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The aim of this study was to assess age- and sex-related differences in multiple sleep latency test (MSLT) results and in the performance of the Epworth Sleepiness Scale (ESS) at classifying objective hypersomnia (mean sleep latency (MSL) ≤ 8 min). We studied 480 consecutive adults (39.3 ± 15.3 years old [18–93], 67.7% female) who underwent hypersomnia evaluation. We fit linear regression models to investigate associations between age and sex and sleep latencies (mean and for every nap), after adjusting for total sleep time and sleep efficiency (on polysomnography), and REM-suppressing antidepressant effect. A logistic regression was performed to assess whether age and sex were associated with sleep-onset REM period (SOREMP) occurrence. ROC analysis assessed the diagnostic performance of ESS scores to identify a MSL ≤ 8 min in different age/sex groups. For every 10 years of age, there was 0.41 (95% CI 0.11–0.72, p = 0.008) min reduction in MSL. Objectively (MSL ≤ 8 min) sleepy patients had shortening of latencies in naps 4 and 5 with aging. Female sex was associated with a higher MSL only in patients with MSL > 8 min. A 2.4% reduction in the odds of SOREMP occurrence was observed for every year of age in objectively sleepy patients (p = 0.045). ESS scores had a better diagnostic performance in older (≥ 50 years old) men than younger (< 50 years old) women (p < 0.05). Older patients with objectively confirmed hypersomnia may be sleepier in later naps, possibly due to less restorative naps and/or circadian rhythm factors. Self-reported sleepiness is more predictive of objective sleepiness in older men than younger women. [ABSTRACT FROM AUTHOR]

Central hypersomnia (HS) and delayed sleep–wake phase disorder (DSWPD) appear commonly in adolescents, and they severely reduce quality of life and have an enormous impact on academic performance and other aspects of development. Although these disorders are thought to be considerably different in etiology, it is sometimes difficult to distinguish them because of their similar clinical features. This study aimed to compare psychosocial factors and sleep study findings between HS and DSWPD in teenagers. The clinical data of 89 teenagers who visited the psychiatric section of the Sleep Medicine Center of Nihon University Itabashi Hospital from January 2013 to December 2019 were analyzed. Psychosocial factors were evaluated at the first visit, and polysomnography (PSG) and the multiple sleep latency test (MSLT) were performed for patients deemed to require definitive diagnosis. Compared with patients with HS, those with DSWPD had a higher rate of mother's employment, introversion, adjustment problems, events that triggered the disorder, concurrent mental disorders, habitual lateness, and difficulty attending school or work. PSG did not show any differences in sleep parameters between the two disorders, except for sleep latency. On the MSLT, sleep latency was shorter in those with HS on the second, third, and fourth tests. The present results suggest that focusing on psychosocial factors could be useful for differential diagnosis of the two disorders that appear commonly in adolescents. [ABSTRACT FROM AUTHOR]

A woman in her 50 s with Kleine–Levin syndrome (KLS) was referred to our sleep clinic for recurrent episodes of sleep hypersomnia lasting for two to 3 days, despite attempts to remain awake. These episodes were unaccompanied by anxiety or depression, increased appetite, increased sex drive, irritability, or hallucinations, and had first appeared during chemotherapy for malignant lymphoma. Video polysomnography revealed mild obstructive sleep apnea syndrome (apnea–hypopnea index 7.9/h), but no other abnormalities. All blood tests and brain imaging investigations, including brain MRI and A 123I-ioflupane SPECT, yielded normal results. Oral L-carnitine was found to be effective for shortening the period of hypersomnolence, reducing the degree of hypersomnolence, and prolonging the inter-episode period. Since it has been reported that alkylating agents may induce carnitine deficiency, the present observations appear to support the involvement of carnitine in the onset of KLS. [ABSTRACT FROM AUTHOR]

Purpose: Multiple sleep-onset rapid eye movement periods (SOREMPs) are involved in the pathophysiology of narcolepsy, but it is not clear whether the lack of multiple SOREMPs is associated with the pathophysiology of idiopathic hypersomnia or not. We examined the significance of multiple SOREMPs in patients with pathological sleep prolongation. Methods: Participants were consecutive patients complaining of unexplained sleepiness and agreed to a 3-day-sleep studies; 24 h polysomnography (PSG) followed by standard PSG and multiple sleep latency test (MSLT). Forty-one (26 females, 21.9 ± 8.1 years old, BMI 20.4 ± 2.3 kg/m2) of 54 eligible patients without other sleep pathologies showed pathological sleep prolongation. We subdivided them into those with and without multiple SOREMPs on MSLT and compared clinical and PSG variables between groups. Results: Six of 41 (14.6%) patients showed multiple SOREMPs on MSLT. There were almost no differences in sleep variables between those with and without multiple SOREMPs. We only found shorter mean sleep latency on MSLT and more REM cycles on 24 h PSG in those with multiple SOREMPs (adjusted p = 0.016 and 0.031). The frequencies of REM-related phenomena and clinical symptoms related to idiopathic hypersomnia were not different between groups. Conclusion: Our results indicated that patients with pathological sleep prolongation had the same clinical profiles regardless of the status of SOREMPs, suggesting the absence of multiple SOREMPs, prerequisite for the diagnosis of idiopathic hypersomnia, is not a specific feature of pathological sleep prolongation. Confirmation of sleep prolongation alone could be a diagnostic tool for idiopathic hypersomnia. [ABSTRACT FROM AUTHOR]

Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer's disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations. [ABSTRACT FROM AUTHOR]

The aims of the study are to investigate the prevalence of ADHD in delayed sleep phase disorder (DSPD) patients and to explore the relationship between circadian phase and ADHD symptoms, using the dim light melatonin onset (DLMO), and to compare this relationship with patients with sleep problems other than DSPD. 353 adult patients with sleep problems were assessed for self-reported ADHD symptoms using ADHD rating scale, self-reported sleep disorders using Holland Sleep Disorders Questionnaire (HSDQ), and circadian rhythmicity using salivary DLMO. From the 353 patients with sleep problems, 63 were designated as DSPD and 107 (30.3%) reported probable ADHD. Probable ADHD was reported by 47.6% of the DSPD patients and by 26.9% of the non-DSPD patients (p = 0.059). The DSPD group showed significant higher total ADHD-RS scores (p = 0.011). In the probable ADHD group more patients were designated as DSPD (28%) compared to the non-ADHD group (13.6% [χ2 = 10.402, p = 0.001]). Also 20 min later, DLMO (22:46 h) was found (p = 0.017) and more positive HSDQ scores on insomnia, parasomnia, hypersomnia, and sleep-related breathing disorders were reported in the probable ADHD group than in the non-probable ADHD group (χ2 resp. 16.07; p < 0.001, 9.245; p = 0.002, 19.391; p < 0.00 and 5.865; p = 0.059). The data suggest a high prevalence of probable ADHD in DSPD patients and increased prevalence of DSPD and other sleep disorders in patients with probable ADHD. Consequence is that awareness of these findings might help with treatment of both DSPD and ADHD. [ABSTRACT FROM AUTHOR]

Purpose: Symptomatic narcolepsy is characterized as low orexin (hypocretin) levels (≤ 110 pg/ml) due to neurological diseases. However, we have experienced the cases that show symptoms similar to narcolepsy, complaining of pathological sleepiness even in cases with intermediate orexin levels (110-200 pg/ml). Therefore, we reevaluated the previously reported cases to make the concept of disease to the group in which the orexin concentration is intermediate.Methods: Although orexin-deficient symptomatic narcolepsy has been reported worldwide, facilities that are capable of measuring orexin are still limited. Currently, our laboratory handles with almost all the CSF samples from Asian countries for determining orexin levels. We measured over 2500 cases including 182 cases suspected of symptomatic narcolepsy/hypersomnolence. Therefore, we subdivided these cases into three groups according to CSF orexin levels, low orexin group (≤ 110 pg/ml), intermediate orexin group (110-200 pg/ml), and normal orexin group (> 200 pg/ml). We defined "symptomatic hypersomnia" for hypersomnolence cases with intermediate CSF orexin levels. MSLT was recommended but not necessary. Short sleep latency (< 8 min) without SOREMPs should be observed on MSLT when performed. We compared symptoms (excessive daytime sleepiness and cataplexy) and objective measures (mean sleep latency and number of SOREMPs in MSLT) among the three groups, attempting to characterize the "symptomatic hypersomnia" group.Result: Among the 182 cases with clinical hypersomnolence, there were 32 cases of symptomatic narcolepsy (16%) and 14 cases of symptomatic hypersomnia (8%). Causative diseases of symptomatic narcolepsy cases consist of immune-mediated demyelinating disorders (34%) and neurodegenerations (19%), whereas those of symptomatic hypersomnia are immune-mediated demyelinating disorders (43%) and encephalopathies (14%). Significant differences were not found between orexin levels and the existence of cataplexy, SOREMPs, and short sleep latency among three hypersomnolence groups. From these results, we found that it is difficult to estimate orexin concentration from subjective symptoms and PSG/MSLT findings.Conclusion: We identified that 32 symptomatic narcolepsy and 14 cases of symptomatic hypersomnolence with intermediate CSF orexin levels. We proposed these latter cases as a novel category of "symptomatic hypersomnia". Currently, symptomatic hypersomnia cases with intermediate orexin levels or short sleep latency (< 8 min) without SOREMPs were not classified as a specific entity. However, symptomatic hypersomnia had similar severity of hypersomnolence symptoms to symptomatic narcolepsy. Therefore, these cases including equivalent pathophysiology are enough to make a comparable category as "symptomatic hypersomnia". Since it is difficult to estimate the orexin concentration from subjective symptoms and physiological findings (PSG/MSLT), further studies for the characterization of "symptomatic hypersomnia" and understanding its pathophysiology are necessary. [ABSTRACT FROM AUTHOR]

Patients with attention deficit/hyperactivity disorder (ADHD) suffer from hypersomnia; indeed, we have often encountered ADHD patients that fulfill the diagnostic criteria for narcolepsy type 2 (NA 2). Because not all patients with NA 2 carry the HLA-DQB1*06:02 allele, which is closely associated with narcolepsy type 1 (NA 1), NA 2 is believed to be heterogeneous. To reveal the contribution of ADHD in hypersomnia, we studied the characteristics of hypersomnia patients with ADHD, especially those diagnosed with NA 2. Participants were 77 of 185 consecutive outpatients who were diagnosed with NA 2 or idiopathic hypersomnia. We investigated sleep variables in (a) participants with hypersomnia with/without ADHD and (b) patients with NA 2 with/without ADHD and those with/without the DQB1*06:02 allele. The proportion of those diagnosed with NA 2 was higher in hypersomnia patients with ADHD compared to those without ADHD. None of the NA 2 patients with ADHD carried the narcolepsy-specific DQB1*06:02 allele. These patients with NA 2 with ADHD exhibited short REM latencies on the MSLT (similarly to DQB1*06:02-positive patients with NA 2 without ADHD), but less REMrelated phenomena than patients with NA 2 without ADHD. Hypersomnia patients with ADHD tended to show short REM latencies, and fulfilled NA 2 diagnostic criteria in the absence of the DQB1*06:02 allele, suggesting a different etiology from NA 1. These findings support the hypotheses of noradrenergic dysregulation and delayed brain maturation that have been proposed for the pathophysiology of ADHD. [ABSTRACT FROM AUTHOR]

Reliability of mean sleep latency testing (MSLT) over consecutive days in patients with hypersomnia is unknown. We reviewed MSLTs of patients with hypersomnia without cataplexy who underwent our two consecutive MSLT protocol ( N = 29). Average MSLs were 10.9 and 10.9 min for day 1 and 2, respectively. Agreement for pathological hypersomnia (defined as MSL ≤8 min) between MSLT days showed k = 0.85 for all ( N = 29) and k = 0.76 for those without sleep apnea ( N = 20). In patients with subjective complaints of hypersomnia, a single MSLT is sufficient (vs. addition of second day MSLT) in the setting of carefully implemented protocol controlling for potential confounding variables. [ABSTRACT FROM AUTHOR]

A sleep diary is often employed for diagnosing and treating hypersomnia. However, its reliability needs to be evaluated because overlooked chronic sleep insufficiency could be misdiagnosed as narcolepsy. In this study, we compared simultaneous sleep measurements using a sleep diary and by actigraphy in patients visiting our sleep clinic for the first time with complaints of excessive daytime sleepiness. Of the 28 patients enrolled, 24 complied with both these requirements. In this population, the results obtained using a sleep diary tended to estimate a statistically significant earlier sleep onset time and longer total sleep time than those via actigraphy. For total sleep time, this tendency was more prominent in patients with a higher Epworth Sleepiness Scale score. In 5 of the 24 (20.8%) patients, the sleep diary records indicated >6 h of total sleep time while the actigraphy records indicated <6 h of total sleep time, with a discrepancy of >1 h. These results suggested that sleep insufficiency in hypersomnia patients may be overlooked when their sleep time is assessed using only a sleep diary in the initial phase of the diagnostic procedure, and the simultaneous use of actigraphy may be preferable in this assessment. [ABSTRACT FROM AUTHOR]

This study tested a well-known but as yet nonoperationalized means for measuring REM sleep disturbance in patients with narcolepsy at night. We retrospectively analyzed polysomnographies of patients with narcolepsy with cataplexy (n = 18), narcolepsy without cataplexy (n = 12), idiopathic hypersomnia (n = 22) and healthy controls (n = 33) with regard to the number of wake-REM sleep transitions as a measurement for REM sleep disturbance at night. We found a significantly higher number of transitions between wake and REM sleep (14.17 ± 2.00) in patients with narcolepsy with cataplexy than in healthy controls (3.70 ± 1.00; p < 0.001) and patients with idiopathic hypersomnia (5.36 ± 1.00; p = 0.001). These results confirm previous findings that REM sleep disturbance is a specific phenomenon for narcolepsy with cataplexy. Additionally we found that wake-REM sleep transitions provide a useful marker for operationalizing and measuring this sleep disturbance. A possible mediating factor for this observation is the hypocretin-1 system, which is deficient in narcolepsy with cataplexy but intact in idiopathic hypersomnia. The number of wake-REM sleep transitions may thus become a useful additional means for the differential diagnosis of narcolepsy. [ABSTRACT FROM AUTHOR]

Economo observed in 1930 that many cases of lethargy begin with a severe insomnia and fever followed by a long-lasting hypersomnia. We confirmed this evidence in animal cases where chemical lesions of the preoptic region resulted in severe insomnia accompanied with fever. Moreover, a subsequent pharmacological inhibition of neuronal activity of the posterior ventrolateral hypothalamus caused transient hypersomnia in these insomniac animals. However, vigilance states of the experimental animals returned to normal after several weeks, suggesting that the irreversible Economo's lethargy may be due to the damage of passing fibers in the ventral hypothalamus. Similarly, chemical lesions of neurons of the midbrain reticular formation did not induce coma nor hypersomnia, which is inconsistent with lesion studies reported by Lindsley et al. using electrolytic coagulation. This fact further supports the importance of passing fibers in the midbrain. In addition, Mauthner in 1890 observed hypersomnia and abnormal eye movements in lethargic patients infected by 'nona', suggesting the implication of the periaqueductal gray in the vicinity of the 3 nerve. We confirmed this hypothesis: hypersomnia was accompanied by a significant increase in REM sleep after chemical inactivation of a small part of the ventrolateral periaqueductal gray and dorsal portion of the subjacent reticular formation. On the other hand, removal of the tele- and di-encephalon caused an irreversible coma and abolished the daily rhythm of REM. This state of sleep is also regulated by forebrain structures and internal clocks in the suprachiasmatic nucleus. [ABSTRACT FROM AUTHOR]

Narcolepsy is a chronic sleep disorder, and dysfunction in hypocretinergic neurotransmission has been shown to underlie the pathophysiology of this disorder. Recently, two neuromyelitis optica patients with hypersomnia, hypothalamic lesions, serum anti-aquaporin-4 (AQP4) antibodies, and reduced cerebrospinal fluid hypocretin levels were reported. We hypothesized that anti-AQP4 antibodies induce hypocretin dysfunction leading to hypersomonia in a subgroup of narcolepsy or hypersomnia patients. In this study, we screened for anti-AQP4 antibodies in sera from 251 patients with narcolepsy, 34 with other hypersomnias, and 200 healthy controls by using the radioligand binding assay method. A positive result for anti-AQP4 antibodies was found only in one healthy control subject. All the hypersomnia patients were negative for this antibody. Our results indicated that anti-AQP4 antibody is not useful as a diagnostic marker for narcolepsy and other hypersomnias. [ABSTRACT FROM AUTHOR]

Narcolepsy and other sleep disorders are underrecognized in children; therefore, the final diagnosis and initiation of treatment is often delayed. This is due to the fact that the expression of sleep-related symptoms in children is often different from those of adults and polysomnography is generally difficult in children. CSF hypocretin-1 (orexin-A) measurement in adults demonstrated that low levels are highly specific to narcolepsy and this examination is now being established as a new diagnostic tool. In this study, we describe the spectrum of the hypocretin deficiency syndrome by analysis of CSF hypocretin-1 levels and clinical, polysomnography and human leukocyte antigen data in 38 pediatric and teenage patients with various sleep disorders and 120 patients with neurological conditions. The levels of CSF hypocretin-1 were significantly lower in narcolepsy compared to other neurological conditions. The measurement of hypocretin-1 is a useful diagnostic tool in pediatric narcolepsy, especially when other diagnostic information (e.g. polysomnography and human leukocyte antigen) is not sufficient. [ABSTRACT FROM AUTHOR]

The epidemiological study presented here was conducted to examine the association between sleep problems and restless legs syndrome (RLS) among a large sample taken from the general population of Japan. The presence of RLS was established by asking the subjects if they experienced a crawling sensation in their legs after going to bed. This survey was performed in June 2000, targeting a sample that was randomly selected from 300 communities throughout Japan. The questionnaire contained questions focusing on health consciousness, mental health, and sleep. A total of 26 705 participants completed the questionnaire. The prevalence of RLS was 3.0%, with a significant predominance in women. The prevalence of RLS increased significantly with advancing age. Multiple logistic regression analysis revealed that RLS was significantly associated with difficulty initiating sleep (odds ratio, OR = 2.58), excessive daytime sleepiness (OR = 2.28), difficulty maintaining sleep (OR = 1.71), non-restorative sleep (OR = 1.51), subjective insufficient sleep (OR = 1.36), and early morning awakening (OR = 1.21). These results suggest that the prevalence of RLS in Japan is lower than in northern European populations and that RLS is strongly associated with difficulty initiating sleep and excessive daytime sleepiness. [ABSTRACT FROM AUTHOR]

Kleine- Levin syndrome is characterized by recurrent episodes of hypersomnia with cognitive and behavioral impairments. Two years ago, a 56-year-old female patient developed episodic memory loss and calculation difficulties. One year ago, she complained of recurrent hypersomnia with hyperphagia. Episodes developed 1-2 times per month and each episode lasted 3-4 days. Electroencephalography showed 6-7 Hz diffuse background slowing during an episode. Neuropsychological tests revealed cognitive impairment and brain imaging showed normal between episodes. Polysomnography showed increased periodic limb movement and respiratory disturbance index. This is the case of Kleine- Levin syndrome like symptoms in a patient with cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Kleine-Levin syndrome (KLS) is an intriguing, severe, homogenous disease, with well defined clinical features, but no clear cause or treatment. Therefore studies on KLS were done exclusively with case report or series. There are limited systemic study comparing KLS with controls on phenomenology, cause, investigations and management. We report four cases of KLS presented to us along with core symptoms, hypomanic and catatonic features. Response to treatment also different with one case responded to lithium while others required combination of therapy. KLS is still evolving disorder having cluster of varying symptoms and response to treatment. This needs further exploration and higher studies [ABSTRACT FROM AUTHOR]

A 57-year old man became affected by excessive daytime sleepiness. Thereafter, he had difficulty in moving his left limbs and began to walk slowly. He had no particular past or family history. He had taken no medications. Neurologically, Parkinsonism was present. Sleep examinations revealed that the diagnostic criteria of narcolepsy without cataplexy were fulfilled. The orexin level in the cerebrospinal fluid (CSF) was undetectable (<40 pg/mL). HLA DR2 was negative. These factors led to a diagnosis of narcolepsy due to Parkinson's disease (PD). This is the first clear case of narcolepsy due to PD presenting a decreased CSF-orexin level. [ABSTRACT FROM AUTHOR]

In order to clarify the difference in clinical characteristics between narcolepsy-like hypersomnia without cataplexy, which is called essential hypersomnia syndrome (EHS), and narcolepsy, we compared background variables, symptoms and treatment outcomes between 19 EHS patients and 20 narcoleptic patients. The results indicated significantly milder rapid eye movement (REM)-related symptoms, longer sleep latencies on multiple sleep latency test and smaller dosages of psycho-stimulants for suppressing daytime sleepiness in EHS than in narcolepsy. Positive findings of HLA-DQB1*0602 were recognized in less than 40% of EHS patients. We speculated that EHS would form a subgroup of hypersomnia in which disease severity is milder, and treatment response is better than typical narcolepsy. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses topics within the issue including encephalon-related psychic symptoms; clinical studies of periodic somnolence; and treatment of psychiatry and hypersomnia.

Abstract The level of hypocretin-1 (orexin A) is reported to be low in the cerebrospinal fluid (CSF) of subjects with narcolepsy. We measured the CSF level of hypocretin-1 of two young hypersomniacs. The first subject was a 9-year-old boy who exhibited cataplexy, and was demonstrated to be human leukocyte antigen-DR2 (HLA-DR2) positive. The second subject was a 16-year-old boy who exhibited no cataplexy and was HLA-DR2 negative. When excessive daytime sleepiness ensued, appetite and bodyweight were increased in case 1 but not in case 2. The level of CSF hypocretin-1 was undetectably low and within normal limits in case 1 and case 2, respectively. It appears to be important to measure the CSF level of hypocretin-1 in the diagnosis and treatment of narcolepsy. [ABSTRACT FROM AUTHOR]

Presents a study in which a toxin to specifically destroy cells in the hypothalamus expressing a hypocretin receptor. Production of the toxin by conjugating the endogenous ligand, HCRT-2, to the ribosome inactivating protein, saporin; Indication that hypersomnia in the rats with the lesions of the lateral and posterior hypothalamus may be associated not only with the HCRT/OX cell loss , but also with the loss of other neurons.

Measures cerebrospinal fluid (CSF) hypocretin-1 levels in Japanese patients with narcolepsy-cataplexy, narcolepsy without cataplexy, essential hypersomnia, idiopathic hypersomnia and obstructive sleep apnea. Undetectable or very low hypocretin-1 levels in the majority of narcolepsy-cataplexy patients.