Palavras-chave:
Doença de Parkinson - síndrome das pernas inquietas - doenças cardiovasculares - dislipidemias
Restless legs syndrome (RLS) is a disorder characterized by an uncontrollable need
to move the legs, that occurs during rest, and which is relieved by movement of the
lower limbs[1]; however, the sensation may occur in other parts of the body as well. In this way,
RLS interferes markedly with the individuals sleep quality. In its pathophysiology,
there is a decrease in central nervous system dopaminergic levels, especially at night[2],[3], with dopaminergic agonists playing a role in improving symptoms. Other theories,
such as iron accumulation, have also been cited in literature[3].
In previous studies involving diverse populations, RLS seems to increase several cardiovascular
risk factors[4],[5],[6], mainly due to interference in sleep-wake cycle, culminating in an exacerbated sympathetic
activity in this period[4],[5],[6],[7],[8]. There is also evidence that RLS can lead to impairment in cardiovascular system
autonomic control, regardless the presence of changes in sleep quality or periodic
leg movements[9].
Both RLS and Parkinson's disease (PD) present with alterations in dopaminergic transmission
in their pathophysiology. In addition, studies have shown that the prevalence of RLS
in patients with PD is higher than in general population[10],[11],[12]. Taking into account the possible deleterious effect of RLS on cardiovascular function,
it is essential that the associations between these morbidities be established, given
the frequency of the syndrome in this population. The present study sought to establish
the prognostic impact of RLS in Parkinson's disease.
METHODS
This study was initiated after approval by the research ethics committee of Universidade
Positivo under the registration number CAAE 73905517.3.0000.0093 and conducted according
to ethical standards in accordance with Resolution 466/2012.
Participants
The records of patients diagnosed with idiopathic PD who attend a specialized center
in a city in southern Brazil were reviewed. We included patients diagnosed with PD
according to the UK Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria[13]. Only patients with 50 years or older were included in the study. Alcohol abuse
patients, smokers, patients who had diagnosed coronary artery disease before onset
of RLS or who presented with a weight gain of more than 5 kg in the last six months
were excluded from the study.
Data selection
A retrospective observational study was performed. The patients were previously selected
through medical records analysis, according to the inclusion and exclusion criteria.
The patients were divided into two groups: PD+RLS patients and PD patients without
the syndrome (controls). The diagnosis of RLS was made according to the diagnostic
criteria of American Academy of Sleep Medicine[2].
Cardiovascular risk was evaluated using the Framingham Risk Score, a previous vascular
event, blood pressure measurement, laboratory examination and presence of peripheral
arterial disease.
Data analysis
Continuous data were expressed as means. Frequencies were expressed in percentages.
Numerical variables were compared using the ANOVA test, while categorical variables
were analyzed using the chi-square test. Statistical significance was set at p < 0.05.
RESULTS
Population characteristics
Data were analyzed for 202 patients in total: 57.43% were male and the population
mean age was 70.12 ± 9.49 years. The mean age at onset of PD symptoms was 59.86 ±
10.64 years, with a mean duration of symptoms of 9.64 ± 5.68 years at the time of
our evaluation. The prevalence of RLS was 7.92% (16 patients). The sample distribution
in relation to demographics and comorbidities for PD + RLS and control groups is shown
in [Table 1].
Table 1
Characteristics and comorbidities distribution by group.
|
Variable
|
PD+RLS group (n = 16)
|
Control group (n = 186)
|
p-value
|
|
Male %
|
43.75
|
58.60
|
0.249
|
|
Mean age (years) ± SD
|
67.75 ± 12.94
|
70.33 ± 9.07
|
0.183
|
|
Mean disease duration (years) ± SD
|
10.50 ± 7.28
|
9.57 ± 12.35
|
0.787
|
|
PD mean age at onset (years) ± SD
|
56.87 ± 11.17
|
60.44 ± 10.52
|
0.121
|
|
Hypertension %
|
50.00
|
47.85
|
0.976
|
|
Peripheral arterial disease %
|
0
|
2.15
|
-
|
|
Diabetes %
|
18.75
|
17.74
|
0.919
|
PD: Parkinson's disease; RLS: restless legs syndrome; SD: standard deviation
Cardiovascular risk and relations
The occurrence of stroke, acute myocardial infarction and heart failure after the
diagnosis of RLS was verified, although there was no prevalence of these morbidities
in the PD+RLS group. In the control group, the occurrence of these conditions was
7.43%, 2.47% and 1.98%, respectively.
The Framingham Risk Score was calculated for participating patients, with a mean score
of 15.27 ± 7.76 for control group and 12.90±4.53 for PD+RLS group. However, the difference
found between groups wasn't statistically significant (p = 0.605).
Regarding systolic blood pressure, a mean of 121.43±30.23 mmHg (median 120) was observed
for control group and 121.20 ± 18.23 mmHg (median 120) for PD+RLS group. This difference
wasn't statistically significant (p = 0.976).
Participants lipid profile of was also evaluated, with a mean in general population
of 179.50 ± 38.02 mg/dL for total cholesterol. The separate groups analysis is shown
in [Table 2]. Among control group, 19.35% of patients had a diagnosis of dyslipidemia and had
received statin prescriptions in previous consultations, compared with 43.75% of the
PD+RLS group.
Table 2
Lipid profile by group.
|
Variable
|
PD + RLS group
|
Control group
|
p-value
|
|
mean TC (mg/dL) ± SD
|
216.60 ± 49.73
|
176 ± 35.34
|
0.021
|
|
mean HDL (mg/dL)) ± SD
|
41.68 ± 6.71
|
49.17 ± 15.69
|
0.292
|
|
mean LDL (mg/dL)) ± SD
|
145 ± 39.35
|
94 ± 37.20
|
0.007
|
PD: Parkinson's disease; RLS: restless legs syndrome; TC: total cholesterol; HDL:
high density lipoprotein; LDL: low density lipoprotein; SD: standard deviation.
DISCUSSION
It's believed that subcortical dopaminergic dysfunctions play an important role in
RLS genesis, as well as in PD, with dopaminergic agonists responsible for symptoms
improvement in both conditions[3]. In addition, a risk relation can be established between RLS and PD[14], with a greater occurrence of the syndrome in patients with PD[10],[11],[12]. Impairment in dopaminergic transmission, common in the etiology of PD and RLS,
may explain why the prevalence of RLS in patients with PD is high.
The relation between RLS and cardiovascular risk has previously been explored, but
at present, there is no confirmation of this relation in PD population, specifically.
It's postulated that RLS can lead to heart disease through several potential mechanisms:
its negative effect on sleep quality and duration, coexisting sympathetic activation
accompanying periodic limb movements during sleep, or presence of common risk factors
for heart disease[8]. In addition, interruption of sleep, common in patients with RLS, increases the
daytime heart rate and blood pressure through elevated peripheral sympathetic tonus[5],[15]. The present study, however, didn't directly assess the impact of this morbidity
on sleep quality.
In our study, RLS prevalence was compatible with previous literature findings for
general population, ranging from 5% to 10%[16],[17],[18],[19] and involving more women than men. The difference between genders may be due to
the fact that women generally perceive and report symptoms more often than men and
because of hormonal differences. In previous studies addressing RLS in PD exclusively,
showed prevalence rates with great variability (0% to 50%)[11],[12],[20],[21]. However, due to the fact that the treatment of PD involves dopaminergic compounds,
which also alleviate RLS symptoms[17], the true prevalence of RLS maybe masked in this population[22]. This risk, however, is called into question by studies that have reported an increased
prevalence of RLS, compared with general population, in patients with long-term dopamine
use, indicating the possible contradictory correlation of RLS increasing with the
duration of previous dopaminergic drug treatment[23],[24]. Because the present study showed a statistically significant difference for lipid
profile changes, it's important to reconsider the role of dopamine as unique in genesis
of this syndrome, taking into account the probability of other questions related to
the possible increase in cardiovascular risk of these patients, such as common risk
factors. Moreover, in our study, no statistically significant difference was found
regarding the length of PD treatment and presence of RLS.
Regarding cardiovascular risk, we analyzed the Framingham Risk Score, blood pressure
measurements and lipid profiles, and found a statistically significant relation only
for high values of total cholesterol and LDL (low density lipoprotein), which appeared
to be higher in PD patients with RLS. We could find no data in literature comparing
RLS and lipid profiles in PD population. There is already evidence that the prevalence
of dyslipidemia is higher in individuals with RLS than in individuals without the
syndrome[25],[26]. A prospective study found that elevated levels of total cholesterol were associated
with a higher risk of developing RLS, which didn't change significantly after exclusion
of patients using statins, indicating that the correlation didn't occur due to drug
side effects[27]. There was also a correlation between sleep quality in patients with RLS and dyslipidemia,
with an association between poorer sleep quality and LDL levels, shorter sleep duration
and total cholesterol levels, and greater daytime dysfunction and LDL levels in patients
with RLS[28]. Metabolic disorders may occur along with activation of the hypothalamic-pituitary-adrenal
axis and with inflammation, which may trigger a role in RLS genesis[29]. In addition, there are reports of RLS caused by microembolization of cholesterol
crystals[30]. These data corroborate this study findings, indicating a correlation between dyslipidemia
and RLS; however, the findings described here are new as they are specific for the
PD population.
Regarding the relation between cardiovascular risk factors and RLS in other morbidities,
we found conflicting evidence. A prospective study in United Kingdom revealed an association
between RLS and incidence of stroke, but an association wasn't found between RLS and
ischemic heart disease[31]. This finding was corroborated by another paper, in which it was also observed that
the syndrome was more frequent in individuals with various comorbidities, including
high body mass index, hypertension and diabetes[32]. Contrary to this analysis, some studies have shown that RLS is associated with
cardiovascular disease in patients with frequent symptoms and RLS diagnosed for more
than three years[8],[33]. Li et al.[8] identified a significant association between long-term RLS and coronary disease.
According to their study, women with RLS for more than three years were at increased
risk for coronary heart disease, an association that was independent of the main risk
factors for coronary disease. Other studies have suggested a lower cardiac vagal modulation
and lower heart rate response to orthostatic stress in subjects with RLS[34],[35]. The positive correlation between RLS and cardiovascular risk obtained by these
studies maybe explained by the reduction of cardiovascular baroreflex gain and greater
peripheral vascular resistance observed in patients with RLS - factors not attributed
to differences in sleep quality, suggesting that the syndrome can directly contribute
to changes in cardiovascular system autonomic control [9]. Corroborating the above findings, another study indicated that RLS may be related
to cardiovascular disease, coronary disease and hypertension, but with different relative
risks according to primary or secondary classification of RLS. Primary RLS would be
a risk factor for hypertension, but not for cardiovascular disease or coronary disease.
However, when secondary to another morbidity, including PD, RLS would be associated
with the three conditions: hypertension, cardiovascular disease and coronary disease[36].
A previous study by Oh et al.[31] failed to find a statistically significant association between PD, RLS and cardiovascular
diseases; however, according to a study by Banno et al.[25], nocturnal hypertension and supine hypertension occurred more frequently in patients
with PD and RLS than in patients with PD without RLS. In the present study, there
were no significant differences in blood pressure values between the control group
and the PD+RLS group, while other cardiovascular comorbidities were not frequent enough
for an adequate comparison.
This article is limited by being retrospective, and the sample analyzed was relatively
small, which may justify not identifying the correlation of RLS with other factors,
such as a statistically significant difference for the Framingham Risk Score or blood
pressure, already described in previous studies with various populations. Regarding
the overlap between PD and RLS treatment as a possible factor for diagnostic masking,
our results test the dopaminergic substrate as the main factor in the RLS genesis,
as even with the use of dopaminergic agonists in both groups, PD+RLS and control,
it was possible to observe differences between the strata, a theory corroborated by
previous findings[3],[24]. A hypothesis is generated, as well, of the real interference of the treatment of
RLS syndrome as a protection factor for cardiovascular risk.
Our findings, which indicated a relationship between an unfavorable lipid profile
of patients with PD (high total cholesterol and LDL) and the presence of RLS, are
new and not previously reported in the literature, but consistent with findings in
other populations. Future research is needed to confirm this possible relationship.
Based on this, it's possible that new forms of primary prevention and overall care
may be found for patients with PD.
