Epidemiology and Pathophysiology of Restless Legs Syndrome

Tae-Joon Kim; Min Hye Kim

doi:10.13078/jsm.250007

J Sleep Med > Volume 22(2); 2025 > Article

Kim and Kim: Epidemiology and Pathophysiology of Restless Legs Syndrome

Review Article

J Sleep Med 2025;22(2):41-48.

Published online: July 2, 2025

DOI: https://doi.org/10.13078/jsm.250007

Epidemiology and Pathophysiology of Restless Legs Syndrome

Tae-Joon Kim^1,²

, Min Hye Kim²

¹Department of Neurology, Ajou University School of Medicine, Suwon, Korea

²Department of Neurology, Ajou University Hospital, Suwon, Korea

Address for correspondence Tae-Joon Kim, MD, PhD Department of Neurology, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon 16499, Korea Tel: +82-31-219-5175 Fax: +82-31-219-5178 E-mail: tjkim23@ajou.ac.kr

Received March 17, 2025 Revised April 21, 2025 Accepted May 28, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Restless legs syndrome (RLS) is a chronic neurological disorder characterized by an overwhelming urge to move the legs, typically accompanied by unpleasant sensations that worsen at rest, particularly in the evening and night. The diagnosis of RLS is primarily symptom-based, with a recent revision of the diagnostic criteria in 2012 emphasizing the distinction between true RLS and conditions that mimic it, such as leg cramps or arthritis. This has led to variations in the prevalence of RLS, particularly in different diagnostic criteria and methodologies, with higher rates observed in simple questionnaires and lower rates in differential diagnoses and detailed interviews. The pathophysiology of RLS is complex and involves dopaminergic dysfunction and brain-specific iron deficiency. Dopamine dysregulation contributes significantly to this disorder, as evidenced by the efficacy of dopaminergic treatment. Additionally, iron deficiency in the brain, especially in areas such as the striatum and substantia nigra, plays a critical role in RLS, with studies indicating reduced iron levels in affected individuals and improvement in symptoms following iron supplementation. This article provides an in-depth review of the epidemiology and pathophysiology of RLS, particularly in Asia, focusing on the importance of accurate diagnostic criteria and the roles of dopamine and iron in the development of this disorder.

Keywords: Restless legs syndrome, Epidemiology, Prevalence, Dopamine, Brain iron deficiency

INTRODUCTION

Restless legs syndrome (RLS) is a chronic neurological sensorimotor disorder characterized by an irresistible urge to move the legs, often accompanied by various unpleasant sensations. Symptoms of patients with RLS worsen during rest and in the evening or at night and are at least partially relieved by movement [1]. RLS has a relatively complex pathophysiology characterized by a variety of symptoms and is diagnosed primarily through symptomatology, thus exhibiting highly diverse epidemiological characteristics.

Since the revision of the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria in 2012 [2], there have been changes in epidemiological studies. The 2012 revision of the IRLSSG diagnostic criteria emphasized the importance of differentiating RLS from common mimics such as positional discomfort, leg cramps, arthritis, and anxiety [3,4]. Distinguishing between these conditions is crucial for accurate diagnosis and treatment decisions in clinical and epidemiological contexts, as their co-occurrence can complicate both diagnostic and therapeutic approaches. The epidemiology of RLS is significantly related to racial differences, familial aggregation, and genetic associations [5]. However, owing to the varied prevalence rates reported in existing studies [6], it is essential to summarize and comprehend these findings.

The pathophysiology of RLS is not yet fully elucidated and requires further investigation. It is currently thought that the underlying pathophysiology of RLS involves brain-specific iron deficiency along with dopaminergic and glutamate dysfunction as key mechanisms [7-9].

This article provides a comprehensive overview of the present knowledge regarding the epidemiology and pathogenesis of RLS, with particular emphasis on recent advancements and its epidemiology in Asia. The pathophysiology of RLS is primarily addressed in this review, with a focus on dopamine and iron. The clinical features, diagnosis, and treatment of RLS are beyond the scope of this review, and have been addressed in other literature [1,9].

EPIDEMIOLOGY OF RLS

General prevalence

Epidemiological studies have revealed significant geographic variation in the prevalence of RLS [5]. The reported prevalence of RLS in Europe ranges from 3%–25% [10], whereas it is generally lower in Asian countries, with rates typically under 2% [11-13]. However, previous epidemiological studies conducted in Korean adults have consistently reported relatively higher prevalence rates, up to 12.1% [14-16].

A systematic review and meta-analysis conducted by Broström et al. [6] recently evaluated the prevalence of RLS in the general adult population worldwide. They identified 97 studies with 483,079 participants from 33 different countries. The corrected overall pooled prevalence of RLS in their study was 3% (95% confidence interval [CI]: 1.4–3.8). The pooled prevalence differed between males (2.8%; 95% CI: 2.0–3.7) and females (4.7%; 95% CI: 3.2–6.3). In addition, the prevalence of RLS was affected by methodological quality and study design. Moreover, its prevalence is higher in developed countries and the elderly population.

Asian prevalence

An electronic search of the MEDLINE database was conducted to identify epidemiological studies of RLS in Asian populations. The search terms “restless legs syndrome” and “prevalence” were employed, and studies involving Asian populations published between January 2000 and August 2024 were selected, excluding special populations with comorbidities such as hemodialysis, Parkinson’s disease, or pregnancy that may influence the overall prevalence of RLS (Supplementary Fig. 1 in the online-only Data Supplement). The studies were categorized according to their geographical location or country of origin. Population characteristics, diagnostic methods, and reported prevalences were extracted.

We analyzed the reported prevalence of RLS in relation to the diagnostic tools employed in the reviewed studies, considering that the prevalence of RLS varies depending on the diagnostic criteria used. These methods were classified into four categories: 1) a questionnaire asking only about the sensorimotor features of RLS, 2) written questionnaires satisfying only the four essential RLS features without differential diagnosis, 3) face-to-face or telephone interview utilizing only the four symptom criteria without differential diagnosis, and 4) any method including diagnostic criteria that distinguish RLS from RLS-mimicking conditions. The first classification identified the key symptoms of RLS using a screening question such as “Have you ever experienced an urge to move your legs or unpleasant sensations like creepy-crawling feelings in your legs before sleep?.” The fourth classification encompassed studies that conducted a differential diagnosis through either remote or face-to-face interviews and neurological examinations, as well as those that utilized questionnaires incorporating elements of differential diagnosis.

A total of 30 studies on the prevalence of RLS in Asian populations were selected based on the predefined inclusion criteria (Supplementary Table 1 in the online-only Data Supplement). In the two studies that defined RLS based on the presence of a key symptom of RLS features, the prevalences were 11.4% and 12.1%, respectively [14,17]. In the six studies that utilized the four essential RLS features by questionnaires, RLS prevalence ranged from 4.5%–9.7% [18-23]. In the 10 studies where RLS was diagnosed through direct interviews based on the presence of four essential clinical features, the prevalence ranged from 0.9%–10.2% [11,12,24-31]. A differential diagnostic approach was applied in 12 studies with reported prevalence ranging from 0.4%–8.3% [13,15,16,32-40]. Notably, the prevalence of RLS tended to be lower in studies employing more accurate diagnostic methods, and the prevalence was generally lower in studies conducted in East and Southeast Asia compared to those in other parts of Asia (Fig. 1).

Factors affecting prevalence

The discrepancy in the prevalence of RLS among the collected studies may be partially attributed to variations in the diagnostic criteria and survey methodologies employed across the studies. Specifically, when RLS is diagnosed solely based on the presence of the four essential clinical features in the initial screening phase, the reported prevalence tends to be relatively high, though this approach has a low positive predictive value (<60%) [13,33,34]. In contrast, when diagnostic criteria that assess RLS severity or employ valid tools to differentiate RLS from RLS mimics are utilized, the prevalence of RLS is typically lower, even within the same ethnic group [3,41]. In many of the earlier epidemiological studies conducted in Korea, where diagnosis relied solely on the presence of these essential features by questionnaire, RLS prevalence was reported to range from 4.5%–9.5%, suggesting a potential over-estimation of the true prevalence [19-21,23].

To explore these discrepancies further, recent studies have provided more refined diagnostic approaches to clarify the true prevalence of RLS. Specifically, Kim et al. [40] explored two different Korean populations, yielding RLS prevalence rates of 0.4% and 1.3%, who met the revised 2012 diagnostic criteria of the IRLSSG. The prevalence of individuals exhibiting only the four essential features of RLS was 5.5% and 3.4%, respectively. Most of these individuals were classified as RLS mimics, including positional discomfort and leg cramps. Their study found a relatively low prevalence of RLS compared to that reported in previous Korean studies, yet it aligns more closely with the lower prevalence rates observed in other Asian populations.

The revised 2012 IRLSSG criteria underscore the importance of distinguishing true RLS from RLS mimics by introducing a fifth element [2]. In addition to the four core clinical features, the fifth criteria specify that presenting symptoms should not be attributable to other medical or behavioral conditions, such as positional discomfort, leg cramps, arthritis, myalgias, venous stasis, neurological disorders (e.g., peripheral neuropathy, radiculopathy, or myelopathy), habitual foot tapping, or anxiety [2,40]. Since these conditions share overlapping features with RLS, such as symptom distribution, onset timing, and response to movement or tactile stimulation, accurate differentiation is essential for both clinical diagnosis and epidemiological research.

The seven studies from Asian countries that incorporated differential diagnosis assessments through exams by neurologists reported relatively low prevalence rates, ranging from 0.7%–4.5% [13,32-35,38,39]. Six out of the ten studies that used face-to-face or telephone interviews based on symptom criteria similarly showed a generally low prevalence, ranging from 0.9%–5.5% [11,12,24,25,27,29]. In contrast, other questionnaire-based studies that did not incorporate differential diagnoses reported higher prevalence rates (≥4.5%) [18-23]. Notably, one study from Korea, two from Japan, and one from China employed a stepwise approach to determine RLS prevalence [13,33,34,40]. In these studies, the prevalence of RLS symptoms was relatively high at the initial screening stage using questionnaire or telephone interview but decreased significantly following face-to-face interview, with prevalence rates of 1.1%–4.6% [33], 1.0%–5.6% [34], and 0.7%–9.9% [13], respectively. A Korean study also demonstrated a stepwise reduction in prevalence from 5.5% to 0.4% and 3.4% to 1.3% [40], following the application of differential diagnoses. Overall, the diagnostic method employed was the most significant factor influencing the estimated RLS prevalence. Taken together, these findings suggest that more consistent estimates of RLS prevalence in Asian populations can be achieved using reliable diagnostic tools capable of differentiating RLS from its mimics.

Sex differences in the prevalence and clinical features of RLS have been consistently observed in epidemiological studies (Supplementary Table 1 in the online-only Data Supplement) [2,41]. Females typically exhibit lower serum ferritin and hemoglobin levels than males, suggesting potential sex-related variations in body iron stores. This may contribute to the higher prevalence of RLS in females, which may be influenced by factors such as pregnancy, menstruation, and hormonal fluctuations. Additionally, a study examining sex differences in the clinical and polysomnographic features of RLS found that men tended to have more frequent periodic leg movements during sleep (PLMS), while females often experienced more severe manifestations of the disorder [42].

Familial aggregation, racial differences in prevalence, and findings from genome-wide association studies collectively suggest that genetic factors play a significant role in the development of RLS [10,41,43-45]. Notably, variants in genes, such as BTBD9 and MAP2K5/LBXCOR1, have been strongly associated with the disorder. However, these genetic variants are less common in Asian populations compared to populations of European descent [43-45]. In this regard, RLS may be more frequently observed in European descent than in those of Asian or African descent, suggesting that genetic factors may play a role in the epidemiology of this disorder [10,41].

PATHOPHYSIOLOGY OF RLS

Dopaminergic pathway

The dopaminergic pathophysiology of RLS is substantiated by the efficacy of dopaminergic treatment. In 1993, Kaplan et al. [46] conducted a double-blind, placebo-controlled trial comparing carbidopa/levodopa with the opioid propoxyphene, revealing significant reductions in PLMS and associated arousals per hour following carbidopa/levodopa administration compared to propoxyphene. Given that PLMS are observed in approximately 80% of people with RLS and show similar responses to dopaminergic medications, common mechanisms are suspected. Therefore, research indicates that dopaminergic treatment is effective in treating RLS and PLMS.

Subsequent studies have confirmed the therapeutic effects of dopamine in patients with RLS. A recent meta-analysis demonstrated reductions in International Restless Legs Scale (IRLS) scores as a measure of efficacy for pramipexole and ropinirole [47]. From 2006 to 2011, pramipexole exhibited an IRLS reduction of -6.73 (95% CI: -8.49 to -4.96) across seven studies, while ropinirole showed an improvement of -3.99 (95% CI: -5.97 to -2.01) from 2004 to 2006 across five studies. However, it is noteworthy that the updated guidelines from the American Academy of Sleep Medicine incorporate the most recent evidence regarding RLS and PLMS [48]. Importantly, dopamine agonists, which were previously considered first-line therapy, are now conditionally recommended because of their association with symptom augmentation over time.

To understand the dopamine abnormalities in RLS, it is essential to understand the dopamine pathways in the human body. Dopamine receptors, including D1R and D5R, function as G protein-coupled receptors. D1R and D5R, categorized as D1-like receptors, convey excitatory signals predominantly postsynaptically and exhibit pronociceptive characteristics. Conversely, D2R, D3R, and D4R, classified as D2-like receptors, transmit inhibitory signals, with distributions both pre-and postsynaptically and possess antinociceptive properties. These receptors mediate diverse physiological functions of dopamine, ranging from voluntary movement and rewards to hormonal regulation and hypertension.

Among the four major brain dopaminergic pathways, the mesolimbic, mesocortical, nigrostriatal, and tuberoinfundibular pathways and sensorimotor dysfunction in RLS appear to be associated with diminished functional connectivity within these pathways. Notably, dopamine receptors, which are neural substrates localized in the RLS, are prominently expressed in the basal ganglia and spinal cord.

A historically significant cell group involved in RLS dopamine pathology is the A11 system. Ondo et al. [49] demonstrated that lesioning the A11 hypothalamic site in mice led to locomotor activity similar to RLS symptoms, suggesting a hypodopaminergic state at the spinal cord level and failure of diencephalospinal modulation. However, Qu et al. [50] observed normal dopaminergic neurons in the A11 system in RLS autopsies, indicating that the A11 hypothesis may not be directly applicable to humans. Therefore, subsequent studies have investigated the pathophysiology related to dopamine in patients with RLS through metabolic changes, neuroimaging, and autopsy.

Regarding dopamine alterations in patients with RLS, initial studies utilized metabolite analyses of the cerebrospinal fluid (CSF). Previous studies have reported no significant changes in homovanillic acid (HVA), tetrahydrobiopterin, or 3-O-methyldopa (3-OMD) levels in patients with RLS. However, subsequent research has indicated nocturnal increases in 3-OMD in patients with RLS, along with elevated HVA, decreased CSF ferritin levels, and correlations with an increased PLMS index, suggesting that increased dopamine metabolite levels signify increased dopamine synthesis [51].

Nuclear imaging studies of dopamine receptors have yielded varying results. Studies such as those by Turjanski et al. [52] revealed decreased D2 receptor binding on 11C-raclopride positron emission tomography or single-photon emission computed tomography scans. In contrast, few studies reported increased D2 receptor binding, whereas other studies indicated no changes. Overall, a trend towards decreased D2 receptor binding was predominant in the summarized studies.

These dopamine metabolites and imaging findings were corroborated by autopsy studies. Connor et al. [53] observed significant decreases in D2 receptors in the putamen of subjects with RLS, correlating with disease severity along with increased levels of tyrosine hydroxylase and its phosphorylated (active) form.

In summary, these results collectively support the following dopamine hypothesis of RLS: 1) increased tyrosine hydroxylase activity leads to increased dopamine synthesis and decreased dopamine reuptake due to reduced transporter activity; 2) elevated intrasynaptic dopamine levels and increased dopamine metabolites; and 3) reduced D2 receptor sensitivity, affinity, and quantity, accompanied by diminished inhibitory feedback on tyrosine hydroxylase synthesis (Fig. 2).

Brain iron deficiency

Iron deficiency is a strong risk factor for RLS and several studies have demonstrated that iron supplementation improves the characteristic neurological symptoms of the disorder [1,54]. Notably, conditions such as anemia, chronic kidney disease, pregnancy, and female sex are associated with a higher prevalence of RLS, suggesting a direct link between iron deficiency and the pathophysiology of RLS. When iron deficiency occurs because of systemic causes such as anemia or chronic kidney disease, this form of RLS is classified as secondary RLS. Surprisingly, RLS can also develop in patients without clear systemic iron deficiency.

In cases where serum iron and ferritin levels are normal, low ferritin levels have been observed in the CSF, particularly in people with idiopathic RLS [7]. This suggests that the underlying cause of RLS in these individuals may be a specific localized iron deficiency in the central nervous system. Postmortem studies further support this hypothesis, revealing evidence of iron depletion in the brain, which is likely a contributing factor to RLS [8]. A subsequent postmortem study on people with RLS found hypomyelination in the brain, which is indicative of iron deficiency [55]. Additionally, iron transport proteins such as transferrin were found to be reduced in the blood–brain barrier of patients with RLS compared to healthy controls [8]. These findings highlight the importance of iron in maintaining normal brain function and suggest that disruptions in iron metabolism within the brain contribute to the neurological symptoms of RLS.

Several imaging studies have provided further insights into the role of iron in the brains of patients with RLS. Magnetic resonance imaging techniques, such as T2 relaxometry, phase imaging, and quantitative magnetic susceptibility (QSM), have been used to detect differences in brain iron levels. Specific brain regions such as the substantia nigra, thalamus, putamen, and pallidum exhibit reduced iron content in patients with RLS [56]. For example, a study using R2* imaging showed that the severity of RLS symptoms correlated with the degree of iron depletion in the substantia nigra, a critical brain region involved in dopamine metabolism [57].

Iron supplementation has been shown to improve RLS symptoms in patients with iron deficiency, with randomized controlled trials providing strong evidence for its efficacy [54]. The improvement in RLS severity after iron therapy further supports the role of iron deficiency in the pathogenesis of the disorder. Recent guidelines recommend iron treatment as a part of the management strategy for patients with RLS, especially those with low iron stores [58].

To assess the effects of iron therapy on brain iron levels, several studies have utilized advanced imaging techniques [59,60]. One such study involved observing changes in brain iron levels before and after intravenous ferric carboxymaltose iron treatment using QSM [60]. Results showed significant changes in brain iron concentrations over time in key regions such as the caudate nucleus, putamen, and pulvinar thalamus. Specifically, QSM values increased in the caudate nucleus over the first 6 weeks, whereas QSM values in the putamen decreased between 6 and 24 weeks. However, no significant changes were observed in other brain regions such as the substantia nigra, red nucleus, or cerebellum. Another recent study using transcranial sonography to measure echogenicity in the substantia nigra before and after ferric carboxymaltose administration found that patients with severe hypoechogenicity were more likely to respond to intravenous iron therapy, suggesting that substantia nigra echogenicity may serve as a predictor of treatment response [59]. However, the use of transcranial sonography exclusively to observe the substantia nigra highlights the need for future research comparing sonography and magnetic resonance imaging methods.

Brain-specific iron deficiency appears to be a key mechanism underlying the pathogenesis of RLS. This deficiency predominantly affects the brain regions involved in dopamine production, such as the substantia nigra and striatum, suggesting a link between iron metabolism and dopamine dysregulation in RLS. Findings from CSF analyses, postmortem studies, brain imaging, and iron treatment trials collectively indicated that iron deficiency, particularly within the central nervous system, is fundamental to the neurological symptoms observed in RLS (Fig. 2). Therefore, addressing iron deficiency through appropriate supplementation and treatment strategies remains critical for managing RLS.

In summary, both systemic and brain-specific iron deficiencies play crucial roles in the development and progression of RLS. Targeted iron therapy has been proven to be effective in reducing symptoms and improving the quality of life of affected individuals. Continued research on the specific mechanisms of iron metabolism in RLS is essential to further advance treatment options and understand the underlying pathophysiology of the disorder.

CONCLUSION

In conclusion, the prevalence of RLS varies significantly due to differences in diagnostic criteria and methodologies. More accurate diagnostic approaches yield lower prevalence rates, particularly in differentiating RLS from mimicking conditions. Genetic factors, sex differences, and regional variations in prevalence further highlight the complexity of understanding RLS in diverse populations. Both dopaminergic dysfunction and iron deficiency within the central nervous system play pivotal roles in the pathophysiology of RLS, as supported by therapeutic responses to dopamine agonists and iron supplementation. These findings underscore the importance of targeting dopaminergic pathways and addressing iron deficiency to alleviate symptoms in the management of RLS.

Supplementary Materials

The online-only Data Supplement is available with this article at https://doi.org/10.13078/jsm.250007.

Supplementary Table 1.

Prevalence of RLS from 30 studies in Asian populations

jsm-250007-supplementary-Table-1.pdf

Supplementary Figure 1.

Review flow diagram according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) reporting guidelines. etc. are studies (n<4) with specific populations, including migraine, cerebrovascular disease, spinal disorders, obstructive sleep apnea, epilepsy, diabetic peripheral neuropathy, patients attending neurology clinic, iron deficiency anemia, sickle cell disease, heart failure, irritable bowel syndrome, chronic obstructive pulmonary disease, coronary artery disease, chronic liver disease, ulcerative colitis, rheumatic disease, visitors of primary care centers, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, leprosy, psychiatric patients, attention-deficit/hyperactivity disorder, schizophrenia, somatoform pain disorder, opioid dependent patients, neuroleptic-induced restless legs syndrome, nurses, postmenopausal females, rotational shift workers, medical students, high altitude, and pandemic period.

jsm-250007-supplementary-Fig-1.pdf

Notes

Conflicts of Interest

The authors have no potential conflicts of interest to disclose.

Author Contributions

Conceptualization: Tae-Joon Kim, Min Hye Kim. Data curation: Tae-Joon Kim, Min Hye Kim. Supervision: Tae-Joon Kim. Writing—original draft: Tae-Joon Kim, Min Hye Kim. Writing—review & editing: Tae-Joon Kim, Min Hye Kim.

Funding Statement

None

Acknowledgments

None

Fig. 1.

Restless legs syndrome (RLS) prevalence reviewed in this paper according to diagnostic methods and populations in Asia.

Fig. 2.

Dopaminergic and iron mechanisms of restless legs syndrome with supporting evidence, associated brain substrates, and pathophysiology.

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