Comorbidity of obstructive sleep apnea and narcolepsy: A challenging diagnosis and complex management.

Introduction: Narcolepsy and obstructive sleep apnea syndrome (OSA) are relevant causes of excessive daytime sleepiness (EDS); although different for etiopathogenesis and symptoms, differential diagnosis is sometimes difficult, and guidelines are lacking concerning their management when coexisting in a same patient. Methods: A narrative review of the literature was realized including PubMed, Scopus and Embase, aimed to regroup studies and case reports evaluating epidemiology, clinical and instrumental features and treatment of patients presenting comorbid NT1 and OSA. Moreover, a snowball search on the pathophysiology underpinnings of the association of the two disorder was realized. Results: For adults, the prevalence of OSA in NT1 ranged from 24.8 % to 51.4 %. No studies were found concerning the treatment of EDS in double-diagnosis patients, but only case reports; these latter and the experience on patients with either NT or OSA suggest that modafinil, methylphenidate, pitolisant and solriamfetol are effective. Discussion: Adults with NT1 showed a higher prevalence of OSA compared to the general population, but the reach of the results reviewed here is limited by the retrospective design of most of the studies and by the inhomogeneous utilization of diagnostic criteria. The association with OSA is likely to be explained by the involvement of orexin in hypercapnic-hypoxic responses: a deficit of orexin may promote obstructive events during sleep. Open questions warrant further investigation, especially orexin's involvement in other sleep disorders associated with EDS, and the more appropriate treatment for the OSA-narcolepsy comorbidity.

Depressive symptoms in patients with hypersomnia measured with Beck Depression Inventory.

BACKGROUND: 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. METHODS AND MATERIAL: 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). RESULTS: 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. CONCLUSION: 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.

Probabilistic Sleep Staging in MSLTs across Hypersomnia Disorders.

STUDY OBJECTIVES: This study aimed to identify novel markers of narcolepsy type 1 (NT1) using between-nap opportunity periods ('Lights On') and in-nap opportunity periods ('Lights Off') features of Multiple Sleep Latency Test (MSLT) recordings. We hypothesized that NT1 could be identified both from sleep-wake instability and patterns of sleepiness during wakefulness. Further, we explored if MSLTs from NT1 and narcolepsy type 2 (NT2) patients could be distinguished despite having the same diagnostic thresholds. METHODS: We analyzed 'Lights On' and 'Lights Off' periods of the MSLT, extracting 163 features describing sleepiness, microsleep, and sleep stage mixing using data from 177 patients with NT1, NT2, Idiopathic Hypersomnia (IH), and Subjective Hypersomnia (sH) from three sleep centers. These features were based on automated probabilistic sleep staging, also denoted as hypnodensities, using U-Sleep. Hypersomnias were differentiated using either or both features from 'Lights On' and 'Lights Off'. RESULTS: Patients with NT1 could be distinguished from NT2, IH, and sH using features solely from 'Lights On' periods with a sensitivity of 0.76 and specificity of 0.71. When using features from all periods of the MSLT, NT1 was distinguished from NT2 alone with a sensitivity of 0.77 and a specificity of 0.84. CONCLUSIONS: The findings of this study demonstrate microsleeps and sleep stage mixing as potential markers of the sleep attacks and unstable sleep-wake states common in NT1. Further, NT1 and NT2 could be frequently distinguished using 'Lights Off' features.

Recent insights into the pathophysiology of narcolepsy type 1.

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

CSF-profile and hypocretin levels in children with narcolepsy type 1 and 2.

BACKGROUND: Narcolepsy is a rare neurological disease caused by dysfunction of hypocretin-producing neurons. Hypocretin concentrations in the cerebrospinal fluid (CSF) of less than 110 pg/ml are considered pathological in adults. OBJECTIVES: To compare hypocretin levels of children with narcolepsy type 1, type 2 and disease control groups, in addition to a detailed CSF analysis, clinical and polysomnographic parameters. METHODS: In a retrospective, cross-sectional study, children diagnosed with narcolepsy based on clinical and polysomnographic parameters, who received a CSF analysis and hypocretin measurement, in addition to controls, were included. CSF was analyzed for the presence of cells, total protein, lactate, intrathecal synthesis of antibodies against measles, rubella and/or varicella zoster, and oligoclonal bands. All children had a complete sleep study including a multiple sleep latency test (MSLT). RESULTS: 49 children with narcolepsy type 1, 15 children with type 2 and 37 children with other (suspected) neurological diseases were included. CSF routine analysis did not reveal any differences between the three groups. All children with narcolepsy type 1 had hypocretin levels of less than 110 pg/ml (range: 10-101 pg/ml). Hypocretin levels in type 2 patients ranged from 43 to 436 pg/ml (median 157 pg/ml). The median hypocretin level in the control cohort was 365 pg/ml (range: 153-583 pg/ml). In 4 children with narcolepsy type 2 the diagnosis was changed to narcolepsy level 1 because of a CSF hypocretin level of less than 110 pg/ml according to the recently proposed criteria, which consider the measurement of hypocretin in CSF. CONCLUSION: Children with narcolepsy type 1 showed significantly lower CSF hypocretin levels than children with narcolepsy type 2 and controls. As suggested by the recently published narcolepsy criteria, hypocretin levels of less than 110 pg/ml should be used as an additional criterion for the presence of narcolepsy type 1 in children.

RESTORE: Once-nightly oxybate dosing preference and nocturnal experience with twice-nightly oxybates.

Objective/Background: Preference for extended-release, once-nightly sodium oxybate (ON-SXB, FT218) vs twice-nightly immediate-release (IR) oxybate was assessed in participants switching from IR oxybate to ON-SXB in an open-label/switch study, RESTORE (NCT04451668). Patients/Methods: Participants aged ≥16 years with narcolepsy who completed the phase 3 REST-ON trial, were oxybate-naive, or were on a stable IR oxybate dose (≥1 month) were eligible for RESTORE. For participants who switched from twice-nightly dosing to ON-SXB, initial doses were closest or equivalent to their previous nightly IR oxybate dose. These participants completed a questionnaire at baseline about nocturnal adverse events associated with the middle-of-the-night IR oxybate dose in the preceding 3 months, a preference questionnaire after 3 months of stable-dose ON-SXB, and an end-of-study (EOS) questionnaire. Results: There were 130 switch participants; 92/98 (93.9 %) who completed the preference questionnaire preferred ON-SXB. At baseline, 69.2 % reported missing their second IR oxybate dose at least once; in these cases, 80 % felt worse the next day. Approximately 39 % reported taking a second nightly IR oxybate dose >4 h after the first dose, 51 % of whom felt somewhat to extremely groggy/unsteady the next morning; 120 participants (92 %) reported getting out of bed after their second oxybate dose. Of those, 9 (8 %) reported falls and 5 (4 %) reported injuries. Of the switch participants who completed the EOS questionnaire, 91.2 % felt better able to follow the recommended ON-SXB dosing schedule. Conclusions: The second nightly IR oxybate dose presents significant treatment burdens and adherence concerns. Participants overwhelmingly preferred the once-nightly dosing regimen of ON-SXB.

TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models.

Narcolepsy type 1 (NT1) is associated with severe loss of orexin neurons and characterized by symptoms including excessive daytime sleepiness and cataplexy. Current medications indicated for NT1 often show limited efficacy, not addressing the full spectrum of symptoms, demonstrating a need for novel drugs. We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. However, danavorexton has limited oral availability and TAK-994 has a risk of off-target liver toxicity. To avoid off-target-based adverse events, a highly potent molecule with low effective dose is preferred. Here, we show that a novel OX2R-selective agonist, TAK-861 [N-{(2S,3R)-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide], activates OX2R with a half-maximal effective concentration of 2.5 nM and promotes wakefulness at 1 mg/kg in mice and monkeys, suggesting ~ tenfold higher potency and lower effective dosage than TAK-994. Similar to TAK-994, TAK-861 substantially ameliorates wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 and orexin-tTA;TetO DTA mice (NT1 mouse models). Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile.

Behavioral and Electrophysiological Markers of Attention Fluctuations in Children with Hypersomnolence.

Background. No device is yet available to effectively capture the attentional repercussions of hypersomnolence (HYP). The present study aimed to compare attentional performance of children with HYP, attention deficit hyperactivity disorder (ADHD), and controls using behavioral and electrophysiological (EEG) markers, and to assess their relationship with conventional sleepiness measurements. Methods. Children with HYP underwent a multiple sleep latency test (MSLT) and completed the adapted Epworth sleepiness scale (AESS). Along with age-matched children with ADHD, they were submitted to a resting EEG followed by the Bron-Lyon Attention Stability Test (BLAST). The control group only performed the BLAST. Multivariate models compared reaction time (RT), error percentage, BLAST-Intensity, BLAST-Stability, theta activity, and theta/beta ratio between groups. Correlations between these measures and conventional sleepiness measurements were conducted in children with HYP. Results. Children with HYP had lower RT and BLAST-Stability than controls but showed no significant difference in BLAST/EEG markers compared to children with ADHD. The AESS was positively correlated with the percentage of errors and negatively with BLAST-Intensity. Conclusions. Children with HYP showed impulsivity and attention fluctuations, without difference from children with ADHD for BLAST/EEG markers. The BLAST-EEG protocol could be relevant for the objective assessment of attentional fluctuations related to hypersomnolence.

Clinical features and mechanisms of neck myoclonus in narcolepsy.

STUDY OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Knowledge of Narcolepsy Among Physicians in Makkah Region, Saudi Arabia: A Cross-Sectional Study.

Background Narcolepsy is a chronic sleep disorder that is characterized by excessive daytime sleepiness and cataplexy. It has been increasingly diagnosed over the years, impacting productivity and employment rates. Awareness of healthcare providers is crucial for the early identification and management of this condition. Objectives This study assessed physicians' knowledge of narcolepsy in the Makkah region of Saudi Arabia. Method This cross-sectional study was conducted from February to November 2023. An online self-administered questionnaire has been used to target physicians working in the Makkah region of Saudi Arabia. The utilized questionnaire assessed demographic and professional data as well as the participants' knowledge of narcolepsy. Statistical analysis was performed using RStudio (R version 4.3.1.). Statistical differences in knowledge were assessed using Pearson's chi-squared and Fisher's exact tests. Factors associated with knowledge of narcolepsy were investigated through univariable and multivariable regression analyses expressed using beta coefficients and 95% confidence intervals (95% CIs). Statistical significance was considered at p < 0.05. Results A total of 226 physicians participated in this study. Male physicians (54.4%, n = 123), practicing in governmental hospitals (77.9%, n = 176) and residing in Makkah City (43.4%, n = 98) were predominant. Non-surgical specialties represented 73.5% (n = 166) of the sample. Around 81% (n = 184) of the participants were aware of narcolepsy, with a significant difference according to professional status (p = 0.045). The majority of physicians have correctly identified narcolepsy as a sleep disorder (78.3%, n = 177), but only 32.3% (n = 73) have identified its typical onset age group and recognized that there are two types of narcolepsy. Almost half of the respondents indicated a lack of knowledge about the diagnostic criteria for narcolepsy in the DSM-5 (52.2%, n = 118). Only 27.4% (n = 62) recognized the correct diagnostic criteria. Half of the sample (51.3%, n = 116) recognized the use of multiple sleep latency tests for the diagnosis. For factors associated with higher participants' knowledge, non-surgical specialties showed significantly higher knowledge scores compared to surgical specialties (beta = 0.91, 95% CI, 0.13 to 1.7, p = 0.024). Conclusion This study has revealed a significant lack of knowledge about narcolepsy among physicians in Makkah region. This raises concerns about the timely identification, proper understanding, and accurate diagnosis of patients with narcolepsy. Adequate understanding of narcolepsy is crucial to avoid its misdiagnosis or delays in receiving appropriate treatment and support, ultimately impacting their quality of life.

Efficacy of once-nightly sodium oxybate (FT218) on daytime symptoms in individuals with narcolepsy with or without concomitant alerting agent use: A post hoc analysis from the phase 3 REST-ON trial.

OBJECTIVE/BACKGROUND: Extended-release, once-nightly sodium oxybate (ON-SXB) significantly improved narcolepsy symptoms in participants in the phase 3, randomized, double-blind, placebo-controlled REST-ON trial. This post hoc analysis of REST-ON data evaluated ON-SXB efficacy in participants with or without concomitant alerting agent use. PATIENTS/METHODS: Participants with narcolepsy aged >16 years were randomized 1:1 to ON-SXB (week 1: 4.5 g, weeks 2-3: 6 g, weeks 4-8: 7.5 g, weeks 9-13: 9 g) or placebo. Primary endpoints in this post hoc analysis included change from baseline in mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement (CGI-I) rating, and number of weekly cataplexy episodes. The secondary endpoints were change from baseline in the Epworth Sleepiness Scale (ESS) score and in objective and subjective disrupted nighttime sleep parameters. Post hoc analyses assessed participants with and without alerting agent use across 6-, 7.5-, and 9-g doses. RESULTS: In the modified intent-to-treat population, 119 (63 %) were (ON-SXB, n = 66; placebo, n = 53) and 71 (37 %) were not (ON-SXB, n = 31; placebo, n = 40) taking alerting agents. Regardless of alerting agent use, treatment with ON-SXB resulted in significant improvements vs placebo (all doses, P < 0.05) for MWT, CGI-I, and number of weekly cataplexy episodes. Significant improvements in ESS (all doses, P < 0.05) with ON-SXB vs placebo were observed in the alerting agent use cohort. Directional improvements in ESS were reported with all doses in the no alerting agent use group. CONCLUSIONS: Regardless of concomitant alerting agent use, ON-SXB improved daytime and nighttime narcolepsy symptoms vs placebo.

Predicting Depression Among Chinese Patients with Narcolepsy Type 1: A Machine-Learning Approach.

Objective: Depression is a common psychiatric issue among patients with narcolepsy type 1 (NT1). Effective management requires accurate screening and prediction of depression in NT1 patients. This study aims to identify relevant factors for predicting depression in Chinese NT1 patients using machine learning (ML) approaches. Methods: A total of 203 drug-free NT1 patients (aged 5-61), diagnosed based on the ICSD-3 criteria, were consecutively recruited from the Sleep Medicine Center at Peking University People's Hospital between September 2019 and April 2023. Depression, daytime sleepiness, and impulsivity were assessed using the Center for Epidemiologic Studies Depression Scale for Children (CES-DC) or the Self-Rating Depression Scale (SDS), the Epworth Sleepiness Scale for adult or children and adolescents (ESS or ESS-CHAD), and the Barratt Impulse Scale (BIS-11). Demographic characteristics and objective sleep parameters were also analyzed. Three ML models-Logistic Regression (LR), Random Forest (RF), and Support Vector Machine (SVM)-were used to predict depression. Model performance was evaluated using receiver operating curve (AUC), accuracy, precision, recall, F1 score, and decision curve analysis (DCA). Results: The LR model identified hallucinations (OR 2.21, 95% CI 1.01-4.90, p = 0.048) and motor impulsivity (OR 1.10, 95% CI 1.02-1.18, p = 0.015) as predictors of depression. Among the ML models, SVM showed the best performance with an AUC of 0.653, accuracy of 0.659, sensitivity of 0.727, and F1 score of 0.696, reflecting its effectiveness in integrating sleep-related and psychosocial factors. Conclusion: This study highlights the potential of ML models for predicting depression in NT1 patients. The SVM model shows promise in identifying patients at high risk of depression, offering a foundation for developing a data-driven, personalized decision-making tool. Further research should validate these findings in diverse populations and include additional psychological variables to enhance model accuracy.

Searching for sleep in all the right places: My career in sleep research.

My research has always focused on sleep, whether monitoring neural activity (microwires, c-Fos, calcium imaging), triggering it with optogenetics or pharmacologically (anandamide, cholinergic agonists), or measuring levels of endogenous sleep agents such as adenosine. A recurring theme of my research is to use new tools to find the sweet spot in the brain where the signal to sleep begins. My goal is to identify the circuit, determine whether it degrades with age or disease, and repair the circuit when it fails. I am deeply grateful to my mentors for introducing me to the science of sleep, to my students and colleagues for helping me in my quest, and to the NIH and VA Research for supporting the research. Because of the collective efforts of sleep researchers, the public is more aware of the importance of sleep to a healthy lifestyle.

Exploring the correlation between paediatric narcolepsy and serum neurofilament light chain levels: An exploratory study.

BACKGROUND: The study seeks to assess serum neurofilament light chain (NfL) levels in paediatric narcolepsy-diagnosed patients. Moreover, it aims to explore the correlation between NfL levels and the severity of narcolepsy symptoms, sleep quality, and manifestations of anxiety and depression. METHODS: This retrospective analysis included 98 paediatric narcolepsy cases and 100 controls matched for age and gender. The study focused on comparing serum NfL levels across these groups. Severity of EDS in patients was measured with the Epworth Sleepiness Scale (ESS). Moreover, the Pittsburgh Sleep Quality Index (PSQI), Hamilton Depression Rating Scale-24 (HAMD-24), and Hamilton Anxiety Scale-14 (HAMA-14) were used to assess narcolepsy symptoms, sleep quality, and psychological conditions. RESULTS: Patients with paediatric narcolepsy had significantly higher serum NfL levels than controls (P < 0.05). Additionally, a positive correlation was found between serum NfL levels and ESS scores (P < 0.001). An independent link between serum NfL and paediatric narcolepsy was established via multiple logistic regression (OR = 0.943, 95 % CI = 0.921-0.993, P = 0.004). Moreover, serum NfL's diagnostic precision for paediatric narcolepsy was evident from the ROC curve area of 0.938 (95 % CI: 0.86-0.99, P < 0.001). CONCLUSION: The study implies a positive correlation between increased serum NfL levels and the severity of paediatric narcolepsy. Nevertheless, the causative link between serum NfL levels and paediatric narcolepsy remains uncertain, highlighting the need for larger sample sizes and well-structured cohort studies to offer more definitive.

Major Alteration Of Motor Control During Rem Sleep In Mice Models Of Sleep Disorders.

Alteration of motor control during REM sleep has been extensively described in sleep disorders, in particular in isolated REM sleep behavior disorder (iRBD) and narcolepsy type 1 (NT1). NT1 is caused by the loss of orexin/hypocretin (ORX) neurons. Unlike in iRBD, the RBD comorbid symptoms of NT1 is not associated with alpha-synucleinopathies. To determine whether the chronic absence of ORX neuropeptides is sufficient to induce RBD symptoms, we analyzed during REM sleep the EMG signal of the prepro-hypocretin knockout mice (ORX-/-), a recognized mouse model of NT1. Then, we evaluated the severity of motor alterations by comparing EMG data of ORX-/- mice to those of mice with a targeted suppression of the sublaterodorsal glutamatergic neurotransmission, a recognized rodent model of iRBD. We found a significant alteration of tonic and phasic components of EMG during REM sleep in ORX-/- mice, with more phasic events and more REM sleep episodes without atonia compared to the control wild-type mice. However, these phasic events were fewer, shorter and less complex in ORX-/- mice compared to the RBD-like ORX-/- mice. We thus show that ORX-deficiency, as seen in NT1, is sufficient to impair muscle atonia during REM sleep with a moderate severity of alteration as compared to isolated RBD mice. As described in NT1 patients, we report a major inter-individual variability in the severity and the frequency of RBD symptoms in ORX-deficient mice.

Weight Loss With Once-nightly Sodium Oxybate for the Treatment of Narcolepsy: Analysis From the Phase III Randomized study Evaluating the efficacy and SafeTy of a ONce nightly formulation of sodium oxybate (REST-ON) Trial.

PURPOSE: Individuals with narcolepsy are more likely to be obese than the general population. Changes in weight-related measures with extended-release, once-nightly sodium oxybate (ON-SXB) and characteristics of participants with ≥5% weight loss were assessed in a Randomized study Evaluating the efficacy and SafeTy of a ONce nightly formulation of sodium oxybate (REST-ON) trial post hoc analysis. METHODS: REST-ON (NCT02720744) was a Phase III, double-blind, placebo-controlled, multicenter, randomized clinical trial. Participants aged ≥16 years with narcolepsy type 1 (NT1) or NT2 received ON-SXB or placebo for 13 weeks (week 1, 4.5 g; weeks 2-3, 6 g; weeks 4-8, 7.5 g; and weeks 9-13, 9 g). Weight and body mass index were measured at baseline and study end. FINDINGS: Weights were similar between groups at baseline (mean [SD]; ON-SXB, 81.2 [20.8] kg; N = 107 [NT1, n = 80; NT2, n = 27]; placebo, 82.1 [22.5] kg; N = 105 [NT1, n = 82; NT2, n = 23]). At week 13 (9 g), mean (SD) weight decreased 1.3 (3.6) kg with ON-SXB and increased 0.2 (2.6) kg with placebo; 17.8% (19/107; NT1, n = 14; NT2, n = 5) of participants receiving ON-SXB had ≥5% weight loss versus 3.8% receiving placebo (4/105; NT1, n = 3; NT2, n = 1; P = 0.001). At week 13, least squares mean (SE) body mass index change from baseline was ‒0.51 (0.13) kg/m2 with ON-SXB and 0.08 (0.13) kg/m2 with placebo (least squares mean difference [95% CI], -0.59 [-0.95 to -0.23] kg/m2; P = 0.001). Excessive daytime sleepiness improved for both groups with ON-SXB, the ≥5% weight-loss subgroup exhibited larger improvement in the Maintenance of Wakefulness Test and Epworth Sleepiness Scale versus the other subgroup (weight loss <5%, no change, or weight gain) (Maintenance of Wakefulness Test, P = 0.019; Epworth Sleepiness Scale score, P < 0.001). IMPLICATIONS: Narcolepsy is often associated with obesity, which may increase cardiometabolic risks. ON-SXB, an effective treatment for excessive daytime sleepiness and cataplexy, may be preferred in overweight or obese individuals to provide a more tailored treatment approach. GOV IDENTIFIER: NCT02720744.

Improvements in daytime sleepiness and disrupted nighttime sleep with once-nightly sodium oxybate in people with narcolepsy type 1 and type 2: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a published article in the journal Sleep. Narcolepsy is a sleep condition that has 2 different subtypes: narcolepsy type 1 and narcolepsy type 2. These are called NT1 and NT2 for short. Sodium oxybate (SXB) is approved to treat excessive daytime sleepiness (EDS) and cataplexy. People with NT1 and NT2 both have EDS, but cataplexy is only present in people with NT1. Limited information is available about how SXB works in people with NT2. This is because previous trials have included only people with NT1 or people with unspecified narcolepsy. For more than 20 years, the only available formulation of this medicine had to be given twice during the night. Many people with narcolepsy find that chronically waking up in the middle of the night for a second dose of SXB is disruptive to themselves or others in their household. People have also reported sleeping through alarm clocks, missing their second dose, and feeling worse the next day. Some people have accidentally taken the second dose too early, putting them at risk for serious adverse effects. These adverse effects may include slow breathing, low blood pressure, or sedation. The US Food and Drug Administration (FDA) approved a medicine called LUMRYZ™ (sodium oxybate) for extended-release oral suspension in May 2023. LUMRYZ is a once-nightly formulation of SXB (ON-SXB for short) and is taken as a single dose before bedtime. This medicine treats EDS and muscle weakness (also known as cataplexy) in people with narcolepsy. A clinical trial called REST-ON studied ON-SXB to find out if it was better at treating narcolepsy symptoms than a medicine with no active ingredients (placebo). This summary describes a study that tested whether ON-SXB was better than placebo at treating narcolepsy symptoms in people with NT1 or NT2. WHAT WERE THE RESULTS?: This study showed that compared to people who took placebo, people who took ON-SXB were able to stay awake longer during the day, felt less sleepy during the daytime, had less cataplexy, and had more improvements in their symptoms overall than people who took placebo. WHAT DO THE RESULTS MEAN?: ON-SXB has been proven effective for people with NT1 or NT2. Unlike prior formulations of SXB, ON-SXB is taken once at bedtime, without requiring waking up in the middle of the night for a second dose.

"I know when to stop": Sentinels and counter-strategies against drowsy driving in narcolepsy and idiopathic hypersomnia.

STUDY OBJECTIVES: To collect prodromal symptoms experienced by participants with narcolepsy and idiopathic hypersomnia (considered "hypersomnolence experts") prior to drowsy driving and counter-strategies used to maintain alertness. METHODS: Systematic, face-to-face interview (using a semi-structured questionnaire), including clinical measures, frequency of car accidents/near misses, and symptoms experienced before impending drowsy driving episodes and counter-strategies. RESULTS: Among 61 participants (32 with narcolepsy, 29 with idiopathic hypersomnia; 56 drivers), 61% of drivers had at least one lifetime accident/near miss. They had a higher sleepiness score (14 ± 4 vs. 11 ± 5, P<0.04) than those without an accident/near miss, but no other differences in demographics, driving experience, medical conditions, symptoms, sleep tests, and treatment. All but three participants experienced prodromal symptoms of drowsy driving, which included postural and motor changes (86.9%: axial hypotonia - e.g., eyelid droop, stereotyped movements), cognitive impairment (53.3%: automatic steering, difficulty concentrating/shifting, dissociation, mind wandering, dreaming), sensory (65%: paresthesia, pain, stiffness, heaviness, blunted perceptions such as a flat dashboard with loss of 3D, illusions and hallucinations), and autonomic symptoms (10%, altered heart/breath rate, penile erection). Counterstrategies included self-stimulation from external sources (pain, cold air, music, drinks, driving with bare feet), motor changes (upright posture, movements), and surprise (sudden braking). CONCLUSIONS: Drowsy driving symptoms can result from "local" NREM, entry in N1 sleep, and hybrid wake/REM sleep states. These rich qualitative insights from participants with narcolepsy and idiopathic hypersomnia, as well as sophisticated counter-strategies, can be gathered to reduce the crash risk in this population, but also in inexperienced healthy drivers.

Online screening for excessive daytime sleepiness: a feasibility study.

Purpose: Excessive daytime sleepiness (EDS) can have a significant impact on health and quality of life but may remain undiagnosed due to low awareness and underestimation of the clinical impact of the symptoms. An online screening tool supported by media campaigns might increase awareness and help detect undiagnosed cases of EDS and narcolepsy. The aim of this study was to develop an online screening method, along with a media campaign focusing on EDS, and evaluate its feasibility. Methods: Online screening supported by a media campaign targeting young and middle-aged adults (18-45 years old) were developed and implemented over a period of 1 year starting from November 2022. The Epworth Sleepiness Scale was used to identify EDS, and the Swiss Narcolepsy Scale was used to identify narcolepsy. In addition, the data on sociodemographic characteristics, selected sleep and health indicators and lifestyle behaviors were collected to indicate the etiology of the EDS. Feasibility, e.g., implementation and practicality, was assessed by the response rate, response to the promotion strategy, time spent on the tool, sample characteristics, and the prevalence of identified EDS and narcolepsy cases. Results: A total of 2,390 people opened the screening link; 568 of them completed the online screening (23.8%), and most of them (n = 437, 76.9%) left their contact data to receive feedback. We identified 171 (30.1%) respondents at risk of EDS and 61 (10.7%) at risk of narcolepsy. The mean time of the screening was 15 min. Conclusion: An online screening tool supported with a campaign seems to be a feasible way to increase awareness about EDS and prevent delayed detection of EDS cases.

Loss of rapid eye movement atonia in rapid eye movement sleep behaviour disorder and narcolepsy.

A reduction of physiological muscle atonia during rapid eye movement sleep is characteristic in patients with rapid eye movement sleep behaviour disorder, however, it can also be found in narcolepsy patients. We evaluated rapid eye movement sleep associated electromyographic activity to set cut-off values of rapid eye movement sleep without atonia, differentiating rapid eye movement sleep behaviour disorder and narcolepsy patients from controls to enable more precise future diagnostic criteria for these disorders. We retrospectively analysed polysomnography recordings of 16 rapid eye movement sleep behaviour disorder patients, 15 narcolepsy patients, and 19 controls. The combination of phasic and tonic electromyographic activity was recorded in the mentalis and tibialis anterior muscles and analysed in 3 second miniepochs. The cut-off value for a diagnosis of rapid eye movement sleep behaviour disorder was 17.07% (100% sensitivity, 94.7% specificity, area under the curve 0.997). For the diagnosis of narcolepsy, we yielded a cut-off value of 8.4% (86.4% sensitivity, 68.4% specificity, area under the curve 0.850). Rapid eye movement sleep without atonia significantly (p = 0.046) increased in the second night half in rapid eye movement sleep behaviour disorder patients, while it remained moderately increased in the narcolepsy group. Polysomnographic evaluation proves significantly higher rates of rapid eye movement sleep without atonia in rapid eye movement sleep behaviour disorder than in narcolepsy patients, allowing differentiation from controls with high sensitivity and specificity. An increase throughout the night is characteristic for rapid eye movement sleep behaviour disorder, whereas a consistent elevation is typical in narcolepsy patients.