Exploring sex differences in periodic leg movements during sleep across the lifespan of patients with restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) and periodic leg movements during sleep (PLMS) are prevalent sleep disorders with significant implications for health and well-being. While previous research has highlighted sex-related disparities in RLS and PLMS prevalence, comprehensive understanding of these differences across the lifespan remains limited. This study aims to explore sex differences in RLS and PLMS across diverse age groups, spanning ages 2 to over 80 years, and to investigate the underlying mechanisms influenced by sex hormones. METHODS: A retrospective analysis was conducted on drug-free patients diagnosed with RLS, including 95 females (age range: 2-83.2 years) and 89 males (age range: 2-79.5 years). Polysomnographic recordings were analyzed to assess leg movement activity, including PLMS index and Periodicity index. RESULTS: A more rapid increase in PLMS index was observed in women starting before age 10, plateauing lower than men until around age 55. An increase in women occurred after 55, lasting over a decade, while in men, PLMS index continued to rise after 75. Conversely, Periodicity index displayed a simpler pattern, increasing progressively from prepuberty to around 35 in males and 45-50 in females. Females maintained a slightly higher Periodicity index than males for over a decade after this age. CONCLUSION: These findings underscore the complex interplay between sex hormones, age, and sleep disorders, highlighting the need for tailored approaches to diagnosis and management across diverse demographic cohorts. Further research is warranted to elucidate the underlying mechanisms and develop targeted interventions to optimize sleep health outcomes.

Automated explainable wavelet-based sleep scoring system for a population suspected with insomnia, apnea and periodic leg movement.

Sleep is an integral and vital component of human life, contributing significantly to overall health and well-being, but a considerable number of people worldwide experience sleep disorders. Sleep disorder diagnosis heavily depends on accurately classifying sleep stages. Traditionally, this classification has been performed manually by trained sleep technologists that visually inspect polysomnography records. However, in order to mitigate the labor-intensive nature of this process, automated approaches have been developed. These automated methods aim to streamline and facilitate sleep stage classification. This study aims to classify sleep stages in a dataset comprising subjects with insomnia, PLM, and sleep apnea. The dataset consists of PSG recordings from the multi-ethnic study of atherosclerosis (MESA) cohort of the national sleep research resource (NSRR), including 2056 subjects. Among these subjects, 130 have insomnia, 39 suffer from PLM, 156 have sleep apnea, and the remaining 1731 are classified as good sleepers. This study proposes an automated computerized technique to classify sleep stages, developing a machine-learning model with explainable artificial intelligence (XAI) capabilities using wavelet-based Hjorth parameters. An optimal biorthogonal wavelet filter bank (BOWFB) has been employed to extract subbands (SBs) from 30 seconds of electroencephalogram (EEG) epochs. Three EEG channels, namely: Fz_Cz, Cz_Oz, and C4_M1, are employed to yield an optimum outcome. The Hjorth parameters extracted from SBs were then fed to different machine learning algorithms. To gain an understanding of the model, in this study, we used SHAP (Shapley Additive explanations) method. For subjects suffering from the aforementioned diseases, the model utilized features derived from all channels and employed an ensembled bagged trees (EnBT) classifier. The highest accuracy of 86.8%, 87.3%, 85.0%, 84.5%, and 83.8% is obtained for the insomniac, PLM, apniac, good sleepers and complete datasets, respectively. Using these techniques and datasets, the study aims to enhance sleep stage classification accuracy and improve understanding of sleep disorders such as insomnia, PLM, and sleep apnea.

Response to iron supplementation is similar between boys and girls with pediatric sleep movement disorders.

OBJECTIVES: This study aims to investigate sex differences in response to iron supplementation in children and adolescents suffering from sleep-related movement disorders such as Restless Legs Syndrome (RLS), Periodic Limb Movement Disorder (PLMD), and Restless Sleep Disorder (RSD). METHODS: Data were retrieved and reanalyzed from previous studies involving children with RLS, PLMD, or RSD. The analysis included 54 patients treated with intravenous (IV) ferric carboxymaltose (FCM) and 31 patients treated with oral ferrous sulfate (FS). Demographic, biological, and clinical parameters were compared between sexes. Clinical outcomes were measured using the Clinical Global Impression rating scales for severity (CGI-S) and improvement (CGI-I). RESULTS: In the group treated with IV FCM, no significant differences were found between males and females in demographic (age), biological (ferritin, iron, total iron-binding capacity, transferrin), or clinical parameters (CGI-S and CGI-I). However, among adolescents, females showed significantly better clinical improvement (CGI-I) compared to males (t-value 2.428, p < 0.024). In the group treated with oral FS, no significant sex differences were observed in any parameters. Side effects were reported by a small number of patients, with no significant difference between sexes. CONCLUSION: The findings indicate no major significant sex-based differences in response to iron supplementation for treating sleep-related movement disorders in children and adolescents, despite distinct hormonal and physiological differences in iron metabolism. Both boys and girls benefit similarly from iron treatment during this developmental stage, suggesting that a standardized approach to iron supplementation may be effective. However, individual assessment and monitoring remain crucial to ensure optimal outcomes.

Periodic limb movements during sleep in children with neuromuscular disease or cerebral palsy - An important potential contributor to sleep-related morbidity.

OBJECTIVES: Poor sleep is frequently reported in children with neuromuscular diseases (NMD) and cerebral palsy (CP) however breathing disorders during sleep are often the clinical focus. Periodic limb movements (PLMs) have an increased prevalence in adults with NMD and may contribute to sleep disturbance in this population. We assessed the prevalence of PLMs in children with NMD or CP. METHODS: Retrospective review of polysomnography (PSG) with leg electromyography in children age 1-18 years with NMD (including Duchenne muscular dystrophy, myotonic dystrophy, spinal muscular atrophy) or CP performed at a paediatric sleep centre 2004-2022. RESULTS: Leg electromyography was available in at least 1 PSG in 239 children (125 NMD, 114 CP), and in 2 PSGs in 105 children (73 NMD, 32 CP). At initial PSG, 72 (30 %) were female with a median age 9y and respiratory disturbance index 3.5/h (interquartile range 1.3-9.9/h). Elevated PLM index (PLMI; >5/h) occurred in 9.6 % of each of the CP and NMD groups, quantified by initial PSG. Overall, PLMI increased from baseline (median 0, maximum 33/h) to follow-up (median 0, maximum 55.8/h; p < 0.05). In those with an elevated PLMI, arousal percentage attributable to PLMs was up to 25 % (median 7.5 %). CONCLUSIONS: Elevated PLMI occurred at a higher prevalence in children with NMD and CP than reported in other clinic-referred paediatric populations. It is important that PLMs are not overlooked as identification and treatment may help improve sleep outcomes. Further research is required to understand the pathophysiology and consequences of PLMs specifically in this population.

Manual scoring of periodic limb movements in children: is it still necessary?

OBJECTIVE: Although manual scoring has been classically considered the gold standard to identify periodic leg movements (PLM), it is a very time consuming and expensive process, also subject to variability in interpretation. In the last decades, different authors have observed reasonably good agreement between automated PSG scoring algorithms and manual scoring in adults, according to established criteria. We aim to compare the automatic software analysis of our polysomnogram with the manual staging in children with sleep-disordered breathing. METHODS: We performed a semiautomatic method, in which an experienced technician watched the video recording and removed from the automatic analysis those movements that did not correspond to true candidate leg movement (LM). RESULTS: A total of 131 PSGs were studied; applying the established criteria, 65 children were diagnosed of obstructive sleep apnea, and 66 presented snoring but with no sleep apnea. The mean age was 6.7 years (±1.7) and twenty-five children (19.08 %) had a PLMI >5/h. Statistical differences were found not only for PLMI (manual: 2.20 (0.7, 4.1) vs automatic (6.4 (3.85,9.5); p < 0.001), but for almost of all indexes assessed between the automatic and the manual scoring analysis. The level of concordance was only moderate for PLM index (0.63 [0.51-0.72]); showing that, unlike the articles published in the adult population, automatic analysis is not accurate in children and, manually or semi-automatically analysis as ours need to be done. CONCLUSION: It seems that PLM detection algorithm might work accurately but, the real need would be a true LM detection algorithm.

Effect of positive airway pressure treatment on excessive fragmentary myoclonus in 100 sleep-related breathing disorder patients.

STUDY OBJECTIVES: Excessive fragmentary myoclonus (EFM) is a frequent finding in patients undergoing video-polysomnography (VPSG). We aimed to evaluate the potential effect of sleep-related breathing disorder's treatment with positive airway pressure (PAP) therapy on EFM. METHODS: One hundred consecutive patients with EFM and sleep-related breathing disorder subsequently treated with PAP at the sleep lab of the Medical University of Innsbruck, Department of Neurology, Austria, were included. Each patient underwent two nights of VPSG: the first night without and the second night with PAP therapy. Fragmentary myoclonus was automatically scored with validated software, and fragmentary myoclonus index (FMI) and minutes of non-rapid eye movement (NREM) sleep with EFM (minNREM+EFM) were calculated. RESULTS: Under PAP therapy there was a significant decrease in the minNREM+EFM - 60.5 (9.5-161.8) at baseline vs. 37.5 (6.3-168.8) minutes under PAP, p = 0.025. No significant differences were observed for FMI between the two nights. Sleep variables, sleep diagnoses, comorbidities, and medication did not influence FMI or the minNREM+EFM. CONCLUSIONS: The initiation of PAP treatment led to a significant reduction of minNREM+EFM, but not of FMI. The results suggest that PAP therapy might influence the distribution of FM potentials.

A Historical Overview of the Role of Benzodiazepines including Clonazepam in the Treatment of Adult Restless Legs Syndrome and Periodic Limb Movements in Sleep.

In a recent survey of 16,694 people receiving treatment for Restless Legs Syndrome (RLS), approximately 25% were treated with benzodiazepines either singly or in combination with other RLS treatments. Because of the large number of people receiving benzodiazepines for treatment of RLS, we conducted a historical overview of the therapeutic role of benzodiazepines in RLS and its associated condition Periodic Limb Movements in Sleep (PLMS). We found 17 articles on the use of clonazepam in RLS, PLMS, or both, 3 on triazolam and PLMS, 1 on alprazolam and RLS, 1 on temazepam and PLMS, and 1 on nitrazepam and PLMS. The order of benefit of benzodiazepines from the summarized literature is Sleep>RLS>PLMS and arousals > PLMS. Most of the studies on clonazepam employed dosages of 0.5-2.0 mg. Dosages of 3 or 4 mg caused lethargy, somnolence and confusion. An epidemiological study on the therapy of RLS suggests that treatment of RLS with most types of RLS medications including benzodiazepines in combination with other RLS therapies lowers the future cardiovascular risk associated with RLS. The major effect of benzodiazepines is through potentiation of the effect of GABA on the GABA A receptor. Neuroimaging studies suggest that GABA is altered either positively or negatively in various brain regions in RLS and genetic studies suggest that there are alterations in the GABA receptor in RLS. These results suggest that medications with different GABAergic mechanisms such as tiagabine (Gabitril) or others should be investigated in RLS for their possible therapeutic benefit. Highlights: Benzodiazepines are frequently used as therapy in Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep. The order of benefit is Sleep>RLS>PLMS and arousals > PLMS. For clonazepam dosages of 0.5 mg-2.0 mg/day are most frequently employed. Benzodiazepines exert their therapeutic effect through GABA-ergic mechanisms.

Periodic limb movement disorder in children: A systematic review.

This systematic review evaluates the scientific literature on pediatric periodic limb movement disorder (PLMD), adhering to PRISMA guidelines and utilizing PICOS criteria. The search across PubMed, EMBASE, and Scopus yielded 331 articles, with 17 meeting inclusion criteria. Diagnostic criteria evolved, with polysomnography and PLMS index ≥5 required since 2003. Also, PLMD diagnosis mandates clinical consequences like insomnia, hypersomnia, and fatigue, excluding comorbidities causing sleep disruption. Prevalence in children is low (0.3%), emphasizing the need for meticulous investigation. Comorbidities, particularly the bidirectional relationship with ADHD, were explored. Challenges in diagnosis and understanding arise from overlapping conditions such as sleep disordered breathing, psychotropic medication, and criteria non-adherence. Despite generally good study quality, weaknesses include sample size justification and biases. The periodic leg movement index shows high sensitivity but low specificity, underscoring strict diagnostic criteria adherence. Diverse metrics for symptoms necessitate standardized approaches. Family history of RLS in children with PLMD suggests unexplored aspects. Treatment, mainly iron supplementation, lacks standardized assessment metrics. The review emphasizes diagnostic and treatment challenges, recommending unbiased studies with precise techniques. Comprehensive research, quantifying PLMS and objectively assessing sleep parameters, is crucial for advancing understanding in pediatric PLMD. PROSPERO REGISTRATION NUMBER: CRD42021251406.

Elevated periodic limb movement index is associated with hypoxemia in children with early onset scoliosis.

PURPOSE: Patients with early onset scoliosis are at high risk of sleep disordered breathing, sleep disruption, and adverse consequences of poor sleep. In this study, we aim to assess the prevalence of periodic limb movements of sleep in a cohort of children with early onset scoliosis and identify factors that correlate with the presence of periodic limb movements. METHODS: This is a retrospective chart review of 40 patients with EOS (ages 1-17 years) who underwent a PSG from 2003 through 2019. Data collected included age, sex, and polysomnography parameters. Descriptive statistics were used: independent T test and Pearson correlation. RESULTS: The average age was 9.6 years (SD 5.2); 22 were female. Eleven patients (27.5%) had elevated periodic limb movement index (PLMI) (≥ 5). Those with PLMI ≥ 5 had arousal index of 15.4 (SD 7.2) and those with normal PLMI having an arousal index of 9.4 (SD 4.9); this reached statistical significance (p < 0.05). Those with elevated PLMI spent 4.9 (SD 8.3) minutes with saturations below 88%, while those with normal PLMI spent 1.0 (SD 1.8); this was statistically significant. There was a moderate positive correlation between arousal index, hypoxemia, and PLMI. CONCLUSION: The study suggests that children with early onset scoliosis have higher frequency of periodic limb movements during sleep, and these may be correlated with increased arousal and with hypoxemia.

Changes in time structure of periodic leg movements during sleep in restless legs syndrome: Effects of sex and age.

BACKGROUND: The objective of this study was to check the hypothesis that in women with restless legs syndrome (RLS) different changes occur in periodic leg movements during sleep (PLMS) during the post-menopausal period (using >50 years as a proxy) than in men of the same age. METHODS: We recruited 36 untreated patients aged 18-50 years (19 men, median age 40 years, and 17 women, median age 37 years) while the remaining 67 were >50 years old (24 men, median age 66.6 years, and 43 women, median age 60.0 years). Leg movement activity during sleep was analyzed by means of an approach utilizing indexes especially suitable to assess leg movement periodicity. RESULTS: No significant difference was seen between men in the two age groups; conversely, in women, a clear and significant increase in Periodicity Index was observed in the older group, along with a decrease in isolated leg movements. In women, a clear age-related enhancement of PLMS was found in the intermovement interval graphs, especially in the 16-22 s range, which was more evident than that observed in men. The results remained unchanged also when they were replicated by selecting only subjects aged 18-45 years vs. those aged >55 years. CONCLUSIONS: Our findings indicate that assessing PLMS in women after menopause is clinically relevant because they are probably connected with the hormonal fluctuations of this period of life. Translationally, identifying and addressing PLMS in post-menopausal women is crucial for optimizing their sleep health and addressing potential health risks associated with sleep disturbances.

Coexistence of periodic limb movements during sleep with restless legs syndrome and its association with hypertension in Japanese patients.

BACKGROUND: Caucasian patients with restless legs syndrome (RLS) frequently exhibit periodic limb movements during sleep (PLMS), which may increase the risk of hypertension. We evaluated the positivity rate of PLMS and factors associated with positivity in Japanese patients with RLS, and tested whether the complications of PLMS are associated with the presence of hypertension. METHODS: We retrospectively investigated polysomnographic data and the presence or absence of hypertension in patients with RLS. Patients with systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or those taking antihypertensive medication were categorized as the group with hypertension. RESULTS: Among 468 patients, 200 (42.7%) had periodic limb movement index (PLMI) values ≥ 15/h and 108 (23.1%) met the criteria of positivity for hypertension. Multiple logistic regression analysis revealed that only higher age was significantly associated with PLMI values ≥ 15/h. Multiple linear regression analyses of factors associated with an increased PLMI also showed that increased PLMI was significantly correlated with higher age and male sex, but not with the international restless legs scale scores. Multiple logistic regression analysis also revealed that higher age and body mass index, not PLMI values ≥ 15/h, were significantly associated with the presence of hypertension. CONCLUSION: The PLMS-positivity rate may be lower in Japanese patients with RLS than in Caucasian patients, and it increases with age and male sex, but not with the severity of the disorder. Furthermore, PLMS complications were not associated with the risk of hypertension in Japanese patients with RLS.

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 leg movements during sleep and cognitive functioning in the older general population.

OBJECTIVE: The current evidence of a relationship between periodic leg movements during sleep (PLMS) and cognitive functioning is limited and inconsistent. This cross-sectional study assessed associations between PLMS and cognitive functioning among community-dwelling older adults. METHODS: We included community-dwelling older adults who underwent a polysomnography and a cognitive assessment. The PLMS index (PLMI) and PLMS arousal index (PLMAI) were categorized into tertiles: PLMI <5/h (reference), 5-29.9/h, ≥30/h; and PLMAI <1/h (reference), 1-4.9/h, ≥5/h. The cognitive assessment consisted of ten scores covering the main cognitive domains: global cognition, processing speed, executive function, language, episodic verbal memory, and visuospatial function. Associations between PLMI, PLMAI, and cognitive scores were assessed using regression unadjusted and adjusted models. RESULTS: A total of 579 individuals without dementia were included (mean age: 71.5 ± 4.4 years; men 45.4%). The number of participants in the high-PLMI categories, 5-29.9/h and ≥30/h, was 185 (32.0%) and 171 (29.5%), respectively. Participants in the high-PLMI categories showed no significant difference compared to the reference group regarding their cognitive performance according to the unadjusted and adjusted models. Similarly, we found no association between PLMAI severity and cognitive functioning. CONCLUSIONS: This study shows no cross-sectional association between PLMS severity and cognitive functioning among community-dwelling older adults. However, given the paucity of data in this field, further studies are needed to clarify the relationship between PLMS and cognitive functioning.