[Idiopathic hypersomnia: a kind of sleep disorder that cannot be ignored].

Idiopathic hypersomnia(IH) is a chronic central disorders of hypersomnolence that manifests as excessive daytime sleepiness occurring despite normal or prolonged sleep time. Due to the individual heterogeneity of disease, the high overlap of clinical, poor repeatability of polysomnography monitoring results and the lack of clear disease biomarkers, clinical diagnosis and differential diagnosis are still difficult. This article summarizes the update of diagnostic criteria, clinical manifestations, diagnosis and treatment strategies of IH, in order to receive attention, increase the recognition rate of clinical diagnosis, reduce the misdiagnosis rate and missed diagnosis rate.

Validation and performance of the sleep inertia questionnaire in central disorders of hypersomnolence.

BACKGROUND: Optimal measurement tools for problematic sleep inertia, common in some central disorders of hypersomnolence (CDH), have not yet been determined. We evaluated the performance of the Sleep Inertia Questionnaire (SIQ) in CDH, and how well it distinguished hypersomnolent groups from controls, and IH (idiopathic hypersomnia) from narcolepsy type 1 (NT1). METHODS: This prospective, bi-centric study included 63 control, 84 IH, 16 NT1, 18 narcolepsy type 2 (NT2), and 88 subjective excessive daytime sleepiness (sEDS) participants, using ICSD-3 criteria. 126 (47.2 %) participants were on any medication at the time of SIQ completion. We assessed construct validity of SIQ scores, and sleep inertia duration (SID), and compared them across diagnoses, controlling for age and center. We derived cutpoints to distinguish hypersomnolent patients from controls and IH from NT1. Sensitivity analyses for depression, chronotype, and medication were performed. RESULTS: The SIQ sum and composite score were significantly lower in controls than in other groups (p < 0.0001), demonstrating outstanding ability to distinguish patients from controls (AUCs 0.92), without differences among hypersomnolent groups. SID (AUC 0.76) was significantly shorter in controls than in all hypersomnolent groups except NT1, and was shorter in NT1 than in IH or sEDS. Optimal SIQ sum cutpoint was 42 (J = 0.71) for patients versus controls. Optimal SID cutpoint in distinguishing IH from NT1 was 25 min (J = 0.39). CONCLUSION: The SIQ has excellent ability to distinguish hypersomnolent patients from healthy controls, after controlling for depression, eveningness, and medication. SID is best at distinguishing IH from NT1.

Sleep architecture in idiopathic hypersomnia: the influence of age, sex, and body mass index.

This study aimed to progress the understanding of idiopathic hypersomnia (IH) by assessing the moderating influence of individual characteristics, such as age, sex, and body mass index (BMI) on sleep architecture. In this retrospective study, 76 IH participants (38.1 ± 11.3 years; 40 women) underwent a clinical interview, an in-laboratory polysomnography with a maximal 9-h time in bed and a multiple sleep latency test (MSLT). They were compared to 106 healthy controls (38.1 ± 14.1 years; 60 women). Multiple regressions were used to assess moderating influence of age, sex, and BMI on sleep variables. We used correlations to assess whether sleep variables were associated with Epworth Sleepiness Scale scores and mean sleep onset latency on the MSLT in IH participants. Compared to controls, IH participants had shorter sleep latency (p = 0.002), longer total sleep time (p < 0.001), more time spent in N2 sleep (p = 0.008), and showed trends for a higher sleep efficiency (p = 0.023) and more time spent in rapid eye movement (REM) sleep (p = 0.022). No significant moderating influence of age, sex, or BMI was found. More severe self-reported sleepiness in IH patients was correlated with shorter REM sleep latency and less N1 sleep in terms of proportion and duration (ps < 0.01). This study shows that, when compared to healthy controls, patients with IH had no anomalies in their sleep architecture that can explain their excessive daytime sleepiness. Moreover, there is no moderating influence of age, sex, and BMI, suggesting that the absence of major group differences is relatively robust.

Clinical considerations in the treatment of idiopathic hypersomnia.

Idiopathic hypersomnia typically is a chronic and potentially debilitating neurologic sleep disorder, and is characterized by excessive daytime sleepiness. In addition to excessive daytime sleepiness, idiopathic hypersomnia symptoms can include severe sleep inertia; long, unrefreshing naps; long sleep time; and cognitive dysfunction. Patients with idiopathic hypersomnia may experience a significant impact on their quality of life, work or school performance, earnings, employment, and overall health. Given the complex range of symptoms associated with idiopathic hypersomnia and the array of treatments available, there is a need to provide guidance on the treatment of idiopathic hypersomnia and the clinically relevant recommendations that enhance effective disease management. Identifying appropriate treatment options for idiopathic hypersomnia requires timely and accurate diagnosis, consideration of individual patient factors, and frequent reassessment of symptom severity. In 2021, low-sodium oxybate was the first treatment to receive approval by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. However, many off-label treatments continue to be used. Adjunct nonpharmacologic therapies, including good sleep hygiene, patient education and counseling, and use of support groups, should be recognized and recommended when appropriate. This narrative review describes optimal treatment strategies that take into account patient-specific factors, as well as the unique characteristics of each medication and the evolution of a patient's response to treatment. Perspectives on appropriate symptom measurement and management, and potential future therapies, are also offered.

Potential immunological triggers for narcolepsy and idiopathic hypersomnia: Real-world insights on infections and influenza vaccinations.

OBJECTIVE: It is hypothesized that narcolepsy type 1 (NT1) develops in genetically susceptible people who encounter environmental triggers leading to immune-mediated hypocretin-1 deficiency. The pathophysiologies of narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) remain unknown. The main aim of this study was to collect all reported immunological events before onset of a central disorder of hypersomnolence. METHODS: Medical records of 290 people with NT1, and 115 with NT2 or IH were retrospectively reviewed to extract infection and influenza vaccination history. Prevalence, distribution of immunological events, and time until hypersomnolence onset were compared between NT1 and the combined group of NT2 and IH. RESULTS: Immunological events were frequently reported before hypersomnolence disorder onset across groups. Flu and H1N1 influenza vaccination were more common in NT1, and Epstein-Barr virus and other respiratory and non-respiratory infections in NT2 and IH. Distributions of events were comparable between NT2 and IH. Rapid symptom onset within one month of infection was frequent across groups, especially after flu infection in NT1. Hypersomnolence disorder progression after an immunological event was reported in ten individuals. CONCLUSIONS: Our findings suggest a variety of immunological triggers potentially related to NT1, including H1N1 influenza infection or vaccination, infection with other flu types, and other respiratory and non-respiratory infections. Frequent reports of immunological events (other than those reported in NT1) immediately prior to the development of NT2 and IH support the specificity of triggers for NT1, and open important new research avenues into possible underlying immunological mechanisms in NT2 and IH.

Idiopathic hypersomnia with a video recording of a spontaneous sleep attack: A case report.

RATIONALE: Although patients with central disorders of hypersomnolence (CDH) exhibit characteristic symptoms of hypersomnia frequently, it takes 5 to 15 years from the onset for its diagnosis due to the lack of symptom recognition. Here, we present a case of idiopathic hypersomnia (IH), a CDH, wherein early diagnosis was aided by a video footage of a spontaneous sleep attack. PATIENT CONCERNS: A 21-year-old man lost consciousness while driving and experienced an accident. He had complained of excessive daytime sleepiness (EDS) over half a year. During his hospitalization for close monitoring of the loss of consciousness, an in-room surveillance camera captured a 14-minutes long spontaneous sleep attack, during which he experienced general muscle weakness and loss of consciousness without warnings or convulsions leading to a fall from the bed. There were no abnormalities in vital signs. DIAGNOSES: There was no significant cataplexy and less than 2 sleep-onset rapid eye movements (SOREM) in 2 sleep latency tests, with a mean sleep latency of 2.1 and 4.6 minutes. Other sleep deprivation syndromes were excluded from differential diagnosis and finally, a diagnosis of IH was confirmed according to the criteria of the Third Edition of the International Classification of Sleep Disorders. During the course of the disease, attention-deficit/hyperactive disorder (ADHD) and a gaming disorder also diagnosed. INTERVENTIONS: Pharmacological treatment with modafinil was administered for IH and methylphenidate for ADHD. Cognitive behavioral therapy was performed for the gaming disorder. OUTCOMES: The EDS improved, and sleep attacks were no longer observed. The disruption of daily life caused by the gaming disorder was also reduced. LESSONS: Video recordings of sleep attacks are beneficial for identifying the cause of loss of consciousness. Home video recordings may be helpful in the early diagnosis of IH.

Long sleep time and excessive need for sleep: State of the art and perspectives.

The mechanisms underlying the individual need for sleep are unclear. Sleep duration is indeed influenced by multiple factors, such as genetic background, circadian and homeostatic processes, environmental factors, and sometimes transient disturbances such as infections. In some cases, the need for sleep dramatically and chronically increases, inducing a daily-life disability. This "excessive need for sleep" (ENS) was recently proposed and defined in a European Position Paper as a dimension of the hypersomnolence spectrum, "hypersomnia" being the objectified complaint of ENS. The most severe form of ENS has been described in Idiopathic Hypersomnia, a rare neurological disorder, but this disabling symptom can be also found in other hypersomnolence conditions. Because ENS has been defined recently, it remains a symptom poorly investigated and understood. However, protocols of long-term polysomnography recordings have been reported by expert centers in the last decades and open the way to a better understanding of ENS through a neurophysiological approach. In this narrative review, we will 1) present data related to the physiological and pathological variability of sleep duration and their mechanisms, 2) describe the published long-term polysomnography recording protocols, and 3) describe current neurophysiological tools to study sleep microstructure and discuss perspectives for a better understanding of ENS.

Is there a role for repeating the multiple sleep latency test across childhood when initially non-diagnostic?

BACKGROUND: The gold standard investigation for central disorders of hypersomnolence is the Multiple Sleep Latency Test (MSLT). As the clinical features of these disorders of hypersomnolence evolve with time in children, clinicians may consider repeating a previously non-diagnostic MSLT. Currently there are no guidelines available regards the utility and timing of repeating paediatric MSLTs. METHODS: Retrospective review of children aged 3-18years with ≥2MSLTs between 2005 and 2022. Narcolepsy was defined as mean sleep latency (MSL) <8min with ≥2 sleep onset REM (SOREM); idiopathic hypersomnia (IH) was defined as MSL <8min with <2 SOREM. MSLTs not meeting these criteria were labelled non-diagnostic. RESULTS: 19 children (9 female) with initial non-diagnostic MSLT underwent repeat MSLT, with 6 proceeding to a 3rd MSLT following 2 non-diagnostic MSLTs. The 2nd MSLT resulted in diagnosis in 6/19 (32 %) (3 narcolepsy, 3 IH); and 2/6 (33 %) 3rd MSLT were diagnostic (2 IH). Median age at initial MSLT was 7.5y (range 3.4-17.8y), with repeat performed after median of 2.9y (range 0.9-8.2y), and 3rd after a further 1.9 years (range 1.2-4.2y). Mean change in MSL on repeat testing was -2min (range -15.5min to +4.9min, p = 0.18). Of the 8 diagnostic repeat MSLTs, in addition to the MSL falling below 8 min, 2 children also developed ≥2 SOREM that had not been previously present. CONCLUSIONS: A third of repeat MSLTs became diagnostic, suggesting repeat MSLT should be considered in childhood if clinical suspicion persists. Further work needs to address the ideal interval between MSLTs and diagnostic cut-points specific to the paediatric population.

Narcolepsy Severity Scale-2 and Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and consequences in Narcolepsy type 2.

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.

Prevalence and Course of Idiopathic Hypersomnia in the Wisconsin Sleep Cohort Study.

BACKGROUND AND OBJECTIVES: Idiopathic hypersomnia (IH) is a CNS disorder of hypersomnolence of unknown etiology. Due to the requirement for objective sleep testing to diagnose the disorder, there are currently no population-based estimates of the prevalence of IH nor data regarding the longitudinal course of IH in naturalistic settings. METHODS: Subjective and objective data from the Wisconsin Sleep Cohort study were used to identify cases with probable IH from participants with polysomnography and multiple sleep latency test data. Demographic, polysomnographic, and symptom-level data were compared between those with and without IH. Longitudinal trajectories of daytime sleepiness among those with IH were assessed to evaluate symptom persistence or remission over time. RESULTS: From 792 cohort study participants with available polysomnography and multiple sleep latency test data, 12 cases with probable IH were identified resulting in an estimated prevalence of IH of 1.5% (95% CI 0.7-2.5, p < 0.0001). Consistent with inclusion/exclusion criteria, cases with IH had more severe sleepiness and sleep propensity, despite similar or longer sleep times. Longitudinal data (spanning 12.1 ± 4.3 years) demonstrated a chronic course of sleepiness for most of the cases with IH, though pathologic somnolence remitted in roughly 40% of cases. DISCUSSION: These results demonstrate IH is more common in the working population than generally assumed with a prevalence on par with other common neurologic and psychiatric conditions. Further efforts to identify and diagnose those impaired by unexplained daytime somnolence may help clarify the causes of IH and the mechanisms underlying symptomatic remission.

Sleepy Kids: are the current diagnostic criteria for multiple sleep latency tests enough?

Excessive daytime sleepiness (EDS) is common in childhood and is currently quantified using adult criteria on a multiple sleep latency test (MSLT). This study aimed to describe paediatric MSLT results, particularly focussing on a previously proposed alternative mean sleep latency (MSL) threshold for children of 12 min, and assess the impact of a 5th nap. We performed a retrospective analysis of MSLTs at a single paediatric centre from 2004 to 2021. Narcolepsy was defined as a mean sleep latency (MSL) ≤8min with ≥2 sleep onset REM (SOREM) periods. Idiopathic Hypersomnia (IH) was defined as a MSL ≤8min with <2 SOREMs. An ambiguous MSLT result was defined as a MSL 8-12min and/or ≥2 SOREM periods. Of 214 MSLTs [50 % female, median age 14.0y (range 3.3-20.1y)], narcolepsy was diagnosed in 48 (22 %), IH in 22 (10 %) and the result was ambiguous in 44 (21 %). Those with ambiguous MSLT results were older (15.6 vs 13.4y, p = 0.006) with a higher proportion of females (61 % vs 35 %, p = 0.01) in comparison to the narcolepsy group. A 5th nap was performed in 60 (28 %) of MSLTs and only changed the outcome in one case. In conclusion, MSLT results are borderline in 21 % of paediatric cases, suggesting that current adult diagnostic criteria may miss narcolepsy and IH in children. A 5th nap usually makes no difference or increases the MSL, suggesting that a four nap MSLT protocol could be used apart from rare cases where the result is borderline after the 4th nap.

Brain fog in central disorders of hypersomnolence: a review.

Brain fog is an undefined term describing a cluster of symptoms related to fatigue and impaired memory, attention, and concentration. Brain fog or brain fog-like symptoms have been reported in central disorders of hypersomnolence and in a range of seemingly unrelated disorders, including coronavirus disease 2019, major depressive disorder, multiple sclerosis, lupus, and celiac disease. This narrative review summarizes current evidence and proposes a consensus definition for brain fog. Brain fog is prevalent in narcolepsy and idiopathic hypersomnia, with more than three-quarters of patients with either disorder reporting this symptom in a registry study; it has also been reported as particularly difficult to treat in idiopathic hypersomnia. Studies directly evaluating brain fog are rare; tools for evaluating this symptom cluster typically are patient reports, with few objective measures validated in any disorder. Evaluating brain fog is further complicated by confounding symptoms, such as excessive daytime sleepiness, which is a hallmark of hypersomnolence disorders. No treatments specifically address brain fog. The paucity of literature, assessment tools, and medications for brain fog highlights the need for research leading to better disambiguation and treatment. Until a clear consensus definition is established, we propose brain fog in hypersomnia disorders be defined as a cognitive dysfunction that may or may not be linked with excessive sleepiness, related to an underlying neuronal dysfunction, which reduces concentration and impairs information processing, leading to a complaint of lack of clarity of mental thinking and awareness. CITATION: Rosenberg R, Thorpy MJ, Doghramji K, Morse AM. Brain fog in central disorders of hypersomnolence: a review. J Clin Sleep Med. 2024;20(4):643-651.

Idiopathic hypersomnia years after the diagnosis.

Little attention has been paid to the long-term development of idiopathic hypersomnia symptoms and idiopathic hypersomnia comorbidities. The aim of this study was to describe the general health of patients with idiopathic hypersomnia years after the initial diagnosis, focusing on current subjective hypersomnolence and the presence of its other possible causes. Adult patients diagnosed with idiopathic hypersomnia ≥ 3 years ago at sleep centres in Prague and Kosice were invited to participate in this study. A total of 60 patients were examined (age 47.3 ± SD = 13.2 years, 66.7% women). In all participants, their hypersomnolence could not be explained by any other cause but idiopathic hypersomnia at the time of diagnosis. The mean duration of follow-up was 9.8 + 8.0 years. Fifty patients (83%) reported persisting hypersomnolence, but only 33 (55%) had no other disease that could also explain the patient's excessive daytime sleepiness and/or prolonged sleep. In two patients (3%), the diagnosis in the meantime had changed to narcolepsy type 2, and 15 patients (25%) had developed a disease or diseases potentially causing hypersomnolence since the initial diagnosis. Complete hypersomnolence resolution without stimulant treatment lasting longer than 6 months was reported by 10 patients (17%). To conclude, in a longer interval from the diagnosis of idiopathic hypersomnia, hypersomnolence may disappear or may theoretically be explained by another newly developed disease, or the diagnosis may be changed to narcolepsy type 2. Thus, after 9.8 years, only 55% of the examined patients with idiopathic hypersomnia had a typical clinical picture of idiopathic hypersomnia without doubts about the cause of the current hypersomnolence.

Guardians of Rest? Investigating the gut microbiota in central hypersomnolence disorders.

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.

Idiopathic Hypersomnia and Kleine-Levin Syndrome: Primary Disorders of Hypersomnolence Beyond Narcolepsy.

Daytime sleepiness is common amongst children and adolescents. Inadequate sleep duration, inappropriate school start times, and the delay in sleep phase of adolescence may all contribute. Nocturnal sleep disruption due to sleep disorders such as obstructive sleep apnea or restless legs syndrome/periodic limb movement disorder may also lead to daytime sleepiness. Profound sleepiness however, when occurring in the setting of adequate sleep duration, is rare amongst children and adolescents and may prompt consideration of a central disorder of hypersomnolence (CDH). Narcolepsy is the archetypal and most studied form of CDH and a detailed review of the presentation, evaluation, treatment of narcolepsy is included separately in this edition of Seminars in Pediatric Neurology. In addition to narcolepsy, 2 other forms of primary CDH exist, idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS). Onset of IH and KLS occurs most frequently during the pediatric age range and presentation may include signs of encephalopathy in addition to hypersomnolence. As such, they are of particular relevance to pediatric neurology and associated fields. Unfortunately, when compared to narcolepsy little is known about IH and KLS, at both the physiologic and clinical level. This review will focus on the presentation, evaluation, and management of idiopathic hypersomnia and Kleine-Levin syndrome in the pediatric population.

Clinical Evaluation and Management of Narcolepsy in Children and Adolescents.

While sleepiness is common among children, and particularly adolescents, profound sleepiness in the setting of apparently adequate sleep should prompt consideration of a central disorder of hypersomnolence. These disorders, which include narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, and others, are likely underrecognized in the pediatric population. Narcolepsy in particular should be of interest to child neurologists as the unique signs and symptoms of this disease often prompt evaluation in pediatric neurology clinics. While sleepiness may appear to be a straightforward complaint, its evaluation requires a nuanced approach. Cataplexy, a hallmark of narcolepsy, can be confused for other neurologic conditions, though understanding its various manifestations makes it readily identifiable. Clinicians should be aware of these symptoms, as delay in diagnosis and misdiagnosis are common in childhood narcolepsy. While treatment options have been limited in the past, many new therapeutic options have become available and can result in significant improvement in symptoms. Given the age at presentation, paroxysmal and chronic features, diagnostic modalities, and available treatment options, the field of child neurology is well equipped to see patients with narcolepsy. In this review, I will focus on the presentation, evaluation, and management of pediatric patients with narcolepsy.

Idiopathic hypersomnia and Kleine-Levin syndrome.

Idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS) are rare disorders of central hypersomnolence of unknown cause, affecting young people. However, increased sleep time and excessive daytime sleepiness (EDS) occur daily for years in IH, whereas they occur as relapsing/remitting episodes associated with cognitive and behavioural disturbances in KLS. Idiopathic hypersomnia is characterized by EDS, prolonged, unrefreshing sleep at night and during naps, and frequent morning sleep inertia, but rare sleep attacks, no cataplexy and sleep onset in REM periods as in narcolepsy. The diagnosis requires: (i) ruling out common causes of hypersomnolence, including mostly sleep apnea, insufficient sleep syndrome, psychiatric hypersomnia and narcolepsy; and (ii) obtaining objective EDS measures (mean latency at the multiple sleep latency test≤8min) or increased sleep time (sleep time>11h during a 18-24h bed rest). Treatment is similar to narcolepsy (except for preventive naps), including adapted work schedules, and off label use (after agreement from reference/competence centres) of modafinil, sodium oxybate, pitolisant, methylphenidate and solriamfetol. The diagnosis of KLS requires: (i) a reliable history of distinct episodes of one to several weeks; (ii) episodes contain severe hypersomnia (sleep>15h/d) associated with cognitive impairment (mental confusion and slowness, amnesia), derealisation, major apathy or disinhibited behaviour (hypersexuality, megaphagia, rudeness); and (iii) return to baseline sleep, cognition, behaviour and mood after episodes. EEG may contain slow rhythms during episodes, and rules out epilepsy. Functional brain imaging indicates hypoactivity of posterior associative cortex and hippocampus during symptomatic and asymptomatic periods. KLS attenuates with time when starting during teenage, including less frequent and less severe episodes. Adequate sleep habits, avoidance of alcohol and infections, as well as lithium and sometimes valproate (off label, after agreement from reference centres) help reducing the frequency and severity of episodes, and IV methylprednisolone helps reducing long (>30d) episode duration.

Are unrefreshing naps associated with nocturnal sleep architecture specificities in idiopathic hypersomnia?

STUDY OBJECTIVES: Unrefreshing naps are supportive clinical features of idiopathic hypersomnia (IH) and are reported by more than 50% of IH patients. They are, however, not mandatory for the diagnosis, and their pathophysiological nature is not understood. This study aimed at verifying whether IH patients with and without unrefreshing naps constitute two subtypes of IH based on their demographic/clinical characteristics, and sleep architecture. METHODS: One hundred twelve IH patients underwent a polysomnography (PSG) followed by a multiple sleep latency test (MSLT). They completed questionnaires on excessive daytime sleepiness, mood, and sleep quality. They were met by sleep medicine physicians who conducted a semi-structured clinical interview and questioned them on refreshing aspects of their naps. Patients who reported unrefreshing naps were compared to patients reporting refreshing naps on questionnaires, MSLT and PSG variables, with age as a covariable. As sensitivity analyses, we performed the same comparisons in participants presenting objective markers of IH and those diagnosed with IH based only on clinical judgment (subjective IH), separately. RESULTS: In the whole sample, 61% of patients reported unrefreshing naps. These participants had less awakenings, a lower percentage of N1 sleep, less sleep stage transitions, and a higher percentage of REM sleep on the nighttime PSG compared to the refreshing naps subgroup. When subjective and objective IH patients were tested separately, more group differences were observed on PSG for subjective IH patients. CONCLUSIONS: Patients with unrefreshing naps have less fragmented sleep compared to those with refreshing naps. Future studies should investigate whether this group difference indicates a weaker arousal drive.

Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia.

STUDY OBJECTIVES: To evaluate 6-month efficacy and safety of low-sodium oxybate in people with idiopathic hypersomnia during an open-label extension period (OLE) of a phase 3 clinical trial. METHODS: Efficacy measures included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change (PGIc), Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Treatment-emergent adverse events were collected throughout the OLE. RESULTS: The OLE population included 106 participants. Most were female (71%) and White (83%), and the mean (SD) age was 41.0 (13.8) years. ESS scores decreased (improved) during the OLE (mean [SD], study baseline: 16.3 [2.8]; OLE week 2: 6.7 [4.7]; OLE end: 5.3 [3.7]), and IHSS total scores trended toward a decrease (study baseline: 32.6 [7.3]; OLE week 2: 16.2 [8.9]; OLE end: 14.8 [8.6]. Median (minimum, maximum) paired differences from OLE week 2 to OLE end were ESS, -1.0 (-20, 7; nominal P = .012); IHSS, -1.0 (-31, 19; nominal P = .086). The proportion of participants reporting PGIc ratings of "very much improved" increased from 36.7% at OLE week 2 to 53.8% at the OLE end. The FOSQ-10 and WPAI:SHP scores remained stable during OLE. The incidence of newly reported treatment-emergent adverse events decreased over the duration of the OLE. CONCLUSIONS: Efficacy and safety of low-sodium oxybate were maintained or improved during the 6-month OLE, supporting long-term treatment with low-sodium oxybate in adults with idiopathic hypersomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) With an Open-label Safety Extension; URL: https://clinicaltrials.gov/study/NCT03533114; Identifier: NCT03533114 and Registry: EU Clinical Trials; Name: A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) with an Open-label Safety Extension; URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-001311-79/results; Identifier: 2018-001311-79. CITATION: Morse AM, Dauvilliers Y, Arnulf I, et al. Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia. J Clin Sleep Med. 2023;19(10):1811-1822.

Face validation and pharmacologic analysis of Sik3Sleepy mutant mouse as a possible model of idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a chronic neurologic disorder with unknown mechanisms that result in long night-time sleep, daytime sleepiness, long non-refreshing naps, and difficult awakening presenting as sleep drunkenness. IH patients are typically diagnosed by shorter sleep latency on multiple sleep latency test (MSLT) along with long sleep time. Only symptomatic drug treatments are currently available for IH and no animal model to study it. Sleepy mice carry a splicing mutation in the Sik3 gene, leading to increased sleep time and sleep need. Here we used a mouse version of MSLT and a decay analysis of wake EEG delta power to validate the Sleepy mutant mouse as an animal model for IH. Sleepy mice had shorter sleep latency in the dark (active) phase than wild-type mice. They also showed lower decay of EEG delta density during wakefulness, possibly reflecting increased sleep inertia. These data indicate that the Sleepy mouse may have partial face validity as a mouse model for idiopathic hypersomnia. We then investigated the effect of orexin-A and the orexin receptor 2-selective agonist YNT-185 on the sleepiness symptoms of the Sleepy mouse. Intracerebroventricular orexin-A promoted wakefulness for 3 h and decreased wake EEG delta density after injection in Sleepy mice and wild-type mice. Moreover, Sleepy mice but not wild-type mice showed a sleep rebound after the orexin-A-induced wakefulness. Intraperitoneal YNT-185 promoted wakefulness for 3 h after injection in Sleepy mice, indicating the potential of using orexin agonists to treat not only orexin deficiency but hypersomnolence of various etiologies.