Introduction

Restless legs syndrome (RLS) is a common neurological movement disorder with a prevalence of 5-15% in different populations [1-3]. This disorder is accompanied by periodic limb movements during sleep (PLMs), in 80% to 90% of cases which in turn contributes to an increase in fatigue and excessive daytime sleepiness which is due to inefficient nocturnal sleep [4, 5]. Age and sex are the two contributing factors in the frequency of RLS as it is about twice more frequent in women and it is more prevalent in the elderly [3, 6, 7]. The causes of RLS are divided into idiopathic e.g. genetic factors and symptomatic, e.g., secondary to some neurologic and non-neurologic disorders. Iron deficiency anemia [8], chronic renal failure [9], pregnancy [10, 11], antidopaminergic, and antidepressant consumption are the known non-neurologic causes of RLS [12]. Polyneuropathy, Parkinson’s disease, and spinocerebellar ataxia are among the neurologic causes [12].

Several studies have suggested a higher prevalence of RLS in the patients with multiple sclerosis (MS). The prevalence range of RLS in MS is from 13.3% reported by Gómez-Choco et al. [13] to 65.1% by Shaygannejad et al. [14]. Some other studies have reported that ALS in patients with MS is five times more frequent than that of the healthy controls [15-17]. Old age, longer duration of the disease, a primary, progressive form of MS, higher severity, and cervical spinal cord involvement increase the possibility of RLS in MS [15, 18]. In addition to more severe symptoms of RLS which is associated with MS [17], the usual co-occurrence of RLS with PLMs, leads to the repeated arousal or microarousal during sleep which can aggravate excessive daytime sleepiness and fatigue in these patients [15]. The aim of the current study is to evaluate the frequency of RLS in the studied MS patients and its effect on the frequency of fatigue and excessive daytime sleepiness in these patients.

Material and Methods

In this study, a cross-sectional study was performed. The population size was calculated based on the result of a previous study [14]:

α=0.05 p=65.1% d=9% n=108

From June 2014 to March 2015, by a convenient sampling method, 120 MS patients who referred to the Inpatient Neurology Ward of Chamran hospital, affiliated with the Shiraz University of Medical Sciences, were enrolled in this study. All patients received a routine laboratory test and were visited by a neurologist. After explaining the objectives and methods of the study, a written informed consent form was obtained from all of the participants and they were assisted throughout the study by the assistant researcher. This study was approved by the Medical Research Ethics Committee of Shiraz University of Medical Sciences (approval number: 92-6358).

Patient Selection

The inclusion criteria were: the patients who were between 16–65 years old with a definite diagnosis of MS according to the 2010 revised McDonald criteria for the diagnosis of MS [19] regarding their clinical course and treatment and those with expanded severity status scale (EDSS) ≤ 5.5.

The Exclusion criteria were: the concurrent history of anaemia (Hb <14mg/dl and Hb <12mg/dl for men and women respectively), renal failure (serum creatinine >1.4 and >1.2 mg/dl for men and women respectively), hypothyroidism (serum TSH >5mIu/dl), pregnancy, diabetes (serum FBS >120mg/dl), the current history of depression and taking antidepressant, alcohol consumption, and the concomitant taking of sedatives (e.g. clonazepam), and antidopaminergic drugs and high dose steroid therapy during the past three months prior to the study.

RLS Assessment

The signs and symptoms of RLS were diagnosed in each patient using the International RLS Study Group (IRLSSG) criteria [1]. IRLSSG criteria comprise of four items: 1) unpleasant sensations in their legs; 2) worsening of the symptoms during rest; 3) the relief of symptoms of movement, and 4) exacerbation of the symptoms in the evening or at night. Due to more frequent sensory symptoms in patients with MS, to exclude RLS misdiagnosis, only patients who had all these four criteria were considered having RLS.

Daytime Sleepiness Assessment

The Epworth sleepiness scale (ESS) [20] questionnaire was used to evaluate daytime sleepiness. We used the validated Persian version of ESS [21] in our study. This scale comprises of eight items, in which each item is rated on a 4-point rating scale. The total ESS score ranges between 0 and 24, and the score ≥10 is accepted as having excessive daytime sleepiness.

Fatigue Assessment

All patients completed the validated Persian version of fatigue severity scale (FSS) [22] to evaluate the impact of fatigue. The FSS is a 9-item questionnaire that assesses the general effect of fatigue on some personal and social aspects of life. Each item is rated on a 7-point scale from 1 (strongly disagree) to 7 (strongly agree). After totaling scores of all the items the cut-off ≥ 36 was considered as exhaustibility.

Statistical Analysis

SPSS software version 17 (SPSS Inc, Chicago, IL) was used for the statistical analysis of the data. The frequency (%), mean and standard deviation (SD) were used for the description of the variables. The Chi-square test was used to compare qualitative variables. A T-test and Mann-Whitney tests were also used to compare quantitative variables. A P value less than 0.05 was considered as statistically significant.

Results

For the 120 patients who enrolled in this study with the age range of 18 to 55 years, the mean age was 33.1 ± 7.4 and the disease duration of 6.39 ± 5.16 years. 91 cases (75.5%) were female, and 29 (24.2%) were male. In this study, 78 MS patients (65%) with the mean age of 33.6±7.26 met all the four criteria for RLS diagnosis. Fatigue was observed in 77 (64.2%) of the MS patients who achieved the score of >36 by FSS assessment. The mean age and disease duration of MS patients with fatigue were 34.5±7.12 and the disease duration of 7.23±5.03 years, respectively. Also the frequency of 36 (30%), for daytime sleepiness results which were assessed by ESS was included. The mean age and the disease duration of the MS patients with daytime sleepiness were 33.86 ± 7.37 and 6.6±5.53 years, respectively. Table 1, represents the frequency of RLS and its relation to some demographic and clinical characteristics, fatigue, and daytime sleepiness. As indicated in Table 1, the MS patients with RLS experienced more fatigue symptoms and signs (P = 0.018), but there was no statistically significant difference in the age, gender, durations of MS and the evidence of daytime sleepiness between MS patients with or without RLS.

Discussion

The prevalence of RLS in the general population is reported to be between 1% to 12% in different studies [15, 23]. Some studies have indicated the lower frequency of RLS in Asian countries [24], with a prevalence of 7.5% in South Korea [25] and 1.06 % in a non-institutionalized Japanese elderly population [26]. Also, in a population-based study of 2,099 Iranian healthy people, Najafi, et al. [24] reported a prevalence of 8% and a female to male ratio of 1.75 for RLS.

The association between MS and RLS has been investigated in several studies. In a case-control study of 202 patients with MS and 212 healthy controls, Deriue et al. [17] reported a frequency of 45% for RLS in the MS patients in comparison with the frequency of 14.4% in the healthy controls. Moreover, they did not find any relationship between age, gender, MS course and durations, EDSS scores and developing RLS. The high prevalence of RLS in MS had no relation to age, sex, and MS duration and the frequency of RLS in this study [17] was similar to that of our findings.

In another study conducted by Manconi et al. [16], they reported that RLS in the patients with MS was 5.4 times more prevalent than that of the controls. This study also documented that the risk factors for developing RLS in MS patients were old age, primary progressive type, longer duration and more severe course of MS, which was measured by EDSS score [16]. Moreover, the involvement of the spinal cord by demyelinating lesions of MS is also a risk factor for RLS [18].

In a Brazilian multicenter study with a meta-analysis of the literature [27], the authors showed that the patients with MS had four times higher chance of getting RLS. Also, some case-control studies have reported that RLS was 2.25 to 5.4 times more frequent in patients with MS than that of the general population [16, 28].

Similar to our findings, in a case-control study of 126 Iranian patients with MS and 126 healthy controls, Shaygannejad et al. [14] found that the prevalence of RLS in their patients and controls were respectively 65.1% and 12.7%, but the frequency of RLS was not related to the age, gender and durations of MS. However, in this study [14], they found that RLS was more frequent in patients with MS, who had disabilities like higher EDSS score. Based on our exclusion criteria, the patients with EDSS > 5.5 were not evaluated. Hence, we did not evaluate the effect of the disability status of MS on the frequency of RLS. In another study of 205 Iranian patients with MS, Miri, et al. [29] found RLS in 27.8% of patients which was similar to that of our findings. They reported there was no difference between MS with or without RLS regarding age, gender, MS durations and course.

The other findings of the present study revealed that the frequency of fatigue and excessive daytime sleepiness in MS patients was 64.1% and 30%, respectively. These results also showed that MS patients with RLS, complain of fatigue more than those without RLS (P=0.018), but there was no difference between MS patients with or without RLS regarding excessive daytime sleepiness. It seems that fatigue is the most common symptom in MS patients, which has multifactorial causes such as central, peripheral, immunological, hormonal, psychosomatic and pharmacological [15]. Moreira et al. [30], in an evaluation of 44 patients with MS to find the evidence of RLS, fatigue and sleep quality, reported the frequency of 73% and 6.8% for fatigue and excessive daytime sleepiness, respectively. Nevertheless, they did not find any relation between RLS and fatigue and excessive daytime sleepiness in their study. In another study which was conducted on 100 Iranian MS patients [31], the frequency of fatigue and excessive daytime sleepiness was 64% and 4%, respectively. They also found that depression had a negative effect on fatigue of the studied subjects [31]. Recently, Sieminski et al. [32] studied RLS in the patients with MS and found the negative effect of RLS on fatigue and sleep quality of patients and postulated that iron deficiency and chronic inflammation may have contributed to the development of RLS in patients with MS.

The limitations of our study are the lack of normal healthy controls, and we did not consider the effect of clinical course, treatment and disability status of MS on the studied variables.

Conclusion

RLS, as a common co-morbidity of multiple sclerosis, was established by the results of this study. At the same time, the patients with MS who suffered from RLS have experienced significantly higher fatigue symptoms than those without RLS. The appropriate diagnosis and management of RLS may improve both RLS and fatigue in these patients. Hence, we believe that further studies are required to scrutinize this issue in more depth.

Acknowledgments

The current article was extracted from the thesis written by Dr. Z. Shamszadeh, an Iranian Neurologist and was supported by the Shiraz University of Medical Sciences (grant number: 92-6358). The authors would like to thank Ms. Mehrnaz Gholami of the Shiraz Neuroscience Research Center for editing the language of the manuscript and Ms. Hosseini for her help.

Conflict of Interests

The authors report that there is no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

 Correspondence to: Nahid Ashjazadeh, Shiraz Neuroscience Research Center, Department of Neurology, Shiraz University of Medical Sciences, Shiraz, Iran. Telephone Number: +987136234508 Email Address: nashjazadeh@yahoo.com

GMJ. 2016;5(1):7-12

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Table 1. Frequency of RLS in the Studied MS Patients and its Relations with Some Demographic Data, Fatigue, and Excessive Daytime Sleepiness.

MS Patients	Female n (%)	Male n (%)	MS Duration Mean years ± SD	Age Mean ± SD	FSS+ n (%)	FSS- n (%)	ESS+ n (%)	ESS- n (%)
RLS+	62 (79.5)	16 (20.5)	6.8±5.1	33.6±7.26	56 (71.8)	22 (28.2)	26 (33.3)	52 (66.7)
RLS-	29 (69)	13 (31)	5.91±5.23	32.2±7.67	21 (50)	21 (50)	19 (23.8)	23 (76.2)
P value	NS*		NS§	NS†	0.018*		NS*

*chi-square; § Mann-Whitney; †t-test

References

1. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003; 4(2): 101-19.
2. Ekbom KA. Restless legs: a clinical study. Acta Med Scand 1945; 158 (Suppl. 1): 1-122.
3. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005; 165(11): 1286-92.
4. Ferri R, Zucconi M, Manconi M, Bruni O, Ferini-Strambi L, Vandi S, et al. Different periodicity and time structure of leg movements during sleep in narcolepsy/cataplexy and restless legs syndrome. Sleep 2006; 29(12): 1587-94.
5. Hornyak M, Feige B, Riemann D, Voderholzer U. Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev 2006; 10(3): 169-77.
6. Tison F, Crochard A, Léger D, Bouée S, Lainey E, El Hasnaoui A. Epidemiology of restless legs syndrome in French adults: a nationwide survey. The INSTANT study. Neurology 2005; 65(2): 239-46.
7. Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and morbidity in Augsburg elderly. Neurology 2000; 54(5): 1064-8.
8. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep 1998; 21(4): 371-7.
9. Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis 1996; 28(3): 372-8.
10. Goodman JD, Brodie C, Ayida GA. Restless leg syndrome in pregnancy. BMJ 1988; 297(6656): 1101-2.
11. Lee KA, Zaffke ME, Baratte-Beebe K. Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J Womens Health Gend Based Med 2001; 10(4): 335-41.
12. Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010; 6(6): 337-46.
13. Gómez-Choco MJ, Iranzo A, Blanco Y, Graus F, Santamaria J, Saiz A. Prevalence of restless legs syndrome and REM sleep behavior disorder in multiple sclerosis. Mult Scler 2007; 13(6): 805-8.
14. Shaygannejad V, Ardestani PE, Ghasemi M, Meamar R. Restless legs syndrome in Iranian multiple sclerosis patients: a case-control study. Int J Prev Med 2013; 4(Suppl 2): S189-93.
15. Caminero A, Bartolomé M. Sleep disturbances in multiple sclerosis. J Neurol Sci 2011; 309(1-2): 86-91.
16. Italian REMS Study Group, Manconi M, Ferini-Strambi L, Filippi M, Bonanni E, Iudice A, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep 2008; 31(7): 944-52.
17. Deriu M, Cossu G, Molari A, Murgia D, Mereu A, Ferrigno P, et al. Restless legs syndrome in multiple sclerosis: a case-control study. Mov Disord 2009; 24(5): 697-701.
18. Manconi M, Rocca MA, Ferini-Strambi L, Tortorella P, Agosta F, Comi G, et al. Restless legs syndrome is a common finding in multiple sclerosis and correlates with cervical cord damage. Mult Scler 2008; 14(1): 86-93.
19. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revision to the Mcdonald criteria. Ann Neurol 2011; 69(2): 292-302.
20. Johns MW. A new method for measuring daytime sleepiness; the Epworth Sleepiness Scale. Sleep 1991; 14(6): 540-5.
21. Sadeghniiat Haghighi K, Montazeri A, Khajeh Mehrizi A, Aminian O, Rahimi Golkhandan A, Saraei M, et al. The Epworth Sleepiness Scale: translation and validation study of the Iranian version. Sleep Breath 2013; 17(1): 419-26.
22. Azimian M, Shahvarughi Farahani A, Dadkhah A, Fallahpour M, Karimlu M. Fatigue severity scale: the psychometric properties of the Persian-version in patients with multiple sclerosis. Res J Biol Sci 2009; 4: 974-7.
23. Ondo WG. Restless legs syndrome. Neurol Clin 2009; 27(3): 779-99.
24. Najafi MR, Saadatnia M, Saffarifard A, Keyhanian K, Davoudi V. Epidemiology of restless legs syndrome in the Iranian population. Sleep Biol Rhythms 2011; 9(1): 56-9.
25. Cho YW, Shin WC, Yun CH, Hong SB, Kim JH, Allen RP, et al. Epidemiology of restless legs syndrome in Korean adults. Sleep 2008; 31(2): 219-23.
26. Mizuno S, Miyaoka T, Inagaki T, Horiguchi J. Prevalence of restless legs syndrome in non-institutionalized Japanese elderly. Psychiatry Clin Neurosci 2005; 59(4): 461-5.
27. Fragoso YD, Finkelsztejn A, Gomes S, Kaimen-Maciel DR, Oliveira CL, Lopes J, et al. Restless legs syndrome and multiple sclerosis: a Brazilian multicenter study and meta-analysis of the literature. Arq Neuropsiquiatr 2011; 69(2A): 180-3.
28. Aydar G, Kurt S, Karaer Unaldi H, Erkorkmaz U. Restless legs syndrome in multiple sclerosis. Eur Neurol 2011; 65(5): 302-6.
29. Miri S, Rohani M, Sahraian MA, Zamani B, Shahidi GA, Sabet A, et al. Restless legs syndrome in Iranian patients with multiple sclerosis. Neurol Sci 2013; 34(7): 1105-8.
30. Moreira NC, Damasceno RS, Medeiros CA, Bruin PF, Teixeira CA, Horta WG, et al. Restless leg syndrome, sleep quality and fatigue in multiple sclerosis patients. Braz J Med Biol Res 2008; 41(10): 932-7.
31. Ghajarzadeh M, Sahraian MA, Fateh R, Daneshmand A. Fatigue, Depression and Sleep Disturbances in Iranian Patients with Multiple Sclerosis. Acta Med Iran 2012; 50(4): 244-9.
32. Sieminski M, Losy J, Partinen M. Restless legs syndrome in multiple sclerosis. Sleep Med Rev 2015; 22: 15-22.