Search

Monica M Shieu,1 Tiffany J Braley,1 Jill Becker,2 Galit Levi Dunietz1 1Neurology, Medical School, University of Michigan, Ann Arbor, MI, USA; 2Psychology, Medical School, University of Michigan, Ann Arbor, MI, USACorrespondence: Monica M Shieu, Division of Sleep Medicine, Department of Neurology, University of Michigan, Neurology, C728 Med Inn Building, 1500 E. Medical Center Dr, Ann Arbor, MI, 48109, USA, Tel +1 734-764-5415, Fax +1 734-232-9986, Email mshie@umich.eduPurpose: The interrelationships among age at menopause, sleep, and brain health have been insufficiently studied. This study sought to examine the influence of age at natural menopause and insomnia symptoms on long-term cognitive function among US women.Patients and Methods: Our study included a nationally representative cohort of US adults age 50+ from the Health and Retirement Study (2008– 2018). We restricted this cohort to 5880 women age 50+, from a diverse racial and ethnic groups. Age at menopause was retrieved from baseline (2008) for women having natural menopause. Five questions were used to identify women with insomnia symptoms (2010 and 2012): trouble falling asleep, nighttime awakenings, early morning awakenings, feelings of nonrestorative sleep, and use of sleep aids. A battery of four neuropsychological tests was conducted biennially (years) to evaluate cognitive function. Longitudinal associations between age at natural menopause and cognitive function were estimated with mixed effects models with a random intercept. Insomnia symptoms were examined as potential mediators or modifiers in the pathway between age at menopause and cognition.Results: One year earlier in age at menopause was associated with a 0.49 lower mean in composite cognitive score, in any given survey year (adjusted p = 0.002). Earlier age at menopause was associated with higher risk of developing insomnia symptoms (eg, trouble falling asleep OR = 0.97; 95% CI: 0.96, 0.99), and insomnia symptoms were associated with worse cognitive performance (eg, trouble falling asleep, beta = − 0.5, p-value = 0.02). Therefore, insomnia symptoms could potentially mediate the association between age at natural menopause and cognition.Conclusion: Earlier age at menopause is associated with a lower score in cognitive performance. This association may be mediated by insomnia symptoms. Our findings spotlight that among women who experience early menopause, there is the need for studies of sleep-based interventions to mitigate cognitive decline.Keywords: age at menopause, cognitive performance, mediation, effect modification, natural menopause, population-based study

Background: Fatigue is one of the most disabling symptoms reported by people with multiple sclerosis. Although behavioural and pharmacological interventions might be partly beneficial, their combined effects have not been evaluated for multiple sclerosis fatigue, or examined with sufficient consideration of characteristics that might affect treatment response. In this comparative effectiveness research trial, we compared the effectiveness of cognitive behavioural therapy (CBT), modafinil, and their combination for treating multiple sclerosis fatigue., Methods: This randomised, analyst-blinded, parallel-arm, comparative effectiveness trial was done at two universities in the USA. Adults (aged ≥18 years) with multiple sclerosis and problematic fatigue (Fatigue Severity Scale [FSS] score ≥4) were randomly assigned (1:1:1), using a web-based treatment assignment system with minimisation, to receive CBT, modafinil, or both for 12 weeks. Statisticians were masked to group assignment, but participants, study neurologists, CBT interventionalists, and coordinators were not masked to treatment assignment. The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity. Analyses were done by intent to treat. The trial was registered with clinicaltrials.gov, NCT03621761, and is completed., Findings: Between Nov 15, 2018, and June 2, 2021, 336 participants were randomly assigned treatment (114 assigned to CBT, 114 assigned to modafinil, and 108 assigned to combination therapy). At 12 weeks, CBT (n=103), modafinil (n=107), and combination therapy (n=102) were associated with clinically meaningful within-group MFIS reductions of 15·20 (SD 11·90), 16·90 (15·90), and 17·30 (16·20) points, respectively. Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI -2·21 to 5·96) for CBT and 1·20 (-2·83 to 5·23) for modafinil. Most common adverse events for modafinil-containing treatment groups included insomnia (eight [7%] for modafinil and eight [7%] for combination therapy) and anxiety (three [3%] for modafinil and nine [8%] for combination therapy)., Interpretation: Modafinil, CBT, and combination therapy were associated with similar reductions in the effects of multiple sclerosis fatigue at 12 weeks. Combination therapy was not associated with augmented improvement compared with the individual interventions. Further research is needed to determine whether effects of these interventions on multiple sclerosis-related fatigue is influenced by sleep hygiene and sleepiness. No serious adverse events related to the study drug were encountered., Funding: Patient-Centered Outcomes Research Institute and National Multiple Sclerosis Society., Competing Interests: Declaration of interests TJB reports current or recent grants from the National Institutes of Health, the International Progressive MS Alliance, and the National MS Society, and an award from the Patient-Centered Outcomes Research Institute. She has received support from Michigan Humane for her research. She has received travel and meeting support from Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the American Academy of Neurology. She reports a patent held by the University of Michigan related to treatment of sleep apnoea. She receives material support, but no financial compensation, from Jazz Pharma for a National Institutes of Health-funded investigator-initiated trial. She holds unpaid service and leadership positions for the National MS Society and the ACTRIMS Program Committee. She has served as site principal investigator for trials of multiple sclerosis therapeutics sponsored by Genentech, Genyzme, and Novartis, but received no direct compensation for this work. KNA reports grants from the National Institutes of Health and the National MS Society and an award from the Patient-Centered Outcomes Research Institute. He has received royalties for licensing of materials to Actelion Pharmaceuticals. DME reports grants from the National Institutes of Health, the National MS Society, the National Institute of Disability, Independent Living, and Rehabilitation Research, Administration for Community Living, and the State of Washington, and an award from the Patient-Centered Outcomes Research Institute. She receives honoraria from the American Psychological Association for her role as Editor for the journal Rehabilitation Psychology. She has received royalties for licensing of materials to Actelion Pharmaceuticals. She serves without compensation in leadership and service roles for the National MS Society National Advisory Board on Medical Rehabilitation Research and on the editorial board for Archives of Physical Medicine and Rehabilitation. GvG reports grants from the Patient-Centered Outcomes Research Institute and the National MS Society and a contract from Novartis; she also serves on a National Institute for Neurological Disorders and Stroke board. TRV reports a grant from the National MS Society. ARR reports research effort support from the National Institutes of Health and travel and meeting support from ACTRIMS. RDC reports grants from the National Institutes of Health and the National MS Society, and an award from the Patient-Centered Outcomes Research Institute. He receives royalties from UpToDate for roles as an editor and author and is a paid Eli Lilly consultant (contract through University of Michigan). He reports patents and copyrighted material held by the University of Michigan for screening, diagnosis, and treatment of sleep disorders. He has held unpaid leadership positions on the board of directors and as treasurer and president elect for the International Pediatric Sleep Association. He serves on the advisory board of The Pajama Program. BMS reports grants from the National Institute of Health and Wings for Life Foundation. He has received travel support from ACTRIMS and International Society for Neuroimmunology for speaking engagements and programmatic activities. He serves as Secretary and Director for the ACTRIMS Program Committee. He has participated on a data and safety monitoring board for Data Safety Monitoring Committee, AACI Trailblazer Clinical Trial, Eli Lilly (2020–21). He holds filed or issued patents for an immune cell based neuroregenerative therapy, a treatment for sleep apnoea, and lymphoid chemokines, through the Ohio State University, University of Michigan, and University of Rochester, respectively. ALK reports grants from the National Institutes of Health, the National MS Society, the Craig H Neilsen Foundation, the National Institute of Disability, Independent Living, and Rehabilitation Research, Administration for Community Living, and the State of Michigan, and an award from the Patient-Centered Outcomes Research Institute. She receives honoraria from the American Psychological Association for her role as Editor for the journal Rehabilitation Psychology. She has received royalties for licensing of materials to Actelion Pharmaceuticals and she served as a paid consultant for Twill Health. She serves without compensation on committees for the United State Association for The Study of Pain and Society for Ambulatory Assessment and on the editorial boards for Journal of Pain and Arthritis Care & Research. RL, YTN, AJ, MH, MS, NL, YZ, and DC report no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Study Objectives: To evaluate sex-specific associations between known or suspected obstructive sleep apnea (OSA) and dementia risk over 10 years among older women and men., Methods: This study included 18 815 women and men age 50+ years (dementia-free at baseline) who participated in the Health and Retirement Study (HRS), a nationally representative cohort of US adults. Presence of OSA was defined by self-reported diagnosis or key HRS items that correspond to elements of a validated OSA screening tool (STOP-Bang). Incident dementia cases were identified using a validated, HRS-based algorithm derived from objective cognitive assessments. Survey-weighted regression models based on pseudo-values were utilized to estimate sex- and age-specific differences in cumulative incidence of dementia by OSA status., Results: Data from 18 815 adults were analyzed, of which 9% of women and 8% of men (weighted proportions) met criteria for incident dementia. Known/suspected OSA was more prevalent in men than in women (weighted proportions 68% vs. 31%). Unadjusted sex-stratified analyses showed that known/suspected OSA was associated with higher cumulative incidence of dementia across ages 60-84 years for women and men. By age 80, relative to adults without known/suspected OSA, the cumulative incidence of dementia was 4.7% higher (CI 2.8%, 6.7%) for women with known/suspected OSA, and 2.5% (CI 0.5%, 4.5%) for men with known/suspected OSA, respectively. Adjusted associations between age-specific OSA and cumulative incidence of dementia attenuated for both women and men but remained statistically significant., Conclusions: OSA contributes to dementia risk in older adults, particularly women. This study illuminates the impact of a potentially modifiable yet frequently overlooked risk factor for dementia onset., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society.)

Background and Aims: Smoking is a risk factor for multiple sclerosis (MS) development, symptom burden, decreased medication efficacy, and increased disease-related mortality. Veterans with MS (VwMS) smoke at critically high rates; however, treatment rates and possible disparities are unknown. To promote equitable treatment, we aim to investigate smoking cessation prescription practices for VwMS across social determinant factors., Methods: We extracted data from the national Veterans Health Administration electronic health records between October 1, 2017, and September 30, 2018. To derive marginal estimates of the association of MS with receipt of smoking-cessation pharmacotherapy, we used propensity score matching through the extreme gradient boosting machine learning model. VwMS who smoke were matched with veterans without MS who smoke on factors including age, race, depression, and healthcare visits. To assess the marginal association of MS with different cessation treatments, we used logistic regression and conducted stratified analyses by sex, race, and ethnicity., Results: The matched sample achieved a good balance across most covariates, compared to the pre-match sample. VwMS (n = 3320) had decreased odds of receiving prescriptions for nicotine patches ([Odds Ratio]OR = 0.86, p < .01), non-patch nicotine replacement therapy (NRT; OR = 0.81, p < .001), and standard practice dual NRT (OR = 0.77, p < .01), compared to matches without MS (n = 13,280). Men with MS had lower odds of receiving prescriptions for nicotine patches (OR = 0.88, p = .05), non-patch NRT (OR = 0.77, p < .001), and dual NRT (OR = 0.72, p < .001). Similarly, Black VwMS had lower odds of receiving prescriptions for patches (OR = 0.62, p < .001), non-patch NRT (OR = 0.75, p < .05), and dual NRT (OR = 0.52, p < .01). The odds of receiving prescriptions for bupropion or varenicline did not differ between VwMS and matches without MS., Conclusion: VwMS received significantly less smoking cessation treatment, compared to matched controls without MS, showing a critical gap in health services as VwMS are not receiving dual NRT as the standard of care. Prescription rates were especially lower for male and Black VwMS, suggesting that under-represented demographic groups outside of the white female category, most often considered as the "traditional MS" group, could be under-treated regarding smoking cessation support. This foundational work will help inform future work to promote equitable treatment and implementation of cessation interventions for people living with MS., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Multiple sclerosis (MS) is a progressive, autoimmune disease of the central nervous system that affects nearly one million Americans. Despite the existence of immunomodulatory therapies to slow physical and cognitive disability progression, interventions to ameliorate common symptoms of MS, including fatigue and pain, remain limited. Poor understanding of risk factors for these symptoms may contribute to treatment challenges. In recent years, childhood stress has been investigated as a risk factor for chronic autoimmune conditions including MS; yet remarkably few studies have investigated the relationship between childhood stressors and chronic MS symptoms. Our aim was to examine clusters of stressors and three key features of MS: fatigue, pain interference, and psychiatric morbidity., Methods: Cross-sectional data were collected from a sample of People with MS (PwMS) via a national web-based survey that assessed the presence and type of childhood stressors and MS clinical features. Hierarchical block regression was used to assess associations among emotional, physical, and environmental childhood stressors and three clinical features commonly experienced by PwMS., Results: N = 719 adults with MS (aged 21-85) completed the survey. Childhood emotional and physical stressors were significantly associated with overall presence of fatigue (p = 0.02; p<0.03) and pain interference (p<0.001; p<0.001) in adulthood, as well as the magnitude of both outcomes. Environmental stressors (p<0.001), in addition to emotional (p<0.001) and physical (p<0.001) stressors were significantly associated with psychiatric morbidity in PwMS., Conclusion: Childhood stress may predict fatigue, psychiatric morbidity, and pain in adults with MS. Further research is needed to show cause and effect; however, if an association exists, strategies to mitigate the impact of childhood stress could offer new pathways to reduce the severity of these symptoms. Broadly, this work adds to the body of evidence supporting upstream preventive measures to help address the stress on children and families., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: A majority of women with multiple sclerosis (MS) are diagnosed prior to menopause, yet their experiences during this transition are not well characterized., Objectives: To explore associations between mental health, sleep, and other quality of life metrics, and vasomotor symptoms (VMSs) in ambulatory, menopausal women with MS., Methods: A secondary analysis was performed of baseline data from two trials enrolling ambulatory peri/postmenopausal women with MS: NCT02710214 ( N = 24, bothersome VMS) and NCT04002934 (ongoing, N = 35, myelin repair). Measures analyzed were 36-Item Short-Form Survey (SF-36) (primary scale: general mental health), subjective sleep quality (Pittsburg Sleep Quality Index), VMS (daily diary, interference), mood (Center for Epidemiologist Studies-Depression Scale (CES-D)), walking impairment (timed 25-foot walk (T25FW)), and global disability (Expanded Disability Status Scale (EDSS))., Results: Participants' characteristics ( N = 59) were: mean age 51.8 years ( SD = 3.4), mean disease duration 11.3 years ( SD = 7.6), median EDSS 3.0 (IQR = 2.0-4.0). Mental health was associated with better sleep quality (rho = -0.41, p = 0.019) and better mood (rho = -0.75, p < 0.001), but not with EDSS or T25FW (rho < 0.20, p > 0.10). Worse sleep quality also correlated with more frequent VMS (rho = 0.41, p = 0.02) and VMS interference (rho = 0.59, p < 0.001)., Conclusions: Findings suggest that optimizing sleep quality, mood, and hot flash quantity/interference could substantially improve mental health in menopausal women with MS-and highlight an important care gap in this population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.M., A.A., A.N., S.H., J.S., W.R., CW., and T.B. have nothing to disclose. R.B. is the recipient of a National Multiple Sclerosis Harry Weaver Award. She has received research support from the National Multiple Sclerosis Society, the National Institutes of Health, and the Department of Defense. She has also received research support from Biogen, Novartis, and Roche Genentech. She has received personal compensation for consulting from Alexion, EMD Serono, Horizon, Jansen, and TG Therapeutics.

Study Objectives: Concerns regarding the risk of positive airway pressure (PAP)-associated respiratory infection (RI) have shaped consumer views toward PAP device use and maintenance. However, data regarding temporal associations between PAP use and risk for RIs are limited. The purpose of the present study was to examine longitudinal associations between PAP use and risk of clinically significant RIs in a cohort of patients with obstructive sleep apnea., Methods: The frequency of clinically reported respiratory RIs pre- and post-PAP use were compared in a sample of 482 adult patients with obstructive sleep apnea who underwent PAP titration at a large academic sleep center between 2011 and 2014. RIs were identified by clinical record review beginning two years before and ending two years after the participants' PAP titration. Presence of longitudinal standard PAP data download reports identified PAP users from nonusers. PAP adherence was defined as at least 4 hours of use per day, five days per week for at least 70% of days. Poisson regression models, adjusted for age, sex, body mass index, and the number of pre-PAP use RIs were utilized to examine associations between PAP use and subsequent RIs., Results: Poisson regression models adjusted for age, sex, body mass index, and the number of pre-PAP use RIs did not show associations between PAP therapy use and rate of post-PAP use RIs (rate ratio = 1.27, 95% confidence interval: 0.86-1.86). A sensitivity analysis that included only PAP users with difference in PAP adherence showed similar results (rate ratio = 0.65, 95% confidence interval: 0.32-1.30)., Conclusions: Among adults with obstructive sleep apnea, we did not find evidence for association between PAP use/adherence and increased RI frequency. These data offer new information that could assuage patients with obstructive sleep apnea who are considering PAP deferral based on RI concerns., Citation: Gavidia R, Shieu MM, Dunietz GL, Braley TJ. Respiratory infection risk in positive airway pressure therapy users: a retrospective cohort study. J Clin Sleep Med . 2023;19(10):1769-1773., (© 2023 American Academy of Sleep Medicine.)

Introduction: Stress and adversity during childhood, adolescence, and adulthood could impact the present and future health and well-being of people with multiple sclerosis (PwMS); however, a lifespan approach and nuanced stressor data are scarce in this nascent area of research. Our aim was to examine relationships among comprehensively measured lifetime stressors and two self-reported MS outcomes: (1) disability and (2) relapse burden changes since COVID-19 onset., Methods: Cross-sectional data were collected from a nationally distributed survey of U.S.-based adults with MS. Hierarchical block regressions were used to sequentially evaluate contributions to both outcomes independently. Likelihood ratio (LR) tests and Akaike information criterion (AIC) were used to evaluate additional predictive variance and model fit., Results: A total of 713 participants informed either outcome. Most respondents (84%) were female, 79% had relapsing remitting multiple sclerosis (MS), and mean (SD) age was 49 (12.7) years. Childhood (R 2  = .261, p < .001; AIC = 1063, LR p < .05) and adulthood stressors (R 2  = .2725, p < .001, AIC = 1051, LR p < .001) contributed significantly to disability, above and beyond prior nested models. Only adulthood stressors (R 2  = .0534, p < .001; AIC = 1572, LR p < .01) significantly contributed above the nested model for relapse burden changes since COVID-19., Conclusions: Stressors across the lifespan are commonly reported in PwMS and could contribute to disease burden. Incorporating this perspective into the "lived experience with MS" could facilitate personalized health care by addressing key stress-related exposures and inform intervention research to improve well-being., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Sleep disorders are common in people with multiple sclerosis (PwMS) and could contribute to cognitive dysfunction. However, effects of pathological sleep on cognitive domains are insufficiently characterized., Objective: To evaluate associations between cognitive performance and polysomnographic (PSG)-based sleep disturbances in PwMS., Methods: PwMS with known/suspected untreated obstructive sleep apnea (OSA, N = 131) underwent PSG and cognitive tests: Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test-II (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R Total and Delayed), Judgment of Line Orientation (JLO), Controlled Oral Word Association Test (COWAT), Trail Making Test, Go/No-Go, and Nine-Hole Peg Test (NHPT)., Results: Apnea severity measures were associated with worse processing speed, attention, and working memory (SDMT); immediate and delayed visual memory (BVMT-R Total and Delayed); attention, psychomotor speed, and cognitive flexibility (Trails); and manual dexterity and visuomotor coordination (NHPT) ( p s ⩽ 0.011). Sleep macrostructure measures showed stronger associations with verbal memory and response inhibition (CVLT-II Total Recognition Discriminability Index), and immediate visual memory (BVMT-R Total) ( p s ⩽ 0.011)., Conclusions: Pathological sleep, including hypoxia, sleep fragmentation, and disturbances in sleep/wake states, are differentially associated with worse cognitive performance in PwMS. These findings could inform future personalized approaches to cognitive impairment in PwMS with sleep disorders., Trial Registration: ClinicalTrials.gov identifier: NCT02544373 (https://clinicaltrials.gov/ct2/show/NCT02544373).

Objectives: To examine associations between sustained ownership of a pet and cognitive outcomes among a national sample of U.S. adults. Methods: Weighted linear mixed models were estimated using the Health and Retirement Study (2010-2016, n = 1369) to compare repeated measures of cognitive function between respondents who endorsed owning a pet in a sustained manner (>5 years), versus those who owned a pet ≤5 years, and non-pet owners. Results: Respondents aged 65+ who owned a pet >5 years demonstrated higher composite cognitive scores, compared to non-pet owners (β = .76, p = .03). Sustained pet ownership was associated with higher immediate (β = .3, p = .02) and delayed (β = .4, p = .007) word recall scores. There were no significant differences in cognitive scores between pet owners and non-owners aged < 65. Discussion: Sustained ownership of a pet could mitigate cognitive disparities in older adults. Further studies are needed to examine potential causal pathways, including physical activity and stress buffering, versus selection effects.

Background: The potential mediating and moderating effects of sleep disorders on cognitive outcomes in multiple sclerosis (MS) have been insufficiently studied., Objectives: To determine direct and indirect longitudinal associations between sleep disorders and perceived cognitive dysfunction in women with MS., Methods: The 2013 and 2017 waves of the Nurses' Health Study ( n  = 63,866) were utilized. All diagnoses and symptoms including MS ( n  = 524) were self-reported. Subjective cognitive function was measured using a composite score of four memory items and three binary outcomes that assessed difficulty following instructions, conversations/plots, and street navigation. Moderating and mediating effects of diagnosed/suspected obstructive sleep apnea (OSA), sleepiness, and insomnia between MS and cognition were estimated using the four-way decomposition method., Results: Prevalence of diagnosed/suspected OSA, sleepiness, and insomnia in 2013 were higher for nurses with MS (NwMS). NwMS were more likely to report cognitive difficulties in 2017. Insomnia mediated 5.4%-15.1% of the total effect between MS and following instructions, conversations/plots, and memory impairment, while sleepiness mediated 8.6%-12.3% of the total effect for these outcomes. In interaction analyses, OSA significantly accounted for 34% of the total effect between MS and following instructions., Conclusion: Prevalent OSA, insomnia, and sleepiness could differentially moderate or mediate the effect of MS on cognition in women with MS.

Background and Objectives: Alzheimer disease (AD) and other forms of dementia represent a rising global public health crisis. Because effective treatments to prevent, cure, or slow progression of dementia are unavailable, identification of treatable risk factors that increase dementia risk such as obstructive sleep apnea (OSA) could offer promising means to modify dementia occurrence or severity. Here, we systematically reviewed the impact of positive airway pressure (PAP) therapy on the incidence of cognitive disorders and cognitive decline among middle-aged and older adults with OSA., Methods: We performed a systematic search of MEDLINE, EMBASE, Scopus, and CINAHL before May 2021 to identify articles that focused on associations between PAP therapy use and cognitive disorders. We included studies that examined the effects of PAP treatment on (1) the incidence of cognitive disorders among individuals ≥40 years of age diagnosed with OSA and (2) the progression of cognitive decline among people with preexisting cognitive disorders and OSA., Results: We identified 11 studies (3 clinical trials and 8 observational studies). In these studies, 96% participants had OSA (n = 60,840) and 9% had baseline cognitive impairment (mild cognitive impairment [MCI] or AD) (n=5,826). Of all study participants, 43,970 obtained PAP therapy, and 16,400 were untreated or in a placebo group. Nine out of 11 studies reported a protective effect of PAP therapy on MCI and AD incidence, e.g., delayed age at MCI onset, reduced MCI or AD incidence, slower cognitive decline, or progression to AD., Discussion: These findings suggest a role for OSA as a modifiable risk factor for cognitive decline. Identification of modifiable risk factors is imperative for alleviating the impact of cognitive disorders on aging adults and their family members. Future research should build on this review and focus on PAP interventions as a potential means to alleviate the incidence of cognitive disorders and cognitive decline, particularly among ethnoracial groups who have been underrepresented and underinvestigated in the extant literature., (© 2022 American Academy of Neurology.)

Background and Objectives: The effects of the SARS-CoV-2 vaccination and infection on clinical outcomes, including relapse risk, have been insufficiently explored in people with multiple sclerosis (PwMS). The objectives of this study were to determine the incidence of new neurologic symptoms or symptom recrudescence among PwMS who received the SARS-CoV-2 vaccine, characterize outcomes after SARS-CoV-2 infection, and assess MS-specific determinants of vaccine hesitancy., Methods: Online surveys that assessed incidence and severity of SARS-CoV-2 infection, vaccination status/type, reasons for vaccine deferral, and postvaccination symptoms were administered to PwMS. Medical charts were reviewed for consenting respondents. Associations between infection, postvaccination outcomes, and clinical characteristics were compared using χ 2 tests, 2-sample t tests, and adjusted logistic regression models., Results: In total, 292 of 333 respondents were vaccinated, of whom 58% reported postvaccination side effects, most commonly among mRNA vaccine recipients ( p = 0.02), younger patients ( p < 0.01), and people with relapsing-remitting MS ( p = 0.03). Twelve percent endorsed recrudescence of existing MS symptoms, while 3% endorsed new neurologic symptoms postvaccination. Sixty-two participants reported SARS-CoV-2 infection since the start of the pandemic, more frequent in younger individuals (1-year odds ratio [OR] = 0.958, 10-year OR = 0.649, p < 0.01). Neither disease-modifying therapy nor B-cell therapies specifically were associated with vaccine side effects, neurologic symptoms, or SARS-CoV-2 infection. Twenty-one percent of unvaccinated cited a desire for provider guidance before vaccination., Discussion: Our findings provide new data to suggest that among PwMS who received SARS-CoV-2 vaccination, clinical disease worsening is rare and mostly associated with symptom recrudescence, as opposed to new relapses. Postvaccination side effects may occur more often among mRNA vaccine recipients and in younger individuals., (© 2022 American Academy of Neurology.)

Study Objectives: To examine the association between obstructive sleep apnea (OSA) risk and cognitive disorders among US adults., Methods: Data from the 2016 wave of the Health and Retirement Study (HRS) were utilized. Probable OSA cases were identified with survey items that resembled critical elements of a clinically validated OSA screen (STOP-Bang questionnaire). Weighted prevalences of cognitive impairment not dementia (CIND) and dementia among individuals with and without probable OSA were assessed. Cross-sectional analyses of associations between OSA risk and cognitive outcomes, along with effect modification by race and ethnicity, were estimated using imputed data., Results: Of the 20,910 HRS participants, 60% had probable OSA. CIND and dementia were more common among adults with probable OSA as compared with those without (12.7% vs 8.0% for CIND; 3.2% vs 2.0% for dementia). Probable OSA was associated with CIND (odds ratio [OR] = 1.22, 95% confidence interval [CI] = 1.08-1.37) and dementia (OR = 1.27, 95% CI = 1.04-1.54). Race/ethnicity significantly modified the association between probable OSA and CIND, with a higher risk for CIND in Whites (OR = 1.35, 95% CI = 1.17-1.57) as compared with non-Whites (OR = 0.98, 95% CI = 0.81-1.19)., Conclusions: CIND and dementia are more common among older adults who are at high risk for OSA, as compared with low-risk individuals. These data highlight the importance of consideration of OSA risk in large-scale studies of OSA and cognitive disorders., Citation: Shieu MM, Dunietz GL, Paulson HL, Chervin RD, Braley TJ. The association between obstructive sleep apnea risk and cognitive disorders: a population-based study. J Clin Sleep Med . 2022;18(4):1177-1185., (© 2022 American Academy of Sleep Medicine.)

Background: Improved screening for obstructive sleep apnea (OSA) could enhance multiple sclerosis (MS) clinical care; yet the utility of current screening tools for OSA have yet to be evaluated in persons with multiple sclerosis (PwMS)., Objectives: The STOP-Bang Questionnnaire is an 8-item screening tool for OSA that is commonly used in non-MS samples. The aim of this study was to assess the validity of the STOP-Bang in PwMS., Methods: STOP-Bang and polysomnography data were analyzed from n = 200 PwMS. Sensitivity, specificity, positive-, and negative-predictive value (PPV and NPV) were calculated, with receiving operating characteristic (ROC) curves, for each STOP-Bang threshold score, against polysomnography-confirmed OSA diagnosis at three apnea severity thresholds (mild, moderate, and severe)., Results: Nearly 70% had a STOP-Bang score of ⩾3% and 78% had OSA. The STOP-Bang at a threshold score of 3 provided sensitivities of 87% and 91% to detect moderate and severe OSA, respectively; and NPV of 84% and 95% to identify PwMS without moderate or severe OSA, respectively. Sensitivity to detect milder forms of OSA was 76%. The NPV to identify persons without milder forms of OSA was 40%., Conclusion: The STOP-Bang Questionnaire is an effective tool to screen for moderate and severe OSA in PwMS, but may be insufficient to exclude mild OSA.

Background: Although sleep disturbances are common among people with Multiple Sclerosis (PwMS), understanding of their impact has been stymied by limitations in approaches to sleep measurement within this population. The aim of this study was to comprehensively phenotype sleep patterns in PwMS through application of an emerging seven-domain framework that includes sleep duration, continuity, timing, quality, rhythmicity, regularity, and sleepiness., Methods: Sleep domains were estimated from wrist-worn accelerometry, Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index responses. Extreme sleep values within each domain were constructed using previously published guidelines. A composite score of extreme values was calculated for each participant. Associations between sleep domains and severity of MS symptoms were explored (pain, fatigue, depressive symptoms, and cognitive dysfunction)., Results: Among n = 49 participants, median total sleep time was 456.3 min. Median time spent awake after sleep onset was 37 min. Sleepiness, abnormal sleep timing, and poor sleep quality affected 33%, 35%, and 45% of participants, respectively. Seventy-six percent had ≥2 sleep domains in extreme ranges. PwMS had longer sleep duration and decreased sleep regularity compared to a non-MS historical cohort of older men. Greater daytime sleepiness, poorer sleep quality, and higher composite sleep health score were associated with more depressive symptoms, and lower sleep rhythmicity was associated with higher fatigue. Associations were observed between measures of cognitive function and sleep fragmentation, duration, quality, rhythmicity, and composite score., Conclusion: Application of a seven-domain sleep health framework that captures the dynamic and multifaceted aspects of sleep is feasible in PwMS, and offers potential for an improved understanding of the scope and impact of sleep disturbances in PwMS., (Copyright © 2021. Published by Elsevier B.V.)

Hospital-based protocols to support pet care needs for hospitalized patients may have potential to benefit patient health and wellbeing, but must be informed by experiences of hospitalized pet owners. The aim of this study was to determine the scope and need for pet care services among hospitalized patients. A panel of prior inpatients and their family members at a tertiary care center were surveyed about preferences, experiences, and need for assistance with pet care during hospitalization. Respondents (n = 113) expressed interest in a low/no-cost pet-boarding or foster program for adult patients struggling to find pet care assistance. The majority of respondents (n = 71; 63%) reported challenges securing pet care during a prior hospitalization, and/or knew someone who encountered similar challenges. Respondents also indicated that these challenges had a negative impact on health, recovery, or their own decision to receive medical care. Pet care challenges during hospitalization are likely common and have the potential to hamper medical decision-making and health outcomes of inpatients., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Study Objectives: To examine associations between positive airway pressure (PAP) therapy, adherence and incident diagnoses of Alzheimer's disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) in older adults., Methods: This retrospective study utilized Medicare 5% fee-for-service claims data of 53,321 beneficiaries, aged 65 and older, with an obstructive sleep apnea (OSA) diagnosis prior to 2011. Study participants were evaluated using ICD-9 codes for neurocognitive syndromes (AD [n = 1,057], DNOS [n = 378], and MCI [n = 443]) that were newly identified between 2011 and 2013. PAP treatment was defined as the presence of at least one durable medical equipment (Healthcare Common Procedure Coding System [HCPCS]) code for PAP supplies. PAP adherence was defined as at least two HCPCS codes for PAP equipment, separated by at least 1 month. Logistic regression models, adjusted for demographic and health characteristics, were used to estimate associations between PAP treatment or adherence and new AD, DNOS, and MCI diagnoses., Results: In this sample of Medicare beneficiaries with OSA, 59% were men, 90% were non-Hispanic whites and 62% were younger than 75 years. The majority (78%) of beneficiaries with OSA were prescribed PAP (treated), and 74% showed evidence of adherent PAP use. In adjusted models, PAP treatment was associated with lower odds of incident diagnoses of AD and DNOS (odds ratio [OR] = 0.78, 95% confidence interval [95% CI]: 0.69 to 0.89; and OR = 0.69, 95% CI: 0.55 to 0.85). Lower odds of MCI, approaching statistical significance, were also observed among PAP users (OR = 0.82, 95% CI: 0.66 to 1.02). PAP adherence was associated with lower odds of incident diagnoses of AD (OR = 0.65, 95% CI: 0.56 to 0.76)., Conclusions: PAP treatment and adherence are independently associated with lower odds of incident AD diagnoses in older adults. Results suggest that treatment of OSA may reduce the risk of subsequent dementia., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The aim of this study was to validate the Pittsburgh Fatigability Scale in three different groups: adults with multiple sclerosis ( n = 65), fibromyalgia ( n = 64), and healthy adults ( n = 86). Participants completed the Pittsburgh Fatigability Scale and other self-report measures. While findings supported the internal consistency of the Pittsburgh Fatigability Scale (all Cronbach's alpha ⩾ 0.85), standard error of measurement estimates were larger than hypothesized. In addition, while item-level reliability was generally supported, item-total correlations for two items were lower than expected. Convergent and discriminant validity were supported, and the Pittsburgh Fatigability Scale was able to distinguish between individuals with and without chronic disease. Overall, the Pittsburgh Fatigability Scale exhibited acceptable psychometric properties.

Objective/background: Adults with multiple sclerosis (MS) often present with conditions that mimic restless legs syndrome (RLS), thereby adding complexity into the assessment of RLS severity. The current gold-standard measures of RLS severity rely on a fixed seven-day time frame, which limits the ability of these measures for studying acute changes in RLS severity. The present study examined if subjective and objective scores from the suggested immobilization test (SIT) provide a valid and reliable acute measure of RLS severity in persons with MS., Patients/methods: Participants with MS and RLS (n = 20) and MS without RLS (n = 20) were matched by age, gender, and disability. All participants completed validated questionnaires for RLS severity followed by the SIT, conducted at 18:00 (±15 min) on the same day of the week for two consecutive weeks. Participants wore accelerometer devices for seven nights to capture periodic limb movements (PLMs) during the night., Results: Self-reported RLS severity during the SIT had excellent construct validity and convergent validity, but moderate test-retest reliability. Device-measured PLMs, while not themselves a direct measure of RLS severity, were significantly associated with PLMs during the night and had excellent test-retest reliability during the SIT in adults with MS., Conclusions: Our results suggest that the SIT represents a valid acute measure for capturing self-reported sensory aspects of RLS severity and should be considered in future research and clinical practice as a standardized acute measure of subjective RLS severity in adults with MS who present with RLS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing characterized by intermittent partial or complete closure of the upper airway during sleep. If left untreated, OSA is associated with adverse cardiovascular outcomes such as hypertension, coronary heart disease, heart failure, cardiac arrhythmia, stroke, and death. Positive airway pressure (PAP) is often considered the first-line treatment for OSA. While PAP can be very effective in reducing the number of obstructive apneas and hypopneas, its impact on prevention of adverse cardiovascular consequences remains controversial, and treatment adherence is often poor. Hence, the necessity for novel treatment options to help those who cannot adhere to positive airway pressure treatment. Different classes of medications have been tested with regards to their effect on OSA severity. This review 1) provides an update on the epidemiology and pathophysiology of OSA, 2) outlines the mechanistic rationale for medication classes tested as OSA treatment and 3) discusses the effects of these medications on OSA. Several wake-promoting medications are approved for management of persistent sleepiness despite OSA treatment; discussion of these symptomatic treatments is outside the scope of this review. Herein, the authors review the current evidence for pharmacological management of OSA and provide future directions., Competing Interests: Conflicts of interest Sonja G. Schütz: no financial conflicts to disclose; Abbey Dunn: no financial conflicts to disclose; Tiffany J. Braley: no financial conflicts to disclose; Bertram Pitt: consultant to Bayer, Astra Zeneca, Sanofi/Lexicon, Phasebio, KBP pharmaceuticals ∗, SCPharmaceuticals ∗, SQinnovastions ∗, G3Pharmaceuticals ∗, Cereno scientific ∗, Sarfez∗ (∗ = stock options). Dr. Pitt holds the US Patent 9,931,412-site specific delivery of eplerenone to the myocardium; Anita V. Shelgikar(:) no financial conflicts to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Abstract: Chronic pain is highly prevalent in multiple sclerosis (MS). Pain heterogeneity may contribute to poor treatment outcomes. The aim of this study was to characterize pain phenotypes distributions in persons with MS and compare pain phenotypes in terms of pain intensity, frequency of chronic overlapping pain conditions, and use and analgesic effects of different classes of pain medications. Data were collected through a national web-based survey with measures of neuropathic (painDETECT) and nociplastic pain (Fibromyalgia Survey Criteria), chronic overlapping pain conditions, and pain medication use and pain relief. In a sample of N = 842 adults with chronic pain and MS, the largest proportion (41%) showed evidence of nociceptive pain, 27% had mixed neuropathic/nociplastic pain, 23% had nociplastic pain, and 9% had neuropathic pain. Nociplastic pain was associated with significantly higher pain intensity and frequency of chronic overlapping pain conditions. Across all pain types, high frequency of pain medication use along with poor-modest pain relief was reported. Cannabis use for pain was more common, and pain relief ratings were higher among those with nociplastic pain, relative to nociceptive pain. Although NSAID use was highest among those with nociplastic pain (80%), pain relief ratings for NSAIDs were highest among those with nociceptive pain. These findings underscore the need for multidimensional assessment of pain in MS with greater emphasis on the identification of pain phenotype. An improved characterization of pain as a multifaceted condition in MS could inform therapeutic approaches., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Study Objectives: Obstructive sleep apnea (OSA) is prevalent among older adults. Although treatment with positive airway pressure (PAP) lowers subsequent morbidity, PAP adherence is inconsistent. Socioeconomic disparities have been observed in OSA treatment, but regional differences in OSA care are unknown. This study examined geographic variations in PAP treatment and adherence among older Americans., Methods: This study utilized a representative 5% sample of all Medicare fee-for-service beneficiaries aged 65+ years. An OSA diagnosis, treatment, and PAP adherence were confirmed with International Classification of Diseases, Ninth Revision, HCPCS (Health Care Common Procedure Coding System) codes, and ≥2 HCPCS claims for PAP supplies respectively. Descriptive statistics were used to examine proportions of Medicare beneficiaries who obtained and adhered to PAP. Maps described the proportion of treated and adherent beneficiaries by state and hospital referral region., Results: For state-level data, PAP treatment and adherence proportions among beneficiaries with an OSA diagnosis ranged between 54-87% and 59-81%, respectively. Proportions of treated patients were higher in Midwest states (>80%), in comparison to Northwest, Northeast, and Southern states (<73%). Southern states and California had lowest proportions of PAP adherence (<70%). Within-state variability in treatment patterns were apparent along the East and West coasts. Correlations of PAP treatment and adherence proportions were low in Washington, DC, New York, and New Jersey. Discordant treatment and adherence proportions were observed in Alabama and Mississippi., Conclusions: Significant state-level and regional disparities of PAP treatment and adherence among Medicare beneficiaries with OSA suggest gaps in delivery of OSA care for older Americans., (© 2021 American Academy of Sleep Medicine.)

Background: Postoperative multiple sclerosis (MS) relapses are a concern among patients and providers., Objective: To determine whether MS relapse risk is higher postoperatively., Methods: Data were extracted from medical records of MS patients undergoing surgery at a tertiary center (2000-2016). Conditional logistic regression estimated within-patient unadjusted and age-adjusted odds of postoperative versus preoperative relapse., Results: Among 281 patients and 609 surgeries, 12 postoperative relapses were identified. The odds of postoperative versus preoperative relapse in unadjusted (odds ratio (OR) = 0.56, 95% confidence interval (CI) = 0.18-1.79; p  = 0.33) or age-adjusted models (OR = 0.66, 95% CI = 0.20-2.16; p  = 0.49) were not increased., Conclusions: Surgery/anesthesia exposure did not increase postoperative relapse risk. These findings require confirmation in larger studies.

Background: Up-to-date information regarding the scope and impact of cannabinoid use among persons with MS (PwMS) is necessary to guide clinical practice and cannabinoid research., Objectives: To assess utilization patterns and perceived impact of cannabinoid use among a national cohort of PwMS., Methods: Data collected were part of a nationwide survey to characterize pain in PwMS. Items included questions about current/recent cannabinoid use, reasons for use, preferred THC/CBD formulations, and perceived benefits/side effects. PROMIS short-forms assessed symptom severity. Pain phenotype was assessed with the painDETECT questionnaire and FMSurvey Criteria Questionnaires., Results: Among n = 1,027 respondents, 42% endorsed recent cannabinoid use, of which 18% endorsed healthcare provider guidance regarding use. PROMIS scores (except cognitive abilities), and pain centralization and neuropathic pain scores, were higher among recent/current users (each p < 0.0001). Sleep and pain were the most frequently reported reasons for use. Benefit from cannabinoids for sleep and pain were strongly correlated (r = 0.65, p < 0.0001). For those who expressed a preference for specific THC/CBD ratios, CBD-predominant formulations were favored., Conclusion: Cannabinoid use is common in PwMS, despite a paucity of provider guidance. The range of perceived benefits, and potential differential effects of THC and CBD, highlight the need for personalized, evidence-based guidelines regarding cannabinoid use., (© The Author(s) 2020.)

Objective: The objective of the study was to characterize obstructive sleep apnea treatment patterns among older Americans with neurological conditions., Setting and Participants: Claims data from a 5% fee-for-service sample of Medicare beneficiaries were analyzed to determine the proportion of older adults with OSA who received and were adherent to continuous positive airway pressure therapy and examine potential gaps in OSA care among neurological populations. Logistic regression was used to determine whether gender or race/ethnicity modified the associations between neurological morbidities and OSA treatment or adherence., Results: Data from n = 102,618 beneficiaries with OSA were identified. The prevalence of stroke, cognitive disorders, or Parkinson's disease in this sample was 7%, 3%, and 2% respectively. Overall, OSA-diagnosed individuals (73%) obtained treatment, and most treated were adherent to CPAP (72%). Lower proportions of OSA treatment and adherence were observed in neurological conditions, particularly stroke. In logistic regression models, gender and race/ethnicity each modified associations between neurological comorbidity and OSA treatment and adherence. Women as compared to men with a given neurological condition were uniformly less likely to receive CPAP or adhere to treatment (P < .01 for each condition). Similarly, in comparison to whites with the same neurological condition, OSA treatment was significantly lower among all other races with stroke, and among blacks with cognitive disorders., Conclusions: Older women and minorities with neurological conditions may be more vulnerable to gaps in OSA care. Targeted strategies to improve treatment disparities and neurological outcomes in older adults could be informed by these data., (Copyright © 2020 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: To examine whether sleep disturbance modifies the association between physical activity and incident pain., Design: Prospective population-based study., Setting: Health and Retirement Study., Participants: American adults aged ≥50 years who reported no troublesome pain in 2014 were re-assessed for pain in 2016. Of 9828 eligible baseline respondents, 8036 (82%) had complete follow-up data for adjusted analyses (weighted analysis population N=42 407 222)., Exposures: Physical activity was assessed via interview with questions about time spent in moderate and vigorous physical activity. Sleep disturbance, assessed using a modified form of the Jenkins Sleep Scale, was examined as a potential moderator., Main Outcome Measure: Troublesome pain., Results: In weighted analyses, 37.9% of the 2014 baseline pain-free sample participated in moderate or vigorous physical activity once a week or less, with an overall mean Physical Activity Index Score of 9.0 (SE=0.12). 18.6% went on to report troublesome pain in 2016. Each one-point higher on the Physical Activity Index Score was associated with a reduced odds ratio (OR) of incident pain for those who endorsed sleep disturbance never/rarely (OR=0.97, 95% CI 0.94 to 0.99), but not for those who endorsed sleep disturbance sometimes (OR=0.99, 95% CI 0.97 to 1.01) or most of the time (OR=1.01, 95% CI 0.99 to 1.03). The analysis of possible interaction demonstrated that frequency of sleep disturbance moderated the physical activity and incident pain association (Wald test: p=0.02)., Conclusions: The beneficial association of physical activity on reduced likelihood of later pain was only observed in persons who endorsed low levels of sleep disturbance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Restless legs syndrome (RLS) is a sleep disorder that may exacerbate many of the symptoms and consequences of multiple sclerosis (MS), and may have further implications for health-related quality of life (HRQOL). The present study examined the relationships among RLS, symptoms and HRQOL in people with MS. Participants with MS (n = 275) completed the Cambridge-Hopkins Restless Legs Syndrome Questionnaire, the International Restless Legs Syndrome Study Group Scale, the Multiple Sclerosis Impact Scale, the Pittsburgh Sleep Quality Index, the Fatigue Severity Scale, the Hospital Anxiety and Depression Scale and the Patient Determined Disease Steps. There were 74 (26.9%) persons with MS who had RLS (MS + RLS). The MS + RLS group reported worse physical and psychological HRQOL (p = 0.020 and p = 0.017, respectively) and greater perceived fatigue (p = 0.006) and anxiety symptoms (p = 0.042) than the MS-only group. Within the MS + RLS group, RLS severity was associated with physical (r = 0.43) and psychological (r = 0.46) HRQOL, sleep quality (r = 0.38), perceived fatigue (r = 0.28), depression (r = 0.38) and anxiety (r = 0.28). The relationships between RLS severity and the domains of HRQOL were attenuated when accounting for fatigue, depression and/or anxiety. Worse RLS severity was associated with reduced HRQOL, which was accounted for by fatigue, depression and anxiety., (© 2019 European Sleep Research Society.)

The present study examined the relationships among parameters (i.e., volume and pattern) of physical activity and sedentary behavior with the presence and severity of restless legs syndrome(RLS) in adults with multiple sclerosis(MS). Participants with MS (N = 253) wore an accelerometer for a 7-day period and completed the Cambridge-Hopkins Restless Legs Syndrome Questionnaire, the International Restless Legs Syndrome Study Group Scale (IRLS), and the Patient Determined Disease Steps scale. Sixty-six (26%) persons with MS had RLS (MS + RLS). There were no differences between the MS + RLS and MS group for parameters of physical activity or sedentary behavior. Among participants with IRLS scores in the mild range (n = 26), more time spent in light physical activity (r s  = 0.39), fewer sedentary bouts per day (r s  = 0.55), less time in sedentary bouts per day (r s  = 0.51), and fewer breaks in sedentary time per day (r s  = 0.57) were associated with lower RLS severity. This study represents the first step toward recognizing a relationship between physical activity, patterns of sedentary behavior, and RLS severity in MS and these results suggest that light physical activity and the pattern of sedentary behavior may be important targets for prospective behavioral interventions that target the management of RLS in persons with MS who have mild RLS severity., (Published by Elsevier B.V.)

Poor sleep quality has been associated with greater pain and fatigue in people living with osteoarthritis (OA). The objective of this micro-longitudinal study was to determine whether sleep impacts the diurnal pattern of next-day OA-related pain and fatigue. Community-dwelling older adults (≥65 years) with hip and/or knee OA provided data over 5 days using daily diaries and wrist-worn actigraphs. Pain and fatigue intensity were measured on awakening, at 11 am, 3 pm, 7 pm, and bedtime. Subjective previous night sleep quality was measured on awakening. Multilevel linear regression models examined interactions between sleep variables and time of next-day symptom reports. One hundred sixty participants provided 785 days of data (median age = 71 years; 62% female). Analysis of time interaction effects identified an association between poor sleep quality and more morning pain and fatigue. Although the effect on awakening was more pronounced for fatigue, differences in both symptoms attributable to sleep quality attenuated as the day progressed. Investigation of actigraphy-based sleep parameters revealed no significant interactions with time of symptom measurement. These findings observed in a sample of older adults with mild-to-moderate OA symptoms warrant further investigation in a sample with more severe symptoms and more pronounced sleep dysfunction and/or sleep disorders. PERSPECTIVE: This article investigates the impact of sleep on next-day pain and fatigue of older adults with OA. On awakening from a night of poor quality sleep, pain and fatigue intensity were heightened. However, the effect was not sustained throughout the day, suggesting the morning may be an optimal time for symptom interventions., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fatigue is one of the most common and disabling chronic symptoms in multiple sclerosis (MS). Optimization of available treatments for MS-related fatigue has been stymied by lack of comparative effectiveness research that focuses on real-world treatment delivery methods and potential modification of treatment effect by other chronic MS symptoms or disability level. This report describes the design of a patient centered, comparative effectiveness trial of cognitive behavioral-therapy (CBT), modafinil, and combination therapy of both for fatigue in MS ("COMBO-MS")., Methods: We describe the methods of this pragmatic comparative effectiveness trial that is guided by a team of patient, family, provider, community, and payer stakeholders. Eligible participants with MS and significant fatigue severity are randomly assigned (1:1:1) to received either CBT, modafinil, or a combination of CBT and modafinil for 12 weeks. The primary outcome is change in fatigue impact as measured by the Modified Fatigue Impact Scale (MFIS) at 12 weeks. Secondary outcome measures include ecological momentary assessment (EMA) measures of fatigue intensity, fatigue interference, and fatigability (measured over 7 days' time at baseline and at 12 weeks), and change in MFIS score at 24 weeks., Projected Outcomes: We hypothesize that combination therapy will more effectively ameliorate fatigue severity than either monotherapy, and that heterogeneity of treatment effects will be found based on depression status, presence of known or suspected sleep disorder, and disease severity. Study findings will assist patients, providers, payers, and policy makers to provide more effective care for managing fatigue in MS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Perceived fatigability, reflective of changes in fatigue intensity in the context of activity, has emerged as a potentially important clinical outcome and quality of life indicator. Unfortunately, the nature of perceived fatigability is not well characterized. The aim of this study is to define the characteristics of fatigability through the development of a conceptual model informed by input from key stakeholders who experience fatigability, including the general population, individuals with multiple sclerosis (MS), and individuals with fibromyalgia (FM)., Methods: Thirteen focus groups were conducted with 101 participants; five groups with n = 44 individuals representing the general population, four groups with n = 26 individuals with MS, and four groups with n = 31 individuals with FM. Focus group data were qualitatively analyzed to identify major themes in the participants' characterizations of perceived fatigability., Results: Seven major themes were identified: general fatigability, physical fatigability, mental fatigability, emotional fatigability, moderators of fatigability, proactive and reactive behaviors, and temporal aspects of fatigability. Relative to those in the general sample, FM or MS groups more often described experiencing fatigue as a result of cognitive activity, use of proactive behaviors to manage fatigability, and sensory stimulation as exacerbating fatigability., Conclusions: Fatigability is the complex and dynamic process of the development of physical, mental, and/or emotional fatigue. Trait- and state-like biological, psychological, social, and environmental moderators contribute to tremendous variability in fatigability (both between and within-person variability). Future research to further characterize fatigability across populations, test treatments for fatigability, and develop new measures of this construct are greatly needed.

Background: Symptom severity is negatively associated with physical activity in multiple sclerosis (MS). However, it is unclear how physical activity and symptoms correlate on a day-to-day basis in persons with MS., Purpose: To determine the temporal within-person associations of pain, fatigue, depressed mood, and perceived cognitive function with physical activity in MS., Methods: Ambulatory adults with MS (N = 107) completed 7 days of home monitoring. Continuous physical activity data (assessed via wrist-worn accelerometer) and concurrent ecological momentary assessment (5X/day) of pain, fatigue, depressed mood, and perceived cognitive function were collected. Data were analyzed using multilevel mixed modeling., Results: Fatigue and depressed mood demonstrated bidirectional associations with physical activity, whereas pain and cognitive function did not. Higher than usual fatigue (B = -5.83, p = .001) and depressed mood (B = -4.12, p = .03) were followed by decreased physical activity. In contrast, higher than usual physical activity was associated with subsequent decline in fatigue (B = -0.001, p = .02) and depressed mood (B = -0.0007, p = .02); however, the association between physical activity and fatigue varied across the day., Conclusions: Physical activity is dynamically related to fatigue and mood on a moment-to-moment basis in MS. Efforts to increase physical activity in MS must incorporate a focus on how symptoms affect and are affected by activity.

Pain is common among older adults and negatively impacts functioning. Sleep disturbances and mood disorders, specifically depression and anxiety, are closely associated with pain in older individuals, but the directionality of these associations remains unclear. In this study, we deconstruct long-term temporal effects of two key insomnia symptoms on incident pain into direct and indirect pathways, with focus on depression and anxiety symptoms, within a nationally representative sample. We utilized 2011-2013 data from the National Health and Aging Trends Study, a longitudinal survey of 2239 community-dwelling Medicare beneficiaries. Participants completed annual in-person interviews with assessments of sleep initiation and maintenance; depression, and anxiety (using the Patient Health Questionnaire-2 [PHQ-2] and the Generalized Anxiety Disorder Scale-2 [GAD-2] respectively); and bothersome pain. Causal mediation analysis was applied to examine direct effects of the two insomnia symptoms at baseline on incident pain, and their indirect effects through depression and anxiety symptoms. Almost one-third of the study participants were 69 years old or younger. A similar proportion reported bothersome pain in 2013. The two baseline insomnia symptoms predicted the development of pain. Adjusted analyses suggested that compared to older adults without the two baseline insomnia symptoms, participants with sleep initiation or maintenance difficulties had 24% (95% confidence interval [CI] 2%,51%) and 28% (95% CI 4%,55%) higher odds of incident pain, respectively. Anxiety symptoms partially mediated the relationship between the insomnia symptoms and incident pain, accounting for up to 17% of the total effect, but depressive symptoms did not. These results suggest that improved sleep or anxiety could reduce the risk for future pain.

Study Objectives: To investigate the therapeutic effect of dimethyl fumarate (DMF, an immunomodulatory agent) on obstructive sleep apnea (OSA), and potential influence of any such effect by selected proinflammatory molecules., Methods: Patients with OSA who deferred positive airway pressure therapy were randomized (2:1) to receive DMF or placebo for 4 months. Participants underwent polysomnography before randomization and at 4 months. Blood was collected monthly. The primary outcome was the mean group change in respiratory disturbance index (δ-RDI). Secondary analyses focused on the association between treatment effect of DMF (on RDI) and expression of plasma cytokines and chemokines, or nuclear factor κ-B (NFκB) signaling molecules in peripheral blood mononuclear cells., Results: N = 65 participants were randomized. N = 50 participants (DMF = 35, placebo = 15) had complete data for final analyses. The mean difference in δ-RDI between groups was 13.3 respiratory events/hour of sleep: -3.1+/-12.9 vs. 10.2+/-13.1 in DMF and placebo groups, respectively (mixed-effects model treatment effect: β = -0.14, SE = 0.062, p = 0.033). Plasma levels of TNF-α showed only nonsignificant decreases, and IL-10 and IL-13 only nonsignificant increases, in DMF-treated participants compared with placebo. No significant interaction or main effect on RDI for selected cytokines and chemokines was found. Participants with a therapeutic response to DMF did experience significant reductions in intracellular NFκB signaling molecules at 4 months. Overall, DMF was well-tolerated., Conclusions: The immunomodulatory drug DMF partially ameliorates OSA severity. Suppression of systemic inflammation through reduction of NFκB signaling may mediate this effect., Clinical Trials: ClinicalTrials.gov, NCT02438137, https://clinicaltrials.gov/ct2/show/NCT02438137?term=NCT02438137&rank=1.

Objectives: To estimate the proportion of older Americans at risk for obstructive sleep apnea (OSA) who receive OSA evaluations, diagnosis, and treatment., Design: Cross sectional study., Setting: National Health and Aging Trends Study (NHATS), Round 3 survey., Participants: Community-dwelling Medicare beneficiaries age 65 and older (N=1,052)., Measurements: NHATS participants were asked specific questions about sleep disturbances, including items that resembled critical elements of a validated instrument used to assess OSA risk (the STOP-Bang questionnaire). The proportion of older Americans at risk for OSA who received evaluations with home or in-laboratory sleep studies, OSA diagnosis, and OSA treatment was examined, as well as clinical, social, and demographic correlates of OSA., Results: Of 1,052 participants who completed the sleep module, 56% (95% confidence interval (CI)=53-59%) were estimated to be at high risk of OSA. Only 8% (95% CI=5-11%) of the high-risk individuals had been tested for it. Of those tested, 94% (95% CI=87-100%) were diagnosed with OSA. Treatment with positive airway pressure was prescribed for 82% (95% CI=65-99%) of participants with an OSA diagnosis., Conclusions: Evidence from this nationally representative sample of community-dwelling Medicare beneficiaries suggests that high OSA risk is common but seldom investigated. When investigated, OSA is almost always confirmed and usually treated. These findings suggest a significant gap in OSA assessment for older Americans that could have public health implications., (© 2018, Copyright the Authors Journal compilation © 2018, The American Geriatrics Society.)

Purpose of Review: This review will focus on the causes, consequences, workup, and treatment of sleep disordered breathing, insomnia, and restless legs syndrome in patients with MS. An approach to the discussion of sleep problems and associated symptoms with MS patients, to facilitate timely and accurate diagnosis, is emphasized., Recent Findings: Recent research suggests that sleep disordered breathing, insomnia, and restless legs syndrome disproportionately affect patients with MS, and contribute to substantial morbidity in this population., Summary: Sleep disordered breathing, insomnia, and restless legs syndrome are common but frequently under-recognized conditions in patients with MS. Additional efforts are needed to incorporate discussions about sleep into the clinical evaluation of MS patients. Neuroanatomical features, concomitant comorbidities, and medications associated with MS may partially explain the high prevalence of these disorders in MS. Prompt identification and treatment of sleep disorders may reduce fatigue, and a thorough discussion with the MS patient about their sleep will facilitate fatigue management. Research that further characterizes recently identified relationships between sleep disturbances and other chronic symptoms in MS such as pain, depression and cognitive dysfunction could identify new pathways to improve some of the most debilitating symptoms of MS.

Objective: To examine the relative association between daily change in pain, fatigue, depressed mood, and cognitive function and 4 outcomes-positive affect and well-being, ability to participate in social roles and activities, upper extremity (UE) functioning, and lower extremity (LE) functioning., Design: Data analysis, multilevel mixed modeling., Setting: General community., Participants: Ambulatory adults (N=102) with multiple sclerosis., Interventions: Not applicable., Main Outcome Measures: Customized short-forms of the Quality of Life in Neurological Disorders positive affect and well-being, UE functioning, and LE functioning item banks and the Patient-Reported Outcomes Measurement Information System ability to participate in social roles and activities item bank adapted for daily use and administered as end-of-day diaries., Results: Above and beyond the effects of demographic and clinical covariates, daily pain was associated with 3 of the 4 outcomes; days of higher than usual pain were related to lower same-day social participation (unstandardized β, B=-1.00; P=.002), UE functioning (B=-1.04; P=.01), and LE functioning (B=-.71; P=.04). Daily fatigue and depressed mood were independently related to daily positive affect and well-being; days of worse fatigue (B=-.54; P=.006) and depressed mood (B=-1.17; P<.0001) were related to lower same-day well-being., Conclusions: The results indicate the role of fluctuations in symptoms in daily functioning and quality of life of individuals with multiple sclerosis. Daily increases in pain intensity are related to social and physical functioning, whereas increases in fatigue and depressed mood are related to lower daily well-being. Findings implicate a person-centered approach to monitoring and treating symptoms., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the temporal associations, within day and day to day, between pain, fatigue, depressed mood, and cognitive function in multiple sclerosis (MS)., Design: Repeated-measures study involving 7 days of ecological momentary assessment (EMA) of symptoms 5 times a day; multilevel mixed models were used to analyze data., Setting: Community., Participants: Ambulatory adults (N=107) with MS., Interventions: Not applicable., Main Outcome Measure: EMA of pain, fatigue, depressed mood, and cognitive function rated on a 0 to 10 scale., Results: Fatigue and pain were linked within day such that higher pain was associated with higher subsequent fatigue (B=.09, P=.04); likewise, higher fatigue was associated with higher pain in the following time frame (B=.05, P=.04). Poorer perceived cognitive function preceded increased subsequent pain (B=.08, P=.007) and fatigue (B=.10, P=.01) within day. Depressed mood was not temporally linked with other symptoms. In terms of day-to-day effects, a day of higher fatigue related to decreased next day fatigue (B=-.16, P=.01), and a day of higher depressed mood related to increased depressed mood the next day (B=.17, P=.01). There were no cross-symptom associations from one day to the next., Conclusions: Findings provide new insights on how common symptoms in MS relate to each other and vary within and over days. Pain and fatigue show evidence of a dynamic bidirectional relation over the course of a day, and worsening of perceived cognitive function preceded worsening of both pain and fatigue. Most temporal associations between symptoms occur within the course of a day, with relatively little carryover from one day to the next., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the daily variability and patterns of pain, fatigue, depressed mood, and cognitive function in persons with multiple sclerosis (MS)., Design: Repeated-measures observational study of 7 consecutive days of home monitoring, including ecological momentary assessment (EMA) of symptoms. Multilevel mixed models were used to analyze data., Setting: General community., Participants: Ambulatory adults (N=107) with MS recruited through the University of Michigan and surrounding community., Interventions: Not applicable., Main Outcome Measure: EMA measures of pain, fatigue, depressed mood, and cognitive function rated on a 0 to 10 scale, collected 5 times a day for 7 days., Results: Cognitive function and depressed mood exhibited more stable within-person patterns than pain and fatigue, which varied considerably within person. All symptoms increased in intensity across the day (all P<.02), with fatigue showing the most substantial increase. Notably, this diurnal increase varied by sex and age; women showed a continuous increase from wake to bedtime, whereas fatigue plateaued after 7 pm for men (wake-bed B=1.04, P=.004). For the oldest subgroup, diurnal increases were concentrated to the middle of the day compared with younger subgroups, which showed an earlier onset of fatigue increase and sustained increases until bed time (wake-3 pm B=.04, P=.01; wake-7 pm B=.03, P=.02). Diurnal patterns of cognitive function varied by education; those with advanced college degrees showed a more stable pattern across the day, with significant differences compared with those with bachelor-level degrees in the evening (wake-7 pm B=-.47, P=.02; wake-bed B=-.45, P=.04)., Conclusions: Findings suggest that chronic symptoms in MS are not static, even over a short time frame; rather, symptoms-fatigue and pain in particular-vary dynamically across and within days. Incorporation of EMA methods should be considered in the assessment of these chronic MS symptoms to enhance assessment and treatment strategies., (Copyright © 2017 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Study Objectives: To examine associations between cognitive performance and polysomnographic measures of obstructive sleep apnea in patients with multiple sclerosis (MS)., Methods: Participants underwent a comprehensive MS-specific cognitive testing battery (the Minimal Assessment of Cognitive Function in MS, or MACFIMS) and in-laboratory overnight PSG., Results: In adjusted linear regression models, the oxygen desaturation index (ODI) and minimum oxygen saturation (MinO2) were significantly associated with performance on multiple MACFIMS measures, including the Paced Auditory Serial Addition Test (PASAT; 2-sec and 3-sec versions), which assesses working memory, processing speed, and attention, and on the Brief Visuospatial Memory Test-Revised, a test of delayed visual memory. The respiratory disturbance index (RDI) was also significantly associated with PASAT-3 scores as well as the California Verbal Learning Test-II (CVLT-II) Discriminability Index, a test of verbal memory and response inhibition. Among these associations, apnea severity measures accounted for between 12% and 23% of the variance in cognitive test performance. Polysomnographic measures of sleep fragmentation (as reflected by the total arousal index) and total sleep time also showed significant associations with a component of the CVLT-II that assesses response inhibition, explaining 18% and 27% of the variance in performance., Conclusions: Among patients with MS, obstructive sleep apnea and sleep disturbance are significantly associated with diminished visual memory, verbal memory, executive function (as reflected by response inhibition), attention, processing speed, and working memory. If sleep disorders degrade these cognitive functions, effective treatment could offer new opportunities to improve cognitive functioning in patients with MS., Commentary: A commentary on this article appears in this issue on page 1489., (© 2016 Associated Professional Sleep Societies, LLC.)

Recent studies suggest that individuals with multiple sclerosis (MS) are at increased risk for sleep disturbances and that sleep disturbances contribute to fatigue and other chronic symptoms in MS. Although fatigue occurs commonly in people with MS, this symptom is often attributed to MS-specific pathology. Consequently, sleep disorders are often unrecognized and untreated in this population. Timely diagnosis and treatment of sleep problems in MS offer a new opportunity to ameliorate some of the daytime fatigue experienced by patients with MS. To increase this opportunity, the practitioner should be comfortable performing basic screening for common sleep complaints among patients with MS. The objectives of this review are to summarize the latest relevant data on sleep disorders in MS and offer a helpful approach to the identification and workup of the most common sleep problems in this population. Unexplored research avenues and opportunities to address important questions at the interface of sleep and MS are also discussed.

Patients with multiple sclerosis (MS) are at increased risk for comorbid sleep disturbances, which can profoundly contribute to poor functional status and fatigue. Insomnia, sleep-disordered breathing, and restless legs syndrome are among the most common sleep disorders experienced by patients with MS. Despite their impact, these underlying sleep disorders may escape routine clinical evaluations in persons with MS, thereby leading to missed opportunities to optimize functional status and quality of life in patients with MS. A practical, systematic approach to the evaluation and treatment of sleep disorders in MS, in the context of MS-specific variables that may influence risk for these conditions or response to therapy, is recommended to facilitate early diagnosis and successful treatment. This review summarizes the most common sleep disorders experienced by persons with MS, and offers a practical approach to diagnosis and management of these conditions.