Plasma apelin level in patients with restless legs syndrome and its association with periodic leg movements.

OBJECTIVES: Apelin is an antioxidant and anti-inflammatory molecule secreted by adipose tissue and has a protective effect on cardiac and neuronal tissue. Recent studies have reported that the risk of vascular disease is increased in restless legs syndrome (RLS). We aimed to measure plasma levels of apelin in patients with RLS. Additionally, we wanted to determine if there is any relationship between apelin levels and RLS disease severity and the periodic leg movement index (PLMI). METHOD: A total of 14 RLS patients with moderate-to-severe symptoms and 14 age- and body mass index (BMI)-matched healthy controls participated in the study. All participants had no concomitant medical disorder nor took medications. The international RLS rating scale (IRLSS) was used to determine disease severity. Polysomnography (PSG) served to exclude other sleep disorders such as sleep-related breathing disorders and to measure sleep parameters. RESULTS: The mean plasma apelin level was significantly lower in the patient group compared to the control group independent of IRLSS score and PSG findings (p = 0.004). After comparison between the RLS patient group and control group, the patient group was divided into two subgroups based on a PLMI above or below 15 events per hour. A reduced mean apelin level was observed in the patient group having a PLMI above 15 compared to the patient group with PLMI below 15 and the control group (p = 0.003). There was no correlation between plasma apelin levels and disease severity and PLMI in the two patient subgroups. CONCLUSIONS: RLS patients especially those with a PLMI above 15 have low plasma apelin levels independent of disease severity and sleep parameters such as sleep duration and quality. Decreased apelin levels may explain the increased risk for vascular diseases in those patients.

Relationship between hepcidin levels and periodic limb movement disorder in patients with obstructive sleep apnea syndrome.

PURPOSE: This study was aimed to assess potential correlations between periodic leg movement (PLM) index, hepcidin levels, and iron status in patients with obstructive sleep apnea syndrome (OSAS). METHODS: Forty-four newly diagnosed OSAS patients and 49 non-apneic controls were enrolled in this study. All patients underwent polysomnographic evaluation. The hepcidin, iron, ferritin, total iron binding capacity, and C-reactive protein levels were measured. RESULTS: The mean age was 47.4 ± 7.2 years (18-68) in the OSAS group and 44.9 ± 11.1 years (23-65) in the control group. There were no differences in age, gender, and smoking between OSAS patients and controls. Mean apnea-hypopnea index (AHI) was 25.1 events/h. Mean serum hepcidin levels were significantly higher in OSAS subjects (725.9 ng/ml) than in control subjects (646.0 ng/ml) (p < 0.001). Serum iron levels were significantly lower in the OSAS and PLM disorder groups than in control subjects (p < 0.001). Serum hepcidin levels were significantly correlated with AHI (r = 0.453) and PLM index (r = 0.114). Serum iron levels were significantly negatively correlated with AHI (r = -0.169) and PLM index (r = -0.180). CONCLUSIONS: In our study, the level of hepcidin was increased in patients with OSAS. Our study indicates that levels of hepcidin correlate with the AHI and PLM index severity of OSAS.

The additive impact of periodic limb movements during sleep on inflammation in patients with obstructive sleep apnea.

RATIONALE: Both periodic limb movements during sleep (PLMS) and obstructive sleep apnea (OSA) are major causes of sleep disorders and have been associated with systemic inflammation and cardiovascular events. However, it is uncertain whether in combination they promote a higher inflammatory response and greater risk of cardiovascular events than each condition alone. OBJECTIVES: To investigate whether the presence of PLMS is associated with increased inflammation in patients suspected of having OSA. METHODS: In 342 patients who underwent polysomnography to diagnose OSA, plasma C-reactive protein (CRP) and fibrinogen levels were measured. MEASUREMENTS AND MAIN RESULTS: OSA was found in 254 patients, with 46 also having PLMS. Among the 88 patients who did not have OSA, 8 had PLMS. Plasma CRP and fibrinogen levels in the group with both PLMS and OSA were higher than in patients with neither OSA nor PLMS and in patients with OSA only (CRP: 0.20 ± 0.48 vs. 0.09 ± 0.15 vs. 0.13 ± 0.18 mg/dl, P = 0.03; fibrinogen: 298.2 ± 76.1 vs. 269.0 ± 57.1 vs. 270.0 ± 52.6 mg/dl, P < 0.01). Multivariate analysis showed that the presence of PLMS was associated with higher plasma CRP levels (ß = 0.1401, P < 0.01) and fibrinogen levels (ß = 0.1359, P = 0.01) independently from other clinical variables such as body mass index and the severity of OSA. CONCLUSIONS: PLMS were positively associated with plasma CRP and fibrinogen levels in patients suspected of having OSA. Because plasma levels of these proteins have been established as predictive factors of future cardiovascular events, the presence of PLMS may be a useful clinical sign to identify patients with OSA at high risk of cardiovascular events.

The interplay of stress and sleep impacts BDNF level.

BACKGROUND: Sleep plays a pivotal role in normal biological functions. Sleep loss results in higher stress vulnerability and is often found in mental disorders. There is evidence that brain-derived neurotrophic factor (BDNF) could be a central player in this relationship. Recently, we could demonstrate that subjects suffering from current symptoms of insomnia exhibited significantly decreased serum BDNF levels compared with sleep-healthy controls. In accordance with the paradigm indicating a link between sleep and BDNF, we aimed to investigate if the stress system influences the association between sleep and BDNF. METHODOLOGY/PRINCIPAL FINDINGS: Participants with current symptoms of insomnia plus a former diagnosis of Restless Legs Syndrome (RLS) and/or Periodic Limb Movement (PLM) and sleep healthy controls were included in the study. They completed questionnaires on sleep (ISI, Insomnia Severity Index) and stress (PSS, Perceived Stress Scale) and provided a blood sample for determination of serum BDNF. We found a significant interaction between stress and insomnia with an impact on serum BDNF levels. Moreover, insomnia severity groups and score on the PSS each revealed a significant main effect on serum BDNF levels. Insomnia severity was associated with increased stress experience affecting serum BDNF levels. Of note, the association between stress and BDNF was only observed in subjects without insomnia. Using a mediation model, sleep was revealed as a mediator of the association between stress experience and serum BDNF levels. CONCLUSIONS: This is the first study to show that the interplay between stress and sleep impacts BDNF levels, suggesting an important role of this relationship in the pathogenesis of stress-associated mental disorders. Hence, we suggest sleep as a key mediator at the connection between stress and BDNF. Whether sleep is maintained or disturbed might explain why some individuals are able to handle a certain stress load while others develop a mental disorder.

Relationship of serum ferritin levels to sleep fragmentation and periodic limb movements of sleep on polysomnography in autism spectrum disorders.

OBJECTIVE: Although children with autism spectrum disorders experience a range of sleep disturbances, exact mechanisms are not well-characterized. We investigated the association of serum-ferritin to sleep fragmentation and periodic limb movements of sleep using polysomnography in children with autism spectrum disorders. METHODS: We conducted a retrospective chart review of children with autism spectrum disorders followed from 1990 to 2010. Inclusion criteria were availability of polysomnography data and ferritin levels within 12 months of each other. The following variables on polysomnography characterized sleep fragmentation: increased arousal index, alpha intrusions, and reduced sleep efficiency. The data were compared with age- and gender-matched controls. RESULTS: Of 9791 children with autism spectrum disorders identified, 511 had a ferritin level, 377 had polysomnography data, and 53 had both ferritin and polysomnography data. As compared with the controls (86 ng/mL), the median ferritin level was 27 ng/mL in the study autism spectrum disorders population (53 patients) (P < 0.01), 27 ng/mL in autism spectrum disorder subjects with periodic limb movements of sleep (25 patients) (P = 0.01), and 24 ng/mL in autism spectrum disorders subjects with sleep fragmentation (21 patients) (P = 0.02). Within the autism spectrum disorders population, median ferritin levels were significantly lower in patients with poor sleep efficiency (7 ng/mL) versus those with normal sleep efficiency (29 ng/mL) (P = 0.01). The prevalence of periodic limb movements of sleep was 47% in autism spectrum disorders compared with 8% in controls (P < 0.01). CONCLUSION: Children with autism spectrum disorders had significantly lower ferritin levels compared with controls. In addition, they experience a higher prevalence of sleep fragmentation, obstructive sleep apnea, and periodic limb movements of sleep than children with ASD and no sleep complaints. Our preliminary observations, which have not been described before, need to be validated in multicenter prospective studies.

Nocturnal hypoxemia and periodic limb movement predict mortality in patients on maintenance hemodialysis.

BACKGROUND AND OBJECTIVES: Sleep disorders, including sleep-disordered breathing and periodic limb movements during sleep, are associated with an increased risk for cardiovascular diseases, which are the leading causes of death in patients with ESRD. This study investigated the association between sleep disorders and mortality in patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Thirty patients on maintenance hemodialysis, who were clinically stable for >2 months, underwent overnight polysomnography to evaluate sleep parameters. RESULTS: All patients were followed for a median of 48 months (range: 14 to 62 months), and 14 of them died during the follow-up period. Among the sleep parameters, the percent of sleep time with arterial oxygen saturation <90% (T <90%), mean arterial oxygen saturation, and periodic limb movement index score were associated with significant increases in the risk of death. However, associations of the apnea-hypopnea index or oxygen desaturation index with mortality were NS. The hazard ratios (95% confidence intervals) for death per one SD increment in the log-transformed T <90% and periodic limb movement index score were 2.10 (1.06 to 4.15) and 2.48 (1.11 to 5.52), respectively, after adjusting for age. CONCLUSIONS: We found that nocturnal hypoxemia and periodic limb movement during sleep, rather than apnea itself, were associated with an increased risk for death in patients with ESRD. However, conclusions from this study should be drawn with caution, because they are limited by the small sample size.

Iron stores, periodic leg movements, and sleepiness in obstructive sleep apnea.

STUDY OBJECTIVES: Most clinical sleep studies are performed for suspected obstructive sleep apnea (OSA), yet one-quarter to one-half show periodic leg movements (PLMs), for reasons that remain unknown. Several other disparate sleep disorders also increase the risk for PLMs. We examined the novel hypotheses that OSA as a representative sleep disorder could promote lower body iron stores, as reflected by serum ferritin levels, and, through downstream effects on dopaminergic transmission, increase PLMs and daytime sleepiness. METHODS: Subjects were recruited as they underwent laboratory-based polysomnography for suspected OSA. Serum ferritin levels were measured the next morning. Each subject completed an Epworth Sleepiness Scale and a brief questionnaire to assess for restless legs syndrome (RLS). RESULTS: The frequency of apneic events showed no association with serum ferritin levels, before or after adjustment for age, sex, body mass index, and likely RLS (each p value > 0.3). Serum ferritin levels did not predict the frequency of PLMs (p = 0.7) or Epworth scores (p = 0.8). Iron deficiency as a dichotomous variable, determined by ferritin levels less than < 50 microg/L or in combination with low transferrin saturation or mean corpuscular volume, showed similar results. In exploratory analyses, contrary to expectations, lower minimum oxygen saturation and increased sleep-stage shifts predicted increased rather than decreased ferritin levels (p = 0.03 and p = 0.02, respectively). CONCLUSIONS: Results of this study, powered to detect small to moderate effect sizes, strongly suggest that OSA does not cause lower serum ferritin levels, which, in turn, cannot explain PLMs or daytime sleepiness in these patients.

A genetic risk factor for periodic limb movements in sleep.

BACKGROUND: The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. METHODS: To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. RESULTS: In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). CONCLUSIONS: We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease.

A secondary analysis of racial differences in periodic leg movements in sleep and ferritin in hemodialysis patients.

BACKGROUND AND OBJECTIVE: Hemodialysis (HD) is associated with restless legs syndrome (RLS) and periodic leg movements in sleep (PLMS), but the mechanisms underlying these relationships remain unclear. African-American HD patients have been reported previously to have a reduced likelihood of RLS. Alterations in iron metabolism, known to be a risk factor for idiopathic forms of RLS, could represent the basis for these racial differences. PATIENTS AND METHODS: In secondary data analyses from a previously published study, we examined raw and log-transformed values for plasma ferritin and polysomnographically recorded PLMS in Caucasian and African-American HD patients. RESULTS: African-American (n=36) HD patients had higher ferritin and lower PLMS than Caucasians (n=10). However, within the African-American population, ferritin levels were unrelated to PLMS. CONCLUSIONS: These results are compatible with previously reported racial differences in RLS to the extent that PLMS were less common in the African-American population. However, they suggest that if a differential genetic vulnerability underlies those racial differences, it may not manifest as a deficiency in iron metabolism, at least within the constraints of the marker of iron stores used here (e.g. serum ferritin) and in the specific population studied (hemodialysis). Future studies with larger, more representative samples of African-Americans and Caucasians will be required to replicate such differences.

Daytime sleepiness in patients with CRF: impact of nocturnal hemodialysis.

BACKGROUND: Patients with end-stage renal disease (ESRD) have a high prevalence of sleep disorders, which are not improved by conventional hemodialysis (CHD). Although sleep disorders are commonly associated with complaints of excessive daytime sleepiness, the severity and pathogenesis of daytime sleepiness has not been evaluated objectively in patients with ESRD. Nocturnal hemodialysis (NHD) is a new technique that provides better clearance of uremic toxins than CHD and, consequently, may improve sleep quality and daytime sleepiness. The authors wished to determine the severity and pathogenesis of daytime sleepiness in patients with ESRD and evaluate the impact of NHD. METHODS: Sleep quality was monitored by overnight polysomnography, and daytime sleepiness was assessed by the multiple sleep latency test (MSLT). These measurements were performed in 24 patients (15 men and 9 women, 44 +/- 10 years) while on treatment with CHD and were repeated in 15 patients after conversion to NHD. RESULTS: The majority (54%) of patients on CHD were pathologically sleepy (somnolent group, mean sleep latency <5 minutes), and, in comparison with the remaining patients (alert group, mean sleep latency >5 minutes), their blood urea nitrogen (BUN; 77.9 +/- 9.8 v 60.2 +/- 12.0 mg/dL, P < 0.001; 27.8 +/- 3.5 v 21.5 +/- 4.3 mmol/L; P < 0.001), and periodic limb movement (PLM) index (57 +/- 47 v 6 +/- 10/hr; P = 0.002) were significantly higher. Furthermore, sleep latency was correlated with BUN (R = 0.58, P = 0.008). After conversion to NHD, there was a significant fall in BUN and the severity of sleep apnea, but the overall frequency of PLM and sleep fragmentation remained elevated. Nevertheless, there was a trend for the Somnolent group to become less sleepy on NHD, and this was associated with a modest reduction in the frequency of PLM. CONCLUSION: Excessive daytime sleepiness occurs in approximately 50% of patients with ESRD. The etiology appears to be related both to uremia and sleep fragmentation associated with PLM.

Restless legs syndrome and periodic limb movements of sleep: fact, fad, and fiction.

Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) are common disorders seen in sleep disorder centers. Although RLS in universally thought to cause daytime sleepiness, the role of PLMS in causing sleepiness (or any symptom!) has been more controversial. Recent publications have show that PLMS do not cause either subjective or objective sleepiness, but may be a marker for respiratory effort related arousals. In regards to patients with end-stage renal disease, PLMS may mark mortality. In this same group of patients, gabapentin and normalization of hematocrit may be effective therapies for RLS/PLMS. Melatonin may prove to be an alternative therapy for PLMS.