Parkinsonism and Related Disorders 20S1 (2014) S5–S9

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Parkinsonism and Related Disorders

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Restless legs syndrome in Parkinson’s disease

Roselyne M. Rijsman *, Louise F. Schoolderman, Rob S. Rundervoort, Maartje Louter

Center of Sleep and Wake Disorders and Department of Neurology, Medical Center Haaglanden, The Hague, The Netherlands

article info summary

Keywords: The Restless legs syndrome (RLS) and Parkinson’s disease (PD) are two disorders that can co-exist,
Restless legs syndrome whether or not they share a common pathophysiology. If, and to what extent RLS and PD share the
RLS same pathophysiology, is still under debate. Sleep disturbances are prevalent in PD, and as PD progresses,
Parkinson’s disease nocturnal disturbances become even more evident, in association not only with motor symptoms but
PD also with non-motor symptoms. Alertness to, and recognition of, RLS in PD patients with sleep disorders
prevalence could improve customized treatment and quality of life of these patients. In this article the prevalence of
mimics RLS in PD, the clinical profile of RLS in PD, the PD profile of patients with RLS, RLS mimics specifically
sleep related to PD and impact of RLS in PD will be reviewed.
profile © 2013 Elsevier Ltd. All rights reserved.
impact
quality of life

1. Introduction Even though the relationship between RLS and PD is still

Restless legs syndrome (RLS) is a common neurological disorder,
with an estimated prevalence of 4–10% in the general population.
Although the precise pathophysiology remains unknown, it is
assumed that dopaminergic mechanisms play a central role. In the
past few years, several studies have been done which suggest an
association between RLS and Parkinson’s disease (PD). Both RLS and
PD respond to dopaminergic treatment, making the assumption of
a common pathophysiology, and therefore an association between
the two disorders, fairly plausible [1,2]. The RLS symptoms seem
to result from an abnormal sensorimotor integration, due to
dysinhibition at the spinal level which, in turn, results from reduced
inhibitory mechanisms at the supraspinal level. The descending
supraspinal diencephalospinal dopaminergic neurons, originating
in the hypothalamus (A11), are proposed to play an important
role in the pathophysiology of RLS. It is postulated that, in the
course of the PD disease, these neurons degenerate, along with
nigrostriatal neurons, leading to the development of RLS, and,
therefore, to a higher prevalence of RLS among PD patients. But
shared pathophysiology is still under debate [1,2]. Unlike in the
case of PD, no neuronal degeneration or Lewy body deposition has
ever been recognized in RLS post-mortem studies. Furthermore,
until now, no shared disease loci have been identified. Except
for the provocation of both RLS and PD by neuroleptics, and
possibly lower ferritin levels in PD patients with RLS, the secondary
forms of PD and RLS do not form an argument for a common
pathophysiology [2].
* Corresponding author. Medical Center Haaglanden, Center for
Sleep and Wake Disorders, Lijnbaan 32, 2501 CK The Hague,
The Netherlands
controversial, RLS has revealed itself to be co-existing with PD. Sleep
disturbances are prevalent in PD, and as PD progresses, nocturnal
disturbances become even more evident, in association not only
with motor symptoms but also with non-motor symptoms. Thus,
alertness to, and recognition of, RLS in PD patients with sleep
disorders could improve customized treatment and quality of life of
these patients. That is why, in this article, we will specifically look
at studies on the prevalence and on the clinical profile of RLS in PD,
as well as on the impact that RLS has on PD patients.
2. Prevalence of RLS in PD
Good comparisons of the different estimates of RLS prevalence in
PD studies are rather difficult due to variations in methodology, and
so, definite generalisations are hard to make.
In total, 18 cross-sectional studies on the prevalence of RLS in
PD, published in English, were found [3–20]. In all these studies,
the international IRLSSG essential criteria for the diagnosis of RLS
were used, but some studies used the criteria of 1995, whereas
other (more recent) studies used the revised IRLSG diagnostic
criteria of 2003. The methodology, however, for the assessment
of these criteria in the subjects was not identical in all studies.
In addition, the background of the interviewers varied from study
to study, which might influence, of course, the focus, the wording
and the interpretation of the RLS histories that were collected. In
most studies, the definite diagnosis of RLS was based only on the
constellation of the four minimal IRLSSG criteria, but in some other
studies, thresholds on severity, frequency, and on the impact on
quality of life were included. From a purely epidemiological and
pathophysiological point of view, the former procedure may be

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S6 R.M. Rijsman et al. / Parkinsonism and Related Disorders 20S1 (2014) S5–S9
regarded defensible and thoughtful, but from a clinical point of view,
inclusion of the threshold criteria could obviously help to better
define PD patients who actually need treatment for RLS.
The appearance of secondary RLS is usually related with a late
onset of RLS (above 45 years of age). As a result, there may be
more secondary forms of RLS in PD cohorts, besides purely PD-
related RLS, simply because PD is also a disease that becomes more
frequent with age. Some studies, therefore, deliberately excluded
these secondary forms of RLS from their data [3,16], to avoid
confusion with this age-related variable in their assessment of the
true relation between RLS and PD. From a clinical point of view,
one may question whether such an exclusion of these ‘secondary’
forms of RLS from the investigation of the co-morbidity of any sort
of RLS in PD is appropriate, because, in doing this, we can obviously
not assess their impact and, by implication, also not their possible
implications for therapeutic intervention.
There was also variation in the size and composition of the PD
cohorts, and in the way they were treated. And last but not least,
a few studies excluded PD-specific RLS mimics, such as motor
symptoms, akathisia, non-motor symptoms, as pain, and other
sensory symptoms, motor fluctuation, such as dystonia, and non-
motor fluctuation symptoms, even though the possible overlap of
these symptoms with ‘true’ RLS has been discussed explicitly by
some authors.
The prevalence of RLS in the 18 PD cohorts varied from 0% to 50%.
Two of the studies were performed in Latin America; the one
from Brazil showed a very high PD-related RLS prevalence of 50%,
whereas the other one found 18.8% [5,10]. Eight of the 18 studies
were performed in Asian countries, with PD-related RLS prevalence
from 0.98% to 16% [4,11–14,17,19,21]. The PD-related RLS prevalence
in Western countries was generally higher than those in the Asian
countries, namely from 5.5% to 27% in Europe [3,6,8,9,16,18,20], and
20.8% in the USA [15]. Also, the prevalence of RLS in the ‘general
population’ is typically lower in Asian countries than in European
and North American ones, namely from 0.9% to 12.1% in Asia, against
from 3.9% to 18.8% in Europe and the USA [22]. In addition, the
correlation with age is clearly different in these two continents: in
Asia it does not seem to go up with age, whereas in Europe and the
USA, the RLS prevalence in the general population is found to double
every 20 years, with a peak at the age of 65 [22]. Since the mean
age of all the PD cohorts in which RLS prevalence was examined
was at least 59, we may say that the factor age was probably a
less confounding factor for the assessment of RLS prevalence in the
Asian PD cohorts than in the non-Asian ones.
To show a real association between RLS and PD, one should
find a significant increase of RLS prevalence in the PD cohorts
relative to that in the general population. Seven of the 18
studies [3,6,8,13,17,19,20] did not find such a significant increase
and did not support the hypothesis of a similar pathophysiology
between RLS and PD. The actual percentages of RLS in these negative
studies were between 0% and 5.5% in the Asian countries, and
between 5.5% and 12.7% in the Western countries.
The majority of all the RLS-prevalence studies in PD were done
on patient groups with relatively advanced forms of disease, treated
which dopaminergic medication. So there was a serious risk of
including RLS confounders and secondary forms of RLS, stemming
from other causes, in the assessment. Lee and colleagues mention a
prevalence of RLS, not different from that in the general population,
in only one subgroup of patients who were not given dopamine
medication, and who were still in an early stage of PD [12].
After multivariate analysis of the total PD cohort, only duration of
dopaminergic treatment appeared to be a variable that correlated
significantly with the presence of RLS. Their conclusion was that
RLS in PD is associated with long-term dopaminergic treatment,
rather than with PD itself. In 2011, two RLS-prevalence studies were
performed in a cohort with only de novo and dopaminergic naive
PD patients. Angelini and colleagues [3] found that RLS prevalence
in their dopamine-free PD cohort (5.5%) was not significantly
different from that in their control group (2.3%), and concluded
that RLS is not really related to PD pathophysiology. The question
whether an increase in risk of co-morbidity of RLS with the
progression of PD is a result of dopaminergic neuron degeneration,
or of dopaminergic treatment, is not answered by this study.
Gjerstadt et al. [8] performed a case–control study in an early-phase
and dopamine un-medicated PD cohort of 200 patients. Patients
who had an urge to move their legs according to the Johns Hopkins
diagnostic interview for RLS were categorized as ‘true’ RLS if they
fulfilled the four essential IRLSSG criteria, and as ‘Leg Movement
Restlessness’ (LMR) if they did not fulfil all four IRLSSG criteria.
They found similar RLS prevalence in PD patients and controls. But
they demonstrated that LMR grows to almost to a 3-fold higher risk
in early PD, as weighted against controls. The authors speculated
if RLS and akathisia (as one of the possible interpretations of LMR)
may represent overlapping features within the same spectrum of
motor restlessness in PD. Suzuki et al. [17] found significantly
higher nocturnal restlessness (and not RLS), as measured by the
Parkinson disease sleepiness scale (PDSS) sub-items 4 and 5, in PD
compared to controls. This nocturnal restlessness was associated
with the PDSS total score, but not with disease severity and
treatment duration, or total levo-dopa equivalent (LDE) dose. The
nocturnal restlessness was therefore interpreted as being the result
of an endogenous dopamine deficit during night-time, rather than
as a motor complication (i.e., wearing off phenomenon) due to
dopaminergic treatment which can mimic RLS.
By contrast, however, ten studies [4,5,9–12,14–17], did find higher
RLS frequencies in PD, and, thus, support the hypothesis that RLS is
part of the symptomatic profile of PD, and not just an incidental co-
occurrence of RLS in PD. RLS prevalence in these ten studies varied
from 7.9% to 16% in the Asian countries, against from 20.8% to 27%
in the European countries, and from 19.9% to 50% in the South-
American countries.
3. Clinical profile of RLS in PD
3.1. Comparison of PD with and without RLS: risk factor in PD?
All but one [5] of the prevalence studies considered in this article
have to some extent compared the PD profile of patients with RLS
with that of patients without RLS. Several, although not necessarily
consistent, significant differences between the two groups were
found. Again, since the studies differ in methodology, as well as
in composition of PD cohorts, it is not justified to draw definite
conclusions. The following is an overview of the major results.
Onset of RLS in relation to onset of PD was evaluated in several
studies [11,13–16,20]. In all of them, a clear majority of patients
(76–100%) showed an onset of RLS only after, or together with the
onset of PD. Ondo et al. [15] found that, for PD patients with a
positive RLS family history, the RLS onset preceded the PD onset
more often (52%) than for PD patients without a positive RLS family
history (29%). Given such a result, one might be inclined to say
that RLS without a positive family history is more consistent with
the ‘secondary’ forms of RLS in PD, but these results could not be
replicated in later studies [20].
Though lateralization of RLS is found to be rather high in the
PD population (range 35–70%), no correlations were found between
side of PD onset and dominant side of the RLS symptoms [4,11,14]
which immediately counters the suggestion, of course, that RLS in
PD is related to the degeneration of the dopaminergic neurons in
the substantia nigra.
The mean severity of RLS, expressed in terms of the international
RLS severity scale (IRLSS), varied from 11.9±6.3 to 21.3±6.3,
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or from mild to moderately severe RLS [9,10,13,14,20]. Little
or no information was provided about the frequency of RLS
in PD patients. Only one study mentioned that most of the
patients (24%) experienced RLS 2–4 times a month [20].
In some studies, RLS was associated with younger age at time of
investigation of the PD patients [14,16], whereas in other studies
it was associated with older age, as compared with PD patients
without RLS [11].
The possibility of an association between RLS and severity of
PD was addressed in many of the studies with the Hoehn and
Yahr scale [3,10–12,15,18,20,23] and the UPDRS [4,9–11,18]. Only
in two of them, however, a significant, but opposite association was
found [12,18].
The possible association between PD duration and RLS was
specifically addressed in only one study [12], which reported
a positive association: the longer the PD, the more RLS. After
multivariate analysis, however, in which several variables were
included in the analysis, only duration of treatment was found
to be a significant predictor of the presence or absence of RLS
(OR = 1.199, 95% CL 1.014–1.419, P = 0.0334). The authors stated that
the more frequent RLS in PD patients with longer dopaminergic
treatment could be the result of the same mechanisms as those
which induce an augmentation of RLS in prolonged levodopa
exposure. Although these augmentation mechanisms are not
fully clarified yet, Paulus and Trenkwalder have proposed that
the augmentation could be a result of overstimulation by the
dopaminergic medication of the D 1 dopamine receptors, in
comparison with the D 2 receptors, in the spinal cord. The
subsequent finding, in another study, that the RLS severity
was decreased after subthalamic stimulation concomitant with
dopaminergic medication dose reduction, endorses the hypothesis
that RLS in PD can be a result of dopamine receptor over-stimulation
by dopaminergic medication [24]. The idea that RLS symptoms
are correlated with dopamine treatment, rather than with PD
pathology itself, is also supported by some other observations, such
as: (1) more PD patients without RLS, in contrast to PD patients
with RLS, used no levodopa at all (resp. 6.8% and 0%) [9],
(2) the same prevalence of RLS as in the general population,
in a small subgroup of dopamine-medication free PD patients,
compared to an increased prevalence of RLS in the levodopa-treated
PD patients [12], (3) equal levels of RLS prevalence in various
dopamine-free PD cohorts [3,8].
Besides dopamine treatment duration, also level of dopamine
dose might be a factor that leads to overstimulation of the
dopaminergic neurons. Although the dopamine therapy dose of
PD patients with RLS was compared with that of PD patients
without RLS in nine studies [9,11–17,20], only one showed a
significant, though not positive but negative, correlation between
dopamine dose and RLS. These authors suggest that higher
dopaminergic medication could suppress the RLS symptoms. Also
Verbaan et al. [20] discuss the possibility that the relatively high
mean dopaminergic dose in their cohort could have resulted in
an underestimation of RLS patients. This hypothesis was further
supported by the observation of emerging RLS in 11 of 195
PD patients after subthalamic stimulation with a concurrent
75% reduction of the mean dopaminergic medication. This can
be explained by an unmasking effect of RLS symptoms, which
otherwise would be suppressed by a higher dose of dopaminergic
medication [25].
Also iron deficiency has been associated with RLS. In two
studies [11,15], lower levels of ferritin were found in PD RLS-
positive patients than in PD RLS-negative patients. Ondo and
colleagues, therefore, speculate that low ferritin levels could,
besides reducing the dopaminergic system function, also be a
risk factor for RLS symptoms in PD. In two other studies [10,14],
S7
no such statistically significant differences in level of ferritin were
found, suggesting that not iron deficiency but dysfunction of
the central dopaminergic system itself, due to PD, might be the
underlying pathophysiology of RLS in PD.
3.2. Comparison of the RLS profile in PD with that of idiopathic RLS
It is well known that the prevalence of RLS in the general
population is higher among women than among men. Consistent
with this pattern, also several studies on PD patients found a
higher RLS prevalence among women than among men (range
60–75%) [6,9,12–14,20]. In only two of these studies, however, the
proportion of women was significantly higher in the PD RLS-positive
group than in the PD RLS-negative group [9,20]. In other studies on
PD patients, however, this typical pattern of gender distribution was
not found [3,4,8,10,11,16]. All together, we cannot say that there is a
really consistent pattern of gender distribution among PD patients
with RLS.
Parkinson-related RLS has a remarkably lower rate of RLS
family history (range 0–33%) than is usually seen in idio-
pathic RLS (>50%) [3,9,11,13–15,20].
The age of RLS onset in PD tends to be relatively high, and
goes from 41.7±3.3 years to 62.4±7.3 years [3,9,11,13,14,16,20]. This
is consistent with the onset of other ‘secondary’ RLS symptoms
(typically after the age of 45).
There has been no case–control study in which the severity of
RLS in PD has been compared with that in controls by means
of the IRLSSG severity scale. Only one study mentioned the
complete distribution, showing that 59% of the patients reported
no or mild RLS in the week before the severity scale was filled
out, 38% reported moderate to very severe RLS, and 4% very severe
RLS [20]. On average, the severity of RLS in PD seems to be milder
than in the general population. This finding can be biased by
the fact that, in most studies, the PD patients used dopaminergic
medication, and therefore RLS severity could be suppressed.
Frequency of pain sensation, but not pain intensity, was
significantly higher for PD patients with RLS than for PD patients
without RLS, just like in the case of idiopathic RLS versus healthy
controls [26]. On the basis of this result, the hypothesis was coined
that the presence of pain in PD patients can be exacerbated by RLS
or, stated otherwise, that the presence of RLS may exacerbate pain
in patients who have PD.
4. RLS mimics in PD
A variety of conditions can ‘mimic’ RLS by satisfying the
four diagnostic criteria. Conditions which can do this, and are
not PD specific, include cramps, (poly)neuropathy, positional
discomfort, and local leg pathology. Besides PD-non-specific, also
PD-specific RLS mimics should be differentiated from ‘real’ RLS in
PD patients. This is important, not only to avoid overestimation of
RLS frequency in prevalence studies, but also and most importantly,
from a clinical viewpoint, to avoid misdiagnosis, and to optimize
therapeutic discussions and interventions. For example, some non-
motor sensory systems, such as motor- and non-motor sensory
fluctuations in PD, could mimic RLS. Fluctuating state sensory
symptoms, like numbness or paraesthesias without objective
sensory loss, are described to be experienced more often in the legs
and arms, and rarely in the face or neck [26]. This is a distribution
which follows the distribution of RLS symptoms, and, thus, can
mimic RLS.
Akathisia in PD is an important mimic of idiopathic RLS, but
even more so for PD-related RLS. The term akathisia is used to
describe a condition in which the patient has an inner restlessness
with an urge to move. Although exposure to neuroleptics is the
S8 R.M. Rijsman et al. / Parkinsonism and Related Disorders 20S1 (2014) S5–S9
most common underlying cause for akathisia, this condition is also
often reported by PD patients (with and without dopaminergic
treatment), with a prevalence from 25% to 45% [27–29]. The motor
restlessness in akathisia differs from RLS, by the fact that it is usually
a generalized whole-body sensation, without sensory discomfort,
without a strong circadian rhythm, and without relief by movement.
Although this is certainly helpful for a proper differentiation, it
is not a hundred percent guarantee. In the case of severe RLS
the circadian rhythmicity, aggravation by rest and suppression
by movement fades away. Moreover, also some overlap between
akathisia symptoms and RLS symptoms in PD is mentioned in the
literature. For example, Comella [30] mentions that 40% of their
patients had akathisia only at certain times of the day, suggesting
an overlap with RLS. Or, as mentioned already earlier in this text,
Gjerstadt and colleagues [8] wonder if, and to what extent, RLS
and akathisia are really two different and separated conditions, or
represent overlapping features within the same spectrum of motor
restlessness in PD. The finding of Peralta et al. [16] that 61% of all
RLS positives mentioned that their RLS symptoms were associated
with a wearing off, also strengthens the possibility of RLS mimics
in fluctuating patients with PD. Therefore true RLS symptoms,
and RLS-like symptoms resulting from levodopa, deserve further
investigation, as stated earlier by several authors. Whether or not
certain leg motor restlessness symptoms that do not fulfill all
RLS criteria can later develop into full-blown RLS in PD patients is
unclear, and is also a subject matter for further investigation [7].
5. Impact of RLS in PD patients
Sleep and wake problems are a very common among PD patients,
as high as 70%. Many factors are thought to play a qualifying
role in the sleep and wake complaints of these patients. Several
studies have focussed on the attributive role of RLS in the sleep
and wake complaints of PD patients [8,9,11,13,15,18,20,23]. Nomura
et al. [23] found a significantly higher (meaning lower sleep
quality) Pittsburgh Sleep Questionnaire Index (PSQI) in PD patients
with RLS than in PD patients without RLS. In another study on
PD patients, RLS had no influence on the PSQI [13]. Excessive
daytime sleepiness, as measured with the Epworth Sleepiness
Scale (ESS), was also not found to be higher (meaning more
sleepiness) among PD patients with RLS than among PD patients
without RLS [9,11,15]. If sleep scales are used that are specially
designed and validated for PD populations, then some studies
find significantly more sleep or wake complaints in PD patients
with RLS than in PD patients without RLS [9,20]. In the cohort
of Gomez-Esteban et al. [9], the Parkinson’s Disease Sleepiness
Scale (PDSS) score was significantly lower (= worse) for PD patients
with RLS than for PD patients without RLS, suggesting more sleep
disturbances in the former group, as indicated by the responses
on the following sub-items: ‘nocturnal restlessness of legs or arms
at night or in the evening, causing sleep disruption’, ‘numbness
or tingling of arms or legs with an awaken effect’, ‘fidgeting in
bed’, and ‘painful muscle cramps in arms or legs whilst sleeping
at night’. However, because these four sub-items describe elements
that can be part, not only of ‘true’ RLS, but also of RLS mimics, the
authors suggest that it is thinkable that some of their patients with
akathisia or with nocturnal motor problems other than RLS, may
have been wrongly diagnosed as RLS. In the cohorts of Gjerstad
et al. [8] and of Bhalsing et al. [4] similar results were found. In
the Norwegian PD population study [18], it was found that three
variables were significantly associated with PDSS score, namely
poor mental health, fatigue and RLS. The significant relationship
between PDSS and RLS persisted, even if the scores on the 4th item
(restlessness of legs or arms at night or in the evening causing sleep
disruptions) was removed from the analysis. In this study, ‘true’
RLS seemed to have an negative effect on the sleep quality.
The impact on quality of life (QoL) of PD is tremendous. The
question of the attributive role of RLS in this impact, however,
has only been addressed explicitly in one study. Gomez-Estaban
and colleagues [9] compared the scores on the Parkinson’s Disease
Questionnaire (PDQ-39) of PD patients with RLS with those of
PD patients without RLS, and found no difference. Some other
studies have looked at the effect of RLS on mental health in
PD patients, as an isolated parameter [8,11,16,20]. In one study it
was found that not the presence of RLS as such, but rather the
severity of RLS was correlated with depressive symptoms [20]. In
another study, depression was not correlated with RLS, but was
significantly more prevalent in PD patients with RLS (40%) than
in PD patients without RLS (10.3%) [16]. In the study of Krishnan
et al. [11], pain, as a possible factor for QoL, was found to be
significantly higher in PD patients with RLS than in PD patients
without RLS. The same was found in a study of Rana et al. [26], but
not in another one by Peralta et al. [16].
6. Summary and conclusion
RLS and PD can co-exist, whether or not they share a common
pathophysiology. If, and to what extent, RLS and PD share the same
pathophysiology, is still under debate. There are arguments for and
arguments against. As the observed disease profiles of PD patients
with RLS were not really consistent over the various studies, no
clear risk factors for RLS in PD can be pointed out unequivocally.
One might be inclined to argue that dopaminergic medication is
a risk factor, but more research is needed before one can give a
clear answer to this hypothesis. The RLS profile in PD, however,
seems to be different from that in the general population. On
average, RLS in PD seems to be less severe than in the general
population. One study suggests that the sensory entity ‘pain’ is more
prevalent in PD-associated RLS than in non-PD-associated RLS. We
also see that RLS in PD patients starts relatively late, the majority
after PD onset, and that most of these patients have no positive
family history. The gender distribution of RLS in most PD cohorts
does not follow the classical gender distribution of RLS in the
general population. Impact on sleep, and psychological aspects of
RLS in PD patients, are found in some studies, but seem to be
more correlated with the severity of RLS than with RLS as such.
Although sensory symptoms and fluctuating symptoms in relation
to dopaminergic medication may mimic RLS, overlap with real RLS
seems to go with these symptoms as well. Awareness of the possible
impact of RLS, whether or not as a co-morbid disorder, or as part of
the profile of PD, could optimize the therapy strategy in PD. Until
now, no studies about what is the best strategy to treat RLS in PD
have been done. The current choice of individualized treatment
strategies, therefore, can only be based on our knowledge from
RLS studies in the idiopathic domain. A point of particular interest
in the future, therefore, should be the construction and validation of
RLS criteria which are specifically designed for the PD population,
so as to exclude as much as possible the confusion with RLS mimics
which are typically seen in PD. With this in hand, better PD profiling,
RLS profiling, neuropathological studies, quality of life studies in the
full range of quality, and treatment studies will become possible in
the future.
Conflict of interests
The authors have no conflicts of interest to declare.
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