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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
article info
Article history:
Received 30 August 2012
Received in revised form
8 December 2012
Accepted 31 December 2012
Keywords:
Parkinson’s Disease
Restless Legs Syndrome
Progressive Supranuclear Palsy
Multiple System Atrophy
Dementia with Lewy Bodies
Sleep disorder
abstract
Background: Restless Legs Syndrome (RLS) is associated with impaired central dopaminergic neuro-
transmission. 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 ¼134, PSP ¼27,
MSA ¼21, DLB ¼5) 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%; p¼0.009) 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 (p¼0.023). 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 char-
acteristics of PD patients with and without RLS.
Ó2013 Elsevier Ltd. All rights reserved.
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
different ethnic populations [2,3]. The disorder can occur as a pri-
mary disorder, most likely caused by a genetic predisposition, or
secondary to other medical conditions, including iron deficiency
anaemia, end-stage renal disease, neuropathy, pregnancy, rheu-
matoid 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 dop-
aminergic 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
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
*Corresponding author. Tel.: þ91 80 26995147; fax: þ91 80 26562829.
E-mail address: pal.pramod@rediffmail.com (P.Kr. Pal).
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders
journal homepage: www.elsevier.com/locate/parkreldis
1353-8020/$ esee front matter Ó2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.parkreldis.2012.12.005
Parkinsonism and Related Disorders 19 (2013) 426e430
involvement of the dopaminergic system in RLS. Hence, a link be-
tween RLS and neurodegenerative disorders (with dopaminergic cell
loss) has beenproposed. 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 eMSA,
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 187patients were recruited between June 2007 and January 2009. One
hundred seventy two age and gender matched healthy individuals, including care-
givers of other patients and hospital employees were recruited as controls. Mini-
mental 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 SyndromeStudy 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 in-
dex (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
Statistical analysis was performed by using SPSS 15.0 software. Data was pre-
sented 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 pvalue <0.05 was considered
significant.
3. Results
A totalof 187patients and 172 controls were recruited.Distribution
of patients was as follows: PD ¼134; PSP ¼27; MSA ¼21 (MSA-
Cerebellar type ¼10; MSA-Parkinsonian type ¼6; MSA-Mixed
type ¼5); DLB ¼5. Themean age of the patients was56.7 13.2 yea rs.
3.1. Prevalence of RLS
The prevalence of RLS was significantly higher in patients than
in the controls (9.6% vs. 2.9%; p¼0.009). Among the patients, the
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.
4. RLS in PD
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.
Fig. 1. Prevalence of Restless Legs Syndrome (RLS) among parkinsonian disorders. PD
eParkinson’s Disease, PSP eProgressive Supranuclear Palsy, MSA eMultiple System
Atrophy, DLB eDementia with Lewy Bodies.
Table 1
Comparison between patients and controls.
Parameters Patients
(n¼187)
Controls
(n¼172)
pvalue
Age (years) 56.7 13.2 55 13.8 NS
Men:women 1.9:1 2.1:1 NS
Subjects with RLS (%) 18 (9.6%) 5 (2.9%) 0.009
Mean age at onset of RLS (years) 57.3 11.1 58 4.7 NS
Global PSQI score 6.4 3.7 3.5 2.3 <0.001
ESS score 6.1 3.9 4.4 2.6 <0.001
ESS eEpworth Sleepiness Scale, NS eNot Significant, PSQI ePittsburgh Sleep
Quality Index, RLS eRestless Legs Syndrome.
K. Bhalsing et al. / Parkinsonism and Related Disorders 19 (2013) 426e430 427
None of the patients with RLS had a family history of RLS. All pa-
tients, 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 symp-
toms, 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 (p¼0.023).
4.2. Severity of RLS and PD
Statistically significant correlation was not observed between
severity of RLS and age at onset of PD (p¼0.76), duration of disease
(p¼0.63), UPDRS (p¼0.84), H & Y stage (p¼0.14), PSQI (p¼0.38),
ESS (p¼0.42) and PDSS (p¼0.17) scores.
5. Discussion
This is the first large study on the prevalence of RLS in parkin-
sonian disorders. We found a higher prevalence of RLS in the pa-
tients than in the controls (9.6% vs. 2.9%; p¼0.009). 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 pop-
ulations studied, as studies have shown that RLS was less frequent
in a Southeast Asian population with prevalence of 0.6e2% com-
pared 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 par-
kinsonian 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 prev-
alence 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 ¼4.6 3.4 years, PSP ¼2.7 1.6 years) compared to
patients studied by Gama et al. (mean disease duration of
PD ¼63.7 years, and of PSP ¼5.7 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 pa-
tients 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 pa-
tients without RLS (p¼0.023), 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.
Table 2
Comparison patients with PD and atypical parkinsonian disorders.
PD
(n¼134)
PSP
(n¼27)
MSA
(n¼21)
DLBD
(n¼5)
Age (years) 55 14.3 62.7 8.3 57.7 8.5 67.2 10.1
Men:women 2.2:1 2:1 1.3:1 2:3
Age at onset (years) 50.5 14.5 60 8.6 54 8.3 65.2 9.9
Duration (years) 4.6 3.4 2.7 1.6 2.7 1.7 2 1
PSQI score 5.8 3.5 7.2 3.1 8.1 4.7 9.4 3.5
ESS score 5.5 3.9 7.3 3.6 8.1 3.5 6.8 4.5
ESS eEpworth Sleepiness Scale, PSQI ePittsburgh Sleep Quality Index.
Table 3
Clinical features of PD patients with and without RLS.
Parameters With RLS
(n¼16)
Without RLS
(n¼118)
Men:women 2.2:1 2.2:1
Age (Years) 55.9 11 54.9 14.7
Age at onset of PD (years) 52.6 11.8 50.2 14.8
Duration of PD (Years) 3.4 2.5 4.8 3.5
Young onset PD (<40 years) 6.3% 18.6%
UPDRS eTotal score 45.4 27.9 43.8 23
UPDRS eMotor score 31.9 18.6 31.4 16.2
UPDRS eTremor subscore 10 2.6 9 2.9
UPDRS eRigidity subscore 8 4.6 7 4.2
UPDRS eBradykinesia subscore 9 2.8 9 2.4
LEDD (mg) 585.02 175.9 608.34 222.3
H & Y stage 2.6 0.7 2.2 0.6
PSQI score 6.9 2.5 5.7 3.6
ESS score 6.3 3 5.4 4
PDSS score* 111.7 15.3 122.1 17.2
*p¼0.023.
ESS eEpworth Sleepiness Scale, H & Y eHoehn and Yahr, PD eParkinson’sDisease,
LEDD elevodopa equivalent daily dose, PDSS eParkinson’s Disease Sleep Scale,
PSQI ePittsburgh Sleep Quality Index, UPDRS eUnified Parkinson’s Disease Rating
Scale.
K. Bhalsing et al. / Parkinsonism and Related Disorders 19 (2013) 426e430428
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 pa-
tients. 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 pre-
sent 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 inter-
preted 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
abroader and more representative sample of patients.
In conclusion, our study found a higher prevalence of RLS in PD
compared to healthy controls and the other parkinsonian disorders
eMSA and PSP. There were no clinical characteristics which dif-
ferentiated 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.
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