Disease duration and anxiety as determinants of clinical burden in primary restless legs syndrome

Authors

Abstract

AimPrimary Restless Legs Syndrome (RLS) is a chronic sensorimotor disorder with considerable variability in symptom severity, functional impact, and psychological burden. The contribution of disease duration to this heterogeneity remains incompletely understood. To evaluate the relationship between disease duration, symptom severity, and anxiety levels in patients with primary RLS, and to explore the clinical relevance of routinely assessed laboratory parameters.
MethodsIn this single-center observational case–control study, 51 patients with primary RLS and 52 age- and sex-matched healthy controls were included. RLS severity was assessed using the International Restless Legs Syndrome Study Group Rating Scale (IRLSSG-RS), and anxiety symptoms were evaluated with the Beck Anxiety Inventory (BAI). Routine laboratory parameters obtained during standard clinical evaluation were analyzed descriptively. Nonparametric statistical tests and Spearman correlation analyses were performed.
ResultsAnxiety scores increased significantly with both symptom severity and disease duration, with the highest levels observed in patients with a disease duration longer than five years. Although some laboratory parameters differed statistically between patients and controls, all values remained within reference ranges and showed no clinically meaningful association with disease burden.
ConclusionClinical heterogeneity in primary RLS appears to be influenced mainly by the cumulative psychological burden of chronic symptoms rather than by biochemical abnormalities. Disease duration is an important determinant of anxiety, highlighting the need to address psychological well-being in the long-term management of patients with RLS.

Keywords

Introduction

Primary Restless Legs Syndrome (RLS) is characterized by marked clinical variability in routine neurological practice. Patients fulfilling identical diagnostic criteria may differ substantially in symptom severity, functional impairment, and overall disease burden.¹ This heterogeneity poses a relevant challenge for clinicians involved in the long-term management of RLS.^2,3
Current models of RLS predominantly focus on dopaminergic dysfunction and alterations in iron metabolism. While these mechanisms are fundamental to disease expression, they do not fully explain the wide range of symptom severity and patient-reported burden observed in clinical practice. Consequently, increasing attention has been directed toward clinical and psychological factors that may modulate disease experience and contribute to phenotypic variability in RLS.^4,5
Anxiety symptoms are commonly reported in patients with RLS and have been linked to greater subjective symptom burden, reduced quality of life, and increased distress.⁶ However, the relationship between anxiety and core clinical features of RLS—particularly disease severity and disease duration—remains incompletely understood, especially in studies focusing exclusively on primary RLS. In addition, psychological features are often evaluated independently, without consideration of routinely assessed clinical parameters available in everyday neurological practice.⁷
Therefore, the present study aimed to evaluate the association between disease duration, symptom severity, and anxiety levels in patients with primary RLS, while exploring the clinical relevance of routinely assessed laboratory findings as secondary observations.

Materials and Methods

ParticipantsPatients aged 18–80 years who fulfilled the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria for RLS were consecutively included. All patients had a normal neurological examination at the time of assessment, with no clinical evidence of focal or peripheral nervous system involvement.¹
To ensure inclusion of primary RLS, medical records were systematically reviewed. Individuals with conditions associated with secondary RLS—including chronic kidney disease, hematological disorders, metabolic or endocrine diseases, peripheral neuropathy, systemic inflammatory or autoimmune disorders, or other neurological conditions—were excluded. Patients with diabetes mellitus or multiple sclerosis were not included. Stable arterial hypertension under regular pharmacological treatment was permitted.
The control group consisted of age- and sex-matched healthy individuals without known chronic neurological or systemic diseases, recruited from hospital staff and relatives of patients.
Clinical AssessmentDemographic data, including age, sex, body mass index (BMI), smoking status, and alcohol consumption, were recorded. In the RLS group, disease duration, family history of RLS, and current pharmacological treatment were documented.
RLS symptom severity was assessed prospectively at study enrollment using the International Restless Legs Syndrome Study Group Rating Scale (IRLSSG-RS). Anxiety symptoms were evaluated prospectively during face-to-face outpatient visits using the Beck Anxiety Inventory (BAI). All clinical assessments were performed at the time of evaluation; no retrospective symptom assessments were conducted.
Laboratory EvaluationLaboratory data were obtained retrospectively through a structured review of medical records. All laboratory parameters had been measured previously as part of routine clinical evaluation and were not specifically requested for this study. For patients with multiple available laboratory results, the values closest to the date of clinical assessment were used for analysis.
Routine laboratory assessments included complete blood count, serum ferritin, vitamin B12, folate, renal and thyroid function tests, electrolytes, and liver enzymes. These parameters were used primarily to exclude secondary causes of RLS and to describe accompanying systemic features, rather than to investigate causal biochemical mechanisms.
Ethical ApprovalThe study was approved by the Ethics Committee of the University of Health Sciences, Kanuni Training and Research Hospital Clinical Research Ethics Committee (Date: 17.01.2022, Decision No: 2022/10).
Statistical AnalysisStatistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Data distribution was assessed using the Kolmogorov–Smirnov test. As most variables were non-normally distributed, nonparametric statistical methods were applied.
Continuous variables are presented as mean ± standard deviation or median (interquartile range), as appropriate. Categorical variables are expressed as frequencies and percentages. Group comparisons were conducted using the Mann–Whitney U test for two independent groups and the Kruskal–Wallis test for multiple groups. Associations between continuous variables were evaluated using Spearman’s rank correlation coefficient. All analyses were exploratory in nature, and a two-tailed p-value<0.05 was considered statistically significant without adjustment for multiple comparisons.
Reporting GuidelinesThis observational study was designed and reported in accordance with the STROBE guidelines.

Results

Participant CharacteristicsThe study included 51 patients with primary Restless Legs Syndrome (RLS) and 52 age- and sex-matched healthy controls. There were no significant differences between the groups with respect to age, sex distribution, or body mass index. Key demographic and clinical characteristics are summarized in Supplementary Table 1.
Among patients with RLS, 35.3% reported a positive family history of the disorder, and 54.9% were receiving pharmacological treatment at the time of evaluation, most commonly dopamine agonists. Detailed clinical characteristics, including disease duration and treatment profiles, are provided in Supplementary Table 1.
Laboratory FindingsSelected routine laboratory parameters comparing patients with RLS and healthy controls are presented in Supplementary Table 2. Patients with RLS showed mildly higher serum vitamin B12 levels and higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with controls; however, all values remained within laboratory reference ranges.
Serum ferritin levels did not differ significantly between groups. Other routine laboratory parameters assessed primarily to exclude secondary causes of RLS showed no clinically meaningful differences between patients and controls. The complete laboratory panel is provided in Supplementary Table 2.
RLS Severity and Clinical CorrelatesBased on IRLSSG-RS scores, patients were classified as having moderate (n = 13), severe (n = 28), or very severe RLS (n = 10); no patients met criteria for mild disease.
Selected laboratory parameters and anxiety scores across RLS severity stages are summarized in Supplementary Table 3. Although serum ferritin levels differed across severity categories, no consistent linear association with overall RLS severity was observed. ALT and AST levels showed modest increases with increasing disease severity, while all values remained within normal limits.
In contrast, anxiety scores increased progressively across RLS severity stages. Patients with very severe RLS had significantly higher Beck Anxiety Inventory scores compared with those with moderate or severe disease. Detailed laboratory parameters according to RLS severity are presented in Supplementary Table 3.
Disease Duration, Disease Severity, and AnxietyThe relationships between disease severity, disease duration, and anxiety scores are summarized in Supplementary Table 3. The distribution of IRLSSG disease severity stages did not differ significantly across disease duration categories. Mean disease severity scores showed a non-significant trend toward higher values in patients with longer disease duration.
In contrast, anxiety scores increased significantly with both disease severity and disease duration. Patients with a disease duration longer than five years exhibited significantly higher Beck Anxiety Inventory scores compared with those with shorter disease durations.
No significant associations were identified between disease duration and routine laboratory parameters. Detailed laboratory comparisons according to disease severity and disease duration are provided in Supplementary Table 3 and Table 4.

Discussion

This study demonstrates that clinical heterogeneity in primary Restless Legs Syndrome (RLS) is more closely related to the cumulative psychological burden of chronic symptoms than to proportional increases in objective disease severity. While longer disease duration was associated with significantly higher anxiety levels, it was not accompanied by a significant shift in IRLSSG disease severity stages. These findings highlight an important dissociation between objective symptom severity and perceived disease burden in primary RLS.
Peripheral iron metabolism has long been a central focus in RLS research because of its role in dopaminergic dysfunction.^8,9 In the present cohort, serum ferritin levels did not differ significantly between patients and controls and showed no consistent linear association with overall disease severity, despite differences observed across severity categories. This finding supports previous evidence suggesting that peripheral iron indices may not reliably reflect central nervous system iron status in primary RLS. Accordingly, routine laboratory measures alone appear insufficient to explain interindividual differences in clinical burden, and symptom-based assessments may be more informative in clinical practice.¹⁰
A key observation of this study is the absence of a significant association between disease duration and IRLSSG severity stages. This suggests that symptom chronicity in primary RLS does not necessarily translate into progressive objective worsening. Rather than following a linear course of deterioration, disease severity may fluctuate over time, with long-term impact driven by factors beyond motor symptom intensity alone. This finding challenges the assumption that longer disease duration inevitably reflects more severe disease and underscores the need for individualized clinical assessment.
In contrast, anxiety emerged as the most prominent clinical correlate. Anxiety scores increased progressively with longer disease duration and higher symptom severity, independent of routine laboratory parameters. Importantly, patients with disease duration longer than five years exhibited significantly higher anxiety levels despite relatively stable objective severity. This pattern highlights the dissociation between measurable disease severity and subjective disease burden and suggests that psychological distress may accumulate over time as a consequence of persistent sensory discomfort, sleep disruption, and uncertainty associated with chronic symptoms.^11,12
Mild elevations in AST and ALT levels were observed in patients with RLS and showed weak associations with disease severity; however, all values remained within normal laboratory ranges. In the absence of clinically relevant hepatic abnormalities, these findings are unlikely to represent meaningful liver pathology. Instead, they may reflect nonspecific systemic stress, interindividual metabolic variability, or physiological responses related to chronic neurological discomfort.^11,12 Taken together, these observations further indicate that routine laboratory parameters have limited utility in explaining clinical heterogeneity in primary RLS.
The exclusion of secondary causes of RLS and known psychiatric disorders strengthens the interpretation that anxiety in this cohort is closely linked to the long-term burden of primary RLS itself rather than to comorbid medical or psychiatric conditions. The absence of patients with mild RLS likely reflects referral patterns to a tertiary neurology outpatient clinic, where individuals with more severe or persistent symptoms are more likely to seek specialized care. While this may limit generalizability, it also emphasizes the clinical relevance of psychological distress in patients requiring long-term follow-up. Additionally, treatment status may influence both symptom perception and anxiety levels, which should be taken into account when interpreting the findings.
Overall, these findings indicate that clinical heterogeneity in primary RLS is driven predominantly by the interaction between prolonged symptom burden and psychological stress rather than by subtle biochemical alterations detectable through routine laboratory testing. This multifactorial perspective underscores the importance of comprehensive management strategies that address not only sensorimotor symptoms but also the psychological consequences of long-standing disease. Integrating mental health assessment into routine RLS care may therefore be essential for improving long-term patient outcomes. Given the cross-sectional design of this study, the observed relationships should be interpreted as associations rather than causal relationships. Longitudinal studies are needed to clarify the directionality of these findings.

Limitations

This study has several limitations. The single-center design and modest sample size may limit generalizability. Laboratory parameters were obtained retrospectively from routine clinical records, and all observed variations remained within reference ranges. Anxiety was assessed using a self-report scale, while other psychological factors were not evaluated. Recruitment from a tertiary care outpatient clinic may have introduced referral bias, and the cross-sectional design precludes causal inference.

Conclusion

This study suggests that clinical heterogeneity in primary Restless Legs Syndrome is largely influenced by the combined effects of chronic disease burden and psychological stress rather than by subtle biochemical alterations. Disease duration is closely associated with increased anxiety, reflecting the cumulative psychological impact of long-standing symptoms. Routine laboratory variations appear insufficient to explain symptom variability. These findings underscore the importance of addressing both sensorimotor symptoms and psychological consequences in the comprehensive management of patients with primary RLS.

Declarations

Abbreviations

ALT: alanine aminotransferase
AST: aspartate aminotransferase
BAI: beck anxiety inventory
BMI: body mass index
IRLSSG: International Restless Legs Syndrome Study Group
IRLSSG-RS: International Restless Legs Syndrome Study Group Rating Scale
RLS: restless legs syndrome
SPSS: statistical package for the social sciences
STROBE: strengthening the reporting of observational studies in epidemiology

References

1. Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med. 2014;15(8):860-873. doi:10.1016/j.sleep.2014.03.025
   Article PubMed Google Scholar
2. Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: a systematic review and new concept. Neurology. 2016;86(14):1336-1343. doi:10.1212/wnl.0000000000002542
   Article PubMed Google Scholar
3. Silber MH, Buchfuhrer MJ, Earley CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc. 2021;96(7):1921-1937. doi:10.1016/j.mayocp.2020.12.026
   Article PubMed Google Scholar
4. Nanayakkara B, Di Michiel J, Yee BJ. Restless legs syndrome. Aust J Gen Pract. 2023;52(9):615-621. doi:10.31128/ajgp-02-23-6722
   Article PubMed Google Scholar
5. Xu Y, Wen H, Li J, Yang J, Luo K, Chang L. The relationship between sleep disorders, anxiety, depression, and cognitive function with restless legs syndrome in the elderly. Sleep Breath. 2022;26(3):1309-1318. doi:10.1007/s11325-021-02477-y
   Article PubMed Google Scholar
6. Ammar LA, Antoun C, Nassar JE, et al. Prevalence and correlates of restless leg syndrome in psychiatric outpatients in Lebanon. Sci Rep. 2025;15(1):29128. doi:10.1038/s41598-025-15036-2
   Article PubMed Google Scholar
7. Tully PJ, Kurth T, Elbaz A, Tzourio C. Convergence of psychiatric symptoms and restless legs syndrome: a cross-sectional study in an elderly French population. J Psychosom Res. 2020;128:109884. doi:10.1016/j.jpsychores.2019.109884
   Article PubMed Google Scholar
8. Beliveau V, Stefani A, Birkl C, et al. Revisiting brain iron deficiency in restless legs syndrome using magnetic resonance imaging. Neuroimage Clin. 2022;34:103024. doi:10.1016/j.nicl.2022.103024
   Article PubMed Google Scholar
9. Margariti PN, Astrakas LG, Tsouli SG, Hadjigeorgiou GM, Konitsiotis S, Argyropoulou MI. Investigation of unmedicated early onset restless legs syndrome by voxel-based morphometry, T2 relaxometry, and functional MR imaging during the night-time hours. AJNR Am J Neuroradiol. 2012;33(4):667-672. doi:10.3174/ajnr.a2829
   Article PubMed Google Scholar
10. Castillo-Álvarez F, Marzo-Sola ME. Restless legs syndrome. Pathophysiology, diagnosis and treatment. Med Clin (Barc). 2025;164(2):84-90.
    PubMed Google Scholar
11. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172(3):367-379. doi:10.1503/cmaj.1040752
    Article PubMed Google Scholar
12. Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: a review. EXCLI J. 2017;16:1057-1072.
    PubMed Google Scholar

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About This Article

Received:

February 6, 2026

Accepted:

May 2, 2026

Published Online:

May 2, 2026