Introduction
Restless legs syndrome (RLS) includes various
sensitive symptoms and is identified if following criteria are
fulfilled: i) the need to move the feet; ii) the patient perceives
this sensation as uncomfortable and unpleasant; iii) this sensation
is relieved by movement; iv) a circadian rhythm was described,
meaning that the unpleasant sensation starts at evening time,
especially when the patient is in bed. The same sensation may
appear during the daytime in advanced cases, especially in the
periods of rest or inactivity (1,2). The
consensus published on 2003 by the International RLS Study Group
(IRLSSG) stipulates that all the above four criteria need to be met
to establish the diagnosis (1).
These criteria were updated in 2014(2) by adding an additional diagnostic
criteria, requiring that no other medical or behavioral condition
may explain the appearance of the symptoms mentioned above
(2).
The prevalence of RLS is approximately 10% in
different epidemiological studies (3-5),
with a predominance of females (3).
Clinically significant RLS has an estimated prevalence of
approximately 2.7%. Worldwide RLS is often underdiagnosed and is
considered to significantly impair sleep and quality of life
(4-7).
According to Allen and colleagues, more than half of the RLS
patients report at least one sleep impairment, for instance
insomnia, sleep fragmentation or daytime sleepiness (6). RLS patients declare worse global
quality of life and important impairments of mental and general
physical status compared to healthy individuals or to patients with
other conditions (6). There are
several diseases/conditions which are suggested to increase the
prevalence of RLS: Renal failure (8), kidney transplantation (9), rheumatoid arthritis (10), fibromyalgia (11), lung transplantation (12), migraine (13), ankylosing spondylitis (14) or multiple sclerosis (15). In pregnancy, the prevalence of RLS
is also high, but in contrast with the aforementioned conditions,
it has a good prognosis, remitting in few weeks/months after
delivery (16). Yet, few studies
have assessed RLS and sleep disturbances in systemic lupus
erythematosus (SLE) (17,18).
Pharmacological treatment of RLS may include iron
supplementation in cases of low serum ferritin levels, dopamine
agonists as first-line therapeutic options and anticonvulsivants or
opioides in refractory cases (10).
The aims of this study were: i) To determine the
prevalence of RLS in SLE patients; ii) to evaluate the clinical
phenotype of RLS in SLE patients; iii) to discover an association
between RLS and sleep characteristics and iv) to assess sleep
disturbances in these patients.
Patients and methods
Design
A prospective study was performed at the Departments
of Immunology and Neurology of the County Emergency Clinic
Hospital, Braşov, Romania, during the period June 2011-August 2013.
This study enrolled 26 patients with SLE and 26 patients without
SLE in an age- and sex-matched control group. No patient was
previously diagnosed with RLS. The protocol for this study received
acceptance from the Ethics Committee of the Transilvania University
from Braşov (78/28.05.2011) and respects the ethical
recommendations of the 1975 Declaration of Helsinki. Informed
consent was signed by all subjects before recruitment. The study
group consists of: i) consecutive patients with confirmed SLE
diagnosed by an immunologist or rheumatologist; ii) patients older
than 18 years of age; iii) able to sign an informed consent. The
SLE patients presented with different affected organs but no
central nervous system (CNS) involvement.
Exclusion criteria included: i) Uncertain SLE
diagnosis; ii) medical or psychiatric comorbidities that could
interfere with the diagnosis of RLS iii) inability/refusal to
provide study consent.
The control group included consecutive patients with
no SLE. Among the symptoms, they presented low back pain
with/without radicular syndrome or different types of headache.
Assessments
We collected demographic data, medical history,
weight, height [for body mass index (BMI)] sleep and RLS
assessment. A RLS-positive diagnosis was based on the four
standardized criteria proposed by the International RLS Study Group
(IRLSSG) as mentioned in the introduction (1). The assessment work included
demographic data, medical history and history of the use of
medications. The patients had to choose from a list of 21 terms
which described the sensory sensations in their legs, according to
Allen et al (1). The
questionnaire comprised also questions related to sleep
characteristics: Time to go to bed, time to wake up, number of
hours that the subject sleeps.
The following scales were applied to both groups:
Restless Legs Syndrome Rating-IRLS (19) to assess the severity of a patient's
RLS symptoms; Restless Legs Syndrome Quality of Life Instrument
(20); Pittsburg Sleep Quality
Index (PSQI) (21); Epworth
Sleepiness Scale (22). According
to the Restless Legs Syndrome Rating Scale-IRLS (19), the scores for all items vary between
0 (without signs of RLS) to 4 (very intense RLS symptoms); the
maximum score being 40. Therefore, according to the obtained
scores, the categories of severity were: Mild, 1-10; moderate,
11-20); severe, 21-30; very severe, 31-40.
Statistical analysis
Statistical analysis was performed using Microsoft
Excel 2010 software (Microsoft) and Matlab 2019b (MathWorks). Data
are presented as the mean ± standard deviation. For demographics
and clinical assessment, we used descriptive statistics.
Statistical differences between groups were analyzed using the
one-way ANOVA test of variance followed by the Tukey's post hoc
test or student's t-test. P<0.05 was considered to indicate a
statistically significant difference.
Results
Competing interests
Demographic data are presented in
Table I
 | Table IDemographic and laboratory data:
Comparison between the study group [patients with SLE, with (+) and
without (-) RLS] and control group [patients without SLE, with (+)
and without (-) RLS]. |
Table I
Demographic and laboratory data:
Comparison between the study group [patients with SLE, with (+) and
without (-) RLS] and control group [patients without SLE, with (+)
and without (-) RLS].
| | Study group
(n=26) | Control group
(n=26) | P-value |
|---|
| | RLS+ (n=9) | RLS- (n=17) | RLS+ (n=2) | RLS- (n=24) | 0.04 |
|---|
| Age (years) | 56.66±10.40 | 50.05±10.52 | 48.5±0.7 | 52.62±11.44 | 0.04 |
| BMI | 27.31±3.90 | 25.79±6.19 | 31.35±2.71 | 28.83±4.87 | 0.12 |
| Sex | | | | | |
|
Male | 2 | 1 | 0 | 3 | 0.07 |
|
Female | 7 | 16 | 2 | 21 | 0.03 |
| Iron deficiency
anemia | 5 | 0 | 1 | 0 | 0.02 |
RLS+ represents all the patients fulfilling the RLS
study group-positive criteria and RLS-were patients without RLS.
The mean patient age was similar in the two groups: 51.65 years in
patients with SLE and 52.07 years in patients without SLE (range
30-74). There were 9/26 patients (34.62%) who fulfilled
RLS-positive criteria (RLS+) (positive answers to all the 4
diagnostic criteria questions) in the study group and 2/26 (7.69%)
RLS+ patients in the control group (P<0.05). Family history was
positive for 2 out of 9 patients with RLS in patients with SLE and
none in the control group. We compared the characteristics of the
patients in the study group with SLE and RLS (RLS+) with those from
control group with RLS (RLS+). In the SLE and RLS+ group, compared
with the control group with RLS (RLS+), we observed that the
patients were older (mean age, 56.66±10.40 years vs. 48.5±0.7
years), predominantly females (7/9 vs. 2/2), with a higher
prevalence of iron deficiency anemia (P<0.05).
According to our results, SLE patients reported more
frequent and more intense symptoms of RLS compared to the control
subgroup. RLS symptoms in the study group (n=9) had as frequency: 1
day/month in 1 patient, 1-2 days/week in 1 patient, 2-3 days/week
in 2 patients, 4-5 days/week in 1 patient and daily in 4 patients.
In the control group, one patient with RLS had daily symptoms and
one had symptoms 1-2 days/week. In the study group, all
participants with RLS, except one, described that the RLS symptoms
became manifest after the diagnosis of SLE. The mean interval from
the diagnosis of SLE and the occurrence of RLS was 3.31±2.2
years.
In the study group (n=9), the mean IRLS score
(19) had the following
distribution: Mild (0-10) in 1 case, moderate (11-20) in 8 cases.
There were no cases considered appropriate from inclusion in the
severe (21-30) or very severe (31-40) group. For the controls there
was one mild case (0-10) and one moderate case (11-20).
We compared clinical and laboratory exams of the SLE
study patients with (RLS+) and without RLS (RLS-). Female
representation was 7/9 (77. 77%) in the RLS+ vs. 16/17 (94.11%) in
the RLS-group. There were 2 patients with polyneuropathy and RLS+
in the SLE group but none with polyneuropathy among RLS-. In the
control group there were no polyneuropathy cases. The SLE study
group patients received standard treatment, according to the
guidelines in use, depending on the disease severity: Non-steroidal
anti-inflammatory drugs, corticosteroids, hydroxychloroquine,
immunosuppressants, biological therapies. No patient was diagnosed
previously with RLS and no specific treatment was administered.
Sleep characteristics are presented in Table II: Epworth Sleepiness Scale score,
PSQI score, time to go to bed (hour:min), wake up time (hour:min),
time in bed (hour:min), sleep duration (mean, hour). The sleep
characteristics were comparatively analyzed in the study and
control group. PSQI score (higher in the RLS+ subgroup, P=0.03),
time to wake up (earlier in the RLS+ subgroup, P=0.04) and sleep
duration (less in the RLS+ subgroup, P=0.03) reached statistical
significance between the study and control groups.
| Table IISummary of sleep characteristics:
Comparison between the study group [patients with SLE, with (+) and
without (-) RLS] and control group [patients without SLE, with (+)
and without (-) RLS]. |
Table II
Summary of sleep characteristics:
Comparison between the study group [patients with SLE, with (+) and
without (-) RLS] and control group [patients without SLE, with (+)
and without (-) RLS].
| | Study group | Control group | |
|---|
| Sleep
characteristics | RLS+ | RLS- | RLS+ | RLS- | P-valuea |
|---|
| Epworth Sleepiness
Scale score (range) | 5.71±1.92 (2-8) | 4.41±2.37 (0-9) | 5.12±1.85 | 4.95±1.96 (0-9) | 0.09 |
| PSQI score | 5.83±2.41 | 3.24±1.42 | 6.14±1.71 | 2.95±2.12 | 0.03 |
| Time to go to bed
(hour:min) | 22:45±1:00 | 22:00±0:47 | 23:50±0:42 | 22:00±0:45 | 0.82 |
| Wake up time
(hour:min) | 6.45±1.25 | 8.00±1.20 | 6.00±1.45 | 7.00±1.10 | 0.04 |
| Time in bed
(hour:min) | 6.5±2.1 | 7.3±2.8 | 6.45±1.92 | 7.00±2.9 | 0.90 |
| Sleep duration (mean,
hour) | 5.5 | 7 | 6 | 7.2 | 0.03 |
Excessive daytime sleepiness [Epworth Sleepiness
Scale score (ESS) >10] was not reported by any patient. ESS
score of 6-10 was reported by 69.23% vs. 46.15% (P=0.01) in the two
groups.
Discussion
This study shows a higher prevalence of restless
legs syndrome (RLS) in systemic lupus erythematosus (SLE) patients
(34.62%) compared with controls (7.69%). The RLS prevalence in the
SLE group was higher compared with the one reported in the general
population, which varies at approximately 10% (4,5).
Hassan et al (17) showed
that 12 of 33 (36.36%) patients with SLE had RLS compared with 4 of
32 control patients (12.5%). Kucuk et al (18) also suggested a high prevalence of
RLS in SLE patients (30.6% vs. 4.8%). Even if RLS prevalence
appears to be higher in SLE patients, the pathological mechanisms
remain unclear. Possible explanations include genetic
susceptibility and the existence of antibodies against dopaminergic
cells in SLE which disturb the dopaminergic functionality,
therefore increasing the risk of RLS occurrence in these patients
(17). Anemia is reported as a risk
factor for RLS prevalence and severity (18). Iron deficiency anemia was more
prevalent in our study in the SLE group. Due to our limited sample,
we were unable to demonstrate an association between RLS and
anemia, as shown by Kucuk et al (18).
The presence of RLS in systemic lupus erythematosus
(SLE) impacts the quality of sleep; higher PSQI scores (meaning
poorer sleep quality), earlier time to wake up and shorter total
sleep time were reported.
There is limited available information regarding
sleep disturbances in SLE patients with RLS, but considering the
potential impairment of sleep quality induced by RLS, further
studies (including also objective sleep assessments) are
required.
There are some limitations in our study: i)
Enrollment of a population visiting the hospital clinic could have
added more comorbidities and thus more potential factors involved
in the leg sensations; and ii) electromyography and nerve
conduction studies were not performed in any patient. Hence, the
two patients had clinical polyneuropathy.
In conclusion, the present study showed that SLE
patients reported a higher prevalence of RLS, most of them being
females. An association between RLS and iron-deficiency anemia was
identified in the study group. The majority of our patients
reported mild or moderate RLS symptoms, occurring in 58% of cases
in more than 4 nights per week. The co-occurrence of polyneuropathy
in two of our patients may have influenced the perceived severity
of the clinical manifestations of RLS. The existence of RLS
symptoms in SLE patients correlated with the impairment of sleep
parameters, in contrast with SLE patients without RLS.
Acknowledgements
This manuscript was partially presented as an
e-poster at the 3rd European Academy of Neurology Congress, June
2017, Amsterdam.
Funding
Funding: No funding was received.
Availability of data and materials
Available upon reasonable request.
Authors' contributions
All the authors substantially contributed to each of
the following aspects of this paper. CFP performed the design and
conception of the study, recruited the patients, analyzed and
interpreted the data, and drafted the manuscript. AE recruited the
patients, analyzed and interpreted the data, and critical revised
the manuscript for important intellectually content. LD performed
the design and conception of the study, recruited the patients,
analyzed and interpreted the data, and critical revised the
manuscript for important intellectually content. CF recruited the
patients, analyzed and interpreted the data, critical revised the
manuscript for important intellectually content. OFP analyzed and
interpreted the data, and critical revised the manuscript for
important intellectually content. VM analyzed and interpreted the
data, and critical revised the manuscript for important
intellectually content. SD aided in the literature review, analyzed
and interpreted the data, and critical revised the manuscript for
important intellectually content. CAS aided in the literature
review, analyzed and interpreted the data, and critical revised the
manuscript for important intellectually content. All authors read
and approved the final manuscript.
Ethics approval and consent to
participate
Approval for the present study was provided by the
Ethics Committee of the Transilvania University from Brașov,
Romania. Patient consent was not needed as the database was
anonymized.
Patient consent for publication
Not applicable.
Competing interests
All the authors declare that they have no competing
interests.
Authors' information
ORCID ID: Cristian Falup-Pecurariu:
0000-0002-7394-7161; Anca Enache: 0000-0002-4647-5939; Liliana
Duca: 0000-0002-3062-766X; Camil Fotescu: 0000-0002-3251-6947; Oana
Falup-Pecurariu: 0000-0003-1972-6859; Vlad Monescu:
0000-0002-0506-931X; Stefania Diaconu: 0000-0002-0251-4043; Carmen
Adella Sîrbu: 0000-0002-1982-1066.
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