Magnesium citrate monotherapy improves RLS symptoms and multiple suggested immobilization test scores in an open-label pilot study.

STUDY OBJECTIVES: An estimated 3% of the population suffers from clinically significant restless legs syndrome. Given the limited pharmacological options in the arsenal, there is a need for a therapeutic agent with a better side effect profile. METHODS: Twelve treatment naïve adults (10 women and 2 men with a median age of 41.5 [32-48.5] years) with primary RLS were recruited in our open-label pilot study; magnesium citrate 200 mg was administered daily for eight weeks. Serum magnesium levels, IRLS, Kohnen QOL scale, and multiple suggested immobilization tests were performed before and after supplementation. Paired t-tests and Wilcoxon signed-rank tests were used for data analysis. Pearson and Spearman's analyses assessed the association between magnesium levels and RLS variables. RESULTS: Participants had a significant reduction in IRLS scores (- 6.67 [2.33-11] p=0.006) and improved Kohnen QOL scores (-8.5 [2.09-14], p=0.014) without notable differences in serum magnesium levels (p=0.3). Average PLMW across all SIT trials (30.40 [5.20, 122.40] to 8.63 [0.32, 17.47] p=0.043) and subjective measures on mSIT also demonstrated improvement. Serum magnesium levels negatively correlated with m-SIT self-reported scores and the PLMW indices. CONCLUSIONS: Despite the limitations of open-label design, our study's positive results indicate the need for a placebo-controlled trial with a larger sample size. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT04462796).

Restless legs syndrome, periodic limb movements of sleep, and subclinical cardiovascular disease.

Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) have been variably implicated in risk for cardiovascular disease (CVD), but there is lack of consensus on these relationships. We sought to assess subclinical CVD measures and RLS/PLMS in a large cohort to further evaluate these associations. The Emory Center for Health Discovery and Well Being cohort is composed of employed adults, with subclinical CVD measures including endothelial function (flow-mediated vasodilation), microvascular function (reactive hyperemia index, RHI), arterial stiffness (pulse wave velocity and augmentation index), and carotid intima-media thickness (cIMT). Participants were grouped based on presence (N = 50) or absence (N = 376) of RLS and subclinical CVD measures compared between groups. A subset of participants (n = 40) underwent ambulatory monitoring for PLMS and obstructive sleep apnea. PLMS association with subclinical CVD measures was assessed. RLS status was significantly associated with flow-mediated dilation in univariate analyses but not after controlling for potential confounders; RLS was not associated with other subclinical CVD measures. PLMS were significantly correlated with the RHI, augmentation index, and cIMT in univariate analyses; only the association between PLMS and cIMT remained significant (p = 0.04) after controlling for RLS status, age, apnea-hypopnea index, hyperlipidemia, and hypertension. The observed association between higher PLMS and greater cIMT suggests that PLMS may be a marker of subclinical CVD. Further work is needed to determine the relationship between PLMS and CVD risk. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-023-00497-7.

Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement.

The period of the year from spring to fall, when clocks in most parts of the United States are set one hour ahead of standard time, is called daylight saving time, and its beginning and ending dates and times are set by federal law. The human biological clock is regulated by the timing of light and darkness, which then dictates sleep and wake rhythms. In daily life, the timing of exposure to light is generally linked to the social clock. When the solar clock is misaligned with the social clock, desynchronization occurs between the internal circadian rhythm and the social clock. The yearly change between standard time and daylight saving time introduces this misalignment, which has been associated with risks to physical and mental health and safety, as well as risks to public health. In 2020, the American Academy of Sleep Medicine (AASM) published a position statement advocating for the elimination of seasonal time changes, suggesting that evidence best supports the adoption of year-round standard time. This updated statement cites new evidence and support for permanent standard time. It is the position of the AASM that the United States should eliminate seasonal time changes in favor of permanent standard time, which aligns best with human circadian biology. Evidence supports the distinct benefits of standard time for health and safety, while also underscoring the potential harms that result from seasonal time changes to and from daylight saving time. CITATION: Rishi MA, Cheng JY, Strang AR, et al. Permanent standard time is the optimal choice for health and safety: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2024;20(1):121-125.

sPDGFRß and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. METHODS: Adults (45-65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2. RESULTS: CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aß)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor ß (sPDGFRß) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aß40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRß and tau were significantly lower in B/AA than NHW. DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. HIGHLIGHTS: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

Novel Objective Measures of Hypersomnolence.

Purpose of review: To provide a brief overview of current objective measures of hypersomnolence, discuss proposed measure modifications, and review emerging measures. Recent findings: There is potential to optimize current tools using novel metrics. High-density and quantitative EEG-based measures may provide discriminative informative. Cognitive testing may quantify cognitive dysfunction common to hypersomnia disorders, particularly in attention, and objectively measure pathologic sleep inertia. Structural and functional neuroimaging studies in narcolepsy type 1 have shown considerable variability but so far implicate both hypothalamic and extra-hypothalamic regions; fewer studies of other CDH have been performed. There is recent renewed interest in pupillometry as a measure of alertness in the evaluation of hypersomnolence. Summary: No single test captures the full spectrum of disorders and use of multiple measures will likely improve diagnostic precision. Research is needed to identify novel measures and disease-specific biomarkers, and to define combinations of measures optimal for CDH diagnosis.

At-home wireless sleep monitoring patches for the clinical assessment of sleep quality and sleep apnea.

Although many people suffer from sleep disorders, most are undiagnosed, leading to impairments in health. The existing polysomnography method is not easily accessible; it's costly, burdensome to patients, and requires specialized facilities and personnel. Here, we report an at-home portable system that includes wireless sleep sensors and wearable electronics with embedded machine learning. We also show its application for assessing sleep quality and detecting sleep apnea with multiple patients. Unlike the conventional system using numerous bulky sensors, the soft, all-integrated wearable platform offers natural sleep wherever the user prefers. In a clinical study, the face-mounted patches that detect brain, eye, and muscle signals show comparable performance with polysomnography. When comparing healthy controls to sleep apnea patients, the wearable system can detect obstructive sleep apnea with an accuracy of 88.5%. Furthermore, deep learning offers automated sleep scoring, demonstrating portability, and point-of-care usability. At-home wearable electronics could ensure a promising future supporting portable sleep monitoring and home healthcare.

Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABAAR Activation.

GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABAARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. We determined modulation with both conventional and microfluidic patch clamp methods. We found that receptor activation was variably modulated by all 11 compounds: Rifampicin (RIF), Metronidazole (MET), Minocycline (MIN), Erythromycin (ERY), Ofloxacin (OFX), Chloroquine (CQ), Hydroxychloroquine sulfate (HCQ), Flumazenil (FLZ), Pentylenetetrazol (PTZ), (-)-Epigallocatechin Gallate (EGCG), and clarithromycin (CLR). The computational modeling of modulator-receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. Our findings suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance.

Quality measures for the care of adult patients with obstructive sleep apnea: 2022 update after measure maintenance.

Obstructive sleep apnea (OSA) remains a highly prevalent disorder that can lead to multiple adverse outcomes when undiagnosed and/or when left untreated. There continue to be gaps and variations in the provision of care for the adult patient population with OSA, which emphasizes the importance of the measure maintenance initiative for The Quality Measures for the Care of Adult Patients with Obstructive Sleep Apnea (originally developed in 2015). The American Academy of Sleep Medicine (AASM) convened the Quality Measures Task Force in 2018 to review the current medical literature, other existing quality measures focused on the same patient population, and any performance data or data in the medical literature that show gaps or variations in care, to inform potential revisions to the quality measure set. These revised quality measures will be implemented in the AASM Sleep Clinical Data Registry (Sleep CDR) to capture performance data and encourage continuous improvement in outcomes associated with diagnosing and managing OSA in the adult population. CITATION: Lloyd R, Morgenthaler TI, Donald R, et al. Quality measures for the care of adult patients with obstructive sleep apnea: 2022 update after measure maintenance. J Clin Sleep Med. 2022;18(11):2673-2680.

Age and weight considerations for the use of continuous positive airway pressure therapy in pediatric populations: an American Academy of Sleep Medicine position statement.

This position statement provides guidance for age and weight considerations for using continuous positive airway pressure therapy in pediatric populations. The American Academy of Sleep Medicine commissioned a task force of experts in pediatric sleep medicine to review the medical literature and develop a position statement based on a thorough review of these studies and their clinical expertise. The American Academy of Sleep Medicine Board of Directors approved the final position statement. It is the position of the American Academy of Sleep Medicine that continuous positive airway pressure can be safe and effective for the treatment of obstructive sleep apnea for pediatric patients, even in children of younger ages and lower weights, when managed by a clinician with expertise in evaluating and treating pediatric obstructive sleep apnea. The clinician must make the ultimate judgment regarding any specific care in light of the individual circumstances presented by the patient, accessible treatment options, patient/parental preference, and resources. CITATION: Amos L, Afolabi-Brown O, Gault D, et al. Age and weight considerations for the use of continuous positive airway pressure therapy in pediatric populations: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2022;18(8):2041-2043.

Restless Legs Symptoms and Periodic Leg Movements in Sleep Among Patients with Parkinson's Disease.

BACKGROUND: The association between restless legs syndrome (RLS) and Parkinson's disease (PD) remains controversial, with epidemiologic and descriptive evidence suggesting some potential overlap while mechanistic/genetic studies suggesting relative independence of the conditions. OBJECTIVE: To examine a known, objectively measured endophenotype for RLS, periodic leg movements (PLMS) in sleep, in patients with PD and relate that objective finding to restless legs symptoms. METHODS: We performed polysomnography for one (n = 8) or two (n = 67) consecutive nights in 75 PD patients and examined the association of PLMS with restless legs symptoms. RESULTS: We found no association between restless legs symptoms and PLMS in PD. Prevalence of both was similar to data reported previously in other PD samples. CONCLUSION: We interpret these results as suggesting that restless legs symptoms in PD patients may represent a different phenomenon and pathophysiology than RLS in the non-PD population.

Behavioral validation of the University of Michigan REM behavior disorder questionnaire in the synucleinopathies.

Many questionnaires have been proposed to collect data related to dream enactment. These are typically validated by reference to objective measurements of polysomnography, which incorporate physiologic recording of muscle activity during sleep. Another approach to such questionnaire validation would be the direct behavioral observations of patients' sleep. In the course of an ongoing study, we examined the association between sleep technologists' observations of dream enactment on two consecutive sleep laboratory nights and patients' and bedpartners' responses on the University of Michigan REM Behavior Disorder Questionnaire (UMRBDQ). Results suggested good correspondence between laboratory-based observations and questionnaire responses that did not appear to be impacted by whether the patient or the bedpartner completed the questionnaire. These results suggest utility of the UMRBDQ to identify individuals who have dream enactment during sleep.

The Psychomotor Vigilance Test as a measure of alertness and sleep inertia in people with central disorders of hypersomnolence.

STUDY OBJECTIVES: The central disorders of hypersomnolence (CDH) manifest with daytime sleepiness, often accompanied by cognitive symptoms. Objective tests characterizing cognitive dysfunction may have diagnostic utility. Further, because some people with CDH report worsening cognition upon awakening, cognitive testing before and after napping may provide additional diagnostic information. METHODS: Patients with CDH with idiopathic hypersomnia (n = 76), narcolepsy type 1 (n = 19), narcolepsy type 2 (n = 22), and self-reported excessive daytime sleepiness not meeting current diagnostic criteria (n = 76) and nonsleepy controls (n = 33) underwent testing with the Psychomotor Vigilance Test (PVT), a 10-minute reaction-time test. A subset of participants underwent repeat testing during a Multiple Sleep Latency Test, before and immediately after naps 2 and 4. RESULTS: Most PVT metrics were significantly better in controls than in patients with CDH. Minimal group differences in PVT performance were observed by CDH diagnosis. PVT performance was weakly correlated to Epworth Sleepiness Scale and Multiple Sleep Latency Test mean sleep latency in the CDH group. Before and after naps, PVT metrics were minimally different for controls, while PVT performance generally worsened following naps in the CDH group, with significant worsening compared with controls for nap 2 mean, median, lapses, and fastest 10% of responses and nap 4 lapses and slowest 10% of responses. Change in performance did not differ based on CDH diagnostic group for any metric on either nap. CONCLUSIONS: The PVT, at baseline and following a short nap, may provide adjunctive diagnostic utility in separating individuals with CDH from controls. CITATION: Trotti LM, Saini P, Bremer E, et al. The Psychomotor Vigilance Test as a measure of alertness and sleep inertia in people with central disorders of hypersomnolence. J Clin Sleep Med. 2022;18(5):1395-1403.

Enhancing public health and safety by diagnosing and treating obstructive sleep apnea in the transportation industry: an American Academy of Sleep Medicine position statement.

Obstructive sleep apnea (OSA) may lead to serious health, safety, and financial implications-including sleepiness-related crashes and incidents-in workers who perform safety-sensitive functions in the transportation industry. Evidence and expert consensus support its identification and treatment in high-risk commercial operators. An Advanced Notice of Proposed Rulemaking regarding the diagnosis and treatment of OSA in commercial truck and rail operators was issued by the Federal Motor Carrier Safety Administration and Federal Railroad Administration, but it was later withdrawn. This reversal has led to questions about whether efforts to identify and treat OSA are warranted. In the absence of clear directives, we urge key stakeholders, including clinicians and patients, to engage in a collaborative approach to address OSA by following, at a minimum, the 2016 guidelines issued by a Medical Review Board of the Federal Motor Carrier Safety Administration, alone or in combination with 2006 guidance by a joint task force. The current standard of care demands action to mitigate the serious health and safety risks of OSA. CITATION: Das AM, Chang JL, Berneking M, et al. Enhancing public health and safety by diagnosing and treating obstructive sleep apnea in the transportation industry: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2022;18(10):2467-2470.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline.

INTRODUCTION: This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS: The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. 1: We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). 2: We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). 3: We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). 4: We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). 5: We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). 6: We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). 7: We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). 8: We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). 9: We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 10: We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 11: We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 12: We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). 13: We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). 14: We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). 15: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). 16: We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). 17: We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). 18: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). 19: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). 20: We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). 21: We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). 22: We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.