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.

Blackout of my nights: Contentless, timeless and selfless report from the night in patients with central hypersomnias.

At the extreme spectrum of consciousness during sleep, some patients with rare hypersomnias reported experiencing a specific night 'blackout' when sleeping, i.e., an absence of experiences or recall of them from sleep onset to offset. Thus, we explored through questionnaires the conscious experiences (dreaming experience, mind, self) during the night in 133 patients with idiopathic hypersomnia, 108 patients with narcolepsy, and 128 healthy controls. The night blackout was more frequent in idiopathic hypersomnia than in narcolepsy and control groups. Patients with idiopathic hypersomnia and frequent night amnesia had lower dream recall frequencies, and felt more often sleep as deep and mind as blank during the night. They had a higher proportion of slow wave sleep on their (retrospectively collected) sleep recordings than those without night blackout. This night blackout provides a new model for studying loss of consciousness during sleep, here as a contentless, selfless and timeless feeling upon awakening.

Automatic detection of microsleep episodes with feature-based machine learning.

STUDY OBJECTIVES: Microsleep episodes (MSEs) are brief episodes of sleep, mostly defined to be shorter than 15 s. In the electroencephalogram (EEG), MSEs are mainly characterized by a slowing in frequency. The identification of early signs of sleepiness and sleep (e.g. MSEs) is of considerable clinical and practical relevance. Under laboratory conditions, the maintenance of wakefulness test (MWT) is often used for assessing vigilance. METHODS: We analyzed MWT recordings of 76 patients referred to the Sleep-Wake-Epilepsy-Center. MSEs were scored by experts defined by the occurrence of theta dominance on ≥1 occipital derivation lasting 1-15 s, whereas the eyes were at least 80% closed. We calculated spectrograms using an autoregressive model of order 16 of 1 s epochs moved in 200 ms steps in order to visualize oscillatory activity and derived seven features per derivation: power in delta, theta, alpha and beta bands, ratio theta/(alpha + beta), quantified eye movements, and median frequency. Three algorithms were used for MSE classification: support vector machine (SVM), random forest (RF), and an artificial neural network (long short-term memory [LSTM] network). Data of 53 patients were used for the training of the classifiers, and 23 for testing. RESULTS: MSEs were identified with a high performance (sensitivity, specificity, precision, accuracy, and Cohen's kappa coefficient). Training revealed that delta power and the ratio theta/(alpha + beta) were most relevant features for the RF classifier and eye movements for the LSTM network. CONCLUSIONS: The automatic detection of MSEs was successful for our EEG-based definition of MSEs, with good performance of all algorithms applied.

Precision Medicine for Idiopathic Hypersomnia.

Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female predominance, severe morning inertia, continuous drowsiness (rather than sleep attacks), unrefreshing naps, absence of cataplexy, sleep onset in REM periods, and hypocretin deficiency. In IH, the multiple sleep latency test demonstrates low sensitivity, specificity, and reproducibility, compared with prolonged sleep monitoring. In some IH cases, an endogenous hypnotic peptide stimulating GABA receptors during wakefulness is suspected, which are improved by anti-GABA drugs. The benefits of modafinil, sodium oxybate, mazindol, and pitolisant were found in mostly retrospective studies.

Optimizing Actigraphic Estimation of Sleep Duration in Suspected Idiopathic Hypersomnia.

STUDY OBJECTIVES: To determine the optimal Actiwatch 2 setting configuration for the estimation of total sleep time (TST) in persons with suspected idiopathic hypersomnia. METHODS: Thirty-three patients with a diagnosis of idiopathic hypersomnia (28 female; mean age = 33.7 ± 10.5) underwent ad libitum polysomnography with concurrent use of the Actiwatch 2. Actiwatch 2 sleep-wake activity threshold (SWAT; Low, Medium, and High) and sleep immobility onset and offset (SIOO; 5, 10, 15, 20, 25, and 30 epoch) duration were modified during data processing. The resultant 18 unique setting combinations were subsequently evaluated using Bland-Altman and epoch comparison analyses to determine optimal settings relative to polysomnography. RESULTS: Low SWAT + 25 Epoch SIOO displayed the least divergence from polysomnography (mean difference 3.4 minutes). Higher SWAT and lower SIOO increased sensitivity and accuracy, but at the expense of reducing specificity and the ability to accurately estimate TST. CONCLUSIONS: These results demonstrate that actigraphic settings should be carefully considered when estimating sleep duration. The Low + 25 Epoch configuration is indicated as most optimal for estimating TST in persons with suspected idiopathic hypersomnia. COMMENTARY: A commentary on this article appears in this issue on page 539.

Specific T-cell activation in peripheral blood and cerebrospinal fluid in central disorders of hypersomnolence.

An autoimmune-mediated process in the pathophysiology of narcolepsy type 1 (NT1) is highly suspicious, if this pathomechanism is transferable to other types of central disorders of hypersomnolence (CDH), is still controversial. The association of NT1 with HLA class II system implicates a T-cell-mediated autoimmunity, in which helper CD4+ T-cells and cytotoxic CD8+ T-cells may be pathogenic. This study aimed to identify specific immune profiles in peripheral blood (PB) and cerebrospinal fluid (CSF) in different types of CDH. Forty-three people with polysomnographically confirmed CDH (24 idiopathic hypersomnia [IH], 12 NT1, and 7 NT2) were compared with 24 healthy controls (HC). PB and CSF were analyzed with multiparameter flow cytometry to distinguish between subclasses of peripheral and intrathecal immune cells and specific surface markers of T-cells. The overall proportion of helper CD4+ T-cells and cytotoxic CD8+ T-cells in PB and CSF did not differ between the patients and HC. Activated HLA-DR+ CD4+ T-cells and HLA-DR+ CD8+ T-cells in PB and CSF both in NT1, NT2 and IH were significantly increased compared with HC. A significant correlation of HLA-DR+ CD4+- and HLA-DR+ CD8+ T-cells with higher amounts of excessive daytime sleepiness was found in the NT1 and IH groups, indicating an association of activated T-cells in the central nervous system with an increase in sleepiness. These findings provide further evidence of a T-cell-mediated autoimmunity not only in NT1, but also in NT2 and IH. Moreover, the identification of activated cytotoxic CD8+ T-cells further supports the evidence of T-cell-mediated neuronal damage, which has previously been suggested in NT1.

Disease-specific attention impairment in disorders of chronic excessive daytime sleepiness.

OBJECTIVE: Patients with chronic excessive daytime sleepiness (EDS) complain of substantial attention deficits. However, their underlying neuronal dysfunction is largely unknown. Previous studies showed similar attention performances in central disorders of hypersomnolence suggesting that EDS-related cognitive impairment is independent of its cause. The aim of the current study was to further explore attentional profiles in disorders of chronic EDS. METHODS: Ten patients with narcolepsy type 1 (NT1; age 26.7 ± 9.3 years), 14 patients with idiopathic hypersomnia (IH; age 26.7 ± 9.3 years), 14 patients with subjective EDS (sEDS; age 31.4 ± 14.3 years), ie, a mean sleep latency >8 min in the multiple sleep latency test (MSLT), and 20 healthy controls (HC; age 32.6 ± 11.3 years) performed the vigilance task and the selective attention task of the test battery SLEEP® (Vienna Test System Neuro®). We assessed mean response time (RT) and standard deviation of RT separately for the first and the second half of the vigilance task to evaluate performance changes over time (time on task effect; TOT). RESULTS: A significant interaction effect between group and TOT on the mean RT in the vigilance task suggests partly group-specific attention deficits. Combining paradigms of sustained and selective attention discriminated patients with NT1, IH, sEDS and HC. Behavioral results were unrelated to the mean sleep latency in the MSLT. CONCLUSIONS: Discriminative performance of the sustained and selective attention tasks indicate disease-specific components of attention in NT1, IH, and sEDS. Different temporal dynamics of attentional control efficiency might be one factor underlying group differences.

Ability of the Multisensory Jawbone UP3 to Quantify and Classify Sleep in Patients With Suspected Central Disorders of Hypersomnolence: A Comparison Against Polysomnography and Actigraphy.

STUDY OBJECTIVES: To evaluate the ability of a multisensory fitness tracker, the Jawbone UP3 (JB3), to quantify and classify sleep in patients with suspected central disorders of hypersomnolence. METHODS: This study included 43 patients who completed polysomnography (PSG) and a Multiple Sleep Latency Test (MSLT) with concurrent wrist-worn JB3 and Actiwatch 2 (AW2) recordings for comparison. Mean differences in nocturnal sleep architecture variables were compared using Bland-Altman analysis. Sensitivity, specificity, and accuracy were derived for both devices relative to PSG. Ability of the JB3 to detect sleep onset rapid eye movement periods (SOREMPs) during MSLT naps was also quantified. RESULTS: JB3 demonstrated a significant overestimation of total sleep time (39.6 min, P < .0001) relative to PSG, but performed comparably to AW2. Although the ability of the JB3 to detect epochs of sleep was relatively good (sensitivity = 0.97), its ability to distinguish light, deep, and REM sleep was poor. Similarly, the JB3 did not correctly identify a single SOREMP during any MSLT nap opportunity. CONCLUSIONS: The JB3 did not accurately quantify or classify sleep in patients with suspected central disorders of hypersomnolence, and was particularly poor at identifying REM sleep. Thus, this device cannot be used as a surrogate for PSG or MSLT in the assessment of patients with suspected central disorders of hypersomnolence.

Associations Between Neuropsychological, Neurobehavioral and Emotional Functioning and Either Narcolepsy or Idiopathic Hypersomnia in Children and Adolescents.

STUDY OBJECTIVES: Narcolepsy and idiopathic hypersomnia are chronic neurological sleep disorders characterized by hypersomnolence or excessive daytime sleepiness. This review aims to systematically examine the scientific literature on the associations between narcolepsy and idiopathic hypersomnia and their effect on intellectual functioning, academic achievement, behavior, and emotion. METHODS: Published studies that examined those associations in children and adolescents were included. Studies in which children or adolescents received a clinical diagnosis, and in which the associated function was measured with at least one objective instrument were included. Twenty studies published between 1968 and 2017 were eligible for inclusion in this review. RESULTS: There does not appear to be a clear association between intellectual functioning and narcolepsy or idiopathic hypersomnia; however, limited research is an obstacle to obtaining generalizability. The variability in results from studies investigating associations between academic achievement and these two hypersomnolence disorders suggests that further research using standardized and validated assessment instruments is required to determine if there is an association. Behavior and emotion appear to be significantly affected by narcolepsy. Only two studies included populations of children and adolescents with idiopathic hypersomnia. CONCLUSIONS: Further research using larger populations of children and adolescents with narcolepsy or idiopathic hypersomnia while utilizing standardized and validated instruments is required, because the effect of these conditions of hypersomnolence varies and is significant for each individual.

Nocturnal sleep architecture in idiopathic hypersomnia: a systematic review and meta-analysis.

BACKGROUND: Current sleep medicine nosology places increased importance on nocturnal polysomnographic sleep recordings in the diagnosis of central nervous system disorders of hypersomnolence, particularly idiopathic hypersomnia (IH). OBJECTIVE: Determine what differences in sleep staging and architecture exist between IH and healthy controls using meta-analysis. METHODS: Systematic review identified relevant studies that included nocturnal polysomnography data for IH and healthy control groups. Meta-analysis compared standardized mean differences (Hedge's g) for total sleep time (TST), sleep onset latency (SOL), sleep efficiency (SE), rapid eye movement (REM) sleep percentage, slow wave sleep (SWS) percentage, and REM latency (REML). Moderator analyses were also conducted for variables with significant heterogeneity among studies. RESULTS: The meta-analysis included 10 studies. Relative to controls, IH demonstrated increased TST (pooled g = 0.92; 95% CI: 0.46 to 1.38, p < 0.0001) and REM percentage (pooled g = 0.36, 95% CI: 0.09 to 0.64, p = 0.01), decreased SOL (pooled g = -0.46; 95% CI: -0.81 to -0.12, p = 0.009) and SWS percentage (pooled g = -0.28, 95% CI: -0.50 to -0.07, p = 0.01), without significant differences in SE (pooled g = 0.03; 95% CI: -0.32 to 0.38, p = 0.86) or REML (pooled g = 0.14, 95% CI: -0.21 to 0.49, p = 0.42). Moderator analysis demonstrated a significant effect of sex on SE, with a higher proportion of women to men significantly predicting lower SE between in IH and controls (p < 0.0001). CONCLUSIONS: IH is associated with several changes in sleep staging and architecture relative to healthy persons, including alterations in REM and SWS not currently delineated in nosological constructs. Further research is indicated to clarify how these findings are related the pathophysiology of IH and related disorders.

Update on treatment for idiopathic hypersomnia.

INTRODUCTION: Idiopathic hypersomnia (IH) is a poorly characterized orphan central disorder of hypersomnolence responsible for excessive daytime sleepiness (EDS), prolonged nighttime sleep and sleep inertia that often require long-term symptomatic stimulant medication. To date, no drug has currently the authorization for the treatment of IH patients worldwide. Areas covered: The authors reviewed data on pharmacological treatment of IH obtained from published literature (Medline/PubMed/Web of Science) and Clinicaltrial.gov database from 1997 to 2017. Most of data on treatment of IH derived from observational studies and case series with only three well-designed clinical trials available. Expert opinion: In two recent randomized, double-blind, placebo-controlled trials, modafinil improves EDS in IH. Most of other wakefulness-promoting agents labeled for narcolepsy have similar efficacy in cases series of IH patients. Pitolisant and sodium oxybate show promising results in two retrospective studies. The efficacy of γ-aminobutyric acid-A receptor antagonists on objective EDS needs to be clarified. All these medications are used off-label for the management of EDS in IH. Specific clinical instruments and objective tests are required in IH to better evaluate the severity of EDS and responsiveness to medications, but also prolonged sleep and sleep inertia, to optimize the whole management of IH patients.

Test-Retest Reliability of the Multiple Sleep Latency Test in Central Disorders of Hypersomnolence.

Study Objectives: To assess the test-retest reliability of the polysomnography-multiple sleep latency test (PSG-MSLT) diagnostic classification and measures and to study the determinants of its variability in patients with narcolepsy type 1 (NT1) or with noncataplectic central disorders of hypersomnolence (NCHS): type 2 (NT2), idiopathic hypersomnia (IH), and unspecified hypersomnolence (unspecified excessive daytime sleepiness [UnsEDS]). Methods: PSG-MSLT in drug-free conditions was administered twice (median interval of 1.9 years) in 22 patients with NT1 (10 males, median age 31.2 years) and 75 patients with NCHS (32 males, median age 25.7 years). Results: At the first PSG-MSLT, patients with NCHS were classified as having NT2 (22.7%), IH (26.7%), or UnsEDS (50.6%). A positive PSG-MSLT was confirmed in 72.7% of NT1. The classification consistency at retesting was significantly lower for the NT2 (47.1%), IH (25.0%), and UnsEDS (42.1%) categories than NT1 (81.3%). The between-test mean sleep latency (MSL) variability was significantly different in NT1 and NCHS, with higher changes in NT2 and lower in NT1. A longer test-retest interval was associated with improved MSL and MSLT normalization. Between-test variations in SOREMP number were associated with changes in nocturnal REM sleep parameters and MSL. No association was found with the clinical decision to repeat the evaluation or the disease clinical course. Conclusion: The PSG-MSLT measures and classification are not stable in patients with NCHS, with frequent diagnostic changes, particularly for NT2 and IH, compared with NT1. MSLT needs to be repeated at regular intervals to confirm a stable hypersomnia and provide an accurate diagnosis of NT2 and IH.

Altered Regional Cerebral Blood Flow in Idiopathic Hypersomnia.

Study Objectives: Idiopathic hypersomnia is characterized by excessive daytime sleepiness, despite normal or long sleep time. Its pathophysiological mechanisms remain unclear. This pilot study aims at characterizing the neural correlates of idiopathic hypersomnia using single photon emission computed tomography. Methods: Thirteen participants with idiopathic hypersomnia and 16 healthy controls were scanned during resting wakefulness using a high-resolution single photon emission computed tomography scanner with 99mTc-ethyl cysteinate dimer to assess cerebral blood flow. The main analysis compared regional cerebral blood flow distribution between the two groups. Exploratory correlations between regional cerebral blood flow and clinical characteristics evaluated the functional correlates of those brain perfusion patterns. Significance was set at p < .05 after correction for multiple comparisons. Results: Participants with idiopathic hypersomnia showed regional cerebral blood flow decreases in medial prefrontal cortex and posterior cingulate cortex and putamen, as well as increases in amygdala and temporo-occipital cortices. Lower regional cerebral blood flow in the medial prefrontal cortex was associated with higher daytime sleepiness. Conclusions: These preliminary findings suggest that idiopathic hypersomnia is characterized by functional alterations in brain areas involved in the modulation of vigilance states, which may contribute to the daytime symptoms of this condition. The distribution of regional cerebral blood flow changes was reminiscent of the patterns associated with normal non-rapid-eye-movement sleep, suggesting the possible presence of incomplete sleep-wake transitions. These abnormalities were strikingly distinct from those induced by acute sleep deprivation, suggesting that the patterns seen here might reflect a trait associated with idiopathic hypersomnia rather than a non-specific state of sleepiness.

Hypocretin measurement: shelf age of radioimmunoassay kit, but not freezer time, influences assay variability.

The hypothalamic peptide hypocretin 1 (orexin A) may be assayed in cerebrospinal fluid to diagnose narcolepsy type 1. This testing is not commercially available, and factors contributing to assay variability have not previously been comprehensively explored. In the present study, cerebrospinal fluid hypocretin concentrations were determined in duplicate in 155 patient samples, across a range of sleep disorders. Intra-assay variability of these measures was analyzed. Inter-assay correlation between samples tested at Emory and at Stanford was high (r = 0.79, p < 0.0001). Intra-assay correlation between samples tested in duplicate in our center was also high (r = 0.88, p < 0.0001); intra-assay variability, expressed as the difference between values as a percentage of the higher value, was low at 9.4% (SD = 7.9%). Although both time the sample spent in the freezer (r = 0.16, p = 0.04) and age of the kit used for assay (t = 3.64, p = 0.0004) were significant predictors of intra-kit variability in univariate analyses, only age of kit was significant in multivariate linear regression (F = 4.93, p = 0.03). Age of radioimmunoassay kit affects intra-kit variability of measured hypocretin values, such that kits closer to expiration exhibit significantly more variability.

Diurnal and nocturnal cardiovascular variability and heart rate arousal response in idiopathic hypersomnia.

OBJECTIVES: Autonomic nervous system dysfunction has been described in narcolepsy with cataplexy affecting sympathetic functions. In this study we analyzed whether altered diurnal and nocturnal cardiovascular control is present in idiopathic hypersomnia (IH). METHODS: Fourteen drug-free patients aged 26.2 ± 7 years and 14 age-matched controls were examined. Clinical data, 24-h polysomnography, heart rate (HR) variability, and the HR response to spontaneous arousal were available. RESULTS: Sleep macrostructure was comparable between controls and patients, with the latter having significantly longer sleep time, a higher number of sleep cycles (p < 0.0001), and low sleep efficiency (p < 0.01). The HR variability indices did not differ between groups, except for the rise of high frequency (HF) and HFnu in patients (p < 0.05) associated with blunted sympathetic indices (p < 0.01). These parasympathetic alterations were present for light, slow wave, and rapid eye-movement sleep and persisted for all sleep cycles. Compared to controls, the HR arousal response was significantly higher (p < 0.01) in patients starting before the arousal onset and persisting into the post-arousal period. CONCLUSIONS: In IH patients a dysfunction of the parasympathetic activity during awake and sleep and an altered autonomic response to arousals are present. These findings suggest an impaired parasympathetic function that may explain some vegetative symptoms present in this type of central hypersomnia.

Decreased sleep stage transition pattern complexity in narcolepsy type 1.

OBJECTIVE: To analyze the complexity of the nocturnal sleep stage sequence in central disorders of hypersomnolence (CDH), with the hypothesis that narcolepsy type 1 (NT1) might exhibit distinctive sleep stage sequence organization and complexity. METHODS: Seventy-nine NT1 patients, 22 narcolepsy type 2 (NT2), 22 idiopathic hypersomnia (IH), and 52 patients with subjective hypersomnolence (sHS) were recruited and their nocturnal sleep was polysomnographically recorded and scored. Group between-stage transition probability matrices were obtained and compared. RESULTS: Patients with NT1 differed significantly from all the other patient groups, the latter, in turn, were not different between each other. The individual probability of the R-to-N2 transition was found to be the parameter showing the difference of highest significance between the groups (lowest in NT1) and classified patients with or without NT1 with an accuracy of 78.9% (sensitivity 78.5% and specificity 79.2%), by applying a cut-off value of 0.15. CONCLUSIONS: The main result of this study is that the structure of the sleep stage transition pattern of hypocretin-deficient NT1 patients is significantly different from that of other forms of CDH and sHS, with normal hypocretin levels. SIGNIFICANCE: The lower probability of R-to-N2 transition occurrence in NT1 appears to be a reliable polysomnographic feature with potential application at the individual level, for supportive diagnostic purposes.

Which diagnostic findings in disorders with excessive daytime sleepiness are really helpful? A retrospective study.

Due to extensive clinical and electrophysiological overlaps, the correct diagnosis of disorders with excessive daytime sleepiness is often challenging. The aim of this study was to provide diagnostic measures that help discriminating such disorders, and to identify parameters, which don't. In this single-center study, we retrospectively identified consecutive treatment-naïve patients who suffered from excessive daytime sleepiness, and analyzed clinical and electrophysiological measures in those patients in whom a doubtless final diagnosis could be made. Of 588 patients, 287 reported subjective excessive daytime sleepiness. Obstructive sleep apnea is the only disorder that could be identified by polysomnography alone. The diagnosis of insufficient sleep syndrome relies on actigraphy as patients underestimate their sleep need and the disorder shares several clinical and electrophysiological properties with both narcolepsy type 1 and idiopathic hypersomnia. Sleep stage sequencing on MSLT appears helpful to discriminate between insufficient sleep syndrome and narcolepsy. Sleep inertia is a strong indicator for idiopathic hypersomnia. There are no distinctive electrophysiological findings for the diagnosis of restless legs syndrome. Altogether, EDS disorders are common in neurological sleep laboratories, but usually cannot be diagnosed based on PSG and MSLT findings alone. The diagnostic value of actigraphy recordings can hardly be overestimated.

Decline of CSF orexin (hypocretin) levels in Prader-Willi syndrome.

Prader-Willi syndrome is a congenital neurodevelopmental disorder resulting from deletion of the paternal copies of genes within the chromosome region 15q11-q13. Patients with Prader-Willi syndrome often exhibit excessive daytime sleepiness, excessive appetite, and obesity. As is the case in narcolepsy, orexin (hypocretin) may be responsible for these symptoms. However, reports showing cerebrospinal fluid orexin levels in Prader-Willi syndrome patients have been limited. The aim of this study was to examine the relationship between the characteristic symptoms of Prader-Willi syndrome and cerebrospinal fluid orexin levels. We clinically identified 14 Prader-Willi syndrome patients and examined their cerebrospinal fluid orexin levels. A total of 12 patients with a 15q11-q13 deletion and two patients with maternal uniparental disomy of chromosome 15 were identified. A total of 37 narcoleptic patients and 14 idiopathic hypersomnia patients were recruited for comparison. Cerebrospinal fluid orexin levels (median [25-75 percentiles]) in the 14 Prader-Willi syndrome patients were intermediate (192 [161-234.5] pg/ml), higher than in the narcoleptic patients, but lower than in the idiopathic hypersomnia patients. Body mass index of the Prader-Willi syndrome patients was higher than in the narcoleptic and idiopathic hypersomnia patients. There was also a negative correlation between Epworth sleepiness scale scores and orexin levels in Prader-Willi syndrome patients. Decreased cerebrospinal fluid orexin levels in Prader-Willi syndrome may play an important role in severity of obesity and excessive daytime sleepiness.

Idiopathic hypersomnia.

Idiopathic hypersomnia continues to evolve from the concept of "sleep drunkenness" introduced by Bedrich Roth in Prague in 1956 and the description of idiopathic hypersomnia with two forms, polysymptomatic and monosymptomatic, by the same Bedrich Roth in 1976. The diagnostic criteria of idiopathic hypersomnia have varied with the successive revisions of the International classifications of sleep disorders, including the recent 3rd edition. No epidemiological studies have been conducted so far. Disease onset occurs most often during adolescence or young adulthood. A familial background is often present but rigorous studies are still lacking. The key manifestation is hypersomnolence. It is often accompanied by sleep of long duration and debilitating sleep inertia. Polysomnography (PSG) followed by a multiple sleep latency test (MSLT) is mandatory, as well as a 24 h PSG or a 2-wk actigraphy in association with a sleep log to ensure a total 24-h sleep time longer than or equal to 66O minutes, when the mean sleep latency on the MSLT is longer than 8 min. Yet, MSLT is neither sensitive nor specific and the polysomnographic diagnostic criteria require continuous readjustment and biologic markers are still lacking. Idiopathic hypersomnia is most often a chronic condition though spontaneous remission may occur. The condition is disabling, sometimes even more so than narcolepsy type 1 or 2. Based on neurochemical, genetic and immunological analyses as well as on exploration of the homeostatic and circadian processes of sleep, various pathophysiological hypotheses have been proposed. Differential diagnosis involves a number of diseases and it is not yet clear whether idiopathic hypersomnia and narcolepsy type 2 are not the same condition. Until now, the treatment of idiopathic hypersomnia has mirrored that of the sleepiness of narcolepsy type 1 or 2. The first randomized, double-blind, placebo-controlled trials of modafinil have just been published, as well as a double-blind, placebo-controlled trial of clarithromycine, a negative allosteric modulator of the γ-aminobutyric acid-A receptor.

Polysomnographic Assessment of Sleep Comorbidities in Drug-Naïve Narcolepsy-Spectrum Disorders--A Japanese Cross-Sectional Study.

This is a large cross-sectional study which aimed to investigate comorbidity rate, degree of sleep-related breathing disorder, polysomnigraphically diagnosible rapid eye movement sleep behavior disorder/rapid eye movement sleep without atonia and periodic limb movements during sleep in Japanese drug-naïve patients with narcolepsy-spectrum disorders. A total of 158 consecutive drug naïve patients with narcolepsy with cataplexy, 295 patients with narcolepsy without cataplexy and 395 patients with idiopathic hypersomnia without long sleep time were enrolled. From retrospectively analyzed data of nocturnal polysomnography and multiple sleep latency test, higher rates of periodic limb movements during sleep (> = 15 h(-1)) (10.2%) and polysomnographically diagnosable rapid eye movement sleep behavior disorder (1.9%) were found in patients with narcolepsy with cataplexy. They had more severe periodic limb movements during sleep especially during rapid eye movement sleep and higher percentages of rapid eye movement sleep without atonia than the other two patient groups. In the present large sample study, Japanese drug naïve patients with narcolepsy with cataplexy showed the highest comorbidity rates of periodic limb movements during sleep, polysomnographically diagnosable rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia among those with the other narcolepsy-spectrum disorders; the rates were lower than those for Western patients.