Association of Periodic Limb Movements and Obstructive Sleep Apnea With Risk of Cardiovascular Disease and Mortality.

BACKGROUND: Obstructive sleep apnea is a well-established risk factor for cardiovascular disease (CVD). Recent studies have also linked periodic limb movements during sleep to CVD. We aimed to determine whether periodic limb movements during sleep and obstructive sleep apnea are independent or synergistic factors for CVD events or death. METHODS AND RESULTS: We examined data from 1049 US veterans with an apnea-hypopnea index (AHI) <30 events/hour. The primary outcome was incident CVD or death. Cox proportional hazards regression assessed the relationships between the AHI, periodic limb movement index (PLMI), and the AHI×PLMI interaction with the primary outcome. We then examined whether AHI and PLMI were associated with primary outcome after adjustment for age, sex, race and ethnicity, obesity, baseline risk of mortality, and Charlson Comorbidity Index. During a median follow-up of 5.1 years, 237 of 1049 participants developed incident CVD or died. Unadjusted analyses showed an increased risk of the primary outcome with every 10-event/hour increase in PLMI (hazard ratio [HR], 1.08 [95% CI, 1.05-1.13]) and AHI (HR, 1.17 [95% CI, 1.01- 1.37]). Assessment associations of AHI and PLMI and their interaction with the primary outcome revealed no significant interaction between PLMI and AHI. In fully adjusted analyses, PLMI, but not AHI, was associated with an increased risk of primary outcome: HR of 1.05 (95% CI, 1.00-1.09) per every 10 events/hour. Results were similar after adjusting with Framingham risk score. CONCLUSIONS: Our study revealed periodic limb movements during sleep as a risk factor for incident CVD or death among those who had AHI <30 events/hour, without synergistic association between periodic limb movements during sleep and obstructive sleep apnea.

Generalised linear model of periodic limb movements.

During sleep, the lower extremities exhibit periodic repetitive movements which are referred to as Period Limb Movement (PLM). Polysomnography (PSG) is the gold standard for diagnosing periodic limb movement disorder. The frequency of PLM episodes per hour of sleep (PLMI) determines the severity of the condition. PLM are generated by a dynamic process, however PLMI measures only the average PLM rate and does not capture the dynamic properties of PLM. Here, we characterise PLM dynamics using a generalised dynamic model as a function of sleep stage, timing of past PLM events and adjacent sleep disordered-breathing events. We analysed PSG recordings of 237 men and 222 women enrolled in the Multi-ethnic Study of Atherosclerosis (MESA) dataset to model dynamic PLM features. We statistically analysed whether these dynamics are associated with sex, age, and BMI. Modelling suggests instantaneous PLM rates are greater in men than women and higher in N1 and N2 non-rapid eye movement sleep than N3 and rapid eye movement sleep. The generalised model constitutes statistically robust approach towards the characterisation of periodic limb movement.Clinical Relevance- The generalised model may enable differentiated diagnostics of periodic limb movement disorder.

[Restless sleep disorder a new entity to considered in children]. / Trastorno de sueño inquieto: una nueva entidad clínica a considerar en niños.

Restless sleep disorder (RSD) is a condition recently described by a group of sleep experts who developed diagnostic and polysomnographic criteria after conducting a comprehensive review of the available literature where poor sleep or restless sleep is a symptom alone or that accompanies other disorders. This group defined RSD as a condition characterized by parental complaints of frequent jerking movements during sleep, position changes, and sleep disruption that cause significant impairment during the day. Diagnostic criteria include the presence of symptoms for at least 3 months, 3 times a week, and at least 5 movements per hour on polysomnography. Changes in behavior during the day, such as drowsiness, irritability, and hyperactivity that are not explained by a medical, pharmacological, or behavioral condition, should be considered. Its estimated prevalence is 7.7% of children referred for sleep problems. Children often have ferritin levels below 50 µg/l, a point in common with restless legs syndrome. Treatment consists of iron supplements, which have shown benefits in these children. To establish the diagnosis, secondary symptoms of medical origin or other sleep disorders such as restless legs syndrome or periodic limb movement disorder must be ruled out. The objective of this report is to review the current recommendations on this entity, describe the clinical, pathophysiological, and polysomnographic keys, in order to highlight the need to publicize this condition and expand studies in age groups other than those already defined and to generate treatment guidelines.

[Abnormal nocturnal behavior mimicking REM sleep behavior disorder episodes in a patient with periodic limb movement disorder].

Periodic limb movement disorder (PLMD) is a condition in which patients experience frequent periodic limb movements of sleep (PLMS). Synchronized arousal responses cause sleep fragmentation, resulting in insomnia, daytime sleepiness, and fatigue. A 59-year-old man was identified as having intense sleep-talking and body movements, suggesting rapid eye movement (REM) sleep behavior disorder (RBD). Attended video-polysomnography (PSG) revealed that sleep-talking and body movements occurred only during non-REM sleep and were associated with PLMS-induced arousals (periodic leg movement arousal index, 53.2/h). Pramipexole administration improved events during sleep and daytime sleepiness, and the PSG findings and clinical course led to a diagnosis of PLMD. This case demonstrates that PLMD mimics the symptoms of RBD and that a detailed analysis of monitored video PSG is crucial to confirm the diagnosis of RBD and to identify or exclude other causes of sleep talking and behavior.

[Periodic limb movements in sleep and cerebral small vessel disease progression: a prospective cohort study]. / Periodicheskie dvizheniya konechnostei vo sne i progressirovanie tserebral'noi mikroangiopatii: prospektivnoe kogortnoe issledovanie.

OBJECTIVE: To determine the predictive role of periodic limb movements in sleep (PLMS) in cerebral small vessel disease (cSVD) progression rate. MATERIAL AND METHODS: Fifty patients with cSVD, aged 60-75 y.o., were enrolled. The study protocol included MRI assessment of white matter hyperintensities (WMH), nocturnal actigraphy and cognitive assessment. Depending on the PLMS, the main (PLM index ≥15) and the control (PLM index <15) groups were formed. The second visit was carried out in one year follow-up period, the examination consisted of brain MRI and cognitive assessment under the same protocol. ANCOVA was performed to determine if PLMS influence the degree of MRI- and neuropsychological changes. RESULTS: A significant effect of PLMS on the increase in the volume of WMH was revealed, both in the form of an increase in the index by more than 15 movements per hour (p=0.03), and quantitatively in the form of a connection with the index value (p=0.048). The influence of PLMS on the progression of cognitive dysfunction has not been found, however, it has been shown that the presence of PLMS is associated with lesions in the deep white matter (r=0.42, p<0.0001), and the results of neuropsychological tests are associated with lesions in the periventricular and juxtacortical WMH (p < 0.05 for each test). CONCLUSION: PLMS predict WMH progression in cSVD.

Time to rest a hypothesis? Accumulating evidence that periodic leg movements during sleep are not increased in children with attention-deficit hyperactivity disorder (ADHD): results of a case-control study and a meta-analysis.

STUDY OBJECTIVES: To address the hypothesis that periodic leg movements during sleep (PLMS) are more frequent in children with attention-deficit hyperactivity disorder (ADHD) when compared with typically developing (TD) children. To that end, we analyzed PLMS in a recent case-control study and conducted a systematic review and meta-analysis of PLMS frequency in children with ADHD and TD children. METHODS: In our case-control study, we compared the PLMS frequency of 24 children with ADHD (mean age 11 years, 17 males) to that of 22 age-matched typically developing (TD) children (mean age 10 years, 12 males). A subsequent meta-analysis included 33 studies that described PLMS frequency in groups of children with ADHD and/or groups of TD children. RESULTS: The case-control study did not show any differences in the frequency of PLMS between children with ADHD and TD children, a result that was consistent across a range of different definitions of PLMS, which in turn had a significant and systematic effect on PLMS frequency. The meta-analysis compared the average PLMS indices and the proportion of children with elevated PLMS indices between children with ADHD and TD children and across a number of analyses did not find any meta-analytic results that supported the hypothesis that PLMS are more frequent in children with ADHD. CONCLUSIONS: Our results suggest that PLMS are not more frequent in children with ADHD compared with TD children. A finding of frequent PLMS in a child with ADHD should therefore be considered a separate disorder and prompt specific diagnostic and therapeutic strategies.

Association between Self-Perceived Periodic Limb Movement during Sleep and Excessive Daytime Sleepiness Depend on Restless Leg Symptoms in Korean Adolescents.

Although periodic limb movement during sleep (PLMS) and restless legs syndrome (RLS) are common in children and adolescents, they are relatively overlooked as a target of treatment. PLMS has been evaluated as having a lower clinical significance than RLS. This study examined the relationship of socio-behavioral factors of PLMS in Korean adolescents and checked whether PLMS is associated with excessive daytime sleepiness (EDS), depending on whether restless legs symptoms accompany it. In a cross-sectional study, 25,789 adolescents between 12 and 18 years of age (15.76 ± 1.73 years; female 51.49%) were evaluated using an online survey. Various self-report questionnaires were used to assess PLMS and RLS symptoms, EDS, sleep habits, and various socio-behavioral factors. The prevalence of self-perceived PLMS and restless legs symptoms were 903 (3.50%) and 1311 (5.08%), respectively. Of the 1311 participants, 399 had self-perceived PLMS. The odds ratios (ORs) for self-perceived PLMS in participants with restless legs symptoms were: males (OR = 1.528; 95% CI: 1.145-2.040), usually/always experienced apnea apnea (OR, 3.006; 95% CI, 1.954-4.624), increased proneness to Internet addiction (OR = 1.013; 95% CI: 1.001-1.025), sometimes/often consuming coffee (OR = 1.312; 95% CI: 1.015-1.695), EDS (OR = 0.826; 95% CI: 0.488-1.398), and perceived insufficient sleep (OR = 1.143; 95% CI: 0.835-1.565). The male gender, witness apnea, consuming coffee, and being prone to Internet addiction were identified as factors significantly associated with self-perceived PLMS in participants with restless legs symptoms. However, EDS and insufficient sleep were associated with self-perceived PLMS in the absence of restless legs symptoms.

Large body movements on video polysomnography are associated with daytime dysfunction in children with restless sleep disorder.

Restless sleep disorder (RSD) is a newly defined sleep-related movement disorder characterized by large muscle movements (LMM) in sleep. We examined the sleep study, clinical characteristics, and daytime functioning in children with RSD and compared them to children with periodic limb movement disorder (PLMD) or restless legs syndrome (RLS). Video polysomnography from 47 children with restless sleep was retrospectively reviewed for LMM and age- and sex-matched to 34 children with PLMD and 12 children with RLS. Data examined included PSG characteristics, ferritin, Pediatric Quality of Life (PedsQL), and Epworth Sleepiness Scale (ESS). Fourteen children met the clinical criteria for RSD with an LMM index of 5 or more per hour of sleep. Mean ESS was elevated in patients with RSD compared to either the PLMD or RLS groups though the result did not reach statistical significance (RSD = 10.20 ± 6.81, PLMD = 6.19 ± 4.14, RLS = 6.25 ± 4.90). The PedsQL score was significantly decreased in the RLS group compared to RSD and was reduced overall in all three groups (PedsQL Total RSD = 70.76 ± 18.05, PLMD = 57.05 ± 20.33, RLS = 53.24 ± 16.97). Serum ferritin values were similar in all three groups (RSD = 26.89 ± 10.29, PLMD = 33.91 ± 20.31, RLS = 23.69 ± 12.94 ng/mL, p = ns). Children with RSD demonstrate increased daytime sleepiness compared to PLMD or RLS and all three disease groups showed decreased quality of life. Further studies are needed to examine long-term consequences of RSD.

Restless sleep disorder, restless legs syndrome, and periodic limb movement disorder-Sleep in motion!

Sleep-related movement disorders (SRMDs) represent an important part of pediatric sleep disorders. The most common complaint in SRMD is restless sleep at night. Restless sleep is reported in up to 80% of children with restless legs syndrome (RLS) and children with periodic limb movements of sleep (PLMS) disorder (PLMD). However, restless sleep causing daytime behavioral consequences can be seen in children without another apparent condition and has recently been identified as a new independent primary pediatric sleep disorder, called restless sleep disorder (RSD). This study describes these three main SRMDs (RSD, RLS, and PLMD), explains the new consensus criteria for RSD, emphasizes the rapidly evolving areas of research in this field, and proposes recommendations for future research. In particular, the published data constitute convincing evidence that sleep-related movements are disruptors of sleep quality and continuity. However, while important advancements have recently been reported in adults, a detailed analysis of the phenomenology and consequences of sleep-related movements has just started in children. New approaches, standardized diagnostic methods, and specific guidelines are needed in the field of pediatric SRMD.

Periodic Leg Movements During Sleep.

Periodic leg movements during sleep (PLMS) are a frequent finding in nocturnal sleep registrations that include tibialis anterior electromyographic signals. Different PLMS scoring rules exist and can have a major impact on PLMS frequency, which tends to be underappreciated. There is no consistent evidence that frequent PLMS are a causal risk factor for clinically significant outcomes. Several critical open questions are identified that need to be addressed, including but not limited to the consideration of the full range of all sleep-related leg movement activity.

Restless legs syndrome and periodic limb movements in 86 patients with multiple sclerosis.

STUDY OBJECTIVES: To assess the frequency of restless legs syndrome (RLS), periodic limb movements during sleep (PLMS), and their overlap in a large sample of patients with multiple sclerosis (MS). To compare clinical and paraclinical findings among four subgroups of patients: RLS-/PLMS- (patients without RLS and PLMS), RLS+/PLMS- (patients with RLS and without PLMS), RLS-/PLMS (patients without RLS and with PLMS), and RLS+/PLMS+ (patients with both RLS and PLMS). METHODS: In this cross-sectional, observational, instrumental study, 86 patients (M/F: 27/59; mean age 48.0 ± 10.8 years) with a diagnosis of MS underwent a telephone interview assessing the five standard diagnostic criteria for RLS. Seventy-six participants underwent polysomnography (PSG) and maintenance of wakefulness test (MWT). Instrumental and clinical findings were subsequently statistically compared to investigate their association with RLS and PLMS index (PLMSI). RESULTS: RLS and PLMS (PLMSI ≥15/h) frequency in patients with MS were of 31.4% and 31.6%, respectively. Among patients with RLS, 37.5% had a PLMSI of at least 15/h. RLS-/PLMS+ group showed higher wake after sleep onset (p = 0.01), stage shifts per hour (p = 0.03), increased stage N1 (p = 0.03), and reduction in stage N3 (p = 0.01) compared to RLS-/PLMS-. RLS had no influence on clinical and PSG parameters (p = 0.45). CONCLUSIONS: RLS is highly frequent in patients with MS. The frequency of PLMS is comparable to the general population. The low percentage of patients with RLS having a high PLMSI, together with the absence of correlation between RLS and female gender and older age, supports the existence of a distinct symptomatic form of RLS in MS.

Effects of new PLM scoring rules on PLM rate in relation to sleep and resting wake for RLS and healthy controls.

PURPOSE: This study evaluates the differences in periodic leg movement (PLM) rates for Restless Legs Syndrome (RLS) and healthy controls when using the updated PLM scoring criteria developed by IRLSSG in 2016 versus the prior PLM scoring criteria developed by IRLSSG in 2006. Four major problems with the prior standards had been objectively identified, i.e. minimum inter-movement interval should be 10 not 5 s, non-PLM leg movements should end any preceding PLM sequence, a leg movement (LM) can be any length > 0.5 s, and a PLM should be a persisting movement not a couple or a series of closely spaced, very brief events. Each of these led to including, erroneously, various random leg movements as PLM. Correcting these problems was expected to increase specificity, reducing the number of PLM detected, particularly in situations producing relatively more random leg movements, e.g. wake vs. sleep and controls without PLMD vs. RLS patients. METHODS: This study evaluated the putative benefits of the updated, 2016-scoring criteria. The LMs from 42 RLS patients and 30 age- and gender-matched controls were scored for PLMS and PLMW from standard all-night PSG recordings using both 2006 and 2016 WASM criteria. RESULTS/CONCLUSION: The results confirmed that that the 2016 compared to the 2006 criteria generally decreased the PLM rates with particularly large decreases for the conditions with more random non-PLM events, e.g. wake times and normal healthy controls. This supported the view that the new criteria succeeded in increasing the specificity of PLM detection. Moreover, the changes in PLM rates were generally small for the conditions with relatively few random LM, e.g. RLS and sleep. Thus the bulk of existing PLMS research does not require reconsideration of results, with possible exception of special situations with relatively more random leg movements than periodic leg movements, e.g. wake, healthy normals and children.

Cyclic Alternating Pattern Analysis in Periodic Leg Movements in Sleep in Patients With Obstructive Sleep Apnea Syndrome Before and After Positive Airway Pressure Treatment.

PURPOSE: Cyclic alternating pattern (CAP) is known to increase in many conditions of sleep disruption and sleep disorders, including obstructive sleep apnea syndrome and periodic limb movements in sleep (PLMS). Periodic limb movements in sleep associated with obstructive sleep apnea syndrome may vanish after positive airway pressure treatment, may persist, or emerge at treatment night. Here, the authors aimed to investigate the underlying pathophysiology of nonvanishing, vanishing, or newly emergent PLMS. METHODS: The authors designed a prospective study and included 10 patients with nonvanishing PLMS during positive airway pressure therapy, 10 patients with vanishing PLMS, 10 patients with newly emergent PLMS, and 10 patients without PLMS at both nights. The CAP analysis was performed in detail at diagnostic polysomnography recording and at positive airway pressure titration. The changes in CAP parameters were evaluated in regard to nonvanishing, vanishing, or newly emergent PLMS. RESULTS: Periodic limb movements in sleep related to A1 subtype of CAP were observed to decrease under positive airway pressure titration more than PLMS related to A3 subtype of CAP. The A3 subtype of CAP was higher in patients with vanishing PLMS than those with newly emergent PLMS. The newly emergent PLMS were mostly related to A1 subtype of CAP compared with A3 subtype of CAP. CONCLUSIONS: This study showed that vanishing, nonvanishing, or newly emerging PLMS may indeed represent different underlying pathophysiology. The authors suggest that organization of sleep and preservation of ultradian rhythms during titration may determine whether PLMS will be vanished or persist. Newly emergent PLMS may probably arise from a separate central generator by the activation of higher cortical areas.

Restless Legs Syndrome and Other Common Sleep-Related Movement Disorders.

PURPOSE OF REVIEW: In this article, the different sleep-related movement disorders are discussed with special attention given to restless legs syndrome (RLS). RECENT FINDINGS: The differential diagnosis of sleep-related movement disorders can often be challenging; therefore, it is essential to have accurate information to make a correct diagnosis. This article focuses on RLS, highlighting the change in the paradigm of initial treatment, the role played by iron (pathophysiologic and therapeutic), and how to approach possible complications occurring with long-term treatment. SUMMARY: RLS is one of the most common neurologic conditions, and it is common in clinical practice to find patients experiencing symptoms suggestive of RLS. Neurologists must be careful and thorough in the diagnosis, excluding RLS mimics. The decisions regarding which specific sleep-related movement disorder is present and how it should be treated are important because in certain cases, especially in RLS, adverse effects and long-term complications are frequently reported with the use of certain drugs.

Design of a deep learning model for automatic scoring of periodic and non-periodic leg movements during sleep validated against multiple human experts.

OBJECTIVE: Currently, manual scoring is the gold standard of leg movement scoring (LMs) and periodic LMs (PLMS) in overnight polysomnography (PSG) studies, which is subject to inter-scorer variability. The objective of this study is to design and validate an end-to-end deep learning system for the automatic scoring of LMs and PLMS in sleep. METHODS: The deep learning system was developed, validated and tested, with respect to manual annotations by expert technicians on 800 overnight PSGs using a leg electromyography channel. The study includes data from three cohorts, namely, the Wisconsin Sleep Cohort (WSC), Stanford Sleep Cohort (SSC) and MrOS Sleep Study. The performance of the system was further compared against individual expert technicians and existing PLM detectors. RESULTS: The system achieved an F1 score of 0.83, 0.71, and 0.77 for the WSC, SSC, and an ancillary study (Osteoporotic Fractures in Men Study, MrOS) cohorts, respectively. In a total of 60 PSGs from the WSC and the SSC scored by nine expert technicians, the system performed better than two and comparable to seven of the individual scorers with respect to a majority-voting consensus of the remaining scorers. In 60 PSGs from the WSC scored accurately for PLMS, the system outperformed four previous PLM detectors, which were all evaluated on the same data, with an F1 score of 0.85. CONCLUSIONS: The proposed system performs better or comparable to individual expert technicians while outperforming previous automatic detectors. Thereby, the study validates fully automatic methods for scoring LMs in sleep.

Comorbidities in children with elevated periodic limb movement index during sleep.

STUDY OBJECTIVES: Little is known about comorbidities in children who have elevated periodic limb movement index (PLMI) during overnight polysomnogram (PSG). The aim of this study is to identify comorbidities in children with elevated PLMI (PLMI > 5) versus children with PLMI < 5 presenting to a pediatric sleep center. METHODS: This study was a retrospective review of all clinically indicated PSGs obtained consecutively from 3/2017-3/2019 at Seattle Children's Sleep Disorders Center. Data collected included demographics, clinical presentation, medications, medical history, family history specifically for restless legs syndrome (RLS), ferritin levels, and PSG metrics. Characteristics between those with (cases) elevated PLMI (AASM criteria) and without (controls) were summarized. RESULTS: We identified 148 subjects with elevated PLMI (67% male, mean age 7.95 years, range 1-20), yielding a PLMI > 5 prevalence of 5%. There were 188 controls included (58% male, mean age 8.0 years, range 1-19). Neither sex (chi-square = 2.8, NS) nor age (Mann-Whitney U = 1339.5, NS) differed between groups. Case subjects had a higher prevalence of RLS, snoring, insomnia, mood disorders, behavioral problems, morning headaches, chronic kidney disease, epilepsy, and chronic heart disease. Similarly, the use of antidepressants, antipsychotics, antiseizure medication, and other medications was statistically more frequent in children with elevated PLMS. The prevalence of PLMI > 5 was 5% and the prevalence of periodic limb movement disorder (PLMD) was 0.3% in children referred to polysomnography. Ferritin levels did not differ. CONCLUSIONS: We identified the prevalence of PLMD in a sleep medicine-referred population. We have also identified comorbidities and medications associated with elevated PLMI in children.No clinical trial.

Sleep spindles, K-complexes, limb movements and sleep stage proportions may be biomarkers for amnestic mild cognitive impairment and Alzheimer's disease.

PURPOSE: Sleep disturbances are common in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients. Non-rapid eye movement stage 3 (N3), rapid eye movement stage (REM), spindle density, and K-complex (KC) density are decreased in MCI and AD patients. Periodic limb movements in sleep (PLMS) are increased in other neurodegenerative diseases. We aimed to distinguish amnestic mild cognitive impairment (aMCI) patients from the overall population of MCI patients by comparing the N3 and REM proportions, the morphological characteristics of spindles and KCs and the periodic limb movement index (PLMI) among control, aMCI and AD subjects. METHODS: In 92 subjects (30 controls, 32 aMCI and 30 AD), sleep stages, spindles, KCs and PLMS were recorded during the second of two nights of polysomnography (PSG). We compared the above parameters among the three groups. RESULTS: AD and aMCI subjects had lower proportions of N3 and REM, poorer spindle and KC activities and more frequent PLMS than controls. These alterations were associated with decreased Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. We determined cut-off values for distinguishing aMCI and AD using logistic regression and receiver operating characteristic (ROC) analyses. CONCLUSIONS: AD and aMCI patients have abnormal sleep stage proportions, spindles, KCs and PLMS. The combination of the above alterations may distinguish aMCI and AD patients from controls with high specificity and sensitivity.