Type III home sleep testing versus pulse oximetry: is the respiratory disturbance index better than the oxygen desaturation index to predict the apnoea-hypopnoea index measured during laboratory polysomnography?

OBJECTIVES: In its guidelines on the use of portable monitors to diagnose obstructive sleep apnoea, the American Academy of Sleep Medicine endorses home polygraphy with type III devices recording at a minimum airflow the respiratory effort and pulse oximetry, but advises against simple pulse oximetry. However, oximetry is widely available and simple to use in the home. This study was designed to compare the ability of the oxygen desaturation index (ODI) based on oximetry alone with a stand-alone pulse oximeter (SPO) and from the oximetry channel of the ApneaLink Plus (ALP), with the respiratory disturbance index (RDI) based on four channels from the ALP to predict the apnoea-hypopnoea index (AHI) from laboratory polysomnography. DESIGN: Cross-sectional diagnostic accuracy study. SETTING: Sleep medicine practice of a multispecialty clinic. PARTICIPANTS: Patients referred for laboratory polysomnography with suspected sleep apnoea. We enrolled 135 participants with 123 attempting the home sleep testing and 73 having at least 4 hours of satisfactory data from SPO and ALP. INTERVENTIONS: Participants had home testing performed simultaneously with both a SPO and an ALP. The 2 oximeter probes were worn on different fingers of the same hand. The ODI for the SPO was calculated using Profox software (ODI(SOX)). For the ALP, RDI and ODI were calculated using both technician scoring (RDI(MAN) and ODI(MAN)) and the ALP computer scoring (RDI(RAW) and ODI(RAW)). RESULTS: The receiver-operator characteristic areas under the curve for AHI ≥ 5 were RDI(MAN) 0.88 (95% confidence limits 0.81-0.96), RDI(RAW) 0.86 (0.76-0.94), ODI(MAN) 0.86 (0.77-0.95), ODI(RAW) 0.84 (0.75-0.93) and ODI(SOX) 0.83 (0.73-0.93). CONCLUSIONS: We conclude that the RDI and the ODI, measured at home on the same night, give similar predictions of the laboratory AHI, measured on a different night. The differences between the two methods are small compared with the reported night-to-night variation of the AHI.

Genetic variants associated with sleep disorders.

OBJECTIVE: The diagnostic boundaries of sleep disorders are under considerable debate. The main sleep disorders are partly heritable; therefore, defining heritable pathophysiologic mechanisms could delineate diagnoses and suggest treatment. We collected clinical data and DNA from consenting patients scheduled to undergo clinical polysomnograms, to expand our understanding of the polymorphisms associated with the phenotypes of particular sleep disorders. METHODS: Patients at least 21 years of age were recruited to contribute research questionnaires, and to provide access to their medical records, saliva for deoxyribonucleic acid (DNA), and polysomnographic data. From these complex data, 38 partly overlapping phenotypes were derived indicating complaints, subjective and objective sleep timing, and polysomnographic disturbances. A custom chip was used to genotype 768 single-nucleotide polymorphisms (SNPs). Additional assays derived ancestry-informative markers (eg, 751 participants of European ancestry). Linear regressions controlling for age, gender, and ancestry were used to assess the associations of each phenotype with each of the SNPs, highlighting those with Bonferroni-corrected significance. RESULTS: In peroxisome proliferator-activated receptor gamma, coactivator 1 beta (PPARGC1B), rs6888451 was associated with several markers of obstructive sleep apnea. In aryl hydrocarbon receptor nuclear translocator-like (ARNTL), rs10766071 was associated with decreased polysomnographic sleep duration. The association of rs3923809 in BTBD9 with periodic limb movements in sleep was confirmed. SNPs in casein kinase 1 delta (CSNK1D rs11552085), cryptochrome 1 (CRY1 rs4964515), and retinoic acid receptor-related orphan receptor A (RORA rs11071547) were less persuasively associated with sleep latency and time of falling asleep. CONCLUSIONS: SNPs associated with several sleep phenotypes were suggested, but due to risks of false discovery, independent replications are needed before the importance of these associations can be assessed, followed by investigation of molecular mechanisms.

Circadian polymorphisms in night owls, in bipolars, and in non-24-hour sleep cycles.

People called night owls habitually have late bedtimes and late times of arising, sometimes suffering a heritable circadian disturbance called delayed sleep phase syndrome (DSPS). Those with DSPS, those with more severe progressively-late non-24-hour sleep-wake cycles, and those with bipolar disorder may share genetic tendencies for slowed or delayed circadian cycles. We searched for polymorphisms associated with DSPS in a case-control study of DSPS research participants and a separate study of Sleep Center patients undergoing polysomnography. In 45 participants, we resequenced portions of 15 circadian genes to identify unknown polymorphisms that might be associated with DSPS, non-24-hour rhythms, or bipolar comorbidities. We then genotyped single nucleotide polymorphisms (SNPs) in both larger samples, using Illumina Golden Gate assays. Associations of SNPs with the DSPS phenotype and with the morningness-eveningness parametric phenotype were computed for both samples, then combined for meta-analyses. Delayed sleep and "eveningness" were inversely associated with loci in circadian genes NFIL3 (rs2482705) and RORC (rs3828057). A group of haplotypes overlapping BHLHE40 was associated with non-24-hour sleep-wake cycles, and less robustly, with delayed sleep and bipolar disorder (e.g., rs34883305, rs34870629, rs74439275, and rs3750275 were associated with n=37, p=4.58E-09, Bonferroni p=2.95E-06). Bright light and melatonin can palliate circadian disorders, and genetics may clarify the underlying circadian photoperiodic mechanisms. After further replication and identification of the causal polymorphisms, these findings may point to future treatments for DSPS, non-24-hour rhythms, and possibly bipolar disorder or depression.

FMR1, circadian genes and depression: suggestive associations or false discovery?

BACKGROUND: There are several indications that malfunctions of the circadian clock contribute to depression. To search for particular circadian gene polymorphisms associated with depression, diverse polymorphisms were genotyped in two samples covering a range of depressed volunteers and participants with normal mood. METHODS: Depression mood self-ratings and DNA were collected independently from a sample of patients presenting to a sleep disorders center (1086 of European origin) and from a separate sample consisting of 399 participants claiming delayed sleep phase symptoms and 406 partly-matched controls. A custom Illumina Golden Gate array of 768 selected single nucleotide polymorphisms (SNPs) was assayed in both samples, supplemented by additional SNPlex and Taqman assays, including assay of 41 ancestry-associated markers (AIMs) to control stratification. RESULTS: In the Sleep Clinic sample, these assays yielded Bonferroni-significant association with depressed mood in three linked SNPs of the gene FMR1: rs25702 (nominal P=1.77E-05), rs25714 (P=1.83E-05), and rs28900 (P=5.24E-05). This FMR1 association was supported by 8 SNPs with nominal significance and a nominally-significant gene-wise set test. There was no association of depressed mood with FMR1 in the delayed sleep phase case-control sample or in downloaded GWAS data from the GenRED 2 sample contrasting an early-onset recurrent depression sample with controls. No replication was located in other GWAS studies of depression. Our data did weakly replicate a previously-reported association of depression with PPARGC1B rs7732671 (P=0.0235). Suggestive associations not meeting strict criteria for multiple testing and replication were found with GSK3B, NPAS2, RORA, PER3, CRY1, MTNR1A and NR1D1. Notably, 16 SNPs nominally associated with depressed mood (14 in GSK3B) were also nominally associated with delayed sleep phase syndrome (P=3E10-6). CONCLUSIONS: Considering the inconsistencies between samples and the likelihood that the significant three FMR1 SNPs might be linked to complex polymorphisms more functionally related to depression, large gene resequencing studies may be needed to clarify the import for depression of these circadian genes.

Hypnotics' association with mortality or cancer: a matched cohort study.

OBJECTIVES: An estimated 6%-10% of US adults took a hypnotic drug for poor sleep in 2010. This study extends previous reports associating hypnotics with excess mortality. SETTING: A large integrated health system in the USA. DESIGN: Longitudinal electronic medical records were extracted for a one-to-two matched cohort survival analysis. SUBJECTS: Subjects (mean age 54 years) were 10 529 patients who received hypnotic prescriptions and 23 676 matched controls with no hypnotic prescriptions, followed for an average of 2.5 years between January 2002 and January 2007. MAIN OUTCOME MEASURES: Data were adjusted for age, gender, smoking, body mass index, ethnicity, marital status, alcohol use and prior cancer. Hazard ratios (HRs) for death were computed from Cox proportional hazards models controlled for risk factors and using up to 116 strata, which exactly matched cases and controls by 12 classes of comorbidity. RESULTS: As predicted, patients prescribed any hypnotic had substantially elevated hazards of dying compared to those prescribed no hypnotics. For groups prescribed 0.4-18, 18-132 and >132 doses/year, HRs (95% CIs) were 3.60 (2.92 to 4.44), 4.43 (3.67 to 5.36) and 5.32 (4.50 to 6.30), respectively, demonstrating a dose-response association. HRs were elevated in separate analyses for several common hypnotics, including zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates and sedative antihistamines. Hypnotic use in the upper third was associated with a significant elevation of incident cancer; HR=1.35 (95% CI 1.18 to 1.55). Results were robust within groups suffering each comorbidity, indicating that the death and cancer hazards associated with hypnotic drugs were not attributable to pre-existing disease. CONCLUSIONS: Receiving hypnotic prescriptions was associated with greater than threefold increased hazards of death even when prescribed <18 pills/year. This association held in separate analyses for several commonly used hypnotics and for newer shorter-acting drugs. Control of selective prescription of hypnotics for patients in poor health did not explain the observed excess mortality.

Genotyping sleep disorders patients.

OBJECTIVE: The genetic susceptibility factors underlying sleep disorders might help us predict prognoses and responses to treatment. Several candidate polymorphisms for sleep disorders have been proposed, but there has as yet inadequate replication or validation that the candidates may be useful in the clinical setting. METHODS: To assess the validity of several candidate associations, we obtained saliva deoxyribonucleic acid (DNA) samples and clinical information from 360 consenting research participants who were undergoing clinical polysomnograms. Ten single nucleotide polymorphisms (SNPs) were genotyped. These were thought to be related to depression, circadian sleep disorders, sleep apnea, restless legs syndrome (RLS), excessive sleepiness, or to slow waves in sleep. RESULTS: With multivariate generalized linear models, the association of TEF rs738499 with depressive symptoms was confirmed. Equivocal statistical evidence of association of rs1801260 (the C3111T SNP in the CLOCK gene) with morningness/eveningness and an association of Apolipoprotein E (APOE) rs429358 with the Epworth Sleepiness Scale (ESS) were obtained, but these associations were not strong enough to be of clinical value by themselves. Predicted association of SNPs with sleep apnea, RLS, and slow wave sleep were not confirmed. CONCLUSION: The SNPs tested would not, by themselves, be of use for clinical genotyping in a sleep clinic.

Wrist actigraphic scoring for sleep laboratory patients: algorithm development.

Wrist actigraphy is employed increasingly in sleep research and clinical sleep medicine. Critical evaluation of the performance of new actigraphs and software is needed. Actigraphic sleep-wake estimation was compared with polysomnographic (PSG) scoring as the standard in a clinical sleep laboratory. A convenience sample of 116 patients undergoing clinical sleep recordings volunteered to participate. Actiwatch-L recordings were obtained from 98 participants, along with 18 recordings using the newer Spectrum model (Philips Electronics), but some of the actigraphic recordings could not be adequately aligned with the simultaneous PSGs. Of satisfactory alignments, 40 Actiwatch recordings were used as a training set to empirically develop a new Scripps Clinic algorithm for sleep-wake scoring. The Scripps Clinic algorithm was then prospectively evaluated in 39 Actiwatch recordings and 16 Spectrum recordings, producing epoch-by-epoch sleep-wake agreements of 85-87% and kappa statistics averaging 0.52 (indicating moderate agreement). Wake was underestimated by the scoring algorithm. The correlations of PSG versus actigraphic wake percentage estimates were r = 0.6690 for the Actiwatch and r = 0.2197 for the Spectrum. In general, using a different weighting of activity counts from previous and subsequent epochs, the Scripps Clinic algorithm discriminated sleep-wake more successfully than the manufacturer's Actiware algorithms. Neither algorithm had fully satisfactory agreement with PSG. Further evaluations of algorithms for these actigraphs are needed, along with controlled comparisons of different actigraphic designs and software.

Meta-analyses of hypnotics and infections: eszopiclone, ramelteon, zaleplon, and zolpidem.

STUDY OBJECTIVES: Recent meta-analyses raising concern about risks of hypnotics suggest a need for more clarification of these risks. METHODS: Because of preliminary suggestions that eszopiclone causes infections, we studied US Food and Drug Administration files on the 4 most-recently approved hypnotics, combined with published studies, to compile the risk ratios of infections for groups randomly assigned to receive hypnotics versus those assigned to receive placebos in controlled trials. Parallel controlled clinical trials of eszopiclone, ramelteon, zaleplon, and zolpidem were included when data on subjects, duration of exposure, and adverse effects were available. Results of trials were combined by meta-analyses. RESULTS: Of 8828 participants assigned to the 4 hypnotics and 4383 participants who randomly received placebos, 606 in the hypnotics groups and 200 in the placebo groups were reported to develop some kind of infection (risk ratio = 1.44, 95% confidence interval 1.25-1.64, p < 0.00001). Most infections were apparently mild and did not lead to dropouts. Subanalyses for individual drugs indicated that eszopiclone and zolpidem individually were associated with reported infections. There were insufficient data concerning individual studies of zaleplon and ramelteon for valid secondary meta-analyses of zaleplon or ramelteon by themselves. CONCLUSIONS: Research is needed to objectively determine whether the use of hypnotics increases the risk of infections. Immune compromise or esophageal reflux and aspiration should be studied as possible mechanisms.

Evaluation of immobility time for sleep latency in actigraphy.

BACKGROUND: Actigraphy has become an important tool in sleep research, however, most actigraphic models have had little evaluation of their sleep scoring software. Some reports have described poor agreement of actigraph and polysomnogram (PSG) results. In this study, we examined the accuracy of the Actiwatch-L instrument with Actiware((R)) software version 5.0 (Minimitter-Respironics, Bend, Oregon). METHODS: We analyzed the sleep latencies and total sleep times in 33 actigraph recordings and compared performance to simultaneous polysomnography. For scoring sleep latency, the default criterion for scoring sleep onset (10min of immobility) was compared with criteria of 4, 5, 6, and 15min of immobility, and low, middle, and high activity thresholds were compared. RESULTS: Of 4, 5, 6, 10 and 15min of actigraphic immobility, the 5min criterion yielded the most accurate sleep latencies. The 5min criterion also yielded near-optimal estimates for total sleep time and wake after sleep onset. CONCLUSIONS: We found that a default 10-min immobility parameter for sleep onset was not as accurate as 5min for scoring sleep latency and total sleep time in this clinical sample. There is a need for expanded samples to further evaluate algorithm scoring parameters and the search for superior alternatives.

CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep.

BACKGROUND: Type 2 diabetes and obstructive sleep apnea (OSA) are frequently comorbid conditions. OSA is associated with increased insulin resistance, but studies of continuous positive airway pressure (CPAP) have shown inconsistent effects on glycemic control. However, endpoints such as hemoglobin A1c and insulin sensitivity might not reflect short-term changes in glycemic control during sleep. METHODS: We used a continuous glucose-monitoring system to measure interstitial glucose every 5 minutes during polysomnography in 20 patients with type 2 diabetes and newly diagnosed OSA. The measurements were repeated after an average of 41 days of CPAP (range 26-96 days). All patients were on a stable diet and medications. Each 30-second epoch of the polysomnogram was matched with a continuous glucose-monitoring system reading, and the sleeping glucose level was calculated as the average for all epochs scored as sleeping. RESULTS: The mean sleeping glucose decreased from untreated (122.0 +/- 61.7 mg/dL) to treated (102.9 +/- 39.4 mg/dL; p = 0.03 by Wilcoxon paired rank test). The sleeping glucose was more stable after treatment, with the median SD decreasing from 20.0 to 13.0 mg/dL (p = 0.005) and the mean difference between maximum and minimum values decreasing from 88 to 57 mg/dL (p= 0.003). The change in the mean hemoglobin A1c from 7.1% to 7.2% was not significant. CONCLUSIONS: Our study is limited by the lack of a control group, but the results suggest that sleeping glucose levels decrease and are more stable after patients with type 2 diabetes and OSA are treated with CPAP.

Melatonin effects on luteinizing hormone in postmenopausal women: a pilot clinical trial NCT00288262.

BACKGROUND: In many mammals, the duration of the nocturnal melatonin elevation regulates seasonal changes in reproductive hormones such as luteinizing hormone (LH). Melatonin's effects on human reproductive endocrinology are uncertain. It is thought that the same hypothalamic pulse generator may both trigger the pulsatile release of GnRH and LH and also cause hot flashes. Thus, if melatonin suppressed this pulse generator in postmenopausal women, it might moderate hot flashes. This clinical trial tested the hypothesis that melatonin could suppress LH and relieve hot flashes. METHODS: Twenty postmenopausal women troubled by hot flashes underwent one week of baseline observation followed by 4 weeks of a randomized controlled trial of melatonin or matched placebo. The three randomized treatments were melatonin 0.5 mg 2.5-3 hours before bedtime, melatonin 0.5 mg upon morning awakening, or placebo capsules. Twelve of the women were admitted to the GCRC at baseline and at the end of randomized treatment for 24-hour sampling of blood for LH. Morning urine samples were collected twice weekly to measure LH excretion. Subjective responses measured throughout baseline and treatment included sleep and hot flash logs, the CESD and QIDS depression self-ratings, and the SAFTEE physical symptom inventory. RESULTS: Urinary LH tended to increase from baseline to the end of treatment. Contrasts among the 3 randomized groups were statistically marginal, but there was relative suppression combining the groups given melatonin as contrasted to the placebo group (p < 0.01 one-tailed, Mann-Whitney U = 14). Similar but not significant results were seen in blood LH. There were no significant contrasts among groups in hot flashes, sleep, depression, or side-effect measures and no significant adverse effects of any sort. CONCLUSION: The data are consistent with the hypothesis that melatonin suppresses LH in postmenopausal women. An effect related to the duration of nocturnal melatonin elevation is suggested. Effects of melatonin on reproductive endocrinology should be studied further in younger women and in men. Larger studies of melatonin effects on postmenopausal symptoms would be worthwhile.

Nasal cytology: a marker of clinically silent inflammation in patients with obstructive sleep apnea and a predictor of noncompliance with nasal CPAP therapy.

STUDY OBJECTIVES: Patients with obstructive sleep apnea treated with nasal continuous positive airway pressure (CPAP) often complain of nasal side effects. We studied patients before and after initiation of nasal CPAP to see how treatment affected nasal function and markers of nasal inflammation. We searched for pretreatment findings that might help to predict noncompliance. METHODS: Nasal symptom scores, nasal flow by anterior rhinomanometry, mediator levels (intercellular adhesion molecule-1, interleukin-6, interleukin-8 and interleukin-13), and nasal scrapes for cytology were obtained at baseline and monthly for up to 3 months of nasal CPAP therapy. Compliance was assessed from the patient's report and by recording hours of usage for up to 19 months of follow-up. RESULTS: Thirty-eight patients with newly diagnosed obstructive sleep apnea were classified as having no rhinitis (42%), allergic rhinitis (37%), or nonallergic rhinitis (21%). There was no significant difference in compliance in patients with and without rhinitis. Compliant and noncompliant patients showed no significant differences in their baseline nasal symptom scores, nasal flow, and mediator levels. Nasal neutrophil counts before treatment were greater in noncompliant than in compliant patients (p = .004) and greater in those discontinuing because of nasal symptoms than in patients who quit for other reasons (p = .05). There was a positive correlation between neutrophil counts and nasal bacterial scores, both before and after treatment with nasal CPAP. CONCLUSIONS: Patients with increased neutrophil counts in the nasal scrape before beginning nasal CPAP are at increased risk of discontinuing therapy. They appear to have subclinical nasal inflammation that cannot be identified from clinical assessment, nasal symptom scores or rhinomanometry.

Zolpidem for postanoxic spasticity.

A 28-year-old male sustained anoxic brain damage following aborted cardiac arrest, and subsequently developed severe muscular rigidity and spasticity involving all extremities. The spasticity was refractory to the standard regimens used for spastic hypertonia. Zolpidem dramatically inhibited muscular rigidity, spasticity, and dystonic posturing in a dose-dependent manner, resulting in a sustained improvement of his global performance over four years. The authors postulate a central mechanism of action by selective inhibition of GABAergic inhibitory neurons, and suggest a controlled clinical study to investigate the potential efficacy of zolpidem in relieving spasticity related to postanoxic brain injury.