Do you have restless leg syndrome? I understood from your eyes.

PURPOSE: According to many studies in the literature, there is a strong association between restless leg syndrome and dopaminergic dysfunction. Dopamine is also the major catecholamine in the retina and is also a possible transmitter of the amacrine and interplexiform cells. The aim of this study is to investigate the possible association between RLS and retinal thickness. METHODS: In this study, we included 33 patients who were diagnosed with idiopathic RLS according to the "International RLS Study Group" criteria and 31 healthy subjects. All the patients and controls underwent routine ophthalmologic examination and had spectral-domain optical coherence tomography (OCT) performed. We compared the retinal thickness of the patients and control subjects. RESULTS: In the RLS group, foveal thickness was thinner then controls. Also, only inferior, superior, and temporal quadrant retina nerve fiber layer (RNFL) thickness were significantly thinner in the RLS group. The parafoveal ganglion cell complex (GCC) in the superior temporal, inferior temporal, inferior nasal quadrant, and perifoveal superior nasal thickness was also significantly thinner in the patient group. Pearson correlation analyses showed that there were statistically significant negative correlations between disease duration and macular GCC and RNFL thickness. Negative correlations were also detected between parafoveal superior, temporal, inferior and nasal macular thickness, parafoveal superior nasal, inferior temporal GCC thickness, and perifoveal superior nasal GCC thickness and disease duration. CONCLUSION: According to our results; most retinal layers are thinner in RLS patients, so it can be considered that OCT has a predictive value for progression of RLS.

Mood Symptoms and Restless Legs Syndrome Without Periodic Limb Movements During Sleep: Is it a Clinical Subtype?

Frequently co-occurring restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) are postulated to share common pathophysiology. The authors compared clinical characteristics and polysomnography (PSG) parameters among 155 idiopathic, untreated RLS patients who were stratified into three groups based on periodic limb movement index (PLMI). The authors found that RLS patients without PLMS (PLMI <5) had higher depression and anxiety scores, a lower total arousal index, longer latency to REM, and a higher spontaneous arousal frequency on PSG than RLS patients with PLMS. RLS severity was associated with PLMI in RLS patients with PLMS but not without PLMS. RLS without PLMS seems to be a phenotypically distinct clinical subtype of RLS. Future study should examine whether RLS without PLMS has a different clinical course, treatment response, and pathophysiology than RLS with PLMS.

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.

Sleep Disorders in Multiple Sclerosis.

Recent studies suggest that individuals with multiple sclerosis (MS) are at increased risk for sleep disturbances and that sleep disturbances contribute to fatigue and other chronic symptoms in MS. Although fatigue occurs commonly in people with MS, this symptom is often attributed to MS-specific pathology. Consequently, sleep disorders are often unrecognized and untreated in this population. Timely diagnosis and treatment of sleep problems in MS offer a new opportunity to ameliorate some of the daytime fatigue experienced by patients with MS. To increase this opportunity, the practitioner should be comfortable performing basic screening for common sleep complaints among patients with MS. The objectives of this review are to summarize the latest relevant data on sleep disorders in MS and offer a helpful approach to the identification and workup of the most common sleep problems in this population. Unexplored research avenues and opportunities to address important questions at the interface of sleep and MS are also discussed.

Restless legs syndrome/Willis Ekbom disease: new diagnostic criteria according to different nosology.

Restless Legs Syndrome/Willis Ekbom Disease (RLS/WED) is a common neurological disorder characterized by uncomfortable and unpleasant sensations in the legs, with an urge to move. The symptoms typically begin or worsen during periods of rest, in particular during the evening and at night, while the activity may typically relieve them. The majority of patients complains of poor sleep. Recent studies reported the prevalence is ranging from 5 to 10%. RLS/WED can be divided into primary (patients without associated conditions that may explain the symptoms) and secondary forms (mostly iron deficiency). RLS/WED is typically a chronic condition. The clinical course varies according to the age of onset. A great load of accumulating research and clinical data have led to an extended consensus for a need to enhance the diagnostic criteria. The aim of this paper is to provide a critical comparison among different diagnostic criteria, taking into account respectively the International Classification of Sleep Disorders (ICSD), the International RLS Study Group (IRLSSG) and the Diagnostic and Statistical Manual of Mental Disorders (DSM). There are several remarkable distinctions between the IRLSSG revised criteria, ICSD-3 and DSM-V. Contrary to the DSM-V criteria, ICSD-3 diagnostic criteria are more aligned to the IRLSSG ones. In fact, the five essential criteria of the IRLSSG are also required for the diagnosis of RLS/WED according to ICSD-3. The new IRLSSG criteria provide a more rigorous approach to case ascertainment and a better characterization of patients by specifying clinical significance and course. Future ascertainment of correct diagnosis should include documentation that all five diagnostic criteria are considered.

The association between restless legs syndrome, cardiovascular and metabolic diseases: hypotheses and evidence from the literature.

The association between RLS and both CVRFs, such as hypertension and diabetes, and CVDs still remains elusive. Although several shared physiopathological causes could explain these possible relationships, the emerging body of literature focusing on these disorders remains controversial. The reasons for these inconsistent findings are mainly due to the different methodologies applied. First, considering that RLS, CVRFs and CVDs are influenced by age and sex, many clinical and population-based studies performed a selection bias by restricting the sample collection to these covariates. Second, assessments of covariates are often incomparable and the methods applied for diseases assessment are often affected by low sensitivity and specificity. Only few population-based studies collected data by means of face-to-face interview or physical examination in order to limit the false positive rate compared to questionnaires administered by mail or telephone. The assessment of RLS was not always performed according to IRLSSG criteria and anyway the four diagnostic criteria did not allow the exclusion of other disorders that may act as mimics (Hening et al., 2009; Allen et al., 2014). Disease assessment ranged from a self-reported diagnosis, information on the use of specific medications, or a direct measurement of BP and blood glucose levels. Moreover, some antihypertensive medications, such as beta-blockers and certain calcium channel blockers, could both ameliorate and aggravate RLS symptoms (Innes et al., 2012) and therefore it would be important to consider medications as confounding factors. In addition, the co-occurrence of several CVRFs is frequent and they may influence each other. Therefore, the cross-sectional nature of most studies cannot assess the causal relationship between them and the variables of interest (i.e., RLS and/ or CVDs). Finally, only few studies adjusted their analyses for other cardiovascular risk factors, such as diabetes mellitus, history of myocardial infarction, BMI, dyslipidemia, and smoking status, that might act as confounders or mediators. In summary, longitudinal population-based studies and meta-analyses will be necessary in order to build a sufficiently robust body of evidence on this topic.

Restless legs syndrome: impact on sleep-related breathing disorders.

Restless legs syndrome (RLS) is a common chronic sensory-motor neurological disorder that remains a clinical diagnosis. Most RLS patients present with sleep complaints in the form of initiation and/or maintenance insomnia as RLS has a circadian rhythmicity. An increased number of periodic leg movements during sleep (PLMS) is a supportive criterion in the diagnosis of RLS. Abnormalities in the central dopaminergic and iron systems are involved in the physiopathology of RLS. There is a higher prevalence of RLS and PLMS in sleep-disordered breathing patients, particularly those with obstructive sleep apnoea (OSA), the most common sleep disorder in western societies. The complex mechanisms underlying the association between OSA, RLS and PLMS remain unclear. Untreated OSA can lead to adverse cardiovascular consequences due to cardio-metabolic dysfunction. It remains controversial whether RLS could further adversely impact the cardiovascular consequences of OSA. The PLMS do not have an additive effect on the hypersomnia experienced by some sleep-disordered breathing patients. Continuous positive airway pressure (CPAP) therapy is the most effective therapy for OSA. The presence of PLMS during CPAP treatment could be a marker of an incomplete resolution of sleep-disordered breathing in the form of increased upper airway resistance syndrome, despite treatment. Dopaminergic agonists are the preferred agent for the treatment of RLS, and are indicated when RLS symptoms are frequent and affect quality of life. PLMS and RLS do not seem to contribute to the residual hypersomnia that can be observed in some sleep-disordered breathing patients despite adequate compliance and effective CPAP therapy.

Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment.

PURPOSES: Restless legs syndrome (RLS) is underdiagnosed and poorly understood by clinicians and the general public alike; accordingly, a broad literature review with information most relevant to general practice is needed to help dispel misconceptions and improve level of care. METHODS: Specifically, this review comprehensively provides an epidemiological analysis of RLS and examines the risk factors and treatment options for RLS by compiling the findings of past RLS studies. These RLS studies were identified through a retrospective PubMed search. The epidemiological analysis was conducted by calculating a weighted mean average of all the relevant general population RLS prevalence studies, separated into geographical/racial categories. RESULTS: A comprehensive analysis of RLS epidemiological studies finds the prevalence rate of RLS to be 5-15% in the general population with 2.5% of adults having symptoms severe enough to require medical intervention. Some of the risk factors for RLS include female gender, pregnancy, low iron levels, lower socioeconomic status, poor health, elderly age, comorbidity with Parkinson's disease, positive family history of RLS, and comorbidity with psychiatric disorders. A wide array of treatment options exist for RLS including pharmacological and nonpharmacologic interventions. CONCLUSIONS: Clinicians' understanding of RLS enigma has recently improved due to the increased intensity of RLS research over the past decade. This review summarizes the current findings in the RLS field as well as providing guidelines for future RLS-related research.

[Clinical features of idiopathic restless legs syndrome in Japanese patients].

BACKGROUND: Little is known about the diagnosis and management of restless legs syndrome (RLS) in Japanese neurology clinics. OBJECTIVE: To validate the diagnostic criteria of the International RLS Study Group (IRLSSG) and the treatment algorithm of the Mayo Clinic in a Japanese neurology clinic setting and to clarify the features of Japanese patients with idiopathic RLS. METHODS: Patients with RLS symptoms were examined by a neurologist and the assessment included neurological examination, tests for periodic limb movements (PLM) and dopaminergic response, and the clinical diagnosis was made according to IRLSSG diagnostic criteria. Patients diagnosed with idiopathic RLS were treated with dopaminergic agents and the efficacy was evaluated. RESULTS: The study subjects were 151 Japanese patients who presented with RLS symptoms. Idiopathic RLS was diagnosed in 113 patients, secondary RLS in 16 and RLS mimics in 22. The cause of RLS mimics was either myelopathy, radiculopathy or neuropathy in 11 patients. The mean age of patients with idiopathic RLS was 50.1 (SD 20.0) years, 63% were woman, 97% had daily RLS, 31% had family history (40% of the early-onset subgroup), 86% reported unpleasant sensations in the lower legs, 43% had PLM in the daytime suggested immobilization test, 81% suffered from insomnia, 49% had limitations of work and activities, 71% reported impaired mood, 27% had consulted physicians about their symptoms, 4% had been diagnosed with RLS, 73% improved after dopaminergic treatments, and 33% experienced complete remission. CONCLUSIONS: The clinical features of Japanese patients with idiopathic RLS were identical to those reported in western countries, which suggests that IRLSSG diagnostic criteria and Mayo Clinic treatment algorism are valid in Japanese neurology clinics. Both patients and physicians were not fully aware of RLS in this country. Neurological examination was important in excluding RLS mimics and making a diagnosis of RLS.

Clinical features and subtypes of restless legs syndrome in Chinese population: a study of 359 patients.

BACKGROUND: The clinical spectrum of restless legs syndrome (RLS) has not been described in a Chinese population. We aim to evaluate the detailed clinical profile in a cohort of unselected RLS patients in China. METHODS: We enrolled RLS patients continuously according to the diagnostic criteria. Laboratory examinations were performed to exclude mimics and notable comorbidities. RESULTS: A total of 359 patients with RLS were enrolled. RLS symptoms were mostly symmetrical (65.2%), and purely unilateral RLS was not common (5.6%); however, unilateral dominant RLS was relatively more common. Only 1.1% of RLS patients reported no unpleasant sensations in the legs. The largest proportion of RLS patients described their uncomfortable sensation as indescribable (43.5%) and reported soreness (40.4%). In all, 8.9% of RLS patients described their abnormal sensation as painful, and 34.5% of RLS patients reported their symptoms fluctuated with seasonal trends. This population had a higher likelihood of an RLS family history. RLS patients with summer exacerbation had a younger age at RLS onset and longer disease duration (p < 0.01). Iron deficiency without anemia was common in Chinese RLS patients. Early-onset RLS patients were more likely to have a positive family history (p < 0.01), more summer worsening of symptoms (p < 0.01) and more severely disturbed peripheral iron status (p < 0.01) when compared to late-onset RLS patients. CONCLUSION: The subjective description is somewhat different, with Chinese RLS patients reporting less pain and more soreness than patients from Western countries. Seasonal fluctuation and iron deficiency without anemia are frequently seen in Chinese RLS patients and predict some other features. Differentiating these various subtypes can facilitate optimal management.

Restless legs syndrome in type 2 diabetes: implications to diabetes educators.

PURPOSE: The purpose of this study was to provide a background of restless legs syndrome (RLS), present the prevalence and demographic findings of a descriptive study of type 2 diabetes with RLS, and provide implications to diabetes educators on the management and education of RLS. METHODS: Participants with type 2 diabetes who met the diagnostic criteria for RLS based on the International RLS Study Group Criteria were recruited from the PENN Rodebaugh Diabetes Center from July 2005 through September 2006. Participants who met inclusion and exclusion criteria were mailed a survey to collect data. RESULTS: Of 121 patients with type 2 diabetes, 54 (45%) of the screened sample met the 4 diagnostic criteria for RLS. Of those who met the inclusion and exclusion criteria of the primary study, 18 patients with type 2 diabetes with RLS participated in this study. Along with diabetes, the participants had a variety of comorbid health conditions including hypertension, neuropathies, rheumatoid arthritis, renal failure, and irritable bowel syndrome. Only one third of the participants were being treated for RLS. Thirty-nine percent of the participants with type 2 diabetes were using insulin to manage their diabetes with other oral agents. CONCLUSIONS: RLS is a sleep disorder that may affect the management of type 2 diabetes. Diabetes educators must know that sleep disorders can affect long-term health outcomes, and RLS is frequently seen in this cohort of patients.

The influence of different definition criteria on the PLM index.

BACKGROUND: Different criteria for the scoring of periodic leg movements (PLM) have been recently proposed. We investigated to what extent changes in PLM criteria for leg movement duration, intermovement interval and combination of bilateral leg movements (LM) influence the PLM index. METHODS: The nocturnal polysomnographies of 40 consecutive patients (20 males, 20 females, mean age 52+/-16 years) with sleep-wake complaints but without severe sleep-related breathing disorders (AHI<20) were evaluated. All patients showed a minimum of 100 LMs during the night. For each night eight PLM indices during sleep (PLMS) and eight PLM indices during wakefulness (PLMW) were computed by systematically varying the following criteria: LM duration (0.5-5s vs. 0.5-10s), intermovement interval (5-90s vs. 10-90s), and separation criteria for LMs occurring in both legs (<5s onset to onset vs. <0.5s offset to onset). Data were analyzed using linear mixed models. RESULTS: The two different intermovement intervals and the leg movement durations both had a statistically significant influence on the PLMS and PLMN indices. These variations were highly systematic but numerically small for the PLMS index while they were substantially larger for the PLMW index. The separation criteria or possible two-way interactions between the criteria had no influence on the PLM indices. CONCLUSIONS: Different criteria had a negligible influence on the PLM index during sleep. Across-study or sleep-laboratory comparability can be assumed within our parameter set. This does not apply to the PLM index during wakefulness.

Improving RLS diagnosis and severity assessment: polysomnography, actigraphy and RLS-sleep log.

Restless legs syndrome (RLS) has proven to often have both a difficult differential diagnosis and also problems with assessing severity. These problems contribute to some of the confusion about medication effects on RLS and also to the large placebo effect seen in clinical trials. We need to find better diagnostic and evaluative methods. The following three promising methods for better diagnosis and evaluation have been somewhat overlooked. (1) The polysomnogram with a preceding suggested immobilization test offers objective measures of the motor sign of RLS, the periodic leg movements in sleep (PLMS) under standard conditions of sleep and during quiet resting, both of which provoke RLS symptoms. The diagnostic sensitivity and specificity for these measures is about the same as that for MSLT diagnosis of narcolepsy and the use of these tests deserves to be reconsidered. (2) Leg activity measures provide an attractive less costly and more accessible alternative to the polysomnogram and can be used on repeated nights, reducing measurement problems occurring because of the well-recognized variability in symptom expression across days. (3) RLS-logs provide a more concurrent assessment of RLS symptom occurrence that provide a more direct measure of severity than questionnaires completed at clinic visits. Similar logs have been found useful in evaluating other sensory disorders such as headache. These methods need to be developed and evaluated in both our research and clinical trials of RLS because they may enhance accuracy of diagnosis and reduce the placebo response to treatments.

RLS assessment and sleep questionnaires in practice--lessons learned from Parkinson's disease.

In recent years, a whole range of interesting and useful scales have been made available for the assessment of patients with restless legs syndrome (RLS). These can be more or less divided into severity scales (IRLS, RLS-6, JHSS), quality of life scales, and instruments for specific details (e.g. to improve diagnostic accuracy; RLS-DI), or to assess the presence and severity of augmentation (ASRS, SIDA). This manuscript reviews these scales, their specific strengths and weaknesses, validation status and results of their use in RLS populations. Specific scales are already well established in Parkinson's disease, and a more widespread and frequent use of scales and questionnaires will also enhance clinical care and long-term monitoring of patients with RLS.

Suggestive evidence of erythropoietin level abnormality in patients with sporadic and familial cases of the restless legs syndrome.

BACKGROUND: The restless legs syndrome (RLS) is divided into two forms: idiopathic and secondary. About half the cases of the former are found to have a positive family history. The lack of objective and quantitative parameters in familial RLS also represents a drawback for genetic studies. We tried to find a feature distinguishing the sporadic from the familial forms of the RLS. METHODS: RLS patients were examined for clinical picture and laboratory markers including erythropoietin levels. Patients with a priori known causes of secondary RLS, were excluded. All biochemical and hematological parameters were standardized for sex and age groups relative to the population mean and standard deviation. RESULTS: In our set of 311 patients (65.3% women, mean age 54.6 years, SD 14.7 years) 96 reported positive family history (64.6% women, mean age 53.1 years, SD 15.8 years). We found a significantly lower age at the onset of RLS symptoms in familial cases (mean 29.3 vs. 44.0, Z 5.9, p<0.0001), and, in sporadic cases, a significantly lower absolute count of red blood cells (Z -2.02, p=0.043 respectively). Erythropoietin levels in the familial cases were significantly lower than in the reference population (median -2.26 SDs from the mean). None of the other parameters were significantly different between the groups. CONCLUSIONS: Our results confirm previously published lower age at symptom onset in familial RLS and provide the first evidence of lower erythropoietin levels in RLS patients. These observations might help to identify the specific phenotype for genetic association studies.

[Classification of sleep disorders]. / Clasificación de los trastornos del sueño.

Sleep disorders are frequent processes, both as a symptom associated with other diseases and as independent disorders. However, only in the last 4 decades has Sleep medicine gained its position among the medical specialties. In fact, it was only in these years that significant advances were obtained in the study of the etiology and treatment of these disorders. Similarly, the different classifications have been evolving over the years. First, they were based upon the clinical symptom; later on, more emphasis was given to the diseases. Finally, in 2005, the new classification was once again based on the symptoms. More than 90 disorders are listed in this latest classification, and an attempt is made to include the symptoms and the diseases of sleep, as well as those in which sleep disorders are fundamental. It is essential to have a clear idea of this complete classification of sleep disorders in order to deal with these patients appropriately.

Bilateral leg movements during sleep: detailing their structure and features in normal controls and in patients with restless legs syndrome.

OBJECTIVE: The aim of this study was to analyze statistically the number of single leg movements (LMs) forming bilateral LMs during sleep, along with their combined duration, to eventually provide evidence-based data for the adjustment of the current scoring rules defining bilateral LMs. METHODS: Polysomnographic recordings of 111 untreated patients with RLS with a median age of 56.0 years, along with 42 normal controls with a mean age of 60.0 years, were included. In each recording, we identified all LMs that were considered as bilateral when two or more LMs were overlapping or the onset of the following movement was <0.5 second after the offset of the preceding LM. The remaining LMs were classified as monolateral. A series of parameters were computed for both bilateral and monolateral LMs. RESULTS: The duration of monolateral LMs in RLS patients was significantly longer than that of normal controls. For bilateral LMs, the maximum number of single LMs forming a bilateral movement and the maximum duration were slightly higher in RLS patients; however, the distribution of the number of individual LMs forming a single bilateral LM was similar. Only 0.12% and 0.27% of bilateral LMs consisted of >4 individual movements, and only 0.16% and 1.90% of bilateral LMs were >15 seconds in RLS patients and healthy controls, respectively. CONCLUSION: Our results strongly suggest that bilateral LMs during sleep should be constituted by no more than four individual LMs and should have a maximum duration of 15 seconds.

Epidemiology of familial and sporadic restless legs syndrome in Iran.

Restless legs syndrome is one of the most common sleep and movement disorders. For lack of sufficient information on this syndrome in Iran, this study was conducted at Alzahra Hospital, Isfahan, Central Iran, to determine the epidemiology of idiopathic, familial and sporadic forms of the syndrome. From September 1999 to April 2003, 61 patients in two groups were selected. A questionnaire with emphasis on sleep history and neurological history was completed and a thorough physical examination was performed for each patient. Familial and sporadic groups had mean +/- SD ages of 22 +/- 2.1 and 41 +/- 3.2 years, respectively (P < 0.05). Female to male ratio was 2:1. The mean +/- SD ages for women and men were 31 +/- 5.3 and 42 +/- 6.1 years (P < 0.05), respectively. Our findings support the current opinion that restless legs syndrome should be divided into the early-onset disease with a clear genetic component and the late-onset disease with an unclear etiology.