Perceptions of exercise and restless legs syndrome: Results from a nationwide survey.

Restless legs syndrome is a prevalent, sensorimotor sleep disorder temporarily relieved by movement, with evidence of symptomatic improvement with regular exercise. The present study describes perceptions of the effects of exercise on symptoms of restless legs syndrome. Participants (N = 528) completed a mixed-methods (i.e. numerical and narrative), nationwide survey including items assessing personal experiences with exercise and restless legs syndrome (both positive and negative), as well as restless legs syndrome diagnosis, restless legs syndrome severity, and demographic and clinical characteristics. Responses varied widely on specific experiences with exercise, but a higher percentage of participants indicated positive experiences with exercise than those who reported negative experiences (72%-40%, respectively) with exercise. Further, 54% of respondents reported that exercise only improves restless legs syndrome, while 24% reported exercise only worsens symptoms. Participants described that any abrupt change in exercise routine would almost always elicit restless legs syndrome symptoms (e.g. hiking for a long time, stopping an exercise routine), and that a consistent pattern of exercise improved restless legs syndrome symptoms with an overall beneficial effect on the frequency of symptomatic bouts. Participants further described time of day as impactful for their exercise experience, with > 50% indicating morning exercise improves symptoms and evening exercise worsens symptoms. Participants described several questions that they wanted answered regarding the evidence for exercise in restless legs syndrome and specific exercise prescription recommendations. The present study describes information crucial to the creation of stakeholder-informed health promotion programs for individuals with restless legs syndrome to optimize personalized treatment plans that could prevent and manage symptoms.

Physical Activity and Sedentary Behavior Timing in Fatigued and Nonfatigued Adults With Multiple Sclerosis.

OBJECTIVE: To examine device-measured physical activity levels and sedentary behavior participation during different times of the day (ie, morning, midday, and evening) in adults with multiple sclerosis (MS) who differed in fatigue status. DESIGN: Cross-sectional survey. SETTING: Remote survey study managed by a university-based research laboratory. PARTICIPANTS: A population-based sample of 1000 participants with MS were sent recruitment materials by the North American Research Committee on Multiple Sclerosis and 218 participants completed all relevant outcomes (N=218). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants (N=218) completed the Fatigue Severity Scale (FSS) as a measure of fatigue severity and were divided into subgroups of fatigued (FSS score ≥4) and nonfatigued (FSS score <4). Participants wore an ActiGraph GT3X+ on the nondominant hip for 7 days to measure physical activity (ie, light physical activity [LPA], moderate-to-vigorous physical activity [MVPA], steps) and sedentary behavior. RESULTS: Fatigued participants engaged in less MVPA (F[1216]=18.5, P<.001), fewer steps (F[1216]=27.8, P<.001), and more sedentary time (F[1216]=8.2, P=.005) than nonfatigued participants. Regardless of group, the highest levels of LPA (F[1.7355.7]=72.9, P<.001) and MVPA (F[1.8395.3]=23.0,P<.001) occurred in the morning and middle of the day, with the lowest levels in the evening. Regardless of group, the highest levels of sedentary behavior occurred in the evening, with similar levels in the morning and evening (F[1.6354.5]=84.3,P<.001). Regardless of group, participants had more steps in the middle of the day, followed by morning and then evening (F[1.8383.9]=84.7,P<.001). CONCLUSIONS: Our results suggest that physical activity timing should be considered in future development and delivery of behavior interventions that focus on increasing physical activity and reducing sedentary behavior among adults with MS who have fatigue.

Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response.

Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea−hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.

Symptom clusters and quality of life in persons with multiple sclerosis across the lifespan.

PURPOSE: To describe symptom clusters based on severity of co-occurring symptoms among adults with multiple sclerosis (MS) by age groups and to further examine symptom clusters as a correlate of quality of life (QOL) by age groups. METHODS: This cross-sectional study enrolled persons with MS between 20 and 79 years of age who completed measures of fatigue, depression, anxiety, sleep quality, and QOL using the 36-Item Short Form Health Survey. Bivariate correlation and partial correlation analyses examined associations among symptoms, QOL, and MS characteristics. K-means cluster analyses determined symptom clusters among the full sample and pre-determined age groups (i.e., 20-39, 40-59, and 60-79). One-way ANOVAs examined differences in QOL among clusters for the overall sample and by age groups. RESULTS: Among the overall sample of 205 participants, symptoms were significantly correlated with QOL and three distinct clusters were identified and differentiated by the magnitude of symptom experience (i.e., mild, moderate, and severe). Results were consistent among young and middle-aged adults; however, among older adults two severe sleep problem clusters were identified that were distinguished by moderate versus severe fatigue, depression, and anxiety. ANOVAs among the overall sample indicated that the three symptom clusters varied significantly for both physical component scores, F(2, 202) = 12.03, p < .001, η2 = .10, and mental component scores, F(2, 202) = 137.92, p < .001, η2 = .58; severe symptom cluster was associated with worse QOL. Patterns in the age subgroup ANOVAs were consistent. CONCLUSIONS: Given the strong association between severity of symptom clusters and QOL, approaches for targeting co-occurring symptoms are critically needed.

Restless legs syndrome and health-related quality of life in adults with multiple sclerosis.

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.

Step-rate threshold for physical activity intensity in Parkinson's disease.

OBJECTIVES: To examine the relationship between step-rate and energy expenditure during treadmill walking in persons with PD and then further develop a step-rate cut-point for moderate-to-vigorous physical activity (MVPA) for persons with PD. MATERIALS AND METHODS: The sample consisted of 30 persons with mild-to-moderate PD and 30 controls matched by age and sex. Participants performed a 6-minute bout of over-ground walking at comfortable speed, and then completed three, 6-minute bouts of treadmill walking at 13.4 m/min slower, comfortable, and 13.4 m/min faster than comfortable speeds. The three treadmill speeds were based on the initial over-ground walking speed. The total number of steps per treadmill walking bout was recorded using a hand-tally counter, and energy expenditure was measured using a portable, indirect spirometry system. RESULTS: The results indicated a strong association between step-rate and energy expenditure for persons with PD (R2  = .92) and controls (R2  = .92). The analyses further indicated a steeper slope of the association for persons with PD compared with controls (t(58) = -1.87, P < .05), resulting in a lower step-rate threshold (t(58) = 2.19, P < .05) for persons with PD (~80 steps·per minutes) than controls (~93 steps·per minutes). CONCLUSION: Collectively, these results support the application of this disease-specific step-rate threshold for MVPA among persons with PD. This has important implications for physical activity promotion, prescription, and monitoring using accelerometers and pedometers for persons with PD to manage health and symptoms of PD.

Quantitative Synthesis of Timed 25-Foot Walk Performance in Multiple Sclerosis.

OBJECTIVE: To provide a meta-analysis of articles that have included the timed 25-foot walk (T25FW) in persons with multiple sclerosis (MS), quantify differences in T25FW scores between those with MS and controls without MS, and quantify differences between categories of disability status and clinical disease courses within MS. DATA SOURCES: The literature search was conducted using 4 databases (Google Scholar, PubMed, Cumulative Index to Nursing and Allied Health, EBSCO Host). We searched reference lists of published articles to identify additional articles. STUDY SELECTION: A systematic literature search identified articles reporting average T25FW performance in seconds between those with MS and controls without MS, between those with MS who had mild and moderate and/or severe disability status, and between relapsing-remitting and progressive clinical courses of MS. DATA EXTRACTION: Information was extracted and categorized based on reported data: comparisons of controls without MS and MS, comparisons of mild and moderate and/or severe MS based on study-defined Expanded Disability Status Scale groups, and comparisons of relapsing-remitting and progressive MS clinical courses. DATA SYNTHESIS: We performed a random effects meta-analysis to quantify differences between groups as estimated by effect sizes (ESs). We expressed the differences in Cohen d as well as the original units of the T25FW (ie, seconds). CONCLUSIONS: There was a large difference in T25FW performance in MS compared with controls without MS (ES=-0.93, mean difference=2.4s, P<.01). Persons with moderate and/or severe disability walked substantially slower compared with mild disability (ES=-1.02, mean difference=5.4s, P<.01), and persons with progressive courses of MS walked substantially slower than relapsing-remitting MS (ES=-1.4, mean difference=13.4s, P<.01).

Does restless legs syndrome impact cognitive function via sleep quality in adults with Parkinson's disease?

Purpose: Restless legs syndrome (RLS) is a sleep disorder that results in sleep dysfunction. Sleep disruption can have profound negative consequences in adults with Parkinson's disease (PD), potentially including cognitive dysfunction. This study examined the relationships among RLS, cognition, and sleep quality in persons with PD.Materials and methods: Participants (N = 79) with idiopathic PD completed six questionnaires evaluating RLS, sleep quality, daytime sleepiness, global cognitive function, sleep apnea risk, and depression. Participants were further examined for body mass index composition and motor symptom severity (MDS-UPDRS Part III).Results: Persons with RLS (n = 25) had significantly worse cognitive function (p = 0.035, d = -0.56) and sleep quality (p < 0.0001, d = -1.19), and more daytime sleepiness (p = 0.009, d = 0.67) than those without RLS (n = 54). Cognitive function was not significantly correlated with sleep quality (rs = 0.113) or daytime sleepiness (rs = -0.001). The association between RLS and cognition was not attenuated by controlling for sleep quality or daytime sleepiness.Conclusions: This study is unique as it is the first to consider the possibility that RLS in PD may be associated with cognitive deficits through a pathway involving sleep quality. Persons with RLS and PD have greater deficits in both sleep quality and cognitive function than individuals without RLS; however, cognitive dysfunction among those with PD and RLS in this sample is not accounted for by sleep quality.

Changes in Cognitive Performance With Age in Adults With Multiple Sclerosis.

BACKGROUND: Cognitive impairment is one of the most common consequences of multiple sclerosis (MS), yet there is a shortage of data regarding how cognition changes during the life span of individuals with MS. This information is of increasing importance given the growing proportion of older adults with MS. OBJECTIVE: To study possible changes in cognitive function in correlation with increasing age in individuals with MS. METHODS: Participants (N=129) were recruited and a priori allocated into one of three age groups (young, middle-aged, and older). All participants completed the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) during a single laboratory testing session. The BICAMS measures cognitive processing speed as well as verbal and visuospatial learning and memory. RESULTS: A multivariate analysis of variance indicated that cognitive function significantly differed by age group, and these differences were not explained by amount of physical activity, years of education, years since diagnosis, or race. Older adults displayed significantly worse cognitive processing speed than young and middle-aged adults. The older and middle-aged adults also demonstrated significantly worse visuospatial learning and memory than the younger adults. Effect sizes indicated that cognitive processing speed and verbal learning and memory were more affected in late adulthood than early adulthood, whereas visuospatial learning and memory was affected similarly in early and late adulthood. CONCLUSIONS: Older adults with MS demonstrated significant impairments in cognitive function compared to young and middle-aged adults with MS. Future studies should determine the predictors of cognitive decline in this age cohort.

Self-Regulatory Strategies as Correlates of Physical Activity Behavior in Persons With Multiple Sclerosis.

OBJECTIVE: To examine self-regulation strategies as correlates of physical activity in persons with multiple sclerosis (MS). DESIGN: Cross-sectional, or survey, study. SETTING: University-based research laboratory. PARTICIPANTS: Convenience sample of persons with MS (N=68). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Exercise Self-Efficacy Scale (EXSE), 12-item Physical Activity Self-Regulation Scale (PASR-12), and Godin Leisure-Time Exercise Questionnaire (GLTEQ). RESULTS: Correlation analyses indicated that GLTEQ scores were positively and significantly associated with overall self-regulation (r=.43), self-monitoring (r=.45), goal-setting (r=.27), reinforcement (r=.30), time management (r=.41), and relapse prevention (r=.53) PASR-12 scores. Regression analyses indicated that relapse prevention (B=5.01; SE B=1.74; ß=.51) and self-monitoring (B=3.65; SE B=1.71; ß=.33) were unique predictors of physical activity behavior, and relapse prevention demonstrated a significant association with physical activity behavior that was accounted for by EXSE. CONCLUSIONS: Our results indicate that self-regulatory strategies, particularly relapse prevention, may be important correlates of physical activity behavior that can inform the design of future behavioral interventions in MS.

Physical Activity, Sedentary Behavior, and Physical Function in Older Adults With Multiple Sclerosis.

Older adults with multiple sclerosis (MS) experience the combined effects of aging and a chronic, disabling neurological disease on physical activity, sedentary behavior, and physical function. This study examined associations among light and moderate-to-vigorous physical activity (LPA and MVPA), sedentary behavior, and physical function in older adults with MS. Forty older adults with MS (median age = 60 years) who had a median Expanded Disability Status Scale score of 4.5 wore an accelerometer for a 7-day period and completed the Short Physical Performance Battery (SBBP), 6-minute walk (6MW), and timed 25-foot walk (T25FW). LPA was associated with SPPB (rs = .551, p < 0.01), 6MW (rs = .660, p < 0.01), and T25FW (rs = .623, p < 0.01) scores; MVPA was associated with 6MW (rs = .529, p < 0.01) and T25FW (rs = .403, p < 0.01) scores. There were significant associations between LPA, but not MVPA, with SPPB (ß = .583, p < 0.01), 6MW (ß = .613, p < 0.01), and T25FW (ß = .627, p < 0.01) scores in linear regression analyses. Older adults with MS who engaged in more LPA demonstrated better physical function and therefore LPA might be a target of future behavioral interventions.

Stakeholder involvement in the optimization of a patient-centered exercise intervention for people with restless legs syndrome.

STUDY OBJECTIVES: Previous research supports exercise as a behavioral approach to manage symptoms of restless legs syndrome (RLS); however, completion rates in exercise studies are low. This study obtained key stakeholder feedback from people with RLS to modify and optimize a 12-week, evidence-based exercise program for RLS. METHODS: Participants with RLS (n = 513) completed a nationwide survey to provide feedback on the necessity, interest, feasibility, and efficacy of the program as well as perceived barriers and proposed modifications to improve the exercise program. RESULTS: Most respondents (67%) expressed the need for an exercise program designed specifically for people with RLS and 64% were interested in the program. Only 6% of participants thought the program would not be well tolerated and 6% responded that it would likely exacerbate symptoms. However, only 58% said they would be likely to participate in the program if it was available to them locally. Key barriers to participation were (1) accessibility, (2) personal factors, (3) trustworthiness, and (4) fear of injury, illness, or symptom exacerbations. Respondents highlighted modification considerations for the individualization of exercise features, adaptations for specific impairments/personal factors, inclusion of flexibility and balance exercises, and flexibility for more home-based activities. CONCLUSIONS: Interest in the program was driven by the desire to reduce medications and improve overall quality of life. Appropriately educated and trained exercise providers knowledgeable about RLS are integral to buy-in from stakeholders. This study provides an imperative step in clinical research that can increase the success of subsequent implementation efforts and may accelerate the adoption of exercise programs into practice. CITATION: Cederberg KLJ, Sikes EM, Mignot E. Stakeholder involvement in the optimization of a patient-centered exercise intervention for people with restless legs syndrome. J Clin Sleep Med. 2024;20(4):535-543.

Proteomic insights into the pathophysiology of periodic limb movements and restless legs syndrome.

OBJECTIVES: We used a high-throughput assay of 5000 plasma proteins to identify biomarkers associated with periodic limb movements (PLM) and restless legs syndrome (RLS) in adults. METHODS: Participants (n = 1410) of the Stanford Technology Analytics and Genomics in Sleep (STAGES) study had blood collected, completed a sleep questionnaire, and underwent overnight polysomnography with the scoring of PLMs. An aptamer-based array (SomaScan) was used to quantify 5000 proteins in plasma. A second cohort (n = 697) that had serum assayed using a previous iteration of SomaScan (1300 proteins) was used for replication and in a combined analysis (n = 2107). A 5% false discovery rate was used to assess significance. RESULTS: Multivariate analyses in STAGES identified 68 proteins associated with the PLM index after correction for multiple testing (ie, base model). Most significantly decreased proteins were iron-related and included Hepcidin (LEAP-1), Ferritin, and Ferritin light chain. Most significantly increased proteins included RANTES, Cathepsin A, and SULT 1A3. Of 68 proteins significant in the base model, 17 were present in the 1300 panel, and 15 of 17 were replicated. The most significant proteins in the combined model were Hepcidin (LEAP-1), Cathepsin A, Ferritin, and RANTES. Exploration of proteins in RLS versus non-RLS identified Cathepsin Z, Heme oxygenase 2 (HO-2), Interleukin-17A (upregulated in the combined cohort), and Megalin (upregulated in STAGES only) although results were less significant than for proteins associated with PLM index. CONCLUSIONS: These results confirm the association of PLM with low iron status and suggest the involvement of catabolic enzymes in PLM/RLS.

Circadian protein expression patterns in healthy young adults.

OBJECTIVES: To explore how the blood plasma proteome fluctuates across the 24-hour day and identify a subset of proteins that show endogenous circadian rhythmicity. METHODS: Plasma samples from 17 healthy adults were collected hourly under controlled conditions designed to unmask endogenous circadian rhythmicity; in a subset of 8 participants, we also collected samples across a day on a typical sleep-wake schedule. A total of 6916 proteins were analyzed from each sample using the SomaScan aptamer-based multiplexed platform. We used differential rhythmicity analysis based on a cosinor model with mixed effects to identify a subset of proteins that showed circadian rhythmicity in their abundance. RESULTS: One thousand and sixty-three (15%) proteins exhibited significant daily rhythmicity. Of those, 431 (6.2%) proteins displayed consistent endogenous circadian rhythms on both a sleep-wake schedule and under controlled conditions: it included both known and novel proteins. When models were fitted with two harmonics, an additional 259 (3.7%) proteins exhibited significant endogenous circadian rhythmicity, indicating that some rhythmic proteins cannot be solely captured by a simple sinusoidal model. Overall, we found that the largest number of proteins had their peak levels in the late afternoon/evening, with another smaller group peaking in the early morning. CONCLUSIONS: This study reveals that hundreds of plasma proteins exhibit endogenous circadian rhythmicity in humans. Future analyses will likely reveal novel physiological pathways regulated by circadian clocks and pave the way for improved diagnosis and treatment for patients with circadian disorders and other pathologies. It will also advance efforts to include knowledge about time-of-day, thereby incorporating circadian medicine into personalized medicine.

Vitamin D and Restless Legs Syndrome: A Review of Current Literature.

This review presents a detailed summary of the current literature regarding RLS and vitamin D deficiency. To our knowledge it is the first review of its kind. We review the prevalence of vitamin D deficiency in RLS as well as the evidence for the use of vitamin D supplementation in RLS management. We further examine the literature for proteomic and genetic evidence of a role for vitamin D in the pathogenesis of RLS. An alteration in vitamin D binding protein in RLS is one of the most consistent findings in the proteomic studies. Furthermore, we examine the interaction of vitamin D with calcium, phosphorus, and parathyroid hormone and the possible role of these connections in RLS. We also explore the possible nexus between RLS and vitamin D in renal disease, cardiovascular and cerebrovascular disease as well as inflammation. In addition, we review the potential interaction between vitamin D and RLS with iron, dopamine and other neurotransmitter systems including the endogenous opiate, serotoninergic, glutamatergic and adenosinergic systems. We also explore the role of vitamin D in RLS Augmentation (i.e., the paradoxical worsening of RLS symptoms when dopaminergic agents are used as a therapy for RLS). Although the literature is not entirely consistent in affirming vitamin D deficiency in RLS or the amelioration of RLS symptoms with vitamin D therapy, the collective studies overall indicate that vitamin D deficiency is common enough in RLS patients to suggest that RLS patients should have their vitamin D levels checked and any deficiency corrected as a standard of care. Highlights  Patients with Restless Legs Syndrome (RLS) may be deficient in vitamin D and therapy with vitamin D may ameliorate RLS. We present the first review dedicated solely to evaluating the relationship between RLS and vitamin D and present a case for the role of vitamin D in RLS pathogenesis.

Do fatigue and depression have a bivariate association with device-measured physical activity behavior in persons with multiple sclerosis?

PURPOSE: This study examined the bivariate association between fatigue and depression symptoms and physical activity behavior in persons with multiple sclerosis (MS). METHODS: The sample of adults with MS completed the Fatigue Severity Scale (FSS) and the Hospital Anxiety and Depression Scale (HADS) and wore a waist mounted accelerometer during waking hours for 7 days. We categorized participants as having elevated fatigue and depression based on cut-points for the FSS (i.e., 4+ as indicative of severe fatigue) and the HADS (i.e., 8+ as indicative of elevated depressive symptoms). We used a two-way multivariate analysis of variance (MANOVA) to examine the contribution of fatigue and depression to volume and pattern of sedentary, light (LPA) and moderate-to-vigorous physical activity (MVPA). RESULTS: Results indicated no bivariate association between fatigue and depression and measures of physical activity behavior. The MANOVA indicated there was a significant association between fatigue and MVPA (F = 2.30, p = 0.032) and steps/day (F = 13.6, p < 0.001), independent of depression symptoms. There was no association between depression symptoms and physical activity behavior. CONCLUSIONS: This study demonstrated an interrelation between fatigue symptoms and MVPA and steps/day in MS, independent of depression symptoms, and this should be considered in the future design and delivery of physical activity interventions in MS.IMPLICATIONS FOR REHABILIATIONFatigue and depression are prevalent and burdensome symptoms of multiple sclerosis (MS).These symptoms can collectively worsen psychological and functional outcomes in MS.Fatigue symptoms may impact ambulatory physical activity to a greater degree than depression symptom status in persons with MS.Fatigue is an important consideration when designing behavior change interventions targeted at promoting physical activity in persons with MS.

The genetic etiology of periodic limb movement in sleep.

STUDY OBJECTIVES: Periodic limb movement in sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a genome-wide association study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects. METHODS: The MrOS study and Wisconsin Sleep Cohort Study (N = 1745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using Mendelian randomization. RESULTS: We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 × 10-12, ß = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, ß = 0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS. CONCLUSIONS: Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.

Restless legs syndrome severity associated with reduced physical function in adults with multiple sclerosis.

BACKGROUND: Restless legs syndrome (RLS) is a sleep disorder that occurs in approximately 26 % of adults with multiple sclerosis (MS) and may be associated with reduced physical function. RESEARCH QUESTION: The present study examined the relationship between RLS symptomology (i.e., overall severity, frequency, and occurrence) and physical function outcomes in adults with MS who had RLS. METHODS: Participants (N = 22) with MS who had RLS came into the laboratory for a single session wherein a rater performed a brief neurological examination for scoring the Expanded Disability Status Scale (EDSS) and completed a demographics questionnaire, the International Restless Legs Syndrome Study Group Scale (IRLS), and the Restless Legs Syndrome Scale-6 (RLS-6) followed by the Short Physical Performance Battery (SPPB) and the Six-minute Walk Test (6 MW). RESULTS: Bivariate Spearman's rho correlation analyses indicated total IRLS had a strong, negative association with total distance traveled during the 6 MW (ρ = -0.50) and a moderate association with SPPB scores (ρ = -0.43), but not EDSS scores (ρ = 0.28). RLS severity during the day while active had strong, negative associations with total distance traveled during the 6 MW (ρ = -0.61) and SPPB scores (ρ = -0.52), but not EDSS scores (ρ = 0.13). SIGNIFICANCE: We observed associations between worse overall RLS severity and RLS severity during the day while active with reduced performance during the 6 MW and lower SPPB scores. The management of RLS may offer an opportunity for mitigating reductions in physical function in adults with MS who have RLS.

Discrepancies between self-reported and device-measured sleep parameters in adults with multiple sclerosis.

STUDY OBJECTIVES: Sleep problems are a common consequence of multiple sclerosis; however, there is limited evidence regarding the agreement between device-measured and self-reported sleep parameters in adults with multiple sclerosis. The present study examined the agreement between self-reported and device-measured parameters of sleep quality in a sample of adults with multiple sclerosis. METHODS: Participants (n = 49) completed a 7-day sleep diary and wore a wrist-worn ActiGraph GT3×+ (ActiGraph Corp., Pensecola, FL) for seven consecutive nights to quantify self-reported and device-measured sleep parameters, respectively. RESULTS: There was a significant discrepancy between self-reported and device-measured parameters of total time in bed (mean difference = 19.8 [51.3] min), sleep onset latency (mean difference = 22.2 [19.5] min), and frequency of awakenings during the night (mean difference = 12.8 [6.8]). Intraclass correlation estimates indicated poor agreement between methods on most parameters, except for total time in bed (intraclass correlation = 0.80). Bland-Altman plots suggested that total time in bed and total sleep time had acceptable levels of agreement and linear regression analyses indicated that sleep onset latency (F = 113.91, B = -1.34, P < .001), number of awakenings (F = 543.34, B = 1.85, P < .001), and sleep efficiency (F = 18.39, B = -0.77, P < .001) had significant proportional bias. CONCLUSIONS: Our results draw attention to the discrepancies between sleep parameter measurements and highlight the importance of including both self-report and device-measured outcomes for a complete and accurate representation of sleep in adults with multiple sclerosis. CITATION: Cederberg KLJ, Mathison BG, Schuetz ML, Motl RW. Discrepancies between self-reported and device-measured sleep parameters in adults with multiple sclerosis. J Clin Sleep Med. 2022;18(2):415-421.

Restless Legs Syndrome Severity and Cognitive Function in Adults With Multiple Sclerosis: An Exploratory Pilot Study.

BACKGROUND: Restless legs syndrome (RLS) is a sleep disorder present in as many as 26% of persons with multiple sclerosis (MS) and can be associated with cognitive function. The present study examined the relationships between RLS symptoms (severity, frequency, occurrence) and cognitive function in adults with MS who have RLS. METHODS: Twenty-two participants attended 1 laboratory session and completed the International Restless Legs Syndrome Study Group Rating Scale (IRLS), the Restless Legs Syndrome-6 Scale, and then the Brief International Cognitive Assessment for Multiple Sclerosis battery consisting of the Symbol Digit Modalities Test; California Verbal Learning Test, Second Edition; and Brief Visuospatial Memory Test-Revised. RESULTS: Nonparametric bivariate correlations indicated that worse IRLS total severity was associated with slower processing speed (ρ = -0.42), worse verbal memory (ρ = -0.63), and worse visual memory (ρ = -0.61); worse RLS severity at falling asleep was associated with worse verbal memory (ρ = -0.45) and worse visual memory (ρ = -0.55); and worse RLS severity during the day while active was associated with slower processing speed (ρ = -0.58), worse verbal memory (ρ = -0.52), and worse visual memory (ρ = -0.60). CONCLUSIONS: These results suggest that those with more severe RLS, including worse symptoms at falling asleep and during the day while active, might experience worse cognitive function, particularly processing speed and memory. Future research should evaluate whether treatment of RLS symptoms can offer new opportunities for managing cognitive dysfunction in adults with MS.