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Prevalence and profile of Restless Legs Syndrome in Parkinson's disease and other neurodegenerative disorders: A case-control study
Parkinsonism and Related Disorders 19 (2013) 426e430
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Editor’s comment: Given how common restless legs syndrome is, and its link with dopaminergic dysfunction, it is perhaps surprising that the association between PD and RLS is in fact quite poorly documented. The study by Bhalsing and colleagues confirms that RLS has a higher prevalence in PD than in controls. Interestingly, this study, and others, has failed to show a connection between PD stage and severity of RLS. Furthermore, the authors found that, as occurs with RLS in patients without PD, patients with RLS and PD have indicators of excessive daytime sleepiness. Of the non-motor symptoms of PD, RLS is eminently treatable, and it is important to routinely enquire as to its presence. Jonathan Carr, Associate Editor, Head Division of Neurology, Tygerberg Hospital & University of Stellenbosch, Tygerberg 7505, South Africa
Prevalence and profile of Restless Legs Syndrome in Parkinson’s disease and other neurodegenerative disorders: A case-control study [Universally Available] Ketaki Bhalsing, K. Suresh, Uday B. Muthane, Pramod Kr. Pal* Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Hosur Road, Bangalore 560029, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 August 2012 Received in revised form 8 December 2012 Accepted 31 December 2012
Background: Restless Legs Syndrome (RLS) is associated with impaired central dopaminergic neurotransmission. Though a link between RLS and parkinsonism has been proposed, the prevalence of RLS in parkinsonian disorders is poorly documented. Objective: To determine the prevalence of RLS in patients with Parkinson’s Disease (PD), Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). Methods: We evaluated 187 consecutive patients with parkinsonian disorders (PD ¼ 134, PSP ¼ 27, MSA ¼ 21, DLB ¼ 5) and 172 healthy controls. RLS was diagnosed using the International RLS Study Group (IRLSSG) criteria and the severity of RLS was assessed in patients with definite RLS. Quality of sleep was evaluated with established scales. Results: The prevalence of RLS was higher in patients compared to controls (9.6% vs. 2.9%; p ¼ 0.009) and was highest in PD (11.9%). RLS was present in only one patient each with MSA and PSP and none with DLB. The mean IRLSSG severity score of patients was 16.2 6.5. The global Pittsburgh Sleep Quality Index score and Epworth Sleepiness Scale score were significantly higher in patients compared to controls (p < 0.001). PD patients with RLS had lower Parkinson’s Disease Sleep Scale (PDSS) score compared to patients without RLS (p ¼ 0.023). There was no significant difference in gender, age, duration and severity of PD between the two groups. Conclusions: Our study found a higher prevalence of RLS in PD compared to healthy controls or other parkinsonian disorders. Apart from PDSS score, there was no significant difference in the clinical characteristics of PD patients with and without RLS. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Parkinson’s Disease Restless Legs Syndrome Progressive Supranuclear Palsy Multiple System Atrophy Dementia with Lewy Bodies Sleep disorder
1. Introduction Restless Legs Syndrome (RLS) is primarily a sensory condition characterised by an abnormal urge to move the limbs that occurs during rest and improves with voluntary movement of the affected limb [1]. The prevalence of RLS varies from 0.1% to 15% among
* Corresponding author. Tel.: þ91 80 26995147; fax: þ91 80 26562829. E-mail address: [email protected] (P.Kr. Pal). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2012.12.005
different ethnic populations [2,3]. The disorder can occur as a primary disorder, most likely caused by a genetic predisposition, or secondary to other medical conditions, including iron deficiency anaemia, end-stage renal disease, neuropathy, pregnancy, rheumatoid arthritis and diabetes mellitus. The aetiology of RLS is still poorly understood, but one important clue to its aetiology may be its beneficial response with dopaminergic treatment [4]. The ability of dopaminergic antagonists to aggravate RLS and evidence of central dopaminergic hypo function on various neuroimaging studies [5] further supports the
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involvement of the dopaminergic system in RLS. Hence, a link between RLS and neurodegenerative disorders (with dopaminergic cell loss) has been proposed. From this point of view, several studies have examined the possible etiological association between RLS and Parkinson’s disease (PD). These studies have showed prevalence of RLS in PD ranging from 0.5% to 19.5% [6,7]. However there are only few studies which have evaluated the prevalence of RLS in atypical parkinsonian disorders. In this study, we prospectively studied prevalence of RLS and its influence on sleep in patients with PD, Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). 2. Subjects and methods Consecutive patients with a diagnosis of PD and other parkinsonian disorders e MSA, PSP or DLB, who fulfilled the inclusion criteria (see below), were recruited from the outpatient clinic of Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), India. The diagnosis of various neurodegenerative disorders was made based on standard clinical criteria i.e. United Kingdom Parkinson’s Disease Society Brain Bank criteria for PD [8], National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-PSP) clinical criteria for PSP [9], diagnostic criteria by Gilman for MSA [10], revised criteria by Mc Keith for DLB [11]. A total of 187 patients were recruited between June 2007 and January 2009. One hundred seventy two age and gender matched healthy individuals, including caregivers of other patients and hospital employees were recruited as controls. Minimental status Examination (MMSE) was done in all subjects. Subjects with MMSE score of 25 or less, family history of neurodegenerative disorders or history of exposure to any neuroleptic drugs were excluded. The study was approved by the Institution’s Ethics Committee and all subjects consented to participate in this study. 2.1. Assessment of subjects (a) For RLS: i. Diagnosis: A positive diagnosis of RLS was made (in both patients and controls) only when they had symptoms in agreement with all four statements listed in the International Restless Legs Syndrome Study Group (IRLSSG) criteria [12]. ii. Severity: The severity of RLS in patients was measured with the IRLSSG rating scale [13]. (b) Sleep scales: All subjects underwent assessment of sleep by Pittsburgh sleep quality index (PSQI) [14] questionnaire and of excessive daytime sleepiness by Epworth sleepiness scale (ESS) [15]. In addition, PD patients underwent further evaluation of sleep by the revised Parkinson’s Disease Sleep Scale (PDSS) [16]. (c) Assessment of stage and severity of PD: All PD patients underwent Hoehn and Yahr (H&Y) [17] staging and rating by the Unified Parkinson’s Disease Rating Scale (UPDRS) [18]. The assessments were performed at the time of recruitment irrespective of time of intake of dopaminergic drugs. 2.2. Statistical analysis
Fig. 1. Prevalence of Restless Legs Syndrome (RLS) among parkinsonian disorders. PD e Parkinson’s Disease, PSP e Progressive Supranuclear Palsy, MSA e Multiple System Atrophy, DLB e Dementia with Lewy Bodies.
highest prevalence was in PD patients (16 out of 134 patients; 11.9%). Only one patient each of MSA and PSP had RLS and none in the DLB group had RLS (Fig. 1). 3.2. Severity of RLS The mean IRLSSG severity score of patients was 16.2 6.5. Four PD patients had mild RLS (score: 1e10); 10 had moderate RLS (score: 11e20) and 2 had severe RLS (score 21e30). The IRLSSG severity score was 13 in the PSP patient and 26 in the MSA patient. No patient had very severe RLS (score: 31e40). 3.3. Quality of sleep In general, patients showed higher PSQI and ESS scores than controls (p < 0.001) (Table 1). These scores were higher in atypical parkinsonian disorders than in PD patients (Table 2) though the difference did not reach statistical significance. In PD, the mean global PSQI 6.9 2.5 and the mean total ESS score was 6.3 3.0 respectively, whereas PSP patient with RLS had PSQI and ESS score of 11 and 7 and MSA patient with RLS had score of 9 and 8 respectively. Table 2 shows individual scores of PSQI and ESS in patients with PD, PSP, MSA and DLB. The comparison of patients and controls is summarised in Table 1.
Statistical analysis was performed by using SPSS 15.0 software. Data was presented as mean SD in case of continuous measurements and as number (%) in case of categorical measurements. Differences between groups were analysed with Analysis of variance (ANOVA) test in case of continuous variables and by Chi-square/ Fisher Exact test in case of categorical variable. A p value <0.05 was considered significant.
4. RLS in PD
3. Results
Table 1 Comparison between patients and controls.
A total of 187 patients and 172 controls were recruited. Distribution of patients was as follows: PD ¼ 134; PSP ¼ 27; MSA ¼ 21 (MSACerebellar type ¼ 10; MSA-Parkinsonian type ¼ 6; MSA-Mixed type ¼ 5); DLB ¼ 5. The mean age of the patients was 56.7 13.2 years. 3.1. Prevalence of RLS The prevalence of RLS was significantly higher in patients than in the controls (9.6% vs. 2.9%; p ¼ 0.009). Among the patients, the
RLS was present in 16 (11.9%) of 134 PD patients. The age at onset of RLS was 55.9 11 years and duration of RLS was 1.6 0.9 years.
Parameters
Patients (n ¼ 187)
Controls (n ¼ 172)
p value
Age (years) Men:women Subjects with RLS (%) Mean age at onset of RLS (years) Global PSQI score ESS score
56.7 13.2 1.9:1 18 (9.6%) 57.3 11.1 6.4 3.7 6.1 3.9
55 13.8 2.1:1 5 (2.9%) 58 4.7 3.5 2.3 4.4 2.6
NS NS 0.009 NS <0.001 <0.001
ESS e Epworth Sleepiness Scale, NS e Not Significant, PSQI e Pittsburgh Sleep Quality Index, RLS e Restless Legs Syndrome.
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5. Discussion
Table 2 Comparison patients with PD and atypical parkinsonian disorders.
Age (years) Men:women Age at onset (years) Duration (years) PSQI score ESS score
PD (n ¼ 134)
PSP (n ¼ 27)
55 2.2:1 50.5 4.6 5.8 5.5
62.7 2:1 60 2.7 7.2 7.3
14.3 14.5 3.4 3.5 3.9
8.3
8.6 1.6 3.1 3.6
MSA (n ¼ 21)
DLBD (n ¼ 5)
57.7 1.3:1 54 2.7 8.1 8.1
67.2 2:3 65.2 2 9.4 6.8
8.5 8.3 1.7 4.7 3.5
10.1
9.9 1 3.5 4.5
ESS e Epworth Sleepiness Scale, PSQI e Pittsburgh Sleep Quality Index.
None of the patients with RLS had a family history of RLS. All patients, except one, reported that the RLS symptoms appeared after the onset of PD, and the mean period between the onset of PD and RLS was 1.5 1.0 years. 4.1. Anatomical distribution of RLS All patients reported symmetrical appearance of RLS symptoms, without any correlation between the predominantly affected side of RLS and that of PD. All but one patient reported that RLS symptoms were clearly restricted only to the lower limbs. One patient reported arm restlessness in addition to leg restlessness. A comparison of clinical features between PD patients with and without RLS is shown in Table 3. The levodopa equivalent daily dose (LEDD) was comparable between the two groups and there was no significant difference in any of the clinical parameters, including the H&Y stage, UPDRS total, motor and the subscores of tremor, rigidity or bradykinesia. Among the sleep scores, though the PSQI and ESS were comparable, the PDSS score was lower in RLS patients (111.7 15.3) compared to those without RLS (122.1 17.2), the difference being statistically significant (p ¼ 0.023). 4.2. Severity of RLS and PD Statistically significant correlation was not observed between severity of RLS and age at onset of PD (p ¼ 0.76), duration of disease (p ¼ 0.63), UPDRS (p ¼ 0.84), H & Y stage (p ¼ 0.14), PSQI (p ¼ 0.38), ESS (p ¼ 0.42) and PDSS (p ¼ 0.17) scores.
Table 3 Clinical features of PD patients with and without RLS. Parameters
With RLS (n ¼ 16)
Without RLS (n ¼ 118)
Men:women Age (Years) Age at onset of PD (years) Duration of PD (Years) Young onset PD (<40 years) UPDRS e Total score UPDRS e Motor score UPDRS e Tremor subscore UPDRS e Rigidity subscore UPDRS e Bradykinesia subscore LEDD (mg) H & Y stage PSQI score ESS score PDSS score*
2.2:1 55.9 52.6 3.4 6.3% 45.4 31.9 10 8 9 585.02 2.6 6.9 6.3 111.7
2.2:1 54.9 50.2 4.8 18.6% 43.8 31.4 9 7 9 608.34 2.2 5.7 5.4 122.1
11 11.8 2.5
27.9 18.6 2.6 4.6 2.8 175.9 0.7 2.5 3 15.3
14.7 14.8 3.5
23 16.2 2.9 4.2 2.4 222.3 0.6 3.6 4 17.2
*p ¼ 0.023. ESS e Epworth Sleepiness Scale, H & Y e Hoehn and Yahr, PD e Parkinson’s Disease, LEDD e levodopa equivalent daily dose, PDSS e Parkinson’s Disease Sleep Scale, PSQI e Pittsburgh Sleep Quality Index, UPDRS e Unified Parkinson’s Disease Rating Scale.
This is the first large study on the prevalence of RLS in parkinsonian disorders. We found a higher prevalence of RLS in the patients than in the controls (9.6% vs. 2.9%; p ¼ 0.009). The prevalence of RLS in our patients is lower than in the Caucasian population [2,19]. This finding could be due to ethnic differences in the populations studied, as studies have shown that RLS was less frequent in a Southeast Asian population with prevalence of 0.6e2% compared to 6e20% in Caucasian population [3,20]. Among the patients, the highest prevalence was in PD. RLS was present in only one patient each of MSA and PSP, but none in those with DLB. RLS has not been commonly reported in atypical parkinsonian disorders. A study by Gama et al. [21] found that RLS was less frequent in MSA than in PSP and PD. Among the 14 patients with PSP studied, RLS was found in 58% in contrast to 3.7% among the 27 PSP patients reported here. In 16 PD patients studied by Gama et al. 50% had RLS in contrast to our observation of 11.9% in 134 PD patients. Although the reasons for this difference in prevalence of RLS is not clear, possible explanations include: (a) younger age of patients in our cohort, as RLS prevalence increases with age [22], (b) neurodegeneration progresses along with disease duration and our patients had disease of a lesser duration (mean disease duration: PD ¼ 4.6 3.4 years, PSP ¼ 2.7 1.6 years) compared to patients studied by Gama et al. (mean disease duration of PD ¼ 6 3.7 years, and of PSP ¼ 5.7 2.3 years), (c) there may be cultural and ethnic differences. 5.1. Quality of sleep In our study patients showed higher PSQI and ESS scores than controls (p < 0.001). PSQI and ESS scores were higher in atypical parkinsonian disorders than PD, despite having lower prevalence of RLS. The finding is similar to that of Ghorayeb et al. [23] suggesting, causes other than RLS (RBD, stridor, sleep-disordered breathing etc.) responsible for poor sleep quality in these patients. A study by Gama et al. reported a higher risk of sleep apnea than RLS in patients with MSA [21]. 5.2. RLS in PD Among PD patients, 11.9% experienced RLS compared to 2.9% in the control group, a finding which probably supports an etiological link between RLS and PD, and is comparable to previous studies [24,25]. Dysfunction of dopaminergic diencephalo-spinal pathway (A11) in the hypothalamus is proposed to play an important role in the pathophysiology of RLS [26]. It is possible that in PD, during the course of the disease, these neurons degenerate, along with nigrostriatal neurons, leading to the development of RLS and thus a higher prevalence rate [27]. PD patients with RLS scored lower on PDSS compared to patients without RLS (p ¼ 0.023), suggesting higher severity of sleep disturbances in PD patients with RLS. The finding is similar to the study by Nomura et al. [7]. The difference in the score was observed mainly in questions related with limb restlessness, numbness or tingling and painful muscle cramps. The prevalence of RLS is known to be more among women [22]. Hormonal factors and iron deficiency may predispose women to RLS. Our results did not reveal gender based difference between the two groups of PD. However, there are conflicting reports on the influence of gender on RLS in PD patients. Findings by Krishnan et al. [24] and Nomura et al. [7] are similar to our study whereas study by Loo and Tan [28] had demonstrated higher prevalence of RLS in women PD patients.
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The prevalence of RLS has been reported to increase with age [22]. However an association between RLS and age in PD patients is inconsistent. Results of our study are in agreement with the study by Ondo et al. [25] who observed that there was no difference in the age of PD patients with and without RLS. In contrast to the above observations, Krishnan et al. [24] found that PD patients with RLS were older and Nomura et al. [7] reported that PD patients with RLS were younger. In idiopathic RLS, a family history, with an autosomal dominant mode of inheritance may be present in more than half of the cases [29]. In the present study as well as the study by Krishnan et al. [24], none of the patients had a family history of RLS, whereas Nomura et al. [7] found a positive family history of RLS in only 2 such patients. These findings suggest a lack of genetic basis in case of RLS in PD. The relation between the duration of PD and onset of RLS symptoms has been evaluated. In many studies including the present one, duration of PD did not differ significantly in patients with and without RLS [7,24,28], whereas Peralta et al. [30] found earlier onset of PD in patients with RLS. All patients, except one, reported onset of RLS after the onset of motor symptoms of PD, supporting the hypothesis that PD may be one of the risk factors for RLS. Arm restlessness has been reported in 22e50% of patients with idiopathic RLS [29], although we found this distribution in a single patient only and Krishnan et al. [24] found none. In idiopathic RLS, though most cases have bilateral symptoms, a significant proportion of patients (41.7%) report either right or left lateralisation [29]. In patients with PD and RLS, Krishnan et al. observed that while most had bilateral symptoms, majority of them (70%) were able to lateralise to a side, mostly to the right. Similarly, Nomura et al. observed that 35% of their PD patients with RLS were able to lateralise RLS symptoms. But in both these studies, laterality did not correlate with the side of onset of motor symptoms of PD. In our study, while all patients with PD with RLS had bilateral symptoms, lateralisation of severity of RLS was not observed though the motor symptoms of PD were asymmetric. A lack of correlation between the side of motor symptom of PD and RLS and the absence of arm restlessness suggest degeneration in other dopaminergic pathways than the nigrostriatal in the pathogenesis of RLS in idiopathic PD [26]. We did not observe any significant difference in the severity and/or stage of PD between patients with and without RLS. This finding is in accordance with previous studies [24,28]. However, since the assessment was performed regardless of the time of intake of dopaminergic drugs, these observations should be interpreted with caution. In general RLS was of moderate severity and no one was on treatment for RLS at the time of interview, which supports the report by Nomura et al. [7] that RLS in PD is often mild. However, at the time of investigation, all patients were on dopaminergic drugs, which are well known to suppress RLS. This bias should be taken into consideration when analysing the severity of RLS in PD patients. 5.3. Limitations Even though care was taken to exclude other conditions that mimic RLS, the overlap of symptoms of RLS with sensorimotor manifestations of PD could not be ruled out. A detailed neurological examination was done in all subjects, but conditions such as iron deficiency anaemia, peripheral neuropathy were not excluded. Our study was a questionnaire based study which may suffer from recall bias. At the same time such studies make it possible to screen a broader and more representative sample of patients.
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In conclusion, our study found a higher prevalence of RLS in PD compared to healthy controls and the other parkinsonian disorders e MSA and PSP. There were no clinical characteristics which differentiated PD patients with and without RLS, except for greater abnormalities of sleep on PDSS scale in patients with RLS. Further studies on larger cohorts of patients with parkinsonism and RLS are required to validate our findings. Financial Disclosure None of the authors have any financial disclosure to make. Source of funding Nil. Conflict of Interest None of the authors have any conflict of interest. References [1] Ekbom KA. Restless legs syndrome. Neurology 1960 Sep;10:868e73. [2] 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 Mar 14;54(5):1064e8 [Research Support, Non-U.S. Gov’t]. [3] Tan EK, Seah A, See SJ, Lim E, Wong MC, Koh KK. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord 2001 May;16(3):577e9 [Comparative Study]. [4] Brodeur C, Montplaisir J, Godbout R, Marinier R. Treatment of restless legs syndrome and periodic movements during sleep with L-dopa: a double-blind, controlled study. Neurology 1988 Dec;38(12):1845e8 [Clinical Trial Controlled Clinical Trial Research Support, Non-U.S. Gov’t]. [5] Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless legs syndrome: 18F-dopa and 11C-raclopride PET studies. Neurology 1999 Mar 23; 52(5):932e7. [6] Angelini M, Negrotti A, Marchesi E, Bonavina G, Calzetti S. A study of the prevalence of restless legs syndrome in previously untreated Parkinson’s disease patients: absence of co-morbid association. J Neurol Sci 2011 Nov 15; 310(1e2):286e8. [7] Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K. Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson’s disease. Mov Disord 2006 Mar;21(3):380e4. [8] Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology 1992 Jun;42(6):1142e6 [Research Support, Non-U.S. Gov’t]. [9] Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (SteeleRichardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996 Jul;47(1):1e9 [Review]. [10] Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C, et al. [Consensus on the diagnosis of multi-system atrophy]. Neurologia 1999 Nov; 14(9):425e8 [Consensus Development Conference Review]. [11] McKeith IG. Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. Neurol Clin 2000 Nov;18(4):865e902 [Review]. [12] 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 Mar;4(2):101e19 [Consensus Development Conference Consensus Development Conference, NIH Research Support, Non-U.S. Gov’t Review]. [13] Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003 Mar;4(2):121e32 [Multicenter Study Validation Studies]. [14] Buysse DJ, Reynolds 3rd CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989 May;28(2):193e213 [Research Support, U.S. Gov’t, P.H. S.]. [15] Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991 Dec;14(6):540e5. [16] Martinez-Martin P, Salvador C, Menendez-Guisasola L, Gonzalez S, Tobias A, Almazan J, et al. Parkinson’s Disease Sleep Scale: validation study of a Spanish version. Mov Disord 2004 Oct;19(10):1226e32 [Validation Studies]. [17] Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967 May;17(5):427e42.
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[18] Movement Disorder Society Task Force on Rating Scales for Parkinson’s D. The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003 Jul;18(7):738e50 [Comparative Study Review]. [19] Chokroverty S, Jankovic J. Restless legs syndrome: a disease in search of identity. Neurology 1999 Mar 23;52(5):907e10 [Editorial]. [20] Nomura T, Inoue Y, Kusumi M, Uemura Y, Nakashima K. Prevalence of restless legs syndrome in a rural community in Japan. Mov Disord 2008 Dec 15; 23(16):2363e9. [21] Gama RL, Tavora DG, Bomfim RC, Silva CE, de Bruin VM, de Bruin PF. Sleep disturbances and brain MRI morphometry in Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy e a comparative study. Parkinsonism Relat Disord 2010 May;16(4):275e9 [Comparative Study Research Support, Non-U.S. Gov’t]. [22] Garcia-Borreguero D, Egatz R, Winkelmann J, Berger K. Epidemiology of restless legs syndrome: the current status. Sleep Med Rev 2006 Jun;10(3): 153e67. [23] Ghorayeb I, Yekhlef F, Chrysostome V, Balestre E, Bioulac B, Tison F. Sleep disorders and their determinants in multiple system atrophy. J Neurol Neurosurg Psychiatr 2002 Jun;72(6):798e800 [Research Support, Non-U.S. Gov’t].
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Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Editor’s comment: Given how common restless legs syndrome is, and its link with dopaminergic dysfunction, it is perhaps surprising that the association between PD and RLS is in fact quite poorly documented. The study by Bhalsing and colleagues confirms that RLS has a higher prevalence in PD than in controls. Interestingly, this study, and others, has failed to show a connection between PD stage and severity of RLS. Furthermore, the authors found that, as occurs with RLS in patients without PD, patients with RLS and PD have indicators of excessive daytime sleepiness. Of the non-motor symptoms of PD, RLS is eminently treatable, and it is important to routinely enquire as to its presence. Jonathan Carr, Associate Editor, Head Division of Neurology, Tygerberg Hospital & University of Stellenbosch, Tygerberg 7505, South Africa
Prevalence and profile of Restless Legs Syndrome in Parkinson’s disease and other neurodegenerative disorders: A case-control study [Universally Available] Ketaki Bhalsing, K. Suresh, Uday B. Muthane, Pramod Kr. Pal* Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS), Hosur Road, Bangalore 560029, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 August 2012 Received in revised form 8 December 2012 Accepted 31 December 2012
Background: Restless Legs Syndrome (RLS) is associated with impaired central dopaminergic neurotransmission. Though a link between RLS and parkinsonism has been proposed, the prevalence of RLS in parkinsonian disorders is poorly documented. Objective: To determine the prevalence of RLS in patients with Parkinson’s Disease (PD), Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). Methods: We evaluated 187 consecutive patients with parkinsonian disorders (PD ¼ 134, PSP ¼ 27, MSA ¼ 21, DLB ¼ 5) and 172 healthy controls. RLS was diagnosed using the International RLS Study Group (IRLSSG) criteria and the severity of RLS was assessed in patients with definite RLS. Quality of sleep was evaluated with established scales. Results: The prevalence of RLS was higher in patients compared to controls (9.6% vs. 2.9%; p ¼ 0.009) and was highest in PD (11.9%). RLS was present in only one patient each with MSA and PSP and none with DLB. The mean IRLSSG severity score of patients was 16.2 6.5. The global Pittsburgh Sleep Quality Index score and Epworth Sleepiness Scale score were significantly higher in patients compared to controls (p < 0.001). PD patients with RLS had lower Parkinson’s Disease Sleep Scale (PDSS) score compared to patients without RLS (p ¼ 0.023). There was no significant difference in gender, age, duration and severity of PD between the two groups. Conclusions: Our study found a higher prevalence of RLS in PD compared to healthy controls or other parkinsonian disorders. Apart from PDSS score, there was no significant difference in the clinical characteristics of PD patients with and without RLS. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Parkinson’s Disease Restless Legs Syndrome Progressive Supranuclear Palsy Multiple System Atrophy Dementia with Lewy Bodies Sleep disorder
1. Introduction Restless Legs Syndrome (RLS) is primarily a sensory condition characterised by an abnormal urge to move the limbs that occurs during rest and improves with voluntary movement of the affected limb [1]. The prevalence of RLS varies from 0.1% to 15% among
* Corresponding author. Tel.: þ91 80 26995147; fax: þ91 80 26562829. E-mail address: [email protected] (P.Kr. Pal). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2012.12.005
different ethnic populations [2,3]. The disorder can occur as a primary disorder, most likely caused by a genetic predisposition, or secondary to other medical conditions, including iron deficiency anaemia, end-stage renal disease, neuropathy, pregnancy, rheumatoid arthritis and diabetes mellitus. The aetiology of RLS is still poorly understood, but one important clue to its aetiology may be its beneficial response with dopaminergic treatment [4]. The ability of dopaminergic antagonists to aggravate RLS and evidence of central dopaminergic hypo function on various neuroimaging studies [5] further supports the
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involvement of the dopaminergic system in RLS. Hence, a link between RLS and neurodegenerative disorders (with dopaminergic cell loss) has been proposed. From this point of view, several studies have examined the possible etiological association between RLS and Parkinson’s disease (PD). These studies have showed prevalence of RLS in PD ranging from 0.5% to 19.5% [6,7]. However there are only few studies which have evaluated the prevalence of RLS in atypical parkinsonian disorders. In this study, we prospectively studied prevalence of RLS and its influence on sleep in patients with PD, Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB). 2. Subjects and methods Consecutive patients with a diagnosis of PD and other parkinsonian disorders e MSA, PSP or DLB, who fulfilled the inclusion criteria (see below), were recruited from the outpatient clinic of Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), India. The diagnosis of various neurodegenerative disorders was made based on standard clinical criteria i.e. United Kingdom Parkinson’s Disease Society Brain Bank criteria for PD [8], National Institute of Neurological Disorders and Stroke and the Society for PSP (NINDS-PSP) clinical criteria for PSP [9], diagnostic criteria by Gilman for MSA [10], revised criteria by Mc Keith for DLB [11]. A total of 187 patients were recruited between June 2007 and January 2009. One hundred seventy two age and gender matched healthy individuals, including caregivers of other patients and hospital employees were recruited as controls. Minimental status Examination (MMSE) was done in all subjects. Subjects with MMSE score of 25 or less, family history of neurodegenerative disorders or history of exposure to any neuroleptic drugs were excluded. The study was approved by the Institution’s Ethics Committee and all subjects consented to participate in this study. 2.1. Assessment of subjects (a) For RLS: i. Diagnosis: A positive diagnosis of RLS was made (in both patients and controls) only when they had symptoms in agreement with all four statements listed in the International Restless Legs Syndrome Study Group (IRLSSG) criteria [12]. ii. Severity: The severity of RLS in patients was measured with the IRLSSG rating scale [13]. (b) Sleep scales: All subjects underwent assessment of sleep by Pittsburgh sleep quality index (PSQI) [14] questionnaire and of excessive daytime sleepiness by Epworth sleepiness scale (ESS) [15]. In addition, PD patients underwent further evaluation of sleep by the revised Parkinson’s Disease Sleep Scale (PDSS) [16]. (c) Assessment of stage and severity of PD: All PD patients underwent Hoehn and Yahr (H&Y) [17] staging and rating by the Unified Parkinson’s Disease Rating Scale (UPDRS) [18]. The assessments were performed at the time of recruitment irrespective of time of intake of dopaminergic drugs. 2.2. Statistical analysis
Fig. 1. Prevalence of Restless Legs Syndrome (RLS) among parkinsonian disorders. PD e Parkinson’s Disease, PSP e Progressive Supranuclear Palsy, MSA e Multiple System Atrophy, DLB e Dementia with Lewy Bodies.
highest prevalence was in PD patients (16 out of 134 patients; 11.9%). Only one patient each of MSA and PSP had RLS and none in the DLB group had RLS (Fig. 1). 3.2. Severity of RLS The mean IRLSSG severity score of patients was 16.2 6.5. Four PD patients had mild RLS (score: 1e10); 10 had moderate RLS (score: 11e20) and 2 had severe RLS (score 21e30). The IRLSSG severity score was 13 in the PSP patient and 26 in the MSA patient. No patient had very severe RLS (score: 31e40). 3.3. Quality of sleep In general, patients showed higher PSQI and ESS scores than controls (p < 0.001) (Table 1). These scores were higher in atypical parkinsonian disorders than in PD patients (Table 2) though the difference did not reach statistical significance. In PD, the mean global PSQI 6.9 2.5 and the mean total ESS score was 6.3 3.0 respectively, whereas PSP patient with RLS had PSQI and ESS score of 11 and 7 and MSA patient with RLS had score of 9 and 8 respectively. Table 2 shows individual scores of PSQI and ESS in patients with PD, PSP, MSA and DLB. The comparison of patients and controls is summarised in Table 1.
Statistical analysis was performed by using SPSS 15.0 software. Data was presented as mean SD in case of continuous measurements and as number (%) in case of categorical measurements. Differences between groups were analysed with Analysis of variance (ANOVA) test in case of continuous variables and by Chi-square/ Fisher Exact test in case of categorical variable. A p value <0.05 was considered significant.
4. RLS in PD
3. Results
Table 1 Comparison between patients and controls.
A total of 187 patients and 172 controls were recruited. Distribution of patients was as follows: PD ¼ 134; PSP ¼ 27; MSA ¼ 21 (MSACerebellar type ¼ 10; MSA-Parkinsonian type ¼ 6; MSA-Mixed type ¼ 5); DLB ¼ 5. The mean age of the patients was 56.7 13.2 years. 3.1. Prevalence of RLS The prevalence of RLS was significantly higher in patients than in the controls (9.6% vs. 2.9%; p ¼ 0.009). Among the patients, the
RLS was present in 16 (11.9%) of 134 PD patients. The age at onset of RLS was 55.9 11 years and duration of RLS was 1.6 0.9 years.
Parameters
Patients (n ¼ 187)
Controls (n ¼ 172)
p value
Age (years) Men:women Subjects with RLS (%) Mean age at onset of RLS (years) Global PSQI score ESS score
56.7 13.2 1.9:1 18 (9.6%) 57.3 11.1 6.4 3.7 6.1 3.9
55 13.8 2.1:1 5 (2.9%) 58 4.7 3.5 2.3 4.4 2.6
NS NS 0.009 NS <0.001 <0.001
ESS e Epworth Sleepiness Scale, NS e Not Significant, PSQI e Pittsburgh Sleep Quality Index, RLS e Restless Legs Syndrome.
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5. Discussion
Table 2 Comparison patients with PD and atypical parkinsonian disorders.
Age (years) Men:women Age at onset (years) Duration (years) PSQI score ESS score
PD (n ¼ 134)
PSP (n ¼ 27)
55 2.2:1 50.5 4.6 5.8 5.5
62.7 2:1 60 2.7 7.2 7.3
14.3 14.5 3.4 3.5 3.9
8.3
8.6 1.6 3.1 3.6
MSA (n ¼ 21)
DLBD (n ¼ 5)
57.7 1.3:1 54 2.7 8.1 8.1
67.2 2:3 65.2 2 9.4 6.8
8.5 8.3 1.7 4.7 3.5
10.1
9.9 1 3.5 4.5
ESS e Epworth Sleepiness Scale, PSQI e Pittsburgh Sleep Quality Index.
None of the patients with RLS had a family history of RLS. All patients, except one, reported that the RLS symptoms appeared after the onset of PD, and the mean period between the onset of PD and RLS was 1.5 1.0 years. 4.1. Anatomical distribution of RLS All patients reported symmetrical appearance of RLS symptoms, without any correlation between the predominantly affected side of RLS and that of PD. All but one patient reported that RLS symptoms were clearly restricted only to the lower limbs. One patient reported arm restlessness in addition to leg restlessness. A comparison of clinical features between PD patients with and without RLS is shown in Table 3. The levodopa equivalent daily dose (LEDD) was comparable between the two groups and there was no significant difference in any of the clinical parameters, including the H&Y stage, UPDRS total, motor and the subscores of tremor, rigidity or bradykinesia. Among the sleep scores, though the PSQI and ESS were comparable, the PDSS score was lower in RLS patients (111.7 15.3) compared to those without RLS (122.1 17.2), the difference being statistically significant (p ¼ 0.023). 4.2. Severity of RLS and PD Statistically significant correlation was not observed between severity of RLS and age at onset of PD (p ¼ 0.76), duration of disease (p ¼ 0.63), UPDRS (p ¼ 0.84), H & Y stage (p ¼ 0.14), PSQI (p ¼ 0.38), ESS (p ¼ 0.42) and PDSS (p ¼ 0.17) scores.
Table 3 Clinical features of PD patients with and without RLS. Parameters
With RLS (n ¼ 16)
Without RLS (n ¼ 118)
Men:women Age (Years) Age at onset of PD (years) Duration of PD (Years) Young onset PD (<40 years) UPDRS e Total score UPDRS e Motor score UPDRS e Tremor subscore UPDRS e Rigidity subscore UPDRS e Bradykinesia subscore LEDD (mg) H & Y stage PSQI score ESS score PDSS score*
2.2:1 55.9 52.6 3.4 6.3% 45.4 31.9 10 8 9 585.02 2.6 6.9 6.3 111.7
2.2:1 54.9 50.2 4.8 18.6% 43.8 31.4 9 7 9 608.34 2.2 5.7 5.4 122.1
11 11.8 2.5
27.9 18.6 2.6 4.6 2.8 175.9 0.7 2.5 3 15.3
14.7 14.8 3.5
23 16.2 2.9 4.2 2.4 222.3 0.6 3.6 4 17.2
*p ¼ 0.023. ESS e Epworth Sleepiness Scale, H & Y e Hoehn and Yahr, PD e Parkinson’s Disease, LEDD e levodopa equivalent daily dose, PDSS e Parkinson’s Disease Sleep Scale, PSQI e Pittsburgh Sleep Quality Index, UPDRS e Unified Parkinson’s Disease Rating Scale.
This is the first large study on the prevalence of RLS in parkinsonian disorders. We found a higher prevalence of RLS in the patients than in the controls (9.6% vs. 2.9%; p ¼ 0.009). The prevalence of RLS in our patients is lower than in the Caucasian population [2,19]. This finding could be due to ethnic differences in the populations studied, as studies have shown that RLS was less frequent in a Southeast Asian population with prevalence of 0.6e2% compared to 6e20% in Caucasian population [3,20]. Among the patients, the highest prevalence was in PD. RLS was present in only one patient each of MSA and PSP, but none in those with DLB. RLS has not been commonly reported in atypical parkinsonian disorders. A study by Gama et al. [21] found that RLS was less frequent in MSA than in PSP and PD. Among the 14 patients with PSP studied, RLS was found in 58% in contrast to 3.7% among the 27 PSP patients reported here. In 16 PD patients studied by Gama et al. 50% had RLS in contrast to our observation of 11.9% in 134 PD patients. Although the reasons for this difference in prevalence of RLS is not clear, possible explanations include: (a) younger age of patients in our cohort, as RLS prevalence increases with age [22], (b) neurodegeneration progresses along with disease duration and our patients had disease of a lesser duration (mean disease duration: PD ¼ 4.6 3.4 years, PSP ¼ 2.7 1.6 years) compared to patients studied by Gama et al. (mean disease duration of PD ¼ 6 3.7 years, and of PSP ¼ 5.7 2.3 years), (c) there may be cultural and ethnic differences. 5.1. Quality of sleep In our study patients showed higher PSQI and ESS scores than controls (p < 0.001). PSQI and ESS scores were higher in atypical parkinsonian disorders than PD, despite having lower prevalence of RLS. The finding is similar to that of Ghorayeb et al. [23] suggesting, causes other than RLS (RBD, stridor, sleep-disordered breathing etc.) responsible for poor sleep quality in these patients. A study by Gama et al. reported a higher risk of sleep apnea than RLS in patients with MSA [21]. 5.2. RLS in PD Among PD patients, 11.9% experienced RLS compared to 2.9% in the control group, a finding which probably supports an etiological link between RLS and PD, and is comparable to previous studies [24,25]. Dysfunction of dopaminergic diencephalo-spinal pathway (A11) in the hypothalamus is proposed to play an important role in the pathophysiology of RLS [26]. It is possible that in PD, during the course of the disease, these neurons degenerate, along with nigrostriatal neurons, leading to the development of RLS and thus a higher prevalence rate [27]. PD patients with RLS scored lower on PDSS compared to patients without RLS (p ¼ 0.023), suggesting higher severity of sleep disturbances in PD patients with RLS. The finding is similar to the study by Nomura et al. [7]. The difference in the score was observed mainly in questions related with limb restlessness, numbness or tingling and painful muscle cramps. The prevalence of RLS is known to be more among women [22]. Hormonal factors and iron deficiency may predispose women to RLS. Our results did not reveal gender based difference between the two groups of PD. However, there are conflicting reports on the influence of gender on RLS in PD patients. Findings by Krishnan et al. [24] and Nomura et al. [7] are similar to our study whereas study by Loo and Tan [28] had demonstrated higher prevalence of RLS in women PD patients.
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The prevalence of RLS has been reported to increase with age [22]. However an association between RLS and age in PD patients is inconsistent. Results of our study are in agreement with the study by Ondo et al. [25] who observed that there was no difference in the age of PD patients with and without RLS. In contrast to the above observations, Krishnan et al. [24] found that PD patients with RLS were older and Nomura et al. [7] reported that PD patients with RLS were younger. In idiopathic RLS, a family history, with an autosomal dominant mode of inheritance may be present in more than half of the cases [29]. In the present study as well as the study by Krishnan et al. [24], none of the patients had a family history of RLS, whereas Nomura et al. [7] found a positive family history of RLS in only 2 such patients. These findings suggest a lack of genetic basis in case of RLS in PD. The relation between the duration of PD and onset of RLS symptoms has been evaluated. In many studies including the present one, duration of PD did not differ significantly in patients with and without RLS [7,24,28], whereas Peralta et al. [30] found earlier onset of PD in patients with RLS. All patients, except one, reported onset of RLS after the onset of motor symptoms of PD, supporting the hypothesis that PD may be one of the risk factors for RLS. Arm restlessness has been reported in 22e50% of patients with idiopathic RLS [29], although we found this distribution in a single patient only and Krishnan et al. [24] found none. In idiopathic RLS, though most cases have bilateral symptoms, a significant proportion of patients (41.7%) report either right or left lateralisation [29]. In patients with PD and RLS, Krishnan et al. observed that while most had bilateral symptoms, majority of them (70%) were able to lateralise to a side, mostly to the right. Similarly, Nomura et al. observed that 35% of their PD patients with RLS were able to lateralise RLS symptoms. But in both these studies, laterality did not correlate with the side of onset of motor symptoms of PD. In our study, while all patients with PD with RLS had bilateral symptoms, lateralisation of severity of RLS was not observed though the motor symptoms of PD were asymmetric. A lack of correlation between the side of motor symptom of PD and RLS and the absence of arm restlessness suggest degeneration in other dopaminergic pathways than the nigrostriatal in the pathogenesis of RLS in idiopathic PD [26]. We did not observe any significant difference in the severity and/or stage of PD between patients with and without RLS. This finding is in accordance with previous studies [24,28]. However, since the assessment was performed regardless of the time of intake of dopaminergic drugs, these observations should be interpreted with caution. In general RLS was of moderate severity and no one was on treatment for RLS at the time of interview, which supports the report by Nomura et al. [7] that RLS in PD is often mild. However, at the time of investigation, all patients were on dopaminergic drugs, which are well known to suppress RLS. This bias should be taken into consideration when analysing the severity of RLS in PD patients. 5.3. Limitations Even though care was taken to exclude other conditions that mimic RLS, the overlap of symptoms of RLS with sensorimotor manifestations of PD could not be ruled out. A detailed neurological examination was done in all subjects, but conditions such as iron deficiency anaemia, peripheral neuropathy were not excluded. Our study was a questionnaire based study which may suffer from recall bias. At the same time such studies make it possible to screen a broader and more representative sample of patients.
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