Jed Black

Upper Airway Sleep-Disordered Breathing in Women

Most surveys of the obstructive sleep apnea syndrome have emphasized the predominance of the syndrome in men, and the few reports [1-3] describing adult women with this syndrome have emphasized its frequent association with massive obesity. Previous reports have suggested that the appearance of the obstructive sleep apnea syndrome is 10 to 20 times more common in men than in women. Recently, however, a survey of the general population aged 30 to 60 years by Young and colleagues [4] concluded that sleep-disordered breathing or obstructive sleep apnea associated with excessive daytime sleepiness has a prevalence of 4% in middle-aged men and of 2% in middle-aged women; Gislason and colleagues [5] estimated the prevalence at 2.5% for women in Iceland aged 40 to 59 years. The discrepancy between previous estimates of the prevalence of sleep-disordered breathing in women and these recent reports suggests that sleep-disordered breathing in women is underdiagnosed. We studied the clinical presentation and consequences of sleep-disordered breathing in a large sample of women seen during the past 4 years at the Stanford Sleep Disorders Clinic for symptoms of excessive daytime sleepiness. Methods Participants All women 18 years of age and older who contacted the clinic between 1988 and 1993 with symptoms of daytime tiredness, daytime fatigue, or daytime sleepiness were identified using our computerized clinic database. Inclusion Criteria For study inclusion, participants must have had a complete sleep-wake evaluation and a complete report in their chart that included the results of polygraphic evaluation. All participants included in our study had daytime sleepiness, based on either a score of 9 or more on the Epworth sleepiness scale [6, 7] or a score of 8 minutes or less on the multiple sleep latency test [8]. Nocturnal recordings included an electroencephalogram, an electrooculogram, a chin and a leg electromyogram (one lead), measurements of body position, and monitoring of respiration. Breathing patterns during sleep had to have indicated the presence of partial or complete upper airway obstruction. Initially, we looked for obstructive patterns that lasted 10 seconds and for a respiratory disturbance index (the number of apneas and hypopneas per hour of sleep) of 5 or more. In 1991, however, it was shown that clinical consequences could be seen with a respiratory disturbance index of less than 5, even in the absence of classically defined hypopneas. In this group of affected participants (with a respiratory disturbance index < 5), flow remains more or less constant, but breathing effort (as reflected by esophageal pressure) is substantially increased, leading to arousals on the electroencephalograms (the upper airway resistance syndrome) [9]. From this point on, we included participants with obstructive patterns of a shorter duration (one to two obstructed breaths) that induced sleep disturbances and daytime symptoms but who had a respiratory disturbance index of less than 5. The abnormal breathing patterns may have been shown by different means, from the use of complex protocols involving a facemask and pneumotachometer to simpler protocols that used measurements of esophageal pressure (Pes) with inductive respiratory plethysmography, monitoring of airflow, pulse oximetry, microphone monitoring, and intercostal electromyography (Figure 1). The minimum accepted protocol for inclusion involved monitoring of airflow, inductive plethysmography, and pulse oximetry, with the addition of Pes measurements after 1991. Finally, participants had to have shown clinical improvement in response to treatment using nasal continuous positive airway pressure (or nasal bilevel positive airway pressure in obese participants with a body mass index > 36.0 kg/m2). Figure 1. Polygraph showing a progressive increase in respiratory effort over time in a woman with symptoms of sleep-disordered breathing. Exclusion Criteria After reviewing their chart and test results, we excluded patients with sleepiness, a history of cataplexy, and two or more periods of sleep onset with rapid eye movement on the multiple sleep latency test. These patients were diagnosed as having narcolepsy. Patients with sleepiness and specific organic disorders (repetitive nocturnal epileptic seizures, brain tumor, neuromuscular disorders, untreated hypothyroidism) were also excluded. Patients with sleepiness and specific congenital or genetic defects or both (for example, trisomy 21 and substantial craniomandibular abnormalities such as the Hurler, the Hunter, the Traecher-Collin, and the Pierre Robin syndromes and other neurocrestopathies) were excluded even if their daytime sleepiness was related to an upper airway problem during sleep. Patients with major, noncongenital craniofacial deformities (particularly those associated with mandibular involvement) were also excluded, as were patients with psychiatric mood disorders in whom daytime somnolence was clearly a symptom of depression. All other participants 18 years and older were considered for the study and had polygraphic investigation. Selection of Controls Women with Insomnia We selected 60 women with insomnia, aged 18 years or older, who were seen during the same period as the index cases to serve as a control group. Use of this group as a control allowed us to compare the severity of the symptoms of these two groups of women with different sleep disorders. The control participants reported insomnia of at least 6 months duration; all were diagnosed with psychophysiologic insomnia on the basis of interviews, questionnaires, sleep logs, actigraphy, and nocturnal polygraphic recordings [10]. The control group was subdivided into six age groups (18 to 30 years, 31 to 40 years, 41 to 50 years, 51 to 60 years, 61 to 70 years, and > 70 years). Ten women were in each age group. Women with insomnia were examined successively in order of first clinic visit. When a woman met the criteria for any group, she was selected as an appropriate control for the breathing disorders group. The upper limit of normal weight for women in the control and index groups was defined as 26.8 kg/m2 [11]. A participant was considered overweight if her body mass index was more than 27.0 kg/m2 [11]. Participants in the control and sleep-disordered breathing groups were matched for weight on the basis of the above classifications and for menopausal status. Exact matching for obesity was difficult. Our two most obese controls with insomnia had body mass indices of 35.0 kg/m2 and 32.5 kg/m2,respectively, whereas our heaviest case patient with sleep-disordered breathing had a body mass index of 59.0 kg/m2. Men with Insomnia We selected 100 men who had been diagnosed during the past 3 years with upper airway sleep-disordered breathing as a second control group. Controls in this group met the same inclusion and exclusion criteria as female participants. Male controls were matched with case patients for body mass index (2 kg/m2) and respiratory disturbance index (<5 or 5). Exact matching for obesity was easy; we were able to match the men with the womens index group for highest body mass index. Geographic Distribution of Participants The Stanford Sleep Disorders Clinic has a high visibility locally and nationally and has frequent exposure in the media. Forty percent of the patients seen at the clinic are self-referred. These patients come to the Clinic for various reasons: Some have already seen sleep specialists and want second opinions, some are seeking different treatment options, and some have used the telephone book and come because our location is convenient. Twenty-five percent of our patients are referred by surgeons after consultation for a snoring problem; 35% are referred by general practitioners, internists, and pulmonary physicians who may be part of a health maintenance organization or a preferred provider organization that includes Stanford Medical Center as part of its referral list. Collected Variables and Analysis Data on the three groups of participants were collected from interviews. We used the Sleep Questionnaire and Assessment of Wakefulness, a previously validated questionnaire covering sleep-wake symptoms, past and present sleep-wake history, medical history, and drug intake [12, 13]. The sleep specialist reviewed answers to the questionnaire at the time of the patients interview. Demographic, familial, and social histories are also included in this sleep questionnaire and in the clinic administrative questionnaire, and these data were used in our analysis. Body mass index [14], neck circumference [15-18], and fatty distribution [19] were taken from records of the initial evaluation (done within 1 month of polysomnography). Upper airway anatomy was examined, and a diagram of anatomic abnormalities of the region was made on a standard form. In women, hormonal status was derived from their histories, and, if necessary, a follicle-stimulating hormone test was done after determining whether the women were receiving hormonal treatment (including birth control pills or estrogen as prophylaxis for osteoporosis). Daytime sleepiness indices and sleep variables for statistical analysis before and after treatment were collected from the monitored nights. Data and Statistical Analyses All participants were given a number, and their data were processed anonymously. Histograms were generated to describe the overall group of participants. Simple, descriptive statistics were generated using the Statview statistical computer package (Abacus Concepts, Inc., Berkeley, California). Correlation matrices were obtained. We did linear and multiple regression analyses to evaluate the effect of independently collected variables on dependent variables, such as respiratory disturbance index. Analysis of variance (ANOVA) was used for analyses of noncontinuous variables, and ANOVAs were also used, in conjunction with nonparametric statistics, to compare d

γ-Hydroxybutyrate/Sodium Oxybate Neurobiology, and Impact on Sleep and Wakefulness

Abstractγ-Hydroxybutyrate (GHB) is an endogenous short chain fatty acid and a, mostly oral, pharmacological compound that has been utilised in a variety of ways. Endogenously, GHB is synthesised locally within the CNS, mostly from its parent compound GABA. Sodium oxybate is the sodium salt of GHB and is used for the exogenous oral administration of GHB. It is likely that supraphysiological concentrations of GHB from exogenous administration produce qualitatively different neuronal actions than those produced by endogenous GHB concentrations.Evidence suggests a role for GHB as a neuromodulator/neurotransmitter. Under endogenous conditions and concentrations, and depending on the cell group affected, GHB may increase or decrease neuronal activity by inhibiting the release of neurotransmitters that are co-localised with GHB. After exogenous administration, most of the observed behavioural effects appear to be mediated via the activity of GHB at GABAB receptors, as long as the concentration is sufficient to elicit binding, which does not happen at endogenous concentrations. Endogenous and exogenous GHB is rapidly and completely converted into CO2 and H2O through the tricarboxylic acid cycle (Krebs cycle).Sodium oxybate has been observed to modulate sleep in nonclinical study participants, and sleep and wakefulness in clinical populations, including groups with insomnia, fibromyalgia and narcolepsy. In narcolepsy, sodium oxybate has shown dose-related effects on various properties of sleep, including increases in slow-wave sleep duration and delta power, and a reduced number of night-time awakenings. Furthermore, multiple measures of daytime sleepiness and cataplexy demonstrated consistent short- and long-term improvement in response to nighttime sodium oxybate therapy. The most common reported adverse events include dose-related headache, nausea, dizziness and somnolence.

Exploring the electrocardiogram as a potential tool to screen for premotor Parkinson's disease†

The aim of this study was to test the hypothesis that patients with REM sleep behavior disorder, many of whom will develop Parkinsons disease (PD) or a related synucleinopathy, will demonstrate decreased heart rate variability (HRV) compared with a group of age‐matched controls as measured by an electrocardiogram during wakefulness. We compared HRV in 11 untreated idiopathic REM sleep behavior disorder patients (9 men and 2 women; mean age, 63.3 years; SD, 7.5 years) and 11 control subjects with idiopathic insomnia without REM sleep behavior disorder (7 men and 4 women; mean age, 59.5 years; SD, 8.7 years). Subjects with other causes of reduced HRV were excluded. HRV was determined from 5‐minute presleep segments of a single channel electrocardiogram recorded during polysomnographic evaluations, using R‐R intervals during wakefulness. Time domain, geometric measures, and spectral analysis of the R‐R intervals were significantly different between cases and controls. A discriminant function analysis correctly classified 95.5% of subjects (overall model fit, P = 0.016). Leave‐one‐out cross‐validation correctly classified 77.3% of subjects. HRV during wakefulness is significantly decreased in patients with idiopathic REM sleep behavior disorder compared with control subjects, suggesting abnormalities of both sympathetic and parasympathetic function. Patients with RBD may later develop motor and cognitive features of a Lewy body disorder, such as PD. Cardiac autonomic dysfunction is also impaired in PD, suggesting that impaired HRV may be an early sign of PD. HRV measured by routine electrocardiograms could be used to screen for Lewy body disorders such as PD.

Investigations into the neurologic basis of narcolepsy

The understanding of narcolepsy has been enhanced by neurophysiologic investigations in humans and by pharmacologic and biochemical studies using the canine model of narcolepsy. Repetitive microsleeps have a more deleterious effect on performance than several short complete naps during the day. Under normal living conditions, the nocturnal sleep of narcoleptic patients is disrupted, and the spectral analysis of central EEG leads shows less delta power density per epoch than it does in age-matched controls, who have an absence or decrease of the usual decay in delta power across the night. Cataplexy is associated with a drop in H-reflex, even during partial cataplectic attacks. Monitoring of heart rate and intra-arterial blood pressure during cataplexy in humans shows a decrease in heart rate and an increase in blood pressure with onset of cataplexy, but the change in heart rate is secondary to the change in blood pressure. Investigations of narcoleptic Doberman pinschers have implicated several neurotransmitters in the brainstem and amygdala. In vivo dialysis and in situ injections of carbachol indicate that the pontine reticular formation is not the only muscarinic cholinergic region involved, but data support the existence of a multisynaptic descending pathway involved in the muscle atonia of cataplexy. Carbachol injections into the basal forebrain induce status cataplecticus. Experimental findings suggest a hypersensitivity of the overall muscarinic cholinergic system and that this hypersensitive cholinergic system is linked to the limbic system. An increase in the postsynaptic D2 dopaminergic receptor is observed in the amygdala of narcoleptic dogs compared with controls, with impairment of dopamine release. The associated findings suggest that an abnormal cholinergic-dopaminergic interaction could underlie the pathophysiology of narcolepsy.

Late-onset narcolepsy presenting as rapidly progressing muscle weakness: Response to plasmapheresis

polymorphisms (SNPs), we confirmed the results obtained with the univariate approach ( 2578C/A, 2 p 0.015). Concerning the haplotype analysis, the three main SNPs analyzed showed a linkage disequilibrium for each pair of loci ( 2578/ 1190 D :0.85; 2578/ 1154 D :0.82; 1190/ 1154 D :0.92). Inferred haplotype frequencies and related p values, before and after the permutation approach, are shown in the Table; haplotype AGG was significantly overrepresented in AD populations and associated with increased risk for the disease ( 2 test, p 0.001 and p 0.008, respectively). Moreover, the CGG frequency was higher in controls group than in cases. Finally, the overall haplotype frequencies were significantly different between patients and controls (p 0.009, 2 test 5df). In conclusion, the haplotype analysis of the VEGF gene promoter polymorphisms further confirms the previously reported genotype-based observations about the increased risk for AD.

A clinical investigation of obstructive sleep apnea syndrome (OSAS) and upper airway resistance syndrome (UARS) patients.

Objective: (i) Evaluation of the clinical differences and similarities presented by patients diagnosed as OSAS and UARS subjects. (ii) Evaluation of the ability of a sleep disorders specialist to dissociate the two syndromes based upon clinical evaluation.Population: 314 subjects were included. They were referred to a sleep disorders clinic with complaints of loud snoring during a 3 month period.Method: The evaluation consisted of: (i) Clinical interview and evaluation. (ii) Administration of validated questionnaires (Sleep Disorders Questionnaire and Epworth Sleepiness Scale). (iii) Establishment of clinical diagnostic and results of polygraphic recording.Results: After clinical evaluation and polygraphic recordings (performed within 3 weeks of initial evaluation) patients were subdivided into two groups: 176 OSAS and 128 UARS. The misclassification of patients by specialists correlated with body mass index (BMI) measurement, with an over classification of patient as OSAS when a high BMI was noted and vice-versa for UARS. The only significant difference between OSAS and UARS patients was an older age and a wider neck circumference in the OSAS group than in UARS patients.Conclusion: Clinical presentation including daytime sleepiness complaint and ESS score is similar for patients with and without drop of oxygen saturation below 90% during sleep. There was always a male predominance within both syndromes, but more women were diagnosed with UARS than with OSAS.

A multicenter evaluation of oral pressure therapy for the treatment of obstructive sleep apnea

OBJECTIVE We aimed to evaluate the impact of a novel noninvasive oral pressure therapy (OPT) (Winx®, ApniCure) system on polysomnographic measures of sleep-disordered breathing, sleep architecture, and sleep stability in obstructive sleep apnea (OSA). SUBJECTS AND METHODS A 4-week, multicenter, prospective, open-label, randomized, crossover, first-night order of control vs treatment, single-arm trial was conducted in five American Academy of Sleep Medicine (AASM) - accredited sleep clinics and one research laboratory. Sixty-three subjects (analysis cohort) were studied from a screening cohort of 367 subjects. The analysis cohort was 69.8% men, ages 53.6±8.9 years (mean±SD), body mass index of 32.3±4.5kg/m(2), with mild to severe OSA. At treatment initiation, subjects received random assignment to one night with and one without (control) treatment, and they were assessed again following 28 nights of treatment. Breathing and sleep architecture were assessed each night based on blind scoring by a single centralized scorer using AASM criteria. RESULTS Average nightly usage across the take-home period was 6.0±1.4h. There were no severe or serious device-related adverse events (AEs). Median apnea-hypopnea index (AHI) was 27.5 events per hour on the control night, 13.4 events per hour on the first treatment night, and 14.8 events per hour after 28days of treatment. A clinically significant response (treatment AHI ⩽10/h and ⩽50% of control values) was seen in 20 of the 63 subjects evaluated. Rapid eye movement percentage (REM%) was significantly increased, and N1%, stage shifts to N1 sleep, overall stage shifts, total awakenings, and arousals per hour were all significantly reduced at both treatment nights compared to controls. Mean Epworth sleepiness scale (ESS) was significantly reduced from 12.1 to 8.6 (Cohen d effect size, 0.68) in those untreated for two or more weeks prior to OPT study participation and remained unchanged in subjects who directly switched from continuous positive airway pressure (CPAP) therapy to OPT. CONCLUSION Clinically significant improvements in sleep quality and continuity, AHI, ODI, ESS, and overall clinical status were achieved in an easily identified subgroup. OPT was safe and well-tolerated and nightly usage was high.

Sleepiness and residual sleepiness in adults with obstructive sleep apnea.

Sleepiness is a common, but not necessary symptom of the obstructive sleep apnea syndrome (OSA) and is a frequent chief complaint of patients with OSA who seek medical attention. While sleepiness may seem simple in nature, the underlying mechanisms producing daytime sleepiness in OSA are complex and poorly characterized. Moreover, the meaningful assessment of pathological sleepiness is frequently far from straightforward. Effective treatment of OSA is generally expected to resolve or ameliorate daytime sleepiness. An unknown percentage of treated OSA patients, however, remain sleepy during waking hours. The assessment and treatment of residual sleepiness in treated OSA can range from simple to difficult, depending on the nature and causes of the continued sleepiness. Recently, however, data from clinical trials have been generated which provide direction in the evaluation and management of the OSA patient suffering residual daytime sleepiness.

The nightly administration of sodium oxybate results in significant reduction in the nocturnal sleep disruption of patients with narcolepsy

BACKGROUND Previous studies indicate that nightly sodium oxybate administration reduces nocturnal sleep disruption in narcolepsy. The present study provided an opportunity to further characterize these sleep-related effects in patients with narcolepsy during treatment with sodium oxybate as monotherapy or in combination with modafinil. METHODS This double-blind, placebo-controlled study enrolled 278 patients with narcolepsy taking modafinil 200-600 mg daily for the treatment of excessive daytime sleepiness (EDS). Following a baseline polysomnogram (PSG) and Maintenance of Wakefulness Test (MWT), patients were randomized to receive treatment with: (1) placebo, (2) sodium oxybate, (3) modafinil, or (4) sodium oxybate+modafinil. PSGs and MWTs were repeated after 4 and 8 weeks. Other efficacy measures included Epworth Sleepiness Scale scores and daily diary recordings. RESULTS After 8 weeks, significant changes in sleep architecture among patients receiving sodium oxybate and sodium oxybate/modafinil included a median increase in Stage 3 and 4 sleep (43.5 and 24.25 min, respectively) and delta power and a median decrease in nocturnal awakenings (6.0 and 9.5, respectively). No significant changes in PSG parameters were noted in patients treated with placebo or modafinil alone. CONCLUSIONS In addition to its established efficacy for the treatment of cataplexy and EDS, nightly sodium oxybate administration significantly reduces measures of sleep disruption and significantly increases slow-wave sleep in patients with narcolepsy.

The Burden of Narcolepsy Disease (BOND) study: health-care utilization and cost findings.

OBJECTIVES The aim of this study was to characterize health-care utilization, costs, and productivity in a large population of patients diagnosed with narcolepsy in the United States. METHODS This retrospective, observational study using data from the Truven Health Analytics MarketScan Research Databases assessed 5 years of claims data (2006-2010) to compare health-care utilization patterns, productivity, and associated costs among narcolepsy patients (identified by International Classification of Diseases, Ninth Revision (ICD9) narcolepsy diagnosis codes) versus matched controls. A total of 9312 narcolepsy patients (>18 years of age, continuously insured between 2006 and 2010) and 46,559 matched controls were identified. RESULTS Compared with controls, narcolepsy subjects had approximately twofold higher annual rates of inpatient admissions (0.15 vs. 0.08), emergency department (ED) visits w/o admission (0.34 vs. 0.17), hospital outpatient (OP) visits (2.8 vs. 1.4), other OP services (7.0 vs. 3.2), and physician visits (11.1 vs. 5.6; all p<0.0001). The rate of total annual drug transactions was doubled in narcolepsy versus controls (26.4 vs. 13.3; p<0.0001), including a 337% and 72% higher usage rate of narcolepsy drugs and non-narcolepsy drugs, respectively (both p<0.0001). Mean yearly costs were significantly higher in narcolepsy compared with controls for medical services (