Sleep apnea detection: accuracy of using automated ECG analysis compared to manually scored polysomnography (apnea hypopnea index).

INTRODUCTION: Adequate sleep is fundamental to wellness and recovery from illnesses and lack thereof is associated with disease onset and progression resulting in adverse health outcomes. Measuring sleep quality and sleep apnea (SA) at the point of care utilizing data that is already collected is feasible and cost effective, using validated methods to unlock sleep information embedded in the data. The objective of this study is to determine the utility of automated analysis of a stored, robust signal widely collected in hospital and outpatient settings, a single lead electrocardiogram (ECG), using clinically validated algorithms, cardiopulmonary coupling (CPC), to objectively and accurately identify SA. METHODS: Retrospective analysis of de-identified PSG data with expert level scoring of Apnea Hypopnea Index (AHI) dividing the cohort into severe OSA (AHI > 30), moderate (AHI 15-30), mild (AHI 5-15), and no disease (AHI < 5) was compared with automated CPC analysis of a single lead ECG collected during sleep for each subject. Statistical analysis was used to compare the two methods. RESULTS: Sixty-eight ECG recordings were analyzed. CPC identified patients with moderate to severe SA with sensitivity of 100%, specificity of 81%, and agreement of 93%, LR+ (positive likelihood ratio) 5.20, LR- (negative likelihood ratio) 0.00 and kappa 0.85 compared with manual scoring of AHI. CONCLUSION: The automated CPC analysis of stored single lead ECG data often collected during sleep in the clinical setting can accurately identify sleep apnea, providing medically actionable information that can aid clinical decisions.

Excessive daytime sleepiness is associated with changes in salivary inflammatory genes transcripts.

Excessive daytime sleepiness (EDS) is a ubiquitous problem that affects public health and safety. A test that can reliably identify individuals that suffer from EDS is needed. In contrast to other methods, salivary biomarkers are an objective, inexpensive, and noninvasive method to identify individuals with inadequate sleep. Although we have previously shown that inflammatory genes are elevated in saliva samples taken from sleep deprived individuals, it is unclear if inflammatory genes will be elevated in clinical populations with EDS. In this study, salivary samples from individuals with sleep apnea were evaluated using the Taqman low density inflammation array. Transcript levels for 3 genes, including prostaglandin-endoperoxide synthase 2 (PTGS2), were elevated in patients with sleep apnea. Interestingly, PTGS2 was also elevated in patients with EDS but who did not have sleep apnea. These data demonstrate the feasibility of using salivary transcript levels to identify individuals that self-report excessive daytime sleepiness.

γ-Hydroxybutyric acid-induced electrographic seizures.

We describe a case of absence-like electrographic seizures during NREM sleep in a patient who was taking sodium oxybate, a sodium salt of γ-hydroxybutyric acid (GHB). An overnight full montage electroencephalography (EEG) study revealed numerous frontally predominant rhythmic 1.5-2 Hz sharp waves and spike-wave activity during stage N2 and N3 sleep at the peak dose time for sodium oxybate, resembling atypical absence-like electrographic seizures. The patient was later weaned off sodium oxybate, and a repeat study did not show any such electrographic seizures. Absence-like seizures induced by GHB had previously been described in experimental animal models. We present the first reported human case of absence-like electrographic seizure associated with sodium oxybate.

Effect of armodafinil on cortical activity and working memory in patients with residual excessive sleepiness associated with CPAP-Treated OSA: a multicenter fMRI study.

STUDY OBJECTIVE: To assess the effect of armodafinil on task-related prefrontal cortex activation using functional magnetic resonance imaging (fMRI) in patients with obstructive sleep apnea (OSA) and excessive sleepiness despite continuous positive airway pressure (CPAP) therapy. METHODS: This 2-week, multicenter, prospective, randomized, double-blind, placebo-controlled, parallel-group study was conducted at five neuroimaging sites and four collaborating clinical study centers in the United States. Patients were 40 right-handed or ambidextrous men and women aged between 18 and 60 years, with OSA and persistent sleepiness, as determined by multiple sleep latency and Epworth Sleepiness Scale scores, despite effective, stable use of CPAP. Treatment was randomized (1:1) to once-daily armodafinil 200 mg or placebo. The primary efficacy outcome was a change from baseline at week 2 in the volume of activation meeting the predefined threshold in the dorsolateral prefrontal cortex during a 2-back working memory task. The key secondary measure was the change in task response latency. RESULTS: No significant differences were observed between treatment groups in the primary or key secondary outcomes. Armodafinil was generally well tolerated. The most common adverse events (occurring in more than one patient [5%]) were headache (19%), nasopharyngitis (14%), and diarrhea (10%). CONCLUSIONS: Armodafinil did not improve fMRI-measured functional brain activation in CPAP-treated patients with OSA and excessive sleepiness. STUDY REGISTRATION: Double-Blind, Placebo-Controlled, Functional Neuroimaging Study of Armodafinil (200 mg/Day) on Prefrontal Cortical Activation in Patients With Residual Excessive Sleepiness Associated With Obstructive Sleep Apnea/Hypopnea.

Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1.

Children with neurodevelopmental disorders are at increased risk for sleep issues, which affect quality of life, cognitive function, and behavior. To determine the prevalence of sleep problems in children with the common neurodevelopmental disorder neurofibromatosis type 1, a cross-sectional study was performed on 129 affected subjects and 89 unaffected siblings, age 2 to 17 years, using the Sleep Disturbance Scale for Children questionnaire. Children with neurofibromatosis type 1 were significantly more likely to have disturbances in initiating and maintaining sleep, arousal, sleep-wake transition, and hyperhidrosis, but not problems with abnormal sleep breathing, or excessive somnolence. Although the overall sleep scores were higher in children with neurofibromatosis type 1, this was not related to a coexisting attention deficit disorder, cognitive impairment, or stimulant medication use. Collectively, these results demonstrate that children with neurofibromatosis type 1 are more likely to have sleep disturbances, and support the use of appropriate interventions for this at-risk population.

Cross-translational studies in human and Drosophila identify markers of sleep loss.

Inadequate sleep has become endemic, which imposes a substantial burden for public health and safety. At present, there are no objective tests to determine if an individual has gone without sleep for an extended period of time. Here we describe a novel approach that takes advantage of the evolutionary conservation of sleep to identify markers of sleep loss. To begin, we demonstrate that IL-6 is increased in rats following chronic total sleep deprivation and in humans following 30 h of waking. Discovery experiments were then conducted on saliva taken from sleep-deprived human subjects to identify candidate markers. Given the relationship between sleep and immunity, we used Human Inflammation Low Density Arrays to screen saliva for novel markers of sleep deprivation. Integrin αM (ITGAM) and Anaxin A3 (AnxA3) were significantly elevated following 30 h of sleep loss. To confirm these results, we used QPCR to evaluate ITGAM and AnxA3 in independent samples collected after 24 h of waking; both transcripts were increased. The behavior of these markers was then evaluated further using the power of Drosophila genetics as a cost-effective means to determine whether the marker is associated with vulnerability to sleep loss or other confounding factors (e.g., stress). Transcript profiling in flies indicated that the Drosophila homologues of ITGAM were not predictive of sleep loss. Thus, we examined transcript levels of additional members of the integrin family in flies. Only transcript levels of scab, the Drosophila homologue of Integrin α5 (ITGA5), were associated with vulnerability to extended waking. Since ITGA5 was not included on the Low Density Array, we returned to human samples and found that ITGA5 transcript levels were increased following sleep deprivation. These cross-translational data indicate that fly and human discovery experiments are mutually reinforcing and can be used interchangeably to identify candidate biomarkers of sleep loss.

Sleep quality and preclinical Alzheimer disease.

IMPORTANCE: Sleep and circadian problems are very common in Alzheimer disease (AD). Recent animal studies suggest a bidirectional relationship between sleep and ß-amyloid (Aß), a key molecule involved in AD pathogenesis. OBJECTIVE: To test whether Aß deposition in preclinical AD, prior to the appearance of cognitive impairment, is associated with changes in quality or quantity of sleep. DESIGN: Cross-sectional study conducted from October 2010 to June 2012. SETTING: General community volunteers at the Washington University Knight Alzheimer's Disease Research Center. PARTICIPANTS: Cognitively normal individuals (n = 145) 45 years and older were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. Valid actigraphy data were recorded in 142. The majority (124 of 142) were recruited from the Adult Children Study, in which all were aged 45 to 75 years at baseline and 50% have a parental history of late-onset AD. The rest were recruited from a community volunteer cohort in which all were older than 60 years and healthy at baseline. MAIN OUTCOME MEASURES: Sleep was objectively measured using actigraphy for 2 weeks. Sleep efficiency, which is the percentage of time in bed spent asleep, was the primary measure of sleep quality. Total sleep time was the primary measure of sleep quantity. Cerebrospinal fluid Aß42 levels were used to determine whether amyloid deposition was present or absent. Concurrent sleep diaries provided nap information. RESULTS: Amyloid deposition, as assessed by Aß42 levels, was present in 32 participants (22.5%). This group had worse sleep quality, as measured by sleep efficiency (80.4% vs 83.7%), compared with those without amyloid deposition, after correction for age, sex, and APOEε4 allele carrier status (P = .04). In contrast, quantity of sleep was not significantly different between groups, as measured by total sleep time. Frequent napping, 3 or more days per week, was associated with amyloid deposition (31.2% vs 14.7%; P = .03). CONCLUSIONS AND RELEVANCE: Amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality but not with changes in sleep quantity.

Obstructive sleep apnea screening and postoperative mortality in a large surgical cohort.

OBJECTIVE: A recent investigation at Barnes-Jewish Hospital located in St. Louis, Missouri, found that an estimated 22% of adults presenting for inpatient surgery screened as high risk for obstructive sleep apnea (OSA). Surgical patients with OSA have multiple comorbidities and are at increased risk for perioperative complications. Our objective was to determine if a prior diagnosis of OSA or a positive screen for OSA was associated with increased risk for 30-day and one-year mortality. METHODS: B-J APNEAS (Barnes-Jewish Apnea Prevalence in Every Admission Study) was a prospective cohort study. Unselected adult surgical patients at Barnes Jewish Hospital were prospectively enrolled between February 2006 and April 2010. All patients completed preoperative OSA screening and those who were at risk for OSA according to a combination of the Berlin and Flemons screening tools received targeted postoperative interventions. STOP (loud Snoring, daytime Tiredness, Observed apneas, and high blood Pressure) and STOP-BANG (STOP, plus body mass index [BMI], age, neck circumference, and gender) scores also were obtained. RESULTS: Overall, the sample included 14,962 patients, of whom 1939 (12.9%) reported a history of OSA. All four screening tools identified a high prevalence of undiagnosed patients at risk for OSA (9.5%-41.6%), but agreement among screens was not strong with κ statistic ranging from 0.225 to 0.611. There was no significant difference in 30-day postoperative mortality between patients with possible OSA (based on their history or on a positive OSA screen with any of the four instruments) and the rest of the surgical population. Significant differences in one-year mortality were noted between the low-risk and high-risk groups as identified by the Flemons' (4.96% vs 6.91%; p<0.0001), STOP (5.28% vs 7.57%; p<0.0001) and STOP-BANG (4.13% vs 7.45%; p<0.0001) screens. After adjusting for risk factors, none of the OSA screening tools independently predicted mortality rate up to one year postoperatively. CONCLUSION: Neither a prior diagnosis of OSA nor a positive screen for OSA risk was associated with increased 30-day or one-year postoperative mortality. Differences in 1 year postoperative mortality were noted with three of the screening tools. The results of our study highlight uncertainties and research priorities for the medical community.

Neurological disorders: towards a mechanistic understanding of restless legs syndrome.

Restless legs syndrome is a curious neurological disorder of unknown aetiology. A new study has found that Drosophila mutants in the fly homologue of a human gene, BTBD9, that has been implicated as a risk factor for restless legs display important features of the syndrome.

Effects of age and amyloid deposition on Aß dynamics in the human central nervous system.

BACKGROUND: The amyloid hypothesis predicts that increased production or decreased clearance of ß-amyloid (Aß) leads to amyloidosis, which ultimately culminates in Alzheimer disease (AD). OBJECTIVE: To investigate whether dynamic changes in Aß levels in the human central nervous system may be altered by aging or by the pathology of AD and thus contribute to the risk of AD. DESIGN: Repeated-measures case-control study. SETTING: Washington University School of Medicine in St Louis, Missouri. PARTICIPANTS: Participants with amyloid deposition, participants without amyloid deposition, and younger normal control participants. MAIN OUTCOME MEASURES: In this study, hourly cerebrospinal fluid (CSF) Aß concentrations were compared with age, status of amyloid deposition, electroencephalography, and video recording data. RESULTS: Linear increases were observed over time in the Aß levels in CSF samples obtained from the younger normal control participants and the older participants without amyloid deposition, but not from the older participants with amyloid deposition. Significant circadian patterns were observed in the Aß levels in CSF samples obtained from the younger control participants; however, circadian amplitudes decreased in both older participants without amyloid deposition and older participants with amyloid deposition. Aß diurnal concentrations were correlated with the amount of sleep but not with the various activities that the participants participated in while awake. CONCLUSIONS: A reduction in the linear increase in the Aß levels in CSF samples that is associated with amyloid deposition and a decreased CSF Aß diurnal pattern associated with increasing age disrupt the normal physiology of Aß dynamics and may contribute to AD.

Measuring the impact of apnea and obesity on circadian activity patterns using functional linear modeling of actigraphy data.

BACKGROUND: Actigraphy provides a way to objectively measure activity in human subjects. This paper describes a novel family of statistical methods that can be used to analyze this data in a more comprehensive way. METHODS: A statistical method for testing differences in activity patterns measured by actigraphy across subgroups using functional data analysis is described. For illustration this method is used to statistically assess the impact of apnea-hypopnea index (apnea) and body mass index (BMI) on circadian activity patterns measured using actigraphy in 395 participants from 18 to 80 years old, referred to the Washington University Sleep Medicine Center for general sleep medicine care. Mathematical descriptions of the methods and results from their application to real data are presented. RESULTS: Activity patterns were recorded by an Actical device (Philips Respironics Inc.) every minute for at least seven days. Functional linear modeling was used to detect the association between circadian activity patterns and apnea and BMI. Results indicate that participants in high apnea group have statistically lower activity during the day, and that BMI in our study population does not significantly impact circadian patterns. CONCLUSIONS: Compared with analysis using summary measures (e.g., average activity over 24 hours, total sleep time), Functional Data Analysis (FDA) is a novel statistical framework that more efficiently analyzes information from actigraphy data. FDA has the potential to reposition the focus of actigraphy data from general sleep assessment to rigorous analyses of circadian activity rhythms.

Changes in gene expression with sleep.

There is general agreement within the sleep community and among public health officials of the need for an accessible biomarker of sleepiness. As the foregoing discussions emphasize, however, it may be more difficult to reach consensus on how to define such a biomarker than to identify candidate molecules that can be then evaluated to determine if they might be useful to solve a variety of real-world problems related to insufficient sleep. With that in mind, a goal of our laboratories has been to develop a rational strategy to expedite the identification of candidate biomarkers. 1 We began with the assumption that since both the genetic and environmental context of a gene can influence its behavior, an effective test of sleep loss will likely be composed of a panel of multiple biomarkers. That is, we believe that it is premature to exclude a candidate analyte simply because it might also be modulated in response to other conditions (e.g., illness, metabolism, sympathetic tone, etc.). Our next assumption was that an easily accessible biomarker would be more useful in real-world settings. Thus, we have focused on saliva, as opposed to urine or blood, as a rich source of biological analytes that can be mined to optimize the chances of bringing a biomarker out into the field. Finally, we recognize that conducting validation studies in humans can be expensive and time consuming. Thus, we have exploited genetic and pharmacological tools in the model organism Drosophila melanogaster to more fully characterize the behavior of the most exciting candidate biomarkers.

Sleep disordered breathing in the elderly.

Sleep-disordered breathing, especially obstructive sleep apnea (OSA), has a high prevalence among the elderly, where it may present with atypical symptoms. Untreated OSA can reduce quality of life and have adverse health consequences. Effective treatment is available, so all physicians treating the elderly should be aware of the clinical presentation, diagnostic methods, and treatment options for OSA.

Notch signaling modulates sleep homeostasis and learning after sleep deprivation in Drosophila.

The role of the transmembrane receptor Notch in the adult brain is poorly understood. Here, we provide evidence that bunched, a negative regulator of Notch, is involved in sleep homeostasis. Genetic evidence indicates that interfering with bunched activity in the mushroom bodies (MBs) abolishes sleep homeostasis. Combining bunched and Delta loss-of-function mutations rescues normal homeostasis, suggesting that Notch signaling may be involved in regulating sensitivity to sleep loss. Preventing the downregulation of Delta by overexpressing a wild-type transgene in MBs reduces sleep homeostasis and, importantly, prevents learning impairments induced by sleep deprivation. Similar resistance to sleep loss is observed with Notch(spl-1) gain-of-function mutants. Immunohistochemistry reveals that the Notch receptor is expressed in glia, whereas Delta is localized in neurons. Importantly, the expression in glia of the intracellular domain of Notch, a dominant activated form of the receptor, is sufficient to prevent learning deficits after sleep deprivation. Together, these results identify a novel neuron-glia signaling pathway dependent on Notch and regulated by bunched. These data highlight the emerging role of neuron-glia interactions in regulating both sleep and learning impairments associated with sleep loss.

Changing demographics in REM sleep behavior disorder: possible effect of autoimmunity and antidepressants.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) has been described predominantly in elderly men and in association with neurodegenerative disease. But an increasing proportion of cases in recent reports and in clinical practice do not fit this description; thus we sought to describe a current RBD population and possibly identify new subgroups with RBD. METHODS: Records of 115 consecutive patients with polysomnogram-confirmed RBD at an academic sleep center were retrospectively reviewed. RESULTS: Male to female ratio was 2:1, and 1.25:1 for early-onset (age <50) cases. Mean age at diagnosis was 53.7±16.4years. Most (60%) cases were idiopathic, and neurodegenerative disease was coincident primarily in older men. Autoimmune disease was unexpectedly common in women (20%) particularly in the 30-49 age groups (40%). Antidepressant use was frequent (46.1%), especially in early-onset cases (57.8%). CONCLUSIONS: RBD is diagnosed more equally between men and women and in younger individuals than previously reported. While neurodegenerative disease is frequently co-incident with RBD in older men, most women and early-onset cases have "idiopathic" RBD. High prevalence of autoimmune disease among women with RBD suggests an intriguing link between immune dysfunction and RBD. A high rate of antidepressant use provides support for a potentially causal role for antidepressants in RBD.

Celiac disease is associated with restless legs syndrome.

PURPOSE: Celiac disease may be associated with restless legs syndrome (RLS) because of an association with iron deficiency. Often, RLS negatively affects quality of life but may remain undiagnosed. This study evaluated the association between celiac disease and RLS. RESULTS: The incidence of RLS among 85 patients with celiac disease was 35%, with a prevalence of 25% compared with 10% of spouses (P<0.02). In 79% of patients with RLS and celiac disease, neuromuscular symptoms began during or after onset of gastrointestinal symptoms. Iron deficiency was present in 40% of celiac patients with active RLS compared with 6% of patients without RLS (P<0.001). After 6 months of a gluten-free diet, RLS symptoms improved in 50% of 28 patients. CONCLUSION: Screening for celiac disease in patients with RLS is important since this commonly overlooked silent disease may be a correctable factor for some patients with idiopathic RLS.