Journal of the Neurological Sciences 266 (2008) 145 – 149

www.elsevier.com/locate/jns

Case–control study of restless legs syndrome and quality of

sleep in Parkinson's disease
Hui-Voon Loo, Eng-King Tan ⁎
Departments of Neurology, Singapore General Hospital National Neuroscience Institute SingHealth, Singapore
Received 2 April 2007; received in revised form 29 July 2007; accepted 14 September 2007
Available online 17 October 2007

Abstract

In a case–control study involving 400 study subjects, we found a higher prevalence of restless legs syndrome (RLS) in our Parkinson's
disease (PD) patients compared to controls (3.0% vs 0.5%) (odds ratio 6.2) (p = 0.07). Polysomnographic studies confirmed that study
subjects with RLS had grossly elevated PLMS index, PLMS arousal index and reduced sleep efficiency. None of these PD patients reported a
family history of PD or RLS. The average age of onset of RLS was 61.7 ± 10.8 years old.
The mean global Pittsburg Sleep Quality Index (PSQI) score of PD patients was significantly higher than the controls (9.1 ± 4.5 vs 4.3 ± 2.8,
p b 0.0001). All the seven components of PSQI in PD patients were significantly different from controls (p b 0.0001). Multivariate analysis
revealed that only Hoehn and Yahr staging correlated with the global PSQI score (p b 0.0001). Similar results were obtained when we compared
the PSQI score between PD patients without RLS with controls.
Our case–control study demonstrated a weak association between RLS and PD. PD patients have significant poor quality of sleep, and
this correlated with the severity of PD. RLS did not play an important role in sleep dysfunction in our PD cohort. A high index of suspicion
for sleep problems in advanced PD patients is important as early management could improve their quality of life.
© 2007 Elsevier B.V. All rights reserved.

Keywords: Restless legs syndrome; Parkinson's disease

1. Introduction amongst Caucasians (10–15%) [8–10] than in some Asian

Parkinson's disease (PD) is a progressive neurodegener-
ative disorder characterized by rest tremor, rigidity, bradyki-
nesia and postural instability [1]. Apart from motor
symptoms, patients with PD often complain of sleep
disturbances. The prevalence of sleep problems in PD
patients has been estimated to be between 50–80% [2,3].
One of the common sleep disturbances that might occur in PD
is restless legs syndrome (RLS) [2,3]. RLS is characterized by
the urge to move the lower extremities with unpleasant
sensations and the symptoms are particularly worse at night
[4–7]. The reported prevalence of RLS appears higher
⁎ Corresponding author. Department of Neurology, Singapore General
Hospital Outram Road Singapore 169608, Singapore. Fax: +65 6220 3321.
E-mail address: gnrtek@sgh.com.sg (E.-K. Tan).
0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2007.09.033
populations (0.1–1.0%) [11,12].
Limited observational and case–control studies give
differing findings regarding the association of RLS and PD
[13–17]. To our knowledge, since the introduction of the
International Restless Legs Syndrome Study Group
(IRLSSG) and National Institute of Health (NIH) criteria
[6,7], there has only been two case–control studies that
investigated RLS in PD patients, both showing a positive
association between the two conditions [13,14]. In a non-
controlled observational study, we previously found none of
our PD patients reported RLS symptoms [15].
The exact underlying pathophysiology of sleep disorders
in PD is still unknown. Advanced age, disease severity,
medications or co-existing illnesses may be contributory
causes [3,18,19]. Some studies suggest that sleep problems
correlate with severity of PD [18], while others report sleep
146 H.-V. Loo, E.-K. Tan / Journal of the Neurological Sciences 266 (2008) 145–149

problems in only PD patients with RLS [13], suggesting that alpha = 0.05. Thus our case–control study was sufficiently
RLS maybe one of the major causes of sleep problems. powered to detect an approximate 5% difference of RLS
The current limited literature on the association between prevalence between PD and controls.
RLS and PD, and the potential concern of under-diagnosis in
our earlier observational study prompted us to conduct a 4. Results
prospective case–control study of RLS in PD patients of
Asian ethnicity. In addition, we investigated the predictive A total of 400 study subjects comprising 200 PD and 200
factors of quality of sleep using the Pittsburgh Sleep Quality (10 were spouses or relatives of patients, the rest were
Index (PSQI) scale in the study subjects. healthy individuals) controls were prospectively recruited.
The mean age, mean age at onset of the PD patients, and
2. Method mean age of controls was 65.3 ± 10.7 (range 37– 90 years),
59.2 ± 11.0 (range 27–87 years), and 60.5 ± 10.5 (range 36–
Patients newly diagnosed to have PD according to 89 years), comprising 48.0% and 58.5% women. Six of the
standardized clinical criteria in a tertiary referral center in 200 patients (3.0%) and one of the 200 controls (0.5%) were
Singapore General Hospital were prospectively recruited diagnosed clinically with RLS. The difference was only
from 2002–2005. None of the patients who were included marginally significant (odds ratio 6.2) (p = 0.07).
participated in our earlier study [15]. The controls, frequency Among the six PD patients with RLS, four underwent
matched for age (+ 5 years), gender and race were either overnight polysomnography. The mean Periodic Limbs
spouses or relatives of the patients or healthy volunteers and Movements (PLMS) index, Sleep efficiency and PLMS
recruited over the same period. Only subjects with a mini arousal index was 59.6 ± 64.7/h (normal b 5/h), 49.2 ± 16.2%
mental state examination score of ≥ 25/30 were included. (normal N 75%) and 17.0 ± 13.0/h (normal b 5/h) respective-
The diagnosis of RLS was made by a movement disorder ly. The mean IRLSSG score was 21.3 ± 6.1, with two patients
neurologist (EK-T) according to the NIH criteria: (1) an urge having mild (total score b 16), two with moderate (total score
to move the legs usually accompanied by uncomfortable 16–25) and one with severe RLS. None of these PD patients
sensation in the legs; (2) worsening of symptoms during reported a family history of PD or RLS. The average age of
periods of rest; (3) partial or total relief of symptoms by onset of RLS was 61.7 ± 10.8 years old. PD patients with
movement; and (4) the symptoms being worse at night or in RLS (63.2 ± 10.3 years old) were only slightly younger than
the evening [7]. In addition, the PSQI was administered to those without RLS (65.4 ± 10.7 years old) (p N 0.05). Three
the study subjects. We also collected information on age, patients reported symptoms of RLS after being diagnosed
gender, age of onset of disease, family history, severity of PD with PD, two had symptoms of RLS prior to onset of PD
(Hoehn and Yahr stage, H&Y), levodopa dosage, and the use whereas one complained of symptoms of RLS simultaneous
of dopamine agonists were tabulated and analyzed. As the
number of patients on dopamine agonists was small, the dose Table 1
was not tabulated. The score of the seven components of the Demographics variables of PD patients with and without RLS
PSQI, which included (i) subjective sleep quality, (ii) sleep PD patients PD patients p value
latency, (iii) sleep duration, (iv) habitual sleep efficiency, (v) without RLS with RLS
sleep dysfunction, (vi) use of sleeping medication, and (vii) Number 194 6
daytime dysfunction were also individually analyzed. Our Age at presentation (year) 65.4 ± 10.7 63.2 ± 10.3 0.67
study received approval from the institution ethics Male (%) 104 (52.0) 2(33.3) 0.43
committee. Female (%) 96 (48) 4 (66.7) 0.43
Age of onset of PD (year) 59.2 ± 11.1 57.8 ± 10.6 0.80
Duration of disease (year) 7.2 ± 4.7 6.3 ± 1.9 0.79
3. Statistical analysis Family history of PD (%) 15(7.73) 0 0.48
Hoehn and Yahr stage 2.5 ± 0.5 2.4 ± 0.4 0.52
Statistical analyses were carried out using SPSS software. (Number of patients)
Fischer exact test was used to compare the categorical (mg/day)
Levodopa 180 (428.1 ± 203.0) 5 (294.3 ± 183.2) 0.07
variables and Student's t-test or Mann–Whitney test for the
Selegiline 22 (7.4 ± 4.0) 2 (10.0 ± 0.0) 0.12
continuous variables. A multivariate logistic regression Piribedil 7 (121.4 ± 26.7) 0 0.13
analysis was used to determine whether age, gender, age of Entacapone 15 (1.9 ± 1.4) 0 0.59
onset, H&Y stage, and dose of levodopa predicted the global Ropinirole 17 (2.4 ± 1.3) 2 (3.4 ± 1.9) 0.41
PSQI score. Data were presented as mean ± standard Bromocriptine 3 (9.2 ± 1.4) 0 0.76
Biochemical tests
deviation (SD) unless otherwise stated. We defined statistical
Mean hemoglobin a 13.0 ± 1.2 14.0 ± 1.3 0.20
significance at p b 0.05. Statistical power calculation: Based (G/DL) (10.0–15.4) (13.0–16.0)
on a 1% prevalence of RLS in our population, and an Mean RBC distribution a 13.4 ± 1.2 13.1 ± 0.8 0.80
estimated prevalence of RLS in PD to be 10%, a sample size width (%) (11.7–17.2) (12.3–14.5)
of 122 PD patients and 122 controls would be needed for the p value was obtained either through Mann–Whitney or Fischer exact test.
a
study to have 80% power to detect the difference at Random samples from 50 PD without RLS.
 H.-V. Loo, E.-K. Tan / Journal of the Neurological Sciences 266 (2008) 145–149 147

Table 3
RLS-like conditions or “misinterpretations” that did not satisfy RLS
diagnostic criteria
RLS-like conditions/patient's misinterpretations
Anxiety
Restlessness from motor fluctuation
Joint aches from osteoarthritis
Habitual leg shaking
Lower limb levodopa-induced dyskinesias
Lower limb tremor

Fig. 1. Distribution of global PSQI scores in PD and controls.
with the onset of PD. Five out of the 6 patients were on
levodopa, at doses ranging from 262.5 to 562.5 mg/day
(mean, 245.3 ± 203.2 mg/day). Only two patients with RLS
were on dopamine agonists (Table 1). Clinical examination
and biochemical tests in these RLS patients did not show
evidence of iron deficiency anemia, renal or other organ
failure. Specifically, the hemoglobin concentration (Hb),
mean corpuscular volume (MCV), mean red cell hemoglobin
content (MCHC), and red cell distribution width (RDW) of
all the PD patients with RLS were within normal range. Their
mean Hb was 13.1 ± 0.8 (normal range 12.0–16.0 g/dl);
mean MCV 90.8 ± 3.9 (normal range 76.0–96.0 fL); mean
MCHC 34.5 ± 1.4 (normal range 32.0–36.0 g/dL); mean
RDW 13.1 ± 0.8 (normal range 10.9–15.7%.). The mean Hb
and RDW were not different between PD with and without
RLS (see Table 1).
A total of 150 patients (mean age 64.4 ± 10.6 years; range
45–90 years) and 150 age and sex-matched controls (mean
age 62.2 ± 9.5; range 51– 85 years) completed the PSQI
assessment. There were 76 men and 74 women in PD and 75
men and 75 women in controls. For PD, the mean age of
onset was 57.9 ± 11.19 and the mean duration of disease was
7.4 ± 4.91.
The mean global PSQI score of PD patients was
significantly higher (9.1 ± 4.5) than the controls (4.3 ± 2.8)
(p b 0.0001)(Fig. 1). All the seven components of PSQI in
PD patients were significantly higher compared to controls
(p b 0.0001) (Table 2). The mean value of all components
was N 1 in PD patients except for “habitual sleep efficiency”
and “use of sleeping medication”. Multivariate analysis
revealed that only H&Y staging correlated with the global
PSQI score, while no correlation was observed with age,
gender, age of onset of PD, and dose of levodopa. The mean
H&Y stage of the 150 patients was 2.5 ± 0.5 (range 1 to 4).
138 patients were on levodopa. The average levodopa dose
was 417.9 mg/day ± 233.5 mg/day, ranging from 140.63 to
1050 mg/day. 44 out of the 150 patients were on dopamine
agonists.
We also compared the PSQI values of PD patients without
RLS with controls. The findings were identical to the
findings tabulated in Table 2 (for all components of PSQI,
the statistical difference between PD and controls was
p b 0.0001). A multivariate analysis in PD patients without
RLS also similarly revealed that the H&Y stage was
associated with PSQI score. However, no association was
found with the other clinical variables.
5. Discussion

Table 2 We present the largest case–control study to date which

Component PSQI scores in PD and controls examined for RLS in PD patients in a prospective manner.
Components of Controls (n = 150) PD (n = 150) p
There was a marginally higher prevalence of RLS in our PD
PSQI patients compared to controls (3.0% vs 0.5%), with a trend
Values (mean ± Values (mean ±
towards significance (p = 0.07). The 0.5% prevalence of RLS
standard deviation) standard deviation)
in our controls was compatible with the historical RLS
I: Subjective sleep 0.67 ± 0.7 1.23 ± 0.9 b0.0001
prevalence of b 1% in a previous epidemiological study in
quality
II: Sleep latency 0.81 ± 0.9 1.39 ± 1.0 b0.0001 our general population [11].
III: Sleep duration 1.09 ± 0.9 1.99 ± 1.0 b0.0001 Krishan et al. [14] in a study of 126 PD patients and 128
IV: Habitual sleep 0.25 ± 0.7 0.86 ± 1.2 b0.0001 healthy age- and sex-matched controls in India, found RLS
efficiency to be present in ten (7.9%) and one control (0.8%) (p = 0.01).
V: Sleep 1.02 ± 0.5 1.43 ± 0.6 b0.0001
PD patients with RLS were older than those without RLS
disturbances
VI: Use of sleeping 0.02 ± 0.1 0.81 ± 1.0 b0.0001 and had higher prevalence of depression. The prevalence of
medication RLS was also significantly higher in PD patients than in
VII: Daytime 0.49 ± 0.7 1.42 ± 1.0 b0.0001 control subjects (12% vs 2.3%) in a study of 165 PD and 131
dysfunction controls in the Japanese population [13]. However, PD
Global PSQI score 4.33 ± 2.8 9.12 ± 4.5 b0.0001
patients with RLS were younger than those without RLS
148 H.-V. Loo, E.-K. Tan / Journal of the Neurological Sciences 266 (2008) 145–149
[13]. In a non-controlled study, Ondo et al. [16] evaluated
303 PD patients and found 63 (20.8%) had symptoms of
RLS. For the vast majority of patients with PD/RLS, the PD
symptoms preceded the RLS symptoms and they were older
at RLS onset, were less likely to have a family history of
RLS, and had lower serum ferritin levels compared to
idiopathic PD. In a report before the IRLSSG criteria were
developed, Riley and Lang [17] did not find any RLS
symptoms in their 100 PD patients.
Our current finding adds to the on-going debate on the
potential overlapping pathophysiology between RLS and
PD. The variance between our study findings compared to
other positive studies could be due to an over- or under-
diagnosis of RLS by the study investigators, a selection
publication bias for studies that report positive association,
or actual ethnic differences between different continents, as
well as within Asia.
In our study, we have attempted to address the potential
problem of under-diagnosis of RLS in our PD patients. In
view of the apparent low prevalence of RLS in our
population, and the potential concern that some individuals
may not volunteer information due to their cultural beliefs,
we actively tried to extract information on RLS symptoms
from our study subjects. The PD patients included in this
study had been assessed on multiple occasions for RLS
symptoms over a three year period, both in the “off” and “on”
state by a neurologist experienced with RLS diagnosis and
management. This enabled us to rule out conditions which
may be mis-interpreted as RLS, including restlessness due to
motor fluctuations, and lower limb dyskinesia or parkinso-
nian tremor which some of our patients interpreted as “the
urge to move”. These tremors could be “relieved” by walking
and be worse at night especially when the effect of levodopa
is wearing off (see Table 3 for common misinterpretations in
our study patients).
The accuracy of our clinical diagnosis was supported by
the observation that the five subjects whom we diagnosed
with RLS (four PD and one control) had grossly elevated
PLMS index and PLMS arousal index, with reduced sleep
efficiency on polysomnographic studies. Serum ferritin, a
well recognized factor which is associated with RLS [16]
was not determined in our PD with RLS. However, the red
cell indices (Hb, MCV, MCHC, RDW) of our patients were
well within normal range, and not different from PD patients
without RLS (Hb, RDW), suggesting that iron deficiency is
unlikely to play a major role. It is interesting to note that
none of our RLS patients reported a positive family history,
and the mean age of RLS onset was 61 years, supporting
previous observations that late onset RLS is more likely to be
associated with a secondary cause. The higher dose of
levodopa in PD without RLS compared to PD with RLS
suggests the phenomenon of augmentation was not observed
in the latter group.
The similarities and differences between RLS and PD
have been well highlighted by many authors [20–22]. Based
on existing literature, it is clear that dopaminergic distur-
bance appears to underpin both diseases. It is possible that
RLS may represent a spectrum of clinical symptoms
associated with dopaminergic dysfunction, and while most
of the common garden variety of RLS (e.g. primary or those
associated with iron deficiency) are fairly distinct in their
presentation, the full spectrum may not be fully expressed in
some dopaminergic diseases. The variable involvement of
the extra-striatal dopaminergic system in the individual PD
patient could be an explanation why “classic” RLS
symptoms may not be common, or only observed in select
patients.
Previous studies have failed to identify consistent
predictive factors of sleep dysfunction in PD. In our study,
we demonstrated that the quality of sleep of PD patients was
significantly worse than controls. The mean PSQI score in
our PD patients was 9.1 ± 4.5 (“poor sleepers” usually have
N 5.0). All the seven components of PSQI of PD patients
were significantly higher from the healthy controls. Our
findings corroborate those by Pal et al. [19] where certain
components, such as the ‘subjective sleep quality’, ‘habitual
sleep efficiency’, ‘sleep disturbances’ and ‘daytime dysfunc-
tion’, were also found significantly different from the
controls. The severity of PD (mean H&Y stage was 2.52 ±
0.54.) correlated with global PSQI score (p b 0.0001). This is
similar to studies that showed that a direct relationship exists
between severity of disease and quality of sleep since the
intensity and frequency of sleep disturbances increase as the
disease progress [18,23]. However, other studies have shown
that the PSQI scores were not statistically different between
de novo PD patients and controls, whereas they were
significantly higher only in treated PD or PD with RLS
[13,24].
Dopamine plays an important role in modulation of
wakefulness and sleep [25]. It is well recognized that
dopaminergic agents can cause hyper-somnolence [26,27].
However, the effect of dopaminergic agents on sleep quality
in PD is debatable. Some reported improvement in sleep
[28,29] while others reported disruption of sleep after
administration of these drugs [30]. Levodopa dose and on/
off phenomena were reported to be significantly associated
with sleep disturbance in PD patients [31]. It has been shown
that suppression of rapid eye movement occurred after
administration of levodopa and complete suppression of
sleep on higher dose of levodopa, highlighting the effect of
levodopa on sleep [32]. However, multivariate analysis in
our study showed that levodopa dose was not significantly
associated with a poorer quality of sleep in our PD patients.
This suggests that other factors such as severity of disease
may be more important predictors of quality of sleep or
intrinsic factors (e.g. genes) could play a modulatory role in
some populations.
To address whether RLS symptoms influenced the quality
of sleep, we also compared the PSQI scores in PD patients
without RLS with controls. Identical findings (compared to
those observed when PD with RLS patients had been
included) were demonstrated in both the univariate and
 H.-V. Loo, E.-K. Tan / Journal of the Neurological Sciences 266 (2008) 145–149
multivariate analysis. This suggests that RLS did not play an
important role in sleep dysfunction in our PD cohort.
In conclusion, our case–control study demonstrated a
weak association between RLS and PD. PD patients have
significant poor quality of sleep, and this correlated with the
severity of PD. A high index of suspicion for sleep problems
in advanced PD patients is important as early management
could improve their quality of life.
Acknowledgement
The authors have no competing interests to declare. We
thank Jennie Lee for her help, Stephanie Fook-Chong for
statistical analysis, and the staff of Neurology, Singapore
General Hospital for their support.
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