Rochelle S. Zak

The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses.

The International Classification of Sleep Disorders, Second Edition (ICSD-2) distinguishes 5 subtypes of central sleep apnea syndromes (CSAS) in adults. Review of the literature suggests that there are two basic mechanisms that trigger central respiratory events: (1) post-hyperventilation central apnea, which may be triggered by a variety of clinical conditions, and (2) central apnea secondary to hypoventilation, which has been described with opioid use. The preponderance of evidence on the treatment of CSAS supports the use of continuous positive airway pressure (CPAP). Much of the evidence comes from investigations on CSAS related to congestive heart failure (CHF), but other subtypes of CSAS appear to respond to CPAP as well. Limited evidence is available to support alternative therapies in CSAS subtypes. The recommendations for treatment of CSAS are summarized as follows: CPAP therapy targeted to normalize the apnea-hypopnea index (AHI) is indicated for the initial treatment of CSAS related to CHF. (STANDARD)Nocturnal oxygen therapy is indicated for the treatment of CSAS related to CHF. (STANDARD)Adaptive Servo-Ventilation (ASV) targeted to normalize the apnea-hypopnea index (AHI) is indicated for the treatment of CSAS related to CHF. (STANDARD)BPAP therapy in a spontaneous timed (ST) mode targeted to normalize the apnea-hypopnea index (AHI) may be considered for the treatment of CSAS related to CHF only if there is no response to adequate trials of CPAP, ASV, and oxygen therapies. (OPTION)The following therapies have limited supporting evidence but may be considered for the treatment of CSAS related to CHF after optimization of standard medical therapy, if PAP therapy is not tolerated, and if accompanied by close clinical follow-up: acetazolamide and theophylline. (OPTION)Positive airway pressure therapy may be considered for the treatment of primary CSAS. (OPTION)Acetazolamide has limited supporting evidence but may be considered for the treatment of primary CSAS. (OPTION)The use of zolpidem and triazolam may be considered for the treatment of primary CSAS only if the patient does not have underlying risk factors for respiratory depression. (OPTION)The following possible treatment options for CSAS related to end-stage renal disease may be considered: CPAP, supplemental oxygen, bicarbonate buffer use during dialysis, and nocturnal dialysis. (OPTION) .

The treatment of restless legs syndrome and periodic limb movement disorder in adults - An update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses

A systematic literature review and meta-analyses (where appropriate) were performed to update the previous AASM practice parameters on the treatments, both dopaminergic and other, of RLS and PLMD. A considerable amount of literature has been published since these previous reviews were performed, necessitating an update of the corresponding practice parameters. Therapies with a STANDARD level of recommendation include pramipexole and ropinirole. Therapies with a GUIDELINE level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use). Therapies with an OPTION level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation. The committee recommends a STANDARD AGAINST the use of pergolide because of the risks of heart valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed. However, it should be mentioned that because PLMD therapy typically mimics RLS therapy, the primary focus of this review is therapy for idiopathic RLS.

Update to the AASM Clinical Practice Guideline: “The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults—An Update for 2012: Practice Parameters with an Evidence-Based Systematic Review and Meta-Analyses”

In January 2012, the AASM Board of Directors approved the Standards of Practice paper titled “The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults - An Update for 2012: Practice Parameters with an Evidence-Based Systematic Review and Meta-Analyses.” The 2012 update included a new drug not reviewed in the previous 2004 AASM guidelines for the treatment of Restless Legs Syndrome (RLS) and Periodic Limb Movement Disorder (PLMD) – rotigotine. Rotigotine was originally approved by the US Food and Drug Administration (FDA) for the treatment of signs and symptoms associated with early stage idiopathic Parkinson’s disease. Additionally, rotigotine had been shown in clinical trials to be effective for the treatment of moderate-to-severe RLS. In 2008, rotigotine was withdrawn from the US market due to concerns about inconsistent absorption from the patch; therefore, rotigotine was not an FDA-approved treatment option for RLS or PLMD when the 2012 update was accepted for publication. Thus, despite high level evidence supporting the efficacy of this drug for the treatment of moderate-to-severe RLS, the Standards of Practice Committee (SPC) made no recommendation regarding the use of rotigotine in the setting of RLS. The issue of drug absorption was subsequently resolved by the manufacturer, and the new formulation of rotigotine received FDA approval in April 2012. Rotigotine is currently FDA approved both for the treatment of signs and symptoms associ

Practice Parameters for the Non-Respiratory Indications for Polysomnography and Multiple Sleep Latency Testing for Children

BACKGROUND Although a level 1 nocturnal polysomnogram (PSG) is often used to evaluate children with non-respiratory sleep disorders, there are no published evidence-based practice parameters focused on the pediatric age group. In this report, we present practice parameters for the indications of polysomnography and the multiple sleep latency test (MSLT) in the assessment of non-respiratory sleep disorders in children. These practice parameters were reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine (AASM). METHODS A task force of content experts was appointed by the AASM to review the literature and grade the evidence according to the American Academy of Neurology grading system. RECOMMENDATIONS FOR PSG AND MSLT USE PSG is indicated for children suspected of having periodic limb movement disorder (PLMD) for diagnosing PLMD. (STANDARD)The MSLT, preceded by nocturnal PSG, is indicated in children as part of the evaluation for suspected narcolepsy. (STANDARD)Children with frequent NREM parasomnias, epilepsy, or nocturnal enuresis should be clinically screened for the presence of comorbid sleep disorders and polysomnography should be performed if there is a suspicion for sleep-disordered breathing or periodic limb movement disorder. (GUIDELINE)The MSLT, preceded by nocturnal PSG, is indicated in children suspected of having hypersomnia from causes other than narcolepsy to assess excessive sleepiness and to aid in differentiation from narcolepsy. (OPTION)The polysomnogram using an expanded EEG montage is indicated in children to confirm the diagnosis of an atypical or potentially injurious parasomnia or differentiate a parasomnia from sleep-related epilepsy (OPTION)Polysomnography is indicated in children suspected of having restless legs syndrome (RLS) who require supportive data for diagnosing RLS. (OPTION) RECOMMENDATIONS AGAINST PSG USE: Polysomnography is not routinely indicated for evaluation of children with sleep-related bruxism. (STANDARD) CONCLUSIONS: The nocturnal polysomnogram and MSLT are useful clinical tools for evaluating pediatric non-respiratory sleep disorders when integrated with the clinical evaluation.

Cytokine polymorphisms are associated with poor sleep maintenance in adults living with human immunodeficiency virus/acquired immunodeficiency syndrome.

STUDY OBJECTIVES Cytokine activity and polymorphisms have been associated with sleep outcomes in prior animal and human research. The purpose of this study was to determine whether circulating plasma cytokines and cytokine polymorphisms are associated with the poor sleep maintenance commonly experienced by adults living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). DESIGN Cross-sectional descriptive study. SETTING HIV clinics and community sites in the San Francisco Bay area. PARTICIPANTS A convenience sample of 289 adults (193 men, 73 women, and 23 transgender) living with HIV/AIDS. INTERVENTIONS None. MEASUREMENTS AND RESULTS A wrist actigraph was worn for 72 h to estimate the percentage of wake after sleep onset (WASO%) and total sleep time (TST), plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1B, IL1R2, IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor-alpha (TNFA). Controlling for demographic variables such as race and sex, and clinical variables such as CD4+ count and medications, higher WASO% was associated with single nucleotide polymorphisms (SNPs) of IL1R2 rs11674595 and TNFA rs1041981 and less WASO% was associated with IL2 rs2069776. IL1R2 rs11674595 and TNFA rs1041981 were also associated with short sleep duration. CONCLUSIONS This study strengthens the evidence for an association between inflammation and sleep maintenance problems. In this chronic illness population, cytokine polymorphisms associated with wake after sleep onset provide direction for intervention research aimed at comparing anti-inflammatory mechanisms with hypnotic agents for improving sleep maintenance and total sleep time.

Updated Adaptive Servo-Ventilation Recommendations for the 2012 AASM Guideline: "The Treatment of Central Sleep Apnea Syndromes in Adults: Practice Parameters with an Evidence-Based Literature Review and Meta-Analyses".

ABSTRACT An update of the 2012 systematic review and meta-analyses were performed and a modified-GRADE approach was used to update the recommendation for the use of adaptive servo-ventilation (ASV) for the treatment of central sleep apnea syndrome (CSAS) related to congestive heart failure (CHF). Meta-analyses demonstrated an improvement in LVEF and a normalization of AHI in all patients. Analyses also demonstrated an increased risk of cardiac mortality in patients with an LVEF of ≤ 45% and moderate or severe CSA predominant sleep-disordered breathing. These data support a Standard level recommendation against the use of ASV to treat CHF-associated CSAS in patients with an LVEF of ≤ 45% and moderate or severe CSAS, and an Option level recommendation for the use of ASV in the treatment CHF-associated CSAS in patients with an LVEF > 45% or mild CHF-related CSAS. The application of these recommendations is limited to the target patient populations; the ultimate judgment regarding propriety of any specific care must be made by the clinician.

Cytokine polymorphisms and plasma levels are associated with sleep onset insomnia in adults living with HIV/AIDS

Sleep disturbance has been associated with inflammation and cytokine activity, and we previously described genetic associations between cytokine polymorphisms and sleep maintenance and duration among adults with HIV/AIDS. Although sleep onset insomnia (SOI) is also a commonly reported sleep problem, associations between cytokine biomarkers and SOI have not been adequately studied. The purpose of this study was to describe SOI in relation to cytokine plasma concentrations and gene polymorphisms in a convenience sample of 307 adults (212 men, 72 women, and 23 transgender) living with HIV/AIDS. Based on the Pittsburgh Sleep Quality Index item that asks the time it usually took to fall asleep in the past month, participants were categorized as either >30min to fall asleep (n=70, 23%) or 30min or less to fall asleep (n=237). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. After adjusting for genomic estimates of ancestry, self-reported race/ethnicity and viral load, SOI was associated with higher IL-13 plasma levels and with six single nucleotide polymorphisms (SNPs): IL1B rs1143642 and rs1143623, IL6 rs4719714, IL13 rs1295686, NFKB1 rs4648110, and TNFA rs2857602. In addition, the IL1B rs1143642 polymorphism was associated with plasma levels of IL-1β in adjusted analyses. This study strengthens the evidence for an association between inflammation and sleep disturbance, particularly self-report of habitual SOI. In this chronic illness population, the cytokine polymorphisms associated with SOI provide direction for future personalized medicine intervention research.

Quality measures for the care of adult patients with restless legs syndrome

ABSTRACT The American Academy of Sleep Medicine (AASM) commissioned several Workgroups to develop quality measures for the care of patients with common sleep disorders, including adults with restless legs syndrome (RLS). Using the AASM process for quality measure development, the RLS Work-group developed three target outcomes for RLS management, including improving the accuracy of diagnosis, reducing symptom severity, and minimizing treatment complications. Seven processes were developed to support these outcomes. To achieve the outcome of improving accuracy of diagnosis, the use of accepted diagnostic criteria and assessment of iron stores are recommended. To realize the outcome of decreasing symptom severity, routine assessment of severity and provision of evidence-based treatment are recommended. To support the outcome of minimizing treatment complications, counseling about potential side effects and assessing for augmentation and impulse control disorders, when indicated, are recommended. Further research is needed to validate optimal practice processes to achieve best outcomes in adult patients with RLS.

Polymorphisms of Interleukin-1 Beta and Interleukin-17Alpha Genes Are Associated With Restless Legs Syndrome

Objective: Dopamine, iron, and inflammatory pathways are considered important to the development of restless legs syndrome (RLS). Recent genetic studies support involvement of dopamine and iron; however, cytokine gene variation in the inflammatory component remains unexplored. A recent study reported a high prevalence of RLS among HIV-infected adults. We estimate occurrence of RLS in an ethnically diverse sample of HIV-infected adults and examine differences in demographic factors, clinical characteristics, and biomarkers relating to dopamine, iron, and inflammation between adults with and without RLS symptoms. Design: A prospective longitudinal study aimed at identifying biomarkers of RLS symptom experience among HIV-infected adults. Method: 316 HIV-positive adults were evaluated using International RLS Study Group criteria. Genes were chosen for hypothesized relationships to dopamine (NOS1, NOS2), iron (HFE) or inflammation-mediated by cytokine genes (interferon [IFN], interleukin [IL], nuclear factor kappa-B [NFKB], and tumor necrosis factor alpha [TNFA]). Results: Similar to general population estimates, 11% of the sample met all four RLS diagnostic criteria. Controlling for race, gender, and hemoglobin, carrying two copies of the minor allele for IL1B rs1143643, rs1143634, or rs1143633 or carrying the minor allele for IL17A rs8193036 was associated with increased likelihood of meeting RLS diagnostic criteria. Conclusion: This study provides preliminary evidence of a genetic association between IL1B and IL17A genes and RLS.

Sleep Disturbances in Midlife Women at the Cusp of the Menopausal Transition

STUDY OBJECTIVES To compare causes of sleep disturbance and to compare self-reported sleep duration among groups of late premenopausal women and early perimenopausal women. METHODS In a longitudinal study of a community-based sample of healthy women 40 to 50 years of age, menstrual cycle and symptom data were collected every 2 months; anthropometric measures, a urine sample for follicle stimulating hormone (FSH), and the Pittsburgh Sleep Quality Index (PSQI) measures were collected every 6 months. RESULTS At 12 to 18 months, 206 women remained premenopausal and 69 women became perimenopausal. Poor sleep quality (PSQI score > 5) was experienced by 42% of the total cohort. Awakening to use the bathroom was the most frequent reason (81%) for sleep disturbance in the entire cohort, followed by feeling too hot (26%). However, premenopausal women were significantly more likely to awaken to use the bathroom than perimenopausal women (P = .047), and perimenopausal women were more likely than premenopausal women to awaken because of feeling too hot (P = .002). Women in early perimenopause reported shorter sleep duration (P = .007) and worse sleep quality (P = .05) than premenopausal women of similar age. CONCLUSIONS Sleep disturbance is a significant issue for midlife women regardless of age or reproductive stage. Identification of salient factors that disrupt sleep, such as nocturia prior to menopausal transition or feeling too hot early in menopausal transition, will provide direction for developing tailored intervention strategies to improve sleep and quality of life. COMMENTARY A commentary on this article appears in this issue on page 1095.