Lipford, Melissa C.

Summary: This article summarizes restless legs syndrome (RLS), periodic limb movements of sleep, and periodic limb movement disorder. RLS is a common sleep disorder with a prevalence of 5% to 15% in the general population. RLS can present in childhood, and incidence increases with age. RLS can be idiopathic or secondary to iron deficiency, chronic renal failure, peripheral neuropathy, and medications such as antidepressants (with higher rates for mirtazapine and venlafaxine, while bupropion may reduce symptoms at least in the short term), dopamine antagonists (neuroleptic antipsychotic agents and antinausea medications), and possibly antihistamines. Management includes pharmacologic agents (dopaminergic agents, alpha-2 delta calcium channel ligands, opioids, benzodiazepines) and nonpharmacologic therapies (iron supplementation, behavioral management). Periodic limb movements of sleep are an electrophysiologic finding commonly accompanying RLS. On the other hand, most individuals with periodic limb movements of sleep do not have RLS. The clinical significance of the movements has been argued. Periodic limb movement disorder is a distinct sleep disorder that arises in individuals without RLS and is a diagnosis of exclusion.

Abstract Study Objectives Isolated REM sleep behavior disorder (iRBD) carries a high lifetime risk for phenoconversion to a defined neurodegenerative disease (NDD) including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. We aimed to examine iRBD patient values and preferences regarding prognostic counseling. Methods One hundred thirteen iRBD patient participants enrolled in the Mayo Clinic iRBD Patient Registry were sent an email survey concerning their values and preferences concerning NDD prognostic counseling and their experiences following diagnosis with iRBD. Results Of 81 respondents (71.7% response rate), the majority were men (74.0%) with an average age of 65.7 (±9.7) years. Responses indicated a strong preference toward receiving prognostic information about possible future NDD development. 92.5% of respondents felt knowledge concerning personal NDD risk was important, while 87.6% indicated prognostic discussions were important to maintaining trust in their physician. 95.7% indicated a desire for more information, while only 4.3% desired less information regarding their NDD prognostic risk. Most respondents strongly agreed that prognostic information was important to discuss with their family and friends and inform future life planning, and most expressed interest in learning more about future neuroprotective therapies and symptomatic treatments for parkinsonism and dementia. Conclusions Most iRBD patients indicated strong preferences for disclosure of NDD prognostic risk and indicated that prognostic information was important for family discussions and future life planning. Future broader surveys and qualitative studies of clinic-based and ultimately community dwelling iRBD patients’ values and preferences are needed to guide appropriately tailored and individualized prognostic counseling approaches following iRBD diagnosis.

Abstract Introduction Discontinuation of opioid medications may be associated with emergence of restless legs syndrome (RLS), which may complicate opioid withdrawal. However, this has not been systematically studied. We aimed to prospectively determine the frequency of the occurrence and severity of RLS symptoms in patients undergoing physician supervised opioid tapering during a 3-week interdisciplinary pain rehabilitation program. Methods Adult patients undergoing prescription opioid taper were prospectively recruited during their participation in the Mayo Pain Rehabilitation Center from 2016 to 2021. Subjects completed the Cambridge-Hopkins RLS Questionnaire 13 and International Restless Legs Syndrome Study Group Rating Scale (IRLS) at baseline, midpoint, and dismissal from the program as well as 2 weeks, 1 and 3 months after dismissal from the program. Results 101 patients participated with 61% being female taking a mean morphine equivalent dose of 46.6 ± 49.0 mg. Baseline prevalence of RLS symptoms was 29% (29/101), increasing to 32% (32/101) at midpoint of treatment and further to 35% (34/97) at dismissal from the program. Frequency of RLS symptoms peaked 2 weeks after dismissal at 38% (30/78) and steadily declined to 35% (28/80) and 31% (21/68) at 1 month and 3 months after dismissal, respectively. Thirty-five percent of patients without baseline RLS symptoms reported de novo RLS symptoms at some point during their opioid taper. RLS severity score followed a similar trend as the presence of symptoms with a baseline of 16.6 ± 10.0. RLS severity score was maximum at 19.1 ± 7.3 one month following dismissal and decreased but remained elevated above baseline at 3 months following dismissal. Conclusion Symptoms of RLS occurred in over a third of patients on chronic opioids and increased during opioid withdrawal, appearing to peak in frequency and severity 2-4 weeks after discontinuation and gradually improved 3 months after discontinuation. Over one-third of patients in our cohort developed de novo symptoms of RLS at some point during their opioid withdrawal. Physicians supervising individuals undergoing opioid withdrawal should be aware of the potential development of RLS symptoms which may hinder successful opioid withdrawal. Support (If Any)

Abstract The American Thoracic Society Sleep Core Curriculum updates clinicians on important sleep topics, presented during the annual meeting, and appearing in summary here. This year’s sleep core theme is sleep-disordered breathing and its management. Topics range from pathophysiological mechanisms for the association of obstructive sleep apnea (OSA) and metabolic syndrome, surgical modalities of OSA treatment, comorbid insomnia and OSA, central sleep apnea, and sleep practices during a pandemic. OSA has been associated with metabolic syndrome, independent of the role of obesity, and the pathophysiology suggests a role for sleep fragmentation and intermittent hypoxia in observed metabolic outcomes. In specific patient populations, surgical treatment modalities for OSA have demonstrated large reductions in objective disease severity compared with no treatment and may facilitate adherence to positive airway pressure treatment. Patient-centered approaches to comorbid insomnia and sleep apnea include evaluating for both OSA and insomnia simultaneously and using shared-decision making to determine the order and timing of positive airway pressure therapy and cognitive behavioral therapy for insomnia. The pathophysiology of central sleep apnea is complex and may be due to the loss of drive to breathe or instability in the regulatory pathways that control ventilation. Pandemic-era sleep practices have evolved rapidly to balance safety and sustainability of care for patients with sleep-disordered breathing.

Introduction: Obstructive sleep apnea (OSA) is an independent risk factor for ischemic stroke; however the causal mechanisms are unknown. Understanding etiology of stroke in OSA patients may: (1) aid in ascertaining how OSA exerts its influence in increasing stroke risk, and (2) facilitate tailoring recurrent stroke prevention management strategies in OSA patients. Our study compares stroke subtypes in OSA cases versus controls without significant sleep disordered breathing. Hypothesis: We hypothesized cardioembolic (CE) strokes would occur more frequently in OSA cases than in controls. Methods: Consecutive patients were identified who underwent polysomnography (PSG) at Mayo Clinic and suffered an ischemic stroke within one year after PSG. Patients with an apnea-hypopnea index (AHI) ≤ 10 were classified as controls; AHI > 10 classified as OSA cases. Mechanism of stroke was determined using (1) the Causative Classification System for Ischemic Stroke (CCS) and (2) the phenotype definitions used in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Information on cardiovascular risk factors, neuroimaging, and echocardiography data were collected on each patient. Results: In 53 total subjects, CE strokes were more common among OSA cases (72% vs 33%, p=0.01). Large artery atherosclerosis and small vessel occlusion strokes were more common in controls. Atrial fibrillation (AF) was more frequent in OSA patients (59% vs 24%, p=0.01). Frequency of CE stroke increased with OSA severity. The association between OSA and CE stroke remained significant after controlling for AF (p=0.03, OR 4.5). Echocardiogram data revealed CE stroke risk factors were more frequent in OSA cases (84% vs 52% p=0.02). There were no significant differences between groups for left ventricular ejection fraction, left atrial volume index, or right ventricular systolic pressure. Conclusions: The results demonstrate a strong association between OSA and CE stroke. In OSA patients presenting with cryptogenic stroke, high clinical suspicion for cardioembolism is warranted. This may lead to consideration of further studies (eg, transesophageal echocardiography, Holter monitoring, or extended cardiac monitoring) to identify cardioembolic risk factors such as paroxysmal AF.

Background The prevalence of excessive daytime sleepiness (EDS) in the general population is reported to be 9 to 28 percent. Various social and biological factors have been reported to contribute to the development of EDS, such as cardiovascular disease, metabolic disorders as well as socioeconomic status. Medically, EDS is associated with poorer prognosis in patients with sleep disorders. However, whether sleepiness is an independent negative prognostic indicator in patients without sleep apnea is poorly understood. Objective To evaluate the relationship between self‐reported excessive daytime sleepiness (assessed by Epworth Sleepiness Scale) and the risk of all‐cause mortality in patients without obstructive sleep apnea (OSA). Methods We performed a retrospective cohort study in a large registry of patients seen at the Mayo Clinic Center for Sleep Medicine between November 17 th , 2009 and April 15 th , 2017. All patients received a diagnostic polysomnography and had completed Epworth Sleepiness Scale (ESS). The primary outcome of all‐cause mortality risk was computed using the Kaplan‐Meier analysis and Cox‐proportional hazard model with age, sex, body mass index (BMI), baseline comorbidities and sleep measurements as confounders. Results A total of 2746 non‐OSA patients were identified. The overall median age (IQR) was computed as 53 (40, 63) with 45% of patients identifying as males. The median follow‐up time was approximately 2.3 years. In a univariate analysis, daytime sleepiness was associated with the female sex, younger age and higher BMI. No significant differences were observed in vascular related diseases between sleepy and non‐sleepy patients. EDS was not significantly associated with all‐cause mortality with an adjusted hazard ratio of 1.23 (95% CI 0.86, 1.76; p =0.257). In addition, there was no significant association of EDS and the risk of all‐cause mortality even after stratifying by sex, age and BMI in non‐OSA patients. Conclusion EDS is not associated with all‐cause mortality in non‐OSA patients. Further prospective studies are needed to confirm this finding. Support or Funding Information This research was supported by NIH HL65176 and NIH HL114024. Kaplan–Meier survival curve of 8 years all‐cause mortality of non‐OSA patients with and without excessive daytime sleepiness (EDS) at baseline. image Kaplan–Meier survival curve of 8 years all‐cause mortality of non‐OSA patients with and without excessive daytime sleepiness (EDS) at baseline. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Abstract Introduction REM sleep behavior disorder (RBD) is characterized by disruptive, violent dream enactment behaviors (DEB), necessitating symptomatic treatment to prevent injury and reduce DEB frequency and severity. Melatonin and clonazepam are regarded as RBD therapeutic mainstays, although outcomes data remains limited. We surveyed RBD patients to determine their outcomes following melatonin, clonazepam, and melatonin-clonazepam combination therapy. Methods Mayo Clinic RBD Patient Registry participants received an electronic survey concerning treatment type(s) and dose(s), efficacy, and adverse effects. The primary outcome was treatment efficacy, determined by comparing DEB frequency/severity ratings on a visual analog scale (VAS). Adverse effects severity was assessed by Likert scales. We comparatively analyzed VAS before and after treatment and adverse effects between treatments using non-parametric statistical tests. Results Sixty-eight of 109 patients responded (62.3%; 64 had analyzable data) with a mean age of 67.7 years. Fifty-seven (85%) were men, with mean RBD symptom duration of 13.9 years. Patients receiving each treatment were: melatonin=30, clonazepam=8, and combination=12; 14 received other or no treatment. Baseline VAS ratings were similar between groups. Only melatonin (p=0.003) and combination therapy (p=0.039) improved VAS ratings; clonazepam monotherapy did not improve VAS. Only melatonin monotherapy was reported to lower VAS compared to untreated patients (p=0.02). Optimally effective mean dosages were melatonin 9.95±5.06 mg and clonazepam 0.81±0.48 mg. Patient frequencies reporting one or more moderately-severe side effect(s) were similar between melatonin (15%), clonazepam (7%), and combination therapies (9%). Twenty-five (36.8%) patients had received only one medication trial, while 41.2% required more than one medication. Of these, 15 (22.1%) tried 2 and 13 (19.1%) tried 3 or more treatments. Conclusion Melatonin therapy at an approximate mean 10 mg dosage improved patient-reported DEB frequency/severity on VAS, compared between both previous intraindividual baseline ratings and with untreated patients, while clonazepam monotherapy did not, without differential adverse effects. Clonazepam monotherapy data were limited. These data inform future prospective melatonin symptomatic therapy trials for RBD. Additionally, 41.2% required more than one RBD pharmacological treatment, suggesting a current therapeutic gap and unmet need for future development of biologically-informed, evidence-based symptomatic RBD therapeutics. Support (if any):

Abstract The American Thoracic Society Core Curriculum updates clinicians annually in adult and pediatric pulmonary disease, medical critical care, and sleep medicine, in a 3–4-year recurring cycle of topics. These topics will be presented at the 2020 Virtual Conference. Below is the adult sleep medicine core that includes topics pertinent to sleep-disordered breathing and insomnia.