Keywords:
Parkinson Disease - Sleep - Restless Legs Syndrome
Palavras-chave:
Doença de Parkinson - Sono - Síndrome das Pernas Inquietas
INTRODUCTION
Restless legs syndrome (RLS) or Willis-Ekbom disease is a disorder characterized by
the need to mobilize the lower limbs, which is sometimes associated with unpleasant
sensations. RLS symptoms are partially or completely alleviated during this mobilization
and they occur or worsen with rest and at night[1]. The onset of symptoms in RLS patients can occur throughout the patient’s lifetime[2],[3]. It often presents a chronic and progressive course, with periods of remission[4]. The association between increased prevalence of RLS and increased age has already
been documented[5],[6],[7].
In the general population, Eckeli et al. showed a RLS lifetime prevalence of 6.4%
in the city of Cássia dos Coqueiros in São Paulo State[8]. In Parkinson disease (PD) patients, studies estimate a prevalence in up to 50%
of them. Some studies have showed a higher prevalence of RLS in PD patients compared
to the Control Group[9],[10],[11],[12],[13],[14]. This variability occurs because many conditions that mimic RLS symptoms, such as
motor symptoms, cramps, polyneuropathy, positional discomfort, and akathisia, occur
in PD patients.
RLS may result from an abnormal integration of sensory-motor pathways due to disinhibition
at the spinal level caused by reduced activity of dopaminergic diencephalon-spinal
pathways from the hypothalamus (A11 cells)[15]. In PD patients, these neurons degenerate together with nigrostriatal pathway neurons,
which may justify a higher prevalence of RLS in PD patients[14]. In addition, dopaminergic medications are provided in order to treat PD motor and
RLS symptoms, reinforcing the dopaminergic deficiency observed in both pathologies[14]. Finally, several studies indicate an iron deficiency in specific areas of the brain
as a cause for RLS[16]. Two papers demonstrated an iron deficiency in PD patients with RLS compared to
the ones without RLS[12],[17].
Several investigations compared PD patients with and without RLS. However, the diversity
of samples and results hampers definitive conclusions[14]. Furthermore, most studies showed RLS onset concomitant or after PD onset[18],[19],[20],[21]. Patients with longer PD onset time and longer dopaminergic therapy time seem to
have higher prevalence of RLS[22]. Some papers have also presented that more severe parkinsonism symptoms are related
to a higher frequency of RLS symptoms[12],[18],[21],[22]. Other studies showed that PD patients with RLS had worse sleep quality, higher
excessive sleepiness, and worse quality of life than patients without RLS[9],[18],[20],[21].
The problems related to RLS in PD patients are frequent, potentially serious, and
possibly have important repercussions for the disease severity. Thus, the present
research is important for a better understanding of these topics in PD patients. This
study aimed to determine the factors associated with the presence of RLS in PD patients.
METHODS
Study design and population
A cross-sectional study was performed in PD patients from the tertiary outpatient
clinic of Movement Disorders of Hospital das Clínicas, School of Medicine of Ribeirão
Preto - University of São Paulo (HC-FMRP-USP), São Paulo, Brazil, for 21 months between
February of 2010 and March of 2012.
In total, 124 consecutive individuals with PD were approached on their routine appointment.
Ninety of these individuals provided an informed consent. Subsequently, the patients
that agreed to participate underwent a clinical assessment with a psychiatrist and
neurologists specialized in sleep medicine and movement disorders. Two individuals
did not attend the polysomnography (PSG). Patients underwent polysomnography with
a maximum interval of two weeks after the initial assessment. During this time, there
was no change in drug treatment.
This study was approved by the Ethics Committee of HC-FMRP-USP, under the protocol
number 13410, in accordance with the ethical principles of the Declaration of Helsinki.
Clinical evaluation
The clinical evaluation was based on standardized scales and assessment of sleep disorders,
cognitive framework, motor, and psychiatric symptoms of PD. We asked the patients
about some symptoms, such as: hypersalivation, dysphagia, dyskinesia, nocturia, anosmia,
excessive sweating, and constipation.
The scales related to the quality of life and sleep used were Epworth Sleepiness Scale
(ESS), Parkinson's Disease Questionnaire (PDQ-39), and Pittsburgh Sleep Quality Index
(PSQI).
A neurologist specialized in sleep medicine performed a clinical evaluation to detect
and diagnose sleep disorders according to the International Classification of Sleep
Disorders - third edition (ICSD-3)[1],[23].
The functional impairment was assessed by a neurologist specialized in movement disorders.
The following scales were used: Unified Parkinson’s Disease Rating Scale (UPDRS),
Hoehn & Yahr (H&Y) Parkinsonian Staging, and Schwab & England (S&E) activities of
the daily living score. The Mini-Mental State Examination (MMSE) and Global Deterioration
Score (GDS) were applied for cognitive assessment. Patients were evaluated during
the best ‘on’ period as possible for motor and cognitive assessment. In addition,
the International Restless Legs Syndrome Study Group rating scale (IRLS) was applied
for evaluating the severity of RLS.
To achieve psychiatric diagnosis, following the criteria of the Diagnostic and Statistical
Manual of Mental Disorders (fourth edition), American Psychiatric Association (DSM-IV),
a structured clinical interview for Axis I mental disorders of the DSM-IV was used
in the translated form that was adapted to Portuguese (SCID-I)[24].
Polysomnography
Time-synchronized video-PSG (v-PSG) was performed with a digital polygraph (computerized
sleep system; Biologic Sleepscan VISION PSG, Natus Bio-logic Systems Inc., San Carlos,
CA). Data were collected using an electroencephalogram - EEG (according to the International
10-20 System) (Fp1-M1, Fp2-M2, F3-M1, F4-M2, C3-M1, C4-M2, P3-M1, P4-M2, F7-M1, F8-M2,
T3-M1, T4-M2, T5-M1, T6-M2, O1-M1, O2-M2, Fz-Cz, Cz-Pz), bilateral electrooculogram
(E1-M2, E2-M1), electrocardiogram (modified V2 lead), and surface electromyography
of the mental and submental muscles. Surface electrodes were placed on both anterior
tibialis muscles, masseters, and extensors of fingers. Digital video was recorded
by an infrared camera (Sony Ipela., CA) synchronized with the PSG data. Respiration
was monitored as follows: airflow was measured by a nasal pressure transducer system
(AcSleep 119, Biolink Medical, São Paulo, Brazil) and nasal and mouth thermocouple
airflow sensor (Pro-Tech Services Inc., Mukilteo, WA); chest and abdominal efforts
were measured by respiratory inductive plethysmographic belts (Pro-Tech zRIP module,
Pro-Tech Services Inc.); arterial SaO2 was measured by pulse oximetry (Netlink Headbox, Natus Bio-logic Systems Inc.); snoring
sounds were measured using a snoring microphone; and body position was determined
using a sensor (Netlink Body Sensor Position, Natus Bio-logic Systems Inc.). All of
the technical parameters were performed by the AASM Manual for the Scoring of Sleep
and Associated Events: Rules, Terminology, and Technical Specification (2007)[25].
Statistical analysis
Kolmogorov-Smirnov test was applied to determine the distribution type of the variables.
Parametric tests such as Student’s t-test or analysis of variance (ANOVA) were used for normal distribution variables,
whereas nonparametric Mann-Whitney or Kruskal-Wallis test were applied for those without
a normal distribution. Pearson's coefficient was used in the correlation analysis
of numeric variables with a normal distribution, and Spearman's correlation coefficient,
for the analysis of numerical variables without a normal distribution. The hypothesis
tests were conducted to verify the nullity of the correlation coefficients. In the
analysis of categorical variables into two or more groups, chi-square or Fisher’s
exact tests were used according to the expected frequency in cells. Linear regression
analysis was performed to calculate the predictive coefficients for dependent quantitative
variables. For the multiple correlation analysis, logistic regression analysis was
used for binary categorical dependent variables. Microsoft Office Excel, IBM SPSS
Statistics 19, and R 3.1.0 were used to construct and analyze the database.
RESULTS
A total of 31 individuals complained about unpleasant sensations associated with the
need to mobilize their lower limbs. Of these patients, 25 were diagnosed with RLS,
four had motor fluctuations with “off” periods at night, and two had symptoms compatible
with cramps.
The mean IRLS values were 25.14±8.1, with a minimum value of 6 and a maximum of 37.
Four subjects had mild intensity of RLS symptoms, five subjects presented moderate
intensity, nine patients had severe severity, and 7 presented very severe gravity.
In the univariate analysis, a higher prevalence of women was observed in the RLS group.
Furthermore, RLS patients had a high score in the PSQI and PDQ-39 scales compared
to PD patients without RLS ([Table 1]). A moderate correlation was also observed between IRLSRS and PDQ-39 (r=0.45; p=0.03).
Table 1
Comparison of sociodemographic and clinical variables between groups of Parkinson
disease patients with and without restless legs syndrome (n=88).
|
Variables
|
•PD+RLS
•(n=25)
|
•PD-RLS
•(n=63)
|
p-value
|
|
Age (years), mean±SD
|
61±9
|
61±12
|
0.95
|
|
Sex (% of male)
|
44.0
|
69.8
|
0.03
|
|
Schooling (years)
|
7±6
|
6±4
|
0.79
|
|
PD onset time (months), mean±SD
|
108±64
|
100±65
|
0.31
|
|
Equivalent dose of levodopa (mg), mean±SD
|
937±364
|
802±470
|
0.08
|
|
BMI, mean±SD
|
25±4
|
25±5
|
0.58
|
|
ESS, mean±SD
|
13±6
|
11±5
|
0.14
|
|
PSQI, mean±SD
|
12±4
|
8±4
|
0.000
|
|
PDQ-39, mean±SD
|
54.8±12.3
|
39.5±17.5
|
0.000
|
|
UPDRS-III, mean±SD
|
19±13
|
18±12
|
0.78
|
|
GDS, mean±SD
|
2±1.0
|
2±1.0
|
0.68
|
|
MMSE, mean±SD
|
24.8±3.8
|
24.1±4.2
|
0.61
|
|
Hoehn & Yahr, mean±SD
|
2±0.3
|
2±0.5
|
0.66
|
|
Schawb & England, mean±SD
|
82.0±12.0
|
84.0±16.0
|
0.26
|
|
Presence of RBD (%) (n=55)
|
85.0
|
70.9
|
0.25
|
|
Presence of OSAS (%)
|
64.0
|
61.9
|
1.0
|
|
Presence of insomnia (%)
|
80.0
|
46.0
|
0.004
|
|
Presence of Excessive Fragmentary Myoclonus (%)
|
56.0
|
61.9
|
0.63
|
|
Presence of bruxism (%)
|
4.2
|
8.1
|
1.0
|
|
Presence of ALMA and/or HFT (%)
|
12.0
|
12.7
|
1.0
|
|
Presence of PLM index >15 events/h (%)
|
28.0
|
12.7
|
0.11
|
|
Presence of depression (%)
|
36.0
|
25.4
|
0.43
|
|
Presence of psychotic disorder (%)
|
20.0
|
11.1
|
0.31
|
|
Presence of anxiety disorder (%)
|
28.0
|
11.1
|
0.10
|
|
Presence of hypersalivation (%)
|
12.0
|
3.2
|
0.14
|
|
Presence of dysphagia (%)
|
0
|
1.6
|
1.0
|
|
Presence of dyskinesia (%)
|
56.0
|
33.9
|
0.09
|
|
Presence of nocturia (%)
|
64.0
|
54.0
|
0.47
|
|
Presence of anosmia (%)
|
44.0
|
11.3
|
0.002
|
|
Presence of excessive sweating (%)
|
36.0
|
25.8
|
0.43
|
|
Presence of constipation (%)
|
60.0
|
35.5
|
0.05
|
|
Antidepressant use (%)
|
24.4
|
25.4
|
0.54
|
|
Dopaminergic agonists use (%)
|
55.4
|
54.8
|
0.55
|
*p<0.05. RBD: REM Sleep Behavior Disorder; PD: Parkinson disease; SD: standard deviation;
OSAS: Obstructive Sleep Apnea Syndrome; RLS: restless legs syndrome; BMI: body mass
index; PDQ-39: Parkinson’s Disease Quality of Life - 39; UPDRS-III: Unified Parkinson
Disease Rating Scale - part III; PSQI: Pittsburgh Sleep Quality Index; MMSE: Mini-mental
state examination; ESS: Epworth Sleepiness Scale; GDS: Global Deterioration Scale;
ALMA: alternate leg movement activation; HFT: hypnagogic foot tremor.
RLS patients had a higher prevalence of chronic insomnia (80%) than those patients
without RLS (46%; p=0.004). RLS individuals also had a higher proportion of anosmia
and constipation symptoms than the ones without RLS ([Table 1]). No difference was observed between the polysomnographic values of the groups ([Table 2]).
Table 2
Comparison of polysomnographic variables between groups of Parkinson disease patients
with and without restless legs syndrome (n=88).
|
Polysomnographic variables
|
•PD+RLS
•(n=25)
|
•PD-RLS
•(n=63)
|
p-value
|
|
Total sleep time (h), mean±SD
|
5.0±1.5
|
4.9±1.4
|
0.91
|
|
Sleep efficiency (%), mean±SD
|
66.6±19.5
|
67.0±19.5
|
0.91
|
|
WASO (min), mean±SD
|
143.3±91.0
|
125.1±68.4
|
0.66
|
|
WAFA (min), mean±SD
|
9.2±14.3
|
12.9±21.7
|
0.55
|
|
Sleep onset latency (min), mean±SD
|
22.9±30.6
|
28.5±42.9
|
0.58
|
|
REM sleep onset latency, mean±SD
|
140.5±92.6
|
166.0±116.0
|
0.59
|
|
N1 Sleep (%TST), mean±SD
|
19.9±10.7
|
18.6±10.9
|
0.58
|
|
N2 Sleep (%TST), mean±SD
|
46.1±11.7
|
49.0±13.6
|
0.35
|
|
N3 Sleep (%TST), mean±SD
|
22.3±12.6
|
21.6±13.6
|
0.69
|
|
REM Sleep (%TST), mean±SD
|
11.7±8.7
|
10.8±9.2
|
0.56
|
|
Arousal index (events/h), mean±SD
|
25.6±11.9
|
24.9±11.7
|
0.75
|
|
RDI (events/h), mean±SD
|
13.2±14.0
|
13.3±13.8
|
0.95
|
|
AHI in NREM sleep (events/h), mean±SD
|
11.2±14.0
|
13.0±14.9
|
0.78
|
|
AHI in REM sleep (events/h), mean±SD
|
12.3±13.5
|
14.2±20.5
|
0.84
|
|
PLM index (events/h), mean±SD
|
33.1±64.8
|
4.8±11.9
|
0.33
|
RLS: restless legs syndrome; RBD: REM Sleep Behavior Disorder; PD: Parkinson disease;
SD: standard deviation; WAFA: wake time after final arousal; WASO: wake time after
sleep onset; RDI: Respiratory Disturbance Index; AHI: Apnea-Hypopnea Index; PLM: periodic
leg movements.
Multivariate analysis
For the logistic regression analysis, we have included the variables with p<0.1 (sex,
total UPDRS, levodopa equivalent dose, PSQI, PDQ-39, insomnia, anxiety disorder, dyskinesia,
motor fluctuation, smell loss, and constipation). After initial analysis with the
independent variables, those with higher p values were progressively withdrawn and
only those with p<0.05 remained. Thus, the following independent variables were significant
in the final model: PSQI (estimated coefficient=0.18; p=0.03), PDQ-39 (estimated coefficient=0.05;
p=0.01), and smell loss (estimated coefficient=1.85; p=0.001). The final formula of
the logistic regression model was: presence of RLS= -6.06+(PSQI×0.18)+(PDQ-39×0.05)+(smell
loss×1.85).
DISCUSSION
Several clinical conditions in PD patients could mimic symptoms of RLS, such as motor
fluctuation, cramps, akathisia, and pain related to PD. These factors may confuse
the diagnosis to less experienced physicians. RLS diagnosis needs a careful evaluation
to ward off these RLS mimics.
As far as we know, no previous paper evaluated the association between anosmia, constipation,
and RLS in PD patients. A previous study by Adler et al. compared the olfactory function
of RLS individuals with PD subjects. Such study documented normal olfactory functions
in the RLS group and deficient olfactory function in the PD group[26], but the study did not evaluate the olfactory function in those individuals with
both PD and RLS. A possible explanation for these findings in our study is a higher
deposition of alpha-synuclein in PD individuals with RLS compared with the ones without
it. We have not made standardized olfactory tests in this study, so the presence of
anosmia was only verified by questioning the patient, which is the weakness of this
paper.
Constipation is a frequent symptom in PD patients, like anosmia, especially because
these are symptoms that, in many cases, precede the onset of motor symptoms[27]. They could be explained by deposition of Lewy bodies in the peripheral autonomic
nervous system of PD patients, leading to subsequent sympathetic denervation of the
colon[28]. Shneyder et al. showed a higher proportion of constipation and other autonomic
complaints in RLS individuals compared to the control group[29]. A possible explanation would be that dopaminergic hypofunction, especially of A11
cells, would lead to lower stimulation in pre-ganglionic sympathetic neurons, allowing
a greater sympathetic flow to the peripheral neurons[30]. Constipation was diagnosed through the patient’s complaint. However, no specific
criteria were used, which is a negative aspect of this study.
As in several previous studies in PD patients, we did not observe a difference between
ages[12],[13],[18],[22],[31],[32],[33]. This characteristic is different from what occurs in the general population, in
whom a greater frequency of RLS is observed, as individuals are older, with a peak
prevalence between 61 and 70 years[7],[8],[34],[35],[36]. A possible explanation for these different data was a higher concentration of individuals
over 50 years-old in PD population than in the general population.
No difference between periodic leg movements (PLM) in PD groups with or without RLS
was observed, which is not in agreement with data from Nomura et al.[17]. The diversity of doses, schedules, and pharmacokinetics of dopaminergic agonists
used in PD individuals could modify the prevalence and intensity of PLM in this group
of individuals and explain the large variability of PLM index in PD individuals with
RLS.
The present study had some limitations, such as: conduction in a high-complexity outpatient
hospital, therefore involving patients with greater severity and duration of the disease,
which restricts the possibility of generalization of our data; absence of standardized
olfactory tests and specific diagnostic criteria for constipation in this study; absence
of dose of serum iron and ferritin levels; low number of patients included, considering
a large number of variables analyzed; absence of a control group without PD, reducing
the possibility of comparisons; and the cross-sectional design of the study, making
it difficult to establish cause-and-effect associations.
Finally, it is noteworthy that RLS is a relevant disease in PD patients. It is also
associated with specific characteristics of PD patients, such as smell loss. New controlled
studies with larger numbers of PD patients could answer some controversial topics.
Furthermore, in the clinical care of PD patients, a systematic and comprehensive assessment
of RLS pathology is of mandatory importance.
