The biopsychosocial effects of restless legs syndrome (RLS)

The symptoms of restless legs syndrome (RLS) are associated with reductions in patients’ quality of life (QoL) and mental heath. Sleep disturbance, which is often the most troublesome symptom of RLS, may have a negative impact on patients’ daytime cognitive abilities. Research has established a relationship between the symptoms of RLS and mood symptoms, but causality is unclear. Some studies have indicated that the symptoms of RLS precede those of depression or anxiety, and others relate the severity of mood symptoms to the severity of RLS symptoms. Associations between the sleep disturbance produced by RLS and patients’ mood symptoms have also been demonstrated. The impact of RLS symptoms and their treatment on QoL, mental health, and cognition are reviewed herein.     

Effects of restless legs syndrome (RLS) on sleep

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs, usually accompanied or caused by uncomfortable sensations in the legs. Symptoms are worse in the evening or at night than during the day and generally begin or worsen during periods of rest or inactivity. The chronic sleep disturbance often associated with RLS is likely due, at least in part, to the circadian nature of the symptoms. The relationship between disturbed sleep and reduced daytime functioning is well known and thus the accurate diagnosis and effective management of RLS is imperative.     

Cognitive deficits associated with restless legs syndrome (RLS)

BACKGROUND AND PURPOSE: Restless legs syndrome produces significant chronic sleep loss, which despite not causing expected profound sleepiness, might nonetheless produce cognitive deficits similar to those seen with acute sleep deprivation, i.e. involving mostly pre-frontal cortical (PFC) functioning. PATIENTS AND METHODS: Sixteen patients off RLS treatment for at least 2 weeks and 15 age- and gender-matched control subjects had polysomnograms (PSGs) on two consecutive nights. Cognitive tests were given in the morning after the second night. Six cognitive tests were used: two Verbal Fluency tests and the Trail Making tests were selected to be particularly sensitive to PFC function and sleep loss. Porteus Mazes and the Stroop Test were selected to reflect more general frontal and executive function. The Colored Progressive Matrices were used to assess general cognitive skills. RESULTS: RLS patients compared to controls showed significant (P<0.05) and sizeable (20-40%) deficits on two of the three PFC tests and marginally non-significant deficit (P<0.1) on the third. The other three tests showed no significant differences. CONCLUSIONS: The results indicate that RLS patients show cognitive deficits similar to that reported for one night of sleep loss.     

Sonographic abnormalities in idiopathic restless legs syndrome (RLS) and RLS in Parkinson's disease

We aimed to investigate and compare sonographic abnormalities in the substantia nigra (SN) in patients with idiopathic restless legs syndrome (iRLS), those with RLS and Parkinson's disease (RLS-PD), those with idiopathic Parkinson's disease (iPD), and healthy controls. Study participants totaled 60 patients with RLS (41 iRLS, 19 RLS-PD), 25 iPD patients, and 35 age-matched healthy controls. Comparing all groups, the SN region's echogenicity area in the iRLS patients was significantly decreased compared with that in the PD-RLS, iPD, and control groups (p < 0.0001), and the PD-RLS group demonstrated a significantly increased echogenicity area compared with the control group (p < 0.05) and iRLS group (p < 0.0001). We found that the RLS-PD group's sonological results and clinical findings were different from those of the iRLS group.     

Treatment of idiopathic restless legs syndrome (RLS) with gabapentin.

Nine patients with idiopathic restless legs syndrome (RLS) were treated with 300 mg of gabapentin as an initial dose and an up-titration until relief of symptoms for 4 weeks. Subjective symptoms improved significantly. Polysomnographic data showed a reduction of periodic leg movements during sleep (PLMS) (p = 0.003) and PLMS index (p = 0.001). The authors conclude that gabapentin provides a well-tolerated and effective treatment of idiopathic RLS.     

Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS)

ObjectiveWe conducted a retrospective chart review of children with restless legs syndrome (RLS) to evaluate the efficacy of oral iron treatment, which was administered open-label during the course of clinical care. In addition, we provided detailed clinical information about RLS in this pediatric cohort.Patients and methodsThe study included 30 consecutive Japanese children with RLS who visited the Pediatric Sleep Clinic at Osaka University Hospital, and consisted of 17 boys and 13 girls, aged 2–14 years (mean ± SD, 6.5 ± 2.8). All-night polysomnography was performed in 18 patients and serum ferritin levels were measured in all the patients. After the diagnosis of RLS, iron was administered at doses between 1.6 and 7.8 mg/kg/day (3.2 ± 1.3). Serum ferritin was re-evaluated 3–6 months after iron treatment, or when RLS symptoms had disappeared.ResultsThe patient age at onset of RLS symptoms ranged from six months to 13 years (4.3 ± 3.6). A positive family history was recognized in 19 children (63.3%). Serum ferritin levels before therapy were 9–62 ng/ml (26.6 ± 12.8) and oral iron supplementation was reported to be highly effective in 17 children, effective in 10, and ineffective in three. The serum ferritin level at follow-up was 23–182 ng/ml (83.5 ± 49.8). The onset of treatment effect was within approximately three months.ConclusionsIron treatment could be effective in Japanese pediatric RLS.     

Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation

Background and objectivesAugmentation can occur frequently in restless legs syndrome (RLS) patients treated with dopaminergic agents. Video-polysomnographic (PSG) data from augmented RLS patients are scant. The aim of this study was to evaluate PSG findings in augmented RLS patients and compare them with those of non-augmented RLS patients.Patients and methodsValid PSG data were analyzed from 99 augmented and 84 non-augmented RLS inpatients who underwent one night PSG.ResultsBoth patient groups showed a high subjective burden of RLS symptoms. The mean scores on the International RLS Study Group Rating Scale (IRLS) were significantly higher in the group with augmentation than in the group without. The periodic leg movement index (PLMI) was increased in both groups, mostly on account of the PLM in wakefulness (PLMW). Both groups presented a reduced sleep efficiency and an increased sleep latency. The levodopa equivalent dose (LED) was significantly higher in the augmented group.ConclusionsOur study confirms that RLS patients with augmentation have disturbed sleep due to high amount of leg movements and fragmented sleep. Overall, however, polysomnographic characteristics were not different between insufficiently treated RLS and severely augmented RLS patients, implying that augmentation could represent a severe form of RLS and not a different phenomenon.     

Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset

Objective: RLS varies considerably in both frequency of occurrence in a family and in age of onset of symptoms. Patients whose RLS symptoms start before or at age 45 have many more affected relatives than those whose symptoms start later, suggesting etiological differences. When etiology differs, factors affecting severity may differ. This study compares the effects of current age and serum ferritin on RLS severity for early- and late-onset (over 45) RLS.Design and methods: RLS severity was evaluated using a validated clinical severity scale and sleep efficiency on a standard polysomnogram. Data from 26 consecutive RLS patients (14 early- and 12 late-onset) who met study criteria were analyzed.Results: Age-of-onset groups showed no significant differences in age, gender and RLS symptom severity. Regression analyses showed significant (P<0.05) differences with RLS severity primarily affected by age for early-onset RLS and by serum ferritin for late-onset RLS.Conclusions: The age effect for early-onset RLS indicates a slowly progressive disorder. Thus early-onset RLS appears to occur commonly in families, slowly progress with age and have a limited relation to serum iron status. In contrast, late-onset RLS appears to occur less commonly in families, rapidly progress with age and have a strong relation to serum iron status. Age of symptom onset should be considered to better define the RLS phenotype in future studies.     

Childhood and adult factors associated with restless legs syndrome (RLS) diagnosis

BACKGROUND AND PURPOSE: RLS appears to be caused by a complex interaction of genetic and environmental factors. This study sought to identify some environmental risk factors significantly associated with the occurrence of RLS. PATIENTS AND METHODS: Three adult behaviors and 10 childhood factors potentially related to development of RLS were evaluated for significant association with the occurrence of RLS in a large case-controlled family history study. All available family members of the probands in this study were evaluated for RLS using a validated diagnostic telephone interview that included a background questionnaire covering factors potentially associated with the development of RLS. Where possible, the mothers of the subjects were also interviewed regarding developmental factors that might affect the child's health and perhaps occurrence of RLS. All family members with a definite diagnosis of RLS or Not-RLS were included in the study. Of a total of 973 participants, 262 (27%) had RLS and 711 did not. RESULTS: An odds ratio (OR) with 95% confidence limits (CI) was calculated for the relationship of each factor to RLS diagnosis. Restless sleep in childhood was associated with an increased risk of developing RLS later in life for both men (OR=2.64; 95% CI: 1.31-5.29) and women (OR=2.54; 95% CI: 1.41-4.59). Blood donation was also significantly associated with an increased risk of developing RLS among men only (OR=1.99; 95% CI: 1.10-3.58), which was more pronounced for those donating blood more than the median number of donations for this group of five (OR=2.3, 95% CI: 1.16-4.43). No other factor was significantly associated with the occurrence of RLS. CONCLUSIONS: This is the first case-controlled study that demonstrates a significant association between blood donation and the occurrence of RLS in males. The association was most significant for those men donating five or more times. Smoking and alcohol use were not related to the occurrence of RLS. Neither childhood growing pains nor attention-deficit hyperactivity disorder (ADHD) was related to RLS. The only consistent factor found related to prevalence of RLS for both men and women was the report of 'restless sleep' in childhood.     

Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS)

BACKGROUND: Dopaminergic agents have become first-line treatments for restless legs syndrome (RLS). The most common serious complications of L-Dopa treatment of RLS are "augmentation", in which RLS symptoms appear earlier during the day, and tolerance, in which medication effectiveness wanes over time. The aims of this study were to assess rates of augmentation and tolerance, and their interrelationship, with pramipexole treatment of RLS. PATIENTS AND METHODS: Retrospective assessment of all patients (N=59) treated for RLS with pramipexole for at least 6 months (mean duration=21.2+/-11.4 months) by the senior author. Pramipexole dosing and clinical follow-up were performed in a standardized fashion. L-Dopa was discontinued and other medications for RLS were tapered as tolerated. Rates of augmentation (need for earlier administration of the same dose of pramipexole) and tolerance (need for an increase in pramipexole dose) were determined. RESULTS: Augmentation developed in 32% (19/59), and tolerance occurred in 46% (27/59), of patients. These two complications were statistically related (P<0.05). The only clinical predictors of these complications were previous augmentation or tolerance to L-Dopa. CONCLUSIONS: Augmentation and tolerance are more common with extended pramipexole treatment of RLS than has been previously reported in preliminary studies. However, these complications are generally manageable by earlier dosing or small dose increases of this agent, and only rarely require medication discontinuation.     

Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome

Hypocretin-1 levels were increased in evening CSF samples from subjects with restless legs syndrome, indicating altered hypocretin transmission in this sleep disorder. Increases in CSF hypocretin-1 levels were most striking in patients with early-onset restless legs syndrome.     

Dopamine and iron in the pathophysiology of restless legs syndrome (RLS).

BACKGROUND AND PURPOSE: The evaluation of the pathophysiology of restless legs syndrome (RLS) stems largely from recognition of the information provided by both pharmacological treatment of the disorder and the secondary forms of the disorder. This article examines the pathophysiological implications of each of these clinical aspects of RLS. PATIENTS AND METHODS: The article reviews the existing literature in relation to possible pathology suggested by the clinical data. It will then explore other data supporting each of the possible pathologies and examine the relationships between these pathologies. RESULTS: The pharmacological treatment data strongly support a dopaminergic abnormality for RLS. Other pharmacological data and some imaging data also support this, although the data are not entirely consistent. The secondary forms of RLS strongly support an iron deficiency abnormality for RLS, further documented by several other studies. Some animal studies have shown a relation between iron deficiency and dopaminergic abnormalities that have some similarity to those seen in the RLS patient. CONCLUSIONS: It is concluded that there may be an iron-dopamine connection central to the pathophysiology of RLS for at least some if not most patients with this disorder.     

Dopamine and iron in the pathophysiology of restless legs syndrome (RLS).

BACKGROUND AND PURPOSE: The evaluation of the pathophysiology of restless legs syndrome (RLS) stems largely from recognition of the information provided by both pharmacological treatment of the disorder and the secondary forms of the disorder. This article examines the pathophysiological implications of each of these clinical aspects of RLS. PATIENTS AND METHODS: The article reviews the existing literature in relation to possible pathology suggested by the clinical data. It will then explore other data supporting each of the possible pathologies and examine the relationships between these pathologies. RESULTS: The pharmacological treatment data strongly support a dopaminergic abnormality for RLS. Other pharmacological data and some imaging data also support this, although the data are not entirely consistent. The secondary forms of RLS strongly support an iron deficiency abnormality for RLS, further documented by several other studies. Some animal studies have shown a relation between iron deficiency and dopaminergic abnormalities that have some similarity to those seen in the RLS patient. CONCLUSIONS: It is concluded that there may be an iron-dopamine connection central to the pathophysiology of RLS for at least some if not most patients with this disorder.     

A further evaluation of the cognitive deficits associated with restless legs syndrome (RLS)

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a common sensorimotor disorder that peaks in severity during the night and comes on with rest. As a result, this condition often results in significant chronic sleep loss, especially for those with severe disease. Chronic partial sleep restriction has been associated with conditions such as depression, anxiety, chronic pain, and decline in cognitive function. Furthermore, studies have found that RLS patients suffer from these conditions more than their unaffected peers. Thus, the morbidity rate associated with RLS has often been attributed to the chronic sleep loss that frequently accompanies this condition. However, no study has specifically compared RLS sufferers to otherwise normal sleep-restricted controls in order to assess disease morbidity independent of its sleep deprivation effects. In this study, we compared the cognitive function of RLS patients who were off treatment to sleep-restricted control subjects. SUBJECTS AND METHODS: A novel chronic partial sleep-restriction protocol that utilized a 14-day combined inpatient and outpatient design was implemented in order to test the differences in cognitive functioning between RLS patients and sleep-restricted controls. The brief cognitive battery included instruments assessing general intelligence and global executive function in order to control for baseline cognitive function between the groups, and then the effects of sleep loss were assessed using prefrontal lobe-specific tasks. The final sample consisted of 16 RLS (11 male and 5 female) and 13 sleep-restricted control subjects (7 male and 6 female). RESULTS: In order to examine the differences in cognitive functioning between sleep-restricted controls and RLS subjects, independent samples t-tests were conducted. RLS subjects performed significantly better on both the Letter Fluency (t=2.13, p<0.05) and Category Fluency (t=2.42, p<0.05) than sleep-restricted controls. CONCLUSIONS: RLS subjects performed better than the sleep-restricted controls on two tasks that are particularly sensitive to sleep loss. Although previous studies suggest that sleep deprivation may impact the cognitive function of those with RLS, our data suggests that RLS subjects may show a relative degree of sleep loss adaptation. Future investigations that more closely match the sleep loss pattern of RLS subjects to controls are warranted in order to explore these potential traits further.     

Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa

Summary A double-blind randomized crossover study of 0.125 mg Pergolide (Lilly®) at bedtime versus 250 mg L-Dopa + Carbidopa (Roche®) was conducted in 16-day phases in 11 patients with idiopathic restless legs syndrome. Two patients reported a partial and 9 patients a complete relieve of motor restlessness while receiving Pergolide. Only 1 patient experienced an improvement of restlessness after L-Dopa. The patients showed polysomnographically a mean decrease in NMS cluster disturbed time by 45% from control on L-Dopa (p < 0.025) and by 79% from control on Pergolide (p < 0.001). In addition, Pergolide increased the total sleep time compared to L-Dopa (p < 0.05). In conclusion, the dopamine agonist Pergolide is superior to L-Dopa in the treatment of RLS and NMS.     

The prevalence of restless legs syndrome in Taiwanese adults

Aim: Few studies have examined the prevalence of restless legs syndrome (RLS) in Asian populations, with existing data suggesting substantially lower rates of RLS in Asian populations compared with Caucasians. However, varying definitions of RLS as well as problematic methodology make conclusions about RLS prevalence in Asian populations difficult to interpret. The current study therefore examines the prevalence of RLS in Taiwanese adults. Methods: Subjects were 4011 Taiwanese residents over the age of 15 years. Data was collected using a computer‐assisted telephone interviewing (CATI) system between 25 October 2006 and 6 November 2006. Results: The prevalence of RLS in Taiwanese adults was found to be 1.57%. In addition, individuals with RLS had a higher body mass index (BMI) and incidence of chronic conditions and comorbidities including insomnia, hypertension, cardiovascular disease, respiratory disease, arthritis, backache and mental illness. Women with RLS also had a higher incidence of post‐menopausal syndrome. Conclusion: Findings from the current study suggest that the prevalence of RLS in Taiwan is 1.57% by telephone interview. Individuals with RLS had a higher incidence of chronic insomnia and many other chronic disorders. The association and long‐term consequences of RLS with these chronic disorders warrants further longitudinal observation and study.