Modafinil Versus Amphetamine-Dextroamphetamine For Idiopathic Hypersomnia and Narcolepsy Type 2: A Randomized, Blinded, Non-inferiority Trial.

BACKGROUND AND OBJECTIVE: Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine-dextroamphetamine in these disorders. METHODS: Forty-four adults were randomized to modafinil or amphetamine-dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine-dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups. RESULTS: Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine-dextroamphetamine; noninferiority of amphetamine-dextroamphetamine was not demonstrated (P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine-dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine. CONCLUSION: Noninferiority of amphetamine-dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine-dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2. REGISTRATION: Clinicaltrials.gov Registration (NCT03772314) 12/10/18. .

Altered functional connectivity and spatiotemporal dynamics in individuals with sleep disorders.

Idiopathic hypersomnia (IH) is a sleep disorder characterized by highly disruptive symptoms. Like narcolepsy type 1, a well-characterized sleep disorder, individuals with IH suffer from excessive daytime sleepiness, though there is little overlap in metabolic or neural biomarkers across these two disorders. This lack of common pathophysiology, combined with the clear overlap in symptoms presents an ideal paradigm for better understanding the impact of IH on an individual's functional activity and organization, and potentially, the underlying pathophysiology. This study examines the observed functional connectivity in patients with IH, and patients with narcolepsy type 1 (NT1) against healthy control individuals. Static functional connectivity is compared, as are quasi-periodic patterns, acquired from the BOLD timecourse, for all groups. In addition to baseline data comparison, the study also included a post-nap condition, where the individuals included in this analysis napped for at least 10 minutes prior to the scanning session, to explore why individuals with IH do not feel refreshed after a nap like individuals with NT1 do. Assessing the groups' spatiotemporal patterns revealed key differences across both disorders and conditions: static connectivity revealed at baseline higher subcortical connectivity in the NT1 group. There was also observably less connectivity in the IH group both at baseline and post-nap, though none of these static analyses survived multiple comparisons correction to reach significance. The QPP results however found significant differences in the IH group in key networks, particularly the DAN/FPCN correlation is significantly different at baseline vs. post-nap, a trend not observed in either the control or NT1 groups. The DAN and FPCN are drastically altered both at baseline and post-nap when compared to the other groups, and may likely be a disorder-specific result. This study demonstrates that key networks for arousal are more heavily disrupted in IH patients, who are less affected by a nap, confirmed through both subject reporting and functional evidence through spatiotemporal patterns.

Validation and performance of the sleep inertia questionnaire in central disorders of hypersomnolence.

BACKGROUND: Optimal measurement tools for problematic sleep inertia, common in some central disorders of hypersomnolence (CDH), have not yet been determined. We evaluated the performance of the Sleep Inertia Questionnaire (SIQ) in CDH, and how well it distinguished hypersomnolent groups from controls, and IH (idiopathic hypersomnia) from narcolepsy type 1 (NT1). METHODS: This prospective, bi-centric study included 63 control, 84 IH, 16 NT1, 18 narcolepsy type 2 (NT2), and 88 subjective excessive daytime sleepiness (sEDS) participants, using ICSD-3 criteria. 126 (47.2 %) participants were on any medication at the time of SIQ completion. We assessed construct validity of SIQ scores, and sleep inertia duration (SID), and compared them across diagnoses, controlling for age and center. We derived cutpoints to distinguish hypersomnolent patients from controls and IH from NT1. Sensitivity analyses for depression, chronotype, and medication were performed. RESULTS: The SIQ sum and composite score were significantly lower in controls than in other groups (p < 0.0001), demonstrating outstanding ability to distinguish patients from controls (AUCs 0.92), without differences among hypersomnolent groups. SID (AUC 0.76) was significantly shorter in controls than in all hypersomnolent groups except NT1, and was shorter in NT1 than in IH or sEDS. Optimal SIQ sum cutpoint was 42 (J = 0.71) for patients versus controls. Optimal SID cutpoint in distinguishing IH from NT1 was 25 min (J = 0.39). CONCLUSION: The SIQ has excellent ability to distinguish hypersomnolent patients from healthy controls, after controlling for depression, eveningness, and medication. SID is best at distinguishing IH from NT1.

Sleep and sleep disorders in people with Parkinson's disease.

Sleep disorders are common in people with Parkinson's disease. These disorders, which increase in frequency throughout the course of the neurodegenerative disease and impair quality of life, include insomnia, excessive daytime sleepiness, circadian disorders, obstructive sleep apnoea, restless legs syndrome, and rapid eye movement (REM) sleep behaviour disorder. The causes of these sleep disorders are complex and multifactorial, including the degeneration of the neural structures that modulate sleep, the detrimental effect of some medications on sleep, the parkinsonian symptoms that interfere with mobility and comfort in bed, and comorbidities that disrupt sleep quality and quantity. The clinical evaluation of sleep disorders include both subjective (eg, questionnaires or diaries) and objective (eg, actigraphy or video polysomnography) assessments. The management of patients with Parkinson's disease and a sleep disorder is challenging and should be individualised. Treatment can include education aiming at changes in behaviour (ie, sleep hygiene), cognitive behavioural therapy, continuous dopaminergic stimulation at night, and specific medications. REM sleep behaviour disorder can occur several years before the onset of parkinsonism, suggesting that the implementation of trials of neuroprotective therapies should focus on people with this sleep disorder.

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

STUDY OBJECTIVES: An estimated 3% of the population has 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 naive adults (10 women and 2 men with a median age of 41.5 [32-48.5] years) with primary restless legs syndrome were recruited in our open-label pilot study; magnesium citrate 200 mg was administered daily for 8 weeks. Serum magnesium levels, International Restless Legs Syndrome Study Group Rating Scale, Kohnen quality of life scale, and multiple suggested immobilization tests (three 1-hour 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 restless legs syndrome variables. RESULTS: Participants had a significant reduction in International Restless Legs Syndrome Study Group Rating Scale scores (6.67 [2.33-11] P = .006) and improved Kohnen quality of life scores (8.5 [2.09-14], P = .014) without notable differences in serum magnesium levels (P = .3). The median periodic limb movements during wakefulness index (30.40 [5.20, 122.40] to 8.63 [0.32, 17.47] P = .043) and self-reported discomfort score (19 [14, 30.5] to 6 [0, 8] P = .0010) of all 3 multiple suggested immobilization test trials also demonstrated improvement. Serum magnesium levels negatively correlated with multiple suggested immobilization test self-reported scores and the periodic limb movements during wakefulness 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: Registry: ClinicalTrials.gov; Name: The Effect of Magnesium Citrate Supplementation in Restless Legs Syndrome (RLS); URL: https://clinicaltrials.gov/ct2/show/study/NCT04462796; Identifier: NCT04462796. CITATION: Gorantla S, Ravisankar A, Trotti LM. Magnesium citrate monotherapy improves restless legs syndrome symptoms and multiple suggested immobilization test scores in an open-label pilot study. J Clin Sleep Med. 2024;20(8):1357-1361.

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.