Heterogeneity of obstructive sleep apnea phenotypes after ischemic stroke: Outcome variation by cluster analysis.

INTRODUCTION: Obstructive sleep apnea (OSA) is common but under-recognized after stroke. The aim of this study was to determine whether post-stroke phenotypic OSA subtypes are associated with stroke outcome in a population-based observational cohort. METHODS: Ischemic stroke patients (n = 804) diagnosed with OSA (respiratory event index ≥10) soon after ischemic stroke were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) project. Functional, cognitive, and quality of life outcomes were assessed at 90 days post-stroke and long-term stroke recurrence was ascertained. Latent profile analysis was performed based on demographic and clinical features, pre-stroke sleep characteristics, OSA severity, and vascular risk factors. Regression models were used to assess the association between phenotypic clusters and outcomes. RESULTS: Four distinct phenotypic clusters provided the best fit. Cluster 1 was characterized by more severe stroke; cluster 2 by severe OSA and higher prevalence of medical comorbidities; cluster 3 by mild stroke and mild OSA; and cluster 4 by moderate OSA and mild stroke. Compared to cluster 3 and after adjustment for baseline stroke severity, cluster 1 and cluster 2 had worse 90-day functional outcome and cluster 1 also had worse quality of life. No difference in cognitive outcome or stroke recurrence rate was noted by cluster. CONCLUSION: Post-stroke OSA is a heterogeneous disorder with different clinical phenotypes associated with stroke outcomes, including both daily function and quality of life. The unique presentations of OSA after stroke may have important implications for stroke prognosis and personalized treatment strategies.

Mapping neurodevelopment with sleep macro- and micro-architecture across multiple pediatric populations.

Profiles of sleep duration and timing and corresponding electroencephalographic activity reflect brain changes that support cognitive and behavioral maturation and may provide practical markers for tracking typical and atypical neurodevelopment. To build and evaluate a sleep-based, quantitative metric of brain maturation, we used whole-night polysomnography data, initially from two large National Sleep Research Resource samples, spanning childhood and adolescence (total N = 4,013, aged 2.5 to 17.5 years): the Childhood Adenotonsillectomy Trial (CHAT), a research study of children with snoring without neurodevelopmental delay, and Nationwide Children's Hospital (NCH) Sleep Databank, a pediatric sleep clinic cohort. Among children without neurodevelopmental disorders (NDD), sleep metrics derived from the electroencephalogram (EEG) displayed robust age-related changes consistently across datasets. During non-rapid eye movement (NREM) sleep, spindles and slow oscillations further exhibited characteristic developmental patterns, with respect to their rate of occurrence, temporal coupling and morphology. Based on these metrics in NCH, we constructed a model to predict an individual's chronological age. The model performed with high accuracy (r = 0.93 in the held-out NCH sample and r = 0.85 in a second independent replication sample - the Pediatric Adenotonsillectomy Trial for Snoring (PATS)). EEG-based age predictions reflected clinically meaningful neurodevelopmental differences; for example, children with NDD showed greater variability in predicted age, and children with Down syndrome or intellectual disability had significantly younger brain age predictions (respectively, 2.1 and 0.8 years less than their chronological age) compared to age-matched non-NDD children. Overall, our results indicate that sleep architectureoffers a sensitive window for characterizing brain maturation, suggesting the potential for scalable, objective sleep-based biomarkers to measure neurodevelopment.

Hypertension, snoring, and obstructive sleep apnoea during pregnancy: a cohort study.

OBJECTIVE: To assess the frequency of obstructive sleep apnoea among women with and without hypertensive disorders of pregnancy. DESIGN: Cohort study. SETTING: Obstetric clinics at an academic medical centre. POPULATION: Pregnant women with hypertensive disorders (chronic hypertension, gestational hypertension, or pre-eclampsia) and women who were normotensive. METHODS: Women completed a questionnaire about habitual snoring and underwent overnight ambulatory polysomnography. MAIN OUTCOME MEASURES: The presence and severity of obstructive sleep apnoea. RESULTS: Obstructive sleep apnoea was found among 21 of 51 women with hypertensive disorders (41%), but in only three of 16 women who were normotensive (19%, chi-square test, P=0.005). [Author correction added on 16 June 2014, after first online publication: Results mentioned in the abstract were amended.] Non-snoring women with hypertensive disorders typically had mild obstructive sleep apnoea, but >25% of snoring women with hypertensive disorders had moderate to severe obstructive sleep apnoea. Among women with hypertensive disorders, the mean apnoea/hypopnoea index was substantially higher in snorers than in non-snorers (19.9±34.1 versus 3.4±3.1, P=0.013), and the oxyhaemoglobin saturation nadir was significantly lower (86.4±6.6 versus 90.2±3.5, P=0.021). Among women with hypertensive disorders, after stratification by obesity, the pooled relative risk for obstructive sleep apnoea in snoring women with hypertension compared with non-snoring women with hypertension was 2.0 (95% CI 1.4-2.8). CONCLUSIONS: Pregnant women with hypertension are at high risk for unrecognised obstructive sleep apnoea. Although longitudinal and intervention studies are urgently needed, given the known relationship between obstructive sleep apnoea and hypertension in the general population, it would seem pertinent that hypertensive pregnant women who snore should be tested for obstructive sleep apnoea, a condition believed to cause or promote hypertension.

Interactions between sleep disorders and oral diseases.

Dental sleep medicine is a rapidly growing field that is in close and direct interaction with sleep medicine and comprises many aspects of human health. As a result, dentists who encounter sleep health and sleep disorders may work with clinicians from many other disciplines and specialties. The main sleep and oral health issues that are covered in this review are obstructive sleep apnea, chronic mouth breathing, sleep-related gastroesophageal reflux, and sleep bruxism. In addition, edentulism and its impact on sleep disorders are discussed. Improving sleep quality and sleep characteristics, oral health, and oral function involves both pathophysiology and disease management. The multiple interactions between oral health and sleep underscore the need for an interdisciplinary clinical team to manage oral health-related sleep disorders that are commonly seen in dental practice.

Cerebral cortical and subcortical cholinergic deficits in parkinsonian syndromes.

OBJECTIVES: Cholinergic projections to cerebral cortical and subcortical regions are decreased in Parkinson disease (PD), but not evaluated in the parkinsonian syndromes of multiple system atrophy (MSA-P) and progressive supranuclear palsy (PSP). We studied cholinergic innervation in these disorders as compared to age-appropriate normal control subjects. METHODS: We used PET with [(11)C]PMP to measure acetylcholinesterase (AChE) activity in multiple cerebral cortical and subcortical regions. We studied 22 normal controls, 12 patients with PD, 13 patients with MSA-P, and 4 patients with PSP. RESULTS: We found significantly decreased AChE activity in most cerebral cortical regions in PD and MSA-P, and a similar but nonsignificant decrease in PSP. No differences were found between PD and MSA-P. Significantly decreased AChE activity was found in PD in striatum, cerebellum, and thalamus, with a marginally significant decrease in mesencephalon and no change in pons. Significantly greater declines in AChE activity in all subcortical regions were seen in MSA-P and PSP vs in PD. Decreased AChE activity in brainstem and cerebellum of all 3 disorders correlated with disturbances of balance and gait. CONCLUSIONS: Cerebral cortical cholinergic activity is decreased to a similar level in Parkinson disease (PD), parkinsonian syndromes of multiple system atrophy (MSA-P), and progressive supranuclear palsy (PSP) as compared to normal controls. Subcortical cholinergic activity is significantly more decreased in MSA-P and PSP than in PD. The more substantial decrease reflects greater impairment in the pontine cholinergic group, which is important in motor activity, particularly gait. These differences may account for the greater gait disturbances in the early stages of MSA-P and PSP than in PD.

Treating obstructive sleep apnea in adults with epilepsy: a randomized pilot trial.

OBJECTIVE: Small uncontrolled series suggest that treatment of obstructive sleep apnea (OSA) in patients with epilepsy may improve seizure control. Prior to conducting a definitive randomized controlled trial, we addressed critical design issues in a pilot study. METHODS: We identified a cohort of adult patients with medically refractory epilepsy and coexisting OSA, documented by polysomnography (PSG). After an 8-week baseline period, subjects with OSA were randomized to therapeutic or sham continuous positive airway pressure (CPAP) for 10 weeks. Subjects maintained seizure calendars and antiepileptic drug dosages were held constant. RESULTS: Sixty-eight subjects with suspected OSA were enrolled and 35 subjects randomized to therapeutic CPAP (22 subjects) or sham (13 subjects) CPAP. Male gender and an elevated sleep apnea questionnaire score were predictive of OSA on PSG. Nineteen subjects in the therapeutic group and all 13 subjects in the sham group completed the trial. Baseline apnea-hypopnea index (AHI) and CPAP adherence were comparable between groups. A significant reduction in AHI was observed in the therapeutic CPAP group as compared to the sham group. Subjects, study coordinators, and principal investigators were unable to predict treatment allocation. CONCLUSIONS: This pilot study provided critical information related to study design and feasibility for planning a comprehensive trial to test the hypothesis that treating obstructive sleep apnea in patients with epilepsy improves seizure control.

REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA.

OBJECTIVE: To explore the neurochemical basis of REM sleep behavior disorder (RBD) in multiple-system atrophy (MSA). METHODS: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of REM atonia loss by the percentage of REM sleep with tonically increased electromyographic (EMG) activity and the percentage of REM sleep with phasic EMG bursts. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was employed to measure the density of striatal monoaminergic terminals and SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) to measure the density of 123I]IBVM. RESULTS: Age and gender distributions were similar in patient and normal control groups. The MSA subjects showed decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) and decreased [123I]IBVM binding in the thalamus (p < 0.001). Moreover, in the MSA group, striatal [11C]DTBZ binding was inversely correlated with the severity of REM atonia loss (p = 0.003). Thalamic [123I]IBVM binding, however, was not correlated to the severity of REM atonia loss. CONCLUSION: Decreased nigrostriatal dopaminergic projections may contribute to RBD in MSA.

Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA.

OBJECTIVE: To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA). METHODS: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of OSA using the apnea-hypopnea index during sleep. SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) was utilized to measure the density of thalamic cholinergic terminals, which project from the brainstem pedunculopontine and laterodorsal tegmental nuclei. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was also used to measure the density of striatal monoaminergic terminals, which project from the brainstem. Findings in the patient group were compared with data from 12 normal control subjects scanned utilizing [123I]IBVM and 15 normal control subjects utilizing [11C]DTBZ. RESULTS: Age and gender distributions were similar in patient and control groups. The MSA subjects showed decreased [123I]IBVM binding in the thalamus (p < 0.001) and decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) in comparison with the control subjects. In the MSA group, thalamic [123I]IBVM binding was inversely correlated with the severity of OSA (p = 0.011). Striatal [11C]DTBZ binding was not correlated with the severity of OSA (p = 0.19). CONCLUSION: Decreased pontine cholinergic projections may contribute to OSA in MSA.

Periodic leg movements and sleepiness in patients evaluated for sleep-disordered breathing.

Most polysomnograms are performed because sleep-disordered breathing (SDB) is suspected, but periodic leg movements during sleep (PLMS) are frequent incidental findings, and their significance is not well understood. In a clinical series of 1,124 adult patients with suspected or confirmed SDB, we tested for an association between the rate of periodic leg movements and one important outcome, the severity of daytime sleepiness. Objective sleepiness was assessed by the Multiple Sleep Latency Test in all subjects, problem sleepiness by self-rating in 873, and subjective sleep propensity by the Epworth Sleepiness Scale in 201. Increased leg movements were associated with decreased objective sleepiness (p = 0.03) but explained less than 1% of the variance. When nocturnal arousals were scored (n = 321 subjects), rates of leg movements associated with arousals predicted less objective sleepiness (p = 0.008); rates of leg movements without arousals predicted nothing. The rates of leg movements showed no association with subjective problem sleepiness or sleep propensity. We conclude that incidental periodic leg movements during sleep are not associated with excessive daytime sleepiness, and therefore appear unlikely to contribute to this problem. Increased sleepiness may reduce the likelihood of arousal with each leg movement.

Sleep problems seldom addressed at two general pediatric clinics.

OBJECTIVE: Sleep disorders can cause substantial morbidity but often remain undiagnosed among adults. We identified a series of children with sleep-related symptoms and reviewed medical chart notes for the previous 2 years to determine how often sleep problems had been addressed. DESIGN: Observational. Setting. Two university-affiliated but community-based general pediatrics clinics. PATIENTS: Children, ages 2.0 to 13.9 years, with clinic appointments. MEASURES: Parental and child responses to a validated Pediatric Sleep Questionnaire (PSQ) were used to identify patients at risk for chronic sleep-disordered breathing, periodic leg movements during sleep, insomnia, or excessive daytime sleepiness. Chart notes written within the previous 2 years were searched for sleep-related symptoms, diagnoses, or treatments. RESULTS: A total of 830 questionnaires were completed; 1395 chart notes of 86 symptomatic participants (mean age: 6.6 +/- 3.1 years; 51% male) with 103 identified sleep problems were reviewed. Fewer than 15% of patients had current chart notes that mentioned any of the PSQ-defined sleep problems; diagnoses were mentioned for 2 of 86 patients and no treatments were discussed. Among the 103 sleep problems, only 16 received mention in any past or current note; 10 had led to a diagnosis; 4 had led to intervention; and 3 were treated in a manner likely to be effective. Seventy-four of the sleep problems (72%) occurred in children whose charts did mention something about sleep, but such notations rarely related to concerns uncovered by the PSQ. CONCLUSIONS: Children with PSQ-identified sleep problems at 2 general pediatrics clinics seldom had these problems addressed, diagnosed, or treated, despite discussions about some aspect of their sleep in the large majority of cases. These findings support expansion of clinician and parent education about sleep disorders in children.

Hyperactivity and polysomnographic findings in children evaluated for sleep-disordered breathing.

STUDY OBJECTIVES: Children with sleep-disordered breathing (SDB) or periodic leg movements during sleep (PLMS) often have hyperactive behavior that improves when the sleep disorder is treated. Some children with SDB also have PLMS. To determine what polysomnographic features of SDB might be associated with hyperactive behavior, we studied behavior, SDB, and PLMS in a series of patients. DESIGN: Prospective and observational. SETTING: University-based sleep disorders laboratory. SUBJECTS: Children (n=113) aged 2 to 18 years, referred for suspected SDB. INTERVENTIONS: Parents completed the hyperactivity index of the Connors' Parental Rating Scale, and results were converted to age-adjusted t-scores. Children underwent laboratory-based polysomnography, with esophageal pressure monitoring when requested (n=19) by referring physicians. RESULTS: Children with SDB (n=59) showed high hyperactivity scores (mean 59.5+/-18.3 SD, 95% C.I. [54.7, 64.2]) but these scores were no higher than those of children without SDB (59.0+/-15.1, [54.8, 63.1]). Hyperactivity showed no significant associations with the rate of apneas and hypopneas, minimum oxygen saturation, or most negative esophageal pressure (p>0.10), but was associated with the presence of 5 or more PLMS per hour (p=0.02). The rate of PLMS showed a linear association with hyperactivity among those subjects with SDB (p = 0.002), but no association among those subjects without SDB (p = 0.64). CONCLUSIONS: These findings suggest that hyperactive behavior is common among children referred for suspected SDB, regardless of the presence or severity of SDB. Current observations cannot prove causality, but they are consistent with the hypothesis that PLMS may contribute to hyperactivity and SDB may act as an effect modifier.

Quality of life in obstructive sleep apnea: a systematic review of the literature.

OBJECTIVE: To review the literature on obstructive sleep apnea (OSA) and health-related quality of life (HRQOL). BACKGROUND: OSA affects nearly one in four men and one in ten women aged 30-60 years in the United States. Health consequences of OSA can include neuropsychiatric and cardiovascular sequela that disrupt professional, family, and social life and negatively impact HRQOL. METHODS: We conducted a comprehensive review of the literature on HRQOL and OSA, with special attention paid to instruments developed specifically for OSA. RESULTS: Generic instruments used to study HRQOL and OSA include: Medical Outcomes Study Short Form-36, Nottingham Health Profile, Sickness Impact Profile, Functional Limitations Profile, EuroQol, and Munich Life Quality Dimension List. Specific instruments include: Calgary Sleep Apnea Quality of Life Instrument, Functional Outcomes of Sleep Questionnaire, OSA Patient Oriented Severity Index, the OSA-18, and Cohen's pediatric OSA surgery quality of life questionnaire. CONCLUSIONS: OSA patients have impaired HRQOL when compared with healthy age- and gender-matched controls. Treatment with continuous positive airway pressure appears to improve HRQOL. Other treatment modalities have not been rigorously studied. In addition, more data are needed from preference-based measures that allow conversion to utility scores, which can be used to calculate quality-adjusted life years and cost-effectiveness ratios.

Clinical prediction of periodic leg movements during sleep in children.

OBJECTIVE: To assess the utility of several symptoms and a questionnaire-based scale in the identification of children with periodic leg movements during sleep (PLMS). BACKGROUND: PLMS may have important consequences in some children, but the extent to which a diagnosis can be established by clinical history is unknown. METHODS: Subjects were patients aged 2-18 years who underwent polysomnography to assess for sleep-disordered breathing (SDB). Parents completed a Pediatric Sleep Questionnaire which contained items under consideration for inclusion in the desired scale. RESULTS: Subjects (n=113) had a mean age of 9.8+/-4.0 (SD) and 73 (65%) were male; 59 (52%) had SDB and 29 (26%) had five or more PLMS per hour of sleep (PLMI> or =5). Severity of SDB was not different among those with and without PLMI> or =5. Yes/no responses to several question-items--about restless legs, growing pains, leaving the bed at night, waking more than twice per night, waking feeling unrefreshed, and morning headaches--showed some association with PLMI> or =5 and were combined into a composite PLMS score artificially weighted toward the first two items. The PLMS score averaged 0.40+/-0.31 and ranged from 0.0 to 1.0; a 1 SD increase was associated with PLMI> or =5 (odds ratio=1.87, 95% confidence interval (1.15, 3.13), P=0.014) after adjustment for age, sex, and SDB severity. Sensitivity of a PLMS score>0.33 for PLMI> or =5 was 0.79, specificity was 0.56, positive predictive value was 0.38, and negative predictive value was 0.89. Internal consistency was reasonable (Cronbach's alpha=0.71), as was test-retest reliability (rho=0.62, P=0.0026, n=21 separate subjects). CONCLUSIONS: Restless legs, growing pains, sleep-maintenance insomnia, unrefreshing sleep, and morning headaches show moderate associations with polysomnographically-defined PLMS, but several other symptoms do not. These results require confirmation but suggest that clinical assessment and the PLMS score may be helpful but far from definitive.

Assessment of sleepiness in children.

Excessive sleepiness is a common but under-recognized problem in children. This article examines the clinical and laboratory evaluation of sleepiness in children, including the use of polysomnography, the multiple sleep latency test, and other varieties of neurophysiologic testing. Where applicable, technical aspects of laboratory testing are reviewed. Alternative laboratory and neurobehavioral techniques used to investigate daytime sleepiness are also briefly covered.

The pathology of REM sleep behavior disorder with comorbid Lewy body dementia.

A patient with REM sleep behavior disorder who subsequently developed probable Lewy body dementia is now reported to have a definite pathologic diagnosis of Lewy body dementia. Examination of brain revealed Lewy bodies as well as marked neuronal loss in brainstem monoaminergic nuclei-particularly locus coeruleus and substantia nigra-that inhibit cholinergic neurons in the pedunculopontine nucleus mediating atonia during REM sleep.

Decreased striatal dopaminergic innervation in REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [11C]dihydrotetrabenazine binding, particularly in the posterior putamen.