Genetics and epigenetics of rare hypersomnia.

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.

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.

The electroretinography to identify biomarkers of idiopathic hypersomnia and narcolepsy type 1.

Hypersomnia spectrum disorders are underdiagnosed and poorly treated due to their heterogeneity and absence of biomarkers. The electroretinography has been proposed as a proxy of central dysfunction and has proved to be valuable to differentiate certain psychiatric disorders. Hypersomnolence is a shared core feature in central hypersomnia and psychiatric disorders. We therefore aimed to identify biomarkers by studying the electroretinography profile in patients with narcolepsy type 1, idiopathic hypersomnia and in controls. Cone, rod and retinal ganglion cells electrical activity were recorded with flash-electroretinography in non-dilated eye of 31 patients with idiopathic hypersomnia (women 84%, 26.6 ± 5.9 years), 19 patients with narcolepsy type 1 (women 63%, 36.6 ± 12.7 years) and 43 controls (women 58%, 30.6 ± 9.3 years). Reduced cone a-wave amplitude (p = 0.039) and prolonged cone (p = 0.022) and rod b-wave (p = 0.009) latencies were observed in patients with narcolepsy type 1 as compared with controls, while prolonged photopic negative response-wave latency (retinal ganglion cells activity) was observed in patients with idiopathic hypersomnia as compared with controls (p = 0.033). The rod and cone b-wave latency clearly distinguished narcolepsy type 1 from idiopathic hypersomnia and controls (area under the curve > 0.70), and the photopic negative response-wave latency distinguished idiopathic hypersomnia and narcolepsy type 1 from controls with an area under the curve > 0.68. This first original study shows electroretinography anomalies observed in patients with hypersomnia. Narcolepsy type 1 is associated with impaired cone and rod responses, whereas idiopathic hypersomnia is associated with impaired retinal ganglion cells response, suggesting different phototransduction alterations in both hypersomnias. Although these results need to be confirmed with a larger sample size, the electroretinography may be a promising tool for clinicians to differentiate hypersomnia subtypes.

Unrefreshing naps and sleep architecture during the multiple sleep latency test in idiopathic hypersomnia.

Patients with idiopathic hypersomnia frequently report having unrefreshing naps. However, whether they have abnormal sleep architecture during naps that may explain their unrefreshing aspect is unknown. We compared sleep architecture during short daytime naps in patients with idiopathic hypersomnia reporting unrefreshing and refreshing naps. One-hundred and thirty-four patients tested with one-night polysomnography, followed by an adapted version of the Multiple Sleep Latency Test with four naps, were included. They were asked about the refreshing aspect of their habitual naps during a clinical interview. They were classified as having objective (Multiple Sleep Latency Test ≤ 8 min) or subjective idiopathic hypersomnia (Multiple Sleep Latency Test > 8 min), and as presenting refreshing or unrefreshing naps. We tested Group differences (refreshing versus unrefreshing naps) on nap sleep architecture in the whole sample and for subjective and objective idiopathic hypersomnia subgroups separately using ANCOVAs. No Group effects were observed in the Multiple Sleep Latency Test architecture in the whole sample and in objective and subjective idiopathic hypersomnia subgroups. This study provides preliminary evidence that reporting unrefreshing naps is not associated with clinically significant findings in Multiple Sleep Latency Test sleep architecture in patients with idiopathic hypersomnia. Given that naps taken by patients with idiopathic hypersomnia are typically long, future studies should investigate longer daytime sleep episodes.

Identifying time-resolved features of nocturnal sleep characteristics of narcolepsy using machine learning.

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

Association between idiopathic hypersomnia and a genetic variant in the PER3 gene.

We aim to identify genetic markers associated with idiopathic hypersomnia, a disabling orphan central nervous system disorder of hypersomnolence that is still poorly understood. In our study, DNA was extracted from 79 unrelated patients diagnosed with idiopathic hypersomnia with long sleep time at the National Reference Center for Narcolepsy-France according to very stringent diagnostic criteria. Whole exome sequencing on the first 30 patients with idiopathic hypersomnia (25 females and 5 males) allowed the single nucleotide variants to be compared with a control population of 574 healthy subjects from the French Exome project database. We focused on the identification of genetic variants among 182 genes related to the regulation of sleep and circadian rhythm. Candidate variants obtained by exome sequencing analysis were then validated in a second sample of 49 patients with idiopathic hypersomnia (37 females and 12 males). Our study characterised seven variants from six genes significantly associated with idiopathic hypersomnia compared with controls. A targeted sequencing analysis of these seven variants on 49 other patients with idiopathic hypersomnia confirmed the relative over-representation of the A➔C variant of rs2859390, located in a potential splicing-site of PER3 gene. Our findings support a genetic predisposition and identify pathways involved in the pathogeny of idiopathic hypersomnia. A variant of the PER3 gene may predispose to idiopathic hypersomnia with long sleep time.

Skin temperature as a predictor of on-the-road driving performance in people with central disorders of hypersomnolence.

Excessive daytime sleepiness is the core symptom of central disorders of hypersomnolence (CDH) and can directly impair driving performance. Sleepiness is reflected in relative alterations in distal and proximal skin temperature. Therefore, we examined the predictive value of skin temperature on driving performance. Distal and proximal skin temperature and their gradient (DPG) were continuously measured in 44 participants with narcolepsy type 1, narcolepsy type 2 or idiopathic hypersomnia during a standardised 1-h driving test. Driving performance was defined as the standard deviation of lateral position (SDLP) per 5 km segment (equivalent to 3 min of driving). Distal and proximal skin temperature and DPG measurements were averaged over each segment and changes over segments were calculated. Mixed-effect model analyses showed a strong, quadratic association between proximal skin temperature and SDLP (p < 0.001) and a linear association between DPG and SDLP (p < 0.021). Proximal skin temperature changes over 3 to 15 min were predictive for SDLP. Moreover, SDLP increased over time (0.34 cm/segment, p < 0.001) and was higher in men than in women (3.50 cm, p = 0.012). We conclude that proximal skin temperature is a promising predictor for real-time assessment of driving performance in people with CDH.

Pupillometry to differentiate idiopathic hypersomnia from narcolepsy type 1.

Idiopathic hypersomnia is poorly diagnosed in the absence of biomarkers to distinguish it from other central hypersomnia subtypes. Given that light plays a main role in the regulation of sleep and wake, we explored the retinal melanopsin-based pupil response in patients with idiopathic hypersomnia and narcolepsy type 1, and healthy subjects. Twenty-seven patients with narcolepsy type 1 (women 59%, 36 ± 11.5 years old), 36 patients with idiopathic hypersomnia (women 83%, 27.2 ± 7.2 years old) with long total sleep time (> 11/24 hr), and 43 controls (women 58%, 30.6 ± 9.3 years old) were included in this study. All underwent a pupillometry protocol to assess pupil diameter, and the relative post-illumination pupil response to assess melanopsin-driven pupil responses in the light non-visual input pathway. Differences between groups were assessed using logistic regressions adjusted on age and sex. We found that patients with narcolepsy type 1 had a smaller baseline pupil diameter as compared with idiopathic hypersomnia and controls (p < 0.05). In addition, both narcolepsy type 1 and idiopathic hypersomnia groups had a smaller relative post-illumination pupil response (respectively, 31.6 ± 13.9% and 33.2 ± 9.9%) as compared with controls (38.7 ± 9.7%), suggesting a reduced melanopsin-mediated pupil response in both types of central hypersomnia (p < 0.01). Both narcolepsy type 1 and idiopathic hypersomnia showed a smaller melanopsin-mediated pupil response, and narcolepsy type 1, unlike idiopathic hypersomnia, also displayed a smaller basal pupil diameter. Importantly, we found that the basal pupil size permitted to well discriminate idiopathic hypersomnia from narcolepsy type 1 with a specificity = 66.67% and a sensitivity = 72.22%. Pupillometry may aid to multi-feature differentiation of central hypersomnia subtypes.

Retrospective cohort study of hypersomnias of central origin from two Australian tertiary sleep disorders services.

BACKGROUND: Hypersomnias of central origin (HOCO) are diverse in origin and symptomatology and remain poorly described in an Australian population. We hypothesised that the rate of human leukocyte antigen (HLA) DQB1*0602 positivity in the Australian cohort would be comparable to international registries. AIMS: The current study aims to evaluate epidemiological and clinical characteristics of Australian patients with HOCO, including prevalence of HLA DQB1*0602 positivity, the most specific HLA marker associated with narcolepsy. METHODS: This is a retrospective study. Patients ≥ 16 years of age presenting with symptoms of hypersomnolence who attended one of two Australian sleep centres (New South Wales and Queensland) in the preceding 24 months and had undergone both HLA serology and multiple sleep latency tests (MSLTs) were included. Main outcome measures included demographics, HLA DQB1*0602 positivity, MSLT, and clinical parameters (presence of auxiliary narcolepsy symptoms, laboratory tests, relevant prescribed medications). RESULTS: Eighty-eight patients were included. HLA DQB1*0602 positivity was highest in those with type 1 narcolepsy (NT1) (95.7%) and lowest in those without a classifiable disorder (9.1%). Mean sleep latency was lowest and number of sleep-onset rapid eye movement periods (SOREMPs) highest in the NT1 group. Comorbid disorders, particularly depression and overweight/obesity, were prevalent in all cohorts. Across all diagnostic groups, dexamphetamine was the most commonly prescribed agent for excessive daytime sleepiness. CONCLUSIONS: Patients with HOCO assessed in two specialised Australian clinics demonstrate comparable clinical characteristics to other published cohorts internationally; however, available pharmacological agents in Australia do not reflect international standards of care.

Actigraphy measurement of physical activity and energy expenditure in narcolepsy type 1, narcolepsy type 2 and idiopathic hypersomnia: A Sensewear Armband study.

The cause of obesity in narcolepsy type 1 (NT1) patients is not fully understood. The present study investigated if a reduced physical activity could explain weight gain in NT1. Seventy-nine patients were included in this retrospective study and divided into an NT1 group (n = 56) and a non-NT1 group (n = 23), including NT2 and idiopathic hypersomnia (IH). Accelerometry-derived measures of physical activity, total energy expenditure and skin temperature were collected from patients during seven consecutive days without medication. In addition, results from multiple sleep latency tests and the Epworth Sleepiness Scale questionnaire, body weight, height and CSF orexin/hypocretin were acquired. Three measurements of physical activity, including metabolic equivalent of task (MET), the average time of physical activity and step count, were compared without differences between groups. Neither could we find a significant difference in total energy expenditure or skin temperature. Thus, by analysing accelerometric data, we could not find any differences in the amount of physical activity or total energy expenditure explaining overweight in NT1.

Idiopathic Hypersomnia and Depression, the Challenge for Clinicians and Researchers.

The review deals with idiopathic hypersomnia, focusing mostly on the research findings about the presence, onset and severity of excessive daytime sleepiness and depressive symptoms in patients with idiopathic hypersomnia.

Excessive daytime sleepiness in narcolepsy and central nervous system hypersomnias.

PURPOSE: Excessive daytime sleepiness (EDS) is the core complaint of central nervous system (CNS) hypersomnias. In this mini-review, we summarized EDS features in CNS hypersomnias to provide a guide for differential diagnosis purposes. METHODS: A review of recent literature was performed to provide an update in CNS hypersomnias. RESULTS: At clinical evaluation, narcolepsy patients report a good restorative potential of sleep together with the frequent occurrence of dreaming even during short-lasting naps. These features are mirrored by the neurophysiological evidence of REM sleep at sleep onset (SOREMP) during the Multiple Sleep Latency Test (MSLT), a specific marker. Conversely, patients with idiopathic hypersomnia (IH) complain sleep inertia and prolonged nocturnal sleep. Polysomnographic studies show high sleep propensity on the MSLT or high 24-h total sleep time during continuous monitoring. Patients with insufficient sleep syndrome (ISS) can present with variable clinical EDS features in between narcolepsy and IH. ISS diagnosis is based on the clinical evidence of nocturnal sleep curtailment (weekdays versus vacations) associated with the disappearance of EDS complaint after sleep extension. Polysomnographic data are not required, but when the MSLT is performed, ISS patients can present with SOREMP arising from non-REM stage 2 sleep (vs narcolepsy patients entering into SOREM most frequently from wakefulness). Kleine-Levin Syndrome is characterized by recurrent episodes of enormously prolonged sleep time lasting days associated with abnormal cognition and behavior intermixed by asymptomatic periods, a sleep pattern that can be well documented by actigraphy. CONCLUSIONS: Different CNS hypersomnias present with specific features of EDS are useful to guide the clinician to apply and interpret appropriate neurophysiological investigations.

Systemic exertion intolerance disease/chronic fatigue syndrome is common in sleep centre patients with hypersomnolence: A retrospective pilot study.

Symptoms of the central disorders of hypersomnolence extend beyond excessive daytime sleepiness to include non-restorative sleep, fatigue and cognitive dysfunction. They share much in common with myalgic encephalomyelitis/chronic fatigue syndrome, recently renamed systemic exertion intolerance disease, whose additional features include post-exertional malaise and orthostatic intolerance. We sought to determine the frequency and correlates of systemic exertion intolerance disease in a hypersomnolent population. One-hundred and eighty-seven hypersomnolent patients completed questionnaires regarding sleepiness and fatigue; questionnaires and clinical records were used to assess for systemic exertion intolerance disease. Sleep studies, hypocretin and cataplexy were additionally used to assign diagnoses of hypersomnolence disorders or sleep apnea. Included diagnoses were idiopathic hypersomnia (n = 63), narcolepsy type 2 (n = 25), persistent sleepiness after obstructive sleep apnea treatment (n = 25), short habitual sleep duration (n = 41), and sleepiness with normal sleep study (n = 33). Twenty-one percent met systemic exertion intolerance disease criteria, and the frequency of systemic exertion intolerance disease was not different across sleep diagnoses (p = .37). Patients with systemic exertion intolerance disease were no different from those without this diagnosis by gender, age, Epworth Sleepiness Scale, depressive symptoms, or sleep study parameters. The whole cohort reported substantial fatigue on questionnaires, but the systemic exertion intolerance disease group exhibited more profound fatigue and was less likely to respond to traditional wake-promoting agents (88.6% versus 67.7%, p = .01). Systemic exertion intolerance disease appears to be a common co-morbidity in patients with hypersomnolence, which is not specific to hypersomnolence subtype but may portend a poorer prognosis for treatment response.

Growth Hormone Deficiency and Excessive Sleepiness: A Case Report and Review of the Literature.

The somatotropic axis is intricately involved in normal sleep, as evidenced by the fact that hypothalamic growth hormone-releasing hormone (GHRH) has sleep promoting effects and pituitary growth hormone (GH) release is strongly associated with slow-wave sleep (SWS). Abnormalities in the somatotropic axis, such as GH deficiency of hypothalamic or pituitary origin, result in an alteration of normal sleep patterns which may explain the fatigue reported in these individuals. Sleep disorders such as narcolepsy, in which individuals abnormally enter rapid eye movement (REM) sleep at sleep onset are also associated with an altered GHRH circadian rhythm and abnormal GH secretion. While few studies are available, this review explores what is known about sleep abnormalities in GH deficiency, the effect of treatment on sleep in patients with GH deficiency, and GH secretion in narcolepsy. Emerging evidence suggests a hypothalamic link between narcolepsy and GH secretion. We also describe the unique constellation of isolated idiopathic GH deficiency and severe excessive sleepiness in adopted Nicaraguan siblings, one of which has narcolepsy and the other idiopathic hypersomnia.

Treatment of narcolepsy and other organic hypersomnias in children.

The comprehensive management of chronic disorders such as hypersomnias of childhood requires combining life-style changes with rational pharmacotherapy that is based on treating the symptoms that are most bothersome, the age, comorbidities, and metabolic and endocrine status of the patient. The excessive sleepiness of narcolepsy and idiopathic hypersomnia is best treated with dextroamphetamine or methylphenidate preparations or modafinil/armodafinil. Cataplexy treatment requires sodium oxybate, tricyclic agents, selective norepinephrine reuptake inhibitors or selective serotonin reuptake inhibitors. Sodium oxybate is approved only for adults, thus its use in children is only on an off-label basis. Dual therapy, with both anti-cataplectic and stimulant medications may be required, as is close monitoring for treatment-emergent side effects.

Hypersomnolence, Hypersomnia, and Mood Disorders.

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

French consensus. Idiopathic hypersomnia: Investigations and follow-up.

Idiopathic hypersomnia is a rare, central hypersomnia, recently identified and to date of unknown physiopathology. It is characterised by a more or less permanent, excessive daytime sleepiness, associated with long and unrefreshing naps. Night-time sleep is of good quality, excessive in quantity, associated with sleep inertia in the subtype previously described as "with long sleep time". Diagnosis of idiopathic hypersomnia is complex due to the absence of a quantifiable biomarker, the heterogeneous symptoms, which overlap with the clinical picture of type 2 narcolepsy, and its variable evolution over time. Detailed evaluation enables other frequent causes of somnolence, such as depression or sleep deprivation, to be eliminated. Polysomnography and multiple sleep latency tests (MSLT) are essential to rule out other sleep pathologies and to objectify excessive daytime sleepiness. Sometimes the MSLT do not show excessive sleepiness, hence a continued sleep recording of at least 24hours is necessary to show prolonged sleep (>11h/24h). In this article, we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from idiopathic hypersomnia.

French consensus. Management of patients with hypersomnia: Which strategy?

Central hypersomnias principally involves type 1 narcolepsy (NT1), type 2 narcolepsy (NT2) and idiopathic hypersomnia (IH). Despite great progress made in understanding the physiopathology of NT1 with low cerebrospinal fluid hypocretin-1 levels, current treatment remains symptomatic. The same applies to NT2 and IH, for which the physiopathology is still largely unknown. Controlling excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep are key therapeutic targets in NT1. For IH and NT2, reducing EDS is the main objective. Based on European and American directives for the treatment of narcolepsy, we propose French recommendations for managing central hypersomnias as well as strategies in the case of drug-resistance. Stimulating treatments target EDS, and Modafinil is the first-line treatment. Other stimulants such as methylphenidate, pitolisant, and exceptionally dextro-amphetamine can be prescribed. Selective serotonin and noradrenaline reuptake inhibitor antidepressants are effective for the management of cataplexy in NT1. Sodium oxybate is an effective treatment for several symptoms, including EDS, cataplexy and disturbed night-time sleep. Treatment of central hypersomnia must also take into consideration frequent cardiovascular, metabolic and psychiatric comorbidities, particularly in NT1. New therapies are currently under study with the development of new stimulants and anti-cataplectics. The next few years will see innovative emerging therapies, based on a physiopathological approach, aiming to restore hypocretinergic transmission or to interrupt the autoimmune processes causing the loss of hypocretin neurons.

New hypothesis on pontine-frontal eye field connectivity in Kleine-Levin syndrome.

Previous studies have indicated involvement of the thalamus and the pons in Kleine-Levin syndrome. In the present study, functional connectivity of the thalamus and the pons was investigated in asymptomatic patients with Kleine-Levin syndrome and healthy controls. Twelve patients and 14 healthy controls were investigated by functional magnetic resonance imaging during rest. Resting state images were analysed using seed regions of interest in the thalamus and the pons. The results showed significantly lower functional connectivity between the pons and the frontal eye field in persons with Kleine-Levin syndrome compared with healthy controls. There were no connectivity differences involving the thalamus. Based on these findings, a relation is proposed between the sleep disorder Kleine-Levin syndrome and cerebral control of eye movements, which in turn is related to visual attention and working memory. This hypothesis has to be tested in future studies of oculomotor control in Kleine-Levin syndrome.

Different fates of excessive daytime sleepiness: survival analysis for remission.

BACKGROUND: Excessive daytime sleepiness (EDS) is a symptom frequently presented in sleep clinics. Only a paucity of data has addressed clinical courses of sleep disorders with EDS. Therefore, we sought to compare clinical outcomes of patients presenting EDS. METHODS: A retrospective observational study was performed in the setting of sleep laboratory and outpatient department in a university hospital. One hundred and eight patients who presented EDS underwent polysomnography and multiple sleep latency test. Each patient was diagnosed as one of the following four categories: (1) narcolepsy with cataplexy (N + C; n = 29); (2) narcolepsy without cataplexy (N - C; n = 22); (3) idiopathic hypersomnia (IH; n = 24); and (4) subjective hypersomnolence (SH; n = 33) with mean sleep latency >8 min. Remission of EDS and treatment response were determined based on clinical evaluation. Kaplan-Meier survival analysis was performed. RESULTS: Remission rates were significantly different (P < 0.001, overall log-rank test) among four groups except those between N - C and IH (P = 0.489). While N + C showed no remission, predicted remission rates of N - C and IH group were 44.6% at 5 years and 32.5% at 5.5 years after diagnosis. The predicted remission rate of SH group was 71.7% at 3 years after diagnosis. CONCLUSIONS: The similarity of clinical courses between N - C and IH suggests that N - C may be more related to IH compared to N + C. Considering different clinical courses among EDS patients, thorough evaluation of EDS should be warranted before starting treatment.