Restless legs syndrome (RLS) frequency, and its association with depression, anxiety, sleep disorders, and fatigue, has not been previously studied in Latin American patients with multiple sclerosis (MS). We aimed to assess RLS frequency in patients with MS living in Argentina and to examine potential associations with depression, anxiety, and sleep disorders.
A cross-sectional study (n = 427) was conducted using a self-administered questionnaire, including International RLS Study Group criteria, to compare RLS frequency in patients with MS versus controls. The Hospital Anxiety and Depression Scale and the Fatigue Severity Scale were administered to all participants. Insomnia, excessive daytime somnolence, and other risk factors in patients with MS with RLS were analyzed using logistic regression.
We included 189 patients with definite MS and 238 controls. The RLS frequency was 29.1% in patients with MS versus 13.0% in controls (odds ratio [OR] = 2.74, P = .00005). Moreover, clinically significant RLS (csRLS; ie, symptoms present ≥2 days per week) frequency was 19.4% in patients with MS versus 4.2% in controls (OR = 5.37, P < .00001). Longer MS duration and presence of anxiety, depression, insomnia, and smoking cigarettes were all significantly associated with RLS. Multivariate analysis showed that anxiety and fatigue were significantly associated with MS with RLS and MS with csRLS.
Both RLS and csRLS showed strong association with MS, supporting the need to screen for anxiety/depression, sleep quality, and fatigue in this patient population. We believe that identifying the presence and severity of these conditions would contribute to better MS management and treatment.
Restless legs syndrome (RLS), or Willis-Ekbom disease, is a common neurologic movement disorder (sometimes also called sleep-related sensory-motor disorder) characterized by a strong and distressing urge to move one's legs in an attempt to suppress abnormal or uncomfortable sensations brought on by rest.1 Symptoms are usually worse at night or in the evening than at any other time during the day, and they disappear or improve with movement.1,2 Two forms of RLS have been described: idiopathic and secondary.2 In 1995, the International Restless Legs Syndrome Study Group (IRLSSG)1 established RLS diagnostic criteria based on clinical characteristics. These were later validated in 20033 and subsequently revised in 20124 when a fifth criterion was added to improve specificity by excluding “mimics.” Multiple sclerosis (MS) is an autoimmune, inflammatory and neurodegenerative disease of the central nervous system with an estimated prevalence of 38.2 of 100,000 inhabitants in the Buenos Aires, Argentina, area.5–9 An increased association between MS and RLS has been described in several studies,2,10–12 although prevalence rates vary widely (13.3%–65.1%)2 between distinct populations.10–13 Although MS has been described as a form of secondary RLS,2 Gomez-Choco et al14 observed similar RLS prevalences between patients with MS and controls. Certain MS-related clinical conditions strongly associated with poorer quality of life (QOL), such as depression, anxiety, fatigue, and sleep disorders, are often overlooked and may go undiagnosed.2,15–19 A recently published study from Cyprus found that sleep quality, depression, and fatigue were significantly worse in patients with MS with RLS (MS/RLS+) compared with MS patients without RLS (MS/RLS−), affecting QOL.18 In addition, a strong correlation was also observed between patients with MS/RLS+ and impaired lower limb functional strength test performance.18
Given the wide variability in RLS prevalence reported between different MS patient cohorts,10–18 we aimed to assess RLS frequency in a sample of patients with MS from Argentina and to evaluate possible associations with anxiety, depression, sleep disorders, and fatigue, because these factors are likely associated with RLS in patients with MS in an independent manner.
Study Participants and Approval
Between October 1 and December 31, 2017, we conducted a cross-sectional study based on face-to-face interviews or online response to an anonymous self-administered RLS questionnaire, including IRLSSG diagnostic criteria, in a selected group of patients with MS and controls (n = 427). The questionnaire had been previously validated by Persi et al20 in an Argentine population. The study included 189 patients with definite MS and 238 age- and sex-matched controls. Relapsing-remitting (RRMS), primary progressive (PPMS), and secondary progressive (SPMS) MS were diagnosed according to the McDonald criteria as revised in 2010.5 The controls were recruited among health care personnel, spouses, friends, or companions of patients and were not affected by MS. Only patients with RRMS were receiving disease-modifying therapies. Restless legs syndrome mimics,2,21 including individuals with well-established neurologic disorders related to RLS (Parkinson disease, iron deficiency anemia, folate deficiency, chronic renal disease, gastrectomy, neuropathy, radiculopathy, among others), pregnancy, or a history of drug or alcohol abuse, as well as patients receiving levodopa, dopamine agonists, calcium antagonists, or other typical neuroleptics, were excluded.
Four hundred twenty-seven responders to the RLS questionnaire were identified.4,20 To assess RLS diagnosis and its association with fatigue, anxiety and depression, and sleep quality in patients with MS, both the Hospital Anxiety and Depression Scale (HADS)16,22 and the Fatigue Severity Scale (FSS),23 as well as insomnia and excessive daytime somnolence (EDS),24 were evaluated through personal interviews or by completing a Web-based survey, as proposed by the coordinating center (Hospital Alemán de Buenos Aires). Direct patient interviews and neurologic examinations were performed in 68 patients with MS (36%). The remaining 121 patients (64%) were recruited from the local Asociación de Lucha Contra la Esclerosis Múltiple database and responded to the online questionnaire. The controls were invited to respond based on their willingness to participate in the Web-based survey.
Age at MS onset, disease duration, age at time of interview, sex, clinical course of disease (RRMS, PPMS, or SPMS), and smoking habit were evaluated.
This study was approved by the Independent Ethics Committee of the Hospital Alemán. All the participants signed an informed consent form before data collection.
For RLS diagnosis, an anonymous RLS questionnaire consisting of three sections was completed as described previously by Persi et al.20 Part 1 corresponded to demographic data (age and sex); part 2 to RLS symptoms, evaluated using three structured questions comprising four essential IRLSSG criteria4 and based on a modified questionnaire suggested by Allen et al.3,4,21 Participants who responded “yes” to the first question and “yes” to the following two questions of this section were classified as being positive for RLS. Part 3, frequency of symptoms, was used to assess severity (ie, less than once a month, about once a month, 2–4 days a month, 2–3 days a week, 4–5 days a week, or daily [≥6 days a week]). Clinically significant RLS (csRLS) was defined by the presence of symptoms on at least 2 days per week, as recommended by the National Institutes of Health consensus conference on RLS diagnosis.1
Fatigue Severity Scale
Hospital Anxiety and Depression Scale
The HADS22 is a 14-item self-reported questionnaire with two subscales and is used as a brief instrument for detecting depression intensity (HADS-D) and anxiety (HADS-A) in inpatient populations. The HADS yields scores on a scale from 0 to 21, with totals of 8 or greater indicating probable anxiety or depression (HADS has been validated for scores ≥8 in patients with MS16). Scores of 11 or greater on either subscale are considered indicative of clinically significant anxiety or depression. The HADS has shown high sensitivity and specificity in patients with MS in clinical surveys and compared with other mood rating scales.16,22
The presence of sleep disorders such as insomnia and EDS was assessed according to the responses to the following two questions: “Did you experience insomnia more than two times per week during the last 6 months?” and “Did you experience EDS more than two times per week during the last 6 months?” Both questions were taken from the REMS (Restless legs syndrome in Multiple Sclerosis) study (Manconi et al24).
Results are presented as proportions, means ± SD, and median values. Categorical data were assessed using χ2 or Fisher exact tests. The Kolmogorov-Smirnov test was used to evaluate the normal distribution of variables (P < .001), and t or Mann-Whitney U tests were performed to compare continuous data between groups, as appropriate. We applied multivariate logistic regression analysis to assess the impact of different risk factors (age and sex, disease duration, anxiety, depression, fatigue, insomnia, EDS, and current treatment) potentially associated with RLS in MS. Variables included for multivariate regression were selected from univariate analysis results with P < .05. Based on the estimated prevalence of RLS and MS in Argentina, the total study sample size needed for statistical power of 80% and a 95% CI was calculated to be at least 170 individuals for both study groups (patients with MS and controls). A P < .05 was considered statistically significant. Data analysis was performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp, Armonk, NY).
A total of 427 individuals were included: 189 patients with definite MS and 238 controls. Of the 189 patients with MS, 171 (90.5%) had RRMS, 11 (5.8%) had PPMS, and 7 (3.7%) had SPMS. No statistically significant differences in RLS frequency were observed between groups (RRMS: 29.2%, PPMS: 27.2%, SPMS: 28.5%), suggesting that patients with MS receiving disease-modifying therapies do not present less RLS.
Comparison Between Patients with MS and Controls
There were no statistically significant differences in age or sex between groups at the time of interview. As shown in Table 1, 105 patients with MS (55.5%) and 47 controls (19.7%) answered yes to the first question on the RLS questionnaire, namely, “Do you have unpleasant sensations in your legs combined with an urge or need to move your legs?” All three questions were answered positively by 55 patients with MS (29.1%) and 31 controls (13.0%) fulfilling the RLS criteria. Therefore, RLS was more frequently observed in patients with MS than in controls (odds ratio [OR] = 2.74, P = .00005). Moreover, 36 of 189 patients with MS (19.4%) and 10 of 238 controls (4.2%) fulfilled the csRLS criteria according to National Institutes of Health consensus such that csRLS was also more frequently observed in patients with MS than in controls (OR = 5.37, P < .00001). The HADS-D scores (≥8) were significantly higher in patients with MS compared with controls (25.4% vs 13.8%, P = .002). In line with this finding, a trend toward higher HADS-A scores (≥8) was observed in patients with MS (49.7% vs 40.7%, P = .07). However, both mean and median HADS-A scores were significantly associated with MS (P = .041 and P = .035, respectively). Fatigue was also significantly associated with patients with MS compared with controls (44.9% vs 8.8%, P < .00001). For sleep disorders, a trend toward higher frequency of EDS and insomnia was found in patients with MS compared with controls (P = .05 and P = .07, respectively). We found stronger associations between active treatment for both insomnia and fatigue (P < .00001), as well as for depression (P = .09), in patients with MS compared with controls. Comparisons of results for both groups are summarized in Table 1.
Comparison Between MS/RLS+ and MS/RLS− Patients
Longer MS duration (P = .04), cigarette smoking (P = .03), insomnia (P = .03), anxiety (P = .04), and depression (P = .03) were statistically significantly associated with the MS/RLS+ group (n = 55) compared with the MS/RLS− group (n = 134). In addition, we observed an association toward greater anxiety in the MS/RLS+ group after applying the logistic regression model (OR = 1.18, P = .06). Data comparisons between MS/RLS+ patients and the MS/RLS− group are summarized in Table 2.
Comparison Between MS/RLS+ Patients and Controls with RLS
The MS/RLS+ group (n = 55) was found to be significantly older (MS: 42.2 years vs controls with RLS: 34.3 years, P = .006) and have greater fatigue levels (P = .004) compared with the controls with RLS (n = 31). A trend toward higher median HADS-D scores (P = .056) was also observed in patients with MS. Older age (OR = 1.06, 95% CI = 1.01–1.10, P = .006) and fatigue (OR = 1.05, 95% CI = 1.01–1.10, P = .009) were both found to be independently associated with MS/RLS+ after logistic regression analysis. Data comparisons between MS/RLS+ patients and controls with RLS are summarized in Table 3.
Comparison Between MS/csRLS+, MS/csRLS−, and Controls with csRLS
Older age (MS/csRLS+: mean 45.47 years vs MS/csRLS−: 38.47 years, P = .009) and anxiety (P = .02) were significantly associated with the MS/csRLS+ group (n = 36) compared with the MS/csRLS− group (n = 153). In addition, a trend was observed for longer MS duration (P = .051) and for presence of ESD (P = .08) and insomnia (P = .09) in the MS/csRLS+ group. We compared the MS/csRLS+ group (n = 36) with controls with csRLS (n = 10) and observed a trend toward more ESD (P = .08) and insomnia (P = .05) in the MS/csRLS+ group. Applying the logistic regression model, anxiety (OR = 1.13, 95% CI = 1.02–1.26, P = .016) was found to be independently associated with MS/RLS+. Results between the MS/csRLS+ group and the MS/csRLS− group are compared in Table 4.
Few studies have reported on the frequency of RLS in Latin American patients with MS.25–27 To our knowledge, this is the first study evaluating RLS frequency in patients with MS from Argentina. We were also interested in exploring the impact of common symptoms often overlooked or undiagnosed, such as sleep disorders, anxiety, depression, and fatigue, in patients with MS with RLS.
In Asia and Europe, RLS prevalence in the general population has been estimated to be 0.1% to 15%.1,2,9–13 In Argentina, one study reported the RLS prevalence in the general population to be 20.2% and for csRLS to be 10.2%.20 In the present cross-sectional study, we observed lower rates for RLS (13.2%) and csRLS (4.2%) in the general population (controls), in line with some of the reports from Asia and Europe.2,28–30 One explanation for the higher prevalence of RLS in the general population of Argentina could be greater genetic admixture of the main source of ancestry, which is predominantly European.20 Another may be the result of varying settings and assessment methods used in the different studies. However, similar prevalence rates have been reported in North America (24%) using self-reported questionnaires in a primary care population.31 Other factors, such as environment, culture, and lifestyle, could also modify RLS prevalence, even in individuals of similar ethnic and racial background.
Consistent with other studies,24–30 we observed that RLS and csRLS were 2.7 and 5.3 times more frequent in patients with MS than in controls, respectively. A recent meta-analysis reported that the RLS prevalence in patients with MS ranged from 12.12% to 57.50%.25 Likewise, in an Iranian cohort it was reported to be 65.1%.32 Another cross-sectional systematic review and meta-analysis from Brazil found that MS with RLS was 4.33 times more frequent compared with controls.26 The REMS study24 found that 19% of patients with MS had RLS symptoms at least twice per week compared with 4.2% of controls, whereas in the present study, RLS frequency was 10.2%. In addition, they observed that patients with MS had higher symptom frequency (severity) than controls (17.5% vs 14%, P = .003)24 and that RLS in MS was 5.4 times more frequent than in controls (OR = 5.4, 95% CI = 3.56–8.26).24 Gomez-Choco et al,14 on the other hand, found a similar prevalence of RLS in both groups (MS: 13.3% vs controls: 9.3%, P 3 .05).
Neurologic disorders such as Parkinson disease, spinal cord injury, and MS have all been reported to cause secondary RLS.1–4,28 The pathophysiology remains unclear,1,2 but one possible hypothesis is that dopaminergic pathways projecting to the spinal cord,30 and responsible for sensory input suppression and motor excitability, undergo damage as a result of a spinal cord lesion. Clemens et al33 reported that area A11 of the hypothalamus (the major source of dopamine for the spinal cord) may be connected to the spinal cord, and, therefore, focal lesions at this level could cause destruction of descending dopaminergic pathways, explaining RLS symptom emergence. One recent study found that spinal cord lesion presence increased risk of RLS in patients with MS.34 Manconi et al35 and Bruno et al36 reported similar findings. However, an association between RLS and basal ganglia lesions has not been observed in MS/RLS+ patients.35 Peripheral hypoxia has also been reported as a trigger for RLS symptoms.37 Fatigue has been observed in up to 90% of patients with MS2 and was associated with depression, anxiety, and sleep disorders exerting a negative effect on QOL.15,17–19 In the present cohort, fatigue was independently associated with MS/RLS+. In addition, Moreira et al27 and Giannaki et al18 found that MS/RLS+ was associated with poorer sleep quality and fatigue; and insomnia and RLS have been identified as independent risk factors for fatigue in patients with MS.38,39
Anxiety and depression are strongly associated with MS, ultimately undermining QOL.17–19 In the present study, although patients with MS were receiving more hypnotics (16.1% vs 5.04%, P < .0001), antidepressants (10.05% vs 5.4%, P = .09), and stimulants such as amantadine and modafinil (8.4% vs 0.4%, P < .0001) than controls, anxiety and depression remained significantly associated with MS even in treated patients, ie, independently associated with MS/csRLS+.
It is well-known that sleep disorders such as obstructive sleep apnea, RLS, insomnia, and EDS, in particular, are extremely common in patients with MS.28 The REMS study24 reported that sleep disorders such as EDS (58.7% vs 49.1%, P = .05) and insomnia (42.3% vs 33.6%, P = .07) were associated with MS/RLS+ compared with controls. In addition, one recent study reported that patients with MS/RLS+ had significantly poorer sleep quality than those without RLS.18 Herein, we observed an association between MS/RLS+ and insomnia, confirming previous findings.18,24
We acknowledge that this study has several limitations. First, self-reported questionnaires (findings of which have not been confirmed by neurologic evaluation) tend to overestimate RLS frequency, as recognized by Deriu et al.40 However, we applied methods similar to those previously used in several epidemiologic studies (Table 5).2,13,14,26–29,34,35,38,41 Furthermore, we found that csRLS frequency was greater in patients with MS than in controls, potentially decreasing the risk of false-positive diagnoses. Moreover, although the 2003 RLS criteria remain the fundamental basis for diagnosing RLS, as previously validated in an Argentine population (2009), the new 2012 RLS revised criteria were not included in this study. However, patients with well-established RLS mimics were excluded. Second, mood and sleep disorders were not confirmed by direct psychiatric or neurologic evaluation. Third, we did not include disability measures of functional systems; in particular, we did not use the Expanded Disability Status Scale. Fourth, spine and brain magnetic resonance images were not evaluated in this cohort.
In conclusion, this study indicated that RLS was strongly associated in patients with MS compared with controls, supporting the hypothesis that MS is a cause of secondary RLS.2 Likewise, patients with MS who reported insomnia, anxiety and/or depression, or fatigue presented higher rates of RLS, in line with results reported from North America, Europe, and Asia. These findings reinforce the negative impact of RLS on mood disorders, fatigue, and sleep quality. Early identification of MS-related factors associated with RLS is, therefore, very important. Screening for, monitoring for, and treating MS-related factors may help improve QOL in patients with MS. Future prospective studies with larger numbers of patients will help elucidate whether RLS treatment improves sleep quality, mood disorders, and fatigue.
Restless legs syndrome (RLS) was significantly higher in patients with MS than in controls (odds ratio [OR] = 2.74, P < .0001).
Clinically significant RLS (symptoms present ≥2 days per week) was significantly higher in patients with MS than in controls (OR = 5.37, P < .0001).
Anxiety, depression, and insomnia were significantly associated with MS with RLS.
Anxiety and fatigue were independently significantly associated with MS with RLS/clinically significant RLS.
The authors thank the participants for responding to the surveys and Asociación de Lucha Contra la Esclerosis Múltiple for promoting the survey.
The authors declare no conflicts of interest.
From the Neuroimmunology Unit, Department of Neuroscience, Hospital Alemán, Buenos Aires, Argentina (ECC, PAL); and Neuroimmunology Unit, Neurology Department, Hospital de Clinicas “José de San Martin,” Buenos Aires University, Buenos Aires, Argentina (DN, MEB, AMF, VT).