Mary J. Morrell

Changes in brain morphology associated with obstructive sleep apnea

OBJECTIVE Obstructive sleep apnea (OSA) causes hypoxemia and fragmented sleep, which lead to neurocognitive deficits. We hypothesised that focal loss of cortical gray matter generally within areas associated with memory processing and learning and specifically within the hippocampus would occur in OSA. METHODS Voxel-based morphometry, an automated processing technique for magnetic resonance images, was used to characterise structural changes in gray matter in seven right handed, male patients with newly diagnosed OSA and seven non-apneic, male controls matched for handedness and age. RESULTS The analysis revealed a significantly lower gray matter concentration within the left hippocampus (p=0.004) in the apneic patients. No further significant focal gray matter differences were seen in the right hippocampus and in other brain regions. There was no difference in total gray matter volume between apneics and controls. CONCLUSION This preliminary report indicates changes in brain morphology in OSA, in the hippocampus, a key area for cognitive processing.

A high prevalence of sleep disordered breathing in men with mild symptomatic chronic heart failure due to left ventricular systolic dysfunction

Sleep disordered breathing (SDB) is common in severe chronic heart failure (CHF) and is associated with increased morbidity and mortality. The prevalence of SDB in mild symptomatic CHF is unknown.

The Impact of Obesity on Oxygen Desaturation during Sleep-disordered Breathing

RATIONALE Obesity increases the risk and severity of sleep-disordered breathing. The degree to which excess body weight contributes to blood oxygen desaturation during hypopneic and apneic events has not been comprehensively characterized. OBJECTIVES To quantify the association between excess body weight and oxygen desaturation during sleep-disordered breathing. METHODS A total of 750 adult participants in the Wisconsin Sleep Cohort Study were assessed for body mass index (BMI) (kg/m(2)) and sleep-disordered breathing. The amount of Sa(O(2)), duration, and other characteristics of 37,473 observed breathing events were measured during polysomnography studies. A mixed-effects linear regression model estimated the association of blood oxygen desaturation with participant-level characteristics, including BMI, gender, and age, and event-level characteristics, including baseline Sa(O(2)), change in Vt, event duration, sleep state, and body position. MEASUREMENTS AND MAIN RESULTS BMI was positively associated with oxygen desaturation severity independent of age, gender, sleeping position, baseline Sa(O(2)), and event duration. BMI interacted with sleep state such that BMI predicted greater desaturation in rapid eye movement (REM) sleep than in non-REM sleep. Each increment of 10 kg/m(2) BMI predicted a 1.0% (SE, 0.2%) greater mean blood oxygen desaturation for persons in REM sleep experiencing hypopnea events associated with 80% Vt reductions. CONCLUSIONS Excess body weight is an important predictor of the severity of blood oxygen desaturation during apnea and hypopnea events, potentially exacerbating the impact of sleep-disordered breathing in obese patients.

Changes in brain morphology in patients with obstructive sleep apnoea

Background Obstructive sleep apnoea (OSA) is a common disease that leads to daytime sleepiness and cognitive impairment. Attempts to investigate changes in brain morphology that may underlie these impairments have led to conflicting conclusions. This study was undertaken to aim to resolve this confusion, and determine whether OSA is associated with changes in brain morphology in a large group of patients with OSA, using improved voxel-based morphometry analysis, an automated unbiased method of detecting local changes in brain structure. Methods 60 patients with OSA (mean apnoea hypopnoea index 55 (95% CI 48 to 62) events/h, 3 women) and 60 non-apnoeic controls (mean apnoea hypopnoea index 4 (95% CI 3 to 5) events/h, 5 women) were studied. Subjects were imaged using T1-weighted 3-D structural MRI (69 subjects at 1.5 T, 51 subjects at 3 T). Differences in grey matter were investigated in the two groups, controlling for age, sex, site and intracranial volume. Dedicated cerebellar analysis was performed on a subset of 108 scans using a spatially unbiased infratentorial template. Results Patients with OSA had a reduction in grey matter volume in the right middle temporal gyrus compared with non-apnoeic controls (p<0.05, corrected for topological false discovery rate across the entire brain). A reduction in grey matter was also seen within the cerebellum, maximal in the left lobe VIIIb close to XI, extending across the midline into the right lobe. Conclusion These data show that OSA is associated with focal loss of grey matter that could contribute to cognitive decline. Specifically, lesions in the cerebellum may result in both motor dysfunction and working memory deficits, with downstream negative consequences on tasks such as driving.

Adaptive servo-ventilation in heart failure patients with sleep apnea: A real world study

BACKGROUND Congestive heart failure (CHF) patients often present with obstructive and central sleep apnea occurring concurrently within the same night. This study assessed the efficacy of, and improvements associated with, the use of adaptive servo-ventilation (ASV) in CHF patients with all types of sleep apnea. We hypothesized that ASV would be effective at reducing sleep apnea and improving both cardiac status and quality of life. METHODS Eleven male patients with stable CHF and sleep apnea (apnea/hypopnea index (AHI) >15 events/h) were treated with 6 months optimized ASV and compared to 8 patients not receiving ASV. At baseline, both groups were comparable for New York Heart Association class, left ventricular ejection fraction (LVEF), plasma Brain Natriuretric Peptide (BNP) concentrations and AHI. All patients were receiving optimal medical therapy. RESULTS At 6 months ASV significantly reduced AHI (mean (SD), baseline 49.0 (35.1) v ASV 7.6 (14.6); p=0.001) and LVEF was increased (median (inter-quartile range), treatment group: +5.7 (1.6-9.5) v comparison group: -4.0 (-8.9-+4.6)% respectively; p=0.04) but not BNP (p=0.59). The energy/vitality score of the SF-36 quality of life questionnaire was also improved at 6 months (treatment group: +10 (5-35) v comparison group: -12 (-18-+10); p=0.005). CONCLUSION ASV effectively reduces all types of sleep apnea. Six months of use is associated with improvement in LVEF and aspects of quality of life.

Effect of CO2 inhalation on central sleep apnea and arousals from sleep

Background: CO2 inhalation reduces central sleep apnea (CSA) in patients with congestive heart failure (CHF) and idiopathic CSA. CO2 is also a stimulus for cortical arousal, which has been linked to increased sympathetic nerve activity (SNA) and increased mortality in CHF patients with CSA. Objective: We have tested the hypothesis that during sleep, inhalation of CO2 sufficient to reduce the apnea-hypopnea index (AHI) would not reduce the arousal index (AroI). Methods: In 10 male patients with CSA (7 with CHF and 3 with idiopathic CSA), the inspired CO2 concentration was increased to raise the sleeping end-tidal CO2 by 2–4 mm Hg during established stage 2 sleep. Each intervention was maintained for a 10-min period. Sleep stage was monitored with electroencephalograms, electrooculograms, submental electromyogram, airflow with pneumotachometer and respiratory effort and blood gases with oxygen saturation and end-tidal CO2. During periods of air and CO2 breathing, AHI and AroI were compared with paired t tests; patients acted as their own controls. Results: Inhalation of CO2 produced a significant reduction in AHI (mean ± SEM) from 74.4 ± 12.4 events/h during air breathing to 25.8 ± 7.8 events/h with CO2 inhalation (p = 0.002). However, the AroI was not significantly different between the two conditions, air 67.8 ± 12.3 events/h and CO2 inhalation 52.8 ± 12.4 events/h (p = 0.264). Conclusion: CO2 inhalation reverses CSA but not arousals from sleep. Our findings highlight the need for treatment options that reduce both respiratory events and decrease arousals from sleep, with their associated SNA sequelae.

Obstructive Sleep Apnea Syndrome Is Associated with Deficits in Verbal but Not Visual Memory

RATIONALE Although cognitive deficits are well documented in patients with sleep apnea, the impact on memory remains unclear. OBJECTIVES To test the hypotheses that (1) patients with obstructive sleep apnea have memory impairment and (2) memory impairment is commensurate with disease severity. METHODS Patients with obstructive sleep apnea and healthy volunteers (apnea-hypopnea index <5 events/h) completed a test battery specially designed to differentiate between aspects of memory (semantic, episodic, and working) versus attention. Sleepiness was measured on the basis of the Epworth Sleepiness Scale and Oxford Sleep Resistance test. Memory performance in patients versus control subjects was compared (Mann-Whitney U test; P < 0.01, Bonferroni corrected for multiple comparisons) and relationships between performance and disease severity were analyzed by linear regression. MEASUREMENTS AND MAIN RESULTS Sixty patients and healthy control subjects matched for age (mean +/- SD: patients, 51 +/- 9 yr; control subjects, 50 +/- 9 yr) and education (patients, 14 +/- 3 yr; control subjects, 15 +/- 3 yr) participated. Patients demonstrated impaired Logical Memory Test results (immediate recall: patients, median [range], 36 [9-69]; control subjects, 43 [19-64], P = 0.0004; and delayed recall: patients, 22 [6-42]; control subjects, 27 [10-46]; P = 0.0001). There were minimal differences in attention, visual episodic, semantic, or working memory; patients performed better than control subjects on Spatial Span forward and backward. Regression analysis revealed that Logical Memory Test performance was not significantly related to disease severity after controlling for age, education, and sleepiness. CONCLUSIONS Obstructive sleep apnea is associated with impairment in verbal, but not visual, memory. The impairment was present across a range of disease severity and was not explained by reduced attention. Such verbal memory impairment may affect daytime functioning and performance.

Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial

BACKGROUND The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for moderate to severe obstructive sleep apnoea (OSA) syndrome have been established in middle-aged people; however, the benefits in older people are unknown. This trial was designed to address this evidence gap. METHODS This 12-month, multicentre, randomised trial enrolled patients across 14 National Health Service sleep centres in the UK. Consecutive patients aged 65 years or older with newly diagnosed OSA syndrome were eligible to join the trial. Patients were randomly assigned (1:1) into parallel groups to receive either CPAP with best supportive care (BSC) or BSC alone for 12 months. Randomisation was done by the Medical Research Council Clinical Trials Unit with computer-generated randomisation. The main investigator at each centre was masked to the trial randomisation. Coprimary endpoints were Epworth sleepiness score (ESS) at 3 months and cost-effectiveness over the 12-month trial period. Secondary outcomes were subjective sleepiness at 12 months, plus objective sleepiness, quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, and cardiovascular risk factors and events at 3 months and 12 months. The analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN90464927. FINDINGS Between Feb 24, 2010, and May 30, 2012, 278 patients were randomly assigned to the trial, of whom 231 (83%) completed the trial. 140 patients were allocated to and received CPAP plus BSC and 138 were allocated to and received BSC only. CPAP reduced ESS by 2·1 points (95% CI -3·0 to -1·3; p<0·0001) at 3 months for 124 (89%) of 140 patients compared with 124 (90%) of 138 patients given BSC, and by 2·0 points (-2·8 to -1·2; p<0·0001) at 12 months for 116 patients compared with 122 patients given BSC. The effect was greater in patients with higher CPAP usage or higher baseline ESS. Quality-adjusted life-years were similar between the groups (treatment effect 0·01 (95% CI -0·03 to 0·04; p=0·787) and health-care costs were marginally reduced with CPAP (-£35, -390 to 321; p=0·847). CPAP improved objective sleepiness (p=0·024), mobility (p=0·029), total cholesterol (p=0·048), and LDL cholesterol (p=0·042) at 3 months, but these were not sustained at 12 months. Measures of mood, functionality, nocturia, accidents, cognitive function, and cardiovascular events remained unchanged. Systolic blood pressure fell in the BSC group. 37 serious adverse events occurred in the CPAP group, and 22 in BSC group; all were independently classified as being unrelated to the trial and no significant harm was attributed to CPAP use. INTERPRETATION In older people with OSA syndrome, CPAP reduces sleepiness and is marginally more cost effective over 12 months than is BSC alone. On the basis of these results, we recommend that CPAP treatment should be offered routinely to older patients with OSA syndrome. FUNDING National Institute of Health Research (NIHR) Health Technology Assessment, NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.

Symptom burden of sleep-disordered breathing in mild-to-moderate congestive heart failure patients

The symptom burden resulting from sleep-disordered breathing (SDB) in patients with mild-to-moderate congestive heart failure (CHF) is unclear. The current authors monitored 24-h activity levels and compared subjective and objective measures of daytime sleepiness in 39 CHF patients, New York Heart Association class 2–3, on optimal medication. A total of 22 patients were classified as SDB (apnoea/hypopnoea index (AHI) median (range) 22.3 (16.6–100) events·h−1), and 17 as no SDB (NoSDB; AHI 3.7 (0–12.3) events·h−1). SDB was defined as AHI ≥15 events·h−1. Patients were assessed by 24-h activity monitoring (actigraphy) for a period of up to 14 days, a single objective sleepiness test (Oxford Sleep Resistance test) and Epworth Sleepiness Scale. The duration of daytime activity was significantly shorter in the SDB group compared with the NoSDB group. The SDB group also had increased time in bed and poorer sleep quality, as shown by the fragmentation index. Objectively the SDB group when compared with the NoSDB group were significantly sleepier, subjectively the groups did not differ. The amount of napping was similar for both groups. Despite the lack of subjective symptoms of daytime sleepiness, congestive heart failure patients with sleep-disordered breathing were objectively sleepier during the day and had reduced daytime activity with longer periods in bed and poorer sleep quality when compared with those without sleep-disordered breathing.

Sleep apnoea and the brain: a complex relationship

Intermittent hypoxia, reoxygenation, and hypercapnia or hypocapnia occur in both adults and children during untreated apnoea and hypopnoea, along with changes in cerebral blood flow and sleep fragmentation. These effects can result in cognitive deficits with functional effects on work and school efficiency. The assessment of how obstructive sleep apnoea affects cognition depends on the specificity and sensitivity of the tests, which are rarely developed specifically for obstructive sleep apnoea. In this Review, we discuss both the neural adaptive and maladaptive processes in response to hypoxaemia. The net result on cognitive and emotional performance depends on the stage of this dynamic process, effects on other body systems, cognitive reserve, and idiosyncratic susceptibility. We also explore the contribution of fragmented sleep, and the disruption of sleep structure, with focus on the effect at different times in the development of disease. This Review will address the gap in the underlying pathophysiology of new clinical and translational findings, and argue their contribution to the inherent complexity of the association between obstructive sleep apnoea and the brain.