Periodic Leg Movements Research Articles

Association between serum hepcidin level and restless legs syndrome.

To better understand the role of iron homeostasis dysregulation in restless legs syndrome, we compared serum hepcidin and ferritin levels in drug-free patients with primary restless legs syndrome and healthy controls and studied the relationship between hepcidin level and restless legs syndrome severity. One hundred and eight drug-free patients with primary restless legs syndrome (65 women; median age, 61.5 years) and 45 controls (28 women; median age, 53.9 years) were enrolled. Inclusion criteria were: normal ferritin level (>50 ng/mL) and absence of iron disorders, chronic renal or liver failure, and inflammatory or neurological diseases. Each subject underwent a thorough clinical examination and a polysomnography assessment. Serum hepcidin-25 was quantified using a validated mass spectrometry method. Restless legs syndrome severity was evaluated according to the International Restless Legs Syndrome Study Group. Despite no group difference between normal ferritin levels and demographic features, serum hepcidin level and hepcidin/ferritin ratio were higher in patients than in controls. Hepcidin level and hepcidin/ferritin ratio, but not ferritin level, were positively correlated with periodic leg movements during sleep and wakefulness in the whole sample. Hepcidin level seem to be associated with restless legs syndrome severity in a complex U-shaped relationship, without relationship with age at restless legs syndrome onset, positive family history, sleep and depressive symptoms, genetic background, and polysomnographic measurements. No relationship was found between ferritin level and restless legs syndrome severity. In drug-free patients with primary restless legs syndrome, hepcidin level is higher than in controls and may be associated with restless legs syndrome clinical severity. This result emphasizes the complex peripheral iron metabolism deregulation in restless legs syndrome, opening potential perspectives for a personalized approach with a hepcidin antagonist. © 2018 International Parkinson and Movement Disorder Society.

Periodic Leg Movements During Sleep and Cardiovascular and/or Cerebrovascular Morbidity

Purpose of Review To evaluate if periodic leg movements during sleep (PLMS) may be associated with increased cardiovascular or cerebrovascular morbidity

Data-driven approaches to define the upper limit of the intermovement interval of periodic leg movements during sleep.

To define statistically the upper limit of the intermovement interval (IMI, the time interval between the onset of consecutive movements) of periodic leg movements during sleep (PLMS). We computed the IMI distribution of a large sample (n = 141) of patients with restless legs syndrome (RLS) and analyzed it with two independent approaches, based on fitting either empirical functions or normal and exponential functions to the data. The two fitting approaches consistently pointed to an upper limit of the PLMS IMI in the range between 50 and 60 s. Decreasing the upper limit of PLMS IMI from 90 to 60 s evidently decreased the PLMS index in patients with RLS and control participants; nevertheless, the PLMS index remained significantly higher in RLS vs. control participants. Shifting the upper limit of PLMS IMI to 60 s did not significantly modify the effectiveness of discrimination of PLMS between controls and patients with RLS. These results seem to indicate that a conservative, yet data-driven upper limit for IMI contributing to the PLMS in patients with RLS might be 60 s instead of 90 s, as recommended by the present guidelines.

Pivotal Role of Adenosine Neurotransmission in Restless Legs Syndrome.

The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A1 receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the α2δ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS.

Stridor combined with other sleep breathing disorders in multiple system atrophy: a tailored treatment?

ObjectivesTo determine the frequency of sleep breathing disorders in multiple systemic atrophy (MSA, combining Parkinsonism, cerebellar syndrome, and dysautonomia) and evaluate the benefit/tolerance of various modes of ventilation. MethodsWe retrospectively analyzed 45 patients with MSA having undergone a videopolysomnography. Their sleep characteristics were compared to those of 45 patients with Parkinson's disease and 45 healthy controls, matched for age and sex. Patients with MSA received fixed continuous positive airway pressure (CPAP) when stridor was isolated, auto-adjusting CPAP when it was combined with obstructive sleep apnea, and adaptive servo-ventilation (ASV) when combined with central sleep apnea. ResultsHigher periodic leg movements index and more frequent REM sleep behavior disorder were observed in MSA patients, compared to patients with Parkinson's disease and healthy controls. In MSA, 28/45 (62.2%) patients had sleep breathing disorders, including (overlapping samples) stridor (n = 17, 38%), obstructive sleep apnea (n = 14, 31%), central sleep apnea (n = 4, 9%), and ataxic breathing (n = 1). Except for three initial refusals and two yet untreated patients, fixed CPAP (n = 9), auto-adjusting CPAP (n = 8) and ASV (n = 2) were well-tolerated (limited leaks and good compliance) and successfully controlled stridor plus sleep apnea. Treated patients had survival times similar to those of patients without any sleep breathing disorder. ConclusionIn this small group, tailored management of stridor in MSA as an independent issue or combined with obstructive and central sleep apnea, yields a survival similar to survival in patients without sleep breathing disorders.

The secret behind successful treatment for insomnia with periodic leg movements in sleep

The secret behind successful treatment for insomnia with periodic leg movements in sleep

Polysomnographic findings in craniopharyngioma patients.

The purpose of this study is to evaluate whether damage to the hypothalamus due to craniopharyngioma or consequent surgery may involve the sleep-wake regulatory system, resulting in sleep disturbances and sleepiness. Seven craniopharyngioma patients and 10 healthy controls were evaluated with sleep questionnaires including the Epworth Sleepiness Scale, polysomnography, and a multiple sleep latency test (MSLT). Five patients and eight controls had lumbar puncture performed to determine hypocretin-1 levels. Patients tended to feel sleepier than control individuals of the same age (p=0.09). No subjects had symptoms of hypnagogic hallucinations, sleep paralyses, or cataplexies. Four patients and one control had periodic leg movements (PLMs). One patient had fragmented sleep pattern, rapid eye movement (REM) sleep without atonia, and PLMs. One patient had short sleep periods during the daytime. Four patients had fragmented sleep pattern. With the MSLT, four patients and two controls had mean sleep latency of <8min. One patient and three controls had sudden onset of REM sleep in 2/5 and 3/5 sleep periods, respectively. All subjects showed normal hypocretin-1 levels. Four patients had electrophysiological findings indicative of central hypersomnia including one patient meeting the criteria of narcolepsy. The sleep-wake regulatory system may be involved in craniopharyngioma patients.

An Examination of Pain's Relationship to Sleep Fragmentation and Disordered Breathing Across Common Sleep Disorders.

Short sleep duration and insomnia have been linked to higher pain and an increased risk of developing chronic pain, but relatively little research has examined the contribution of sleep disordered breathing (SDB) to pain. This study examined the unique contributions of SDB and insomnia to chronic pain. Adult patients referred to an academic sleep center for overnight polysomnography were invited to participate. Participants (N = 105) completed questionnaires about their sleep and pain, including the Insomnia Severity Index, Medical College of Virginia Pain Questionnaire, and two weeks of sleep/pain diaries. Most participants (80.00%) reported chronic pain, and the likelihood of having chronic pain did not differ by sleep disorder. However, there was a significant difference in pain intensity; individuals with comorbid obstructive sleep apnea (OSA)/insomnia reported an average pain intensity that was 20 points (out of 100) higher than individuals with insomnia or no diagnosis and 28 points higher than those with OSA, controlling for participant sex (Ps < 0.05). In a hierarchical regression, pain was unrelated to measures of sleep fragmentation (apnea-hypopnea index, spontaneous arousals, periodic leg movement arousals) and nocturnal hypoxemia (SaO2 nadir, time at or below 88% SaO2). Polysomnography measures of SDB severity and sleep fragmentation were unrelated to pain intensity. However, comorbid OSA/insomnia was associated with significantly higher pain (compared with either disorder in isolation), a finding that has implications for the treatment of chronic pain and possibly for understanding the mechanisms of chronic pain.

Motor hyperactivity of the iron-deficient rat - an animal model of restless legs syndrome.

BackgroundAbnormal striatal dopamine transmission has been hypothesized to cause restless legs syndrome. Dopaminergic drugs are commonly used to treat restless legs syndrome. However, they cause adverse effects with long‐term use. An animal model would allow the systematic testing of potential therapeutic drugs. A high prevalence of restless legs syndrome has been reported in iron‐deficient anemic patients. We hypothesized that the iron‐deficient animal would exhibit signs similar to those in restless legs syndrome patients.MethodsAfter baseline polysomnographic recordings, iron‐deficient rats received pramipexole injection. Then, iron‐deficient rats were fed a standard rodent diet, and polysomnographic recording were performed for 2 days each week for 4 weeks.ResultsIron‐deficient rats have low hematocrit levels and show signs of restless legs syndrome: sleep fragmentation and periodic leg movements in wake and in slow‐wave sleep. Iron‐deficient rats had a positive response to pramipexole treatment. After the iron‐deficient rats were fed the standard rodent diet, hematocrit returned to normal levels, and sleep quality improved, with increased average duration of wake and slow‐wave sleep episodes. Periodic leg movements decreased during both waking and sleep. Hematocrit levels positively correlated with the average duration of episodes in wake and in slow‐wave sleep and negatively correlated with periodic leg movements in wake and in sleep. Western blot analysis showed that striatal dopamine transporter levels were higher in iron‐deficient rats.ConclusionsThe iron‐deficient rat is a useful animal model of iron‐deficient anemic restless legs syndrome. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Upper-airway flow limitation and transcutaneous carbon dioxide during sleep in normal pregnancy

ObjectiveSleep during pregnancy involves a physiological challenge to provide sufficient gas exchange to the fetus. Enhanced ventilatory responses to hypercapnia and hypoxia may protect from deficient gas exchange, but sleep-disordered breathing (SDB) may predispose to adverse events. The aim of this study was to analyze sleep and breathing in healthy pregnant women compared to non-pregnant controls, with a focus on CO2 changes and upper-airway flow limitation. MethodsHealthy women in the third trimester and healthy non-pregnant women with normal body mass index (BMI) were recruited for polysomnography. Conventional analysis of sleep and breathing was performed. Transcutaneous carbon dioxide (TcCO2) was determined for each sleep stage. Flow-limitation was analyzed using the flattening index and TcCO2 values were recorded for every inspiration. ResultsEighteen pregnant women and 12 controls were studied. Pregnancy was associated with shorter sleep duration and more superficial sleep. Apnea–hypopnea index, arterial oxyhemoglobin desaturation, flow-limitation, snoring or periodic leg movements were similar in the two groups. Mean SaO2 and minimum SaO2 were lower and average heart rate was higher in the pregnant group. TcCO2 levels did not differ between groups but variance of TcCO2 was smaller in pregnant women during non-rapid eye movement (NREM). TcCO2 profiles showed transient TcCO2 peaks, which seem specific to pregnancy. ConclusionsHealthy pregnancy does not predispose to SDB. Enhanced ventilatory control manifests as narrowing threshold of TcCO2 between wakefulness and sleep. Pregnant women have a tendency for rapid CO2 increases during sleep which might have harmful consequences if not properly compensated.

Evaluation of sleep quality in patients with ankylosing spondylitis and efficacy of anti-TNF-α therapy on sleep problems: A polisomnographic study.

This study was conducted to investigate the relationship between sleep quality (SQ) and disease activity (DA) in patients with ankylosing spondylitis (AS) and to evaluate the response to anti-tumor necrosis factor α (anti-TNF-α) therapy on sleep disorders. A total of 34 patients who met the modified New York classification criteria for AS were included in this prospective study. Patients were divided into two groups as follows: Group I (n=15) with high DA and receiving anti-TNF-α therapy, and Group II (n=19) in remission. DA was assessed by the Bath AS Disease Activity Index. Pittsburgh Sleep Quality Index (PSQI) and polysomnography (PSG) were used to determine disorders and patterns of sleep, respectively, in both groups at baseline as well as at the third month of anti-TNF-α therapy in Group I. Baseline evaluation revealed impaired SQ in 57.9% of all patients. PSG demonstrated obstructive sleep apnea syndrome, snoring and periodic leg movements in 73.7%, 74.4% and 26.3% of patients, respectively. Prior to anti-TNF-α therapy, PSQI and snoring score were significantly higher in Group I (P=0.0001, P=0.012, respectively). Although there was a significant reduction in PSQI scores in Group I (P=0.005) at the third month of anti-TNF-α therapy, no change was observed in PSG parameters (P>0.05). Sleep disorders increase in AS, particularly in patients with high DA. Anti-TNF-α therapy has improved SQ without any improvement in PSG. Therefore, it may be concluded that PSG parameters might be more associated with disease pathogenesis rather than DA in patients with AS.

1127 LEG MOVEMENT ACTIVITY DURING SLEEP IN ADULTS WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER

Sleep disturbances are prevalent in Attention Deficit Hyperactivity Disorder (ADHD). The hypothesis that the typical daytime hyperactivity observed in these patients may correspond to an increased motor activity during the night, thus causing sleep disruption, has been studied in children, but rarely in adults. Here we present a first detailed analysis of the nocturnal motor activity in ADHD adults compared to healthy controls, including the time structure of leg movements (LM) during sleep. Fifteen ADHD patients and eighteen control subjects underwent four in-lab polysomnographic sleep recordings. The periodic character of LM was evaluated using validated markers of “periodicity”, i.e. the periodicity index, inter-movement intervals and time distribution of LM during sleep, in addition to standard parameters, such as the periodic leg movement during sleep index (PLMSI) and periodic leg movement during sleep arousal index (PLMSAI). Sleep quality and the prevalence of insomnia symptoms were assessed with the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI). None of the participants had restless legs syndrome. Objective sleep parameters from the baseline night did not differ between ADHD and control subjects, with the exception of a longer sleep latency (p=0.007) in the patient group, as well as a slightly higher PLMSI (p=0.044) and PLMS duration (p=0.023), only in REM sleep. The PSQI questionnaire indicated a poor sleep quality and the ISI the prevalence of subclinical insomnia symptoms in ADHD patients. Leg movement activity during sleep in ADHD adult subjects was neither more frequent than in healthy controls nor did the nocturnal motor events show an increased periodicity. The reduced subjective sleep quality reported by ADHD adults was in contrast to the normal objective polysomnographic parameters, suggesting a sleep-state misperception in these individuals or more subtle sleep abnormalities not picked up by the traditional sleep staging. none

Sleep disturbance in mild cognitive impairment: a systematic review of objective measures.

Sleep disturbance frequently occurs in patients with mild cognitive impairment (MCI) and appears to be involved in the cellular and molecular mechanisms of cognitive decline. The aim of this systematic review is to clarify whether patients with MCI demonstrate alterations in certain sleep parameters: total sleep time (TST), sleep efficiency (SE), sleep latency (SL), rapid eye movement latency (REML), percent of rapid eye movement (REM%), arousal index (AI), wake after sleep onset (WASO), slow-wave sleep (SWS), periodic leg movement in sleep (PLMS), and cyclic alternating pattern (CAP) through polysomnography (PSG) and actigraphy. Databases including PubMed, Web of Science, Embase, ScienceDirect, Cochrane, CBM, CNKI, Wanfang Data, and VIP were searched up to January 2016 to collect literature on the correlation between sleep disturbance and MCI as assessed by objective measures. Meta-analysis was conducted using the Review Manager 5.3 software. A total of ten case-control studies involving 225 MCI patients and 235 healthy elders (HE) were deemed eligible and included in our meta-analysis. Every type of sleep disturbance was present in our studies with significant differences in the MCI subtypes. Compared with HE, overall MCI patients as a group expressed more SL and less SE; MCI patients showed less TST and SE and more SL and CAP; patients with amnestic mild cognitive impairment (aMCI) had less AI; patients with non-amnestic mild cognitive impairment (naMCI) had more TST and less AI. Patients with naMCI expressed more AI than those with aMCI. The results indicate that MCI patients might experience more serious sleep disturbance and that different MCI subtypes have different patterns of sleep disturbance.

0660 SUBGROUP OF NARCOLEPSY TYPE 2: CHARACTERISTICS OF SLEEP VARIABLES IN HYPERSOMNIA PATIENTS WITH ATTENTION-DEFICIT HYPERACTIVITY DISORDER (ADHD)

Patients with attention-deficit hyperactivity disorder (ADHD) have been reported to suffer from subjective and objective sleepiness, and sleepiness is suggested to have pathophysiological relevance to ADHD. Narcolepsy type 2 is reported to be heterogeneous, therefore, we examined the influence of ADHD pathophysiology in narcolepsy type 2. The aim of the present study was to (1) examine sleep variables in hypersomnia patients with ADHD and without ADHD, (2) characterize the narcolepsy type 2 associated with ADHD and (3) explore the correlation of ADHD symptoms with objective and subjective sleepiness. Subjects were 156 consecutive outpatients with hypersomnia diagnosed by standard polysomnography (PSG) and the multiple sleep latency test (MSLT). Patients with narcolepsy type 1, sleep related breathing disorder, or periodic leg movements disorder were excluded. We subdivided hypersomnia patients (narcolepsy type 2; n = 28, idiopathic hypersomnia; n = 41) into patients with ADHD (n = 22) based on DSM-5 and patients without ADHD (non-ADHD) (n = 47) and compared sleep variables on PSG and MSLT. Correlation between the Adult ADHD Self-Report Scale (ASRS), Japanese Epworth Sleepiness Scale (J-ESS) and mean sleep latency on MSLT were examined. Hypersomnia patients with ADHD showed higher percentage of having multiple SOREMPs on MSLT (p < 0.05). In narcolepsy type 2 patients, there was no difference in the percentage of having SOREMP on PSG between patients with ADHD and non-ADHD. The percentages of having REM related symptoms and having HLA positivity were not different between the two groups. There was a correlation between ASRS and J-ESS scores (r = 0.431, p < 0.01) in non-ADHD patients, but not in ADHD patients. Hypersomnia patients with ADHD showed frequent REM transitions only in daytime. This frequent REM transitions may be a characteristic marker of ADHD and this may form one subgroup of narcolepsy type 2. ADHD symptoms may be the consequence of sleepiness in non-ADHD patients, whereas ADHD symptoms (inattention) in ADHD patients might be intrinsic rather than secondary symptoms.

MEIS1 variant as a determinant of autonomic imbalance in Restless Legs Syndrome

Restless Legs Syndrome (RLS) is a genetically complex neurological disorder in which overlapping genetic risk factors may contribute to the diversity and heterogeneity of the symptoms. The main goal of the study was to investigate, through analysis of heart rate variability (HRV), whether in RLS patients the MEIS1 polymorphism at risk influences the sympathovagal regulation in different sleep stages. Sixty-four RLS patients with periodic leg movement index above 15 per hour, and 38 controls underwent one night of video-polysomnographic recording. HRV in the frequency- and time- domains was analyzed during nighttime sleep. All RLS patients were genotyped, and homozygotes for rs2300478 in the MEIS1 locus were used for further analysis. Comparison of the sympathovagal pattern of RLS patients to control subjects did not show significant differences after adjustments for confounding factors in frequency-domain analyses, but showed an increased variability during N2 and N3 stages in time-domain analyses in RLS patients. Sorting of RLS patients according to MEIS1 polymorphism reconfirmed the association between MEIS1 and PLMS, and showed a significant increased sympathovagal balance during N3 stage in those homozygotes for the risk allele. RLS patients should be considered differently depending on MEIS1 genotype, some being potentially at risk for cardiovascular disorders.

Short-interval leg movements during sleep entail greater cardiac activation than periodic leg movements during sleep in restless legs syndrome patients.

Periodic leg movements during sleep (PLMS) are sequences of ≥4 motor events with intermovement intervals (IMI) of 10-90s. PLMS are a supportive diagnostic criterion for restless legs syndrome (RLS) and entail cardiac activation, particularly when associated with arousal. RLS patients also over-express short-interval leg movements during sleep (SILMS), which have IMI <10s and are organized mainly in sequences of two movements (doublets). We tested whether the cardiac activation associated with SILMS doublets differs from that associated with PLMS in a sample of 25 RLS patients. We analysed time-series of R-R intervals synchronized to the onset of SILMS doublets or PLMS that entailed an arousal during non-rapid eye movement (NREM) sleep. We assessed cardiac activation based on the R-R interval decrease with respect to baseline during NREM sleep without leg movements. We found that the duration of the R-R interval decrease with SILMS doublets was significantly longer than that with PLMS, whereas the maximal decrease in R-R interval was similar. Scoring SILMS in RLS patients may therefore be relevant from a cardiac autonomic perspective.

Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel

ObjectivesPerampanel is a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) antagonist that has been approved for the treatment of partial seizures. Here we report on the first open study evaluating its efficacy in idiopathic restless legs syndrome (RLS). MethodsThe study was designed as a prospective two-month open trial. Twenty-two previously untreated patients diagnosed with idiopathic RLS began treatment with 2 mg perampanel, which was increased to 4 mg at week four if clinically necessary. Multiple Suggested Immobilization Tests (mSITs) followed by polysomnography were performed at baseline and at week eight. Severity ratings were performed every two weeks by means of the IRLS scale, and Clinical Global Index (CGI) subscale. The main endpoint was therapeutic response, defined as a 50% improvement in IRLS total score. ResultsTwenty patients completed the study. During the 8-week treatment period, the IRLS score improved from a mean (±standard deviation (SD)) 23.7 ± 4.2 to 11.5 ± 5.3. Twelve of 20 patients were full responders (improvement 50% in IRLS total score), and four responded partially. The mean effective dose of perampanel at the end of treatment was 3.8 mg/day. Treatment with perampanel also resulted in an improvement in the mean (±SD) periodic leg movement index from 27.8 ± 6.9 to 4.36 ± 2.0. Perampanel was well tolerated. The main side effects were dizziness, somnolence, headache, and irritability. ConclusionThese preliminary results suggest that perampanel has significant therapeutic effects on both sensory and motor symptoms. If confirmed by future controlled studies, perampanel might become a promising alternative to existing dopaminergic treatments due to its glutamatergic mechanism of action.The study provides class IV evidence supporting the therapeutic effects of perampanel in RLS/WED.

The Clinical Importance of Periodic Leg Movements in Sleep

Periodic leg movements during sleep (PLMS) are commonly found in patients with restless leg syndrome (RLS), but they may occur in other sleep disorders and several medical conditions. Their prevalence increases with age, but they can also be observed in children. During the last decades, very active research has been devoted to determine and understand the pathophysiology, associated events, and clinical significance of PLMS. This chapter tries to sum up the most relevant PLMS-related findings, focusing on the relationship between PLMS and the cardiovascular system, in order to understand the clinical implication of this complex motor phenomenon. PLMS have been associated with sympathetic overactivity, namely surges in nocturnal blood pressure and heart rate, without modification in global autonomic balance. Also, PLMS have been related to inflammatory cellular pathways, with elevated level of inflammatory markers, which are associated with cardiovascular risk. The PLMS-related modulation of the autonomic system and of inflammation may increase cardiovascular and cerebrovascular risk in subjects with frequent PLMS. Moreover, also, comorbidities associated with PLMS may play a synergic role in worsening the cardiovascular risk and the consequent mortality and morbidity. Furthermore, little is known about pathophysiological correlates in children with PLMS and their chronic implication on the cardiovascular and cerebrovascular systems. A few studies have suggested that treating PLMS with dopaminergic drugs may reduce their associated sympathetic overactivity and modify disease progression. Definitely, further research is needed to assess the clinical impact of PLMS, associated or not with RLS, and above all the long-term impact of treating PLMS on cardiovascular risk, morbidity, and mortality.

Validation of a leg movements count and periodic leg movements analysis in a custom polysomnography system

BackgroundPeriodic leg movements (PLM) during sleep (PLMS) are considered strongly related to restless legs syndrome (RLS), and are associated with polymorphisms in RLS risk genes. Various software for automatic analysis of PLMS are available, but only few of them have been validated. Aim of this study was to validate a leg movements count and analysis integrated in a commercially available polysomnography (PSG) system against manual scoring.MethodsTwenty RLS patients with a PLMS index > 20/h and 20 controls with a PLMS index < 5/h were included. Manual and computerized scoring of leg movements (LM) and PLM was performed according to the standard American Academy of Sleep Medicine (AASM) criteria. LM and PLM indices during sleep and wakefulness, the rate of PLMS associated with respiratory events, intermovement interval and periodicity indices were manually and automatically scored.ResultsThe correlation between manual and computerized scoring was high for all investigated parameters (Spearman correlation coefficients 0.751–0.996, p < 0.001; intraclass correlation coefficients 0.775–0.999, p < 0.001). Bland-Altman plots showed high agreement between manual and automatic analysis.ConclusionsThis study validated an automatic LM count and PLM analysis against the gold standard manual scoring according to AASM criteria. The data demonstrate that the software used in this study has an outstanding performance for computerized LM and PLM scoring, and LM and PLM indices generated with this software can be reliably integrated in the routine PSG report. This automatic analysis is also an excellent tool for research purposes.

Associations of Incident Cardiovascular Events With Restless Legs Syndrome and Periodic Leg Movements of Sleep in Older Men, for the Outcomes of Sleep Disorders in Older Men Study (MrOS Sleep Study).

Both restless legs syndrome (RLS) and periodic leg movements in sleep (PLMS) may be associated with incident cardiovascular disease (CVD). However, the individual contributions of these factors to adverse CVD outcomes are unknown. During the MrOS Sleep Study, 2823 men (mean age = 76.3 years) participated in a comprehensive sleep assessment from 2000 to 2002. RLS was identified by self-report of a physician diagnosis of RLS. A periodic limb movement of sleep index (PLMI) was derived from unattended in-home polysomnography. Incident cardiovascular events were centrally adjudicated during 8.7 ± 2.6 years of follow-up. The primary outcome was all-cause CVD; secondary outcomes included incident myocardial infarction (MI) and cerebrovascular disease. Cox proportional hazards regression models were adjusted for multiple covariates, including PLMI, to examine if there were independent associations of RLS and PLMI to the outcomes. Physician-diagnosed RLS was reported by 2.2% and a PLMI ≥ 15 was found in 59.6% of men. RLS was not associated with the composite CVD outcome. RLS was significantly associated with incident MI (Hazard ratio [HR] = 2.02, 95% CI, 1.04-3.91) even after adjustment for multiple covariates. Results were only modestly attenuated when PLMI was added to the model. PLMI also was found to predict incident MI (per SD increase in PLMI, HR = 1.14, 95% CI, 1.00-1.30, p = .05), and was materially unchanged after addition of RLS. The independent risk that RLS confers for MI suggests a role for non-PLMS factors such as sleep disturbance, shared genetic factors, or PLM-independent sympathetic hyperactivity.