Clete A. Kushida, MD, PhD, FAASM

All Publications

• Non-steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea. Anesthesiology Doufas, A. G., Shafer, S. L., Rashid, N. H., Kushida, C. A., Capasso, R. 2018

  Abstract

  WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Evidence suggests that obstructive sleep apnea promotes postoperative pulmonary complications by enhancing vulnerability to opioid-induced ventilatory depression. We hypothesized that patients with moderate-to-severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression than controls.METHODS: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit.RESULTS: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng · ml (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng · ml (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng · ml (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%.CONCLUSIONS: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 mug · kg of ideal body weight per minute.

  View details for DOI 10.1097/ALN.0000000000002430

  View details for PubMedID 30247202

• Continuous Positive Airway Pressure Therapy on Nonalcoholic Fatty Liver Disease in Patients With Obstructive Sleep Apnea. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Kim, D., Ahmed, A., Kushida, C. 2018; 14 (8): 1315–22

  Abstract

  STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with nonalcoholic fatty liver disease (NAFLD) and related advanced fibrosis. We studied the treatment of OSA with continuous positive airway pressure (CPAP) in a population with NAFLD.METHODS: Using an institutional database (2010-2014), we identified patients with NAFLD and OSA and studied changes in serum aminotransferases before and after CPAP use. We defined suspected NAFLD (sNAFLD) as serum alanine aminotransferase (ALT) > 30 U/L for men and > 19 U/L for women in the absence of known causes of chronic liver disease. The aspartate aminotransferase (AST) to platelet ratio index (APRI) was used to determine significant fibrosis. Consistent CPAP use for more than 3 months with adequate adherence parameters defined good adherence.RESULTS: Of 351 patients with OSA on CPAP treatment, majority (mean age 57.6 years, 59.3% male) had abnormal ALT, and 89.4% met the criteria for sNAFLD. The prevalence of sNAFLD was higher among patients with moderate to severe OSA (90.6%) versus mild OSA (86.3%). There was a statistically significant improvement in AST, ALT, and APRI with CPAP therapy (all P < .01). There was an apparent dose-response relationship: patients with good adherence to CPAP showed a significantly larger decrease in AST and ALT than did those with poor adherence (P < .01). Multivariable logistic regression analysis showed CPAP treatment with adequate adherence (odds ratio = 3.93, 95% confidence interval = 1.29-11.94) was an independent predictor of regression of sNAFLD after adjusting for obesity class and severity of OSA.CONCLUSIONS: OSA treatment with CPAP was associated with significant biochemical improvement and reduction in NAFLD-related fibrosis.

  View details for DOI 10.5664/jcsm.7262

  View details for PubMedID 30092894

• EFFECTIVENESS OF A NASOPHARYNGEAL AIRWAY STENT FOR TREATMENT OF OBSTRUCTIVE SLEEP APNEA Kushida, C., Ding, F., Endo, T., Satoh, M. OXFORD UNIV PRESS INC. 2018: A207

  View details for Web of Science ID 000431183400557

• THE EFFECTS OF CBT-I ON COGNITIVE FUNCTIONING IN INDIVIDUALS WITH INSOMNIA AND MILD COGNITIVE IMPAIRMENT Goldstein-Piekarski, A. N., O'Hora, K., Buchanan, A., Lee, C., Hernandez, B., Zeitzer, J. M., Friedman, L., Kushida, C., Yesavage, J. OXFORD UNIV PRESS INC. 2018: A154–A155

  View details for Web of Science ID 000431183400407

• IMPROVING OUR UNDERSTANDING OF SLEEP BY GENERATING AND SHARING A LARGE SLEEP COHORT AND DATA ANALYTIC TOOLS Leary, E. B., Seeger-Zybok, R. K., Kushida, C., Mignot, E. OXFORD UNIV PRESS INC. 2018: A124

  View details for Web of Science ID 000431183400325

• PATIENT ENGAGEMENT FOR SLEEP RESEARCH Seeger-Zybok, R. K., Leary, E. B., Kushida, C. A., Mignot, E. OXFORD UNIV PRESS INC. 2018: A390–A391

  View details for Web of Science ID 000431183401254

• PATIENT AND PROVIDER PERSPECTIVES ON PATIENT-CENTERED OUTCOMES IN SLEEP APNEA Havens, C., Seixas, A., Jean-Louis, G., Buysse, D., Kushida, C., Mullington, J., Redline, S., Mehra, R., Stone, K., Amdur, A., Stepnowsky, C., Gooneratne, N., Rapoport, D., Parthasarathy, S., Sleep Res Network OXFORD UNIV PRESS INC. 2018: A191

  View details for Web of Science ID 000431183400510

• Vitamin D and obstructive sleep apnea: a systematic review and meta-analysis SLEEP MEDICINE Neighbors, C. P., Noller, M. W., Song, S. A., Zaghi, S., Neighbors, J., Feldman, D., Kushida, C. A., Camacho, M. 2018; 43: 100–108

  Abstract

  Several studies have reported an association between 25-hydroxyvitamin D (25(OH)D) levels and obstructive sleep apnea (OSA) patients. The objective of the current study was to perform a systematic review and meta-analysis of these studies and report the findings.Authors searched for studies (through January 1, 2017) reporting 25(OH)D serum levels in OSA patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed.Fourteen studies with 4937 subjects met inclusion criteria. There were 1513 controls and 3424 OSA patients. The 25(OH)D serum levels for controls and mild OSA patients were 28.16 ± 9.39 ng/mL (95% CI 27.64, 28.68) and 27.41 ± 9.42 ng/mL (95% CI 26.87, 27.95), respectively. The 25(OH)D serum levels for controls and moderate OSA patients were 28.21 ± 9.38 ng/mL (95% CI 27.70, 28.72) and 25.48 ± 10.34 ng/mL (95% CI 24.68, 26.28), respectively. The 25(OH)D serum levels for controls and severe OSA patients were 28.32 ± 9.65 ng/mL (95% CI 27.80, 28.84) and 21.88 ± 10.24 ng/mL (95% CI 21.08, 22.68), respectively. Using random effects modeling, the 25(OH)D serum levels were decreased for patients with OSA when compared to control groups (mean differences were -2.7% for mild OSA, -10.1% for moderate OSA and -17.4% for severe OSA).There was a relative insufficiency in serum 25(OH)D levels among OSA patients compared to control patients, which was incrementally exacerbated with increasing severity of sleep apnea. It was unclear whether a low 25(OH)D was a risk factor for OSA or if OSA was a risk factor for 25(OH)D. It was also possible that the association between 25(OH)D and OSA was due to body mass index (BMI).

  View details for DOI 10.1016/j.sleep.2017.10.016

  View details for Web of Science ID 000425976300019

  View details for PubMedID 29482804

• Reliability of the American Academy of Sleep Medicine Rules for Assessing Sleep Depth in Clinical Practice JOURNAL OF CLINICAL SLEEP MEDICINE Younes, M., Kuna, S. T., Pack, A. I., Walsh, J. K., Kushida, C. A., Staley, B., Pien, G. W. 2018; 14 (2): 205–13

  Abstract

  The American Academy of Sleep Medicine has published manuals for scoring polysomnograms that recommend time spent in non-rapid eye movement sleep stages (stage N1, N2, and N3 sleep) be reported. Given the well-established large interrater variability in scoring stage N1 and N3 sleep, we determined the range of time in stage N1 and N3 sleep scored by a large number of technologists when compared to reasonably estimated true values.Polysomnograms of 70 females were scored by 10 highly trained sleep technologists, two each from five different academic sleep laboratories. Range and confidence interval (CI = difference between the 5th and 95th percentiles) of the 10 times spent in stage N1 and N3 sleep assigned in each polysomnogram were determined. Average values of times spent in stage N1 and N3 sleep generated by the 10 technologists in each polysomnogram were considered representative of the true values for the individual polysomnogram. Accuracy of different technologists in estimating delta wave duration was determined by comparing their scores to digitally determined durations.The CI range of the ten N1 scores was 4 to 39 percent of total sleep time (% TST) in different polysomnograms (mean CI ± standard deviation = 11.1 ± 7.1 % TST). Corresponding range for N3 was 1 to 28 % TST (14.4 ± 6.1 % TST). For stage N1 and N3 sleep, very low or very high values were reported for virtually all polysomnograms by different technologists. Technologists varied widely in their assignment of stage N3 sleep, scoring that stage when the digitally determined time of delta waves ranged from 3 to 17 seconds.Manual scoring of non-rapid eye movement sleep stages is highly unreliable among highly trained, experienced technologists. Measures of sleep continuity and depth that are reliable and clinically relevant should be a focus of clinical research.

  View details for DOI 10.5664/jcsm.6934

  View details for Web of Science ID 000425136900007

  View details for PubMedID 29351821

  View details for PubMedCentralID PMC5786839

• Adjustment for Variable Adherence Under Hierarchical Structure: Instrumental Variable Modeling Through Compound Residual Inclusion MEDICAL CARE Holmes, T. H., Zulman, D. M., Kushida, C. A. 2017; 55 (12): E120–E130

  Abstract

  Variable adherence to assigned conditions is common in randomized clinical trials.A generalized modeling framework under longitudinal data structures is proposed for regression estimation of the causal effect of variable adherence on outcome, with emphasis upon adjustment for unobserved confounders.A nonlinear, nonparametric random-coefficients modeling approach is described. Estimates of local average treatment effects among compliers can be obtained simultaneously for all assigned conditions to which participants are randomly assigned within the trial. Two techniques are combined to address time-varying and time-invariant unobserved confounding-residual inclusion and nonparametric random-coefficients modeling. Together these yield a compound, 2-stage residual inclusion, instrumental variables model.The proposed method is illustrated through a set of simulation studies to examine small-sample bias and in application to neurocognitive outcome data from a large, multicenter, randomized clinical trial in sleep medicine for continuous positive airway pressure treatment of obstructive sleep apnea.Results of simulation studies indicate that, relative to a standard comparator, the proposed estimator reduces bias in estimates of the causal effect of variable adherence. Bias reductions were greatest at higher levels of residual variance and when confounders were time varying.The proposed modeling framework is flexible in the distributions of outcomes that can be modeled, applicable to repeated measures longitudinal structures, and provides effective reduction of bias due to unobserved confounders.

  View details for DOI 10.1097/MLR.0000000000000464

  View details for Web of Science ID 000415960200006

  View details for PubMedID 29135775

  View details for PubMedCentralID PMC4942413

• Predictors of sleepiness in obstructive sleep apnoea at baseline and after 6 months of continuous positive airway pressure therapy EUROPEAN RESPIRATORY JOURNAL Budhiraja, R., Kushida, C. A., Nichols, D. A., Walsh, J. K., Simon, R. D., Gottlieb, D. J., Quan, S. F. 2017; 50 (5)

  View details for DOI 10.1183/13993003.00348-2017

  View details for Web of Science ID 000422739100003

• Laser Assisted Uvulopalatoplasty (LAUP) for Obstructive Sleep Apnea: A Systematic Review and Meta-Analysis. Sleep Camacho, M., Nesbitt, N. B., Lambert, E., Song, S. A., Chang, E. T., Yung Liu, S., Kushida, C. A., Zaghi, S. 2017

  Abstract

  Laser-assisted uvulopalatoplasty (LAUP) has been used as treatment for obstructive sleep apnea (OSA). The objective of this study was to perform a systematic review and meta-analysis for LAUP alone as treatment for OSA in adults.Three authors searched five databases (including PubMed/MEDLINE) from inception through October 30, 2016 for peer-reviewed studies, with any design/language. A study quality assessment tool was used. The PRISMA statement was followed. A meta-analysis was performed.Twenty-three adult studies (717 patients) reported outcomes (age: 50 ± 9 years, body mass index: 29 ± 4 kg/m2). The pre- and post-LAUP means (M) ± standard deviations (SDs) for apnea-hypopnea index (AHI) were 28 ± 13 and 19 ± 12 events/h (32% reduction). Random effects modeling for 519 patients demonstrated an AHI mean difference (MD) of -6.56 [95% CI -10.14, -2.97] events/h. Individual patient data analyses demonstrate a 23% success rate (≥50% reduction in AHI and <20 events/h) and an 8% cure rate. Additionally, 44% of patients had worsening of their AHI after LAUP. Lowest oxygen saturation (LSAT) improved from a M ± SD of 80 ± 8% to 82 ± 7%. A limitation is that most studies were case series studies and only two were randomized controlled trials.In this meta-analysis, LAUP reduced AHI by 32% among all patients; while the LSAT only changed minimally. Individual data demonstrated a success rate of 23%, cure rate of 8%, and worsening of the AHI among 44% of patients. We recommend that LAUP be performed with caution or not performed at all given the unfavorable results of currently published studies.

  View details for DOI 10.1093/sleep/zsx004

  View details for PubMedID 28201808

• Effect of Pioglitazone on Cardiometabolic Risk in Patients With Obstructive Sleep Apnea. American journal of cardiology Liu, A., Abbasi, F., Kim, S. H., Ariel, D., Lamendola, C., Cardell, J., Xu, S., Patel, S., Tomasso, V., Mojaddidi, H., Grove, K., Tsao, P. S., Kushida, C. A., Reaven, G. M. 2017

  Abstract

  Prevalence of insulin resistance is increased in patients with obstructive sleep apnea (OSA). Because insulin resistance is an independent predictor of cardiovascular disease (CVD), this study was initiated to see if pioglitazone administration would improve insulin sensitivity and thereby decrease risk of CVD in overweight/obese, nondiabetic, insulin-resistant patients with untreated OSA. Patients (n = 30) were administered pioglitazone (45 mg/day) for 8 weeks, and measurements were made before and after intervention of insulin action (insulin-mediated glucose uptake by the insulin suppression test), C-reactive protein, lipid/lipoprotein profile, and gene expression profile of periumbilical subcutaneous fat tissue. Insulin sensitivity increased 31% (p <0.001) among pioglitazone-treated subjects, associated with a decrease in C-reactive protein concentration (p ≤0.001), a decrease in plasma triglyceride, and increase in high-density lipoprotein cholesterol concentrations (p ≤0.001), accompanied by significant changes in apolipoprotein A1 and B concentrations and lipoprotein subclasses known to decrease CVD risk. In addition, subcutaneous adipose tissue gene expression profile showed a 1.6-fold (p <0.01) increase in GLUT4 expression and decreased expression in 5 of 9 inflammatory genes (p <0.05). In conclusion, enhanced insulin sensitivity can significantly decrease multiple cardiometabolic risk factors in patients with untreated OSA, consistent with the view that coexisting insulin resistance plays an important role in the association between OSA and increased risk of CVD.

  View details for DOI 10.1016/j.amjcard.2016.12.034

  View details for PubMedID 28219664

  View details for PubMedCentralID PMC5386603

• Understanding Phenotypes of Obstructive Sleep Apnea: Applications in Anesthesia, Surgery, and Perioperative Medicine ANESTHESIA AND ANALGESIA Subramani, Y., Singh, M., Wong, J., Kushida, C. A., Malhotra, A., Chung, F. 2017; 124 (1): 179-191

  Abstract

  Obstructive sleep apnea (OSA) is a prevalent sleep-disordered breathing with potential long-term major neurocognitive and cardiovascular sequelae. The pathophysiology of OSA varies between individuals and is composed of different underlying mechanisms. Several components including the upper airway anatomy, effectiveness of the upper airway dilator muscles such as the genioglossus, arousal threshold of the individual, and inherent stability of the respiratory control system determine the pathogenesis of OSA. Their recognition may have implications for the perioperative health care team. For example, OSA patients with a high arousal threshold are likely to be sensitive to sedatives and narcotics with a higher risk of respiratory arrest in the perioperative period. Supplemental oxygen therapy can help to stabilize breathing in OSA patients with inherent respiratory instability. Avoidance of supine position can minimize airway obstruction in patients with a predisposition to upper airway collapse in this posture. In this review, the clinically relevant endotypes and phenotypes of OSA are described. Continuous positive airway pressure (CPAP) therapy is the treatment of choice for most patients with OSA but tolerance and adherence can be a problem. Patient-centered individualized approaches to OSA management will be the focus of future research into developing potential treatment options that will help decrease the disease burden and improve treatment effectiveness.

  View details for DOI 10.1213/ANE.0000000000001546

  View details for Web of Science ID 000390613500022

  View details for PubMedID 27861433

  View details for PubMedCentralID PMC5429962

• Short Sleep Duration Is Associated With Abnormal Serum Aminotransferase Activities and Nonalcoholic Fatty Liver Disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Kim, D., Kim, H. J., Kushida, C. A., Heo, N. Y., Ahmed, A., Kim, W. R. 2017

  View details for DOI 10.1016/j.cgh.2017.08.049

  View details for PubMedID 28882688

• Implementation of Sleep and Circadian Science: Recommendations from the Sleep Research Society and National Institutes of Health Workshop SLEEP Parthasarathy, S., Carskadon, M. A., Jean-Louis, G., Owens, J., Bramoweth, A., Combs, D., Hale, L., Harrison, E., Hart, C. N., Hasler, B. P., Honaker, S. M., Hertenstein, E., Kuna, S., Kushida, C., Levenson, J. C., Murray, C., Pack, A. I., Pillai, V., Pruiksma, K., Seixas, A., Strollo, P., Thosar, S. S., Williams, N., Buysse, D. 2016; 39 (12): 2061-2075

  View details for DOI 10.5665/sleep.6300

  View details for Web of Science ID 000388932700001

  View details for PubMedID 27748248

  View details for PubMedCentralID PMC5103795

• Impact of continuous positive airway pressure (CPAP) on quality of life in patients with obstructive sleep apnea (OSA) JOURNAL OF SLEEP RESEARCH Batool-Anwar, S., Goodwin, J. L., Kushida, C. A., Walsh, J. A., Simon, R. D., Nichols, D. A., Quan, S. F. 2016; 25 (6): 731-738

  Abstract

  Obstructive sleep apnea is a chronic illness with increasing prevalence. In addition to associated cardiovascular comorbidities, obstructive sleep apnea syndrome has been linked to poor quality of life, occupational accidents, and motor vehicle crashes secondary to excessive daytime sleepiness. Although continuous positive airway pressure is the gold standard for sleep apnea treatment, its effects on quality of life are not well defined. In the current study we investigated the effects of treatment on quality of life using the data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), a randomized controlled trial of continuous positive airway pressure (CPAP) versus sham CPAP. The Calgary Sleep Apnea Quality of Life Index (SAQLI) was used to assess quality of life. Overall we found no significant improvement in quality of life among sleep apnea patients after CPAP treatment. However, after stratifying by OSA severity, it was found that long-term improvement in quality of life might occur with the use of CPAP in people with severe and possibly moderate sleep apnea, and no demonstrable improvement in quality of life was noted among participants with mild obstructive sleep apnea.

  View details for DOI 10.1111/jsr.12430

  View details for Web of Science ID 000393032300015

  View details for PubMedID 27242272

• A review of neurocognitive function and obstructive sleep apnea with or without daytime sleepiness. Sleep medicine Zhou, J., Camacho, M., Tang, X., Kushida, C. A. 2016; 23: 99-108

  Abstract

  Excessive daytime sleepiness (EDS) and neurocognitive dysfunction are commonly observed in patients with obstructive sleep apnea (OSA), and these daytime functional deficits can be reversed partly or completely with treatment such as continuous positive airway pressure (CPAP). Although daytime sleepiness is a possible etiology for neurocognitive dysfunction in OSA patients, EDS is not universally present in all patients with OSA. The objective of this review is to summarize the relationship between neurocognitive function and EDS in OSA, as well as the difference in cognitive domains, improvement, and application of CPAP therapy between patients with and without EDS. Two authors independently searched PubMED/Medline, The Cochrane Library and Scopus through May 27, 2015. Sixty-five articles were included in this review. The literature demonstrated a wide range of neurocognitive deficits in OSA patients with EDS, but no more extensive and complex cognitive domains (eg, executive function) in patients without EDS. However, the current literature had very few studies with large sample sizes and extended follow-up that evaluated the effect of CPAP for OSA in patients with and without sleepiness. CPAP failed to improve cognitive dysfunction in OSA patients without EDS after short-term therapy. The evidence suggests that daytime sleepiness possibly relates to the domain and extent of cognitive impairments in OSA, and CPAP therapy has little effect on the improvement of cognitive deficits in OSA patients without EDS. We recommend that additional prospective studies be performed to further quantify the relationship between neurocognitive function in OSA patients with and without EDS.

  View details for DOI 10.1016/j.sleep.2016.02.008

  View details for PubMedID 27288049

• Does enhanced insulin sensitivity improve sleep measures in patients with obstructive sleep apnea: a randomized, placebo-controlled pilot study. Sleep medicine Liu, A., Kim, S. H., Ariel, D., Abbasi, F., Lamendola, C., Cardell, J., Xu, S., Patel, S., Tomasso, V., Mojaddidi, H., Grove, K., Tsao, P. S., Kushida, C. A., Reaven, G. M. 2016; 22: 57-60

  Abstract

  High fasting insulin levels have been reported to predict development of observed apneas, suggesting that insulin resistance may contribute to the pathogenesis of obstructive sleep apnea (OSA). The aim of this study was to determine whether enhancing insulin sensitivity in individuals with OSA would improve sleep measures.Insulin-resistant, nondiabetic individuals with untreated OSA were randomized (2:1) to pioglitazone (45 mg/day) or placebo for eight weeks in this single-blind study. All individuals had repeat measurements pertaining to sleep (overnight polysomnography and functional outcomes of sleep questionnaire) and insulin action (insulin suppression test).A total of 45 overweight/obese men and women with moderate/severe OSA were randomized to pioglitazone (n = 30) or placebo (n = 15). Although insulin sensitivity increased 31% among pioglitazone-treated compared with no change among individuals receiving placebo (p <0.001 for between-group difference), no improvement in quantitative or qualitative sleep measurements was observed.Pioglitazone administration increased insulin sensitivity in otherwise untreated individuals with OSA, without any change in polysomnographic sleep measures over an eight-week period. These findings do not support a causal role for insulin resistance in the pathogenesis of OSA.

  View details for DOI 10.1016/j.sleep.2016.06.005

  View details for PubMedID 27544837

  View details for PubMedCentralID PMC4996352

• Adjustment for Variable Adherence Under Hierarchical Structure: Instrumental Variable Modeling Through Compound Residual Inclusion. Medical care Holmes, T. H., Zulman, D. M., Kushida, C. A. 2016: -?

  Abstract

  Variable adherence to assigned conditions is common in randomized clinical trials.A generalized modeling framework under longitudinal data structures is proposed for regression estimation of the causal effect of variable adherence on outcome, with emphasis upon adjustment for unobserved confounders.A nonlinear, nonparametric random-coefficients modeling approach is described. Estimates of local average treatment effects among compliers can be obtained simultaneously for all assigned conditions to which participants are randomly assigned within the trial. Two techniques are combined to address time-varying and time-invariant unobserved confounding-residual inclusion and nonparametric random-coefficients modeling. Together these yield a compound, 2-stage residual inclusion, instrumental variables model.The proposed method is illustrated through a set of simulation studies to examine small-sample bias and in application to neurocognitive outcome data from a large, multicenter, randomized clinical trial in sleep medicine for continuous positive airway pressure treatment of obstructive sleep apnea.Results of simulation studies indicate that, relative to a standard comparator, the proposed estimator reduces bias in estimates of the causal effect of variable adherence. Bias reductions were greatest at higher levels of residual variance and when confounders were time varying.The proposed modeling framework is flexible in the distributions of outcomes that can be modeled, applicable to repeated measures longitudinal structures, and provides effective reduction of bias due to unobserved confounders.

  View details for PubMedID 26765149

• Impact of Randomization, Clinic Visits, and Medical and Psychiatric Cormorbidities on Continuous Positive Airway Pressure Adherence in Obstructive Sleep Apnea JOURNAL OF CLINICAL SLEEP MEDICINE Budhiraja, R., Kushida, C. A., Nichols, D. A., Walsh, J. K., Simon, R. D., Gottlieb, D. J., Quan, S. F. 2016; 12 (3): 333-341

  View details for DOI 10.5664/jcsm.5578

  View details for Web of Science ID 000374139600010

• Five-Minute Awake Snoring Test for Determining CPAP Pressures (Five-Minute CPAP Test): A Pilot Study. Sleep disorders Camacho, M., Ruoff, C. M., Kawai, M., Modi, R., Arbee, J., Hekmat, A., Robertson, M., Zaghi, S., Certal, V., Capasso, R., Kushida, C. A. 2016; 2016: 7380874-?

  Abstract

  Objective. To develop a quick, simple, bedside test for determining continuous positive airway pressures (CPAP) for obstructive sleep apnea (OSA) patients. Study Design. Prospective case series at a tertiary medical center. Methods. The Five-Minute Awake Snoring Test for Determining CPAP (Five-Minute CPAP Test) was developed and tested. Patients wear a soft-gel nasal triangle mask while holding a tongue depressor with the wide section (1.75 cm) between the teeth. Fixed pressure nasal CPAP is applied while the patient simulates snoring at 4 centimeters of water pressure. The pressure is incrementally titrated up and then down to determine the lowest pressure at which the patient cannot snore (Quiet Pressure). Results. Overall, thirty-eight patients participated. All could simulate snoring. Correlation coefficients were statistically significant between Quiet Pressures and body mass index (r s = 0.60 [strong positive relationship], p = 0.0088), apnea-hypopnea index (r s = 0.49 [moderate positive relationship], p = 0.039), lowest oxygen saturation (r s = -0.47 [moderate negative relationship], p = 0.048), and oxygen desaturation index (r s = 0.62 [strong positive relationship], p = 0.0057). Conclusion. This pilot study introduces a new concept, which is the final product of over one year of exploration, development, and testing. Five-Minute CPAP Test is a quick, inexpensive, and safe bedside test based on supine awake simulated snoring with nasal CPAP.

  View details for DOI 10.1155/2016/7380874

  View details for PubMedID 26881088

• Chronic intermittent hypoxia leads to insulin resistance and impaired glucose tolerance through dysregulation of adipokines in non-obese rats. Sleep & breathing = Schlaf & Atmung Fu, C., Jiang, L., Zhu, F., Liu, Z., Li, W., Jiang, H., Ye, H., Kushida, C. A., Li, S. 2015; 19 (4): 1467-1473

  View details for DOI 10.1007/s11325-015-1144-8

  View details for PubMedID 25724554

• Obstructive Sleep Apnea Is an Independent Predictor of Postoperative Atrial Fibrillation in Cardiac Surgery JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA Wong, J. K., Maxwell, B. G., Kushida, C. A., Sainani, K. L., Lobato, R. L., Woo, J., Pearl, R. G. 2015; 29 (5): 1140-1147

  View details for DOI 10.1053/j.jvca.2015.03.024

  View details for Web of Science ID 000361782900005

  View details for PubMedID 26154572

• Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion SLEEP Watson, N. F., Badr, M. S., Belenky, G., Bliwise, D. L., Buxton, O. M., Buysse, D., Dinges, D. F., Gangwisch, J., Grandner, M. A., Kushida, C., Malhotra, R. K., Martin, J. L., Patel, S. R., Quan, S. F., Tasali, E., Twery, M., Croft, J. B., Maher, E., Barrett, J. A., Thomas, S. M., Heald, J. L. 2015; 38 (8): 1161-1183

  View details for DOI 10.5665/sleep.4886

  View details for Web of Science ID 000358838100006

• Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Sleep Watson, N. F., Badr, M. S., Belenky, G., Bliwise, D. L., Buxton, O. M., Buysse, D., Dinges, D. F., Gangwisch, J., Grandner, M. A., Kushida, C., Malhotra, R. K., Martin, J. L., Patel, S. R., Quan, S. F., Tasali, E. 2015; 38 (8): 1161-1183

  Abstract

  The American Academy of Sleep Medicine and Sleep Research Society recently released a Consensus Statement regarding the recommended amount of sleep to promote optimal health in adults. This paper describes the methodology, background literature, voting process, and voting results for the consensus statement. In addition, we address important assumptions and challenges encountered during the consensus process. Finally, we outline future directions that will advance our understanding of sleep need and place sleep duration in the broader context of sleep health.

  View details for DOI 10.5665/sleep.4886

  View details for PubMedID 26194576

• Usefulness of Fetuin-A to Predict Risk for Cardiovascular Disease Among Patients With Obstructive Sleep Apnea. American journal of cardiology Liu, A., Lamendola, C., Ariel, D., Abbasi, F., Kim, S. H., Cardell, J., Tomasso, V., Xu, S., Patel, S., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 116 (2): 219-224

  Abstract

  Patients with obstructive sleep apnea (OSA) are at increased risk for cardiovascular diseases (CVDs). Fetuin-A, a novel hepatokine, has been associated with the metabolic syndrome (MetS), insulin resistance, and type 2 diabetes mellitus, all of which are highly prevalent in patients with OSA and associated with increased CVD risk. The goal of this study was to determine whether fetuin-A could be involved in the pathogenesis of CVD risk in patients with OSA, through relations of fetuin-A with MetS components and/or insulin resistance. Overweight or obese, nondiabetic volunteers (n = 120) were diagnosed with OSA by in-laboratory nocturnal polysomnography. Steady-state plasma glucose concentrations derived during the insulin suppression test were used to quantify insulin-mediated glucose uptake; higher steady-state plasma glucose concentrations indicated greater insulin resistance. Fasting plasma fetuin-A and lipoprotein concentrations were measured. Whereas neither the prevalence of MetS nor the number of MetS components was associated with tertiles of fetuin-A concentrations, the lipoprotein components of MetS, triglycerides and high-density lipoprotein cholesterol, increased (p <0.01) and decreased (p <0.05), respectively, across fetuin-A tertiles. Additionally, comprehensive lipoprotein analysis revealed that very low density lipoprotein (VLDL) particles and VLDL subfractions (VLDL1+2 and VLDL3) were increased across fetuin-A tertiles. In contrast, neither insulin resistance nor sleep measurements related to OSA were found to be modified by fetuin-A concentrations. In conclusion, abnormalities of lipoprotein metabolism, but not MetS or insulin resistance per se, may represent a mechanism by which fetuin-A contributes to increased CVD risk in patients with OSA.

  View details for DOI 10.1016/j.amjcard.2015.04.014

  View details for PubMedID 25960379

  View details for PubMedCentralID PMC4475487

• Hypoglossal Nerve Stimulation in the Treatment of Obstructive Sleep Apnea: A Systematic Review and Meta-analysis LARYNGOSCOPE Certal, V. F., Zaghi, S., Riaz, M., Vieira, A. S., Pinheiro, C. T., Kushida, C., Capasso, R., Camacho, M. 2015; 125 (5): 1254-1264

  Abstract

  Poor adherence to continuous positive airway pressure treatment in obstructive sleep apnea (OSA) adversely affects the effectiveness of this therapy. This study aimed to systematically review the evidence regarding the efficacy and safety of hypoglossal nerve stimulation as an alternative therapy in the treatment of OSA.Scopus, PubMed, and Cochrane Library databases were searched (updated through September 5, 2014).Studies were included that evaluated the efficacy of hypoglossal nerve stimulation to treat OSA in adults with outcomes for apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and effect on daytime sleepiness (Epworth Sleepiness Scale [ESS]). Tests for heterogeneity and subgroup analysis were performed.Six prospective studies with 200 patients were included in this review. At 12 months, the pooled fixed effects analysis demonstrated statistically significant reductions in AHI, ODI, and ESS mean difference of -17.51 (95% CI: -20.69 to -14.34); -13.73 (95% CI: -16.87 to -10.58), and -4.42 (95% CI: -5.39 to -3.44), respectively. Similar significant reductions were observed at 3 and 6 months. Overall, the AHI was reduced between 50% and 57%, and the ODI was reduced between 48% and 52%. Despite using different hypoglossal nerve stimulators in each subgroup analysis, no significant heterogeneity was found in any of the comparisons, suggesting equivalent efficacy regardless of the system in use.This review reveals that hypoglossal nerve stimulation therapy may be considered in selected patients with OSA who fail medical treatment. Further studies comparing hypoglossal nerve stimulation with conventional therapies are needed to definitively evaluate outcomes.NA Laryngoscope, 2014.

  View details for DOI 10.1002/lary.25032

  View details for Web of Science ID 000353996900049

  View details for PubMedID 25389029

• Myofunctional Therapy to Treat Obstructive Sleep Apnea: A Systematic Review and Meta-analysis SLEEP Camacho, M., Certal, V., Abdullatif, J., Zaghi, S., Ruoff, C. M., Capasso, R., Kushida, C. A. 2015; 38 (5): 669-?

  View details for DOI 10.5665/sleep.4652

  View details for Web of Science ID 000353876600005

  View details for PubMedID 25348130

• Abnormalities of Lipoprotein Concentrations in Obstructive Sleep Apnea Are Related to Insulin Resistance SLEEP Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-?

  Abstract

  Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The study’s aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/ lipoprotein evaluation was performed by vertical auto profile methodology.Academic medical center.107 nondiabetic, overweight/ obese adults.Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDL1+2) (r = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.Pro-atherogenic lipoprotein abnormalities in OSA are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased CVD risk.

  View details for DOI 10.5665/sleep.4678

  View details for Web of Science ID 000353876600017

  View details for PubMedID 25348129

• Abnormalities of lipoprotein concentrations in obstructive sleep apnea are related to insulin resistance. Sleep Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-799

  Abstract

  Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The study’s aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/ lipoprotein evaluation was performed by vertical auto profile methodology.Academic medical center.107 nondiabetic, overweight/ obese adults.Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDL1+2) (r = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.Pro-atherogenic lipoprotein abnormalities in OSA are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased CVD risk.

  View details for DOI 10.5665/sleep.4678

  View details for PubMedID 25348129

• Myofunctional Therapy to Treat Obstructive Sleep Apnea: A Systematic Review and Meta-analysis. Sleep Camacho, M., Certal, V., Abdullatif, J., Zaghi, S., Ruoff, C. M., Capasso, R., Kushida, C. A. 2015; 38 (5): 669-675

  Abstract

  To systematically review the literature for articles evaluating myofunctional therapy (MT) as treatment for obstructive sleep apnea (OSA) in children and adults and to perform a meta-analysis on the polysomnographic, snoring, and sleepiness data.Web of Science, Scopus, MEDLINE, and The Cochrane Library.The searches were performed through June 18, 2014. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was followed.Nine adult studies (120 patients) reported polysomnography, snoring, and/or sleepiness outcomes. The pre- and post-MT apnea-hypopnea indices (AHI) decreased from a mean ± standard deviation (M ± SD) of 24.5 ± 14.3/h to 12.3 ± 11.8/h, mean difference (MD) -14.26 [95% confidence interval (CI) -20.98, -7.54], P < 0.0001. Lowest oxygen saturations improved from 83.9 ± 6.0% to 86.6 ± 7.3%, MD 4.19 (95% CI 1.85, 6.54), P =0.0005. Polysomnography snoring decreased from 14.05 ± 4.89% to 3.87 ± 4.12% of total sleep time, P < 0.001, and snoring decreased in all three studies reporting subjective outcomes. Epworth Sleepiness Scale decreased from 14.8 ± 3.5 to 8.2 ± 4.1. Two pediatric studies (25 patients) reported outcomes. In the first study of 14 children, the AHI decreased from 4.87 ± 3.0/h to 1.84 ± 3.2/h, P = 0.004. The second study evaluated children who were cured of OSA after adenotonsillectomy and palatal expansion, and found that 11 patients who continued MT remained cured (AHI 0.5 ± 0.4/h), whereas 13 controls had recurrent OSA (AHI 5.3 ± 1.5/h) after 4 y.Current literature demonstrates that myofunctional therapy decreases AHI by approximately 50% in adults and 62% in children. Lowest oxygen saturations, snoring, and sleepiness outcomes improve in adults. Myofunctional therapy could serve as an adjunct to other OSA treatments.

  View details for DOI 10.5665/sleep.4652

  View details for PubMedID 25348130

• 2-Year Sleep Surgery and Medicine Fellowships for Otolaryngologists OTOLARYNGOLOGY-HEAD AND NECK SURGERY Camacho, M., Kushida, C. A., Capasso, R. 2015; 152 (4): 766-767

  View details for DOI 10.1177/0194599815574258

  View details for Web of Science ID 000352580000038

  View details for PubMedID 25833930

• Gender differences in REM sleep behavior disorder: a clinical and polysomnographic study in China SLEEP MEDICINE Zhou, J., Zhang, J., Li, Y., Du, L., Li, Z., Lei, F., Wing, Y., Kushida, C. A., Zhou, D., Tang, X. 2015; 16 (3): 414-418

  Abstract

  Rapid eye movement (REM) sleep behavior disorder (RBD) has been considered a male-predominant parasomnia, and there is little comparative data on potential differences between males and females. Therefore, the aim of our study was to examine and characterize gender difference in RBD.Ninety patients diagnosed with RBD were consecutively recruited from a sleep medicine clinic. All patients were assessed by a RBD questionnaire and overnight video polysomnography. Demographic, clinical data, presence of dreams and dream-enacting behaviors, sleep parameters and electromyographic (EMG) activity were compared for male and female patients with RBD.Females were significantly younger than males, both in the mean age of RBD onset (45.3 ± 19.3 vs. 56.2 ± 14.1; p = 0.027) and the mean age at diagnosis (50.4 ± 18.2 vs. 61.1 ± 14.1; p = 0.022). Secondary RBD was 21% in males and 44% in females (p = 0.021). Antidepressant use was more common among females (22%) than males (2%; p = 0.003). There was no significant gender difference in dream content (eg, violent and frightening dreams) of RBD patients. However, females had less dream-enacting behaviors, especially in movement related dreams and falling out of bed. Interestingly, no significant difference was found in the quantification of EMG activity during REM sleep between male and female patients.We found significant gender differences in demographics, associated comorbidities, and dream-related behaviors in patients with RBD. Female RBD patients reported significantly less behavior during dreams, but there was no significant gender difference in EMG activity during REM sleep.

  View details for DOI 10.1016/j.sleep.2014.10.020

  View details for Web of Science ID 000351714400019

  View details for PubMedID 25660814

• SMART DOCS: A New Patient-Centered Outcomes and Coordinated-Care Management Approach for the Future Practice of Sleep Medicine SLEEP Kushida, C. A., Nichols, D. A., Holmes, T. H., Miller, R., Griffin, K., Cardell, C., Hyde, P. R., Cohen, E., Manber, R., Walsh, J. K. 2015; 38 (2): 315-?

  View details for DOI 10.5665/sleep.4422

  View details for Web of Science ID 000348757800020

  View details for PubMedID 25409112

• The Effect of Nasal Surgery on Continuous Positive Airway Pressure Device Use and Therapeutic Treatment Pressures: A Systematic Review and Meta-Analysis SLEEP Camacho, M., Riaz, M., Capasso, R., Ruoff, C. M., Guilleminault, C., Kushida, C. A., Certal, V. 2015; 38 (2): 279-?

  View details for DOI 10.5665/sleep.4414

  View details for Web of Science ID 000348757800016

  View details for PubMedID 25325439

• Inferior Turbinate classification system, grades 1 to 4: Development and validation study. Laryngoscope Camacho, M., Zaghi, S., Certal, V., Abdullatif, J., Means, C., Acevedo, J., Liu, S., Brietzke, S. E., Kushida, C. A., Capasso, R. 2015; 125 (2): 296-302

  Abstract

  To develop a validated inferior turbinate grading scale.Development and validation study.Phase 1 development (alpha test) consisted of a proposal of 10 different inferior turbinate grading scales (>1,000 clinic patients). Phase 2 validation (beta test) utilized 10 providers grading 27 standardized endoscopic photos of inferior turbinates using two different classification systems. Phase 3 validation (pilot study) consisted of 100 live consecutive clinic patients (n = 200 inferior turbinates) who were each prospectively graded by 18 different combinations of two independent raters, and grading was repeated by each of the same two raters, two separate times for each patient.In the development phase, 25% (grades 1-4) and 33% (grades 1-4) were the most useful systems. In the validation phase, the 25% classification system was found to be the best balance between potential clinical utility and ability to grade; the photo grading demonstrated a Cohen's kappa (κ) = 0.4671 ± 0.0082 (moderate inter-rater agreement). Live-patient grading with the 25% classification system demonstrated an overall inter-rater reliability of 71.5% (95% confidence interval [CI]: 64.8-77.3), with overall substantial agreement (κ = 0.704 ± 0.028). Intrarater reliability was 91.5% (95% CI: 88.7-94.3). Distribution for the 200 inferior turbinates was as follows: 25% quartile = grade 1, 50% quartile (median) = grade 2, 75% quartile = grade 3, and 90% quartile = grade 4. Mean turbinate size was 2.22 (95% CI: 2.07-2.34; standard deviation 1.02). Categorical κ was as follows: grade 1, 0.8541 ± 0.0289; grade 2, 0.7310 ± 0.0289; grade 3, 0.6997 ± 0.0289, and grade 4, 0.7760 ± 0.0289.The 25% (grades 1-4) inferior turbinate classification system is a validated grading scale with high intrarater and inter-rater reliability. This system can facilitate future research by tracking the effect of interventions on inferior turbinates.2c Laryngoscope, 2014.

  View details for DOI 10.1002/lary.24923

  View details for PubMedID 25215619

• Identifying Longitudinal Patterns for Individuals and Subgroups: An Example with Adherence to Treatment for Obstructive Sleep Apnea MULTIVARIATE BEHAVIORAL RESEARCH Babbin, S. F., Velicer, W. F., Aloia, M. S., Kushida, C. A. 2015; 50 (1): 91-108

  View details for DOI 10.1080/00273171.2014.958211

  View details for Web of Science ID 000349540600006

• SMART DOCS: a new patient-centered outcomes and coordinated-care management approach for the future practice of sleep medicine. Sleep Kushida, C. A., Nichols, D. A., Holmes, T. H., Miller, R., Griffin, K., Cardell, C., Hyde, P. R., Cohen, E., Manber, R., Walsh, J. K. 2015; 38 (2): 315-326

  Abstract

  The practice of medicine is currently undergoing a transformation to become more efficient, cost-effective, and patient centered in its delivery of care. The aim of this article is to stimulate discussion within the sleep medicine community in addressing these needs by our approach as well as other approaches to sleep medicine care. The primary goals of the Sustainable Methods, Algorithms, and Research Tools for Delivering Optimal Care Study (SMART DOCS) are: (1) to introduce a new Patient-Centered Outcomes and Coordinated-Care Management (PCCM) approach for the future practice of sleep medicine, and (2) to test the PCCM approach against a Conventional Diagnostic and Treatment Outpatient Medical Care (CONV) approach in a randomized, two-arm, single-center, long-term, comparative effectiveness trial. The PCCM approach is integrated into a novel outpatient care delivery model for patients with sleep disorders that includes the latest technology, allowing providers to obtain more accurate and rapid diagnoses and to make evidence-based treatment recommendations, while simultaneously enabling patients to have access to personalized medical information and reports regarding their diagnosis and treatment so that they can make more informed health care decisions. Additionally, the PCCM approach facilitates better communication between patients, referring primary care physicians, sleep specialists, and allied health professionals so that providers can better assist patients in achieving their preferred outcomes. A total of 1,506 patients 18 y or older will be randomized to either the PCCM or CONV approach and will be followed for at least 1 y with endpoints of improved health care performance, better health, and cost control.http://www.clinicaltrials.gov, NCT02037438.

  View details for DOI 10.5665/sleep.4422

  View details for PubMedID 25409112

• Impact of Randomization, Clinic Visits, and Medical and Psychiatric Cormorbidities on Continuous Positive Airway Pressure Adherence in Obstructive Sleep Apnea. Journal of clinical sleep medicine Budhiraja, R., Kushida, C. A., Nichols, D. A., Walsh, J. K., Simon, R. D., Gottlieb, D. J., Quan, S. F. 2015; 12 (3): 333-341

  Abstract

  To evaluate factors associated with continuous positive airway pressure (CPAP) adherence in patients with obstructive sleep apnea (OSA) in the Apnea Positive Pressure Long-term Efficacy Study (APPLES) cohort.The data from a prospective 6-mo multicenter randomized controlled trial with 558 subjects randomized to active CPAP and 547 to sham CPAP were analyzed to assess adherence to CPAP during first 2 mo (early period) and during months 5-6 (late period).Participants randomized to active CPAP had higher hours of nightly adherence compared to the sham CPAP group at both 2 (4.9 ± 2.0 h versus 4.07 ± 2.14 h, p < 0.001) and 6 mo (4.70 ± 2.08 h versus 3.41 ± 2.19 h, p < 0.001). Those assigned to sham CPAP were more likely to correctly identify their treatment group (70.0% versus 55.2%, p < 0.001). Irrespective of treatment group assignment, those who believed they were receiving active CPAP had higher hours of adherence than those who thought they were in the sham CPAP group at both 2 mo (4.91 ± 2.01 versus 4.17 ± 2.17, p < 0.001) and 6 mo (4.65 ± 2.10 versus 3.65 ± 2.22, p < 0.001). Among those randomized to active CPAP, older age was significantly related to CPAP use > 4 h per night. Presence of cardiovascular disorders was associated with higher hours of CPAP use, whereas presence of anxiety was associated with a trend toward lower hours of CPAP use. Presence of nasal congestion was associated with a decrease in mean daily CPAP use between the early and the late adherence period. The adherence during the week prior to a clinic visit was higher than the average adherence during the 2-mo period prior to the visit.Randomization to active therapy, belief that one is in the active treatment group, older age, and possibly presence of cardiovascular disorders are positively linked to CPAP adherence. Nasal congestion and anxiety are negatively associated with CPAP adherence. CPAP nightly usage increases as clinic visits approach.

  View details for DOI 10.5664/jcsm.5578

  View details for PubMedID 26518698

• Nasal Expiratory Positive Airway Pressure Devices (Provent) for OSA: A Systematic Review and Meta-Analysis. Sleep disorders Riaz, M., Certal, V., Nigam, G., Abdullatif, J., Zaghi, S., Kushida, C. A., Camacho, M. 2015; 2015: 734798-?

  Abstract

  Objective. To quantify the effectiveness of nasal expiratory positive airway pressure (nasal EPAP) devices or Provent as treatment for obstructive sleep apnea (OSA). Methods. PubMed and six other databases were searched through November 15, 2015, without language limitations. Results. Eighteen studies (920 patients) were included. Pre- and post-nasal EPAP means ± standard deviations (M ± SD) for apnea-hypopnea index (AHI) in 345 patients decreased from 27.32 ± 22.24 to 12.78 ± 16.89 events/hr (relative reduction = 53.2%). Random effects modeling mean difference (MD) was -14.78 events/hr [95% CI -19.12, -10.45], p value < 0.00001. Oxygen desaturation index (ODI) in 247 patients decreased from 21.2 ± 19.3 to 12.4 ± 14.1 events/hr (relative reduction = 41.5%, p value < 0.00001). Lowest oxygen saturation (LSAT) M ± SD improved in 146 patients from 83.2 ± 6.8% to 86.2 ± 11.1%, MD 3 oxygen saturation points [95% CI 0.57, 5.63]. Epworth Sleepiness Scale (ESS) M ± SD improved (359 patients) from 9.9 ± 5.3 to 7.4 ± 5.0, MD -2.5 [95% CI -3.2, -1.8], p value < 0.0001. Conclusion. Nasal EPAP (Provent) reduced AHI by 53.2%, ODI by 41.5% and improved LSAT by 3 oxygen saturation points. Generally, there were no clear characteristics (demographic factors, medical history, and/or physical exam finding) that predicted favorable response to these devices. However, limited evidence suggests that high nasal resistance could be associated with treatment failure. Additional studies are needed to identify demographic and polysomnographic characteristics that would predict therapeutic success with nasal EPAP (Provent).

  View details for DOI 10.1155/2015/734798

  View details for PubMedID 26798519

• Mathematical Equations to Predict Positive Airway Pressures for Obstructive Sleep Apnea: A Systematic Review. Sleep disorders Camacho, M., Riaz, M., Tahoori, A., Certal, V., Kushida, C. A. 2015; 2015: 293868-?

  Abstract

  Objective. To systematically review the international literature for mathematical equations used to predict effective pressures for positive airway pressure (PAP) devices. Methods. Google Scholar, PubMed, Scopus, Embase, Web of Science, CINAHL, and The Cochrane Library were searched through June 27, 2015. The PRISMA statement was followed. There was no language limitation. Results. 709 articles were screened, fifty were downloaded, and twenty-six studies presented equations that met the inclusion and exclusion criteria. In total, there were 4,436 patients in the development phases and 3,489 patients in the validation phases. Studies performed multiple linear regressions analyses as part of the equation(s) development and included the following variables: physical characteristics, polysomnography data, behavioral characteristics, and miscellaneous characteristics, which were all predictive to a variable extent. Of the published variables, body mass index (BMI) and mean oxygen saturation are the most heavily weighted, while BMI (eighteen studies), apnea-hypopnea index (seventeen studies), and neck circumference (eleven studies) were the variables most frequently used in the mathematical equations. Ten studies were from Asian countries and sixteen were from non-Asian countries. Conclusion. This systematic review identified twenty-six unique studies reporting mathematical equations which are summarized. Overall, BMI and mean oxygen saturation are the most heavily weighted.

  View details for DOI 10.1155/2015/293868

  View details for PubMedID 26294977

• Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Journal of clinical sleep medicine Watson, N. F., Badr, M. S., Belenky, G., Bliwise, D. L., Buxton, O. M., Buysse, D., Dinges, D. F., Gangwisch, J., Grandner, M. A., Kushida, C., Malhotra, R. K., Martin, J. L., Patel, S. R., Quan, S. F., Tasali, E. 2015; 11 (8): 931-952

  Abstract

  The American Academy of Sleep Medicine and Sleep Research Society recently released a Consensus Statement regarding the recommended amount of sleep to promote optimal health in adults. This paper describes the methodology, background literature, voting process, and voting results for the consensus statement. In addition, we address important assumptions and challenges encountered during the consensus process. Finally, we outline future directions that will advance our understanding of sleep need and place sleep duration in the broader context of sleep health.

  View details for DOI 10.5664/jcsm.4950

  View details for PubMedID 26235159

• Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep Watson, N. F., Badr, M. S., Belenky, G., Bliwise, D. L., Buxton, O. M., Buysse, D., Dinges, D. F., Gangwisch, J., Grandner, M. A., Kushida, C., Malhotra, R. K., Martin, J. L., Patel, S. R., Quan, S. F., Tasali, E. 2015; 38 (6): 843-844

  Abstract

  Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine.

  View details for DOI 10.5665/sleep.4716

  View details for PubMedID 26039963

• Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society. Journal of clinical sleep medicine Watson, N. F., Badr, M. S., Belenky, G., Bliwise, D. L., Buxton, O. M., Buysse, D., Dinges, D. F., Gangwisch, J., Grandner, M. A., Kushida, C., Malhotra, R. K., Martin, J. L., Patel, S. R., Quan, S. F., Tasali, E. 2015; 11 (6): 591-592

  Abstract

  Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine.

  View details for DOI 10.5664/jcsm.4758

  View details for PubMedID 25979105

• Risk of Cardiovascular Disease Associated with a Restless Legs Syndrome Diagnosis in a Retrospective Cohort Study from Kaiser Permanente Northern California. Sleep Van Den Eeden, S. K., Albers, K. B., Davidson, J. E., Kushida, C. A., Leimpeter, A. D., Nelson, L. M., Popat, R., Tanner, C. M., Bibeau, K., Quesenberry, C. P. 2015; 38 (7): 1009-1015

  Abstract

  Recent cross-sectional studies suggest that restless legs syndrome (RLS) may be associated with an increased prevalence of cardiovascular disease (CVD) comorbidity or risk factors. We evaluated whether primary or secondary RLS was associated with an increased risk of incident cardiovascular disease in a retrospective cohort study within Kaiser Permanente Northern California (KPNC).We identified members of KPNC with primary RLS and secondary RLS between 1999 and 2008 by an algorithm that incorporated longitudinal clinical records related to the diagnosis and treatment of RLS and comorbidities. We then matched each RLS case with up to 50 individuals with no clinical records of RLS by age, sex, race/ethnicity, zip code, and membership duration. For the analyses we excluded any individual with coronary artery disease (CAD: angina, acute myocardial infarction, coronary revascularization procedure, CAD death), CVD (CAD plus stroke), and hypertension at baseline. New cardiovascular events were determined from clinical records. Follow-up ended at an outcome event, disenrollment from KPNC, or death, whichever occurred earliest. There were over 473,358 person-y of follow-up in this cohort analysis with a mean follow-up time of 3.91 y and range from 6 mo to 12 y. Survival analysis techniques, including survival curves and proportional hazard regression models, were used to assess the association between RLS status and CVD.There were 7,621 primary RLS and 4,507 secondary RLS cases identified and included in the study. In general, primary RLS cases were younger and had less comorbidity than secondary RLS cases. During the follow-up period, CVD was diagnosed in 478 primary RLS cohort members, CAD was diagnosed in 310, and hypertension events were identified in 1,466. Diagnosis in secondary RLS cohort members was made during the follow-up period with 451, 338, and 598 CVD, CAD, and hypertension events, respectively. Subjects with primary RLS had a similar risk of incident CVD (hazard ratio (HR) = 0.95; 95% confidence interval (CI) = 0.86-1.04) and CAD (HR = 0.99; 95% CI = 0.89-1.13) to the comparison cohort, with a slight elevation in the risk of hypertension events (HR = 1.19; 95% CI = 1.12-1.25), after multivariable adjustment. Individuals classified as secondary RLS had a significant increased risk of CVD (HR = 1.33; 95% CI = 1.21-1.46), CAD (HR = 1.40; 95% CI = 1.25-1.56), and hypertension (HR = 1.28; 95% CI = 1.18-1.40).Primary restless legs syndrome (RLS) was not associated with new-onset cardiovascular disease (CVD) or coronary artery disease (CAD) but was associated with a slight increased risk of hypertension. In contrast, secondary RLS was associated with an increased risk of CVD, CAD, and hypertension.

  View details for DOI 10.5665/sleep.4800

  View details for PubMedID 26083613

• The effect of nasal surgery on continuous positive airway pressure device use and therapeutic treatment pressures: a systematic review and meta-analysis. Sleep Camacho, M., Riaz, M., Capasso, R., Ruoff, C. M., Guilleminault, C., Kushida, C. A., Certal, V. 2015; 38 (2): 279-286

  Abstract

  The relationship between nasal surgery and its effect on continuous positive airway pressure (CPAP) device therapeutic treatment pressures and CPAP device use has not been previously systematically examined.To conduct a systematic review and meta-analysis evaluating the effect of isolated nasal surgery on therapeutic CPAP device pressures and use in adults with obstructive sleep apnea (OSA).MEDLINE, Scopus, Web of Science, and The Cochrane Library were searched through July 15, 2014. The MOOSE consensus statement and PRISMA statement were followed.Eighteen studies (279 patients) reported CPAP data after isolated nasal surgery. Seven studies (82 patients) reported preoperative and postoperative mean therapeutic CPAP device pressures and standard deviations (SD), which reduced from 11.6 ± 2.2 to 9.5 ± 2.0 centimeters of water pressure (cwp) after nasal surgery. Pooled random effects analysis demonstrated a statistically significant pressure reduction, with a mean difference (MD) of -2.66 cwp (95% confidence interval (CI), -3.65 to -1.67); P < 0.00001. Eleven studies (153 patients) reported subjective, self-reported data for CPAP use; and a subgroup analysis demonstrated that 89.1% (57 of 64 patients) who were not using CPAP prior to nasal surgery subsequently accepted, adhered to, or tolerated it after nasal surgery. Objective, device meter-based hours of use increased in 33 patients from 3.0 ± 3.1 to 5.5 ± 2.0 h in the short term (<6 mo of follow-up).Isolated nasal surgery in patients with OSA and nasal obstruction reduces therapeutic CPAP device pressures and the currently published literature's objective and subjective data consistently suggest that it also increases CPAP use in select patients.

  View details for DOI 10.5665/sleep.4414

  View details for PubMedID 25325439

• Nocturia Reported in Nightly Sleep Diaries: Common Occurrence With Significant Implications? HEALTH PSYCHOLOGY Bliwise, D. L., Friedman, L., Hernandez, B., Zeitzer, J. M., Kushida, C. A., Yesavage, J. A. 2014; 33 (11): 1362-1365

  Abstract

  Nocturia (nocturnal awakenings associated with urination) is so common a nocturnal behavior that its association with poor sleep is often overlooked. This study examined nocturia and its potential role in poor sleep by examining reported nightly awakenings and associated bathroom trips.Sleep diaries were kept by 119 adults with poor sleep for intervals up to 14 days. Diaries collected data on nightly number of awakenings and nightly number of bathroom trips. The proportion of nocturnal awakenings accompanied by voiding for each night was calculated and averaged within each individual. Demographics and various health conditions were examined in relation to this measure.Nocturia was defined when at least two-thirds of all awakenings were associated with nocturnal voiding. Absence of nocturia was defined when less than one-third of awakenings were associated with voiding. Remaining cases were defined as having possible nocturia. Estimates of nocturia derived from prestudy screening were related to nocturia as defined by sleep diaries. Neither gender nor sleep apnea was associated with nocturia. Unadjusted analyses indicated that individuals with nocturia were more likely to have arthritis and attribute their nighttime awakenings to urge to void than individuals without nocturia.Nocturia is an exceedingly common phenomenon and may be associated with multiple morbidities. RESULTS are discussed in terms of causality and whether the perceived urge to void precedes or follows nocturnal awakening. Correlates of nocturia have important implications, because they can inform interventions that target brain (e.g., cognitive-behavioral treatments for insomnia, sedative/hypnotic medications) versus bladder (e.g., bladder control exercises, medications affecting urine production or urgency).

  View details for DOI 10.1037/a0034401

  View details for Web of Science ID 000344010300011

  View details for PubMedCentralID PMC4119089

• An fMRI study of cerebrovascular reactivity and perfusion in obstructive sleep apnea patients before and after CPAP treatment. Sleep medicine Prilipko, O., Huynh, N., Thomason, M. E., Kushida, C. A., Guilleminault, C. 2014; 15 (8): 892-898

  Abstract

  Cerebrovascular reactivity is impaired in patients suffering from obstructive sleep apnea syndrome (OSAS) as demonstrated by transcranial Doppler studies. We use magnetic resonance imaging techniques to investigate the anatomical distribution of cerebrovascular reactivity changes in patients with OSAS, as well as their evolution after therapeutic and sham continuous positive airway pressure (CPAP) treatment.Twenty-three men with moderate or severe obstructive sleep apnea were compared to a healthy control group (n=7) using a breath-holding functional magnetic resonance imaging task and the flow-sensitive alternating inversion recovery (FAIR) imaging before and after 2months of therapeutic (active) or sub-therapeutic (sham) CPAP treatment.Significantly higher cerebrovascular reactivity was found in healthy controls as compared to patients in bilateral cortical and subcortical brain regions. Cerebrovascular reactivity increased with therapeutic CPAP in the thalamus and decreased with sham CPAP in medial frontal regions in OSAS patients. Duration of nocturnal hypoxemia and body mass index negatively correlated with cerebrovascular reactivity, particularly in the medial temporal lobe structures, suggesting a possible pathophysiological mechanism for hippocampal injury. There was no difference in perfusion between patients and control group, and no effect of CPAP or sham-CPAP treatment on perfusion in patients.Observed cerebrovascular reactivity changes were neither homogeneous throughout the brain nor followed vascular territories, but rather corresponded to underlying neuronal networks, establishing a relationship between cerebrovascular reactivity and surrounding neuronal activity.

  View details for DOI 10.1016/j.sleep.2014.04.004

  View details for PubMedID 24916094

• Characteristics of early- and late-onset rapid eye movement sleep behavior disorder in China: a case-control study SLEEP MEDICINE Zhou, J., Zhang, J., Du, L., Li, Z., Li, Y., Lei, F., Wing, Y., Kushida, C. A., Zhou, D., Tang, X. 2014; 15 (6): 654-660

  Abstract

  To investigate demography and clinic and polysomnographic characteristics in Chinese rapid eye movement (REM) sleep behavior disorder (RBD) patients across onset ages.Ninety consecutive patients fulfilling the criteria for RBD were recruited for study in our sleep center. Patients were separated into early- and late-onset groups according to age when symptoms began (< or =50 and >50 years, respectively). Ninety age- and gender-matched healthy subjects served as controls. All subjects were interviewed for their clinical history, completed an RBD questionnaire, and underwent an overnight video polysomnography assessment. Demographics, comorbidities, scores on the RBD questionnaire, sleep architecture, and EMG activity were compared between the patients and controls and between the early- and late-onset groups.Of all RBD patients, 63 were male, and mean age of RBD onset was 54.3±15.7 years. In 25 patients (28%), RBD was secondary and associated with neurodegenerative disease, narcolepsy or antidepressant use. Twenty-three patients (26%) had early-onset RBD and 67 (74%) were in the late-onset group. RBD patients had significantly more comorbidities, dreams and dream-enacting behaviors, and poorer sleep quality than did controls. The early-onset group had a high proportion of females (48%) and an increased proportion of cases associated with narcolepsy. The early-onset group also had fewer movements, lower EMG activity during REM sleep, and better sleep quality when compared to the late-onset group. EMG activity was positively correlated with age of onset. The mean follow-up time was 1.57±0.82 years, and four patients in the late-onset group were subsequently diagnosed with neurodegenerative diseases.Stratifying patients into early and late-onset RBD revealed different characteristics from those previously described as typical for RBD. EMG activity during REM sleep was positively correlated with age of onset. We suggest that it will be valuable to explore the relationship between age of onset conversion and neurodegenerative diseases.

  View details for DOI 10.1016/j.sleep.2013.12.020

  View details for Web of Science ID 000338621200011

  View details for PubMedID 24831248

• Effect of armodafinil on cortical activity and working memory in patients with residual excessive sleepiness associated with CPAP-Treated OSA: a multicenter fMRI study. Journal of clinical sleep medicine Greve, D. N., Duntley, S. P., Larson-Prior, L., Krystal, A. D., Diaz, M. T., Drummond, S. P., Thein, S. G., Kushida, C. A., Yang, R., Thomas, R. J. 2014; 10 (2): 143-153

  Abstract

  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.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.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%).Armodafinil did not improve fMRI-measured functional brain activation in CPAP-treated patients with OSA and excessive sleepiness.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.

  View details for DOI 10.5664/jcsm.3440

  View details for PubMedID 24532997

• Strategic opportunities in sleep and circadian research: report of the joint task force of the sleep research society and american academy of sleep medicine. Sleep Zee, P. C., Badr, M. S., Kushida, C., Mullington, J. M., Pack, A. I., Parthasarathy, S., Redline, S., Szymusiak, R. S., Walsh, J. K., Watson, N. F. 2014; 37 (2): 219-227

  View details for DOI 10.5665/sleep.3384

  View details for PubMedID 24501434

• Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life. Southwest journal of pulmonary & critical care Quan, S. F., Budhiraja, R., Batool-Anwar, S., Gottlieb, D. J., Eichling, P., Patel, S., Shen, W., Walsh, J. K., Kushida, C. A. 2014; 9 (1): 44-56

  Abstract

  Obstructive sleep apnea (OSA) is associated with sleepiness, depression and reduced quality of life. However, it is unclear whether mild OSA has these negative impacts. Using data from the Apnea Positive Pressure Long-term Efficacy Study (APPLES), this study determined whether participants with mild OSA had greater sleepiness, more depressive symptoms and poorer quality of life in comparison to those without OSA.239 individuals evaluated for participation in APPLES with a baseline apnea hypopnea index (AHI) < 15 /hour were assigned to 1 of 2 groups: No OSA (N=40, AHI < 5 /hour) or Mild OSA (N=199, 5 to <15 /hour) based on their screening polysomnogram. Scores on their Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), Hamilton Rating Scale for Depression (HAM-D), Profile of Mood States (POMS) and Sleep Apnea Quality of Life Index (SAQLI) were compared between groups.There were no significant differences between the No OSA and Mild OSA groups on any of the 5 measures: ESS (No OSA, 9.8 ± 3.5 vs Mild OSA, 10.6 ± 4.3, p=0.26), SSS,(2.8 ± 0.9 vs. 2.9 ± 1.0, p=0.52), HAM-D (4.6 ± 3.0 vs. 4.9 ± 4.7, p=0.27), POMS (33.5 ± 22.3 vs. 28.7 ± 22.0, p=0.70), SAQLI (4.5 ± 0.8 vs. 4.7 ± 0.7, p=0.39).Individuals with mild OSA in this cohort do not have worse sleepiness, mood or quality of life in comparison to those without OSA.

  View details for PubMedID 25232509

  View details for PubMedCentralID PMC4163952

• Volumetric brain morphometry changes in patients with obstructive sleep apnea syndrome: effects of CPAP treatment and literature review FRONTIERS IN NEUROLOGY Huynh, N. T., Prilipko, O., Kushida, C. A., Guilleminault, C. 2014; 5

  View details for DOI 10.3389/fneur.2014.00058

  View details for Web of Science ID 000209629300058

• Volumetric Brain Morphometry Changes in Patients with Obstructive Sleep Apnea Syndrome: Effects of CPAP Treatment and Literature Review. Frontiers in neurology Huynh, N. T., Prilipko, O., Kushida, C. A., Guilleminault, C. 2014; 5: 58-?

  Abstract

  Obstructive sleep apnea syndrome (OSAS) is a frequent breathing disorder occurring during sleep that is characterized by recurrent hypoxic episodes and sleep fragmentation. It remains unclear whether OSAS leads to structural brain changes, and if so, in which brain regions. Brain region-specific gray and white matter volume (GMV and WMV) changes can be measured with voxel-based morphometry (VBM). The aims of this study were to use VBM to analyze GMV and WMV in untreated OSAS patients compared to healthy controls (HC); examine the impact of OSAS-related variables (nocturnal hypoxemia duration and sleep fragmentation index) on GMV and WMV; and assess the effects of therapeutic vs. sham continuous positive airway pressure (CPAP) treatment. We discuss our results in light of previous findings and provide a comprehensive literature review.Twenty-seven treatment-naïve male patients with moderate to severe OSAS and seven healthy age- and education-matched HC were recruited. After a baseline fMRI scan, patients randomly received either active (therapeutic, n = 14) or sham (subtherapeutic, n = 13) nasal CPAP treatment for 2 months.Significant negative correlations were observed between nocturnal hypoxemia duration and GMV in bilateral lateral temporal regions. No differences in GMV or WMV were found between OSAS patients and HC, and no differences between CPAP vs. sham CPAP treatment effects in OSAS patients.It appears that considering VBM GMV changes there is little difference between OSAS patients and HC. The largest VBM study to date indicates structural changes in the lateral aspect of the temporal lobe, which also showed a significant negative correlation with nocturnal hypoxemia duration in our study. This finding suggests an association between the effect of nocturnal hypoxemia and decreased GMV in OSAS patients.

  View details for DOI 10.3389/fneur.2014.00058

  View details for PubMedID 24808886

• A Novel Adaptive Servoventilation (ASVAuto) for the Treatment of Central Sleep Apnea Associated with Chronic Use of Opioids. Journal of clinical sleep medicine Cao, M., Cardell, C., Willes, L., Mendoza, J., Benjafield, A., Kushida, C. 2014; 10 (8): 855-861

  Abstract

  To compare the efficacy and patient comfort of a new mode of minute ventilation-targeted adaptive servoventilation (ASVAuto) with auto-titrating expiratory positive airway pressure (EPAP) versus bilevel with back-up respiratory rate (bilevel-ST) in patients with central sleep apnea (CSA) associated with chronic use of opioid medications.Prospective, randomized, crossover polysomnography (PSG) study. Eighteen consecutive patients (age ≥ 18 years) who had been receiving opioid therapy (≥ 6 months), and had sleep disordered breathing with CSA (central apnea index [CAI] ≥ 5) diagnosed during an overnight sleep study or positive airway pressure (PAP) titration were enrolled to undergo 2 PSG studies-one with ASVAuto and one with bilevel-ST. Patients completed 2 questionnaires after each PSG; Morning After Patient Satisfaction Questionnaire and PAP Comfort Questionnaire.Patients had a mean age of 52.9 ± 15.3 years. PSG prior to randomization showed an apnea hypopnea index (AHI) of 50.3 ± 22.2 and CAI of 13.0 ± 18.7. Titration with ASVAuto versus bilevel-ST showed that there were significant differences with respect to AHI and CAI. The AHI and CAI were significantly lower on ASVAuto than bilevel-ST (2.5 ± 3.5 versus 16.3 ± 20.9 [p = 0.0005], and 0.4 ± 0.8 versus 9.4 ± 18.8 [p = 0.0002], respectively). Respiratory parameters were normalized in 83.3% of patients on ASVAuto versus 33.3% on bilevel-ST. Patients felt more awake and alert on ASVAuto than bilevel-ST based on scores from Morning After Patient Satisfaction Questionnaire (p = 0.0337).The ASVAuto was significantly more effective than bilevel-ST for the treatment of CSA associated with chronic opioid use.Cao M, Cardell CY, Willes L, Mendoza J, Benjafield A, Kushida C. A novel adaptive servoventilation (ASVAuto) for the treatment of central sleep apnea associated with chronic use of opioids. J Clin Sleep Med 2014;10(8):855-861.

  View details for DOI 10.5664/jcsm.3954

  View details for PubMedID 25126031

• Evaluation of a new pediatric positive airway pressure mask. Journal of clinical sleep medicine Kushida, C. A., Halbower, A. C., Kryger, M. H., Pelayo, R., Assalone, V., Cardell, C., Huston, S., Willes, L., Wimms, A. J., Mendoza, J. 2014; 10 (9)

  Abstract

  The choice and variety of pediatric masks for continuous positive airway pressure (CPAP) is limited in the US. Therefore, clinicians often prescribe modified adult masks. Until recently a mask for children aged < 7 years was not available. This study evaluated apnea-hypopnea index (AHI) equivalence and acceptability of a new pediatric CPAP mask for children aged 2-7 years (Pixi; ResMed Ltd, Sydney, Australia).Patients aged 2-7 years were enrolled and underwent in-lab baseline polysomnography (PSG) using their previous mask, then used their previous mask and the VPAP III ST-A flow generator for ≥ 10 nights at home. Thereafter, patients switched to the Pixi mask for ≥ 2 nights before returning for a PSG during PAP therapy via the Pixi mask. Patients then used the Pixi mask at home for ≥ 21 nights. Patients and their parents/guardians returned to the clinic for follow-up and provided feedback on the Pixi mask versus their previous mask.AHI with the Pixi mask was 1.1 ± 1.5/h vs 2.6 ± 5.4/h with the previous mask (p = 0.3538). Parents rated the Pixi mask positively for: restfulness of the child's sleep, trouble in getting the child to sleep, and trouble in having the child stay asleep. The Pixi mask was also rated highly for leaving fewer or no marks on the upper lip and under the child's ears, and being easy to remove.The Pixi mask is suitable for children aged 2-7 years and provides an alternative to other masks available for PAP therapy in this age group.

  View details for PubMedID 25142768

• Improved sleep MRI at 3 tesla in patients with obstructive sleep apnea. Journal of magnetic resonance imaging Shin, L. K., Holbrook, A. B., Capasso, R., Kushida, C. A., Powell, N. B., Fischbein, N. J., Pauly, K. B. 2013; 38 (5): 1261-1266

  Abstract

  PURPOSE: To describe a real-time MR imaging platform for synchronous, multi-planar visualization of upper airway collapse in obstructive sleep apnea at 3 Tesla (T) to promote natural sleep with an emphasis on lateral wall visualization. MATERIALS AND METHODS: A real-time imaging platform was configured for sleep MR imaging which used a cartesian, partial k-space gradient-echo sequence with an inherent temporal resolution of 3 independent slices every 2 s. Combinations of axial, mid-sagittal, and coronal scan planes were acquired. The system was tested in five subjects with polysomnography-proven obstructive sleep apnea during sleep, with synchronous acquisition of respiratory effort and combined oral-nasal airflow data. RESULTS: Sleep was initiated and maintained to allow demonstration of sleep-induced, upper airway collapse as illustrated in two subjects when using a real-time, sleep MR imaging platform at 3T. Lateral wall collapse could not be visualized on mid-sagittal imaging alone and was best characterized on multiplanar coronal and axial imaging planes. CONCLUSION: Our dedicated sleep MR imaging platform permitted an acoustic environment of constant "white noise" which was conducive to sleep onset and sleep maintenance in obstructive sleep apnea patients at 3T. Apneic episodes, specifically the lateral walls, were more accurately characterized with synchronous, multiplanar acquisitions. J. Magn. Reson. Imaging 2013;. © 2013 Wiley Periodicals, Inc.

  View details for DOI 10.1002/jmri.24029

  View details for PubMedID 23390078

• Habitual shortened sleep and insulin resistance: An independent relationship in obese individuals. Metabolism Liu, A., Kushida, C. A., Reaven, G. M. 2013; 62 (11): 1553-1556

  Abstract

  Short sleep duration has been reported to be associated with obesity, type 2 diabetes, and pre-diabetes. Since excess weight, glucose abnormalities, and insulin resistance tend to cluster, the individual role insulin resistance may have in habitual shortened sleep is unclear. The study purpose was to assess whether habitual sleep curtailment is independently related to insulin resistance in obese individuals.Non-diabetic, overweight/obese individuals from the community were stratified as insulin-resistant (n=35) or insulin-sensitive (n=21) based on steady-state plasma glucose concentrations (SSPG) during the insulin suppression test. Seventy-five gram oral glucose tolerance tests were performed. Participants were asked, "On average, how many hours of sleep do you get per night?" Shortened sleep duration was defined as less than 7h of sleep per night.SSPG concentrations differed 2.5-fold (P<0.001) between insulin-resistant and insulin-sensitive individuals. Impaired fasting glucose and glucose intolerance were prevalent in both groups (>40%); however, body mass index, waist circumference, mean fasting or 2-h post-glucola glucose concentrations were not significantly different. Insulin-resistant individuals reported (mean±SD) fewer hours of sleep than did insulin-sensitive individuals (6.53±1.1 vs 7.24±0.9h, P<0.05). Shortened sleep duration was more prevalent among insulin-resistant as compared with insulin-sensitive individuals (60% vs 24%, P<0.05).Non-diabetic, insulin-resistant individuals averaged fewer hours of sleep and were more likely to report shortened sleep duration as compared with similarly obese insulin-sensitive individuals. There appears to be an independent association between habitual shortened sleep and insulin resistance among obese, dysglycemic adults without diabetes.

  View details for DOI 10.1016/j.metabol.2013.06.003

  View details for PubMedID 23849514

• Agreement in Computer-Assisted Manual Scoring of Polysomnograms across Sleep Centers SLEEP Kuna, S. T., Benca, R., Kushida, C. A., Walsh, J., Younes, M., Staley, B., Hanlon, A., Pack, A. I., Pien, G. W., Malhotra, A. 2013; 36 (4): 583-589

  Abstract

  To determine intersite agreement in respiratory event scoring of polysomnograms (PSGs) using different hypopnea definitions.Technical assessment.Five academic medical centers.N/A.N/A.Seventy good-quality PSGs performed in middle-aged women were manually scored by two experienced technologists at each of the five sleep centers using the particular laboratory's own software system. Studies were scored once by each scorer using American Academy of Sleep Medicine (AASM) standards for scoring sleep stages, arousals, and apneas. Hypopneas were then scored using three different AASM criteria: recommended, alternate, and research (Chicago). Means of each PSG variable for the scorers at each site were used to calculate an across-site intraclass correlation coefficient (ICC). Average AHI across the 10 scorers was 7.4 ± 12.3 (standard deviation) events/h using recommended criteria (ICC 0.984; 95% confidence interval [CI] 0.977-0.990), 12.1 ± 13.3 events/h using alternate criteria (ICC 0.947; 95% CI 0.889-0.972), and 15.1 ± 13.9 events/h with Chicago criteria (ICC 0.800; 95% CI 0.768-0.828). ICC across sites was 0.870 (95% CI = 0.847-0.889) for total sleep time, 0.861 (95% CI 0.837-0.881) for number of obstructive apneas and 0.683 (95% CI 0.640-0.722) for number of central apneas. ICCs across sites for hypopneas were very good using recommended criteria (ICC 0.843; 95% CI 0.820-0.870) but decreased when alternate criteria (ICC 0.728; 95% CI 0.689-0.763) and Chicago criteria (ICC 0.535; 95% CI 0.485-0.583) were used.Experienced scorers at different laboratories have very good agreement in hypopnea and AHI results when good-quality PSGs are scored using AASM-recommended criteria. Substantial degradation of reliability was observed for alternative definitions of hypopneas, particularly that proposed for research.

  View details for DOI 10.5665/sleep.2550

  View details for Web of Science ID 000316939000018

  View details for PubMedID 23565004

• Performance of an Automated Polysomnography Scoring System Versus Computer-Assisted Manual Scoring SLEEP Malhotra, A., Younes, M., Kuna, S. T., Benca, R., Kushida, C. A., Walsh, J., Hanlon, A., Staley, B., Pack, A. I., Pien, G. W. 2013; 36 (4): 573-582

  Abstract

  Manual scoring of polysomnograms (PSG) is labor intensive and has considerable variance between scorers. Automation of scoring could reduce cost and improve reproducibility. The purpose of this study was to compare a new automated scoring system (YST-Limited, Winnipeg, Canada) with computer-assisted manual scoring.Technical assessment.Five academic medical centers.N/A.N/A.Seventy PSG files were selected at University of Pennsylvania (Penn) and distributed to five US academic sleep centers. Two blinded technologists from each center scored each file. Automatic scoring was performed at Penn by a YST Limited technician using a laptop containing the software. Variables examined were sleep stages, arousals, and apnea-hypopnea index (AHI) using three methods of identifying hypopneas. Automatic scores were not edited and were compared to the average scores of the 10 technologists. Intraclass correlation coefficient (ICC) was obtained for the 70 pairs and compared to across-sites ICCs for manually scored results. ICCs for automatic versus manual scoring were > 0.8 for total sleep time, stage N2, and nonrapid eye movement arousals and > 0.9 for AHI scored by primary and secondary American Academy of Sleep Medicine criteria. ICCs for other variables were not as high but were comparable to the across-site ICCs for manually scored results.The automatic system yielded results that were similar to those obtained by experienced technologists. Very good ICCs were obtained for many primary PSG outcome measures. This automated scoring software, particularly if supplemented with manual editing, may increase laboratory efficiency and standardize PSG scoring results within and across sleep centers.

  View details for DOI 10.5665/sleep.2548

  View details for Web of Science ID 000316939000017

  View details for PubMedID 23565003

• Risk for obstructive sleep apnea in obese, nondiabetic adults varies with insulin resistance status SLEEP AND BREATHING Liu, A., Kushida, C. A., Reaven, G. M. 2013; 17 (1): 333-338

  Abstract

  Obstructive sleep apnea (OSA) is an increasingly common sleep disorder, especially among obese adults. Early identification of adults at risk for OSA would be of substantial benefit; however, the magnitude of the obesity epidemic requires that screening be performed judiciously. The study's aim was to utilize questionnaires that assess OSA risk and symptoms to test the hypothesis that the most insulin-resistant subset of obese individuals is at highest risk for OSA.Nondiabetic, overweight to obese volunteers underwent direct quantification of insulin sensitivity by measuring steady-state plasma glucose concentrations during the insulin suppression test. Insulin-sensitive and insulin-resistant individuals were administered the Berlin and STOP questionnaires to determine OSA risk status, and Epworth Sleepiness Scale (ESS) to evaluate daytime sleepiness. Fasting insulin and lipid/lipoprotein measurements were performed.Insulin-mediated glucose disposal differed threefold (p < 0.001) between equally obese, insulin-resistant (n = 22) and insulin-sensitive (n = 14) individuals, associated with higher fasting insulin and triglyceride and lower high-density lipoprotein cholesterol (HDL-C) concentrations in insulin-resistant individuals. Fourteen (64 %) insulin-resistant as compared with 2 (14 %) insulin-sensitive individuals were found to be at high risk for OSA by both questionnaires (p < 0.01). Whereas half of insulin-resistant individuals met the ESS criteria for excessive daytime sleepiness, only one insulin-sensitive individual did (p = 0.011).High risk for OSA and excessive daytime sleepiness is prevalent among the insulin-resistant subgroup of obese individuals. Surrogate estimates of insulin resistance based on fasting insulin, triglycerides, and/or HDL-C can be used to help identify those obese adults who would benefit most from OSA screening and referral for polysomnography.

  View details for DOI 10.1007/s11325-012-0696-0

  View details for Web of Science ID 000315167200052

  View details for PubMedID 22481243

  View details for PubMedCentralID PMC3654654

• Impact of Treatment with Continuous Positive Airway Pressure (CPAP) on Weight in Obstructive Sleep Apnea JOURNAL OF CLINICAL SLEEP MEDICINE Quan, S. F., Budhiraja, R., Clarke, D. P., Goodwin, J. L., Gottlieb, D. J., Nichols, D. A., Simon, R. D., Smith, T. W., Walsh, J. K., Kushida, C. A. 2013; 9 (10): 989-993

  Abstract

  To determine the impact of continuous positive airway pressure (CPAP) on weight change in persons with obstructive sleep apnea (OSA).The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blinded sham-controlled multicenter clinical trial conducted at 5 sites in the United States. Of 1,105 participants with an apnea hypopnea index ≥ 10 events/ hour initially randomized, 812 had body weight measured at baseline and after 6 months of study.CPAP or Sham CPAP.Body weight, height, hours of CPAP or Sham CPAP use, Epworth Sleepiness Scale score.Participants randomized to CPAP gained 0.35 ± 5.01 kg, whereas those on Sham CPAP lost 0.70 ± 4.03 kg (mean ± SD, p = 0.001). Amount of weight gain with CPAP was related to hours of device adherence, with each hour per night of use predicting a 0.42 kg increase in weight. This association was not noted in the Sham CPAP group. CPAP participants who used their device ≥ 4 h per night on ≥ 70% of nights gained the most weight over 6 months in comparison to non-adherent CPAP participants (1.0 ± 5.3 vs. -0.3 ± 5.0 kg, p = 0.014).OSA patients using CPAP may gain a modest amount of weight with the greatest weight gain found in those most compliant with CPAP.A commentary on this article appears in this issue on page 995.Quan SF; Budhiraja R; Clarke DP; Goodwin JL; Gottlieb DJ; Nichols DA; Simon RD; Smith TW; Walsh JK; Kushida CA. Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea.

  View details for DOI 10.5664/jcsm.3064

  View details for Web of Science ID 000325759400002

  View details for PubMedID 24127141

• The Effects of CPAP Treatment on Task Positive and Default Mode Networks in Obstructive Sleep Apnea Patients: An fMRI Study PLOS ONE Prilipko, O., Huynh, N., Schwartz, S., Tantrakul, V., Kushida, C., Paiva, T., Guilleminault, C. 2012; 7 (12)

  Abstract

  Functional magnetic resonance imaging studies enable the investigation of neural correlates underlying behavioral performance. We investigate the effect of active and sham Continuous Positive Airway Pressure (CPAP) treatment on working memory function of patients with Obstructive Sleep Apnea Syndrome (OSAS) considering Task Positive and Default Mode networks (TPN and DMN).An experiment with 4 levels of visuospatial n-back task was used to investigate the pattern of cortical activation in 17 men with moderate or severe OSAS before and after 2 months of therapeutic (active) or sub-therapeutic (sham) CPAP treatment.Patients with untreated OSAS had significantly less deactivation in the temporal regions of the DMN as compared to healthy controls, but activation within TPN regions was comparatively relatively preserved. After 2 months of treatment, active and sham CPAP groups exhibited opposite trends of cerebral activation and deactivation. After treatment, the active CPAP group demonstrated an increase of cerebral activation in the TPN at all task levels and of task-related cerebral deactivation in the anterior midline and medial temporal regions of the DMN at the 3-back level, associated with a significant improvement of behavioral performance, whereas the sham CPAP group exhibited less deactivation in the temporal regions of Default Mode Network and less Task Positive Network activation associated to longer response times at the 3-back.OSAS has a significant negative impact primarily on task-related DMN deactivation, particularly in the medial temporal regions, possibly due to nocturnal hypoxemia, as well as TPN activation, particularly in the right ventral fronto-parietal network. After 2 months of active nasal CPAP treatment a positive response was noted in both TPN and DMN but without compete recovery of existing behavioral and neuronal deficits. Initiation of CPAP treatment early in the course of the disease may prevent or slow down the occurrence of irreversible impairment.

  View details for DOI 10.1371/journal.pone.0047433

  View details for Web of Science ID 000312588200002

  View details for PubMedID 23227139

• Effects of Continuous Positive Airway Pressure on Neurocognitive Function in Obstructive Sleep Apnea Patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) SLEEP Kushida, C. A., Nichols, D. A., Holmes, T. H., Quan, S. F., Walsh, J. K., Gottlieb, D. J., Simon, R. D., Guilleminault, C., White, D. P., Goodwin, J. L., Schweitzer, P. K., Leary, E. B., Hyde, P. R., Hirshkowitz, M., Green, S., McEvoy, L. K., Chan, C., Gevins, A., Kay, G. G., Bloch, D. A., Crabtree, T., Dement, W. C. 2012; 35 (12): 1593-U40

  Abstract

  To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.Active or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.Registered at clinicaltrials.gov. Identifier: NCT00051363.Kushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.

  View details for DOI 10.5665/sleep.2226

  View details for Web of Science ID 000313000600005

  View details for PubMedID 23204602

  View details for PubMedCentralID PMC3490352

• Strategies for De-identification and Anonymization of Electronic Health Record Data for Use in Multicenter Research Studies MEDICAL CARE Kushida, C. A., Nichols, D. A., Jadrnicek, R., Miller, R., Walsh, J. K., Griffin, K. 2012; 50 (7): S82-S101

  Abstract

  De-identification and anonymization are strategies that are used to remove patient identifiers in electronic health record data. The use of these strategies in multicenter research studies is paramount in importance, given the need to share electronic health record data across multiple environments and institutions while safeguarding patient privacy.Systematic literature search using keywords of de-identify, deidentify, de-identification, deidentification, anonymize, anonymization, data scrubbing, and text scrubbing. Search was conducted up to June 30, 2011 and involved 6 different common literature databases. A total of 1798 prospective citations were identified, and 94 full-text articles met the criteria for review and the corresponding articles were obtained. Search results were supplemented by review of 26 additional full-text articles; a total of 120 full-text articles were reviewed.A final sample of 45 articles met inclusion criteria for review and discussion. Articles were grouped into text, images, and biological sample categories. For text-based strategies, the approaches were segregated into heuristic, lexical, and pattern-based systems versus statistical learning-based systems. For images, approaches that de-identified photographic facial images and magnetic resonance image data were described. For biological samples, approaches that managed the identifiers linked with these samples were discussed, particularly with respect to meeting the anonymization requirements needed for Institutional Review Board exemption under the Common Rule.Current de-identification strategies have their limitations, and statistical learning-based systems have distinct advantages over other approaches for the de-identification of free text. True anonymization is challenging, and further work is needed in the areas of de-identification of datasets and protection of genetic information.

  View details for DOI 10.1097/MLR.0b013e3182585355

  View details for Web of Science ID 000314235100016

  View details for PubMedID 22692265

• Respiratory Event Detection by a Positive Airway Pressure Device SLEEP Berry, R. B., Kushida, C. A., Kryger, M. H., Soto-Calderon, H., Staley, B., Kuna, S. T. 2012; 35 (3): 361-367

  Abstract

  Compare automatic event detection (AED) of respiratory events using a positive airway pressure (PAP) device with manual scoring of polysomnography (PSG) during PAP treatment of obstructive sleep apnea (OSA).Prospective PSGs of patients using a PAP device.Six academic and private sleep disorders centers.A total of 148 PSGs from 115 participants with OSA (apnea-hypopnea index [AHI] ≥ 15 events/hr) were analyzed.A signal generated by the PAP device identifying the AED of respiratory events based on airflow was recorded during PSG.The PSGs were manually scored without visualization of the AED signal and scoring of a hypopnea required a ≥ 4% oxygen desaturation. The apnea index (AI), hypopnea index (HI), and AHI by manual score and PAP AED were compared. A customized computer program compared individual events by manual scoring and AED to determine the true positive, false positive, false negative, or true negative events and found a sensitivity of 0.58 and a specificity of 0.98. The AHI, AI, and HI by the two methods were highly correlated. Bland-Altman analysis showed better agreement for AI than HI. Using a manually scored AHI of ≥ 10 events/hr to denote inadequate treatment, an AED AHI ≥ 10 events/hr had a sensitivity of 0.58 and a specificity of 0.94.An AHI < 10 events/hr by PAP AED is usually associated with good treatment efficacy. Differences between manually scored and AED events were primarily due to different criteria for hypopnea detection.

  View details for DOI 10.5665/sleep.1696

  View details for Web of Science ID 000300950400010

  View details for PubMedID 22379242

• A method for estimating normative distributions for study-specific populations of clinical trials CONTEMPORARY CLINICAL TRIALS Holmes, T. H., Nichols, D. A., Thomander, D., Kushida, C. A. 2012; 33 (2): 445-449

  Abstract

  For any particular psychological instrument, published normative distributions have been derived in one to at most a few specific "reference" populations. Here a method is provided for estimating a normative distribution pertinent to the specific population being evaluated in a randomized clinical trial. Normative quantiles are obtained using quantile regression, a method chosen for its flexibility in that no assumptions are made about the parametric form (e.g., Gaussian) of the normative distribution to be estimated. Outcome is regressed on disease severity for the τth quantile using that sample of consented participants who were not randomized because they fell below the trial's disease severity entry criterion. The τth quantile of the normative distribution is then estimated by the intercept of this fitted regression function, which corresponds to severity of zero. Additional covariates that explain variation in outcome may be included to permit adjustment for shifts in their distributions between the randomized and non-randomized samples. The method is illustrated using data on a depression instrument (GRID Hamilton Rating Scale for Depression) and a neurocognitive instrument (CogScreen Pathfinder Number) from a multicenter clinical trial in sleep apnea patients.

  View details for DOI 10.1016/j.cct.2011.11.014

  View details for Web of Science ID 000300962000025

  View details for PubMedID 22138103

• EVALUATION OF A NEW PEDIATRIC POSITIVE AIRWAY PRESSURE MASK 26th Annual Meeting of the Association-of-Professional-Sleep-Societies (APSS) Kushida, C. A., Halbower, A., Kryger, M. H., Pelayo, R., Assalone, V., Cardell, C., Huston, S., Willes, L., Mendoza, J., Wimms, A. J. AMER ACAD SLEEP MEDICINE. 2012: A351–A352

  View details for Web of Science ID 000312996502280

• SLEEP MRI EVALUATION OF THE UPPER AIRWAY IN PATIENTS WITH OBSTRUCTIVE SLEEP APNEA WITH EEG CORRELATION 26th Annual Meeting of the Association-of-Professional-Sleep-Societies (APSS) Shin, L. K., Holbrook, A., Powell, N., Kushida, C., Fischbein, N. J., Capasso, R. AMER ACAD SLEEP MEDICINE. 2012: A136–A136

  View details for Web of Science ID 000312996500394

• Positive Airway Pressure Initiation: A Randomized Controlled Trial to Assess the Impact of Therapy Mode and Titration Process on Efficacy, Adherence, and Outcomes SLEEP Kushida, C. A., Berry, R. B., Blau, A., Crabtree, T., Fietze, I., Kryger, M. H., Kuna, S. T., Pegram, G. V., Penzel, T. 2011; 34 (8): 1083-1092

  Abstract

  (1) To determine the efficacy of automatically adjusted positive airway pressure (APAP) with a comfort feature (A-Flex) at reducing apneas and hypopneas in participants with moderate to severe OSA. (2) To determine the relative difference between A-Flex, continuous positive airway pressure (CPAP), and APAP-derived optimal pressure for CPAP (CPAP(APAP)) on adherence to treatment. (3) To determine the relative difference between APAP with A-Flex, CPAP, and CPAP(APAP) on long-term change in functional outcomes.Randomized, double-blinded, 3-arm, multicenter trial.University and Veterans Affairs medical centers.168 participants were randomized, and 140 completed the 180-day study.(1) A-Flex; (2) CPAP; (3) APAP for 14 days and then switched to CPAP at a fixed pressure.Apnea-hypopnea indices, average and minimum oxygen saturation, time spent < 90% were significantly poorer for A-Flex vs. CPAP at the initiation of study treatment; with the exception of minimum oxygen saturation, these differences were absent at 180 days. A-Flex had lower average leak values at both 3 and 6 months. There were no significant differences between groups in major efficacy, adherence, and outcome (subjective sleepiness, objective vigilance, blood pressure, quality of life) measures. No differences between groups in attitudes toward use were observed at 3 or 6 months; participant ratings for CPAP were significantly higher than A-Flex on treatment satisfaction and benefit, but not different for sleep quality and mask comfort.We found that A-Flex shows equivalency, but non-superiority (except for average leak values), in efficacy, adherence, and functional outcomes compared to CPAP after either 3 or 6 months. CLINICAL TRIAL REGISTRY: Positive Pressure Treatment of Obstructive Sleep Apnea, http://www.clinicaltrials.gov, NCT00636181.

  View details for DOI 10.5665/SLEEP.1166

  View details for Web of Science ID 000293466200013

  View details for PubMedID 21804670

• TIME SERIES ANALYSIS OF ADHERENCE TO TREATMENT FOR OBSTRUCTIVE SLEEP APNEA Babbin, S. F., Velicer, W., Aloia, M., Kushida, C., Berry, R. SPRINGER. 2011: S170–S170

  View details for Web of Science ID 000289297701151

• The Association between Obstructive Sleep Apnea and Neurocognitive Performance-The Apnea Positive Pressure Long-term Efficacy Study (APPLES) SLEEP Quan, S. F., Chan, C. S., Dement, W. C., Gevins, A., Goodwin, J. L., Gottlieb, D. J., Green, S., Guilleminault, C., Hirshkowitz, M., Hyde, P. R., Kay, G. G., Leary, E. B., Nichols, D. A., Schweitzer, P. K., Simon, R. D., Walsh, J. K., Kushida, C. A. 2011; 34 (3): 303-U207

  Abstract

  To determine associations between obstructive sleep apnea (OSA) and neurocognitive performance in a large cohort of adults.Cross-sectional analyses of polysomnographic and neurocognitive data from 1204 adult participants with a clinical diagnosis of obstructive sleep apnea (OSA) in the Apnea Positive Pressure Long-term Efficacy Study (APPLES), assessed at baseline before randomization to either continuous positive airway pressure (CPAP) or sham CPAP.Sleep and respiratory indices obtained by laboratory polysomnography and several measures of neurocognitive performance.Weak correlations were found for both the apnea hypopnea index (AHI) and several indices of oxygen desaturation and neurocognitive performance in unadjusted analyses. After adjustment for level of education, ethnicity, and gender, there was no association between the AHI and neurocognitive performance. However, severity of oxygen desaturation was weakly associated with worse neurocognitive performance on some measures of intelligence, attention, and processing speed.The impact of OSA on neurocognitive performance is small for many individuals with this condition and is most related to the severity of hypoxemia.

  View details for Web of Science ID 000287917600010

  View details for PubMedID 21358847

  View details for PubMedCentralID PMC3041706

• Task Positive and Default Mode Networks during a Parametric Working Memory Task in Obstructive Sleep Apnea Patients and Healthy Controls SLEEP Prilipko, O., Huynh, N., Schwartz, S., Tantrakul, V., Kim, J. H., Peralta, A. R., Kushida, C., Paiva, T., Guilleminault, C. 2011; 34 (3): 293-U193

  Abstract

  Functional magnetic resonance imaging (fMRI) studies enable the investigation of neural correlates underlying behavioral performance. We investigate the working memory (WM) function of patients with untreated obstructive sleep apnea (OSA) from the view point of task positive and default mode networks (TPN and DMN, respectively) and compare the results to those of healthy controls (HC).A parametric fMRI experiment with 4 levels of visuospatial N-back task was used to investigate the pattern of cortical activation in 17 men with untreated moderate or severe OSA and 7 age-matched HC. Categorical and parametrical analysis of the data was performed. Multiple regression analysis of fMRI data of OSA patients was performed with AHI, nocturnal desaturation time, and BMI as covariates.OSA patients demonstrate compensatory spatial recruitment of the TPN (maximal at 3-back) and of the DMN (maximal at 2-back). HC had a different patten of spatial recruitment and deactivation of the DMN at the maximal load of task (3-back). Nocturnal desaturation had significant positive correlation with BOLD signal in bilateral frontal, temporal, and occipital regions, and negative correlations in bilateral frontal and left parietal regions; whereas BMI showed only negative correlations with BOLD signal, predominantly in the PFC. AHI was positively correlated with BOLD signal in bilateral frontal regions.Both TPN and DMN are affected in OSA patients, with nocturnal desaturation affecting both networks; whereas BMI appears to be the major negative factor influencing the TPN and has a significant negative correlation with behavioral performance.

  View details for Web of Science ID 000287917600009

  View details for PubMedID 21358846

• GABAPENTIN ENACARBIL IN SUBJECTS WITH PRIMARY RESTLESS LEGS SYNDROME WITH AND WITHOUT SEVERE SLEEP DISTURBANCE: SECONDARY ANALYSES OF NOVEL SLEEP ENDPOINTS FROM TWO STUDIES 25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS) Kavanagh, S. T., Caivano, C., Ondo, W., Becker, P. M., Bogan, R. K., Ellenbogen, A. L., Kushida, C. A., Ball, E. AMER ACAD SLEEP MEDICINE. 2011: A202–A203

  View details for Web of Science ID 000299834400591

• Ethical Issues in the Conduct of Clinical Trials in Obstructive Sleep Apnea JOURNAL OF CLINICAL SLEEP MEDICINE Brown, D. L., Anderson, C. S., Chervin, R. D., Kushida, C. A., Lewin, D. S., Malow, B. A., Redline, S., Goldman, E. B. 2011; 7 (1): 103-108

  Abstract

  Scientifically rigorous clinical trials are needed to test continuous positive airway pressure's (CPAP) effect on important clinical endpoints known to be associated with obstructive sleep apnea, such as myocardial infarction, cardiac arrhythmias, stroke, mortality, seizures, and cognitive function. In this "Special Article," we review the regulatory and ethical issues that surround the design and conduct of CPAP trials, including selection of the appropriate control condition, exclusion criteria, and follow-up duration.

  View details for Web of Science ID 000292920900015

  View details for PubMedID 21344041

• Best Clinical Practices for the Sleep Center Adjustment of Noninvasive Positive Pressure Ventilation (NPPV) in Stable Chronic Alveolar Hypoventilation Syndromes JOURNAL OF CLINICAL SLEEP MEDICINE Berry, R. B., Chediak, A., Brown, L. K., Finder, J., Gozal, D., Iber, C., Kushida, C. A., Morgenthaler, T., Rowley, J. A., Davidson-Ward, S. L. 2010; 6 (5): 491-509

  Abstract

  Noninvasive positive pressure ventilation (NPPV) devices are used during sleep to treat patients with diurnal chronic alveolar hypoventilation (CAH). Bilevel positive airway pressure (BPAP) using a mask interface is the most commonly used method to provide ventilatory support in these patients. BPAP devices deliver separately adjustable inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP). The IPAP and EPAP levels are adjusted to maintain upper airway patency, and the pressure support (PS = IPAP-EPAP) augments ventilation. NPPV devices can be used in the spontaneous mode (the patient cycles the device from EPAP to IPAP), the spontaneous timed (ST) mode (a backup rate is available to deliver IPAP for the set inspiratory time if the patient does not trigger an IPAP/EPAP cycle within a set time window), and the timed (T) mode (inspiratory time and respiratory rate are fxed). During NPPV titration with polysomnography (PSG), the pressure settings, backup rate, and inspiratory time (if applicable) are adjusted to maintain upper airway patency and support ventilation. However, there are no widely available guidelines for the titration of NPPV in the sleep center. A NPPV Titration Task Force of the American Academy of Sleep Medicine reviewed the available literature and developed recommendations based on consensus and published evidence when available. The major recommendations derived by this consensus process are as follows: General Recommendations: 1. The indications, goals of treatment, and side effects of NPPV treatment should be discussed in detail with the patient prior to the NPPV titration study. 2. Careful mask fitting and a period of acclimatization to low pressure prior to the titration should be included as part of the NPPV protocol. 3. NPPV titration with PSG is the recommended method to determine an effective level of nocturnal ventilatory support in patients with CAH. In circumstances in which NPPV treatment is initiated and adjusted empirically in the outpatient setting based on clinical judgment, a PSG should be utilized if possible to confirm that the final NPPV settings are effective or to make adjustments as necessary. 4. NPPV treatment goals should be individualized but typically include prevention of worsening of hypoventilation during sleep, improvement in sleep quality, relief of nocturnal dyspnea, and providing respiratory muscle rest. 5. When OSA coexists with CAH, pressure settings for treatment of OSA may be determined during attended NPPV titration PSG following AASM Clinical Guidelines for the Manual Titration of Positive Airway Pressure in Patients with Obstructive Sleep Apnea. 6. Attended NPPV titration with PSG is the recommended method to identify optimal treatment pressure settings for patients with the obesity hypoventilation syndrome (OHS), CAH due to restrictive chest wall disease (RTCD), and acquired or central CAH syndromes in whom NPPV treatment is indicated. 7. Attended NPPV titration with PSG allows definitive identification of an adequate level of ventilatory support for patients with neuromuscular disease (NMD) in whom NPPV treatment is planned. Recommendations for NPPV Titration Equipment: 1. The NPPV device used for titration should have the capability of operating in the spontaneous, spontaneous timed, and timed mode. 2. The airflow, tidal volume, leak, and delivered pressure signals from the NPPV device should be monitored and recorded if possible. The airflow signal should be used to detect apnea and hypopnea, while the tidal volume signal and respiratory rate are used to assess ventilation. 3. Transcutaneous or end-tidal PCO2 may be used to adjust NPPV settings if adequately calibrated and ideally validated with arterial blood gas testing. 4. An adequate assortment of masks (nasal, oral, and oronasal) in both adult and pediatric sizes (if children are being titrated), a source of supplemental oxygen, and heated humidification should be available. Recommendations for Limits of IPAP, EPAP, and PS Settings: 1. The recommended minimum starting IPAP and EPAP should be 8 cm H2O and 4 cm H2O, respectively. 2. The recommended maximum IPAP should be 30 cm H2O for patients > or = 12 years and 20 cm H2O for patients < 12 years. 3. The recommended minimum and maximum levels of PS are 4 cm H2O and 20 cm H2O, respectively. 4. The minimum and maximum incremental changes in PS should be 1 and 2 cm H2O, respectively. Recommendations for Adjustment of IPAP, EPAP, and PS: 1. IPAP and/or EPAP should be increased as described in AASM Clinical Guidelines for the Manual Titration of Positive Airway Pressure in Patients with Obstructive Sleep Apnea until the following obstructive respiratory events are eliminated (no specific order): apneas, hypopneas, respiratory effort-related arousals, and snoring. 2. The pressure support (PS) should be increased every 5 minutes if the tidal volume is low (< 6 to 8 mL/kg) 3. The PS should be increased if the arterial PCO2 remains 10 mm Hg or more above the PCO, goal at the current settings for 10 minutes or more. An acceptable goal for PCO, is a value less than or equal to the awake PCO2. 4. The PS may be increased if respiratory muscle rest has not been achieved by NPPV treatment at the current settings for 10 minutes of more. 5. The PS may be increased if the SpO, remains below 90% for 5 minutes or more and tidal volume is low (< 6 to 8 mL/kg). Recommendations for Use and Adjustment of the Backup Rate/ Respiratory Rate: 1. A backup rate (i.e., ST mode) should be used in all patients with central hypoventilation, those with a significant number of central apneas or an inappropriately low respiratory rate, and those who unreliably trigger IPAP/EPAP cycles due to muscle weakness. 2. The ST mode may be used if adequate ventilation or adequate respiratory muscle rest is not achieved with the maximum (or maximum tolerated) PS in the spontaneous mode. 3. The starting backup rate should be equal to or slightly less than the spontaneous sleeping respiratory rate (minimum of 10 bpm). 4. The backup rate should be increased in 1 to 2 bpm increments every 10 minutes if the desired goal of the backup rate has not been attained. 5. The IPAP time (inspiratory time) should be set based on the respiratory rate to provide an inspiratory time (IPAP time) between 30% and 40% of the cycle time (60/respiratory rate in breaths per minute). 6. If the spontaneous timed mode is not successful at meeting titration goals then the timed mode can be tried. Recommendations Concerning Supplemental Oxygen: 1. Supplemental oxygen may be added in patients with an awake SpO2 < 88% or when the PS and respiratory rate have been optimized but the SpO2 remains < 90% for 5 minutes or more. 2. The minimum starting supplemental oxygen rate should be 1 L/minute and increased in increments of 1 L/minute about every 5 minutes until an adequate SpO2 is attained (> 90%). Recommendations to Improve Patient Comfort and Patient-NPPV Device Synchrony: 1. If the patient awakens and complains that the IPAP and/or EPAP is too high, pressure should be lowered to a level comfortable enough to allow return to sleep. 2. NPPV device parameters (when available) such as pressure relief, rise time, maximum and minimum IPAP durations should be adjusted for patient comfort and to optimize synchrony between the patient and the NPPV device. 3. During the NPPV titration mask refit, adjustment, or change in mask type should be performed whenever any significant unintentional leak is observed or the patient complains of mask discomfort. If mouth leak is present and is causing significant symptoms (e.g., arousals) use of an oronasal mask or chin strap may be tried. Heated humidification should be added if the patient complains of dryness or significant nasal congestion. Recommendations for Follow-Up: 1. Close follow-up after initiation of NPPV by appropriately trained health care providers is indicated to establish effective utilization patterns, remediate side effects, and assess measures of ventilation and oxygenation to determine if adjustment to NPPV is indicated.

  View details for Web of Science ID 000282868800015

  View details for PubMedID 20957853

• Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Nguyen, P. K., Katikireddy, C. K., McConnell, M. V., Kushida, C., Yang, P. C. 2010; 12

  Abstract

  Obstructive sleep apnea (OSA) has been associated with cardiovascular disease (CVD), but whether OSA is an independent risk factor for CVD is controversial. The purpose of this study is to determine if patients with OSA have subclinical cardiovascular disease that is detectable by multi-modality cardiovascular imaging and whether these abnormalities improve after nasal continuous positive airway pressure (nCPAP).Of the 35 consecutive subjects with newly diagnosed moderate to severe OSA recruited from the Stanford Sleep Disorders Clinic, 20 patients were randomized to active vs. sham nCPAP. Active nCPAP was titrated to pressures that would prevent sleep disordered breathing based on inpatient polysomnography. OSA patients had baseline vascular function abnormalities including decreased myocardial perfusion reserve (MPR), brachial flow mediated dilation (FMD) and nitroglycerin-induced coronary vasodilation. Patients randomized to active nCPAP had improvement of MPR (1.5 ± 0.5 vs. 3.0 ± 1.3, p = 0.02) and brachial FMD (2.5% ± 5.7% vs. 9.0% ± 6.5%, p = 0.03) after treatment, but those randomized to sham nCPAP showed no significant improvement. There were no significant changes seen in chamber sizes, systolic and diastolic function, valvular function and coronary vasodilation to nitroglycerin.Patients with moderate to severe OSA had decreased MPR and brachial FMD that improved after 3 months of nCPAP. These findings suggest that relief of apnea in OSA may improve microvascular disease and endothelial dysfunction, which may prevent the development of overt cardiovascular disease. Further study in a larger patient population may be warranted.

  View details for DOI 10.1186/1532-429X-12-50

  View details for Web of Science ID 000282342300001

  View details for PubMedID 20815898

  View details for PubMedCentralID PMC2945335

• Long-term Maintenance Treatment of Restless Legs Syndrome With Gabapentin Enacarbil: A Randomized Controlled Study MAYO CLINIC PROCEEDINGS Bogan, R. K., Cramer Bornemann, M. A., Kushida, C. A., Tran, P. V., Barrett, R. W. 2010; 85 (6): 512-521

  Abstract

  To assess maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome (RLS).This study (conducted April 18, 2006, to November 14, 2007) comprised a 24-week, single-blind (SB) treatment phase (gabapentin enacarbil, 1200 mg) followed by a 12-week randomized, double-blind (DB) phase. Responders from the SB phase (patients with improvements on the International Restless Legs Scale [IRLS] and investigator-rated Clinical Global Impression-Improvement scale at week 24 and stable while taking a gabapentin enacarbil dose of 1200 mg for at least 1 month before randomization) were randomized to gabapentin enacarbil, 1200 mg, or placebo once daily at 5 pm with food. The primary end point was the proportion of patients experiencing relapse (worse scores on the IRLS and investigator-rated Clinical Global Impression of Change scale on 2 consecutive visits at least 1 week apart or withdrawal because of lack of efficacy) during the DB phase.A total of 221 of 327 patients completed the SB phase, 194 (96 in the gabapentin enacarbil group and 98 in the placebo group) were randomized to DB treatment, and 168 (84 in the gabapentin enacarbil group and 84 in the placebo group) completed the DB phase. A significantly smaller proportion of patients treated with gabapentin enacarbil (9/96 [9%]) experienced relapse compared with the placebo-treated patients (22/97 [23%]) (odds ratio, 0.353; 95% confidence interval, 0.2-0.8; P=.02). Somnolence and dizziness were the most common adverse events. One death occurred (unintentional choking during the SB phase) and was judged as being unrelated to the study drug. No clinically relevant changes were observed in laboratory values, in vital signs, or on electrocardiograms.Gabapentin enacarbil, 1200 mg, maintained improvements in RLS symptoms compared with placebo and showed long-term tolerability in adults with moderate to severe primary RLS for up to 9 months of treatment.

  View details for DOI 10.4065/mcp.2009.0700

  View details for Web of Science ID 000278284100003

  View details for PubMedID 20511481

• Reliability and validity of two self-administered questionnaires for screening restless legs syndrome in population-based studies SLEEP MEDICINE Popat, R. A., Van Den Eeden, S. K., Tanner, C. M., Kushida, C. A., Rama, A. N., Black, J. E., Bernstein, A., Kasten, M., Chade, A., Leimpeter, A., Cassidy, J., McGuire, V., Nelson, L. M. 2010; 11 (2): 154-160

  Abstract

  A reliable and valid questionnaire for screening restless legs syndrome (RLS) is essential for determining accurate estimates of disease frequency. In a 2002 NIH-sponsored workshop, experts suggested three mandatory questions for identifying RLS in epidemiologic studies. We evaluated the reliability and validity of this RLS-NIH questionnaire in a community-based sample and concurrently developed and evaluated the utility of an expanded screening questionnaire, the RLS-EXP.The study was conducted at Kaiser Permanente of Northern California and the Stanford University Sleep Clinic. We evaluated test-retest reliability in a random sample of subjects with prior physician-assigned RLS (n=87), subjects with conditions frequently misclassified as RLS (n=31), and healthy subjects (n=9). Validity of both instruments was evaluated in a random sample of 32 subjects, and in-person examination by two RLS specialists was used as the gold standard.For the first three RLS-NIH questions, the kappa statistic for test-retest reliability ranged from 0.5 to 1.0, and sensitivity and specificity was 86% and 45%, respectively. For the subset of five questions on RLS-EXP that encompassed cardinal features for diagnosing RLS, kappas were 0.4-0.8, and sensitivity and specificity were 81% and 73%, respectively.Sensitivity of RLS-NIH is good; however, the specificity of the instrument is poor when examined in a sample that over-represents subjects with conditions that are commonly misclassified as RLS. Specificity can be improved by including separate questions on cardinal features, as used in the RLS-EXP, and by including a few questions that identify RLS mimics, thereby reducing false positives.

  View details for DOI 10.1016/j.sleep.2009.01.012

  View details for Web of Science ID 000275584500009

  View details for PubMedID 20089446

• GABAPENTIN ENACARBIL IMPROVES RESTLESS LEGS SYNDROME SYMPTOMS AND SUBJECTIVE MEASURES OF SLEEP IN SUBJECTS WITH PRIMARY RESTLESS LEGS SYNDROME WITH AND WITHOUT SEVERE SLEEP DISTURBANCE: SECONDARY ANALYSES FROM TWO STUDIES Kushida, C., Bogan, R. K., Ellenbogen, A. L., Becker, P. M., Ball, E., Ondo, W., Williams, N. J., Caivano, C. AMER ACAD SLEEP MEDICINE. 2010: A265–A265

  View details for Web of Science ID 000208208001277

• Gabapentin Enacarbil in Restless Legs Syndrome: A Phase 2b, 2-Week, Randomized, Double-Blind, Placebo-Controlled Trial CLINICAL NEUROPHARMACOLOGY Walters, A. S., Ondo, W. G., Kushida, C. A., Becker, P. M., Ellenbogen, A. L., Canafax, D. M., Barrett, R. W. 2009; 32 (6): 311-320

  Abstract

  Assess the efficacy and tolerability of gabapentin enacarbil (GEn), a transported prodrug of gabapentin with improved gabapentin exposure, in adults with moderate-to-severe primary restless legs syndrome.This 14-day, double-blind, randomized, controlled trial of GEn at 1200 or 600 mg or placebo taken once daily, evaluated the mean change from baseline International Restless Legs Scale (IRLS) total score at end of treatment (day 14:primary comparison, GEn at 1200 mg vs placebo). Secondary end points included Clinical Global Impression-Improvement scale outcomes at day 14.Ninety-five subjects were randomized (GEn: 1200 mg, n = 33 and 600 mg, n = 29; placebo, n = 33); 2 subjects (GEn at 1200 mg) withdrew because of adverse events. At day 14,the mean (SD) change from baseline IRLS total score was significantly greater with GEn at 1200 mg (-16.1 [7.93]) compared with placebo (-8.9 [7.72]; adjusted mean treatment difference, -7.2; P < 0.0001). Investigator-rated Clinical Global Impression-Improvement scale responses also significantly favored GEn at 1200 mg compared with placebo (P G 0.0001).The mean (SD) change from baseline IRLS total score with GEn at 600 mg at day 14 was -9.1 (5.95), similar to placebo. The most commonly reported treatment-emergent adverse events were somnolence (GEn: 1200 mg, 36% and 600 mg, 14%; placebo,15%) and dizziness (GEn: 1200 mg, 18% and 600 mg, 14%; placebo, 3%), most of which were rated mild or moderate in intensity.Gabapentin enacarbil at 1200 mg significantly improved restless legs syndrome symptoms compared with placebo. Efficacy outcomes for GEn at 600 mg were similar to placebo. Both GEn doses were generally well tolerated.

  View details for DOI 10.1097/WNF.0b013e3181b3ab16

  View details for Web of Science ID 000272362900002

  View details for PubMedID 19667976

• Primary Hypersomnias of Central Origin SEMINARS IN NEUROLOGY Frenette, E., Kushida, C. A. 2009; 29 (4): 354-367

  Abstract

  Hypersomnia is a frequently encountered symptom in clinical practice. The cardinal manifestation is inappropriate daytime sleepiness, common to all types of hypersomnias. Hypersomnias of central origin are a rare cause of excessive daytime sleepiness, much rarer than the hypersomnia related to other pathologies, such as sleep-disordered breathing. Narcolepsy, with or without cataplexy, remains the most well studied of the primary hypersomnias. Although recognized more than a century ago, it was not until the end of the 20th century that major breakthroughs led to a better understanding of the disease, with hope of more specific therapies. The authors review the major aspects of this disorder, including the newer treatment modalities. Idiopathic hypersomnia is also part of the primary hypersomnias. Although difficult to diagnose, certain peculiarities stand out to help us differentiate it from the more commonly seen narcolepsy. The recurrent hypersomnias, particularly the Kleine-Levin syndrome, will be discussed. This rare disorder has been studied more closely in the last few years with abundant epidemiologic data assembled through literature and worldwide case reviews. Understanding the primary central hypersomnias warrants a thorough look from the original description, as well as a peek at the future, while more efficacious diagnostic and therapeutic interventions are currently being developed.

  View details for DOI 10.1055/s-0029-1237114

  View details for Web of Science ID 000269984500008

  View details for PubMedID 19742411

• Gabapentin Enacarbil 1200 mg Improves Sleep in Subjects with Primary Restless Legs Syndrome 64th Annual Convention of the Society-of-Biological-Psychiatry Becker, P. M., Kushida, C. A., Ellenbogen, A. L., Canafax, D. M., Monaghan, E. T., Barrett, R. W. ELSEVIER SCIENCE INC. 2009: 215S–215S

  View details for Web of Science ID 000265144200681

• Scheduled Bright Light for Treatment of Insomnia in Older Adults JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Friedman, L., Zeitzer, J. M., Kushida, C., Zhdanova, I., Noda, A., Lee, T., Schneider, B., Guilleminault, C., Sheikh, J., Yesavage, J. A. 2009; 57 (3): 441-452

  Abstract

  To determine whether bright light can improve sleep in older individuals with insomnia.Single-blind, placebo-controlled, 12-week, parallel-group randomized design comparing four treatment groups representing a factorial combination of two lighting conditions and two times of light administration.At-home light treatment; eight office therapy sessions.Thirty-six women and fifteen men (aged 63.6+/-7.1) meeting primary insomnia criteria recruited from the community.A 12-week program of sleep hygiene and exposure to bright ( approximately 4,000 lux) or dim light ( approximately 65 lux) scheduled daily in the morning or evening for 45 minutes.Within-group changes were observed for subjective (sleep logs, questionnaires) and objective (actigraphy, polysomnography) sleep measures after morning or evening bright light.Within-group changes for subjective sleep measures after morning or evening bright light were not significantly different from those observed after exposure to scheduled dim light. Objective sleep changes (actigraphy, polysomnography) after treatment were not significantly different between the bright and dim light groups. Scheduled light exposure was able to shift the circadian phase predictably but was unrelated to changes in objective or subjective sleep measures. A polymorphism in CLOCK predicted morningness but did not moderate the effects of light on sleep. The phase angle between the circadian system (melatonin midpoint) and sleep (darkness) predicted the magnitude of phase delays, but not phase advances, engendered by bright light.Except for one subjective measure, scheduled morning or evening bright light effects were not different from those of scheduled dim light. Thus, support was not found for bright light treatment of older individuals with primary insomnia.

  View details for DOI 10.1111/j.1532-5415.2008.02164.x

  View details for Web of Science ID 000263859600008

  View details for PubMedID 19187411

  View details for PubMedCentralID PMC2743069

• Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS NEUROLOGY Kushida, C. A., Becker, P. M., Ellenbogen, A. L., Canafax, D. M., Barrett, R. W. 2009; 72 (5): 439-446

  Abstract

  To assess the efficacy and tolerability of the nondopaminergic agent XP13512/GSK1838262 in adults with moderate to severe primary restless legs syndrome (RLS).Patient Improvements in Vital Outcomes following Treatment in Restless Legs Syndrome I was a 12-week, multicenter, randomized, double-blind, placebo-controlled trial of XP13512 1,200 mg or placebo taken once daily at 5:00 pm with food. Coprimary endpoints were mean change from baseline International Restless Legs Scale (IRLS) total score and proportion of investigator-rated responders (very much improved or much improved on the Clinical Global Impression-Improvement scale) at week 12 (last observation carried forward). Tolerability was assessed using adverse events, vital signs, and clinical laboratory parameters.A total of 222 patients were randomized (XP13512 = 114, placebo = 108) and 192 patients (XP13512 = 100, placebo = 92) completed the study. At week 12, the mean change from baseline IRLS total score was greater with XP13512 (-13.2) compared with placebo (-8.8). Analysis of covariance, adjusted for baseline score and pooled site, demonstrated a mean treatment difference of -4.0 (95% confidence interval [CI], -6.2 to -1.9; p = 0.0003). More patients treated with XP13512 (76.1%) were responders compared with placebo (38.9%; adjusted OR 5.1; 95% CI, 2.8 to 9.2; p < 0.0001). Significant treatment effects for both coprimary measures were identified at week 1, the earliest time point measured. The most commonly reported adverse events were somnolence (XP13512 27%, placebo 7%) and dizziness (XP13512 20%, placebo 5%), which were mild to moderate in intensity and generally remitted.XP13512 1,200 mg, taken once daily, significantly improved restless legs syndrome (RLS) symptoms compared with placebo and was generally well tolerated in adults with moderate to severe primary RLS.

  View details for Web of Science ID 000263188200009

  View details for PubMedID 19188575

• A Randomized, Double-Blind, Placebo-Controlled, Crossover Study of XP13512/GSK1838262 in the Treatment of Patients With Primary Restless Legs Syndrome SLEEP Kushida, C. A., Walters, A. S., Becker, P., Thein, S. G., Perkins, T., Roth, T., Canafax, D., Barrett, R. W. 2009; 32 (2): 159-168

  Abstract

  To evaluate the efficacy and tolerability of XP13512/ GSK1838262, an investigational nondopaminergic agent for the treatment of moderate-to-severe primary restless legs syndrome (RLS).Randomized, double-blind, placebo-controlled, crossover trial.Nine US clinical sites.Thirty-eight treatment-naive subjects with RLS (mean +/- SD age 50.1 +/- 13.2 years).XP13512 1800 mg/day followed by placebo or placebo followed by XP13512 1800 mg/day for 14 days, with a 7-day washout between treatment periods.The primary endpoint was mean change from baseline International RLS Study Group rating scale (IRLS) total score on Day 14, analyzed using analysis of variance with sequence, period, and treatment as fixed effects and subjects within sequence as a random effect. XP13512 significantly reduced IRLS total score on Day 14 compared with placebo (mean +/- SD: XP13512 -12.1 +/-6.5, placebo -1.9 +/- 6.3; P < 0.0001). Polysomnographic data showed that XP13512 significantly improved sleep architecture on Day 14 compared with placebo (mean +/- SD change from baseline sleep time [minutes]: stage 1: XP13512 -9.8 +/- 23.9, placebo 0.4 +/-23.2; adjusted P<0.0054, nominal P<0.0001; stage 3/4 (slow-wave sleep): XP13512 22.8 +/- 40.8, placebo 1.4 +/- 34.3; adjusted P=0.0092, nominal P=0.0002). The most frequently reported adverse events were somnolence (XP13512 30.6%, placebo 2.8%) and dizziness (XP13512 27.8%, placebo 5.6%).XP13512 1800 mg/day significantly reduced RLS symptoms, improved sleep, and was generally well tolerated in subjects with moderate-to-severe primary RLS across 14 days of treatment.

  View details for Web of Science ID 000262890300006

  View details for PubMedID 19238802

• FMRI STUDY OF CPAP TREATMENT ON VERBAL MEMORY ENCODING IN OBSTRUCTIVE SLEEP APNEA PATIENTS IN COMPARISON TO HEALTHY CONTROLS 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Huynh, N. T., Prilipko, O., Tantrakul, V., Nichols, D., Leary, E., Kushida, C., Guilleminault, C. AMER ACAD SLEEP MEDICINE. 2009: A224–A224

  View details for Web of Science ID 000265542001036

• GABAPENTIN ENACARBIL RELIEVES PAIN ASSOCIATED WITH RESTLESS LEGS SYNDROME 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Canafax, D. M., Kushida, C. A., Becker, P. M., Ellenbogen, A. L., Barrett, R. W. AMER ACAD SLEEP MEDICINE. 2009: A299–A300

  View details for Web of Science ID 000265542001265

• GABAPENTIN ENACARBIL IMPROVES MOOD, QUALITY OF LIFE, AND FUNCTIONING IN SUBJECTS WITH PRIMARY RESTLESS LEGS SYNDROME 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Becker, P. M., Kushida, C. A., Ellenbogen, A. L., Canafax, D. M., Barrett, R. W. AMER ACAD SLEEP MEDICINE. 2009: A297–A298

  View details for Web of Science ID 000265542001259

• DIFFERENCES IN CEREBRAL ACTIVATION ON A VISUO-SPATIAL WORKING MEMORY TASK]IN OBSTRUCTIVE SLEEP APNEA PATIENTS AND HEALTHY CONTROLS 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Prilipko, O., Huynh, N., Tantrakul, V., Leary, E., Nichols, D., Henry, M., Kushida, C., Guilleminault, C. AMER ACAD SLEEP MEDICINE. 2009: A225–A225

  View details for Web of Science ID 000265542001041

• GABAPENTIN ENACARBIL IMPROVES SLEEP IN SUBJECTS WITH MODERATE-TO-SEVERE PRIMARY RESTLESS LEGS SYNDROME 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Becker, P. M., Kushida, C. A., Ellenbogen, A. L., Canafax, D. M., Barrett, R. W. AMER ACAD SLEEP MEDICINE. 2009: A299–A299

  View details for Web of Science ID 000265542001264

• A MAINTENANCE OF EFFICACY STUDY OF GABAPENTIN ENACARBIL VERSUS PLACEBO IN SUBJECTS WITH RESTLESS LEGS SYNDROME 23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS) Cramer, B. M., Bogan, R. K., Kushida, C. A., Tran, P., Barrett, R. W. AMER ACAD SLEEP MEDICINE. 2009: A304–A305

  View details for Web of Science ID 000265542001281

• Multiple Sleep Latency Test and Maintenance of Wakefulness Test CHEST Sullivan, S. S., Kushida, C. A. 2008; 134 (4): 854-861

  Abstract

  Excessive daytime sleepiness and fatigue are common complaints in the sleep clinic. The objective evaluation and quantification of these symptoms is important for both the diagnosis of underlying health problems and for gauging treatment response. The multiple sleep latency test measures physiologic sleepiness, whereas the maintenance of wakefulness test (MWT) aims to measure manifest sleepiness. Neither test correlates well with subjective measures of sleep such as the Epworth sleepiness scale and the Stanford sleepiness scale. Although in the past methodological testing differences existed, in 2005 updated practice parameters were published, promoting the standardization of testing procedures. In recent years, there has been an effort to document daytime sleepiness when associated with occupational risk. However, these laboratory-based tests may not reflect or predict real-life experience. Normative data for both tests, particularly the MWT, are limited, and are inadequate for the evaluation of pediatric patients, shift workers, and others.

  View details for DOI 10.1378/chest.08-0822

  View details for Web of Science ID 000260097600032

  View details for PubMedID 18842919

• Patient- and Physician-Rated Measures Demonstrate the Effectiveness of Ropinirole in the Treatment of Restless Legs Syndrome CLINICAL NEUROPHARMACOLOGY Kushida, C. A., Geyer, J., Tolson, J. M., Asgharian, A. 2008; 31 (5): 281-286

  Abstract

  To investigate the effect of twice-daily ropinirole in patients with early evening restless legs syndrome (RLS) symptoms, particularly focusing on the relationship of patient- and physician-rated assessment of treatment outcomes.In this multicenter, double-blind, randomized, 12-week, flexible-dose study, patients with primary RLS, with symptom onset no earlier than 5 PM and a baseline International Restless Legs Syndrome Study Group Rating Scale (IRLS) total score > or = 20 received ropinirole 0.5 to 6.0 mg/d twice daily in equally divided doses, or placebo. First dose was 1 hour before the usual onset of symptoms; second dose was 3 to 8 hours after the first. Primary end point: change from baseline in IRLS total score at week 12 last observation carried forward (LOCF). Key secondary end points: proportion of responders (rated "very much improved" or "much improved") on the Clinical Global Impression-Improvement and the Patient Global Improvement scales.Improvements in IRLS total score were statistically significantly greater for ropinirole (n = 175), compared with placebo (n = 184) at all assessment points beginning at day 3 through to week 12 LOCF (P < 0.001). A statistically significantly greater proportion of patients were classified as responders on the Clinical Global Impression-Improvement scale at all assessment points from day 3 through week 12 LOCF (P < 0.001) and on the Patient Global Improvement scale at all assessment points from day 1 (P = 0.013) through day 7 LOCF (P < or = 0.05 for days 2-7 LOCF) and at week 12 LOCF (P < 0.001).Ropinirole is associated with consistent early and sustained improvements in the symptoms of RLS, as rated by patients and physicians.

  View details for DOI 10.1097/WNF.0B013E31815A3EEC

  View details for Web of Science ID 000260087400005

  View details for PubMedID 18836346

• XP13512 reduces restless legs syndrome symptoms and associated sleep impairment: Results of a double-blind, randomized, placebo-controlled study 22nd Annual Meeting of the Associated-Professional-Sleep-Societies BECKER, P., Kushida, C., Ellenbogen, A., Canafax, D., Tran, P. AMER ACAD SLEEP MEDICINE. 2008: A268–A268

  View details for Web of Science ID 000255419001246

• Clinical Guidelines for the Manual Titration of Positive Airway Pressure in Patients with Obstructive Sleep Apnea JOURNAL OF CLINICAL SLEEP MEDICINE Kushida, C. A., Chediak, A., Berry, R. B., Brown, L. K., Gozal, D., Iber, C., Parthasarathy, S., Quan, S. F., Rowley, J. A. 2008; 4 (2): 157-?

  View details for Web of Science ID 000209776800011

• Apnea positive pressure long-term efficacy cardiovascular outcomes research study (APPLE CORS): Preliminary study 22nd Annual Meeting of the Associated-Professional-Sleep-Societies Kushida, C. A., Yang, P., Chandra, K., Nguyen, P., Cardell, C., Manygian, A., Wong, J., Holmes, T. H., Nichols, D. A., Leary, E. AMER ACAD SLEEP MEDICINE. 2008: A139–A140

  View details for Web of Science ID 000255419000418

• Multimodality cardiovascular imaging detects improvment of subclinical microvascular dysfunction with continuous positive airway pressure therapy in obstructive sleep apnea patients: A prospective, randomized, double-blinded study 80th Annual Scientific Session of the American-Heart-Association (AHA) Katikireddy, C., Nguyen, P., Won, C., Cardell, C., Nichols, D., Leary, E., McConnell, M., Holmes, T. H., Kushida, C. A., Yang, P. LIPPINCOTT WILLIAMS & WILKINS. 2007: 846–46

  View details for Web of Science ID 000250394303813

• XP13512 is well-tolerated and effective in treating symptoms and improving mood in moderate to severe RLS: Results of a 2-week, randomized, double-blind, placebo-controlled exploratory trial 62nd Annual Meeting of the Society-of-Biological-Psychiatry Tran, P., Kushida, C. A., Becker, P. M., Ellenbogen, A. L., Walters, A. S., Canafax, D. M. ELSEVIER SCIENCE INC. 2007: 238S–238S

  View details for Web of Science ID 000245698100762

• Digital analysis and technical specifications. Journal of clinical sleep medicine Penzel, T., Hirshkowitz, M., Harsh, J., Chervin, R. D., Butkov, N., Kryger, M., Malow, B., Vitiello, M. V., Silber, M. H., Kushida, C. A., Chesson, A. L. 2007; 3 (2): 109-120

  Abstract

  Digital acquisition and analysis of sleep data has become more common over the past 20 years. Many investigators have developed strategies to record and analyze sleep in a quantitative way. Initially, digital recording and analysis were restricted by technical limitations. With current technology, the technical limitations of computer acquisition, data storage, and analysis are less constraining, and the development of recommendations for the specifications and scoring of sleep can be more clearly guided by the goal of characterizing physiologic phenomena. In order to develop recommendations and specifications regarding digital acquisition and analysis, a literature search, evidence review, and standardized consensus process focused on 5 questions regarding computer-assisted sleep recording and analysis. These questions included: (1) the reliability of computerized scoring of sleep stages, (2) the analysis of elemental events and waveforms, (3) the physiological and/or clinical significance of digitally-analyzed signals, (4) the importance of proposed changes in standardized scoring that could incorporate digital analysis, and (5) the potential advantages and disadvantages of computerized sleep recordings. Of 154 studies identified by the search, 119 were found to be suitable for evidence review. The evidence review suggested that computer scoring and quantitative analysis of sleep is still in the formative stage of development. For many technical specification decisions, little or no direct evidence was found, although basic engineering principles or standard practices provided some rationale which was utilized to develop the recommendations formulated during the subsequent UCLA/Rand standardized consensus process.

  View details for PubMedID 17557421

• The scoring of movements in sleep. Journal of clinical sleep medicine Walters, A. S., Lavigne, G., Hening, W., Picchietti, D. L., Allen, R. P., Chokroverty, S., Kushida, C. A., Bliwise, D. L., Mahowald, M. W., Schenck, C. H., Ancoli-Israel, S. 2007; 3 (2): 155-167

  Abstract

  The International Classification of Sleep Disorders (ICSD-2) has separated sleep-related movement disorders into simple, repetitive movement disorders (such as periodic limb movements in sleep [PLMS], sleep bruxism, and rhythmic movement disorder) and parasomnias (such as REM sleep behavior disorder and disorders of partial arousal, e.g., sleep walking, confusional arousals, night terrors). Many of the parasomnias are characterized by complex behaviors in sleep that appear purposeful, goal directed and voluntary but are outside the conscious awareness of the individual and therefore inappropriate. All of the sleep-related movement disorders described here have specific polysomnographic findings. For the purposes of developing and/or revising specifications and polysomnographic scoring rules, the AASM Scoring Manual Task Force on Movements in Sleep reviewed background literature and executed evidence grading of 81 relevant articles obtained by a literature search of published articles between 1966 and 2004. Subsequent evidence grading identified limited evidence for reliability and/or validity for polysomnographic scoring criteria for periodic limb movements in sleep, REM sleep behavior disorder, and sleep bruxism. Published scoring criteria for rhythmic movement disorder, excessive fragmentary myoclonus, and hypnagogic foot tremor/alternating leg muscle activation were empirical and based on descriptive studies. The literature review disclosed no published evidence defining clinical consequences of excessive fragmentary myoclonus or hypnagogic foot tremor/alternating leg muscle activation. Because of limited or absent evidence for reliability and/or validity, a standardized RAND/UCLA consensus process was employed for recommendation of specific rules for the scoring of sleep-associated movements.

  View details for PubMedID 17557425

• The Scoring of Movements in Sleep JOURNAL OF CLINICAL SLEEP MEDICINE Walters, A. S., Lavigne, G., Hening, W., Picchietti, D. L., Allen, R. P., Chokroverty, S., Kushida, C. A., Bliwise, D. L., Mahowald, M. W., Schenck, C. H., Ancoli-Israel, S. 2007; 3 (2): 155-?

  View details for Web of Science ID 000209776100006

• Digital Analysis and Technical Specifications JOURNAL OF CLINICAL SLEEP MEDICINE Penzel, T., Hirshkowitz, M., Harsh, J., Chervin, R. D., Butkov, N., Kryger, M., Malow, B., Vitiello, M. V., Silber, M. H., Kushida, C. A., Chesson, A. L. 2007; 3 (2): 109-?

  View details for Web of Science ID 000209776100002

• Clinical presentation, diagnosis, and quality of life issues in restless legs syndrome AMERICAN JOURNAL OF MEDICINE Kushida, C. A. 2007; 120 (1A): 4-12

  View details for DOI 10.1016/j.emjmed.2006.11.002

  View details for Web of Science ID 000243524700002

• Clinical presentation, diagnosis, and quality of life issues in restless legs syndrome AMERICAN JOURNAL OF MEDICINE Kushida, C. A. 2007; 120 (1): S4-S12

  Abstract

  Restless legs syndrome (RLS) is a generally underdiagnosed and undertreated condition. It is a common cause of sleep disturbance that can severely disrupt normal life functioning. However, because of the failure to recognize RLS as a distinct disorder, clinicians have minimized the significance of the morbidity experienced by some patients. A positive family history is present in >50% of patients with RLS. Indeed, a person with RLS is 3 to 6 times more likely to have a positive family history of RLS than is an individual who does not have the disease. The differential diagnosis of RLS includes both movement and sleep disorders. Establishing an accurate diagnosis is crucial because effective treatment is available. In 2002, RLS experts revised diagnostic criteria and established 4 essential criteria for the diagnosis. Assessing the most bothersome symptoms and quantifying the severity of RLS are important because not all patients require medical therapy. Moreover, therapy may vary according to which symptom represents the major problem.

  View details for DOI 10.1016/j.amjmed.2006.11.002

  View details for Web of Science ID 000243201800002

  View details for PubMedID 17198769

• Ropinirole for the treatment of restless legs syndrome. Neuropsychiatric disease and treatment Kushida, C. A. 2006; 2 (4): 407-419

  Abstract

  Dopaminergic agents, anticonvulsants, benzodiazepines, opiates, and iron supplementation comprise the classes of medications commonly used to treat restless legs syndrome (RLS), which is a disorder that is estimated to affect about 1 in 10 individuals worldwide and impacts an affected patient's sleep, mood, daytime function, and quality of life. RLS is characterized by an urge to move the legs that is worse at bedtime and at rest; the symptoms are temporarily relieved by leg movement. It is frequently accompanied by periodic limb movements during sleep (PLMS), which may independently disrupt sleep and may cause daytime drowsiness. Dopaminergic agents are considered to be first-line therapy in the management of RLS as well as PLMS. Ropinirole (Requip((R)), GlaxoSmithKline) is a dopamine agonist that was the first medication approved by the US Food and Drug Administration (FDA) for the treatment of moderate-to-severe primary RLS. Based on several large-scale clinical trials and open-label clinical series, this medication has been demonstrated to be effective and safe in treating the motor symptoms of RLS and improving sleep quality.

  View details for PubMedID 19412490

• Efficacy and safety of pramipexole in restless legs syndrome NEUROLOGY Winkelman, J. W., Sethi, K. D., Kushida, C. A., Becker, P. M., Koester, J., Cappola, J. J., Reess, J. 2006; 67 (6): 1034-1039

  Abstract

  To evaluate the efficacy and safety of pramipexole in patients with moderate to severe restless legs syndrome (RLS) METHODS: The authors conducted a 12-week, double-blind, randomized, placebo-controlled trial of fixed doses of pramipexole (0.25, 0.50, and 0.75 mg/day). Patients (N = 344) were up-titrated to their randomized dose over 3 weeks. The primary efficacy endpoints were patient ratings of symptom severity on the International RLS Study Group Rating Scale (IRLS) and clinician ratings of improvement on the Clinical Global Impressions-Improvement (CGI-I) scale. Secondary efficacy endpoints included visual analogue ratings of sleep and quality of life (QOL) RESULTS: By both primary measures, pramipexole was superior to placebo. For IRLS, the adjusted mean (SE) change from baseline to week 12 was -9.3 (1.0) for placebo, -12.8 (1.0) for 0.25 mg/day, -13.8 (1.0) for 0.50 mg/day, and -14.0 (1.0) for 0.75 mg/day (all p < 0.01). Similarly, pramipexole increased the percentage of patients with a CGI-I rating of "very much improved" or "much improved" at the end of the trial (51.2% for placebo and 74.7%, 67.9%, and 72.9% for pramipexole; all p < 0.05). Pramipexole significantly improved ratings of symptom severity, day and night, and also ratings of sleep satisfaction and QOL. Pramipexole was well tolerated: The most frequent adverse events with higher occurrence in the pramipexole group were nausea (19.0% vs 4.7%) and somnolence (10.1% vs 4.7%)As rated by patients and by clinicians, pramipexole was efficacious and safe in reducing the symptoms of restless legs syndrome.

  View details for Web of Science ID 000240749900022

  View details for PubMedID 16931507

• Countermeasures for sleep loss and deprivation. Current treatment options in neurology Kushida, C. A. 2006; 8 (5): 361-366

  Abstract

  Sleep deprivation is ubiquitous and carries profound consequences in terms of personal and public health and safety. There is no substitute for a good night's sleep. Sleep that is optimal in quality and quantity for individuals, factoring in their age and personal sleep requirements, will minimize sleep debt and maximize daytime performance. Therefore, setting aside an adequate amount of time for sleep should be a priority; sleep should not be sacrificed at the expense of other activities of daily living. Nevertheless, there are certain therapeutic countermeasures available for individuals who are unable to obtain adequate sleep because of medical or sleep-related conditions (eg, narcolepsy, obstructive sleep apnea) when excessive daytime sleepiness is the main feature of the condition, or residual sleepiness despite treatment for the main conditions is present. These therapeutic countermeasures may also be considered in situations in which occupational constraints (eg, rotating shift work, military duty) dictate that constant or heightened vigilance is important or critical to work performance, crucial decision making, and/or survival. Exploration of the causes of sleep loss or deprivation, whether it is voluntary, or work or family induced, and/or the effects of a medical or sleep disorder, is a necessary first step in the evaluation of a patient who has significant daytime fatigue or sleepiness. Wake-promoting substances and medications such as caffeine, modafinil, methylphenidate, and dextroamphetamine may be considered in situations in which sleep loss is unavoidable or persists despite treatment of an underlying disorder that is characterized by or associated with daytime fatigue or sleepiness.

  View details for PubMedID 16901375

• Sustained improvement in quality of life during pramipexole therapy for restless legs syndrome 18th Congress of the European-Sleep-Research-Society Winkelman, J. W., Sethi, K. D., Kushida, C. A., Becker, P. M., Koester, J., Cappola, J. J., Reess, J. WILEY-BLACKWELL. 2006: 180–181

  View details for Web of Science ID 000239966000494

• The Apnea Positive Pressure Long-term Efficacy Study (APPLES): rationale, design, methods, and procedures. Journal of clinical sleep medicine Kushida, C. A., Nichols, D. A., Quan, S. F., Goodwin, J. L., White, D. P., Gottlieb, D. J., Walsh, J. K., Schweitzer, P. K., Guilleminault, C., Simon, R. D., Leary, E. B., Hyde, P. R., Holmes, T. H., Bloch, D. A., Green, S., McEvoy, L. K., Gevins, A., Dement, W. C. 2006; 2 (3): 288-300

  Abstract

  To assess the size, time course, and durability of the effects of long-term continuous positive airway pressure (CPAP) therapy on neurocognitive function, mood, sleepiness, and quality of life in patients with obstructive sleep apnea.Randomized, double-blinded, 2-arm, sham-controlled, multicenter, long-term, intention-to-treat trial of CPAP therapy.Sleep clinics and laboratories at 5 university medical centers and community-based hospitals. Patients or Participants: Target enrollment is 1100 randomly assigned subjects across 5 clinical centers.Active versus sham (subtherapeutic) CPAP. Measurements and Results: A battery of conventional and novel tests designed to evaluate neurocognitive function, mood, sleepiness, and quality of life.The Apnea Positive Pressure Long-term Efficacy Study (APPLES) is designed to study obstructive sleep apnea and test the effects of CPAP through a comprehensive, controlled, and long-term trial in a large sample of subjects with obstructive sleep apnea.

  View details for PubMedID 17561541

• Botulinum toxin A: new hope for RLS? Journal of clinical sleep medicine Kushida, C. A. 2006; 2 (3): 279-280

  View details for PubMedID 17561539

• Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders SLEEP Kushida, C. A., Littner, M. R., Hirshkowitz, M., Morgenthaler, T. I., Alessi, C. A., Bailey, D., Boehlecke, B., Brown, T. M., Coleman, J., Friedman, L., Kapen, S., Kapur, V. K., Kramer, M., Lee-Chiong, T., Owens, J., Pancer, J. P., Swick, T. J., Wise, M. S. 2006; 29 (3): 375-380

  Abstract

  Positive airway pressure (PAP) devices are used to treat patients with sleep related breathing disorders (SRBD) including obstructive sleep apnea (OSA). Currently, PAP devices come in three forms: (1) continuous positive airway pressure (CPAP), (2) bilevel positive airway pressure (BPAP), and (3) automatic self-adjusting positive airway pressure (APAP). After a patient is diagnosed with OSA, the current standard of practice involves performing full, attended polysomnography during which positive pressure is adjusted to determine optimal pressure for maintaining airway patency. This titration is used to find a fixed single pressure for subsequent nightly usage. A task force of the Standards of Practice Committee of the American Academy of Sleep Medicine reviewed the available literature. Based on this review, the Standards of Practice Committee developed these practice parameters as a guideline for using CPAP and BPAP appropriately (an earlier review and practice parameters for APAP was published in 2002). Major conclusions and current recommendations are as follows: 1) A diagnosis of OSA must be established by an acceptable method. 2) CPAP is effective for treating OSA. 3) Full-night, attended studies performed in the laboratory are the preferred approach for titration to determine optimal pressure; however, split-night, diagnostic-titration studies are usually adequate. 4) CPAP usage should be monitored objectively to help assure utilization. 5) Initial CPAP follow-up is recommended during the first few weeks to establish utilization pattern and provide remediation if needed. 6) Longer-term follow-up is recommended yearly or as needed to address mask, machine, or usage problems. 7) Heated humidification and a systematic educational program are recommended to improve CPAP utilization. 8) Some functional outcomes such as subjective sleepiness improve with positive pressure treatment in patients with OSA. 9) CPAP and BPAP therapy are safe; side effects and adverse events are mainly minor and reversible. 10) BPAP may be useful in treating some forms of restrictive lung disease or hypoventilation syndromes associated with hypercapnia.

  View details for Web of Science ID 000240123600014

  View details for PubMedID 16553024

• Pramipexole for the treatment of restless legs syndrome EXPERT OPINION ON PHARMACOTHERAPY Kushida, C. A. 2006; 7 (4): 441-451

  Abstract

  Restless legs syndrome (RLS) is a common disorder that is estimated to affect 10% of Americans. However, it remains largely undiagnosed and untreated by clinicians. The primary symptoms of this condition are leg discomfort or an urge to move that is temporarily relieved by movement and is worse at rest and at bedtime. RLS impacts the quality of life of the sufferer by disrupting sleep and disturbing or curtailing work and social activities. Approximately 80% of RLS sufferers also have periodic limb movements during sleep, in which repetitive leg movements fragment sleep and may result in daytime drowsiness. RLS may be treated by dopaminergic agents, benzodiazepines, anticonvulsants and opiates; dopamine agonists are currently considered first-line therapy for this condition. Pramipexole has been studied in the treatment of RLS since 1998. This article reviews the role of this medication in the management of this serious neurological disorder.

  View details for DOI 10.1517/14656566.7.4.441

  View details for Web of Science ID 000235822800008

  View details for PubMedID 16503816

• Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: An update for 2005 SLEEP Kushida, C. A., Morgenthaler, T. I., Littner, M. R., Alessi, C. A., Bailey, D., Coleman, J., Friedman, L., Hirshkowitz, M., Kapen, S., Kramer, M., Lee-Chiong, T., Owens, J., Pancer, J. P. 2006; 29 (2): 240-243

  Abstract

  These practice parameters are an update of the previously published recommendations regarding use of oral appliances in the treatment of snoring and Obstructive Sleep Apnea (OSA). Oral appliances (OAs) are indicated for use in patients with mild to moderate OSA who prefer them to continuous positive airway pressure (CPAP) therapy, or who do not respond to, are not appropriate candidates for, or who fail treatment attempts with CPAP. Until there is higher quality evidence to suggest efficacy, CPAP is indicated whenever possible for patients with severe OSA before considering OAs. Oral appliances should be fitted by qualified dental personnel who are trained and experienced in the overall care of oral health, the temporomandibular joint, dental occlusion and associated oral structures. Follow-up polysomnography or an attended cardiorespiratory (Type 3) sleep study is needed to verify efficacy, and may be needed when symptoms of OSA worsen or recur. Patients with OSA who are treated with oral appliances should return for follow-up office visits with the dental specialist at regular intervals to monitor patient adherence, evaluate device deterioration or maladjustment, and to evaluate the health of the oral structures and integrity of the occlusion. Regular follow up is also needed to assess the patient for signs and symptoms of worsening OSA. Research to define patient characteristics more clearly for OA acceptance, success, and adherence is needed.

  View details for Web of Science ID 000240123500016

  View details for PubMedID 16494092

• Pramipexole treatment rapidly improves patient ratings of restless legs syndrome symptoms 20th Annual Meeting of the Associated-Professional-Sleep-Societies Corbin, A. E., Sethi, K. D., Kushida, C. A., Becker, P. M., Koester, J., Cappola, J. J., Reess, J., Winkelman, J. W. AMER ACAD SLEEP MEDICINE. 2006: A283–A283

  View details for Web of Science ID 000237916701208

• Effects of pramipexole on subjective measures of sleep quality and symptom severity in patients with restless legs syndrome 20th Annual Meeting of the Associated-Professional-Sleep-Societies Winkelman, J. W., Sethi, K. D., Kushida, C. A., Becker, P. M., Koester, J., Cappola, J. J., Reess, J. AMER ACAD SLEEP MEDICINE. 2006: A281–A281

  View details for Web of Science ID 000237916701202

• XP13512 improves symptoms and sleep disturbance in RLS patients: Results of a 2-week, randomized, double-blind, placebo-controlled cross-over polysomnography trial 20th Annual Meeting of the Associated-Professional-Sleep-Societies Kushida, C., BECKER, P., Perkins, T., Thein, S., Walters, A. S., Canafax, D. AMER ACAD SLEEP MEDICINE. 2006: A278–A279

  View details for Web of Science ID 000237916701195

• The Apnea Positive Pressure Long-term Efficacy Study (APPLES): Rationale, Design, Methods, and Procedures JOURNAL OF CLINICAL SLEEP MEDICINE Kushida, C. A., Nichols, D. A., Quan, S. F., Goodwin, J. L., White, D. P., Gottlieb, D. J., Walsh, J. K., Schweitzer, P. K., Guilleminault, C., Simon, R. D., Leary, E. B., Hyde, P. R., Holmes, T. H., Bloch, D. A., Green, S., McEvoy, L. K., Gevins, A., Dement, W. C. 2006; 2 (3): 288-300

  View details for Web of Science ID 000209775800006

• Practice parameters for the indications for polysomnography and related procedures: An update for 2005 SLEEP Kushida, C. A., Littner, M. R., Morgenthaler, T., Alessi, C. A., Bailey, D., Coleman, J., Friedman, L., Hirshkowitz, M., Kapen, S., Kramer, M., Lee-Chiong, T., Loube, D. L., Owens, J., Pancer, J. P., Wise, M. 2005; 28 (4): 499-521

  Abstract

  These practice parameters are an update of the previously-published recommendations regarding the indications for polysomnography and related procedures in the diagnosis of sleep disorders. Diagnostic categories include the following: sleep related breathing disorders, other respiratory disorders, narcolepsy, parasomnias, sleep related seizure disorders, restless legs syndrome, periodic limb movement sleep disorder, depression with insomnia, and circadian rhythm sleep disorders. Polysomnography is routinely indicated for the diagnosis of sleep related breathing disorders; for continuous positive airway pressure (CPAP) titration in patients with sleep related breathing disorders; for the assessment of treatment results in some cases; with a multiple sleep latency test in the evaluation of suspected narcolepsy; in evaluating sleep related behaviors that are violent or otherwise potentially injurious to the patient or others; and in certain atypical or unusual parasomnias. Polysomnography may be indicated in patients with neuromuscular disorders and sleep related symptoms; to assist in the diagnosis of paroxysmal arousals or other sleep disruptions thought to be seizure related; in a presumed parasomnia or sleep related seizure disorder that does not respond to conventional therapy; or when there is a strong clinical suspicion of periodic limb movement sleep disorder. Polysomnography is not routinely indicated to diagnose chronic lung disease; in cases of typical, uncomplicated, and noninjurious parasomnias when the diagnosis is clearly delineated; for patients with seizures who have no specific complaints consistent with a sleep disorder; to diagnose or treat restless legs syndrome; for the diagnosis of circadian rhythm sleep disorders; or to establish a diagnosis of depression.

  View details for Web of Science ID 000228134900015

  View details for PubMedID 16171294

• Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep Littner, M. R., Kushida, C., Wise, M., Davila, D. G., Morgenthaler, T., Lee-Chiong, T., Hirshkowitz, M., Daniel, L. L., Bailey, D., Berry, R. B., Kapen, S., Kramer, M. 2005; 28 (1): 113-121

  Abstract

  Characterization of excessive sleepiness is an important task for the sleep clinician, and assessment requires a thorough history and in many cases, objective assessment in the sleep laboratory. These practice parameters were developed to guide the sleep clinician on appropriate clinical use of the Multiple Sleep Latency Test (MSLT), and the Maintenance of Wakefulness Test (MWT). These recommendations replace those published in 1992 in a position paper produced by the American Sleep Disorders Association. A Task Force of content experts was appointed by the American Academy of Sleep Medicine to perform a comprehensive review of the scientific literature and grade the evidence regarding the clinical use of the MSLT and the MWT. Practice parameters were developed based on this review and in most cases evidence based methods were used to support recommendations. When data were insufficient or inconclusive, the collective opinion of experts was used to support recommendations. These recommendations were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. The MSLT is indicated as part of the evaluation of patients with suspected narcolepsy and may be useful in the evaluation of patients with suspected idiopathic hypersomnia. The MSLT is not routinely indicated in the initial evaluation and diagnosis of obstructive sleep apnea syndrome, or in assessment of change following treatment with nasal continuous positive airway pressure (CPAP). The MSLT is not routinely indicated for evaluation of sleepiness in medical and neurological disorders (other than narcolepsy), insomnia, or circadian rhythm disorders. The MWT may be indicated in assessment of individuals in whom the inability to remain awake constitutes a safety issue, or in patients with narcolepsy or idiopathic hypersomnia to assess response to treatment with medications. There is little evidence linking mean sleep latency on the MWT with risk of accidents in real world circumstances. For this reason, the sleep clinician should not rely solely on mean sleep latency as a single indicator of impairment or risk for accidents, but should also rely on clinical judgment. Assessment should involve integration of findings from the clinical history, compliance with treatment, and, in some cases, objective testing using the MWT. These practice parameters also include recommendations for the MSLT and MWT protocols, a discussion of the normative data available for both tests, and a description of issues that need further study.

  View details for PubMedID 15700727

• Ropinirole in the treatment of restless legs syndrome. Expert review of neurotherapeutics Kakar, R. S., Kushida, C. A. 2005; 5 (1): 35-42

  Abstract

  Ropinirole is an original nonergoline dopamine agonist indicated for the treatment of Parkinson's disease. However, recent developments in the study of restless legs syndrome have demonstrated another role for this drug. The symptoms of restless legs syndrome are responsive to dopaminergic agents such as ropinirole. The dosage of ropinirole needed to treat the symptoms of restless legs syndrome appears to be much smaller than what is necessary for Parkinson's disease therapy. The liver is primarily responsible for the metabolism of ropinirole, which has an elimination half-life of approximately 6 h. Ropinirole is generally well tolerated, with no serious adverse effects. Clinical studies have indicated that ropinirole can effectively reduce the motor symptoms of restless legs syndrome and improve overall sleep quality.

  View details for PubMedID 15853472

• Practice Parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test - An American Academy of Sleep Medicine Report - Standards of practice committee of the American Academy of Sleep Medicine SLEEP Littner, M. R., Kushida, C., Wise, M., Davila, D. G., Morgenthaler, T., Lee-Chiong, T., Hirshkowitz, M., Loube, D. L., Bailey, D., Berry, R. B., Kapen, S., Kramer, M. 2005; 28 (1): 113-121

  View details for Web of Science ID 000228028000016

• Modeling the causal relationships between symptoms associated with restless legs syndrome and the patient-reported impact of RLS SLEEP MEDICINE Kushida, C. A., Allen, R. P., Atkinson, M. J. 2004; 5 (5): 485-488

  Abstract

  The objective of this study is to examine the causal relationships between the symptoms of restless legs syndrome (RLS) and specific clinical and subjective health-related, quality of life consequences. Structural equation modeling was applied to data from a questionnaire-based observational study. The RLS morbidities of decreased functional alertness and emotional distress in our sample of patients appear to be mostly secondary to the sleep disturbance associated with RLS. There was no clear indication of any other feature of RLS affecting these two aspects of RLS morbidity. A primary treatment goal should be the reduction of the sleep disturbance of RLS, both to decrease the RLS-related nocturnal distress and to improve daytime functioning.

  View details for DOI 10.1016/j.sleep.2004.04.004

  View details for Web of Science ID 000224018100010

  View details for PubMedID 15341894

• Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome SLEEP Allen, R., Becker, P. M., Bogan, R., Schmidt, M., Kushida, C. A., Fry, J. M., Poceta, J. S., Winslow, D. 2004; 27 (5): 907-914

  Abstract

  Polysomnographic study evaluating the efficacy of ropinirole for the treatment of patients with restless legs syndrome (RLS) suffering from periodic leg movements in sleep (PLMS).Double-blinded, placebo-controlled, parallel-group study.15 tertiary referral centers in the USA. Participants: 65 patients with RLS and PLMS.Ropinirole (0.25-4.0 mg per day) or placebo for 12 weeks.Data from 59 patients were included in the primary endpoint analysis. PLMS per hour decreased more with ropinirole (48.5 to 11.8), compared with placebo (35.7 to 34.2; adjusted treatment difference: -27.2; 95% confidence interval [CI]: -39.1, -15.4; P < .0001). Periodic limb movements with arousal per hour decreased from 7.0 to 2.5 with ropinirole but increased from 4.2 to 6.0 with placebo (adjusted treatment difference: -4.3, 95% CI: -7.6, -1.1; P = .0096). Periodic limb movements while awake per hour decreased from 56.5 to 23.6 with ropinirole but increased from 46.6 to 56.1 with placebo (adjusted treatment difference: -39.5; 95% CI: -56.9, -22.1; P < .0001). Ropinirole treatment significantly improved patients' ability to initiate sleep (P < .05) and the amount of Stage 2 sleep compared with placebo (P < .001). There were also non-significant trends toward increases in total sleep time and sleep efficiency. Sleep adequacy (measured on the subjective Medical Outcomes Study sleep scale) was significantly improved with ropinirole treatment (adjusted treatment difference: 12.1; 95% CI: 1.1, 23.1; P = .0316). In contrast, the placebo group showed a greater increase in Stage 3/4 sleep (P < .01). No serious adverse events occurred in either group.Ropinirole is effective in the treatment of both the sleep and waking symptoms of RLS.

  View details for Web of Science ID 000223451400013

  View details for PubMedID 15453549

• Restless legs syndrome and periodic limb movement disorder MEDICAL CLINICS OF NORTH AMERICA Rama, A. N., Kushida, C. A. 2004; 88 (3): 653-?

  View details for DOI 10.1016/j.mcna.2004.01.004

  View details for Web of Science ID 000221049600007

  View details for PubMedID 15087209

• Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder SLEEP Littner, M. R., Kushida, C., Anderson, W. M., Bailey, D., Berry, R. B., Hirshkowitz, M., Kapen, S., Kramer, M., Lee-Chiong, T., Li, K. K., Loube, D. L., Morgenthaler, T., Wise, M. 2004; 27 (3): 557-559

  Abstract

  Dopaminergic agents, particularly dopamine agonists, have been used with increasing frequency in the treatment of restless legs syndrome and periodic limb movement disorder. These evidence-based practice parameters are complementary to the Practice Parameters for the Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder, published in 1999. These practice parameters were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. Recommendations are based on the accompanying comprehensive review of the medical literature regarding the dopaminergic treatment of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD), which was developed by a task force commissioned by the American Academy of Sleep Medicine. The following recommendations serve as a guide to the appropriate use of dopaminergic agents in the treatment of RLS and PLMD. Levodopa with decarboxylase inhibitor, and the dopaminergic agonists pergolide, pramipexole, and ropinirole are effective in the treatment of RLS and PLMD. Other dopamine agonists (talipexole, cabergoline, piribidel, and alpha-dihydroergocryptine) and the dopaminergic agents amantadine and selegiline may be effective in the treatment of RLS and PLMD, but the level of effectiveness of these medications is not currently established. Lastly, no specific recommendations can be made regarding dopaminergic treatment of children or pregnant women with RLS or PLMD.

  View details for Web of Science ID 000223169000031

  View details for PubMedID 15164914

• Validation of the Restless Legs Syndrome quality of life instrument (RLS-QLI): Findings of a consortium of national experts and the RLS Foundation QUALITY OF LIFE RESEARCH Atkinson, M. J., Allen, R. P., DuChane, J., Murray, C., Kushida, C., Roth, T. 2004; 13 (3): 679-693

  Abstract

  This study was designed to assess the initial psychometric properties of a new disease-specific health-related quality of life (HRQL) measure, the Restless Legs Syndrome (RLS) Quality of Life Instrument (RLS-QLI).Draft items were generated from a literature review, consultation with MD and PhD specialists in the fields of neurology and sleep medicine, and input from two patient focus groups. The initial item reduction was accomplished using a survey of 392 persons with self-reported RLS symptoms from the membership of the RLS Foundation. The final (independent) validation sample consisted of 574 of persons on the RLS Foundation's Interest Group List Serve who also reported having RLS. The mean age of participants was 54.5 (SD 12.3), with a sex ratio of 1M:2F, and the majority was on some form of medication for RLS (66%).Four factors were identified (Daily Function, Social Function, Sleep Quality, and Emotional Well-Being) consisting of 17 items that explained 73.3% of the total variance. Each scale had good internal consistency (Cronbach's alpha's between 0.85 and 0.91) and 2-week test retest stability (Pearson Correlations between 0.81 and 0.93). Convergent validity was demonstrated using related scales on the SF-36 (r = 0.47-0.60) and criterion-related validity was shown using the clinical IRLS Scale of Symptom Severity (r = -0.45 to -0.77).The RLS-QLI is a valid disease-specific HRQL instrument that will contribute to our understanding of how RLS impacts the lives of those affected with this CNS disorder.

  View details for Web of Science ID 000220414900009

  View details for PubMedID 15130030

• Abnormal blood pressure in prepubertal children with sleep-disordered breathing PEDIATRIC RESEARCH Guilleminault, C., Khramsov, A., Stoohs, R. A., Kushida, C., Pelayo, R., Kreutzer, M. L., Chowdhuri, S. 2004; 55 (1): 76-84

  Abstract

  The purpose of this study was to investigate the association between low blood pressure (BP) with mild symptoms of orthostatism, sleep-disordered breathing (SDB) and tilt test results in 7- to 12-y-old children. A retrospective chart review of 301 children, ages 7 to 12 y, was initially performed to evaluate the frequency of abnormal BP measurements. Then a prospective study was performed on 7- to 12-y-old prepubertal children with SDB, looking for both abnormal BP and mild orthostatism. All children had polysomnography. Those identified with abnormal (high or low) BP measurements (called "BP outliers") were studied with a new polysomnogram followed by a head-up tilt test as an indicator of autonomic activity. Four of the children with low BP were treated with nasal continuous positive airway pressure and received a second head-up tilt test 3.5 to 7 mo after starting treatment. The prospective study included 78 children, eight of whom were BP outliers. Seven of these outliers had low BP. Compared with all of the SDB subjects, SDB subjects with low BP and indicators of mild orthostatic hypotension had a significantly higher incidence of craniofacial dysmorphism, symptoms of SDB early in life, chronically cold extremities, and dizziness on standing up (chi2, p = 0.01 to 0.0001). They had a significantly greater drop in BP without evidence of autonomic neuropathy than all other children on head-up tilt testing (Kruskal-Wallis ANOVA with Bonferroni adjustment, p = 0.001 to 0.0001). However, the normotensive SDB controls also had significantly different BP drops than the normal controls (p = 0.0001). The four children placed on nasal continuous positive airway pressure had a nonsignificant trend toward normalization of tilt test response. SDB in prepubertal children can lead to different abnormal stimulation of the autonomic nervous system, with different impacts on BP. The severity and frequency of oxygen saturation drops during sleep, nonhypoxic increases in respiratory effort, and the duration of abnormal breathing are suspected of playing a role in the difference in autonomic nervous system stimulation.

  View details for DOI 10.1203/01.PDR.0000099791.29621.62

  View details for Web of Science ID 000187502400011

  View details for PubMedID 14605262

• Non-Rapid Eye Movement Parasomnias. Current treatment options in neurology Farid, M., Kushida, C. A. 2004; 6 (4): 331–37

  Abstract

  Non-rapid eye movement parasomnias are unique physical or experiential phenomena that disrupt sleep. Non-rapid eye movement parasomnias are common in children, but they typically outgrow them. Sleep-stage shifts caused by sleep-disordered breathing and associated arousals may be precipitating events for episodes of parasomnia. Seizure disorders should always be considered in the differential diagnosis for the evaluation of parasomnias. Violent or injurious sleepwalking should be rapidly evaluated and treated.

  View details for PubMedID 15157410

• The use of esophageal manometry in the diagnosis of sleep-related breathing disorders. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference Kushida, C. A. 2004; 5: 3860-3863

  Abstract

  Esophageal manometry is a technique used to detect abnormal sleep-related respiratory events. One method used to measure and score esophageal pressure during sleep is described. The contraindications for esophageal manometry, the methods for scoring esophageal pressure, the use of esophageal manometry as the "gold standard", and directions for future research are discussed.

  View details for PubMedID 17271138

• Exploring ferritin levels from an age- and gender-matched primary care population of patients with and without symptoms of RLS 18th Annual Meeting of the Associated-Professional-Sleep-Societies Nichols, D. A., Kushida, C. A., Allen, R. P., Grauke, J. H., Brown, J. B., Rice, M. L., Hyde, P. R., Dement, W. C. AMER ACAD SLEEP MEDICINE. 2004: 299–299

  View details for Web of Science ID 000223169400671

• Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy SLEEP Hecht, M., Lin, L., Kushida, C. A., Umetsu, D. T., Taheri, S., Einen, M., Mignot, E. 2003; 26 (7): 809-810

  Abstract

  To explore whether acute destruction of hypocretin cells in a patient with narcolepsy could be detected and if the course of the disease could be reversed or altered by the use of prednisone for immunosuppression.Case report.A sleep-clinic population in a tertiary-care hospital.An 8-year-old boy with a very acute recent (< 2 month) onset of sleepiness.Sleep studies; fluid-attenuated inversion recovery and gadolinium magnetic resonance imaging studies with a focus on the hypothalamus; examinations of cerebrospinal fluid for cytology, protein, and hypocretin-1 levels; and HLA typing were performed.A 3-week regimen of 1 mg x kg(-1) x day(-1) of prednisone was administered in an attempt to modify the course of the disease.Sleep evaluations were consistent with a diagnosis of narcolepsy. Hypocretin-1 was absent in the cerebrospinal fluid, and HLA-DQB1*0602 was present. All other results were within normal limits, and prednisone did not have any noticeable effects. Clinical manifestation of narcolepsy might occur when the hypocretin cell damage is too advanced to be reversible.

  View details for Web of Science ID 000186745800007

  View details for PubMedID 14655912

• Restless legs syndrome symptoms in primary care - A prevalence study ARCHIVES OF INTERNAL MEDICINE Nichols, D. A., Allen, R. P., Grauke, J. H., Brown, J. B., Rice, M. L., Hyde, P. R., Dement, W. C., Kushida, C. A. 2003; 163 (19): 2323-2329

  Abstract

  There are relatively few studies on the prevalence of restless legs syndrome (RLS) in the general population, even fewer that used diagnostic questions covering all 4 essential diagnostic criteria defining the RLS symptom complex, and none that have reported on the 2 RLS phenotypes for patients seen by family physicians.To determine the prevalence of the symptom complex, diagnostic for RLS in a primary care patient population, a prospective population-based single-center study was performed. Every adult patient presenting for care in a small rural primary care practice with mostly white patients was surveyed for a 1-year period using a validated RLS diagnostic questionnaire.A total of 2099 patients completed the questionnaire. Analysis revealed that 24.0% of these patients were positive for all 4 of the essential symptoms used to make the diagnosis of RLS and 15.3% reported these symptoms at least weekly. In addition, the RLS symptom complex was reported significantly more often by women than men and, as a whole, patients reporting the RLS symptoms were significantly older than patients without symptoms. The prevalence of symptoms increased with age until about 60 years and then showed a steady decrease thereafter. Further, early-onset RLS was significantly more common in women than men.A high prevalence of RLS symptoms was observed in this primary care population. This finding supports the need for heightened awareness in both the medical community and general population regarding this disorder, which can often be effectively treated within the primary care practice.

  View details for Web of Science ID 000186207400009

  View details for PubMedID 14581252

• Practice parameters for using polysomnography to evaluate insomnia: An update SLEEP Littner, M., Hirshkowitz, M., Kramer, M., Kapen, S., Anderson, W. M., Bailey, D., Berry, R. B., Davila, D., JOHNSON, S., Kushida, C., Loube, D. I., Wise, M., Woodson, T. 2003; 26 (6): 754-760

  Abstract

  Insomnia is a common and clinically important problem. It may arise directly from a sleep-wake regulatory dysfunction and/or indirectly result from comorbid psychiatric, behavioral, medical, or neurological conditions. As an important public-health problem, insomnia requires accurate diagnosis and effective treatment. Insomnia is primarily diagnosed clinically with a detailed medical, psychiatric, and sleep history. Polysomnography is indicated when a sleep-related breathing disorder or periodic limb movement disorder is suspected, initial diagnosis is uncertain, treatment fails, or precipitous arousals occur with violent or injurious behavior. However, polysomnography is not indicated for the routine evaluation of transient insomnia, chronic insomnia, or insomnia associated with psychiatric disorders.

  View details for Web of Science ID 000185472200020

  View details for PubMedID 14572131

• Anterior cervical spine fusion and sleep disordered breathing NEUROLOGY Guilleminault, C., Li, K. K., Philip, P., Kushida, C. A. 2003; 61 (1): 97-99

  Abstract

  The authors reviewed 12 patients who developed obstructive sleep apnea (OSA) syndrome in association with anterior cervical spine fusion. Four subsequent patients were studied prospectively before C2 to C4 anterior fusion and documented to have OSA by questionnaire, visual analogue scales, polysomnography, and multiple sleep latency tests. The authors found that placement of the anterior cervical plates reduced the size of the upper airway. Symptoms and objective findings were controlled with nasal continuous positive airway pressure.

  View details for Web of Science ID 000183978800020

  View details for PubMedID 12847164

• Nasal obstruction in sleep-disordered breathing OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA Chen, W., Kushida, C. A. 2003; 36 (3): 437-?

  Abstract

  It has been 30 years since Cottle suggested that "sleeping patterns are in great measure dependent on good nasal function" [1]. During this time, we have identified the OSAHS and related forms of sleep-disordered breathing such as UARS, and better appreciate the clinical sequelae of recurrent arousals and sleep fragmentation. Yet the exact role that obstructed nasal breathing plays in the pathogenesis of such sleep disorders remains presumptive, and robust clinical studies to corroborate this theory remain elusive; however, patients who may benefit most from correction of nasal obstruction as a sole intervention may be those with the mildest forms of sleep-disordered breathing without other significant predisposing anatomic abnormalities. Clearly, more stringently controlled studies [17,105] are needed, particularly in these types of patients. Until such time, it is reasonable to address issues of nasal obstruction as an adjunct to surgical and nonsurgical treatment in all patients who are diagnosed with a sleep-related breathing disorder.

  View details for DOI 10.1016/S0030-6665(02)00175-5

  View details for Web of Science ID 000183412600004

  View details for PubMedID 12956093

• RLS symptoms in primary care: A one year follow-up study 17th Annual Meeting of the Associated-Professional-Sleep-Societies Nichols, D. A., Kushida, C. A., Allen, R. P., Grauke, J. H., Brown, J. B., Rice, M. L., Hyde, P. R., Dement, W. C. AMER ACAD SLEEP MEDICINE. 2003: A328–A328

  View details for Web of Science ID 000182841100825

• Validation of RLS diagnostic questions in a primary care practice 17th Annual Meeting of the Associated-Professional-Sleep-Societies Nichols, D. A., Kushida, C. A., Allen, R. P., Grauke, J. H., Brown, J. B., Rice, M. L., Hyde, P. R., Dement, W. C. AMER ACAD SLEEP MEDICINE. 2003: A346–A346

  View details for Web of Science ID 000182841100872

• Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: an update for 2002. Sleep Littner, M., Kushida, C. A., Anderson, W. M., Bailey, D., Berry, R. B., Davila, D. G., Hirshkowitz, M., Kapen, S., Kramer, M., Loube, D., Wise, M., Johnson, S. F. 2003; 26 (3): 337-341

  Abstract

  Actigraphy is a method used to study sleep-wake patterns and circadian rhythms by assessing movement, most commonly of the wrist. These evidence-based practice parameters are an update to the Practice Parameters for the Use of Actigraphy in the Clinical Assessment of Sleep Disorders, published in 1995. These practice parameters were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. Recommendations are based on the accompanying comprehensive review of the medical literature regarding the role of actigraphy, which was developed by a task force commissioned by the American Academy of Sleep Medicine. The following recommendations serve as a guide to the appropriate use of actigraphy. Actigraphy is reliable and valid for detecting sleep in normal, healthy populations, but less reliable for detecting disturbed sleep. Although actigraphy is not indicated for the routine diagnosis, assessment, or management of any of the sleep disorders, it may serve as a useful adjunct to routine clinical evaluation of insomnia, circadian-rhythm disorders, and excessive sleepiness, and may be helpful in the assessment of specific aspects of some disorders, such as insomnia and restless legs syndrome/periodic limb movement disorder. The assessment of daytime sleepiness, the demonstration of multiday human-rest activity patterns, and the estimation of sleep-wake patterns are potential uses of actigraphy in clinical situations where other techniques cannot provide similar information (e.g., psychiatric ward patients). Superiority of actigraphy placement on different parts of the body is not currently established. Actigraphy may be useful in characterizing and monitoring circadian rhythm patterns or disturbances in certain special populations (e.g., children, demented individuals), and appears useful as an outcome measure in certain applications and populations. Although actigraphy may be a useful adjunct to portable sleep apnea testing, the use of actigraphy alone in the detection of sleep apnea is not currently established. Specific technical recommendations are discussed, such as using concomitant completion of a sleep log for artifact rejection and timing of lights out and on; conducting actigraphy studies for a minimum of three consecutive 24-hour periods; requiring raw data inspection; permitting some preprocessing of movement counts; stating that epoch lengths up to 1 minute are usually sufficient, except for circadian rhythm assessment; requiring interpretation to be performed manually by visual inspection; and allowing automatic scoring in addition to manual scoring methods.

  View details for PubMedID 12749556

• Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: An update for 2002 - An American academy of sleep medicine report SLEEP Littner, M., Kushida, C. A., Anderson, M., Bailey, D., Berry, R. B., Davila, D. G., Hirshkowitz, M., Kapen, S., Kramer, M., Loube, D., Wise, M., Johnson, S. F. 2003; 26 (3): 337-341

  View details for Web of Science ID 000182439100019

• Preliminary observations on the effects of sleep time in a sleep restriction paradigm SLEEP MEDICINE Guilleminault, C., Powell, N. B., Martinez, S., Kushida, C., Raffray, T., Palombini, L., Philip, P. 2003; 4 (3): 177-184

  Abstract

  To evaluate of the effect of 7 days of sleep restriction--with sleep placed at the beginning of night or early morning hours - on sleep variables, maintenance of wakefulness test, and serum leptin.After screening young adults with questionnaires and actigraphy for 1 week, eight young adult males were recruited to participate in a sleep restriction study. The subjects were studied for baseline data for 2.5 days, with 8.5 h per night in bed, and then over 7 days of sleep restriction to 4 h per night with a 22:30 h bedtime for half the group and a 02:15 h bedtime for the other half. At the end of study, after one night of ad libitum sleep, subjects again had 2 days of 8.5 h in bed. Wakefulness was continuously verified and tests, including Maintenance of Wakefulness (MWT), were performed during the scheduled wake time. Blood was drawn six times throughout the 24 h of the 7th day of sleep restriction and after 2 days of the post-restriction schedule.There was individual variability in response to sleep restriction, but independent of group distribution, MWT was significantly affected by sleep restriction, with the early morning sleep group having less decrease in MWT score. Sleep efficiency was also better in this group, which also had shorter sleep latency. Independent of group distribution there was a greater increase in the percentage of slow wave sleep than rapid eye movement sleep, despite a clear internal variability and variability between subjects. Peak serum leptin was significantly decreased with 7 days of sleep restriction for all subjects.Sleep restriction to 4 h affected all subjects, but there were individual and group differences in MWT and sleep data. In this group of young adult males (mean age 19 years), there was a better overall adaptation to the early morning sleep, perhaps related to the general tendency in most adolescents to present some phase-delay during late teen-aged years.

  View details for DOI 10.1016/S1389-9457(03)00061-3

  View details for Web of Science ID 000188839200004

  View details for PubMedID 14592319

• Factor analysis of the International Restless Legs Syndrome Study Group's scale for restless legs severity SLEEP MEDICINE Allen, R. P., Kushida, C. A., Atkinson, M. J. 2003; 4 (2): 133-135

  Abstract

  The International Restless Legs Syndrome Study Group has developed and validated a ten-item scale for assessing the severity of the restless legs syndrome. This International Restless Legs Severity Scale (IRLS) is reported to have a high degree of internal consistency and it has generally been used as a single scale. This study uses a factor analytic approach to evaluate the IRLS for possibly useful subscales.A large convenience sample (n=516) of self-identified restless leg syndrome patients completed the IRLS over the Internet. Data were analyzed using principal component analyses.Two primary factors were identified, one with six items related to symptom severity and a second with three items related to impact of the symptoms on life. These accounted for 41.8 and 22.5% of the variance, respectively.The IRLS can be evaluated using separate subscale scores: one for symptoms and the other symptom impact. The relative merits of these subscale scores versus the score for the entire test need to be evaluated in different situations in further studies, in especially the ones involving assessing responsiveness to treatment effects.

  View details for DOI 10.1016/S1389-9457(02)00193-4

  View details for Web of Science ID 000188839100006

  View details for PubMedID 14592343

• Behavioral parasomnias. Current psychiatry reports Brooks, S., Kushida, C. A. 2002; 4 (5): 363-368

  Abstract

  Sleep is not a static state. During the sleep period, physiologic changes occur throughout the body and brain. This complex, dynamic process can, at times, result in episodes of unusual or undesirable behaviors. These phenomena are called parasomnias. The accurate diagnosis of this group of treatable disorders is important, because they can have a negative impact on sleep, health, and social function. In addition, some of the parasomnias may provide clues to the presence of other underlying pathologic conditions. The parasomnias may be categorized in more than one way, but any attempt to classify such a diverse collection of entities is likely to be somewhat arbitrary. This article discusses the parasomnias according to the classification of the International Classification of Sleep Disorders, with emphasis on those characterized by observable behavior. As the understanding of these disorders (and sleep, in general) continues to deepen, new entities and schemes of classification may emerge.

  View details for PubMedID 12230965

• Sites of obstruction in obstructive sleep apnea CHEST Rama, A. N., Tekwani, S. H., Kushida, C. A. 2002; 122 (4): 1139-1147

  Abstract

  The aim of this article was to identify the most common sites of obstruction in patients with obstructive sleep apnea (OSA) by a systematic review of published studies.The review was conducted by a MEDLINE search of the English literature published during the years 1980 to 2002. The inclusion criteria were experiments involving five or more adult subjects, total rather than partial obstruction or narrowing of the upper airway, and techniques that were performed on the subjects while they were asleep.Although there was considerable variability in the techniques and the results, the most common site of obstruction detected by these studies was at the level of the oropharynx, with extension to the laryngopharynx commonly observed.

  View details for Web of Science ID 000178685200010

  View details for PubMedID 12377834

• Restless legs syndrome in primary care: A validation study Mahapatra, D., Nichols, D. A., Kushida, C. A., SCHILLINGER, E., LeBaron, S., Allen, R. P., Liu, C., Tekwani, S., Hyde, P. R., Dement, W. C. AMER ACAD SLEEP MEDICINE. 2002: A491–A492

  View details for Web of Science ID 000174927200700

• Treatment of RLS in primary care: Questionnaire-based measures Nichols, D. A., Kushida, C. A., Allen, R. P., Grauke, J. H., Brown, J. B., Rice, M. L., Hyde, P. R., Dement, W. C. AMER ACAD SLEEP MEDICINE. 2002: A492–A493

  View details for Web of Science ID 000174927200701

• Practice parameters for the use of auto-titrating continuous positive airway pressure devices for titrating pressures and treating adult patients with obstructive sleep apnea syndrome. An American Academy of Sleep Medicine report. Sleep Littner, M., Hirshkowitz, M., Davila, D., Anderson, W. M., Kushida, C. A., Woodson, B. T., Johnson, S. F., Merrill, S. W. 2002; 25 (2): 143-147

  Abstract

  Continuous positive airway pressure (CPAP) is used to treat patients with the obstructive sleep apnea syndrome (OSAS). The current standard is for an attendant technician to titrate CPAP during full polysomnography to obtain a fixed single pressure. The patient uses CPAP nightly at this fixed single pressure. Recently, devices using new technology that automatically titrate positive airway pressure (APAP) have become available. Such devices continually adjust pressure, as needed, to maintain airway patency (APAP titration). These adjustments can be made with or without attendant technician intervention. Data obtained during APAP titration can be used to provide a fixed single pressure for subsequent treatment. Alternatively, APAP devices can be used in self-adjusting mode for treatment (APAP treatment). A task force of the Standards of Practice Committee of the American Academy of Sleep Medicine reviewed the available literature. Based on this review, the Standards of Practice Committee developed these practice parameters as a guide to the appropriate use of APAP. Recommendations are as follows: 1) A diagnosis of OSAS must be established by an acceptable method. 2) APAP titration and APAP treatment are not currently recommended for patients with congestive heart failure, significant lung disease (e.g., chronic obstructive pulmonary disease), daytime hypoxemia and respiratory failure from any cause, or prominent nocturnal desaturation other than from OSA (e.g., obesity hypoventilation syndrome). In addition, patients who do not snore (either due to palate surgery or naturally) should not be titrated with an APAP device that relies on vibration or sound in the device's algorithm. 3) APAP devices are not currently recommended for split-night studies since none of the reviewed research studies examined this issue. 4) Certain APAP devices may be used during attended titration to identify by polysomnography a single pressure for use with standard CPAP for treatment of OSA. 5) Once an initial successful attended CPAP or APAP titration has been determined by polysomnography, certain APAP devices may be used in the self-adjusting mode for unattended treatment of patients with OSA. 6) Use of unattended APAP to either initially determine pressures for fixed CPAP or for self-adjusting APAP treatment in CPAP naïve patients is not currently established. 7) Patients being treated with fixed CPAP on the basis of APAP titration or being treated with APAP must be followed to determine treatment effectiveness and safety, and 8) a re-evaluation and, if necessary, a standard attended CPAP titration should be performed if symptoms do not resolve or the CPAP or APAP treatment otherwise appears to lack efficacy.

  View details for PubMedID 11902424

• Practice parameters for the use of auto-titrating continuous positive airway pressure devices for titrating pressures and treating adult patients with obstructive sleep apnea syndrome SLEEP Littner, M., Hirshkowitz, M., Davila, D., Anderson, W. M., Kushida, C. A., Woodson, T., Johnson, S. F., Wise, M. S. 2002; 25 (2): 143-147

  View details for Web of Science ID 000174275400003

• Technical protocol for the use of esophageal manometry in the diagnosis of sleep-related breathing disorders SLEEP MEDICINE Kushida, C. A., Giacomini, A., Lee, M. K., Guilleminault, C., Dement, W. C. 2002; 3 (2): 163-173

  Abstract

  A time-tested protocol for intrathoracic pressure monitoring during sleep is described. This method of esophageal manometry uses a fluid-filled catheter to measure variations in transmitted intrathoracic pressure with respiration. Esophageal manometry is an invaluable tool for the sleep specialist in the diagnosis of sleep-related breathing disorders, especially for detecting cases of upper airway resistance syndrome and for distinguishing subtle central apneas from obstructive events. The methods for scoring esophageal pressure, the indications and contraindications for esophageal manometry, the use of esophageal manometry as the 'gold standard' for the measurement of respiratory effort, and directions for future research are also discussed.

  View details for Web of Science ID 000208301700014

  View details for PubMedID 14592238

• A new questionnaire to detect sleep disorders SLEEP MEDICINE Roth, T., Zammit, G., Kushida, C., Doghramji, K., Mathias, S. D., Wong, J. M., Buysse, D. J. 2002; 3 (2): 99-108

  Abstract

  Sleep disorders remain largely undiagnosed in the general population. The current study assessed whether the Global Sleep Assessment Questionnaire (GSAQ) could: (1), distinguish between sleep disorders (including no sleep disorder); (2), be a reliable and valid sleep disorder screener; and (3), serve as a practical, user-friendly screening tool for primary care and sleep centers.Two hundred and twelve adults from five sleep centers and two primary care clinics completed the GSAQ and received confirmed diagnoses from a sleep specialist. Of the 212 patients, 139 (65.6%) had at least one sleep disorder, 60 (28.3%) had two or more sleep disorders, and 13 (6.1%) had no confirmed sleep disorder. Ninety-one (43%) individuals completed the GSAQ a second time for reliability testing. Scores for each sleep disorder including, but not limited to, primary insomnia (I), insomnia associated with a mental disorder (IME), obstructive sleep apnea (OSA), periodic limb movement (PLM), and parasomnia (P) were computed. The sensitivity and specificity were estimated using comprehensive clinical diagnosis as the gold standard and mean domain scores as a cutpoint.The mean participant age was 45 years, 52% were female. Observed frequencies were: 36 (I), 14 (IME), 31 (OSA), 7 (PLM) and 4% (P). Test-retest reliability ranged from 0.51 to 0.92. Pearson correlation coefficients suggested that the GSAQ discriminated between diagnoses. The sensitivities and specificities were 79/57, 83/51, 93/58, 93/52, and 100/49 for I, IME, OSA, PLM, and P, respectively.Our findings suggest that the GSAQ can aid in recognizing sleep disorders. Future studies should focus on characterizing its predictive values in primary care settings.

  View details for Web of Science ID 000208301700003

  View details for PubMedID 14592227

• Sleep deprivation in the rat: X. Integration and discussion of the findings. 1989. Sleep Rechtschaffen, A., Bergmann, B. M., Everson, C. A., Kushida, C. A., Gilliland, M. A. 2002; 25 (1): 68-87

  Abstract

  The results of a series of studies on total and selective sleep deprivation in the rat are integrated and discussed. These studies showed that total sleep deprivation, paradoxical sleep deprivation, and disruption and/or deprivation of non-rapid eye movement (NREM) sleep produced a reliable syndrome that included death, debilitated appearance, skin lesions, increased food intake, weight loss, increased energy expenditure, decreased body temperature during the late stages of deprivation, increased plasma norepinephrine, and decreased plasma thyroxine. The significance of this syndrome for the function of sleep is not entirely clear, but several changes suggested that sleep may be necessary for effective thermoregulation.

  View details for PubMedID 11833857

• Comparison of actigraphic, polysomnographic, and subjective assessment of sleep parameters in sleep-disordered patients. Sleep medicine Kushida, C. A., Chang, A., Gadkary, C., Guilleminault, C., Carrillo, O., Dement, W. C. 2001; 2 (5): 389-396

  Abstract

  Comparison of polysomnography (PSG)-derived sleep parameters (total sleep time, sleep efficiency, and number of awakenings) to those derived from actigraphy and subjective questionnaires.Actigraphy is commonly used to assist sleep specialists in the diagnosis of various sleep and circadian-rhythm disorders. However, few validation studies incorporate large sample sizes, typical sleep clinic patients, or comparisons with subjective reports of sleep parameters.Clinical series with 100 consecutive sleep-disordered patients (69 men, 31 women, mean age of 49+/-14.7 years) at a tertiary sleep disorders center. Sensitivity, specificity, and accuracy measures were obtained from epoch-by-epoch comparison of PSG and actigraphic data. Subjective sleep parameter data were derived from questionnaires given to subjects in the morning following their recording night.We found that total sleep time and sleep efficiency did not significantly differ between PSG data and the combined data obtained from actigraphy and subjective reports. Using a high-threshold (low-wake-sensitivity) actigraphic algorithm, the number of awakenings was not significantly different from those detected by PSG.We recommend the use of subjective data as an adjunct to actigraphic data in estimating total sleep time and sleep efficiency in sleep-disordered patients, especially those with disorders of excessive somnolence.

  View details for PubMedID 14592388

• Comparison of actigraphic, polysomnographic, and subjective assessment of sleep parameters in sleep-disordered patients SLEEP MEDICINE Kushida, C. A., Chang, A., Gadkary, C., Guilleminault, C., Carrillo, O., Dement, W. C. 2001; 2 (5): 389-396

  View details for Web of Science ID 000208301200003

• Practice parameters for the use of laser-assisted uvulopalatoplasty: An update for 2000 SLEEP Littner, M., Kushida, C. A., Hartse, K., Anderson, W. M., Davila, D., Johnson, S. F., Wise, M. S., Hirshkowitz, M., Woodson, B. T. 2001; 24 (5): 603-619

  Abstract

  Laser-assisted uvulopalatoplasty (LAUP) is an outpatient surgical procedure which is in use as a treatment for snoring. LAUP also has been used as a treatment for sleep-related breathing disorders, including obstructive sleep apnea. The Standards of Practice Committee of the American Academy of Sleep Medicine reviewed the available literature, and developed these practice parameters as a guide to the appropriate use of this surgery. Adequate controlled studies on the LAUP procedure for sleep-related breathing disorders were not found in peer-reviewed journals. This is consistent with findings in the original practice parameters on LAUP published in 1994. The following recommendations are based on the review of the literature: LAUP is not recommended for treatment of sleep-related breathing disorders. However, it does appear to be comparable to uvulopalatopharyngoplasty (UPPP) for treatment of snoring. Individuals who are candidates for LAUP as a treatment for snoring should undergo a polysomnographic or cardiorespiratory evaluation for sleep-related breathing disorders prior to LAUP and periodic postoperative evaluations for the development of same. Patients should be informed of the best available information of the risks, benefits, and complications of the procedure.

  View details for Web of Science ID 000169972400011

  View details for PubMedID 11480657

• Practice parameters for the treatment of narcolepsy: An update for 2000 SLEEP Littner, M., Johnson, S. F., McCall, W. V., Anderson, W. D., Davila, D., Hartse, K., Kushida, C. A., Wise, M. S., Hirshkowitz, M., Woodson, B. T. 2001; 24 (4): 451-466

  Abstract

  Successful treatment of narcolepsy requires an accurate diagnosis to exclude patients with other sleep disorders, which have different treatments, and to avoid unnecessary complications of drug treatment. Treatment objectives should be tailored to individual circumstances. Modafinil, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, selegiline, pemoline, tricyclic antidepressants, and fluoxetine are effective treatments for narcolepsy, but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness, but naps seldom suffice as primary therapy. Regular follow up of patients with narcolepsy is necessary to educate patients and their families, monitor for complications of therapy and emergent of other sleep disorders, and help the patient adapt to the disease.

  View details for Web of Science ID 000169184800011

  View details for PubMedID 11403530

• Cervical positioning for reduction of sleep-disordered breathing in mild-to-moderate OSAS. Sleep & breathing = Schlaf & Atmung Kushida, C. A., Sherrill, C. M., Hong, S. C., Palombini, L., Hyde, P., Dement, W. C. 2001; 5 (2): 71-78

  Abstract

  The objective of this study was to assess whether cervical positioning could improve mild to moderate cases of the obstructive sleep apnea syndrome (OSAS). Eighteen subjects recruited from a tertiary sleep disorders clinic population with mild to moderate cases of OSAS were evaluated using a custom-fitted cervical pillow designed to increase upper airway caliber by promoting head extension. The subjects used their usual pillows during two consecutive recorded baseline nights in our laboratory. They then used the cervical pillow for 5 days at home and returned for 2 consecutive recorded nights at our laboratory to use the cervical pillow. During the nights in our laboratory, the subjects completed questionnaires, were videotaped to record head and body position, and had full polysomnography. The subjects had a significant trend toward improvement in their respiratory disturbance indices with use of the cervical pillow, despite spending more time in the supine position and having similar amounts of REM sleep in the baseline and experimental conditions. They also had nonsignificant trends toward improvements in their sleep efficiency and subjective depth of their sleep as well as significantly fewer arousals and awakenings in the experimental compared with the baseline condition. We propose that cervical positioning (i.e., head extension) with a custom-fitted cervical pillow provides a simple, noninvasive, and comfortable means of reducing sleep-disordered breathing in patients with mild to moderate OSAS.

  View details for PubMedID 11868144

• Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnoea syndrome EUROPEAN RESPIRATORY JOURNAL Guilleminault, C., Kim, Y. D., Chowdhuri, S., Horita, M., Ohayon, M., Kushida, C. 2001; 17 (5): 838-847

  Abstract

  This study has investigated differences in the nocturnal sleep and daytime sleepiness among patients with obstructive sleep apnoea syndrome (OSAS), upper airway resistance (UARS), sleep hypopnoea syndrome, and normal control subjects, using sleep scoring and spectral activity analysis of the electroencephalogram (EEG). Twelve nonobese males with UARS aged 30-60 yrs were recruited. These subjects were strictly matched for age and body mass index with twelve OSAS patients, 12 sleep hypopnoea syndrome patients, and 12 normal controls, all male. Daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the Multiple Sleep Latency Test (MSLT). The macrostructure of sleep was determined using international criteria and spectral analysis of the sleep EEG was obtained from a central lead. The sleep macrostructure of OSAS and UARS patients was significantly different from that of controls. These patients were also sleepier during the daytime than controls. Complaints of tiredness and daytime sleepiness, ESS and MSLT scores were similar in the different patient groups. Mild dysmorphia was present in all three patient groups. However, nocturnal sleep was significantly different among the different groups. OSAS patients had significantly more awake time during sleep than the UARS patients. The spectral activity of the total sleep time of the patient groups also differed significantly from that of controls. When the sleep spectral activity of UARS and OSAS patients were compared, OSAS patients had less slow wave sleep activity than UARS patients. UARS patients had a significantly higher absolute power in the 7-9 Hz bandwidth than OSAS patients. The absolute delta power over the different sleep cycles was also different between controls and patients, and between UARS and OSAS patients. There are clear differences in the macrostructure and spectral activity of sleep between upper airway resistance and obstructive sleep apnoea syndrome patients, demonstrated by differences in the cortical activity recorded in the central lead during sleep. Despite these nocturnal sleep differences, the tests of subjective daytime sleepiness are not significantly different.

  View details for Web of Science ID 000170209000002

  View details for PubMedID 11488314

• Confirmation of a high prevalence of Restless Legs Syndrome in a primary care population Nichols, D. A., Kushida, C. A., Allen, R. P., Grauke, J. H., Brown, J. B., Rice, M. L., Hyde, P. R., Dement, W. C. AMER ACAD SLEEP MEDICINE. 2001: A417–A418

  View details for Web of Science ID 000168230900738

• Obstructive sleep apnea syndrome: A comparison between Far-East Asian and white men LARYNGOSCOPE Li, K. K., Kushida, C., Powell, N. B., Riley, R. W., Guilleminault, C. 2000; 110 (10): 1689-1693

  Abstract

  To investigate the possible differences between Far-East Asian men and white men in obstructive sleep apnea syndrome (OSAS).Prospective nonrandomized controlled study.This study compared consecutive Far-East Asian men with OSAS (n = 50) with two selected groups of White men with OSAS (n = 50 in each group). One group of white men was controlled for age, respiratory disturbance index (RDI), and minimum oxygenation saturation (LSAT). Another group was controlled for age and body mass index (BMI). Cephalometric analysis was performed on all subjects.The majority of the Far-East Asian men were found to be nonobese (mean BMI, 26.7 +/- 3.8) but had severe OSAS (mean RDI, 55.1 +/- 35.1). When controlled for age, RDI, and LSAT, the white men were substantially more obese (mean BMI, 29.7 +/- 5.8, P = .0055). When controlled for age and BMI, the white men had less severe illness (RDI, 34.1 +/- 17.9, P = .0001). Although the posterior airway space and the distance from the mandibular plane to hyoid bone were less abnormal in the Far-East Asian men, the cranial base dimensions were significantly decreased.The majority of the Far-East Asian men in this study were found to be nonobese, despite the presence of severe OSAS. When compared with white men, Far-East Asian men were less obese but had greater severity of OSAS. There may be differences in obesity and craniofacial anatomy as risk factors in these two groups.

  View details for Web of Science ID 000089709500020

  View details for PubMedID 11037826

• Symptom-Based Prevalence of Sleep Disorders in an Adult Primary Care Population. Sleep & breathing = Schlaf & Atmung Kushida, C. A., Nichols, D. A., Simon, R. D., Young, T., Grauke, J. H., Britzmann, J. B., Hyde, P. R., Dement, W. C. 2000; 4 (1): 9-14

  Abstract

  The prevalence of sleep disorders in a primary care physician practice in Moscow, Idaho, was studied between February 7, 1997, and February 6, 1998. This primary care clinic visit population was surveyed for this 1-year period. Every patient above the age of 18 years who visited the Moscow Clinic in this time period was either approached by our on-site researcher during the patient's clinic visit or contacted via mail. Out of a total of 1249 adult patients who met with our on-site researcher during their clinic visit, 962 (77.0%) completed questionnaires and were interviewed for symptoms of sleep disorders. An additional 292 patients completed mailed questionnaires, resulting in a total of 1254 participants in the study. The percentages of patients in our sample reporting symptoms of the following sleep disorders were insomnia (32.3%), obstructive sleep apnea syndrome (23.6%), and restless legs syndrome (29.3%). This study demonstrates the need for heightened awareness and subsequent diagnosis and treatment of sleep disorders in the primary care population.

  View details for PubMedID 11894194

• A comparison of Asian and white patients with obstructive sleep apnea syndrome LARYNGOSCOPE Li, K. K., Powell, N. B., Kushida, C., Riley, R. W., Adornato, B., Guilleminault, C. 1999; 109 (12): 1937-1940

  Abstract

  To evaluate the possible differences between Asian and white patients with obstructive sleep apnea syndrome.A retrospective review of Asian and white patients during a 12-month period was conducted. Patients with respiratory disturbance index (RDI) > or = 15 based on polysomnography were included in the study. Variables examined include age, sex, body mass index (BMI), RDI, lowest oxygen saturation (LSAT), and cephalometric analysis data.Fifty-eight Asian patients (53 men) and 293 white patients (260 men) were studied. The Asians were younger (44.1 +/- 9.8 vs. 47.5 +/- 11.6 y, P = .02), and the mean BMI (kg/m2) was 26.6 +/- 3.7 in the Asians and 30.7 +/- 5.9 in the whites (P < .001). The mean RDI was similar (56.6 +/- 34.9 vs. 55.6 +/- 26.9, P = NS), but the mean LSAT was lower in the whites (77.7 +/- 9.9% vs. 70.0 +/- 15.6%, P < .001). Based on the cephalometric data, the Asians have maxillomandibular protrusion, narrower cranial base angle, larger posterior airway space, and more superiorly positioned hyoid bone compared with the whites.Although male gender was found to be an important risk factor for obstructive sleep apnea syndrome in both Asian and white patients, obesity may be a less significant risk factor in the Asians because the majority of our Asian patients were nonobese. There was also variability in the craniomandibular factors that contributed to obstructive sleep apnea syndrome in the two groups.

  View details for Web of Science ID 000084030700007

  View details for PubMedID 10591350

• The treatment of restless legs syndrome and periodic limb movement disorder SLEEP Hening, W., Allen, R., Earley, C., Kushida, C., Picchietti, D., Silber, M. 1999; 22 (7): 970-999

  Abstract

  A task force consisting of six authors reviewed the published literature on the therapy of the restless legs syndrome or periodic limb movements in sleep available in indices through April, 1998. They selected the 45 articles for detailed review which presented original investigations of therapeutic impact on the restless legs syndrome (RLS) or periodic limb movements (PLM) and which met minimal standards. These articles dealt with a range of pharmacological and other treatment modalities, although most dealt with medications and almost half of those concentrated on dopaminergic agents, especially levodopa in various formulations. Almost half of the articles reviewed used controlled methodologies, most commonly cross-over methodologies with randomized allocation of subjects. Multi-center studies with large numbers of subjects and long-term controlled studies were not found. Information was extracted from the articles and study design, clinical definition, evaluative measures, side effects, and outcomes were tabulated in 6 evidence tables and summarized in the accompanying text. This literature was evaluated for the nature of the studies performed and its coverage of potential therapies. The review concludes with comments on possible future directions for therapeutic investigation based on the current state of the literature.

  View details for Web of Science ID 000083566100016

  View details for PubMedID 10566916

• Cervical positional effects on snoring and apneas. Sleep research online : SRO Kushida, C. A., Rao, S., Guilleminault, C., Giraudo, S., Hsieh, J., Hyde, P., Dement, W. C. 1999; 2 (1): 7-10

  Abstract

  We examined the effects of cervical position on the Obstructive Sleep Apnea Syndrome (OSAS) through the use of a custom-designed cervical pillow which promoted neck extension. Twelve subjects with OSAS were recruited from a tertiary sleep disorder clinic population. Of the twelve subjects, three had mild cases of OSAS, four had moderate cases, and the remaining five had severe cases. The subjects used their usual pillows during two consecutive recorded baseline nights in our laboratory. The subjects then used the cervical pillow for five days at home, and returned for two consecutive recorded nights at our laboratory while using the cervical pillow. During the nights in our laboratory, the subjects completed questionnaires, were videotaped to record head and body position, and had their breathing parameters recorded during sleep. Subjects with mild OSAS cases had a non-significant improvement in the severity of their snoring and a significant improvement in their respiratory disturbance index with the cervical pillow, while subjects with moderate OSAS cases showed no improvement in these parameters. Subjects with severe OSAS cases showed slight improvement in some measures of their abnormal respiratory events during the experimental period.

  View details for PubMedID 11382876

• A predictive morphometric model for the obstructive sleep apnea syndrome ANNALS OF INTERNAL MEDICINE Kushida, C. A., Efron, B., Guilleminault, C. 1997; 127 (8): 581-?

  Abstract

  Mathematical formulas have been used to clinically predict whether patients will develop the obstructive sleep apnea syndrome (OSAS). However, these models do not take into account the disproportionate craniofacial anatomy that accompanies OSAS independently of obesity.To determine the accuracy of a morphometric model, which combines measurements of the oral cavity with body mass index and neck circumference, in predicting whether a patient has OSAS.6-month prospective study.University-based tertiary referral sleep clinic and research center.300 consecutive patients evaluated for sleep disorders for the first time.Body mass index, neck circumference, and oral cavity measurements were obtained, and a model value was calculated for each patient. Polysomnography was used to determine the number of abnormal respiratory events that occurred during sleep. Sleep apnea was defined as more than five episodes of apnea or hypopnea per hour of sleep.The morphometric model had a sensitivity of 97.6% (95% CI, 95% to 98.9%), a specificity of 100% (CI 92% to 100%), a positive predictive value of 100% (CI, 98.5% to 100%), and a negative predictive value of 88.5% (CI, 77% to 95%). No significant discrepancies were revealed in tests of intermeasurer and test-retest reliability.The morphometric model provides a rapid, accurate, and reproducible method for predicting whether patients in an ambulatory setting have OSAS. The model may be clinically useful as a screening tool for OSAS rather than as a replacement for polysomnography.

  View details for Web of Science ID A1997YB41900001

  View details for PubMedID 9341055

• Nasal obstruction and obstructive sleep apnea: A review ALLERGY AND ASTHMA PROCEEDINGS Kushida, C. A., Guilleminault, C., Clerk, A. A., Dement, W. C. 1997; 18 (2): 69-71

  Abstract

  Several groups of investigators have assessed the impact of nasal obstruction on the obstructive sleep apnea syndrome. These studies evaluated patients with either naturally occurring partial nasal obstruction (e.g., allergic rhinitis, septal deviation) or experimentally induced nasal occlusion. The results of these studies are summarized and discussed in this article.

  View details for Web of Science ID A1997WW54000003

  View details for PubMedID 9134062

• Should everyone be monitored for upper-airway resistance and how? Proceedings of the 4th International Symposium on Sleep and Respiration Guilleminault, C., Kushida, C., Stoohs, R., Ohayon, M., Wilson, K., Clerk, A. AMER ACAD SLEEP MEDICINE. 1996: S260–S262

  Abstract

  Preliminary data indicate that the use of a morphometric model, an expert system with standardized questions, and an evaluation of snoring can be effective tools for diagnosing upper-airway sleep-disordered breathing (UASDB) in many cases. This eliminates the need for many sleep recordings.

  View details for Web of Science ID A1996WP54300033

  View details for PubMedID 9085526

• A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS) STROKE Scott, P., Barsan, W., Frederiksen, S., Kronick, S., Zink, B. J., Domeier, R. M., Mitchiner, J. C., JUDGE, F. P., Levy, R. J., Alexiou, A., Reincke, H., Segall, J. D., Walters, B., Swor, R., Gilroy, J., Goetting, M., Jackson, R., Richardson, D., Cisek, J., Randall, J., Schecter, S., Wilkinson, K., Walters, B. L., Adams, R., Carl, E., Nichols, F., Hess, D., Boop, B., Earley, C., Smith, D. R., Kaplan, P., Johnson, C., Morrow, C., Frohman, E., Porter, N., Flanigan, K., Morganstern, L., Holland, N., Stein, A., Aldrich, E., Oyler, G., Faught, E., Mitchell, V., Liu, H., Thomas, F., Wenzel, D., DAJANI, B. M., Pan, J. L., Yapundich, R., Futatsugi, Y., Geerlings, S., Moskowitz, T., Nicholas, A., Brockington, J., Collins, A., Bailey, J. M., Tseng, A., Koroshetz, W. J., Can, U., Felix, A., Cudkowticz, M., Buonanno, F., Schwamm, L., Elkind, M., Kistler, J. P., Finkelstein, S., Cha, J., Murphy, S., Blumenfeld, H., LOPEZBRESNAHAN, M., Can, U., GOSLIN, K., Cramer, S., Suwanwela, N., Homer, D., Carpenter, J., Wityk, R., Michel, N., Grufferman, S., Litt, B., Weiss, H., Guyot, A., Peterson, P., Tvardek, L., Schmidt, J., Deshpande, A., Freij, W., Gandhi, B., Minhas, F., Shah, J., Zahka, C., Penn, A., Sherman, J., Li, Y. L., Elleker, M. G., Stenerson, P., Brooke, H., AlJumah, M., AlAyafy, H., Pokroy, R., Hoppe, B., Pascuzzi, R., Farlow, M., Rightmyer, D., Bales, M., Caress, J., Pettigrew, C., Waugh, C., Rockich, A., Fallis, R., Tikhtman, A., Starkman, S., Schubert, G., Dobkin, B., Martin, N., Saver, J., Hanson, S., Weaver, A., PORTH, K., Magana, R., Davenport, J., Taylor, F., FREKING, D., HEROS, D. O., Schnek, E., Alter, M., Ribeiro, R., Lloyd, M., Scheiner, S., PUFF, A., Boyle, S., Gupta, N., White, K., Carney, S., Moulton, M., LaCapra, S., Hassard, D., Rizwan, S., Shah, A., NEWMARK, A., Gupta, A., Cone, D., Khan, I., Cohen, B., Bopari, R., OCONNELL, J., HUSSIAN, A., Patil, K., Shojari, J., Ribeiro, R., Bell, R., Gzech, D., MAZER, T., Grothusen, J., Reyes, P., Arastu, J., Strassburger, T., Thomas, C., Wolfe, R., Fang, J., Scavina, M., Wolfe, W., Zeidwerg, D., CHAVIN, J., Shachar, O., Sandler, L., McGarren, D., Jamieson, D. G., Gonnella, C., Bosley, T. M., Pollack, D. A., Andrefsky, J. C., Hariharan, S., Chang, A., Lamonte, M. P., Champellone, J., Hooker, H. C., Fellus, J., Sosa, V., RAAF, S., Friedman, M., BURCH, G., Atkins, D., Foley, C., Bivins, D., Elias, W., Nolan, D., Sisk, M., Wilson, J., Lloyd, A., Stephens, G., Surrusco, R., Lothes, C., Humphries, W., Pastemak, S., Donato, M., MANETTA, E., Mitchell, J., Briggs, A., Rorrer, M., Offermann, P., Grover, W., Bolton, B., Lyden, P., Lewis, S., Rapp, K., Brody, M., Rothrock, J., Jackson, C., HUOTT, P., Kushida, C., Liss, J., Zweifer, R., Caylor, L., Phan, D., Mahdavi, Z., Tom, T., Noack, H., Forde, G., Cameron, D., Griesdale, B., Makin, V., BOZEK, C. B., Sheppard, G., Massey, S., ZONTINE, D., Crowe, N., GUSTIN, K., Capone, P., Feasby, T. E., Robertson, C., Rorick, M., Winkelman, M., Liskay, A., SCHMIDLEY, J., Cole, M., ALJABERI, M., Anagnos, A., Anderson, M., Bamford, C., Frederickson, E., Gordon, J., Grosser, S., Kori, A., Kuntz, A., Murad, M., Nasreddine, W., Pettee, A., Riachi, N., Schecht, H., Stahl, J., Soriano, J., Sunshine, J., Suarez, J., VANDERSLUIS, J., AlLanham, Y., Ramahi, A., Shuaib, A., Kadribasic, E., Stewart, B., Beaudry, M., Boivin, D., Lyons, G., Dougal, R. L., Simsarian, J. P., McGarvey, M., Grass, D., SIGMUND, L., KURTZKE, R., Eberly, L., LIPPS, D., FESENMEIER, J. T., Viater, K., ALONZO, R., Cooper, W., Scott, J., Bustion, P., Pappas, J., Frazer, M., Haley, E. C., Alves, W., Kassell, N. F., Johnston, K. C., Ford, G., Solenski, N., SHREVE, D. L., Wilkinson, S. S., Clements, S., Cuccia, E., Elder, L., Keller, M., LACKEY, R., Mimms, K., Protzman, P., Sparrow, L., Lightfoot, A., Lightfoot, A. E., Bocchicchio, B. E., Halley, P., POLIN, A., Polin, R., Hwang, L. J., Wolf, M. C., Truskowski, L. L., Galbrieth, C., Johnson, R., JOHNSON, S., Hill, C., Wilson, B., Bartley, A., Ford, G., Rumfelt, M., Wingate, V., Smith, M., Childress, T., Powers, W. J., Walker, M., FLEISS, J. L., Frankel, M., Simon, R. P., Marler, J., Adams, H. P., Brott, T. G., Choi, S., Kurtzke, J. F., Torner, J. C., Peters, G. R., Eckert, S., Bryan, W. J., Bologa, M. L., Legace, D., Brennan, K. M. 1996; 27 (9): 1453-1458

  View details for Web of Science ID A1996VF03200001

• Upper airway resistance syndrome, nocturnal blood pressure monitoring, and borderline hypertension CHEST Guilleminault, C., Stoohs, R., Shiomi, T., Kushida, C., Schnittger, I. 1996; 109 (4): 901-908

  Abstract

  Upper airway resistance syndrome (UARS) is a sleep-disordered breathing syndrome characterized by complaints of daytime fatigue and/or sleepiness, increased upper airway resistance during sleep, frequent transient arousals, and no significant hypoxemia. Of a population of 110 subjects (58 men) diagnosed as having UARS, we investigated acute systolic and diastolic BP changes seen during sleep in two different samples. First, six patients from the original subject pool were found to have untreated chronic borderline high BP, and were subjected to 48 h of continuous ambulatory BP monitoring before treatment and another 48 h of BP monitoring 1 month after the start of nasal-continuous positive airway pressure (N-CPAP) treatment. Five of six subjects used their equipment on a regular basis and had their chronic borderline high BP completely controlled. No change in BP values was seen in the last subject, who discontinued N-CPAP after 3 days. A second protocol investigated seven normotensive subjects drawn from the initial subject pool. Continuous radial artery BP recording was performed during nocturnal sleep with simultaneous polygraphic recording of sleep/wake variables and respiration. BP changes were studied during periods of increased respiratory efforts and at the time of alpha EEG arousals. Increases in systolic and diastolic BP were noted during the breaths with the greatest inspiratory efforts without significant hypoxemia. A further increase in BP was noted in association with arousals. Three of these subjects also underwent echocardiography during sleep, which demonstrated a leftward shift of the interventricular septum with pulsus paradoxus in association with peak end-inspiratory esophageal pressure more negative than -35 cm H2O. Our study indicates that, in the absence of classic apneas, hypopneas, and repetitive significant drops in oxygen saturation (below 90%), repetitive increases in BP can occur as a result of increased airway resistance during sleep. It also shows that, in some patients with both UARS and borderline high BP, high BP can be controlled with treatment of UARS. We conclude that abnormal upper airway resistance during sleep, often associated with snoring, can play a role in the development of hypertension.

  View details for Web of Science ID A1996UE72400014

  View details for PubMedID 8635368

• PROLONGED CONFUSION WITH NOCTURNAL WANDERING ARISING FROM NREM AND REM-SLEEP - A CASE-REPORT SLEEP Kushida, C. A., Clerk, A. A., Kirsch, C. M., Hotson, J. R., Guilleminault, C. 1995; 18 (9): 757-764

  Abstract

  A 51-year-old man with Machado-Joseph disease had a 3-year history of prolonged confusion following nightly nocturnal wandering. Polysomnography with videotape monitoring revealed 19- to 120-minute sleepwalking episodes emerging from non-rapid eye movement (NREM) sleep and occasionally from rapid eye movement (REM) sleep, followed by 22-47 minutes of prolonged confusion and disorientation. The patient also had a periodic limb movement disorder and obstructive sleep apnea syndrome. Excessive daytime sleepiness was evident by results from the Epworth Sleepiness Scale and Multiple Sleep Latency Test. A sleep-deprived electroencephalogram (EEG) and a polysomnogram with an expanded EEG montage before and during these episodes revealed no epileptiform activity. A contrast-enhanced brain magnetic resonance imaging (MRI) scan demonstrated findings consistent only with Machado-Joseph disease. The patient improved with a combination of temazepam and carbidopa-levodopa.

  View details for Web of Science ID A1995TH48600008

  View details for PubMedID 8638068

• FORENSIC SLEEP MEDICINE AND NOCTURNAL WANDERING SLEEP Guilleminault, C., Kushida, C., Leger, D. 1995; 18 (9): 721-723

  View details for Web of Science ID A1995TH48600002

  View details for PubMedID 8638062

• THE EXPRESSION OF M1-M3 MUSCARINIC RECEPTOR MESSENGER-RNAS IN RAT-BRAIN FOLLOWING REM-SLEEP DEPRIVATION NEUROREPORT Kushida, C. A., Zoltoski, R. K., Gillin, J. C. 1995; 6 (12): 1705-1708

  Abstract

  We used in situ hybridization histochemistry to study the effects of REM sleep deprivation on m1-m3 muscarinic receptor mRNA expression in the rat brain. REM sleep deprivation for 72 h did not affect m1 receptor mRNA expression. However, we found significantly increased m3 receptor mRNA expression in the pontine nuclei and nucleus accumbens-bed nucleus of the stria terminalis region of REM sleep-deprived rats compared with controls. Paradoxically, we found significantly decreased m2 receptor mRNA expression in the pontine nuclei of REM sleep-derived rats vs controls. The present findings implicate these structures in the cholinergic effector pathways of REM sleep, although the type and magnitude of the effects of these structures on REM sleep may vary with different receptor subtypes.

  View details for Web of Science ID A1995RR26200027

  View details for PubMedID 8527746

• CORTICAL ASYMMETRY OF REM-SLEEP EEG FOLLOWING UNILATERAL PONTINE HEMORRHAGE NEUROLOGY Kushida, C. A., Rye, D. B., NUMMY, D., Milton, J. G., Spire, J. P., Rechtschaffen, A. 1991; 41 (4): 598-601

  Abstract

  A 24-year-old woman with a left pontine hematoma showed marked asymmetry in the EEG of REM sleep, suggesting that a unilateral pontine lesion is sufficient to disrupt normal REM sleep EEG in the ipsilateral hemisphere. Other REM sleep characteristics (rapid eye movements, muscle atonia) were unaffected by this lesion.

  View details for Web of Science ID A1991FG37700029

  View details for PubMedID 2011264

• SLEEP-DEPRIVATION IN THE RAT .1. CONCEPTUAL ISSUES SLEEP Rechtschaffen, A., Bergmann, B. M., Everson, C. A., Kushida, C. A., Gilliland, M. A. 1989; 12 (1): 1-4

  Abstract

  Sleep deprivation is a potentially powerful strategy for discovering the function(s) of sleep, but the approach has had limited success. Few studies have described serious physiological consequences of sleep deprivation, perhaps because the deprivation has not been maintained long enough. However, prolonging deprivation usually requires sustained, frequently intense stimulation, which makes it difficult to determine whether subsequent impairment resulted from the sleep loss or from the stimulation per se. Accordingly, several older studies that showed severe impairment have been neglected or discounted, because the impairment could have resulted from the stimulation. To evaluate the effects of sleep deprivation independent of the stimulation used to enforce deprivation, we have used an apparatus that can awaken experimental rats while delivering the same gentle stimulation to control rats according to a schedule that only moderately shortens their sleep.

  View details for Web of Science ID A1989T091200001

  View details for PubMedID 2648532

• SLEEP-DEPRIVATION IN THE RAT .10. INTEGRATION AND DISCUSSION OF THE FINDINGS SLEEP Rechtschaffen, A., Bergmann, B. M., Everson, C. A., Kushida, C. A., Gilliland, M. A. 1989; 12 (1): 68-87

  Abstract

  The results of a series of studies on total and selective sleep deprivation in the rat are integrated and discussed. These studies showed that total sleep deprivation, paradoxical sleep deprivation, and disruption and/or deprivation of non-rapid eye movement (NREM) sleep produced a reliable syndrome that included death, debilitated appearance, skin lesions, increased food intake, weight loss, increased energy expenditure, decreased body temperature during the late stages of deprivation, increased plasma norepinephrine, and decreased plasma thyroxine. The significance of this syndrome for the function of sleep is not entirely clear, but several changes suggested that sleep may be necessary for effective thermoregulation.

  View details for Web of Science ID A1989T091200010

  View details for PubMedID 2648533

• SLEEP-DEPRIVATION IN THE RAT .9. RECOVERY SLEEP Everson, C. A., Gilliland, M. A., Kushida, C. A., Pilcher, J. J., Fang, V. S., Refetoff, S., Bergmann, B. M., Rechtschaffen, A. 1989; 12 (1): 60-67

  Abstract

  Eight rats were subjected to total sleep deprivation, paradoxical sleep deprivation, or high amplitude sleep deprivation until they showed major deprivation-induced changes. Then they were allowed to sleep ad lib. Three rats that had shown the largest temperature declines died within two to six recovery days. During the first 15 days of ad lib sleep, surviving rats showed complete or almost complete reversal of the following deprivation-induced changes: debilitated appearance, lesions on the paws and tail, high energy expenditure, large decreases in peritoneal temperature, high plasma epinephrine and norepinephrine levels, and low thyroxine levels. The most prominent features of recovery sleep in all rats were immediate and large rebounds of paradoxical sleep to far above baseline levels, followed by lesser temporally extended rebounds. Rebounds of high amplitude non-rapid eye movement (NREM) sleep occurred only in some rats and were smaller and less immediate.

  View details for Web of Science ID A1989T091200009

  View details for PubMedID 2538911

• SLEEP-DEPRIVATION IN THE RAT .7. IMMUNE FUNCTION SLEEP Benca, R. M., Kushida, C. A., Everson, C. A., KALSKI, R., Bergmann, B. M., Rechtschaffen, A. 1989; 12 (1): 47-52

  Abstract

  Immune function studies were performed on splenic lymphocytes obtained from rats subjected to total or paradoxical sleep deprivation. Spleen cell counts, in vitro lymphocyte proliferation responses to mitogens, and in vitro and in vivo plaque-forming cell responses to antigens were obtained. Sleep-deprived rats were roughly equivalent to both their yoked controls and home-cage controls in all assays. The results do not support the hypothesis that sleep deprivation results in immune suppression as measured by the above-mentioned parameters.

  View details for Web of Science ID A1989T091200007

  View details for PubMedID 2784583

• SLEEP-DEPRIVATION IN THE RAT .2. METHODOLOGY SLEEP Bergmann, B. M., Kushida, C. A., Everson, C. A., Gilliland, M. A., Obermeyer, W., Rechtschaffen, A. 1989; 12 (1): 5-12

  Abstract

  Methods common to several studies in this series are described. A key feature is a sleep deprivation apparatus in which an experimental and a yoked control rat are housed on opposite sides of a divided disk suspended over shallow water. When the experimental rat enters a "forbidden" sleep stage, the disk is automatically rotated, forcing the experimental rat to walk to avoid being carried into the water. The control rat receives the same physical stimulation but can sleep ad lib when the disk is stationary.

  View details for Web of Science ID A1989T091200002

  View details for PubMedID 2928625

• SLEEP-DEPRIVATION IN THE RAT .4. PARADOXICAL SLEEP-DEPRIVATION SLEEP Kushida, C. A., Bergmann, B. M., Rechtschaffen, A. 1989; 12 (1): 22-30

  Abstract

  Twelve rats were subjected to paradoxical sleep deprivation (PSD) by the disk apparatus. All PSD rats died or were sacrificed when death seemed imminent within 16-54 days. No anatomical cause of death was identified. All PSD rats showed a debilitated appearance, lesions on their tails and paws, and weight loss in spite of increased food intake. Their yoked control (PSC) rats remained healthy. Since dehydration was ruled out and several measures indicated normal or accelerated use of nutrients, the food-weight changes in PSD rats were attributed to increased energy expenditure (EE). The measurement of EE, based upon caloric value of food, weight, and wastes, indicated that all PSD rats increased EE, with mean levels reaching more than twice baseline values. All of these changes had been observed in rats deprived totally of sleep; the major difference was that they developed more slowly in PSD rats.

  View details for Web of Science ID A1989T091200004

  View details for PubMedID 2928623

• SLEEP-DEPRIVATION IN THE RAT .6. SKIN CHANGES SLEEP Kushida, C. A., Everson, C. A., Suthipinittharm, P., Sloan, J., Soltani, K., BARTNICKE, B., Bergmann, B. M., Rechtschaffen, A. 1989; 12 (1): 42-46

  Abstract

  All rats subjected to total or paradoxical sleep deprivation by the disk apparatus developed severe ulcerative and hyperkeratotic skin lesions localized to the plantar surfaces of their paws and to their tails. Yoked control rats only occasionally developed similar appearing lesions, which were always much less severe than in deprived rats. The deprived rat lesions could not be explained by pressure, disk rotation, water immersion, infection, necrotizing vasculitis, tyrosinemia, protein deficiency, or reduced rates of mitosis. Thus, although paw and tail lesions constitute a very reliable and severe symptom of total or selective sleep deprivation in the rat that potentially could yield insights into the pathogenic mechanisms induced by sleep loss, the mediation of the lesions remains unknown.

  View details for Web of Science ID A1989T091200006

  View details for PubMedID 2928624

• SLEEP-DEPRIVATION IN THE RAT .5. ENERGY USE AND MEDIATION SLEEP Bergmann, B. M., Everson, C. A., Kushida, C. A., Fang, V. S., Leitch, C. A., Schoeller, D. A., Refetoff, S., Rechtschaffen, A. 1989; 12 (1): 31-41

  Abstract

  We investigated the use and possible mechanisms mediating the increased energy expenditure (EE) previously described for rats subjected to total or paradoxical sleep deprivation. Bomb calorimetry of wastes showed that during deprivation the efficiency of energy utilization was not reduced. Estimates of CO2 production by the doubly labelled water method of indirect calorimetry correlated with EE estimated from the caloric value of food, weight change, and wastes and confirmed an increase in EE during deprivation. Core temperatures decreased during the later stages of deprivation, suggesting the hypothesis that excessive heat loss may have required increased EE to protect body temperature. The increased EE could not be explained by the metabolic cost of increase wakefulness, water exposure, or motor activity; an increase in resting EE was indicated. The contribution of the hypothalamic-pituitary-adrenal axis, thyroid gland, and sympathoadrenal system to the mediation of the EE increases was evaluated by measuring the plasma levels of their hormones. Results appear to rule out the first as a mediator. Evidence for the other two was equivocal.

  View details for Web of Science ID A1989T091200005

  View details for PubMedID 2538910

• ELECTROENCEPHALOGRAPHIC CORRELATES OF CATAPLECTIC ATTACKS IN NARCOLEPTIC CANINES ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY Kushida, C. A., Baker, T. L., Dement, W. C. 1985; 61 (1): 61-70

  Abstract

  Cataplectic attacks were monitored behaviorally and polygraphically in 4 narcoleptic dogs, of which three inherited the disorder. The recorded EEG signals were evaluated by power spectral analysis. We found 3 distinct stages of cataplexy: an initial stage which resembled wakefulness with tonic suppression of EMG activity, a later stage which was highly similar to REM sleep, and a final transitional stage to wakefulness or NREM sleep. The first stage of cataplexy was characterized by full postural collapse, a waking-like EEG spectrum, visual tracking, and a hypotonic EMG. The second stage of cataplexy differed electrographically from the previous stage by the onset of hypersynchronous hippocampal theta activity, a REM-like EEG spectrum, larger amplitude EEG signals, and a higher peak theta frequency. Glazed eyes, sporadic rapid eye movements and muscle twitches were also present. The final stage of cataplexy was characterized by mixed amplitude, mixed frequency EEG activity, and by the absence of rapid eye movements, visual tracking, directed movements, and muscle twitches. The EEG spectra of two other narcoleptic phenomena, sleep-onset REM periods and NREM sleep onsets from cataplexy, were nearly identical to the spectra of the normally occurring REM and NREM sleep periods.

  View details for Web of Science ID A1985AMD8600009

  View details for PubMedID 2408864