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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.

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Narcolepsy is a sleep disorder caused by an apparent degeneration of orexin/hypocretin neurons in the lateral hypothalamic area and a subsequent decrease in orexin/hypocretin levels in the cerebrospinal fluid. Narcolepsy is classified into type 1 (NT1) and type 2 (NT2). While genetic associations in the human leukocyte antigen (HLA) region and candidate autoantibodies have been investigated in NT1 to imply an autoimmune origin, less is known about the pathogenesis in NT2. Twenty-six NT1 and 15 NT2 patients were included, together with control groups of 24 idiopathic hypersomnia (IH) patients and 778 general population participants. High-resolution sequencing was used to determine the alleles, the extended haplotypes, and the genotypes of HLA-DRB3, -DRB4, -DRB5, -DRB1, -DQA1, -DQB1, -DPA1, and -DPB1. Radiobinding assay was used to determine autoantibodies against hypocretin receptor 2 (anti-HCRTR2 autoantibodies). NT1 was associated with HLA-DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01, -DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01 (odds ratio [OR]: 9.15; p = 8.31 × 10-4) and HLA-DRB5*01:01:01, -DRB1*15:01:01, -DQA1*01:02:01, -DQB1*06:02:01, -DRB4*01:03:01, -DRB1*04:01:01, -DQA1*03:02//03:03:01, -DQB1*03:01:01 (OR: 23.61; p = 1.58 × 10-4) genotypes. Lower orexin/hypocretin levels were reported in the NT2 subgroup (n = 5) that was associated with the extended HLA-DQB1*06:02:01 haplotype (p = .001). Anti-HCRTR2 autoantibody levels were not different between study groups (p = .8524). We confirmed the previous association of NT1 with HLA-DQB1*06:02:01 extended genotypes. A subgroup of NT2 patients with intermediate orexin/hypocretin levels and association with HLA-DQB1*06:02:01 was identified, indicating a possible overlap between the two distinct narcolepsy subtypes, NT1 and NT2. Low anti-HCRTR2 autoantibody levels suggest that these receptors might not function as autoimmune targets in either NT1 or NT2.

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STUDY OBJECTIVES: Narcolepsy type 2 (NT2) is an understudied central disorder of hypersomnolence sharing some similarities with narcolepsy type 1 and idiopathic hypersomnia (IH). We aimed: (1) to assess systematically the symptoms in patients with NT2, with self-reported questionnaires: Epworth Sleepiness Scale (ESS), Narcolepsy Severity Scale (NSS), IH Severity Scale (IHSS), and (2) to evaluate the responsiveness of these scales to treatment. METHODS: One hundred and nine patients with NT2 (31.4 ±â€…12.2 years old, 47 untreated) diagnosed according to ICSD-3 were selected in a Reference Center for Narcolepsy. They all completed the ESS, subgroups completed the modified NSS (NSS-2, without cataplexy items) (n = 95) and IHSS (n = 76). Some patients completed the scales twice (before/during treatment): 42 ESS, 26 NSS-2, and 30 IHSS. RESULTS: Based on NSS-2, all untreated patients had sleepiness, 58% disrupted nocturnal sleep, 40% hallucinations, and 28% sleep paralysis. On IHSS, 76% reported a prolonged nocturnal sleep, and 83% sleep inertia. In the independent sample, ESS and NSS-2 scores were lower in treated patients, with same trend for IHSS scores. After treatment, ESS, NSS-2, and IHSS total scores were lower, with a mean difference of 3.7 ±â€…4.1, 5.3 ±â€…6.7, and 4.1 ±â€…6.2, respectively. The minimum clinically important difference between untreated and treated patients were 2.1 for ESS, 3.3 for NSS-2, and 3.1 for IHSS. After treatment, 61.9% of patients decreased their ESS > 2 points, 61.5% their NSS-2 > 3 points, and 53.3% their IHSS > 3 points. CONCLUSIONS: NSS-2 and IHSS correctly quantified symptoms' severity and consequences in NT2, with good performances to objectify response to medications. These tools are useful for monitoring and optimizing NT2 management, and for use in clinical trials.

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In recent years, there has been an increased interest in elucidating the influence of the gut microbiota on sleep physiology. The gut microbiota affects the central nervous system by modulating neuronal pathways through the neuroendocrine and immune system, the hypothalamus-pituitary-adrenal axis, and various metabolic pathways. The gut microbiota can also influence circadian rhythms. In this study, we observed the gut microbiota composition of patients suffering from narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. We did not observe any changes in the alpha diversity of the gut microbiota among patient groups and healthy controls. We observed changes in beta diversity in accordance with Jaccard dissimilarities between the control group and groups of patients suffering from narcolepsy type 1 and idiopathic hypersomnia. Our results indicate that both these patient groups differ from controls relative to the presence of rare bacterial taxa. However, after adjustment for various confounding factors such as BMI, age, and gender, there were no statistical differences among the groups. This indicates that the divergence in beta diversity in the narcolepsy type 1 and idiopathic hypersomnia groups did not arise due to sleep disturbances. This study implies that using metabolomics and proteomics approaches to study the role of microbiota in sleep disorders might prove beneficial.

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Narcolepsy type 1 (NT1) and type 2 (NT2), also known as narcolepsy with and without cataplexy, are sleep disorders that benefited from major scientific advances over the last two decades. NT1 is caused by the loss of hypothalamic neurons producing orexin/hypocretin, a neurotransmitter regulating sleep and wake, which can be measured in the cerebrospinal fluid (CSF). A low CSF level of hypocretin-1/orexin-A is a highly specific and sensitive biomarker, sufficient to diagnose NT1. Orexin-deficiency is responsible for the main NT1 symptoms: sleepiness, cataplexy, disrupted nocturnal sleep, sleep-related hallucinations, and sleep paralysis. In the absence of a lumbar puncture, the diagnosis is based on neurophysiological tests (nocturnal and diurnal) and the presence of the pathognomonic symptom cataplexy. In the revised version of the International Classification of sleep Disorders, 3rd edition (ICSD-3-TR), a sleep onset rapid eye movement sleep (REM) period (SOREMP) (i.e. rapid occurrence of REM sleep) during the previous polysomnography may replace the diurnal multiple sleep latency test, when clear-cut cataplexy is present. A nocturnal SOREMP is very specific but not sensitive enough, and the diagnosis of cataplexy is usually based on clinical interview. It is thus of crucial importance to define typical versus atypical cataplectic attacks, and a list of clinical features and related degrees of certainty is proposed in this paper (expert opinion). The time frame of at least three months of evolution of sleepiness to diagnose NT1 was removed in the ICSD-3-TR, when clear-cut cataplexy or orexin-deficiency are established. However, it was kept for NT2 diagnosis, a less well-characterized disorder with unknown clinical course and absence of biolo biomarkers; sleep deprivation, shift working and substances intake being major differential diagnoses. Treatment of narcolepsy is nowadays only symptomatic, but the upcoming arrival of non-peptide orexin receptor-2 agonists should be a revolution in the management of these rare sleep diseases.

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OBJECTIVE/BACKGROUND: Evaluation of hypersomnolence disorders ideally includes an assessment of vigilance using the short Sustained Attention to Response Task (SART). We evaluated whether this task can differentiate between hypersomnolence disorders, whether it correlates with subjective and objective sleepiness, whether it is affected by the time of day, and symptoms of anxiety and depression. PATIENTS/METHODS: We analyzed diagnostic data of 306 individuals with hypersomnolence complaints diagnosed with narcolepsy type 1 (n=100), narcolepsy type 2 (n=20), idiopathic hypersomnia (n=49), obstructive sleep apnea (n=27) and other causes or without explanatory diagnosis (n=110). We included the Multiple Sleep Latency Test (MSLT), polysomnography, Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale and SART, which were administered five times during the day (outcomes: reaction time, total, commission and omission errors). RESULTS: The SART outcomes did not differ between groups when adjusted for relevant covariates. Higher ESS scores were associated with longer reaction times and more commission errors (p<.01). The main outcome, total errors, did not differ between times of the day. Reaction times and omission errors were impacted (p<.05). CONCLUSIONS: The SART quantifies disturbed vigilance, an important dimension of disorders of hypersomnolence. Results do not suggest that depressive symptoms influence SART outcomes. A practice session is advised. Testing time should be taken into account when interpreting results. We conclude that the SART does not differentiate between central disorders of hypersomnolence. It may be a helpful addition to the standard diagnostic workup and monitoring of these disorders.

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STUDY OBJECTIVES: Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2). METHODS: Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 4-8; and 9 g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups. RESULTS: The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2. CONCLUSIONS: Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.

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OBJECTIVE: The complexity and delay of the diagnosis of narcolepsy require several diagnostic tests and invasive procedures such as lumbar puncture. Our study aimed to determine the changes in muscle tone (atonia index, AI) at different levels of vigilance during the entire multiple sleep latency test (MSLT) and each nap in people with narcolepsy type 1 (NT1) and 2 (NT2) compared with other hypersomnias and its potential diagnostic value. METHODS: Twenty-nine patients with NT1 (11 M 18F, mean age 34.9 years, SD 16.8) and sixteen with NT2 (10 M 6F, mean age 39 years, SD 11.8) and 20 controls with other hypersomnias (10 M, 10F mean age 45.1 years, SD 15.1) were recruited. AI was evaluated at different levels of vigilance (Wake and REM sleep) in each nap and throughout the MSLT of each group. The validity of AI in identifying patients with narcolepsy (NT1 and NT2) was analyzed using receiver operating characteristic (ROC) curves. RESULTS: AI during wakefulness (WAI) was significantly higher in the narcolepsy groups (NT1 and NT2 p < 0.001) compared to the hypersomniac group. AI during REM sleep (RAI) (p = 0.03) and WAI in nap with sudden onsets of REM sleep periods (SOREMP) (p = 0.001) were lower in NT1 than in NT2. The ROC curves showed high AUC values for WAI (NT1 0.88; Best Cut-off > 0.57, Sensitivity 79.3 % Specificity 90 %; NT2 0.89 Best Cut-off > 0.67 Sensitivity 87.5 % Specificity 95 %; NT1 and NT2 0.88 Best Cut-off > 0.57 Sensitivity 82.2 % Specificity 90 %) in discriminating subjects suffering from other hypersomnias. RAI and WAI in nap with SOREMP showed a poor AUC value (RAI AUC: 0.7 Best cutoff 0.7 Sensitivity 50 % Specificity 87.5 %; WAI in nap before SOREMP AUC: 0.66, Best cut-off < 0.82 sensitivity 61.9 % and specificity 67.35 %) differentiating NT1 and NT2. CONCLUSIONS: WAI may represent an encouraging electrophysiological marker of narcolepsy and suggests a vulnerable tendency to dissociative wake / sleep dysregulation lacking in other forms of hypersomnia. SIGNIFICANCE: AI during wakefulness may help distinguish between narcolepsy and other hypersomnias.

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Herein we focus on connections between genetics and some central disorders of hypersomnolence - narcolepsy types 1 and 2 (NT1, NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS) - for a better understanding of their etiopathogenetic mechanisms and a better diagnostic and therapeutic definition. Gene pleiotropism influences neurological and sleep disorders such as hypersomnia; therefore, genetics allows us to uncover common pathways to different pathologies, with potential new therapeutic perspectives. An important body of evidence has accumulated on NT1 and IH, allowing a better understanding of etiopathogenesis, disease biomarkers, and possible new therapeutic approaches. Further studies are needed in the field of epigenetics, which has a potential role in the modulation of biological specific hypersomnia pathways.

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We analysed the co-existence of psychopathology in patients with narcolepsy at our centre. We performed an observational retrospective descriptive analysis of patients with a diagnosis of narcolepsy, with and without psychopathology, who attended our sleep disorders unit from October 2012 to October 2021. A total of 51patients with narcolepsy (mean [SD] age 41.10 [14.71] years; 23 [45.1%] males and 28 [54.90%] females) were included. In all, 27 patients (52.94%) and 24 patients (47.06%) had narcolepsy with and without cataplexy, respectively. Of the total, 18 (33.33%) had a mood disorder: 18 with anxiety disorder (33.33%). Of these patients 14 (27.45%) had major depression, two (4%) had attempted suicide, one (2%) had manic outbreak, and one (2%) had substance abuse. Of the 18 patients with anxiety and depression, 10 (55.55%) and eight (44.44%) had narcolepsy with and without cataplexy, respectively. In the comparative analysis, a statistically significant relationship was found between younger age and the presence of anxiety. The prevalence of anxiety and depression in patients with narcolepsy was triple that of the general population, especially in younger patients. Psychopathology precedes the diagnosis of narcolepsy in most patients, not being reactive to diagnosis. This high prevalence suggests a possible biological relationship between both disorders, which should be assessed with larger studies.

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Non-sleep symptoms, as depression, anxiety and overweight, are often encountered in narcoleptic patients. The purposes of this study are to evaluate mood, impulsiveness, emotion, alexithymia, and eating behavior in patients with narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) compared to healthy controls and to investigate possible correlations between clinical-demographic data, polysomnographic parameters, and subjective questionnaires. Consecutive patients affected by NT1 and NT2 underwent to Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 Scale, Barratt Impulsivity Scale-11, Difficulties in Emotion Regulation Scale, Toronto Alexithymia Scale, and Eating Disorder Evaluation Questionnaire. Daytime sleepiness was assessed using Epworth sleepiness score. Data were compared with controls. Fourteen NT1, 10 NT2, and 24 healthy subjects were enrolled. Toronto Alexithymia Scale total score was significantly higher in NT1 than NT2. Compared to controls, NT1 patients exhibited significantly higher scores at Patient Health Questionnaire-9 and Difficulties in Emotion Regulation Scale. A positive correlation between hypnagogic hallucinations and Difficulties in emotion regulation was found. NT1 and NT2 share several psycho-emotional aspects, but whereas NT1 patients exhibit more depressive mood and emotion dysregulation compared to controls, alexithymic symptoms are more prominent in NT1 than NT2. Hypnagogic hallucinations, emotion dysregulation, and alexithymia appear to be correlated, supporting the hypothesis of mutual interaction of the above areas in narcolepsy.

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This article addresses the clinical presentation, diagnosis, pathophysiology and management of narcolepsy type 1 and 2, with a focus on recent findings. A low level of hypocretin-1/orexin-A in the cerebrospinal fluid is sufficient to diagnose narcolepsy type 1, being a highly specific and sensitive biomarker, and the irreversible loss of hypocretin neurons is responsible for the main symptoms of the disease: sleepiness, cataplexy, sleep-related hallucinations and paralysis, and disrupted nocturnal sleep. The process responsible for the destruction of hypocretin neurons is highly suspected to be autoimmune, or dysimmune. Over the last two decades, remarkable progress has been made for the understanding of these mechanisms that were made possible with the development of new techniques. Conversely, narcolepsy type 2 is a less well-defined disorder, with a variable phenotype and evolution, and few reliable biomarkers discovered so far. There is a dearth of knowledge about this disorder, and its aetiology remains unclear and needs to be further explored. Treatment of narcolepsy is still nowadays only symptomatic, targeting sleepiness, cataplexy and disrupted nocturnal sleep. However, new psychostimulants have been recently developed, and the upcoming arrival of non-peptide hypocretin receptor-2 agonists should be a revolution in the management of this rare sleep disease, and maybe also for disorders beyond narcolepsy.

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Narcolepsy types 1 (NT1) and 2 (NT2) and idiopathic hypersomnia (IH) are thought to be a disease continuum known as narcolepsy spectrum disorders (NSDs). This study aimed to assess the prevalence of and factors associated with metabolic-syndrome-related disorders (MRDs) among patients with NSD. Japanese patients with NSD (NT1, n = 94; NT2, n = 83; and IH, n = 57) aged ≥35 years were enrolled in this cross-sectional study. MRD was defined as having at least one of the following conditions: hypertension, diabetes, or dyslipidemia. Demographic variables and MRD incidence were compared among patients in the respective NSD categories. Multivariate logistic regression analysis was used to investigate the factors associated with MRDs. Patients with NT1 had a higher body mass index (BMI) and incidence of MRD than that had by those with NT2 or IH. Age, BMI, and the presence of OSA were significantly associated with the incidence of MRD in NSDs. Age and BMI in NT1, BMI and human leukocyte antigen (HLA)-DQB1*06:02 positivity in NT2, and only age in IH were factors associated with the incidence of MRD. Obesity should be carefully monitored in narcolepsy; however, NT2 with HLA-DQB1*06:02 positive should be followed up for the development of MRD even without obesity.

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Idiopathic hypersomnia was first described in 1976 under two forms: polysymptomatic, characterized by excessive daytime sleepiness, long and unrefreshing naps, nocturnal sleep of abnormally long duration and signs of sleep drunkenness upon awakening; monosymptomatic, manifested by excessive daytime sleepiness only. Yet, after 45 years, this sleep disorder is still poorly delineated and diagnostic criteria produced by successive International Classifications of Sleep Disorders are far from satisfactory. The first part of this review is a historical account of the successive names and descriptions of idiopathic hypersomnia: monosymptomatic and polysymptomatic idiopathic hypersomnia in 1976; central nervous system idiopathic hypersomnia in 1979; idiopathic hypersomnia in 1990; idiopathic hypersomnia with and without long sleep time in 2005; idiopathic hypersomnia again in 2014; and, within the last few years, the proposal of separating idiopathic hypersomnia into a well-defined subtype, idiopathic hypersomnia with long sleep duration, and a more heterogeneous subtype combining idiopathic hypersomnia without long sleep duration and narcolepsy type 2. The second part is a critical review of both current ICSD-3 diagnostic criteria and clinical features, scales and questionnaires, electrophysiological and circadian control tests, research techniques, currently used to diagnose idiopathic hypersomnia. The third part proposes a diagnostic evaluation of idiopathic hypersomnia, in the absence of biologic markers and of robust electrophysiological diagnostic criteria.

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BACKGROUND: Narcolepsy is marked by pathologic symptoms including excessive daytime drowsiness and lethargy, even with sufficient nocturnal sleep. There are two types of narcolepsy: type 1 (with cataplexy) and type 2 (without cataplexy). Unlike type 1, for which hypocretin is a biomarker, type 2 narcolepsy has no adequate biomarker to identify the causality of narcoleptic phenomenon. Therefore, we aimed to establish new biomarkers for narcolepsy using the body's systemic networks. METHOD: Thirty participants (15 with type 2 narcolepsy, 15 healthy controls) were included. We used the time delay stability (TDS) method to examine temporal information and determine relationships among multiple signals. We quantified and analyzed the network connectivity of nine biosignals (brainwaves, cardiac and respiratory information, muscle and eye movements) during nocturnal sleep. In particular, we focused on the differences in network connectivity between groups according to sleep stages and investigated whether the differences could be potential biomarkers to classify both groups by using a support vector machine. RESULT: In rapid eye movement sleep, the narcolepsy group displayed more connections than the control group (narcolepsy connections: 24.47 ± 2.87, control connections: 21.34 ± 3.49; p = 0.022). The differences were observed in movement and cardiac activity. The performance of the classifier based on connectivity differences was a 0.93 for sensitivity, specificity and accuracy, respectively. CONCLUSION: Network connectivity with the TDS method may be used as a biomarker to identify differences in the systemic networks of patients with narcolepsy type 2 and healthy controls.

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Central disorders of hypersomnolence (CDH) are characterized by excessive daytime sleepiness not related to comorbid sleep or medical disturbances. We systematically examined scientific literature on cognitive functions in patients suffering from CDH. Forty-eight studies proved eligible and were analyzed separately for Narcolepsy Type 1 (NT1), Narcolepsy Type 2 (NT2), Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS). Results were grouped into the cognitive domains of attention, memory, executive functions and higher order cognition. Consistent attention impairments emerged in NT1, NT2 and IH patients, with NT1 patients showing the most compromised profile. Memory functions are largely unimpaired in CDH patients except for KLS patients who display memory deficit. Executive functions and higher-order cognition have been assessed in NT1 while they received little-to-no attention in the other CDH. NT1 patients display high performance in executive functions but exhibit a complex pattern of impairment in higher-order cognition, showing poor decision-making and impaired emotional processing. Moreover, NT1 patients show increased creative abilities. Assessing and monitoring cognitive impairments experienced by CDH patients will allow the design of personalized interventions, parallel to pharmacological treatment, aimed at improving daytime functioning and quality of life of these patients.

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BACKGROUND: There are limited data available on regional differences in the diagnosis and management of narcolepsy. In order to better understand worldwide trends in clinical assessment and management of narcolepsy, a survey of health-care providers was conducted by the World Sleep Society Narcolepsy task force. METHODS: A total of 146 surveys that included items on the diagnosis and management of narcolepsy were completed by practitioners representing 37 countries. RESULTS: Most of the participants were from Europe, North America, Oceania, Asia and Latin America. A consistent approach to applying the diagnostic criteria of Narcolepsy was documented with the exception of measurement of CSF hypocretin-1, which has limited availability. While the majority of practitioners (58%) reported not using the test, 1% indicated always evaluating CSF hypocretin-1 levels. There was much variability in the availability of currently recommended medications such as sodium oxybate and pitolisant; modafinil and antidepressants were the most commonly used medications. Amphetamines were unavailable in some countries. CONCLUSION: The results of the study highlight clinical and therapeutic realities confronted by worldwide physicians in the management of narcolepsy. While the diagnostic criteria of narcolepsy rely in part on the quantification of CSF hypocretin-1, few physicians reported having incorporated this test into their routine assessment of the condition. Regional differences in the management of narcolepsy appeared to be related to geographic availability and expense of the therapeutic agents.

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BACKGROUND: Endocannabinoids (ECs) modulate both excitatory and inhibitory components in the CNS. There is a growing body of evidence that shows ECs influence both hypothalamic orexinergic and histaminergic neurons involved in narcolepsy physiopathology. Therefore, ECs may influence sleep and sleep-wake cycle. OBJECTIVE: To evaluate EC levels in the CSF of untreated narcoleptic patients to test whether ECs are dysregulated in Narcolepsy Type 1 (NT1) and Type 2 (NT2). METHODS: We compared CSF Anandamide (AEA), 2-Arachidonoylglycerol (2-AG) and orexin in narcoleptic drug-naïve patients and in a sample of healthy subjects. RESULTS: We compared NT1 (n=6), NT2 (n=6), and healthy controls (n=6). We found significantly reduced AEA levels in NT1 patients compared to both NT2 and controls. No differences were found between AEA levels in NT2 versus controls and between 2-AG levels in all groups, although a trend toward a decrease in NT1 was evident. Finally, the CSF AEA level was related to CSF orexin levels in all subjects. CONCLUSION: We demonstrated that the EC system is dysregulated in NT1.

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Narcolepsy type 1 (NT1) is a chronic orphan disorder, caused by the selective and irreversible loss of hypocretin/orexin (ORX) neurons, by a probable autoimmune process. Little is known about NT2 etiology and prevalence, sharing with NT1 excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep, but without cataplexy and loss of ORX neurons. Despite major advances in our understanding of the neurobiological basis of NT1, management remains nowadays only symptomatic. The main and most disabling symptom, EDS, is managed with psychostimulants, as modafinil/armodafinil, methylphenidate, or amphetamines as a third-line therapy. Narcolepsy is an active area for drug development, and new wake-promoting agents have been developed over the past years. Pitolisant, a selective histamine H3 receptor inverse agonist, has been recently approved to treat patients with NT1 and NT2. Solriamfetol, a phenylalanine derivative with dopaminergic and noradrenergic activity will be soon a new therapeutic option to treat EDS in NT1 and NT2. Sodium oxybate, used for decades in adult patients with narcolepsy, was recently shown to be effective and safe in childhood narcolepsy. The discovery of ORX deficiency in NT1 opened new therapeutic options oriented towards ORX-based therapies, especially nonpeptide ORX receptor agonists that are currently under development. In addition, immune-based therapies administered as early as possible after disease onset could theoretically slow down or stop the destruction of ORX neurons in some selected patients. Further well-designed controlled trials are required to determine if they could really impact on the natural history of the disease. Given the different clinical, biological and genetic profiles, narcolepsy may provide a nice example for developing personalized medicine in orphan diseases, that could ultimately aid in similar research and clinical efforts for other conditions.

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INTRODUCTION: Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since hypocretin deficiency is assumed to be the main cause of narcoleptic symptoms, hypocretin replacement will be the most essential treatment for narcolepsy. Unfortunately, this option is still not available clinically. There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy. Together with these options, immunotherapy treatments to prevent hypocretin neuronal death should also be developed. AREAS COVERED: In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments. EXPERT OPINION: Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models. If this option is effective in humans, hypocretin cell transplants or gene therapy technology may become realistic in the future.

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