Pharmacologic and Nonpharmacologic Treatment of Restless Legs Syndrome.

Restless legs syndrome (RLS) is a sleep-related disorder defined by an urgency to move the legs, usually combined with uncomfortable or unpleasant sensations, which occurs or worsens during rest, usually in the evening or at night, and disappears with the movement of the legs. RLS can be classified as idiopathic or primary, and secondary to comorbid conditions (eg, renal disease, polyneuropathy). The pathophysiology of RLS is still unclear. This article provides an updated practical guide for the treatment of primary RLS in adults.

Computer-assisted analysis of polysomnographic recordings improves inter-scorer associated agreement and scoring times.

STUDY OBJECTIVES: To investigate inter-scorer agreement and scoring time differences associated with visual and computer-assisted analysis of polysomnographic (PSG) recordings. METHODS: A group of 12 expert scorers reviewed 5 PSGs that were independently selected in the context of each of the following tasks: (i) sleep staging, (ii) scoring of leg movements, (iii) detection of respiratory (apneic-related) events, and (iv) of electroencephalographic (EEG) arousals. All scorers independently reviewed the same recordings, hence resulting in 20 scoring exercises per scorer from an equal amount of different subjects. The procedure was repeated, separately, using the classical visual manual approach and a computer-assisted (semi-automatic) procedure. Resulting inter-scorer agreement and scoring times were examined and compared among the two methods. RESULTS: Computer-assisted sleep scoring showed a consistent and statistically relevant effect toward less time required for the completion of each of the PSG scoring tasks. Gain factors ranged from 1.26 (EEG arousals) to 2.41 (leg movements). Inter-scorer kappa agreement was also consistently increased with the use of supervised semi-automatic scoring. Specifically, agreement increased from Κ = 0.76 to K = 0.80 (sleep stages), Κ = 0.72 to K = 0.91 (leg movements), Κ = 0.55 to K = 0.66 (respiratory events), and Κ = 0.58 to Κ = 0.65 (EEG arousals). Inter-scorer agreement on the examined set of diagnostic indices did also show a trend toward higher Interclass Correlation Coefficient scores when using the semi-automatic scoring approach. CONCLUSIONS: Computer-assisted analysis can improve inter-scorer agreement and scoring times associated with the review of PSG studies resulting in higher efficiency and overall quality in the diagnosis sleep disorders.

Inter-database validation of a deep learning approach for automatic sleep scoring.

STUDY OBJECTIVES: Development of inter-database generalizable sleep staging algorithms represents a challenge due to increased data variability across different datasets. Sharing data between different centers is also a problem due to potential restrictions due to patient privacy protection. In this work, we describe a new deep learning approach for automatic sleep staging, and address its generalization capabilities on a wide range of public sleep staging databases. We also examine the suitability of a novel approach that uses an ensemble of individual local models and evaluate its impact on the resulting inter-database generalization performance. METHODS: A general deep learning network architecture for automatic sleep staging is presented. Different preprocessing and architectural variant options are tested. The resulting prediction capabilities are evaluated and compared on a heterogeneous collection of six public sleep staging datasets. Validation is carried out in the context of independent local and external dataset generalization scenarios. RESULTS: Best results were achieved using the CNN_LSTM_5 neural network variant. Average prediction capabilities on independent local testing sets achieved 0.80 kappa score. When individual local models predict data from external datasets, average kappa score decreases to 0.54. Using the proposed ensemble-based approach, average kappa performance on the external dataset prediction scenario increases to 0.62. To our knowledge this is the largest study by the number of datasets so far on validating the generalization capabilities of an automatic sleep staging algorithm using external databases. CONCLUSIONS: Validation results show good general performance of our method, as compared with the expected levels of human agreement, as well as to state-of-the-art automatic sleep staging methods. The proposed ensemble-based approach enables flexible and scalable design, allowing dynamic integration of local models into the final ensemble, preserving data locality, and increasing generalization capabilities of the resulting system at the same time.

Sleep-related leg movements in obstructive sleep apnea: definitions, determinants, and clinical consequences.

STUDY OBJECTIVES: To investigate (1) the effect of different scoring rules on leg movement (LM) classification in patients with obstructive sleep apnea (OSA); (2) determinants of respiratory event related leg movements (rLM); and (3) to relate LM parameters to clinical outcomes. METHODS: (1) LM classification was compared between the World Association of Sleep Medicine (WASM) 2006 and the WASM 2016 rules in 336 participants with apnea hypopnea index (AHI) ≥ 5; (2) determinants and features of rLM were investigated with logistic mixed regression in 172 participants with AHI ≥ 10 and respiratory disturbance index (RDI) ≥ 15, and (3) LM parameters were compared for patients with and without cardiovascular events and related to continuous positive airway pressure (CPAP) adherence. RESULTS: WASM-2016 scoring significantly reduced periodic limb movements of sleep (PLMS) frequency in OSA participants even when only considering the new periodicity criteria. Probability of rLM was strongly increased when respiratory events ended with an arousal, but rLM probability was lower for hypopneas and respiratory effort-related sleep arousal (RERAs) than for obstructive apneas. In participants with frequent non-respiratory PLMS, rLM were more frequent and behaved more PLMS-like. In participants without PLMS, rLM probability mostly depended on respiratory event features. LM parameters were neither related to cardiovascular event risk nor to CPAP-adherence. CONCLUSIONS: It is likely that the PLMS frequency in OSA populations has been previously overestimated. Our results suggest that there are two types of rLM, true periodic ones that happen to synchronize with the respiratory events, and periodic appearing but respiratory driven LM, and that the presence of non-respiratory PLMS is instrumental in distinguishing between the two.

Pharmacologic and Nonpharmacologic Treatment of Restless Legs Syndrome.

This article provides an updated practical guide for the treatment of primary restless legs syndrome (RLS). Articles that appeared after the American Academy of Neurology guideline search were reviewed according to the same evidence rating schedule. We found limited evidence for nonpharmacologic treatment options. In moderate to severe primary RLS, pharmacologic options may be considered, including iron suppletion, an α2δ ligand, a dopamine agonist, a combination of an α2δ ligand and a dopamine agonist, or oxycodone/naloxone. This article includes treatment options in case of augmentation.

Effects of 16 Weeks of Methylphenidate Treatment on Actigraph-Assessed Sleep Measures in Medication-Naive Children With ADHD.

Methylphenidate (MPH) improves behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Its effects on sleep, however, are insufficiently known, as trials with MPH in medication-naive children were so far restricted to relatively short trial durations. Here, we assessed effects of prolonged MPH treatment on sleep in medication-naive boys in a 16-weeks double-blind, placebo controlled, multicenter clinical trial with immediate-release MPH (ePOD-MPH trial, NTR3103). Seventy-five medication-naive boys, aged 10-12 years, were screened for eligibility using ADHD DSM-IV criteria. Sleep was assessed using actigraphy, diaries and questionnaires prior to randomization, in week 8, and 1 week after trial end. Fifty boys (mean age 11.4y, SD 0.9) were randomized to MPH or placebo. Linear mixed model analysis demonstrated a significant time-by-treatment interaction effect (p = 0.007) on sleep efficiency. Post-hoc analyses demonstrated that the two groups did not differ from each other (p = 0.94) during treatment (week 8), but that sleep efficiency was significantly improved in the MPH (p = 0.005), but not placebo group (p = 0.87) 1 week after trial end. The lack of MPH's negative effects on sleep during treatment differ from most previous studies and could be explained by the relatively long trial duration in our study and the medication-naive status of our sample; suggesting that evaluating sleep problems only shortly after treatment onset presents an incomplete picture, because it might not be representative for sleep quality after longer treatment periods. Our findings of improved sleep after trial end could be due to rebound effects or longer-term effects of MPH treatment and therefore require replication. CLINICAL TRIAL REGISTRATION: Central Committee on Research Involving Human Subjects (an independent registry, identifier NL34509.000.10) before enrollment of the first subject and The Netherlands National Trial Register, identifier NTR3103.

Pharmacologic and Nonpharmacologic Treatment of Restless Legs Syndrome.

This article provides an updated practical guide for the treatment of primary restless legs syndrome (RLS). Articles that appeared after the American Academy of Neurology guideline search were reviewed according to the same evidence rating schedule. We found limited evidence for nonpharmacologic treatment options. In moderate to severe primary RLS, pharmacologic options may be considered, including iron suppletion, an α2δ ligand, a dopamine agonist, a combination of an α2δ ligand and a dopamine agonist, or oxycodone/naloxone. This article includes treatment options in case of augmentation.

Sleep-Related Leg Movements in Patients with Transient Ischemic Attack and Controls.

BACKGROUND: Periodic leg movements during sleep (PLMS) have been associated with an increased risk for cardiovascular diseases and there is a high prevalence of PLMS found in patients with obstructive sleep apnea syndrome (OSAS). We evaluated patients with transient ischemic attack (TIA) for PLMS and respiratory related leg movements (RRLM), versus a control group without TIA. METHODS: Twenty-five patients with TIA and 34 patients with no vascular diagnosis were referred for polysomnography. Diagnosis of PLMS was made if the periodic leg movement index (PLMI) was ≥5 and clinical significant as PLMI ≥15. RESULTS: There was no significant difference in PLMI ≥5 and ≥15 between patients with and without TIA. In the absence of OSAS, 2 out of 5 TIA patients (40%) had a PLMI ≥15 compared to 1 of the 19 patients without TIA (5%; p = 0.037). There was no increase in RRLMs when OSAS was present. CONCLUSIONS: TIA patients did not have higher PLMI compared to controls, and in the presence of OSAS, there was no increase in RRLMs compared to patients without TIA. In selective patients, PLMS could be associated with cardiovascular diseases, since PLMS was clinically more often found in the TIA group without OSAS.

Stroke and other cardiovascular events in patients with obstructive sleep apnea and the effect of continuous positive airway pressure.

Obstructive sleep apnea (OSA) is a known-risk factor for cardiovascular diseases. There are indications that treatment with continuous positive airway pressure (CPAP) reduces the risk of new cardiovascular events. In this study, we analyzed the incidence of cardiovascular events in patients with OSA and compared for the impact of CPAP therapy. All polysomnographies performed in 2009 and 2010 were selected with an AHI ≥5 and patients older than 18 years. These 1110 patients were approached with a questionnaire about cardiovascular events and CPAP treatment. Finally, 554 patients were included in analyses. CPAP treatment was based on compliance (level 1 treatment) and extended with residual respiratory events (level 2 treatment). OSA was set as AHI ≥5 and classified in mild (AHI 5-15), moderate (AHI 15-30) and severe (AHI ≥30) OSA. 50 cardiovascular events occurred in 44 patients during follow-up (mean follow-up time 5.9 years) in 554 patients. The events were significantly higher in patients with increasing classification of OSA-severity (p = 0.016). A first-ever cardiovascular event did not differ significantly between mild, moderate and severe OSA. Untreated CPAP patients had significantly more cardiovascular events as compared to treated patients with a hazard ratio of 2.66 partially adjusted for age, AHI and smoking. There was no significant contribution of other cardiovascular risk factors. Patients with OSA with an indication for CPAP treatment have more cardiovascular events when untreated compared to treated patients. This indicates that treatment of OSA by CPAP can reduce the risk for cardiovascular events.

Occurrence of Obstructive Sleep Apnea Syndrome in Patients with Transient Ischemic Attack.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a sleep breathing disorder with episodes of upper airway obstructions. Patients with cardiovascular diseases such as myocardial infarction and stroke show a high prevalence of OSAS. Several studies focus on stroke and not on transient ischemic attack (TIA), suggesting it could be a symptom after stroke. We analyzed the occurrence of OSAS in high-risk patients with TIA. METHODS: There were 555 patients suspected for TIA by the general practitioner who were referred to our TIA daycare clinic. They were screened for OSAS using 3 screening factors: snoring (yes/no), body mass index greater than or equal to 30, and Epworth Sleepiness Score greater than 10. When 2 out of 3 were positive, patients received a polysomnography. An apnea-hypopnea index (AHI) of 5-15 is defined as mild OSAS, AHI 15-30 as moderate OSAS, and AHI greater than 30 as severe OSAS. RESULTS: Seventy-seven patients received a polysomnography. Twenty-five patients had a diagnosis of TIA and 18 had a diagnosis of cerebral ischemia, whereas 34 had other diagnoses. Twenty of the 25 (80%) TIA patients had OSAS, compared to 16 of the 34 (47%) patients without a vascular diagnosis (P = .010). When excluding patients with a cardiovascular history, we found 15 of the 20 patients with OSAS, compared to 14 out of 30 patients (P = .047). CONCLUSIONS: There is a significant higher occurrence of OSAS in TIA patients compared to patients without a vascular diagnosis, even after excluding patients with a history of cardiovascular events.

Increased prevalence of restless legs syndrome in patients with Crohn's disease.

OBJECTIVE: To determine (a) the incidence of restless legs syndrome (RLS) in patients with Crohn's disease (CD), (b) whether and how the occurrence and severity of RLS is related to severity of CD, and (c) how RLS influences the quality of life of CD patients. BASIC METHODS: We carried out a cross-sectional questionnaire study in a random selection of 144 CD patients and 80 controls. Differences were calculated using a χ-test (categorical data), an independent T-test (continuous data, normal distribution), or a Mann-Whitney U-test (continuous data, non-normal distribution). Logistic regression analysis was carried out to establish the relation between CD and RLS after adjusting for risk factors. MAIN RESULTS: The prevalence of RLS was 25.7% (37/144) in CD patients compared with 12.5% (10/80) in the control group (P=0.02). CD patients using caffeine and patients with arthralgias had a higher risk for RLS. A higher score on the modified Harvey Bradshaw Index and CD-related surgery were also associated with a higher risk for RLS. CD-related surgery was also associated with a more severe course of RLS. Patients and controls with RLS had a lower score on 'physical functioning', one of the subcategories of the RAND-36 quality-of-life questionnaire. PRINCIPAL CONCLUSION: RLS occurs more frequently in patients with CD compared with healthy individuals. A more severe course of CD seems to be associated with a higher risk for RLS. The presence of RLS has a negative influence on quality of life, mainly interfering with physical activities of daily life.

[Putting sleep disorders in context]. / Plaats slaapproblemen in de juiste context.

The new guidelines show many improvements when compared to the previous set. However, there still are several shortcomings. These mainly involve a lack of discussion of the increasing problem of sleep deprivation in western societies, and a non-consistent use of the terms "fatigue" and "excessive daytime sleepiness".

Effect of sensory stimuli on restless legs syndrome: a randomized crossover study.

STUDY OBJECTIVE: A variety of sensory stimuli relieve restless legs syndrome symptoms. Because systematic evaluations of sensory stimulation in restless legs syndrome are largely lacking, we performed a randomized crossover study to evaluate the effect of external sensory stimulation on restless legs syndrome symptoms. METHODS: Eighteen patients underwent 3 consecutive suggestive immobilization tests with the order of the following 3 conditions randomly assigned: no electrical stimulation (condition 1), tactile and proprioceptive sensory stimulation (condition 2), and tactile sensory stimulation only (condition 3). Restless legs syndrome symptoms were quantified by visual analog scales, and periodic leg movements during wake were measured. RESULTS: Baseline visual analogue scale score was 4.5 (range 0-60) in condition 1, 10.5 (range 0-96) in condition 2, and 8.5 in condition 3 (p = 0.21). There was a tendency towards a higher maximum visual analogue scale score and visual analogue scale score at the end of the suggested immobilization test in the conditions with tactile sensory stimulation, though not significant (p = 0.74 and p = 0.29, respectively). Fifteen patients suffered from periodic leg movements during wake. Median indices were 18 (range 0-145) in condition 1, 26 (range 0-190) in condition 2, and 49 (range 0-228) in condition 3 (p = 0.76). CONCLUSIONS: We found a tendency towards less leg discomfort in the conditions in which an external sensory input was applied. This potential benefit of sensory stimuli on restless legs syndrome severity merits further investigation as this could open new ways towards a better pathophysiological understanding and non-pharmacological treatments.

Restless legs syndrome in Parkinson's disease.

The Restless legs syndrome (RLS) and Parkinson's disease (PD) are two disorders that can co-exist, whether or not they share a common pathophysiology. If, and to what extent RLS and PD share the same pathophysiology, is still under debate. Sleep disturbances are prevalent in PD, and as PD progresses, nocturnal disturbances become even more evident, in association not only with motor symptoms but also with non-motor symptoms. Alertness to, and recognition of, RLS in PD patients with sleep disorders could improve customized treatment and quality of life of these patients. In this article the prevalence of RLS in PD, the clinical profile of RLS in PD, the PD profile of patients with RLS, RLS mimics specifically related to PD and impact of RLS in PD will be reviewed.

Holland Sleep Disorders Questionnaire: a new sleep disorders questionnaire based on the International Classification of Sleep Disorders-2.

The primary objectives of this study were to construct a self-assessment questionnaire for sleep disorders based on the International Classification of Sleep Disorders-2, and to evaluate the questionnaire's psychometric properties with respect to its total score and the individual scores for each of the six sleep disorders. In total, 1269 patients, clinically diagnosed with a sleep disorder, and 412 subjects without sleep complaints were enrolled into this study. Principal components analysis confirmed that the Holland Sleep Disorders Questionnaire differentially represented the six symptom clusters associated with International Classification of Sleep Disorders-2 classifications. The Holland Sleep Disorders Questionnaire's total score distinguished patients with a clinically diagnosed sleep disorder from individuals without sleep complaints, with area under the receiver operating curve P(A) of 0.95. The internal reliability coefficient alpha was 0.90 and, applying the Youden criterion as cutoff score, the overall accuracy was 88% (κ: 0.75). Subsequently, the six diagnostic groups of sleep-disordered patients could be differentiated reliably, with P(A) values ranging between 0.69 and 0.95, alpha coefficients ranging between 0.73 and 0.81 and an overall percentage of 85% correctly classified patients (κ = 0.80), indicating a substantial to excellent agreement between the primary diagnoses and the Holland Sleep Disorders Questionnaire classifications.

Prevalence and clinical profile of restless legs syndrome in Parkinson's disease.

Parkinson's disease (PD) and restless legs syndrome (RLS) have a dopaminergic link. More insight in the clinical profile of RLS in patients with PD may benefit our understanding of this link. The aims of this study were to evaluate the frequency and clinical profile of RLS in a large cohort of PD patients. In 269 nondemented Caucasian PD patients, the four diagnostic criteria for RLS were administered by a RLS trained researcher. In patients with definite RLS, the severity of these symptoms was assessed. Furthermore, in all patients, relevant motor and nonmotor symptoms in PD were evaluated. Definite RLS was present in 11% of the patients. RLS patients were more often female (69% vs. 32%, P < 0.001), but no other significant differences existed between PD patients with and without RLS. Within the PD patients with RLS, severity of RLS correlated positively with PD severity, motor fluctuations, depressive symptoms, daytime sleepiness, cognitive problems, autonomic symptoms, and psychotic symptoms. This study in a large PD cohort shows that prevalence of RLS is similar to that in the general population, which might be caused by underestimation of RLS due to dopaminergic treatment. No relations were found between the presence of RLS and PD symptoms, but the severity of RLS was related to the severity of PD-related, mainly nondopaminergic, symptoms. It is hypothesized that, nondopaminergic systems, such as the noradrenergic system may play a role in the possible link between PD and RLS.

Periodic limb movement disorder and restless legs syndrome in dialysis patients.

BACKGROUND: Sleep disturbances, in particular restless legs or limb movements, during the night are often reported by uremic patients. However, polysomnography (PSG) studies have never been carried out to confirm the actual occurrence of these disorders and the association with other objective and self-reported sleep-wake data. METHODS: Forty-eight participants were subjected to a 2-day PSG. These data on sleep including periodic limb movements, which are associated with restless legs, were correlated with clinical observations, quality of sleep-wake and life questionnaires, and with biochemical and neurographical measures. RESULTS: Restless legs syndrome (RLS) was observed in 58.3% of the patients and periodic limb movement disorder (PLMD) occurred in 70.8% of the patients. PLMD was revealed polysomnographically in almost 90% of the RLS patients. Patients with both PLMD and RLS had significantly poorer sleep quality than those with neither disorder or with PLMD alone, both in terms of self-reported data and the PSG. Quality of life was significantly worse in patients with RLS and PLMD compared to those patients with neither disorder. PLMD patients also tended to have a lower quality of life. All other metabolic measures and the results of a nerve conduction test were not correlated with RLS and/or PLMD. CONCLUSION: There was a high prevalence of severe RLS and PLMD in the present sample of uraemia patients. Nearly all RLS patients had severe PLMD. RLS (in combination with PLMD) in dialysis is associated with poor sleep quality, insomnia complaints, depression and emotional distress. Our results suggest that PLMD per se is also clinically relevant.