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Abstract Study Objectives Periodic limb movements (PLMs) of sleep, which may be linked to increased vascular events via nighttime sympathetic overactivity, have shown associations with cerebral small vessel disease (CSVD) in small studies. This study examined the relationship between PLMs and CSVD in a larger cohort, accounting for comorbidities. Methods Patients with first-ever stroke or transient ischemic attack (TIA) were retrospectively analyzed. Polysomnography assessed the PLM index (PLMI) and PLM arousal index (PLMAI). CSVD was measured using radiographic markers, including the Fazekas score, total age-related white matter changes (ARWMC) score, microbleed counts, and lacunar infarcts. Multivariable regression models analyzed the association between an elevated PLMI and PLMAI with CSVD markers. Results This study included 86 patients (mean age 62.2 ± 14.3 years, 66.3% male, mean BMI 28.1 ± 5.7), 36 with a PLMI ≥ 5 (41.9%) and 11 with a PLMAI ≥ 5 (12.8%). Regression analyses showed that PLMI ≥ 5 and PLMAI ≥ 5 both predicted increased Fazekas and ARWMC total scores after adjusting for age, sex, BMI, and other comorbidities. Sensitivity analyses using age- and sex-specific PLMI cutoffs also showed that a PLMI exceeding the upper limit of normal predicted an increased Fazekas score and approached significance for the ARWMC score. PLMI was not significantly associated with cerebral microbleeds or lacunar infarcts. Conclusions In patients with first-ever minor stroke and TIA, a significant association was observed between PLMI and PLMAI with white matter hyperintensities (WMHs) after adjusting for confounders. Future studies may help determine the directionality of this association and whether PLMs independently predict CSVD. Clinical Trial Information Name: Sleep Disorders Managed and Assessed Rapidly in Transient Ischemic Attack (TIA) and In Early Stroke (SMARTIES). URL: https://clinicaltrials.gov/study/NCT01528462 ClinicalTrials.gov ID: NCT01528462. Name: SLEep APnea Screening Using Mobile Ambulatory Recorders After TIA/Stroke (SLEAP SMART). URL: https://clinicaltrials.gov/study/NCT02454023. ClinicalTrials.gov ID: NCT02454023. Graphical Abstract Graphical Abstract

PurposeThis study investigated the basal autonomic regulation in patients with obstructive sleep apnea (OSA) showing periodic limb movements in sleep (PLMS) emerging after therapy with continuous positive airway pressure (CPAP).MethodsData of patients with OSA undergoing a first polysomnography for diagnosis and a second polysomnography for therapy with CPAP were reviewed. Patients with OSA showing PLMS on the first polysomnography were excluded. By using heart rate variability analysis, epochs without any sleep events and continuous effects from the second polysomnography were retrospectively analyzed.ResultsOf 125 eligible patients, 30 with PLMS after therapy with CPAP (PLMS group) and 30 not showing PLMS on both polysomnography (non-PLMS group) were randomly selected for the analysis. No significant differences in the demographic characteristics and variables of polysomnographies were identified between the groups. Although one trend of low root mean square of successive differences (RMSSD) between intervals of adjacent normal heart beats (NN intervals) in the PLMS group was observed, patients in the PLMS group had significantly low normalized high-frequency (n-HF) and high-frequency (HF) values, but high normalized low frequency (n-LF) and high ratio of LF to HF (LF/HF ratio). After adjustment for confounding variables, PLMS on the second polysomnography was significantly associated with RMSSD (β = − 6.7587, p = 0.0338), n-LF (β = 0.0907, p = 0.0148), n-HF (β = − 0.0895, p = 0.0163), log LF/HF ratio (β = 0.4923, p = 0.0090), and log HF (β = − 0.6134, p = 0.0199).ConclusionsPatients with OSA showing PLMS emerging after therapy with CPAP may have a basal sympathetic predominance with potential negative cardiovascular effects.

Abstract 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.

Abstract Study Objectives: Emerging evidence suggests that periodic limb movements (PLMs) may contribute to the development of cerebrovascular disease. White matter hyperintensities (WMHs), a widely accepted biomarker for cerebral small vessel disease, are associated with incident stroke and death. We evaluated the association between increased PLM indices and WMH burden in patients presenting with stroke or transient ischemic attack (TIA), while controlling for vascular risk factors and stroke severity. Methods: Thirty patients presenting within 2 weeks of a first-ever minor stroke or high-risk TIA were prospectively recruited. PLM severity was measured with polysomnography. WMH burden was quantified using the Age Related White Matter Changes (ARWMC) scale based on neuroimaging. Partial Spearman’s rank-order correlations and multiple linear regression models tested the association between WMH burden and PLM severity. Results: Greater WMH burden was correlated with elevated PLM index and stroke volume. Partial Spearman’s rank-order correlations demonstrated that the relationship between WMH burden and PLM index persisted despite controlling for vascular risk factors. Multivariate linear regression models revealed that PLM index was a significant predictor of an elevated ARWMC score while controlling for age, stroke volume, stroke severity, hypertension, and apnea-hypopnea index. Conclusion: The quantity of PLMs was associated with WMH burden in patients with first-ever minor stroke or TIA. PLMs may be a risk factor for or marker of WMH burden, even after considering vascular risk factors and stroke severity. These results invite further investigation of PLMs as a potentially useful target to reduce WMH and stroke burden.

Study Objectives: To carry out an analysis of leg movement activity during sleep in a polysomnography dataset of patients with multiple sclerosis (MS) in comparison to idiopathic restless legs syndrome (iRLS) and healthy controls. Methods: In this cross-sectional, observational, instrumental study, 57 patients (males/females: 11/46; mean age 46.2 ± 10.2 years) with a diagnosis of MS underwent a telephone interview assessing the 5 standard diagnostic criteria for RLS and polysomnography. Sleep architecture and leg movement activity during sleep were subsequently compared: 1) 40 patients with MS without RLS (MS–RLS) vs 28 healthy controls; 2) 17 patients with MS with RLS (MS+RLS) vs 35 patients with iRLS; 3) MS+RLS vs MS–RLS. Results: MS–RLS and MS+RLS presented increased sleep latency, percentage of sleep stage N1, and reduced total sleep time compared to healthy controls and iRLS, respectively. The periodic limb movements during sleep (PLMS) index was higher in MS–RLS than in healthy controls ( P = .035) and lower in MS+RLS compared to iRLS ( P = .024). PLMS in MS+RLS were less periodic, less often bilateral, and with shorter single movements compared to the typical PLMS in iRLS. Conclusions: MS is a risk factor for RLS, PLMS, and for a lower sleep quality in comparison to healthy patients. PLMS in MS+RLS are fewer and shorter if compared to iRLS. Our results suggest a dissociation between motor (PLMS) and sensory symptoms (RLS sensory component) in RLS secondary to MS, with possible treatment implications. Citation: Ferri R, Sparasci D, Castelnovo A, et al. Leg movement activity during sleep in multiple sclerosis with and without restless legs syndrome. J Clin Sleep Med . 2022;18(1):11–20.

Mirtazapine is a Food and Drug Administration–approved atypical antidepressant used off-label for insomnia. Mirtazapine has been associated with movement disorders in adults. A 9-year-old female was seen in the sleep clinic for symptoms of insomnia, nocturnal awakenings, restless sleep, and growing pains. Mirtazapine was started prior to presentation for severe insomnia. A sleep study showed frequent repetitive leg movements prior to sleep onset as well as significant periodic limb movement disorder with a periodic limb movement index of 25.1/hour. The child was found to have a ferritin level of 23 ng/mL and an iron saturation of 10%. There were concerns that the presence of iron deficiency along with the use of mirtazapine may have contributed to the elevated periodic limb movement index. After starting iron therapy to treat the child’s iron deficiency, mirtazapine was weaned off, with further clinical improvements in sleep quality reported. A follow-up sleep study showed a resolution of her periodic limb movement disorder with a periodic limb movement index of 1.4/hour. This is the first pediatric case to describe a sleep-related movement disorder associated with the use of mirtazapine and polysomnographic data to support resolution after discontinuation of mirtazapine along with iron therapy. Citation: Hawkins M. A 9-year-old female with iron deficiency has severe periodic limb movements while taking mirtazapine for insomnia. J Clin Sleep Med . 2023;19(7):1369–1373.

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.

Background The relationships between sleep and headaches are complex and manifold. About the variety of phenomena that can disrupt the sleep macrostructure and can impact its restorative function, the periodic limb movements disorder (PLMd) can be considered as the most powerful. No studies are known about the role of PLMd in the pathophysiology of migraine in children. Aim of study is to assess the prevalence of PLMd and migraine and their relationship with disability and pain intensity in a pediatric sample, referred for migraine without aura by pediatricians. Methods After a preliminary sleep habits screening with the Sleep Disturbances Scale for Children, 34 migraine subjects affected by migraine without aura (20 M, 14 F) (mean age 9.08; SD ± 2.28) and 51 volunteers healthy children (28 M, 23 F) (mean age 9.37; SD ± 1.81) accepted to underwent overnight PSG recordings in the Sleep Laboratory of the Clinic of Child and Adolescent Neuropsychiatry, in order to define the macrostructural sleep characteristics and the prevalence of PLMd. Subsequently, the migraineurs sample was studied in order to define the relationship between disability, pain intensity, therapeutical responsiveness and the presence of PLMd. Results In the migraineurs children group, the individuals with PLM pathological index (PLMI ≥ 5) represent the 26.47% of sample and present higher frequency (p < 0.001), intensity (p < 0.001), duration (p = 0.006) and life impairment as scored in the PedMIDAS (p < 0.001) of headache and lower efficacy of prophylactic (p = 0.001) and acute (p = 0.006) pharmacological treatment than MoA children without PLM pathological index. Conclusions This preliminary study indicates the potential value of the determination of the PLMd signs, and the importance of the PSG evaluation in children affected by migraine, particularly when the clinical and pharmacological management tend to fail in the attacks control.

Background: Disturbed sleep is a core feature of narcolepsy with cataplexy (NC). Few studies have independently assessed sleep-disordered breathing (SDB) and periodic limb movements (PLMs) in non-homogeneous series of patients with and without cataplexy. We systematically assessed both SDB and PLMs in well-defined NC patients. Methods: We analyzed the clinical and polysomnographic features of 35 consecutive NC patients (mean age 40 ± 16 years, 51% males, 23/23 hypocretin-deficient) to assess the prevalence of SDB (apnea-hypopnea index >5) and PLMs (periodic leg movements in sleep (PLMI) >15) together with their impact on nocturnal sleep and daytime sleepiness using the multiple sleep latency test. Results: 11 (31%) and 14 (40%) patients had SDB and PLMs, respectively. SDB was associated with older age (49 ± 16 vs. 35 ± 13 years, p = 0.02), higher BMI (30 ± 5 vs. 27 ± 6, p = 0.05), and a trend towards higher PLMI (25 ± 20 vs. 12 ± 23, p = 0.052), whereas PLMs with older age (50 ± 16 vs. 33 ± 11 years, p = 0.002) and reduced and fragmented sleep (e.g. sleep efficiency of 82 ± 12% vs. 91 ± 6%, p = 0.015; sleep time of 353 ± 66 vs. 395 ± 28, p = 0.010). SDB and PLMs were also mutually associated (p = 0.007), but not correlated to daytime sleepiness. Conclusions: SDB and PLMs are highly prevalent and associated in NC. Nevertheless, SDB and PLMs are rarely severe, suggesting an overall limited effect on clinical manifestations.