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Journal of Back and Musculoskeletal Rehabilitation 27 (2014) 537–544 DOI 10.3233/BMR-140478 IOS Press
Evaluation of restless legs syndrome in fibromyalgia syndrome: An analysis of quality of sleep and life Gul Mete Civeleka,∗, Pinar Oztop Ciftkayab and Metin Karatasb a
Dıskapı Yıldırım Beyazıt Education and Research Hospital, Physical Medicine and Rehabilitation Clinic, Ankara, Turkey b Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Baskent University, Istanbul, Turkey
Abstract. BACKGROUND AND OBJECTIVE: The aim of this study is to find prevalence and severity of restless legs syndrome (RLS) in patients with fibromyalgia syndrome (FMS) and detect effect of FMS and RLS coexistance on quality of sleep and life. METHODS: In this study, presence and severity of RLS were detected in patients with FMS and Pitsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Fibromyalgia Impact Questionnaire (FIQ) scores of all patients were measured. RESULTS: One hundred and fifteen female patients with median age 49 (39.0–57.0) [median (25–75% interquartile range)] were included in the study. In 42.6% of patients RLS coexisting with FMS was found. RLS was classified as moderate in 42.9% of patients and as severe in 49.0% of patients. In patients with FMS ans RLS sleep quality, daytime sleepiness and quality of life were more severely impaired (PSQI scores were 9.0 ± 4.4 vs 7.8 ± 4.3, p = 0.003; ESS scores were 5.0(3.0–7.5) vs 3.0(1.0–4.3), p = 0.036 and FIQ scores were 68.1 ± 9.8 vs 59.4 ± 16.9, p = 0.027) compared to patients with only FMS. Prevalence of RLS was found higher in FMS than normal population and quality of sleep and quality of life were worse in patients with RLS. CONCLUSIONS: Presence of RLS should be investigated in every patient with FMS and treatment plans should also cover RLS in case of coexistance with FMS. Prospective cohort studies are needed for better explanation of FMS and RLS coexistance. Keywords: Fibromyalgia syndrome, restless legs syndrome, quality of sleep, quality of life
1. Introduction Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by widespread pain lasting three months or more and pain on palpation of at least 11 of 18 tender points. At least 2% of adult population have been reported to have FMS. Although chronic diffuse pain is the main clinical property, symptoms like sleep disturbances, fatigue, irritable bowel symptoms, headache, emotional disturbances, urinary tract ∗ Corresponding author: Gul Mete Civelek, Dıskapı Yıldırım Beyazıt Education and Research Hospital, Physical Medicine and Rehabilitation Clinic, Irfan Bastug Caddesi, Dıskapı, Altındag, Ankara, Turkey. Tel.: +90 312 5962993; Fax: +90 312 3186690; E-mail: [email protected].
symptoms may accompany FMS [1]. Wide spectrum of clinical symptoms of FMS makes it more difficult to treat and is also associated with increased burden for both the patient and the population. A negative impact of FMS on work productivity has been reported in the literature in different studies [2,3]. Hoffman et al. reported that people with FMS had an overall health status burden that was greater in magnitude compared to people with other specific pain conditions that are widely accepted as impairing [4]. Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an urge to move the legs associated with unpleasant leg sensation [5]. These symptoms are induced or exacerbated with rest, relieved on activity, worsen in the evening and night. The prevalence of RLS is between 2–15% in adult population.
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RLS is associated with sleep disorders [6]. In treatment, the first-line drugs are dopaminergic agents. Although RLS is a common and treatable disorder it is usually underdiagnosed. Both FMS and RLS are prevalent disorders, most commonly seen in women, associated with sleep disturbances and lowered quality of life. Prevalence of RLS in FMS was found to be high, varying from 20% to 65.7% in previous studies [7–9]. Common neurotransmitter or neuroendocrine dysfunctions are thought to play role in etiology of both diseases [9]. RLS may be increasing severity of FMS and treating RLS together with FMS in case of coexistance may decrease disease burden resulting in higher quality of life outcomes. To our knowledge, there are no studies in literature investigating effect of RLS on FMS symptoms and co-treatment of these disorders. The aim of this study was to find prevalence and severity of RLS in FMS and investigate the effect of this coexistance on sleep disturbances, daytime sleepiness and quality of life by using standardized and objective measures. We also discussed common disease mechanisms and their clinical significance for daily practice.
2. Methods Subjects were 115 consecutive female patients diagnosed with fibromyalgia attending to Baskent University Physical Medicine and Rehabilitation clinic between 1 October 2009 and 1 March 2010. The patients were required (1) to be > 18 years of age; (2) not to be pregnant; (3) not to have end stage renal failure; (4) not to have Parkinson disease; (5) not to be diagnosed with polyneuropathy before. General physical examinations were made and serum levels of hemoglobin, ferritin, creatinine and TSH were measured in all patients. Diagnosis of FMS was made according to the 1990 American Collage of Rheumatology criteria by confirming the presence of chronic widespread pain and 11 of tender points on examination [10]. Presence of symptoms accompanying FMS (self-reported sleep disturbance, fatigue, irritable bowel symptoms, emotional disturbances, urinary tract symptoms) were also evaluated. RLS was diagnosed according to standardized criteria developed in 1995 by the International Restless Legs Syndrome Study Group (IRLSSG) [11]. These criteria have been refined and reviewed during a Na-
tional Institutes of Health workshop in 2002 [12]. The essential criterias for the syndrome are: (1) an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; (2) the urge to move or unpleasant sensations beginning or worsening during periods of rest or inactivity such as lying or sitting; (3) the urge to move or unpleasant sensations partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; (4) the urge to move or unpleasant sensations which are worse in the evening or night than during the day or only occur in the evening or night. Those who meet all 4 criteria are diagnosed as suffering from RLS. RLS severity was assessed using the validated International RLS Severity Scale. The self-rating questionnaire includes ten items (responses ranging from 0 to 4) evaluating the symptom severity and the impact of symptoms on everyday life activities. A total score of 1 to 10 points indicates mild, 11 to 20 moderate, 21 to 30 severe, and 31 to 40 very severe RLS symptoms [13]. Sleep quality and day-time sleepiness were assessed using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). PSQI score was used to determine sleep disturbance. The PSQI score is a standardized rating scale, which has been validated as differentiating from ‘poor’ to ‘good’ sleep [14]. It evaluates sleep disturbances in seven dimensions: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication and daytime dysfunction. Each dimension is rated on a 4-point scale (0 to 3, with 3 indicating more profound effect), which is summed together to yield a global score. A global score > 5 indicates “poor sleep”. The ESS is a commonly used tool for evaluating recent excessive daytime somnolence. This scale consists of 8 questions concerning situations associated with daily activities. The subjects are asked to evaluate the likelihood of dozing off or falling asleep in these situations. The scores are as follows: 0 = no chance of dozing, 1 = slight chance of dozing, 2 = moderate chance of dozing, 3 = high chance of dozing. The maximum score is 24, and disturbing sleepiness is indicated by scores of > 10 [15]. Turkish validation and reliability studies of both PSQI and ESS have been made [16,17]. Quality of life was evaluated with FIQ (Fibromyalgia Impact Questionnaire). The FIQ measures FMS subject’s status, progress, and outcomes in 10 areas: physical impairment, feeling good, work missed, do-
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Table 1 General characteristics of patients including age, symptom duration, accompanying symptoms, drug usage, quality of sleep and life Age (Years)∗ Symptom duration (years)∗ Accompanying symptoms (%, n) Self reported sleep disturbance Fatigue Irritable bowel symptoms Headache Emotional disturbances Urinary tract symptoms Patients using drug for FMS (%, n) Drugs used for FMS (%, n) Analgesic and antiinflammatory drugs SSRI Amitriptiline Alprazolam Sleep and QoL (%, n) FIQ score∗ PSQI score∗ ESS score∗ PSQI 5 (impaired) (%, n) ESS 11 (impaired) (%, n) Laboratory evaluation Anemia (%, n) Low Ferrritin levels (%, n) High TSH levels (%, n) Abnormal creatinine levels (%, n)
49.0 (39.0–57.0) 5.0 (3.0–10.0) 91.3 (105) 59.1 (68) 68.7 (79) 76.5 (88) 49.6 (57) 91.3 (105) 33.9 (39) 33.9 (39) 9.6 (11) 5.2 (6) 0.9 (1) 67.0 (54.0–73.0) 8.0 (6.0–11.0) 3.0 (2.0–6.0) 76.5 (88) 7.8 (9) 9.6 (11) 16.7 (19) 5.2 (6) 0 (0)
FMS: Fibromyalgia syndrome, SSRI: Selective serotonin reuptake inhibitor, QoL: Quality of life, FIQ: Fibromyalgia impact questionnaire, PSQI: Pittsburgh sleep quality index, ESS: Epworth sleepiness scale. ∗ Median (25–75% interquartile range).
ing work, pain, fatigue/tired, rested, stiffness, anxiety, and depression [18]. The impact of FMS on activities of daily living (i.e., preparing meals, doing laundry, climbing stairs, shopping, yard work, driving a car, visiting friends, washing dishes, vacuuming, making beds, and walking several blocks) was evaluated using the FIQ score which ranges from 0 to 10. The FIQ total score reflects all ten areas and ranges from 0 to 100. Higher scale scores indicate a greater impact of the disease. Validation and reliability study of the Turkish version of FIQ has been made [19]. 2.1. Statistical analysis Firstly all data were classified as continuous, and categoric variables. Percentages of categorical data were found. Distribution characteristics of continuous variables were determined [(mean, median, standard deviation, standard error and 25%–75% interquartile range (IQR)]. Differences between groups were compared with Student’s t test and Mann Whitney U test. Chi-square method was used for comparing frequency of categoric variables.
Fig. 1. Severity of RLS patients in FMS. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/BMR140478)
P value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 15.0 software (SPSS Inc., Chicago, IL, USA).
3. Results One hundred and five female patients with FMS were recruited; the median age was 49.0 (39.0–57.0) [median (25–75% IQR)] years and symptom duration was 5.0 (3.0–10.0) years. Of the patients with FMS, 91.3% had self reported sleep disturbance and more than half had fatigue (59.1%, n = 68), irritable bowel symptoms (68.7%, n = 79), headache (76.5%, n = 88), urinary tract symptoms (91.3%, n = 105) and impaired sleep quality (76.5%, n = 88). 33.9% of the patients reported that they used a drug for FMS. None of the patients had high creatinine levels. General characteristics of patients are shown in Table 1. Forty-nine patients (42.6%) with FMS were found to have RLS according to IRLSSG criteria. Among patients wtih RLS, disease severity was classified as moderate in 42.9% of patients and as severe in 49.0% of patients (Fig. 1). FMS patients were divided into two groups according to presence of RLS; as RLS(+) and RLS(-) and were compared with each other. Mean age (50.8 ± 13.3 vs 47.2 ± 12.2) (mean ± standard deviation) and median symptom duration [(5.0 (2.5–15.0) vs 5.0 (2.8–8.5)] were similar between RLS(+) and RLS(-) groups.
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G.M. Civelek et al. / Evaluation of restless legs syndrome in fibromyalgia syndrome Table 2 Comparison of patients with and without RLS Age (years)∗ Symptom duration (years)† FIQ score∗ PSQI score∗ ESS score† Anemia‡ Low ferritin levels‡ ESS 11 (impaired)‡ PSQI 5 (impaired)‡ Accompanying symptoms‡ Self-reported sleep disturbance Fatigue Irritable bowel symptoms Headache Emotional disturbances Urinary tract symptoms
RLS (-) 47.2 ± 12.2 5.0 (2.8–8.5) 59.4 ± 16.9 7.8 ± 4.3 3.0 (1.0–4.3) 3.1 13.8 9.1 66.7
RLS (+) 50.8 ± 13.3 5.0 (2.5–15.0) 68.1 ± 9.8 9.0 ± 4.4 5.0 (3.0–7.5) 18.4 20.4 6.1 89.8
p 0.598 0.549 0.027 0.003 0.036 0.009 0.498 0.730 0.008
60.6 86.4 56.1 60.6 71.2 47.0
73.5 98.0 63.3 79.6 83.7 53.1
0.214 0.042 0.558 0.042 0.181 0.647
FIQ: Fibromyalgia Impact Questionnaire, PSQI: The Pittsburgh Sleep Quality Index, ESS: Epworth Sleepiness Scale. ∗ Mean ± Standard Deviation (groups were compared with student t test), †: Median (25–75% interquartile range) (groups were compared with Mann Whitney U test), ‡: Column percent (groups were compared with Chisquare test).
Fig. 2. Drug usage of patients with and without RLS for FMS. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/ BMR-140478)
Both PSQI scores (9.0 ± 4.4 vs 7.8 ± 4.3) (mean ± standard deviation) and ESS [(5.0 (3.0–7.5) vs 3.0 (1.0–4.3)] scores were higher in RLS(+) group (p = 0.003, p = 0.036). 89.8% of RLS(+) patients and 66.7% of RLS(-) patients had impaired sleep quality (p = 0.008). Anemia was more common (18.4% vs 3.1%) among RLS(+) patients (p = 0.009). Ferritin levels were low in 20.4% of RLS(+) patients and in 13.8% of RLS(-) patients but this difference was not statistically significant (p = 0.498). RLS(+) patients reported all accompanying symptoms (sleep dis-
turbance, irritable bowel symptoms, headache, emotional disturbances, symptoms of urinary tract disorders) more commonly than RLS(-) patients. Among these symptoms fatigue and headache were significantly more prevalent (98.0% vs 86.4%) in RLS(+) patients (p = 0.042, p = 0.042). Comparison of RLS(+) and RLS(-) patients is shown in Table 2. Also RLS(+) patients tended to use analgesic-antiinflamatory drugs, amitriptiline and SSRI (selective serotonin reuptake inhibitors) more commonly than RLS(-) patients, however differences between the two
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groups were not statistically significant (p = 0.111, p = 0.200, p = 0.699) (Fig. 2). FIQ scores were higher in RLS(+) patients than RLS(-) patients (68.1 ± 9.8 vs 59.4 ± 16.9) (p = 0.027). Also patients with severe and very severe RLS had higher FIQ scores than patients with mild and moderate RLS (p = 0.028).
4. Discussion In our study, 42.6% of patients with FMS had coexistant RLS. Patients with both RLS and FMS had sleep disturbances more commonly and had lowered quality of life than patients with only FMS. This study shows that RLS is common among patients with FMS. Prevalence of RLS was found to be 3.19% in a previously published population based study in adult age group in Turkey [20]. Prevalence of RLS was found to be between 2% and 15% in general population and between 20% and 65% in FMS in previous studies [6–9,21]. Among these, in two recent studies using IRLSSG criteria for diagnosis of RLS, prevalence of RLS was found to be 65% in Sweden and 33% in USA among patients with FMS. We also used IRLSSG criteria for diagnosis of RLS and found prevalence of RLS higher than in USA and lower than in Sweden. Although study results change in different countries or study populations, it is possible to say that RLS is more prevalent in FMS patients than in general population. 4.1. Common disease mechanisms FMS and RLS are common disorders, both are more prevalent in females and at middle age group. There are some possible explanations for the overlap between RLS and FMS. A possible hypothesis is etiological role of central sensitization in a group of diseases named “central sensitization syndromes” reported by Yunus [22]. These are a wide range of diseases including FMS, chronic fatigue syndrome, migraine, RLS, irritable bowel disease, tension type headache, temporomandibular dysfunction and myofasial pain syndrome with some common clinical symptoms like pain, fatigue, sleep and emotional disturbances. According to another hypothesis, a similar pathophysiology of dopaminergic system may be responsible for both of the diseases. RLS is thought to result from dysfunction of dopaminergic system in CNS [23].
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Dopaminergic agents are used for the treatment of RLS and response to treatment is very good even in low doses of these drugs [24]. Dopamine agonists pramipexola and terguride were also found to be effective in treatment of FMS in two different prospective randomized placebo controlled studies [25,26]. Dysregulation of serotonergic pathways may lead to the development of both FMS and RLS. Serotonin and its precursor L-tryptophan in serum of patients with FMS and 5-HIAA – main metabolite of serotonin – were found to be low in cerebrospinal fluid of patients with FMS [27]. In some studies the use of SSRI was found to be associated with RLS [28,29]. In our study patients with both RLS and FMS tended to use SSRI more commonly than patients with only FMS, but difference between the two groups was not statistically significant. Gabaergic agents are used successfully for the treatment of both RLS and FMS. These drugs are effective especially on sleep disturbances which is a frequently seen clinical problem in patients with both FMS and RLS [30,31]. Thus a common dysfunction in gabaergic pathway may be responsible for the etiology of both disorders. Three major secondary causes of RLS; pregnancy, end stage renal failure and iron deficiency anemia are associated with iron deficiency. Iron is cofactor of tyrosine hydroxylase in rate limiting step of dopamine synthesis. Dysfunction of iron metabolism was found to play a role in pathogenesis of RLS in various MRG and autopsy studies [32,33]. Ortancil et al. [34] found low serum ferritin level as a risk factor for FMS. Pamuk et al. [35] reported that FMS was more common among patients with iron deficiency anemia and thalasemia minor. We found that anemia was more prevalent among patients with both RLS and FMS. Although differences were not statistically significant, low ferritin levels were more common in patients with both RLS and FMS. 4.2. Sleep disturbance Prevalence of sleep disturbances is very high among patients with FMS and in some previous studies reached nearly 100% [36]. In our study 91.3% of patients with FMS had self-reported sleep disturbances and 76.5% of patients with FMS had impaired PSQI scores. It is not definitely known whether FMS causes sleep disturbances or vice versa. Sleep disturbances in FMS may be related to an endogenous disorder or symptoms like fatigue, pain and emotional distur-
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bances may lead to sleep disturbances. In our study, patients with FMS reported accompanying symptoms like fatigue, headache and emotional disturbances commonly. High frequency of accompanying symptoms may have led to high frequency of sleep disturbances or vice versa. In RLS, sleep disturbances are a major cause of morbidity. Allen et al found that 75% of patients with RLS had at least one sleep problem and low sleep quality was associated with severity of RLS [37]. We also found that sleep disturbances were more common in patients with both RLS and FMS than in patients with only FMS. 4.3. Quality of life Today it is well known that chronic diseases lower quality of life and result in higher treatment costs. So far, different studies have shown that quality of life is adversely affected in FMS [38]. RLS was also found to be associated with impaired quality of life in previous studies. In a cohort study published in 2009, RLS was found to negatively affect quality of life in conjunction with quality of sleep, social function and emotional well-being [39]. In another study, quality of life of patients with RLS was found to be negatively correlated with disease severity [40]. We found that patients with both RLS and FMS had lower quality of life scores than patients with only FMS. Impairment of quality of life was more more prominent in severe and very severe RLS patients. Although only differences between prevalences of fatigue and headache were found to be statistically significant between the two groups, all accompanying symptoms (sleep disturbance, fatigue, irritable bowel symptoms, headache, emotional disturbances, urinary tract symptoms) were found to be more common in patients with both RLS and FMS than in patients with only FMS.
use analgesic-antiinflamatory drugs, amitriptiline and SSRI more commonly than patients without RLS. All of these findings can be interpreted as presence of coexisting RLS increases FMS severity and vice versa. 4.5. Clinical implications Patients with FMS should routinely be evaluated for the presence of RLS and sleep disorders. Agents such as caffeine or theophyline should be withdrawn at least later in the day when these disorders are present. Also, iron deficiency should be investigated and treated in patients with RLS. Dopaminergic or gabaergic agents can be used for pharmacological treatment of patients with both RLS and FMS. Since antidepressants were found to be associated with RLS, these drugs should be more carefully used in this patient group [41]. 5. Strengths and limitations of study This study has several strong points. Firstly, we conducted the study with face to face interview method in all steps which was not the case in previous studies. In these studies, diagnosis of RLS was based on telephone interviews. This situation makes our results more reliable. Secondly, prevalence of RLS in FMS was evaluated by taking into account severity of RLS, quality of life and accompanying symptoms to FMS. Lastly, diagnosis and severity of RLS were assessed by validated IRLSSG criteria. Limitations of this study include lack of control group and that it was made on patients attending to Physical Medicine and Rehabilitation clinic which may partly have contributed to high prevalence of RLS and sleep disturbances. Unfortunately like previous studies addressing occurance of RLS in FMS, our study was cross-sectional and included a relatively small sample group.
4.4. Interaction of RLS and FMS
6. Conclusion
Previous reports and our study results indicate that RLS is commonly seen in patients with FMS. To our knowledge, our study was the first to evaluate severity of RLS in patients with FMS. RLS was severe or moderate in majority of FMS patients. Patients with both RLS and FMS had self reported sleep disturbance more commonly, had higher scores in sleep measures, had lowered quality of life, had accompanying symptoms more commonly than patients with only FMS. Also, patients with RLS tended to
In summary, our results demonstrated that coexistence of RLS and FMS is very common and also associated with lower quality of life scores, higher prevalence of sleep disturbances and higher incidence of accompanying symptoms. All patients with FMS should be evaluated for the presence of sleep disturbances and RLS and treatment plan should cover these disorders in case of coexistance for higher quality of life outcomes. Further prospective studies analyzing the interaction of FMS and RLS are needed to be conducted in large series.
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Conflict of interest None.
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Journal of Back and Musculoskeletal Rehabilitation 27 (2014) 537–544 DOI 10.3233/BMR-140478 IOS Press
Evaluation of restless legs syndrome in fibromyalgia syndrome: An analysis of quality of sleep and life Gul Mete Civeleka,∗, Pinar Oztop Ciftkayab and Metin Karatasb a
Dıskapı Yıldırım Beyazıt Education and Research Hospital, Physical Medicine and Rehabilitation Clinic, Ankara, Turkey b Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Baskent University, Istanbul, Turkey
Abstract. BACKGROUND AND OBJECTIVE: The aim of this study is to find prevalence and severity of restless legs syndrome (RLS) in patients with fibromyalgia syndrome (FMS) and detect effect of FMS and RLS coexistance on quality of sleep and life. METHODS: In this study, presence and severity of RLS were detected in patients with FMS and Pitsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Fibromyalgia Impact Questionnaire (FIQ) scores of all patients were measured. RESULTS: One hundred and fifteen female patients with median age 49 (39.0–57.0) [median (25–75% interquartile range)] were included in the study. In 42.6% of patients RLS coexisting with FMS was found. RLS was classified as moderate in 42.9% of patients and as severe in 49.0% of patients. In patients with FMS ans RLS sleep quality, daytime sleepiness and quality of life were more severely impaired (PSQI scores were 9.0 ± 4.4 vs 7.8 ± 4.3, p = 0.003; ESS scores were 5.0(3.0–7.5) vs 3.0(1.0–4.3), p = 0.036 and FIQ scores were 68.1 ± 9.8 vs 59.4 ± 16.9, p = 0.027) compared to patients with only FMS. Prevalence of RLS was found higher in FMS than normal population and quality of sleep and quality of life were worse in patients with RLS. CONCLUSIONS: Presence of RLS should be investigated in every patient with FMS and treatment plans should also cover RLS in case of coexistance with FMS. Prospective cohort studies are needed for better explanation of FMS and RLS coexistance. Keywords: Fibromyalgia syndrome, restless legs syndrome, quality of sleep, quality of life
1. Introduction Fibromyalgia syndrome (FMS) is a chronic pain syndrome characterized by widespread pain lasting three months or more and pain on palpation of at least 11 of 18 tender points. At least 2% of adult population have been reported to have FMS. Although chronic diffuse pain is the main clinical property, symptoms like sleep disturbances, fatigue, irritable bowel symptoms, headache, emotional disturbances, urinary tract ∗ Corresponding author: Gul Mete Civelek, Dıskapı Yıldırım Beyazıt Education and Research Hospital, Physical Medicine and Rehabilitation Clinic, Irfan Bastug Caddesi, Dıskapı, Altındag, Ankara, Turkey. Tel.: +90 312 5962993; Fax: +90 312 3186690; E-mail: [email protected].
symptoms may accompany FMS [1]. Wide spectrum of clinical symptoms of FMS makes it more difficult to treat and is also associated with increased burden for both the patient and the population. A negative impact of FMS on work productivity has been reported in the literature in different studies [2,3]. Hoffman et al. reported that people with FMS had an overall health status burden that was greater in magnitude compared to people with other specific pain conditions that are widely accepted as impairing [4]. Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an urge to move the legs associated with unpleasant leg sensation [5]. These symptoms are induced or exacerbated with rest, relieved on activity, worsen in the evening and night. The prevalence of RLS is between 2–15% in adult population.
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RLS is associated with sleep disorders [6]. In treatment, the first-line drugs are dopaminergic agents. Although RLS is a common and treatable disorder it is usually underdiagnosed. Both FMS and RLS are prevalent disorders, most commonly seen in women, associated with sleep disturbances and lowered quality of life. Prevalence of RLS in FMS was found to be high, varying from 20% to 65.7% in previous studies [7–9]. Common neurotransmitter or neuroendocrine dysfunctions are thought to play role in etiology of both diseases [9]. RLS may be increasing severity of FMS and treating RLS together with FMS in case of coexistance may decrease disease burden resulting in higher quality of life outcomes. To our knowledge, there are no studies in literature investigating effect of RLS on FMS symptoms and co-treatment of these disorders. The aim of this study was to find prevalence and severity of RLS in FMS and investigate the effect of this coexistance on sleep disturbances, daytime sleepiness and quality of life by using standardized and objective measures. We also discussed common disease mechanisms and their clinical significance for daily practice.
2. Methods Subjects were 115 consecutive female patients diagnosed with fibromyalgia attending to Baskent University Physical Medicine and Rehabilitation clinic between 1 October 2009 and 1 March 2010. The patients were required (1) to be > 18 years of age; (2) not to be pregnant; (3) not to have end stage renal failure; (4) not to have Parkinson disease; (5) not to be diagnosed with polyneuropathy before. General physical examinations were made and serum levels of hemoglobin, ferritin, creatinine and TSH were measured in all patients. Diagnosis of FMS was made according to the 1990 American Collage of Rheumatology criteria by confirming the presence of chronic widespread pain and 11 of tender points on examination [10]. Presence of symptoms accompanying FMS (self-reported sleep disturbance, fatigue, irritable bowel symptoms, emotional disturbances, urinary tract symptoms) were also evaluated. RLS was diagnosed according to standardized criteria developed in 1995 by the International Restless Legs Syndrome Study Group (IRLSSG) [11]. These criteria have been refined and reviewed during a Na-
tional Institutes of Health workshop in 2002 [12]. The essential criterias for the syndrome are: (1) an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; (2) the urge to move or unpleasant sensations beginning or worsening during periods of rest or inactivity such as lying or sitting; (3) the urge to move or unpleasant sensations partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; (4) the urge to move or unpleasant sensations which are worse in the evening or night than during the day or only occur in the evening or night. Those who meet all 4 criteria are diagnosed as suffering from RLS. RLS severity was assessed using the validated International RLS Severity Scale. The self-rating questionnaire includes ten items (responses ranging from 0 to 4) evaluating the symptom severity and the impact of symptoms on everyday life activities. A total score of 1 to 10 points indicates mild, 11 to 20 moderate, 21 to 30 severe, and 31 to 40 very severe RLS symptoms [13]. Sleep quality and day-time sleepiness were assessed using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). PSQI score was used to determine sleep disturbance. The PSQI score is a standardized rating scale, which has been validated as differentiating from ‘poor’ to ‘good’ sleep [14]. It evaluates sleep disturbances in seven dimensions: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication and daytime dysfunction. Each dimension is rated on a 4-point scale (0 to 3, with 3 indicating more profound effect), which is summed together to yield a global score. A global score > 5 indicates “poor sleep”. The ESS is a commonly used tool for evaluating recent excessive daytime somnolence. This scale consists of 8 questions concerning situations associated with daily activities. The subjects are asked to evaluate the likelihood of dozing off or falling asleep in these situations. The scores are as follows: 0 = no chance of dozing, 1 = slight chance of dozing, 2 = moderate chance of dozing, 3 = high chance of dozing. The maximum score is 24, and disturbing sleepiness is indicated by scores of > 10 [15]. Turkish validation and reliability studies of both PSQI and ESS have been made [16,17]. Quality of life was evaluated with FIQ (Fibromyalgia Impact Questionnaire). The FIQ measures FMS subject’s status, progress, and outcomes in 10 areas: physical impairment, feeling good, work missed, do-
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Table 1 General characteristics of patients including age, symptom duration, accompanying symptoms, drug usage, quality of sleep and life Age (Years)∗ Symptom duration (years)∗ Accompanying symptoms (%, n) Self reported sleep disturbance Fatigue Irritable bowel symptoms Headache Emotional disturbances Urinary tract symptoms Patients using drug for FMS (%, n) Drugs used for FMS (%, n) Analgesic and antiinflammatory drugs SSRI Amitriptiline Alprazolam Sleep and QoL (%, n) FIQ score∗ PSQI score∗ ESS score∗ PSQI 5 (impaired) (%, n) ESS 11 (impaired) (%, n) Laboratory evaluation Anemia (%, n) Low Ferrritin levels (%, n) High TSH levels (%, n) Abnormal creatinine levels (%, n)
49.0 (39.0–57.0) 5.0 (3.0–10.0) 91.3 (105) 59.1 (68) 68.7 (79) 76.5 (88) 49.6 (57) 91.3 (105) 33.9 (39) 33.9 (39) 9.6 (11) 5.2 (6) 0.9 (1) 67.0 (54.0–73.0) 8.0 (6.0–11.0) 3.0 (2.0–6.0) 76.5 (88) 7.8 (9) 9.6 (11) 16.7 (19) 5.2 (6) 0 (0)
FMS: Fibromyalgia syndrome, SSRI: Selective serotonin reuptake inhibitor, QoL: Quality of life, FIQ: Fibromyalgia impact questionnaire, PSQI: Pittsburgh sleep quality index, ESS: Epworth sleepiness scale. ∗ Median (25–75% interquartile range).
ing work, pain, fatigue/tired, rested, stiffness, anxiety, and depression [18]. The impact of FMS on activities of daily living (i.e., preparing meals, doing laundry, climbing stairs, shopping, yard work, driving a car, visiting friends, washing dishes, vacuuming, making beds, and walking several blocks) was evaluated using the FIQ score which ranges from 0 to 10. The FIQ total score reflects all ten areas and ranges from 0 to 100. Higher scale scores indicate a greater impact of the disease. Validation and reliability study of the Turkish version of FIQ has been made [19]. 2.1. Statistical analysis Firstly all data were classified as continuous, and categoric variables. Percentages of categorical data were found. Distribution characteristics of continuous variables were determined [(mean, median, standard deviation, standard error and 25%–75% interquartile range (IQR)]. Differences between groups were compared with Student’s t test and Mann Whitney U test. Chi-square method was used for comparing frequency of categoric variables.
Fig. 1. Severity of RLS patients in FMS. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/BMR140478)
P value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 15.0 software (SPSS Inc., Chicago, IL, USA).
3. Results One hundred and five female patients with FMS were recruited; the median age was 49.0 (39.0–57.0) [median (25–75% IQR)] years and symptom duration was 5.0 (3.0–10.0) years. Of the patients with FMS, 91.3% had self reported sleep disturbance and more than half had fatigue (59.1%, n = 68), irritable bowel symptoms (68.7%, n = 79), headache (76.5%, n = 88), urinary tract symptoms (91.3%, n = 105) and impaired sleep quality (76.5%, n = 88). 33.9% of the patients reported that they used a drug for FMS. None of the patients had high creatinine levels. General characteristics of patients are shown in Table 1. Forty-nine patients (42.6%) with FMS were found to have RLS according to IRLSSG criteria. Among patients wtih RLS, disease severity was classified as moderate in 42.9% of patients and as severe in 49.0% of patients (Fig. 1). FMS patients were divided into two groups according to presence of RLS; as RLS(+) and RLS(-) and were compared with each other. Mean age (50.8 ± 13.3 vs 47.2 ± 12.2) (mean ± standard deviation) and median symptom duration [(5.0 (2.5–15.0) vs 5.0 (2.8–8.5)] were similar between RLS(+) and RLS(-) groups.
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G.M. Civelek et al. / Evaluation of restless legs syndrome in fibromyalgia syndrome Table 2 Comparison of patients with and without RLS Age (years)∗ Symptom duration (years)† FIQ score∗ PSQI score∗ ESS score† Anemia‡ Low ferritin levels‡ ESS 11 (impaired)‡ PSQI 5 (impaired)‡ Accompanying symptoms‡ Self-reported sleep disturbance Fatigue Irritable bowel symptoms Headache Emotional disturbances Urinary tract symptoms
RLS (-) 47.2 ± 12.2 5.0 (2.8–8.5) 59.4 ± 16.9 7.8 ± 4.3 3.0 (1.0–4.3) 3.1 13.8 9.1 66.7
RLS (+) 50.8 ± 13.3 5.0 (2.5–15.0) 68.1 ± 9.8 9.0 ± 4.4 5.0 (3.0–7.5) 18.4 20.4 6.1 89.8
p 0.598 0.549 0.027 0.003 0.036 0.009 0.498 0.730 0.008
60.6 86.4 56.1 60.6 71.2 47.0
73.5 98.0 63.3 79.6 83.7 53.1
0.214 0.042 0.558 0.042 0.181 0.647
FIQ: Fibromyalgia Impact Questionnaire, PSQI: The Pittsburgh Sleep Quality Index, ESS: Epworth Sleepiness Scale. ∗ Mean ± Standard Deviation (groups were compared with student t test), †: Median (25–75% interquartile range) (groups were compared with Mann Whitney U test), ‡: Column percent (groups were compared with Chisquare test).
Fig. 2. Drug usage of patients with and without RLS for FMS. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/ BMR-140478)
Both PSQI scores (9.0 ± 4.4 vs 7.8 ± 4.3) (mean ± standard deviation) and ESS [(5.0 (3.0–7.5) vs 3.0 (1.0–4.3)] scores were higher in RLS(+) group (p = 0.003, p = 0.036). 89.8% of RLS(+) patients and 66.7% of RLS(-) patients had impaired sleep quality (p = 0.008). Anemia was more common (18.4% vs 3.1%) among RLS(+) patients (p = 0.009). Ferritin levels were low in 20.4% of RLS(+) patients and in 13.8% of RLS(-) patients but this difference was not statistically significant (p = 0.498). RLS(+) patients reported all accompanying symptoms (sleep dis-
turbance, irritable bowel symptoms, headache, emotional disturbances, symptoms of urinary tract disorders) more commonly than RLS(-) patients. Among these symptoms fatigue and headache were significantly more prevalent (98.0% vs 86.4%) in RLS(+) patients (p = 0.042, p = 0.042). Comparison of RLS(+) and RLS(-) patients is shown in Table 2. Also RLS(+) patients tended to use analgesic-antiinflamatory drugs, amitriptiline and SSRI (selective serotonin reuptake inhibitors) more commonly than RLS(-) patients, however differences between the two
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groups were not statistically significant (p = 0.111, p = 0.200, p = 0.699) (Fig. 2). FIQ scores were higher in RLS(+) patients than RLS(-) patients (68.1 ± 9.8 vs 59.4 ± 16.9) (p = 0.027). Also patients with severe and very severe RLS had higher FIQ scores than patients with mild and moderate RLS (p = 0.028).
4. Discussion In our study, 42.6% of patients with FMS had coexistant RLS. Patients with both RLS and FMS had sleep disturbances more commonly and had lowered quality of life than patients with only FMS. This study shows that RLS is common among patients with FMS. Prevalence of RLS was found to be 3.19% in a previously published population based study in adult age group in Turkey [20]. Prevalence of RLS was found to be between 2% and 15% in general population and between 20% and 65% in FMS in previous studies [6–9,21]. Among these, in two recent studies using IRLSSG criteria for diagnosis of RLS, prevalence of RLS was found to be 65% in Sweden and 33% in USA among patients with FMS. We also used IRLSSG criteria for diagnosis of RLS and found prevalence of RLS higher than in USA and lower than in Sweden. Although study results change in different countries or study populations, it is possible to say that RLS is more prevalent in FMS patients than in general population. 4.1. Common disease mechanisms FMS and RLS are common disorders, both are more prevalent in females and at middle age group. There are some possible explanations for the overlap between RLS and FMS. A possible hypothesis is etiological role of central sensitization in a group of diseases named “central sensitization syndromes” reported by Yunus [22]. These are a wide range of diseases including FMS, chronic fatigue syndrome, migraine, RLS, irritable bowel disease, tension type headache, temporomandibular dysfunction and myofasial pain syndrome with some common clinical symptoms like pain, fatigue, sleep and emotional disturbances. According to another hypothesis, a similar pathophysiology of dopaminergic system may be responsible for both of the diseases. RLS is thought to result from dysfunction of dopaminergic system in CNS [23].
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Dopaminergic agents are used for the treatment of RLS and response to treatment is very good even in low doses of these drugs [24]. Dopamine agonists pramipexola and terguride were also found to be effective in treatment of FMS in two different prospective randomized placebo controlled studies [25,26]. Dysregulation of serotonergic pathways may lead to the development of both FMS and RLS. Serotonin and its precursor L-tryptophan in serum of patients with FMS and 5-HIAA – main metabolite of serotonin – were found to be low in cerebrospinal fluid of patients with FMS [27]. In some studies the use of SSRI was found to be associated with RLS [28,29]. In our study patients with both RLS and FMS tended to use SSRI more commonly than patients with only FMS, but difference between the two groups was not statistically significant. Gabaergic agents are used successfully for the treatment of both RLS and FMS. These drugs are effective especially on sleep disturbances which is a frequently seen clinical problem in patients with both FMS and RLS [30,31]. Thus a common dysfunction in gabaergic pathway may be responsible for the etiology of both disorders. Three major secondary causes of RLS; pregnancy, end stage renal failure and iron deficiency anemia are associated with iron deficiency. Iron is cofactor of tyrosine hydroxylase in rate limiting step of dopamine synthesis. Dysfunction of iron metabolism was found to play a role in pathogenesis of RLS in various MRG and autopsy studies [32,33]. Ortancil et al. [34] found low serum ferritin level as a risk factor for FMS. Pamuk et al. [35] reported that FMS was more common among patients with iron deficiency anemia and thalasemia minor. We found that anemia was more prevalent among patients with both RLS and FMS. Although differences were not statistically significant, low ferritin levels were more common in patients with both RLS and FMS. 4.2. Sleep disturbance Prevalence of sleep disturbances is very high among patients with FMS and in some previous studies reached nearly 100% [36]. In our study 91.3% of patients with FMS had self-reported sleep disturbances and 76.5% of patients with FMS had impaired PSQI scores. It is not definitely known whether FMS causes sleep disturbances or vice versa. Sleep disturbances in FMS may be related to an endogenous disorder or symptoms like fatigue, pain and emotional distur-
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bances may lead to sleep disturbances. In our study, patients with FMS reported accompanying symptoms like fatigue, headache and emotional disturbances commonly. High frequency of accompanying symptoms may have led to high frequency of sleep disturbances or vice versa. In RLS, sleep disturbances are a major cause of morbidity. Allen et al found that 75% of patients with RLS had at least one sleep problem and low sleep quality was associated with severity of RLS [37]. We also found that sleep disturbances were more common in patients with both RLS and FMS than in patients with only FMS. 4.3. Quality of life Today it is well known that chronic diseases lower quality of life and result in higher treatment costs. So far, different studies have shown that quality of life is adversely affected in FMS [38]. RLS was also found to be associated with impaired quality of life in previous studies. In a cohort study published in 2009, RLS was found to negatively affect quality of life in conjunction with quality of sleep, social function and emotional well-being [39]. In another study, quality of life of patients with RLS was found to be negatively correlated with disease severity [40]. We found that patients with both RLS and FMS had lower quality of life scores than patients with only FMS. Impairment of quality of life was more more prominent in severe and very severe RLS patients. Although only differences between prevalences of fatigue and headache were found to be statistically significant between the two groups, all accompanying symptoms (sleep disturbance, fatigue, irritable bowel symptoms, headache, emotional disturbances, urinary tract symptoms) were found to be more common in patients with both RLS and FMS than in patients with only FMS.
use analgesic-antiinflamatory drugs, amitriptiline and SSRI more commonly than patients without RLS. All of these findings can be interpreted as presence of coexisting RLS increases FMS severity and vice versa. 4.5. Clinical implications Patients with FMS should routinely be evaluated for the presence of RLS and sleep disorders. Agents such as caffeine or theophyline should be withdrawn at least later in the day when these disorders are present. Also, iron deficiency should be investigated and treated in patients with RLS. Dopaminergic or gabaergic agents can be used for pharmacological treatment of patients with both RLS and FMS. Since antidepressants were found to be associated with RLS, these drugs should be more carefully used in this patient group [41]. 5. Strengths and limitations of study This study has several strong points. Firstly, we conducted the study with face to face interview method in all steps which was not the case in previous studies. In these studies, diagnosis of RLS was based on telephone interviews. This situation makes our results more reliable. Secondly, prevalence of RLS in FMS was evaluated by taking into account severity of RLS, quality of life and accompanying symptoms to FMS. Lastly, diagnosis and severity of RLS were assessed by validated IRLSSG criteria. Limitations of this study include lack of control group and that it was made on patients attending to Physical Medicine and Rehabilitation clinic which may partly have contributed to high prevalence of RLS and sleep disturbances. Unfortunately like previous studies addressing occurance of RLS in FMS, our study was cross-sectional and included a relatively small sample group.
4.4. Interaction of RLS and FMS
6. Conclusion
Previous reports and our study results indicate that RLS is commonly seen in patients with FMS. To our knowledge, our study was the first to evaluate severity of RLS in patients with FMS. RLS was severe or moderate in majority of FMS patients. Patients with both RLS and FMS had self reported sleep disturbance more commonly, had higher scores in sleep measures, had lowered quality of life, had accompanying symptoms more commonly than patients with only FMS. Also, patients with RLS tended to
In summary, our results demonstrated that coexistence of RLS and FMS is very common and also associated with lower quality of life scores, higher prevalence of sleep disturbances and higher incidence of accompanying symptoms. All patients with FMS should be evaluated for the presence of sleep disturbances and RLS and treatment plan should cover these disorders in case of coexistance for higher quality of life outcomes. Further prospective studies analyzing the interaction of FMS and RLS are needed to be conducted in large series.
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Conflict of interest None.
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