Adverse Event Reporting System (FAERS) self-reporting database for the period spanning from 2019 to 2023. Various statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network analysis (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to quantify the signals. Finally, a comparative analysis was conducted between demographic data, outcomes, and inherent associations among the medications and the signals. Results: After data analysis, we obtained 50 signals (a cumulative count of 762 cases) for pitolisant, 640 signals (corresponding to 46,962 cases) for sodium oxybate, 40 signals (equivalent to 1,228 cases) for solriamfetol, and finally, 72 signals (representing 632 cases) for modafinil. The majority of these patients were female. Psychiatric and nervous system disorders were identified as the predominant adverse drug events (ADEs). For sodium oxybate, it is crucial to consider psychiatric disorders (such as suicidal ideation), respiratory disorders (including sleep apnea syndrome and respiratory depression), and signs of pregnancy and congenital familial diseases. For solriamfetol, noteworthy new ADEs include drug inefficacy, suicidal ideation, restless legs syndrome, and somnambulism. Furthermore, a relationship has been observed between modafinil use and restricted fetal growth, spontaneous abortion, cognitive disorders, and drug inefficacy and abuse. Conclusion: The majority of observed adverse reactions in this study were consistent with those listed in the product instructions. However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 (NT1) is an uncommon, persistent sleep disorder distinguished by significant daytime sleepiness, episodes of cataplexy, and irregularities in rapid eye movement sleep. The etiology of NT1 is linked to the destruction of hypothalamic neurons responsible for the synthesis of the wake-promoting neuropeptide known as hypothalamic orexin. The pathophysiological mechanisms underlying NT1 remain inadequately elucidated; however, a model that incorporates the interplay of genetic predisposition, environmental influences, immune system factors, and a deficiency in hypocretin (HCRT) provides a framework for elucidating the pathogenesis of NT1. The prevalence of NT1 has been observed to rise following influenza A (H1N1) pdm09 and the administration of the Pandemrix influenza vaccine. The strong association between narcolepsy and the HLA-DQB1*06:02 allele strongly indicates an autoimmune etiology for this condition. Increasing evidence suggests that T cells play a critical role in this autoimmune-mediated HCRT neuronal loss. Studies have identified specific T cell subsets, including CD4+ and CD8+ T cells, that target HCRT neurons, contributing to their destruction. Clarifying the pathogenesis of NT1 driven by autoimmune T cells is crucial for the development of effective therapeutic interventions for this disorder. This review examines the risk factors associated with the pathogenesis of NT1, explores the role of T cells within the immune system in the progression of NT1, and evaluates immune-mediated animal models alongside prospective immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Patients with central hypersomnia (HCO) often show symptoms of depression. Despite of many studies conducted in this field, the link between these two disorders remains unclear. In order to contribute data to this research, we examined the question of which depressive symptoms characterize these patients. Furthermore, we investigated the differences between HCO who were more or less depressed regarding insomnia, sleep quality and daytime tiredness. The retrospective analysis assesses the presence and kind of depressive symptoms as measured by the Beck Depression Inventory (BDI) in 168 HCO including narcolepsy type I (NAR1), narcolepsy type II (NAR2) and idiopathic hypersomnia (HYP). Sleep parameters from one night of polysomnography, scores of questionnaires for insomnia and for daytime sleepiness, and data from sustained attention tests were compared between HCO with and without depression, as determined by BDI scores (cut off >12). According to BDI scores 52% exhibited no depression. The BDI items pertaining to tiredness and work inhibition exhibited elevated scores, whereas those pertaining to suicidality showed low scores. No difference was found between depressed and non-depressed HCO with regard to daytime vigilance performance or daytime sleepiness. However, depression was associated with older age, higher insomnia scores, and a shorter sleep time on polysomnography. A potential interpretation of our findings is that depressive symptoms in HCO may be a consequence of restricted life quality due to hypersomnia. Thus, therapeutical effort should focus more intensely on coping strategies. [ABSTRACT FROM AUTHOR]

Background and Objective: Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine–dextroamphetamine in these disorders. Methods: Forty-four adults were randomized to modafinil or amphetamine–dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine–dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups. Results: Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine–dextroamphetamine; noninferiority of amphetamine–dextroamphetamine was not demonstrated (P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine–dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine. Conclusion: Noninferiority of amphetamine–dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine–dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2. Registration: Clinicaltrials.gov Registration (NCT03772314) 12/10/18.. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effects of neck myoclonus (NM) on sleep quality and daytime sleepiness in patients with narcolepsy (NT) and to further explore possible underlying mechanisms. We included 72 patients with narcolepsy type 1 (NT1), 34 patients with narcolepsy type 2 (NT2) and 33 healthy controls. Patients underwent questionnaires, lumbar puncture procedure, polysomnography, and multiple sleep latency test (MSLT). Healthy controls underwent polysomnography and questionnaires. Orexin-A levels in the cerebrospinal fluid (CSF) were analyzed by radioimmunoassay. Three catecholamines, including dopamine, norepinephrine and epinephrine, in the CSF were measured by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). Both the NT1 and NT2 groups displayed a higher level of NM incidence rate and index compared to the control group in PSG. NT1 displayed greater MSLT REM–-NM incidence rate and index than NT2. NM were often associated with arousal or awakening and body movements, which had a prominent influence on sleep quality in both narcoleptic patients and controls. There was a positive correlation between the NM index and the Pittsburgh Sleep Quality Index (PSQI), Stanford Sleepiness Scale (SSS) and Ullanlinna Narcolepsy Scale (UNS) scores in NT1 patients. In MSLT of NT1 patients, REM–NM index were positively correlated with the CSF dopamine levels, and there were elevated dopamine levels but reduced orexin-A levels in patients with REM–NM. NM incidence rate and index were high in patients with narcolepsy, which had a huge effect on sleep quality and aggravated daytime sleepiness. NM should be considered pathological and viewed as a new sleep-related movement disorder. Orexin-A and dopamine may be involved in the development of NM. • The Incidence rate and index of neck myoclonus were high in patients with narcolepsy. • Neck myoclonus affects patients' sleep quality and aggravates daytime sleepiness. • It should be considered pathological and viewed as a sleep-related movement disorder. • Its mechanism may be related to orexin-A and dopamine signaling pathways. [ABSTRACT FROM AUTHOR]