Nocturnal Sleep Fragmentation Research Articles

Significant nocturnal wakefulness after sleep onset in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystemic disease with a multifactorial pathogenesis involving dietary, environmental, and genetic factors. Previous mouse models suggested that circadian misalignment may additionally influence its development as it influences metabolism in diverse organs including the liver. Further, data from sleep questionnaires proved sleep-wake disruption in patients with MASLD. We objectively assessed sleep-wake rhythms in patients with biopsy-proven MASLD (n = 35) and healthy controls (HC, n = 16) using actigraphy 24/7 for 4weeks. With the aim to re-align sleep rhythms a single standardized sleep hygiene education session was performed after 2weeks. Actigraphy data revealed that MASLD patients had more awakenings per night (MASLD vs. HC 8.5 vs. 5.5, p = 0.0036), longer wakefulness after sleep onset (MASLD vs. HC 45.4min vs. 21.3min, p = 0.0004), and decreased sleep efficiency (MASLD vs. HC 86.5% vs. 92.8%, p = 0.0008) compared with HC despite comparable sleep duration. Patients with MASLD self-reported shorter sleep duration (MASLD vs. HC 6h vs. 6h 45min, p = 0.01) and prolonged sleep latency contributing to poorer sleep quality. Standardized sleep hygiene education did not produce significant changes in sleep parameters. Our findings indicate fragmented nocturnal sleep in patients with MASLD, characterized by increased wakefulness and reduced sleep efficiency, perceived subjectively as shortened sleep duration and delayed onset. A single sleep hygiene education session did not improve sleep parameters.

Measuring energy expenditure in narcolepsy using doubly-labelled water and respiration chamber calorimetry.

Hypocretin deficiency causes type 1 narcolepsy, a condition characterised by excessive daytime sleepiness, cataplexy, and fragmented nocturnal sleep. Two-thirds of people with narcolepsy are also overweight, of which half are obese. The pathophysiology behind weight gain in people with narcolepsy remains unknown. We assessed a possible decrease in energy expenditure as a cause for overweight in narcolepsy using respiration chamber calorimetry and doubly labelled water. Ten males with type I narcolepsy and nine matched (for age, sex, and BMI) healthy controls were enrolled. Subjects stayed in a respiration chamber for 24 hours. They subsequently received doubly labelled water and wore an accelerometer for two weeks to assess energy expenditure and physical activity under daily living conditions. Total daily energy expenditure, resting energy expenditure, overnight metabolic rate, physical activity level and activity-induced energy expenditure were measured. No significant differences were found in resting energy expenditure, mean 24-hour respiration chamber energy expenditure, overnight metabolic rate and activity-induced energy expenditure when comparing people with narcolepsy type 1 to controls. Physical activity was also comparable between groups. Energy expenditure in narcolepsy type 1 is similar to matched controls, suggesting comparable metabolism and physical activity rates. It remains possible that metabolic changes are most pronounced around disease onset. In addition, patients had to discontinue their medication which may have influenced the results. Still, our findings suggest that other factors may also play a role in weight gain in narcolepsy, such as differences in dietary behaviour.

High nocturnal sleep fragmentation is associated with low T lymphocyte P2Y11 protein levels in narcolepsy type 1.

Study ObjectivesNarcolepsy type 1 (NT1) is associated with hypocretin neuron loss. However, there are still unexplained phenotypic NT1 features. We investigated the associations between clinical and sleep phenotypic characteristics, the NT1-associated P2RY11 polymorphism rs2305795, and P2Y11 protein levels in T lymphocytes in patients with NT1, their first-degree relatives and unrelated controls.MethodsThe P2RY11 SNP was genotyped in 100 patients (90/100 H1N1-(Pandemrix)-vaccinated), 119 related and 123 non-related controls. CD4 and CD8 T lymphocyte P2Y11 protein levels were quantified using flow cytometry in 167 patients and relatives. Symptoms and sleep recording parameters were also collected.ResultsWe found an association between NT1 and the rs2305795 A allele (OR = 2, 95% CI (1.3, 3.0), p = 0.001). T lymphocyte P2Y11 protein levels were significantly lower in patients and relatives homozygous for the rs2305795 risk A allele (CD4: p = 0.012; CD8: p = 0.007). The nocturnal sleep fragmentation index was significantly negatively correlated with patients’ P2Y11 protein levels (CD4: p = 0.004; CD8: p = 0.006). Mean MSLT sleep latency, REM-sleep latency, and core clinical symptoms were not associated with P2Y11 protein levels.ConclusionsWe confirmed that the P2RY11 polymorphism rs2305795 is associated with NT1 also in a mainly H1N1-(Pandemrix)-vaccinated cohort. We demonstrated that homozygosity for the A risk allele is associated with lower P2Y11 protein levels. A high level of nocturnal sleep fragmentation was associated with low P2Y11 levels in patients. This suggests that P2Y11 has a previously unknown function in sleep-wake stabilization that affects the severity of NT1.

Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease.

A majority of patients with Alzheimer's disease (AD) experience some form of sleep disruption, including nocturnal sleep fragmentation, increased daytime napping, decreased slow-wave sleep (SWS, stage N3), and decreased rapid-eye-movement sleep (REM). Clinical studies are investigating whether such sleep disturbances are a consequence of the underlying disease, and whether they also contribute to the clinical and pathological manifestations of AD. Emerging research has provided a direct link between several of these sleep disruptions and AD pathophysiology, suggesting that treating sleep disorders in this population may target basic mechanisms of the disease. Here, we provide a comprehensive review of sleep disturbances associated with the spectrum of AD, ranging from the preclinical stages through dementia. We discuss how sleep interacts with AD pathophysiology and, critically, whether sleep impairments can be targeted to modify the disease course in a subgroup of affected AD patients. Ultimately, larger studies that fully utilize new diagnostic and experimental tools will be required to better define the most relevant sleep disturbance to target in AD, the interventions that best modulate this target symptom, and whether successful early intervention can modify AD risk and prevent dementia.

Sleep-related hypermotor epilepsy: prevalence, impact and management strategies.

Sleep-related hypermotor epilepsy (SHE), previously called nocturnal frontal lobe epilepsy (NFLE), is a focal epilepsy characterized by asymmetric tonic/dystonic posturing and/or complex hyperkinetic seizures occurring mostly during sleep. SHE fulfills the definition of rare disease with an estimated minimum prevalence of 1.8/100,000 individuals, and it represents about 10% of drug-resistant surgical cases. Although SHE and autosomal-dominant SHE (ADSHE) have been considered benign epileptic conditions for a long time, emerging data have shed light on the severity of this disorder and some peculiar features can impact negatively on the quality of life of SHE patients. In fact, seizure frequency can be very high, resulting in nocturnal sleep fragmentation with possible diurnal consequences such as excessive sleepiness and fatigue. Moreover, recent studies, adopting a systematic neuropsychological assessment, have shown deficits in memory, executive functions and visuo-spatial abilities in almost half of SHE patients. Intellectual disabilities and psychiatric disorders have also been reported in some genetic forms. SHE may also exert a negative effect on health-related quality of life, especially in domains pertaining to a patient’s role in the family, social context and patient’s illness experience.Despite a good response to pharmacological treatment, especially with carbamazepine, 30% of SHE patients suffer from drug-resistant seizures. Finally, recent studies suggest a poor prognosis in a high percentage of SHE patients with a 20.4% cumulative probability of achieving terminal remission at 10 years from onset. For selected drug-resistant SHE patients, epilepsy surgery is the only treatment offering high probability of recovery, both for seizures and for epilepsy-related sleep alterations.

The Association of Schizophrenia and Narcolepsy in Adolescents

As a rare and disabling neurological sleep disorder that is often diagnosed during adolescence, narcolepsy type 1 (NT1) has been described as a relatively homogeneous clinical syndrome of hypothalamic deficiency in hypocretin-1 (orexin) producing neurons. 1 Longstreth W.T. Koepsell T.D. Ton T.G. Hendrickson A.F. Belle G. The epidemiology of narcolepsy. Sleep. 2007; 30: 13-26 Crossref PubMed Scopus (328) Google Scholar , 2 Mignot E. Lammers G.J. Ripley B. et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002; 59: 1553-1562 Crossref PubMed Scopus (961) Google Scholar As up to 98% of patients are human leukocyte antigen DQB1*06:02 positive, an autoimmune-mediated hypothesis has been supported. 3 Bourgin P. Zeitzer J.M. Mignot E. CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol. 2008; 7: 649-662 Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar The core features include excessive daytime sleepiness (EDS), cataplexy, fragmented nocturnal sleep with vivid dreams, and hallucinations and sleep paralysis during sleep-wake transitions. Commonly, adolescents experience concurrent depression, stigmatization from peers, and their body mass index is higher than 98th percentile. 4 Ohayon M.M. Narcolepsy is complicated by high medical and psychiatric comorbidities: a comparison with the general population. Sleep Med. 2013; 14: 488-492 Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar

Management of Narcolepsy.

Narcolepsy type 1 (NT1) and type 2 (NT2) are two rare neurological diseases, classified as central disorders of hypersomnolence. The pathophysiology of NT1 is well known; it is caused by the selective destruction of hypocretin (Hcrt) neurons, by a highly suspected autoimmune process. On the contrary, little is known about NT2 etiology, sharing with NT1 somnolence and signs of dysregulation of rapid eye movement (REM) sleep, but not cataplexy. Management strategies are rather codified, at least in adults, with a lifelong treatment required in NT1, whereas no pharmacological study focused only on NT2 patients, with sometimes spontaneous improvement or disappearance of their symptoms. We recommend that medications and guidelines in NT2 should be the same as for NT1 (except for cataplexy), but the benefit risk ratio should be reassessed regularly. The main symptom in both diseases is a disabling excessive daytime sleepiness (EDS). First-line medications should be stimulants such as modafinil, armodafinil, or sodium oxybate, second-line methylphenidate and pitolisant, where available, and amphetamines as third-line therapy. Sodium oxybate has the advantage to be also effective to manage the fragmented nocturnal sleep, another common symptom in NT1. We advise to wait a few weeks with a stimulant drug before starting an anticataplectic treatment in NT1, except for severe cataplexy. Furthermore, cataplexy treatment should not be systematic. First-line strategy is the use of sodium oxybate, the only drug approved for cataplexy and EDS in adults. However, antidepressant agents such as venlafaxine are also commonly used, with few adverse effects and a good efficacy, although based on expert consensus only. A clinically relevant tool is required to quantify the severity of narcolepsy, subjective symptoms, and their consequences, to monitor the treatment efficacy, and to finally optimize narcolepsy management. In the future, Hcrt replacement or Hcrt agonists will certainly be options to treat NT1, but for now the different peptides do not cross easily the blood brain barrier. Immune-based therapies are other possibilities in NT1, at disease onset, with already some successful attempts to slow down or stop the autoimmune process.

The Neurological Sleep Index: A suite of new sleep scales for multiple sclerosis.

ObjectiveThe objective of this study was to develop patient-reported outcome measures for sleep dysfunction and sleepiness in multiple sclerosis (MS), since there are currently no MS-specific measurement tools for these clinically important entities.MethodsItems were generated from semi-structured interviews followed by cognitive debrief. A 42-item pool was administered to patients with MS at three neuroscience centres in the UK. Comparator scales were co-administered. Constructs were validated by Rasch analysis, guided by initial exploratory factor analysis.ResultsThere were two supraordinate qualitative themes of diurnal sleepiness and non-restorative nocturnal sleep. Rasch analysis on 722 records produced three scales, which corresponded to diurnal sleepiness, non-restorative nocturnal sleep and fragmented nocturnal sleep. All had excellent fit parameters, were unidimensional and were free from differential item functioning. A summed raw score cut-point of 31/48 in the Diurnal Sleepiness Scale equated to the standard cut-point of 10 on the Epworth Sleepiness Scale (ESS).ConclusionThree high-quality measurement scales were developed, and together they compose the Neurological Sleep Index for MS (NSI-MS). The Diurnal Sleepiness Scale might provide an alternative to the ESS. The Non-Restorative Nocturnal Sleep Scale and the Fragmented Nocturnal Sleep Scale appear to be the only such measures for use in MS.

Narcolepsy during Childhood: An Update.

Narcolepsy type 1 (NT1) is a rare central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and fragmented nocturnal sleep usually arising in adolescence or young adulthood. Recently, the childhood NT1 diagnoses have increased for improved disease awareness and for several cases occurring after the H1N1 pandemic influenza or vaccination. As in adults, the occurrence of NT1 in individuals with a genetic predisposition of the immune system (e.g., human leukocyte antigen, HLA-DQB1*0602) together with the role of environmental triggers (e.g., H1N1 influenza virus, streptococcus β hemolyticus) further supports the autoimmune pathogenesis. Children with NT1 close to disease onset show a peculiar cataplexy phenotype characterized by persistent hypotonia with prominent facial involvement (cataplectic facies) and by a complex mosaic of hyperkinetic movement abnormalities that increase during emotional stimulation. This phenotype progressively vanishes along the disease course leading to the typical picture of cataplexy (i.e., muscle weakness exclusively evoked by strong emotions). This possibly explains in part the misdiagnoses and diagnostic delay. Childhood NT1 also shows behavioral abnormalities and psychiatric disorders, encompassing depressive feelings, hyperactive/aggressive behavior, up to psychotic features. The association with obesity and precocious puberty strikingly suggests that NT1 arising in prepubertal children may reflect a wide hypothalamic derangement secondary to hypocretin neuronal loss. The complexity of the childhood NT1 phenotype claims a multidisciplinary assessment and management, taking behavioral and endocrinological features into account. NT1 indeed is a lifelong disorder with a devastating impact on quality of life, especially when arising across developmental age, and targeted school programs, medicolegal and psychological supports are essential for patients care. Controlled studies are mandatory to assess safety and efficacy of the current symptomatic off-label medications on which also relies the treatment for children with NT1, and hopefully future pathogenetic evidences will pave the way to better disease prevention and therapies to modify the disease course.

Symptomatic Narcolepsy and Generalized Seizures Following Surgery for Rathke’s Cleft Cyst

Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep-related symptoms such as cataplexy, sleep paralysis, and hypnagogic hallucination. Animal studies show that genetic alterations in either hypocretin ligands or hypocretin receptor-2 can cause narcolepsy in mice and dogs. In humans, mutations in hypocretin-related genes appear to be rare, however, a loss of hypocretin-producing neurons has been demonstrated in human pathology. Consequently, patients with narcolepsy have low or no detectable hypocretin in their cerebrospinal fluid (CSF).1 Narcolepsy is strongly associated with the human leukocyte antigen DQB1*0602, suggesting the involvement of an autoimmune process in idiopathic narcolepsy.2 Symptomatic narcolepsy is a rare disorder secondary to the underlying neurological disorder. In this disorder, the signs and symptoms of narcolepsy are temporally associated with the underlying neurological process. One of the most frequent causes of symptomatic narcolepsy is brain tumors, usually in the region of the third ventricle and the diencephalon, including adenoma, angioma, astrocytoma, cerebral sarcoidosis, choroid plexus carcinoma, colloid cyst, craniopharyngioma, glioma, germinoma, glioblastoma, histiocytosis, lymphoma, medulloblastoma, and subependymoma.3 Abnormalities in sleep and wakefulness that can develop after surgical removal of tumors in the hypothalamic area seem to vary from fragmented nocturnal sleep without daytime sleepiness to typical narcolepsy with cataplexy.4 Tachibana et al.5 reported a series of craniophayringioma patients diagnosed with narcolepsy after surgery. We report a woman with symptomatic narcolepsy that developed after surgical removal of Rathke’s cleft cyst, which has never before been reported as a causative factor for symptomatic narcolepsy. Excessive daytime sleepiness and sleep onset REM sleep episodes were demonstrated using the multiple sleep latency test (MSLT). In addition, the patient also had generalized seizures, including myoclonic and/or tonic-clonic seizures, which are rarely comorbid in patients with symptomatic narcolepsy. Received: November 26, 2014 Revised: December 19, 2014 Accepted: December 29, 2014 Correspondence Sang-Ahm Lee, MD Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel +82-2-3010-3445 Fax +82-2-474-4691 E-mail salee@amc.seoul.kr Symptomatic Narcolepsy and Generalized Seizures Following Surgery for Rathke’s Cleft Cyst

Uma criança com narcolepsia

Introduction: Narcolepsy is a chronic disease characterized by sleep attacks, excessive daytime sleepiness and nocturnal sleep fragmentation. It can be associated cataplexy and other disturbance of REM sleep (sleep paralysis and hypnagogic hallu cinations and hypnopompic). Case report: A 10-year old boy was referred to Pedopsychiatry because of behavioural disturbance, irritability, sleepiness and distraction, being interpreted as an “ill-mannered child.” After clinical evaluation and comprehensive laboratory studies we concluded that he presented narcolepsy with cataplexy. Discussion/conclusion: Patients with narcolepsy face several problems due to the disease which, if left untreated or ineffectively treated, cause embarrassing or distressing symptoms, affecting their quality of life. The purpose of this paper is to draw attention to this problem since it is a rare condition and therefore seldom not recognized by the general public or even by health professionals.

Parasomnias in Parkinson’s disease

Sleep disturbances in patients with Parkinson’s disease (PD) are common. PD patients complain of insomnia and fragmented nocturnal sleep. Occurrence of different parasomnias have been largely overlooked and we have not found previous systematic studies on parasomnias. We studied occurrence of parasomnias and their association with other symptoms in PD patients. A structured questionnaire was sent to 1447 patients who were randomly selected from the registry of the Finnish Parkinson Association. The response rate of 59,0%. The questionnaire covered demographic items, and it included questions derived from the Basic Nordic Sleep Questionnaire and items about different parasomnias. The most common parasomnias occurring at least weekly were sleep talking (21.4%), nightmares (17.0%), hallucinations (11.2%), and bruxism (4.6%). At least monthly occurring parasomnias included night terrors (8.3%) and sleep walking (3.1%). Among other sleep related phenomena nocturnal sweating occurred weekly in 28.8%, nocturia (>3 times nightly) in 15.8% and bedwetting monthly in 28.5%. The prevalence of REM sleep behavior disorder (RBD) evaluated by the Marburg RBDSQ ⩾6 was 36.7%. Association of RBD with NREMsleep parasomnia (parasomnia overlap disorder) was found in 18.2% of all participants. Adjusted logistic regression analysis showed weekly nightmares (OR 7.1; 95% CI 3.2–15.5) and weekly sleep talking (OR 7.1; 95% CI 3.8–13.4) predicting the presence of RBD. In Parkinson’s disease the prevalence of RBD is overrepresented and it is often associated with other parasomnias. More attention should be paid to the detection and treatment of parasomnias. This study was supported by the Finnish Parkinson Foundation.

Energy expenditure in narcolepsy patients and controls

Introduction Hypocretin deficiency causes narcolepsy, a condition characterized by excessive daytime sleepiness, cataplexy, and fragmented nocturnal sleep. Co-morbid overweight is present in two thirds of narcolepsy patients. Moreover one third of them is obese. Why narcolepsy patients gain weight is not known. They do not seem to eat and/or sleep more during 24 h than controls. This study was performed to detect a possible decrease in energy expenditure that could be the cause for the overweight in narcolepsy. This is the first study using a respiration chamber to measure Energy Expenditure in narcolepsy. Materials and methods Nine hypocretin deficient male patients with narcolepsy-cataplexy, and nine sex, age and body mass index (BMI) matched controls were enrolled. Energy Expenditure was measured for 24 h in a respiration chamber. Spontaneous physical activity was measured by a radar system based on Doppler principle. Subjects were given a diet to maintain energy balance based on the Harris–Benedict equation. Total Energy Expenditure (TEE), Overnight Metabolic Rate (OMR) and lowest Sleeping Metabolic Rate (SMRmin) were calculated. In addition, measured SMR was compared with SMR calculated with a prediction equation based on body composition. Results Narcolepsy patients did not differ from controls in BMI (27.4 ± 3.9 vs. 27.5 ± 4.2; P = 9.4) or age (38.1 ± 16.0 vs. 36.8 ± 15.2; P = .86) respectively. There were no differences in TEE (10.6 ± 1.2 vs. 10.6 ± .80 MJ/d; P = .99) OMR (5.7 ± .73 vs. 6.0 ± .55 MJ/d; P = .35), SMRmin (5.4 ± .76 vs. 5.4 ± .51 MJ/d; P = .99) and spontaneous activity between narcolepsy patients and matched controls (2862 ± 514 vs. 2732 ± 245 counts/d; P = .50). For both groups, measured SMR was closely related to SMR predicted from body composition. Conclusion Energy expenditure in narcolepsy patients is similar to matched controls. It is conceivable that we were not close enough to onset of the disease, when patients usually gain weight, to detect a possible difference before a new metabolic set point establishes. Acknowledgement This study was supported by a grant from UCB Pharma.

Associations among nocturnal sleep, daytime intradialytic sleep, and mortality risk in patients on daytime conventional hemodialysis: US Renal Data System special study data

Fragmented nocturnal sleep is commonly reported by patients undergoing daytime conventional hemodialysis (CHD) and may be associated with higher mortality risk. Subjective sleepiness during CHD is also frequently observed. We examined the association of reported sleep fragmentation and nocturnal and daytime (intradialytic) sleep durations with survival in a national cohort of 1440 CHD patients who were interviewed in 2005-2007 in a phone survey conducted by the US Renal Data System. Patient survival was followed through September 30, 2010 in the US Renal Data System. A total of 76% of patients reported that they typically dozed off or slept during their treatment, and intradialytic dozing was especially common among patients whose treatment shift started before 1000 hours. There was a trend for patients who reported dozing during CHD to report nocturnal sleep fragmentation (60.4% vs. 55.1%; P = 0.07). With adjustment for intradialytic sleep and other covariates, nocturnal sleep fragmentation was not associated with survival. Mortality risk was higher for patients who reported sleeping 9 or more hours/night compared with the referent category of nocturnal sleep equal to 6-7 hours (hazard ratio: 1.50 [95% confidence interval: 1.04-2.17]; P = 0.03). Continued investigation of the association of timing and duration of sleep with hemodialysis patient outcomes is warranted.

Breastfeeding, sleep and wake circadian rhythms show distinct temporal emerging patterns

The emerging patterns of breastfeeding, sleep and wake circadian rhythms in an infant and the breastfeeding emergence pattern of his elder sister are presented. Both children were raised under regular contact with photic and non-photic Zeitgebers. Data are related to the first four months of life of the infants, which correspond to the exclusive and ad libitum breastfeeding stage of their lives. Discrimination is made of “fasting-associated-wakefulness” (FAW) which is a wake state without feeding. Our data show that while FAW episodes are concentrated in the diurnal phase of the day since the first week of life, breastfeeding rhythm takes longer to show statistically significant circadian periodicity (four weeks) and to become monophasic, concentrated in the diurnal phase of the day (three/four months). This precedence of the consolidation of FAW rhythm indicates tight association between nocturnal sleep fragmentation and the drive to feed, in the first months of life of infants.

Insufficient non-REM sleep intensity in narcolepsy-cataplexy.

To compare electroencephalogram (EEG) dynamics during nocturnal sleep in patients with narcolepsy-cataplexy and healthy controls. Fragmented nocturnal sleep is a prominent feature and contributes to excessive daytime sleepiness in narcolepsy-cataplexy. Only 3 studies have addressed changes in homeostatic sleep regulation as a possible mechanism underlying nocturnal sleep fragmentation in narcolepsy-cataplexy. Baseline sleep of 11 drug-naive patients with narcolepsy-cataplexy (19-37 years) and 11 matched controls (18-41 years) was polysomnographically recorded. The EEG was subjected to spectral analysis. None, baseline condition. All patients with narcolepsy-cataplexy but no control subjects showed a sleep-onset rapid eye movement (REM) episode. Non-REM (NREM)-REM sleep cycles were longer in patients with narcolepsy-cataplexy than in controls (P = 0.04). Mean slow-wave activity declined in both groups across the first 3 NREM sleep episodes (P<0.001). The rate of decline, however, appeared to be steeper in patients with narcolepsy-cataplexy (time constant: narcolepsy-cataplexy 51.1 +/- 23.8 minutes [mean +/- SEM], 95% confidence interval [CI]: 33.4-108.8 minutes) than in controls (169.4 +/- 81.5 minutes, 95% CI: 110.9-357.6 minutes) as concluded from nonoverlapping 95% confidence interval of the time constants. The steeper decline of SWA in narcolepsy-cataplexy compared to controls was related to an impaired build-up of slow-wave activity in the second cycle. Sleep in the second cycle was interrupted in patients with narcolepsy-cataplexy, when compared with controls, by an increased number (P = 0.01) and longer duration (P = 0.01) of short wake episodes. Insufficient NREM sleep intensity is associated with nonconsolidated nocturnal sleep in narcolepsy-cataplexy. The inability to consolidate sleep manifests itself when NREM sleep intensity has decayed below a certain level and is reflected in an altered time course of slow-wave activity across NREM sleep episodes.

Análisis comparativo de un grupo de pacientes con narcolepsia-cataplejía, narcolepsia sin cataplejía e hipersomnia idiopática

To evaluate the distribution of clinical, electrophysiological and biological variables, and their relationship with the CSF hypocretin-1 levels, in patients with central hypersomnias diagnosed as narcolepsy-cataplexy (NC), narcolepsy without cataplexy (NnC) and idiopathic hypersomnia (IH) based on the ICSD-2 criteria. We performed in all patients a clinical interview, a nocturnal polysomnogram and a multiple sleep latency test (MSLT), HLA analysis and measurement of CSF Hcrt-1 levels (low < or = 110 pg/mL). Out of 51 patients, 31 were classified as NC, 11 as NnC and 8 as IH. 34 patients (66.7%) had low CSF Hcrt-1 levels (29 NC, 3 NnC and 1 IH). In the NC group, 96.1% were HLA DQB1*0602 positive and 91% had low CSF Hcrt-1 levels. The most frequent variables found in NC patients and in those with a low CSF Hcrt-1 levels were cataplexy, fragmented nocturnal sleep, short refreshing naps, automatic behavior, HLA DQB1*0602, and, in the MSLT, a short mean sleep latency, a higher number of REM sleep episodes and a short mean latency of REM sleep episodes. A long nocturnal sleep time and morning sleep drunkenness, 2 variables used in the ICSD-2 for the diagnosis of IH, were not different among the three groups of hypersomnias. Central hypersomnias have a superposition of several clinical, electrophysiological and biological variables that makes sometimes difficult the differential diagnosis. The measurement of CSF Hcrt-1 levels may help in the diagnosis of those patients with unclear clinical or electrophysiological forms.

Narcolepsy-cataplexy: How does recent understanding help in evaluation and treatment

Narcolepsy is a substantially disabling disease with profound physical, mental, and social effects. The burden on patients is compounded by delayed and missed diagnoses and by the subsequent undertreatment of narcolepsy and associated symptoms such as cataplexy. The recent advances in the elucidation of the genetics of canine narcolepsy and the pathophysiologic role of hypocretin, in animals and humans, enhances current diagnostic capability and will provide better treatment modalities in the future. The varied symptoms of narcolepsy are challenging to manage and may require treatment with a combination of agents. The recent development of a markedly enhanced characterization of sodium oxybate in the treatment of the excessive daytime sleepiness, nocturnal sleep fragmentation, and cataplexy of narcolepsy offers the potential of treating multiple symptoms simultaneously and marks a dramatic advance in the treatment of narcolepsy.

Dementia severity and Lewy bodies affect circadian rhythms in Alzheimer disease

Sleep disturbance is a symptom shared by all neurodegenerative, dementing illnesses, such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), and its presence frequently precipitates decisions to seek institutional care for patients. Although the sleep disturbances of AD and DLB are qualitatively similar, they appear to be more prominent in patients with DLB. Disturbance of the circadian rhythm has been noted and is a potential factor underlying the nocturnal sleep fragmentation and daytime sleepiness observed in these patients. We studied the circadian variation of core-body temperature and motor activity in a total of 32 institutionalized patients with probable AD by NINCDS-ADRDA criteria, 9 of whom also met pathologic criteria for DLB. Eight, healthy, elderly male controls were studied on a clinical research unit designed to simulate the hospital environment where the dementia patients were studied. Circadian variables generally had greater deviations from normal associated with increasing AD pathology, as measured by postmortem-determined Braak stage, supporting the hypothesis that central changes mediate circadian disturbances in AD and DLB. Patients with a postmortem diagnosis of DLB manifested greater disturbances of locomotor activity circadian rhythms than patients with AD, possibly reflecting the greater sleep disturbances seen in this population, but the differences from normal in the circadian rhythms of the AD and DLB patients were qualitatively similar.

Spectral analysis of all-night human sleep EEG in narcoleptic patients and normal subjects.

To investigate the pathophysiology of narcoleptic patients' sleep in detail, we analysed and compared the whole-night polysomnograms of narcoleptic patients and normal human subjects. Eight drug-naive narcoleptic patients and eight age-matched normal volunteers underwent polysomnography (PSG) on two consecutive nights. In addition to conventional visual scoring of the polysomnograms, rapid eye movement (REM)-density and electroencephalograph (EEG) power spectra analyses were also performed. Sleep onset REM periods and fragmented nocturnal sleep were observed as expected in our narcoleptic patients. In the narcoleptic patients, REM period duration across the night did not show the significant increasing trend that is usually observed in normal subjects. In all narcoleptic patient REM periods, eye movement densities were significantly increased. The power spectra of narcoleptic REM sleep significantly increased between 0.3 and 0.9 Hz and decreased between 1.0 and 5.4 Hz. Further analysis revealed that non-rapid eye movement (NREM) period duration and the declining trend of delta power density in the narcoleptic patients were not significantly different from the normal subjects. Compared with normal subjects, the power spectra of narcoleptic NREM sleep increased in the 1.0-1.4 Hz and 11.0-11.9 Hz frequency bands, and decreased in a 24.0-26.9 Hz frequency band. Thus, increased EEG delta and decreased beta power densities were commonly observed in both the NREM and REM sleep of the narcoleptic patients, although the decrease in beta power during REM sleep was not statistically significant. Our visual analysis revealed fragmented nocturnal sleep and increased phasic REM components in the narcoleptic patients, which suggest the disturbance of sleep maintenance mechanism(s) and excessive effects of the mechanism(s) underlying eye movement activities during REM sleep in narcolepsy. Spectral analysis revealed significant increases in delta components and decreases in beta components, which suggest decreased activity in central arousal mechanisms. These characteristics lead us to hypothesize that two countervailing mechanisms underlie narcoleptic sleep pathology.