Original Paper Received: September 30, 2014 Accepted: January 25, 2015 Published online: March 11, 2015
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
Parkinson’s Disease and Restless Legs Syndrome Ari Ylikoski a, b Kirsti Martikainen d Markku Partinen a, c
a
Vitalmed Research Center, Helsinki Sleep Clinic, and b Hospital of Laakso, and c Institute of Clinical Medicine, Department of Clinical Neurosciences, University of Helsinki, Helsinki, d The Finnish Parkinson Foundation, Turku, Finland
Abstract Aims: Various sleep-related complications are common in Parkinson’s disease (PD). The prevalence of restless legs syndrome (RLS) and its association with other symptoms were studied. Methods: Altogether, 1,447 Parkinson patients, aged 43–89, participated in a questionnaire study. Results: The response rate was 59.0% and of these, 68% returned fully answered questionnaires (n = 577). RLS occurred in 20.3% of the PD subjects. In patients with RLS, the symptoms occurred in 81.9% at least once weekly. The degree of severity was moderate in 42.7%, severe in 23.9% and very severe in 15.4%. Daytime sleepiness, fatigue, chronic insomnia, sleep maintenance insomnia, intense dreaming, and low quality of life were more common in patients with RLS than in patients without RLS. The occurrence of early onset RLS (onset ≤ age of 45 years) was 4.2%. The occurrences of late onset (>45 years) drug naïve RLS and late onset RLS (with dopaminergic medication) were 5.4 and 10.4%, respectively. Conclusion: In patients with PD, the early onset of RLS resembles idiopathic RLS with typical gender distribution and familial trait. Late onset of RLS is more common than idiopathic RLS. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0014–3022/15/0734–0212$39.50/0 E-Mail [email protected] www.karger.com/ene
Introduction
Restless legs syndrome (RLS) is a sensorimotor disorder due to a dysfunction of the dopaminergic system [1, 2]. The prevalence ranges from 4–10% in the general population, and it increases with age up to around 65 years, after which it may even begin to decline [3, 4]. RLS can be divided into an earlier onset disease with a clear genetic component and a preference for female gender, and a later onset disease with unclear etiology [5]. Secondary RLS is related to a late onset of symptoms after 45 years of age. The coexistence of RLS and Parkinson’s disease (PD) is under debate. PD onset rarely begins before 40 years. The prevalence is 0.9 and 5.1% for the age groups 65–69 and 85–89, respectively [6]. Non-motor symptoms, including sleep disorders, for example, RLS, are important features of the disease. The prevalence of RLS in PD cohorts has varied from 5.5 to 27% in European studies [7–11]. The prevalence of RLS in drug-naïve patients with PD has varied from 5.5 to 16.5% [7, 12, 13]. There are differences between these two entities. PD is a chronic disease progressing slowly after onset over the life span, while it is unknown if RLS is a progressive condition or expressing different phenotypes during advancing age. The pathological hallmark of PD is synuclein aggregation to form Lewy neuritis and Lewy bodies associAri Ylikoski Vitalmed Research Center, Clinic of Neurology Hospital of Laakso Helsinki Sleep Clinic, Sitratori 3 FI–00420 Helsinki (Finland) E-Mail ari.ylikoski @ fimnet.fi
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Key Words Parkinson’s disease · Restless legs syndrome · Sleep disorders
Parkinson’s Disease and Restless Legs Syndrome
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
Subjects and Methods
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Altogether 1,500 patients with PD were randomly selected from the registry of the Finnish Parkinson Association including 5,373 PD patients from the total of 10,000–12,000 Finnish PD patients. The random sample was selected by random number generator, based on the registration number in the registry. This allowed us to have a representative sample of all subjects in the registry. After an initial selection, we found that forty-nine subjects were either deceased or hospitalized (unable to answer), two were relatives of Parkinson’s patients, one had dystonia without Parkinson’s disease and one was a healthy person. These persons were excluded and the remaining number of eligible patients was 1,447. A new questionnaire was sent to those participants who did not respond within three months. The patients were defined as having
PD, (a) if their diagnosis had been confirmed by a neurologist and (b) they used a typical antiparkinsonian medication. Due to the nature of a questionnaire study, most likely subjects with a cognitive dysfunction, for example, patients with Lewy body disease, were among non-responders. The structured questionnaire with 207 items included questions derived from the Basic Nordic Sleep Questionnaire [21]. The basic five alternatives for the responses were: (1) ‘never or less than once per month’, (2) ‘less than once per week’, (3) ‘on 1–2 days per week’, (4) ‘on 3–5 days per week’ and (5) ‘daily or almost daily’. The high likelihood for sleep apnea (hlSA) was asked separately with a question: ‘Have you had at least weekly breathing pauses (sleep apnea) at sleep (have other people noticed that you have at least weekly pauses in respiration when you sleep)?’. Daytime fatigue was asked as ‘Do you feel fatigued during daytime?’. Intense dreaming was defined as recalling dreams every night. RLS was defined using the international definition criteria [22]. We used six questions to define RLS: (1) ‘Do you have unpleasant sensations (tingling, burning sensations, pain, other unpleasant sensations) in your legs?’, (2) ‘Do you have an urge to move your legs?’, (3) ‘Do your symptoms of unpleasant sensations or urge to move become worse when you are sitting as compared to when you stand up?’, (4) ‘Do your symptoms of unpleasant sensations or urge to move become worse when you go to bed?’, (5) ‘If you have symptoms of unpleasant sensations and/or urge to move the limbs, do your symptoms get better when move your limbs or when you start to walk?’, (6) ‘Do your symptoms (as asked in the questions above) get worse in the evening or at night?’. The 5-point frequency scale for questions 1 and 2 is described earlier. Diagnosis of RLS was based on the commonly used criteria by Allen et al. [22]. In addition, we asked about the current unpleasantness for pain and urge to move limbs, circadian occurrence and, occurrence of RLS symptoms in the family, and frequency of the RLS symptoms. Alternatives to unpleasantness and urge were: (0) ‘not at all’, (1) ‘a little’, (2) ‘somewhat’, (3) ‘plenty’ and (4) ‘very much’. Discomfort of RLS symptoms was the sum of two questions (score 0–8). Disturbance level of RLS (DLRLS) was defined as 0 = none (score = 0), 1 = mild (1–2), 2 = moderate (3–4), 3 = severe (5–6) and 4 = very severe (7–8). Daytime sleepiness was ascertained with two validated instruments, the Epworth Sleepiness Scale (ESS) [23] and the Skogby Excessive Daytime Sleepiness Index (SEDS) [24]. In both cases, higher scores indicated greater sleepiness, with an 8-item ESSscore maximum of 24, and a 5-item SEDS-score maximum of 25. The REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ) [25] is a patient self-rating instrument with ten questions (yes/no) assessing the various aspects of sleep behavior. The RBDSQ has been validated as a screening tool for secondary RBD among PD patients (the cut-off value is 6 points, with a sensitivity of 0.842 and a specificity of 0.962) [26]. In the ICD-10 [27] criteria A–C must be met for Chronic Insomnia Disorder: (A) difficulties falling asleep, maintaining sleep or non-refreshing sleep. (B) symptoms occur at least 3 nights per week and for longer than one month. (C) the sleep problems cause marked personal distress or interference with personal functioning in daily living. In our study, persons were defined as having insomnia if criteria A–C were met:
ated with the destruction of dopaminergic DA neurons in the substantia nigra pars compacta region [14]. The precise pathophysiology of RLS is not known, but a decrease of brain iron seems to play an important role [1]. On the contrary, there are no shared neuronal degeneration nor Lewy Body deposition nor shared alpha-synuclein pathology with RLS and PD [15]. The CNS iron differs between the two entities. While abnormal accumulation of iron in the brain has been implicated in Parkinson’s disease, significant iron deficiency has been found in the neurons of substantia nigra in RLS patients [1, 16]. In the genetic studies of RLS, a gene has been associated with iron stores, but no genes have been related to dopamine or endogenous opioid systems, and no RLS-related variants have been found to be significantly shared with Parkinson’s disease [1, 17, 18]. Prolonged dopaminergic therapy in RLS patients may result in augmentation symptoms [19, 20]. In a community sample, more than 30 percent of patients on levodopa develop augmentation of RLS. Respective rates for ropinirole and pramipexole were around 24 and 11 percent [20]. It has been estimated that about 8 percent of RLS patients may develop augmentation each year up to about 8 years of treatment after which the rate of augmentation may start to decrease [20]. Augmentation of classical PD symptoms (tremor, rigidity, bradykinesia) is not known to occur after dopaminergic treatment, but patients with PD may develop dyskinesias and motor fluctuations after treatment with dopaminergic agents. The objective of this population study of randomly selected PD patients was to examine the prevalence of idiopathic and secondary RLS, before and after PD diagnosis, taking into account how each of these are related to other sleep disorders.
Results
The response rate was 59% (n = 854), and of these 68% returned fully answered questionnaires (n = 577). As compared to the non-responders, we did not find statisti214
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
cally significant differences in age, gender distribution or duration of PD. In this cohort, the median age of the responders was 67 years (mean 67.4 years, SD 8.7, range 43–89), and 52.2% of them were male. The median duration of PD was 5 years (mean 6.0 years, SD 5.1). One patient was treated with deep brain stimulation. Akineticrigid subtype of PD was found in 35.0% of the participants. Table 1 shows demographic and medication data in subjects with PD without RLS (PDw/oRLS) and PD with RLS. The latter group PD with RLS tended to have an earlier diagnosis of PD and a longer disease duration. Otherwise, both groups had similar ages, genders, educations, BMIs, manners with living, and medications. RLS (constellation of the four IRLSSG criteria) was found to occur in 20.3% (n = 117/577; 54% women, 46% men) of PD subjects. The frequency of RLS was 18.1% ‘never or less than once per month’, 24.1% ‘less than once per week’, 20.7% ‘on 1–2 days per week’, 18.1% ‘on 3–5 days per week’ and 19.0% ‘daily or almost daily’, respectively. DLRLS was none in 1.7% of participants with RLS, mild in 16.2%, moderate in 42.7%, severe in 23.9% and very severe in 15.4%, respectively. The frequency and severity of RLS were highly correlated (Chi square 172.6; p = 0.000). Frequency distribution of RLS symptoms and DLRLS, frequency distribution of RLS symptoms and proportion of patients are shown in the figure 1. The DLRLS (score 0–4) was 1.1 (95% CI 1.0–1.2) in PD without RLS and 2.4 (2.2–2.5) in PD with RLS (p < 0.001). Of the isolated symptoms of RLS, unpleasant sensations at least on three days per week were observed in 34.9% of the PD patients, and urge to move limbs (≥3 days/week) in 31%. Early onset of RLS occurred in 70.6% of women and in 29.4% of men. Among the late onset RLS patients (n = 65) 54% were women and 46% were men. The circadian rhythm differed between groups. The unpleasantness was found during 7.00–12.00 a.m. in 17.2% of PD-non-RLS group and in 14.5% of PD-RLS group (p = 0.492), during 1.00–6.00 p.m. in 22.9% and in 16.2% (p = 0.118), during 7.00–12.00 p.m. in 34.6% and in 68.4% (p < 0.000), and during 1.00–6.00 a.m. in 22.2% and in 54.7% (p < 0.000), respectively. A total of 39.3% of RLS patients (46/117) experienced RLS suffering (discomfort score DLRLS ≥3). Occurrence of hlSA was 76.5% in RLS-sufferers and 22.5% in RLSL-non-sufferers (OR 6.4, 95% CI 1.9–21.3, p = 0.002), depression 54.3 and 45.7% (2.3, 1.04–5.2, p = 0.041), respectively. Otherwise, no significant differences were found in RLS-sufferers compared to RLS-non-sufferers. Occurrence of akinetic-rigid subtype of PD was 35.0%, anosmia 67.0%, constipation 47.1% and nocturia 14.9%. Ylikoski/Martikainen/Partinen
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(A) they had at least one of the following symptoms (same items in ICD-10 [27] and DSM-IV-TR [28]: (a) difficulties falling asleep at least 3 nights per week (b) waking up too early at night without being able to sleep again on least 3 nights per week (c) waking up at least 3 times per night at least 3 nights per week (d) unrefreshing (non restorative) sleep during at least one month (B) they had suffered from insomnia at least for one month, and (C) the sleep disturbance affected negatively their social life, working life or leisure time. (Question: ‘If you suffer from sleep disturbance, exhaustion, and/or tiredness, do you think it gives trouble to your life when you have leisure time (rest, hobbies), or when you socialize with relatives or friends, or when you work (professionally, or with other daily activities)?’ (1) ‘no’, (2) ‘yes’.) Sleep maintenance insomnia (SMI; criterion A.c. of the ICD10) was evaluated asking two questions as ‘How often weekly have you awakened at night during the past three months?’ and ‘If you are used to waking up during night, how many times do you usually wake up during one night?’: (1) ‘usually I don’t wake up at night’, (2) ‘once’, (3) ‘2 times’, (4) ‘3–4 times’, (5) ‘at least 5 times’. SMI index is the sum of the two questions. SMI occurred when index was at least 8. Definition of anosmia was a subjective inability to perceive odor. Constipation was defined as infrequent bowel movements (≤3 times per week), and nocturia as frequent urgency to urinate during night (≥3 times a night). Patients were defined physically active (i.e., exercise >4 h weekly), if they reported to walk either 4 h or more in a week or walk at least 2 h and jog/ run at least 30–60 min in a week. The health-related quality of life was evaluated using the World Health Organization Well-Being Questionnaire (WHO5). The quality of life is considered poor if the standardized percentage score is less than 50 [29]. Depression was evaluated using an easy screening method for general practice, that is, the Short Form of the Beck Depression Inventory (SDI) (score 0–21), since it does not include any question about sleep. The limit for depression is 10 [30–32]. All statistical analyses were conducted using Stata 12.0 (Copyright 1985–2011 StataCorp LP). Quantitative values were expressed as medians, means, standard deviations and ranges. The normality of the distributions was tested with the Shapiro-Wilk normality test. For continuous variables parametric (Student’s ttest) or nonparametric methods (Mann-Whitney U test) were used depending of the distribution. Categorized values were expressed in numbers and percentages and analyzed by the Pearson’s Chisquare test and Fisher’s exact test. Values of p < 0.05 were considered statistically significant. Logistic regression analysis was used to compute odds ratios (OR) and their 95% confidence intervals (CI). The ethical permission was obtained from the local ethical committee and the study was conducted according to the declaration of Helsinki.
Table 1. Demographic and medication data in subjects with Parkinson’s disease without restless legs syndrome (PDw/oRLS) and Par-
kinson’s disease with restless legs syndrome (PD with RLS)
Age, years Sex, % male BMI, kg/m2 BMI at the age of 20 years BMI change1 Waist length, cm Male Female Education, % Primary Lower secondary Upper secondary Postsecondary Tertiary Exercise (>4 h weekly), % Alcohol (≥48 g weekly ), % Smoking, % Caffeine (≥200 mg daily), % PD duration, years Age of PD diagnosis, years Levodopa, % Agonists, % MAO-inhibitors, % DBS, %
All PD (n = 577)
PDw/oRLS (n = 460)
PD with RLS (n = 117)
p
67.4±8.7 52.2 26.5±4.5 21.9±2.5 4.5±4.5
67.6±8.6 53.8 26.3±4.4 21.9±2.5 4.3±4.4
66.3±9.2 45.7 27.2±4.8 22.0±2.8 5.2±4.7
0.14 0.12 0.07 0.81 0.08
100±10 88±12
100±11 88±12
101±8 92±13
0.55 0.04
39.7 22.2 21.0 2.1 15.0 54.0 18.2 6.2 27.3 6.0±5.1 61.2±9.1 75.3 75.5 49.7 1.6
39.6 22.7 21.3 2.0 14.4 55.2 19.3 6.6 26.5 5.6±4.1 61.7±8.8 73.9 76.9 49.9 1.7
40.2 20.5 19.7 2.6 17.1 49.6 14.3 4.5 30.6 7.4±7.9 59.1±9.9 81.0 69.8 49.1 0.9
0.92 0.28 0.24 0.39 0.40 0.005 0.006 0.11 0.11 0.88 0.49
BMI = Body mass index; DBS = deep brain stimulation. 1 BMI change from the age of 20 years to present time.
45
3.5
Proportion of patients (%)
2.5 2.0 1.5 1.0 0.5
a
35 30 25 20 15 10 5
45 years). Table 3 shows occurrences of different variables in subjects with PD and early onset RLS (PD with RLS onset ≤45 years) and PD and late onset RLS (PD with RLS onset >45 years). PD with RLS onset ≤45 216
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
years was more hereditary than PD with RLS onset >45 years (64.7 vs. 22.4%; p < 0.001). The PD with RLS onset >45 years group used more often levodopa and MAO-inhibitors medication (Levodopa and MAO-inhibitors combined 17.6 vs. 46.1%; p = 0.033). Adjusted for age, sex, and disease duration, this difference in medication remained significant (OR 4.7; 95% CI 1.18– 19.0). From the subgroup of secondary RLS, an estimate of drug-naïve RLS prevalence was 5.4% (n = 22, 26.8% of 82 RLS patients; RLS symptoms onset before PD diagnosis). The prevalence of RLS in PD patients could have been the result from the confounding medication in 10.4% (n = 43, 52.4% of 82 RLS patients; RLS symptoms onset after PD diagnosis). In drug-naïve patients, RLS symptoms onset was 6.3 years (95% CI 9.6–3.1) before PD diagnosis compared to the latter group 4.6 years (3.0–6.3) after PD diagnosis. The duration of RLS symptoms was 11.0 years (7.7–14.3) and 5.1 years (1.9–8.2), respectively. In the analyses, drug-naïve RLS had a shorter duration of Parkinson’s disease (4.7 years; 95% CI 3.2–6.2) than secondary RLS with confounding medication group (9.7; 6.3–13.1) (p = 0.022). Otherwise, there were no significant differences between these groups. Ylikoski/Martikainen/Partinen
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1 Adjusted to age, sex and PD duration. RBD = REM sleep behavior disorder; hlSA = high likelihood of sleep apnea; ESS = Epworth sleepiness scale; SEDS = Skogby excessive daytime sleepiness index; SMI = sleep maintenance insomnia index; WHO5 = World Health Organization well-being index.
Table 3. Data in subjects with Parkinson’s disease and early onset RLS (onset ≤45 years) and Parkinson’s disease and late onset RLS
(onset >45 years)
Age, years1 Sex, % female Onset age of RLS, years1 Familial RLS, % RLS discomfort (score ≥5), % PD duration, years1 Age of PD diagnosis, years1 Levodopa, % MAO-inhibitors, % Levodopa and MAO-inhibitors, % Agonists, % Akinetic-rigid subtype of PD, % Anosmia, % Constipation, % Nocturia (≥3 times a night), % RBD, % OSAS, % ESS >10, % SEDS >15, % Fatigue, % Insomnia, % SMI (SMI index ≥8), % Intense dreaming, % Depression, % Poor quality of life (WHO5 45 years (n = 65)
p
64.2 (60.5–67.8) 70.6 27.8 (21.1–34.5) 64.7 41.2 5.2 (3.6–6.7) 59.0 (54.9–63.1) 70.6 35.3 17.6 82.4 55.2 62.5 47.1 17.6 50.0 5.9 23.5 58.8 64.7 40.0 47.1 31.2 25.0 41.2
67.5 (65.2–67.8) 53.8 60.5 (58.0–63.0) 22.4 44.6 8.0 (5.6–10.4) 59.5 (57.0–62.1) 84.6 53.8 46.1 64.6 35.0 68.7 46.9 17.2 49.1 21.9 38.5 54.8 56.9 59.0 40.0 25.4 29.2 58.5
0.170 0.214 0.001 0.799 0.195 0.836 0.183 0.173 0.033 0.162 0.122 0.633 0.989 0.964 0.951 0.131 0.252 0.770 0.562 0.184 0.599 0.636 0.737 0.202
1 Mean, 95% confidence interval. RBD = REM sleep behavior disorder; OSA = obstructive sleep apnea; ESS = Epworth sleepiness scale; SEDS = Skogby excessive daytime sleepiness index; SMI = sleep maintenance insomnia; WHO5 = World Health Organization well-being index.
The Onset of RLS The age of onset of RLS is known to vary widely from childhood to more than 80 years [15]. The prevalence of RLS in adults is around 3% in people aged 18–29 years and 10% in those aged 30–79 years [33]. In patients with PD, symptoms of RLS symptoms have been reported to follow PD diagnosis in 68–82% of PD patients [6, 23]. In our study (PD patients), the occurrence of early onset RLS was 4.2% and occurrence of late onset RLS was 16.1%. In this study, the onset of RLS symptoms followed PD diagnosis in 52.4% of all RLS patients and in 66.2% of the late onset RLS patients.
ever, due to a low number of subjects (n = 17) this difference was not statistically significant. In previous studies on PD patients, this typical gender distribution has not been described [7, 9, 12]. In accordance with these studies, we found no gender difference in the group of all RLS patients (n = 117; 54% women, 46% men) or in late onset RLS patients (n = 65; 54% women, 46% men). The RLS Genetics About 50 percent of people with primary RLS report a positive family history [35]. In PD patients, a familial trait seems to be more common if RLS onset happens ≤45 years [36]. These findings are consistent with our result. A familial occurrence of RLS was found in 64.7% of the early onset RLS.
The Gender Distribution Women are two times more likely than men to have RLS in the general population [34]. We found the same ratio in PD patients, as early onset of RLS occurred twice as often in women (70.6%) than in men (29.4%). How-
The Dopaminergic Medication Symptoms of RLS are known to respond to dopaminergic drugs in both idiopathic RLS and PD. Treating RLS patients, augmentation has been reported less frequently
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Discussion
with dopamine agonists 27% [37] than with levodopa 82% [38]. The more frequent symptoms of RLS in PD patients with longer dopaminergic could be the result of the same augmentation mechanisms, which are not fully known. Our finding of medication difference between early onset versus late onset of RLS groups contradicts the hypothesis that RLS and PD are two different entities that just happen to occur simultaneously, as there was no medication difference between secondary drug-naïve RLS group (RLS onset before PD diagnosis) and possible confounding medication RLS group (RLS onset after PD diagnosis). Since dopaminergic medication help RLS symptoms, the prevalence of secondary RLS in this study may be an underestimation. On the other hand, the prevalence of secondary RLS correlated positively with the use of levodopa, so augmentation could explain a part of the prevalence of RLS. Could it be that at least in some patients symptoms of RLS may be considered nonconventional symptoms of PD? If this is the case, it does not fit with the iron hypothesis of PD (accumulation of iron in the striatum) and RLS (lack of CNS iron). The Frequency and Severity of RLS Previous reports on the frequency and severity of symptoms of RLS in PD are rare. In a series of 29 PD patients with RLS, frequency of RLS was reported as 17% ‘at least once a year but less than once a month’, 24% ‘2 to 4 times a month’ and 10% ‘6 to 7 times a week’ [11]. The severity of RLS, measured with IRLSSG rating scale, was estimated as moderate in 19% of participants, severe in 19% and very severe in 4% [11]. In our series of 117 PD patients with RLS, the weekly frequency of RLS was 81.9%. The degree of difficulty was moderate in 42.7%, severe in 23.9% and very severe in 15.4%. All in all, the dopaminergic medication had no soothing effect on the frequency and severity of RLS in PD patients.
quality of life (WHO5 15), other sleep complaints and low
Disclosure Statement Ari Ylikoski has nothing to declare. Kirsti K. Martikainen has received lecture fees from Boehringer-Ingelheim, lecture and consultant fees from Orion Pharma, UCB Pharma, H. Lundbeck and NordicInfuCare.
Markku Partinen has received lecture fees from BoehringerIngelheim, GSK, MSD, Orion Pharma, lecture and consultant fees from Leiras-Nycomed, UCB, Cephalon, consultant fees from Servier, expert testimony fees from UCB, grants from Academy of Finland, Parkinson Foundation of Finland and Gyllenberg Foundation.
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1 Trenkwalder C, Paulus W: Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010; 6:337–346. 2 Clemens S, Rye D, Hochman S: Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006;67:125–130. 3 Allen RP, et al: Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–1292. 4 Ohayon MM, Roth T: Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res 2002;53:547–554. 5 Hanson M, et al: Analysis of familial and sporadic restless legs syndrome in age of onset, gender, and severity features. J Neurol 2004; 251:1398–1401. 6 de Rijk MC, et al: Prevalence of parkinsonism and Parkinson’s disease in Europe: the EUROPARKINSON collaborative study. European community concerted action on the epidemiology of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997;62:10–15. 7 Angelini M, et al: A study of the prevalence of restless legs syndrome in previously untreated Parkinson’s disease patients: absence of comorbid association. J Neurol Sci 2011; 310: 286–288. 8 Gomez-Esteban JC, et al: Restless legs syndrome in Parkinson’s disease. Mov Disord 2007;22:1912–1916. 9 Peralta CM, et al: Restless legs syndrome in Parkinson’s disease. Mov Disord 2009; 24: 2076–2080. 10 Svensson E, et al: Sleep problems in Parkinson’s disease: a community-based study in Norway. BMC Neurol 2012;12:71. 11 Verbaan D, et al: Prevalence and clinical profile of restless legs syndrome in Parkinson’s disease. Mov Disord 2010;25:2142–2147. 12 Gjerstad MD, Tysnes OB, Larsen JP: Increased risk of leg motor restlessness but not RLS in early Parkinson disease. Neurology 2011;77:1941–1946. 13 Shin HY, et al: Restless legs syndrome in Korean patients with drug-naïve Parkinson’s disease: a nation-wide study. Parkinsonism Relat Disord 2013;19:355–358.
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
Parkinson’s Disease and Restless Legs Syndrome Ari Ylikoski a, b Kirsti Martikainen d Markku Partinen a, c
a
Vitalmed Research Center, Helsinki Sleep Clinic, and b Hospital of Laakso, and c Institute of Clinical Medicine, Department of Clinical Neurosciences, University of Helsinki, Helsinki, d The Finnish Parkinson Foundation, Turku, Finland
Abstract Aims: Various sleep-related complications are common in Parkinson’s disease (PD). The prevalence of restless legs syndrome (RLS) and its association with other symptoms were studied. Methods: Altogether, 1,447 Parkinson patients, aged 43–89, participated in a questionnaire study. Results: The response rate was 59.0% and of these, 68% returned fully answered questionnaires (n = 577). RLS occurred in 20.3% of the PD subjects. In patients with RLS, the symptoms occurred in 81.9% at least once weekly. The degree of severity was moderate in 42.7%, severe in 23.9% and very severe in 15.4%. Daytime sleepiness, fatigue, chronic insomnia, sleep maintenance insomnia, intense dreaming, and low quality of life were more common in patients with RLS than in patients without RLS. The occurrence of early onset RLS (onset ≤ age of 45 years) was 4.2%. The occurrences of late onset (>45 years) drug naïve RLS and late onset RLS (with dopaminergic medication) were 5.4 and 10.4%, respectively. Conclusion: In patients with PD, the early onset of RLS resembles idiopathic RLS with typical gender distribution and familial trait. Late onset of RLS is more common than idiopathic RLS. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 0014–3022/15/0734–0212$39.50/0 E-Mail [email protected] www.karger.com/ene
Introduction
Restless legs syndrome (RLS) is a sensorimotor disorder due to a dysfunction of the dopaminergic system [1, 2]. The prevalence ranges from 4–10% in the general population, and it increases with age up to around 65 years, after which it may even begin to decline [3, 4]. RLS can be divided into an earlier onset disease with a clear genetic component and a preference for female gender, and a later onset disease with unclear etiology [5]. Secondary RLS is related to a late onset of symptoms after 45 years of age. The coexistence of RLS and Parkinson’s disease (PD) is under debate. PD onset rarely begins before 40 years. The prevalence is 0.9 and 5.1% for the age groups 65–69 and 85–89, respectively [6]. Non-motor symptoms, including sleep disorders, for example, RLS, are important features of the disease. The prevalence of RLS in PD cohorts has varied from 5.5 to 27% in European studies [7–11]. The prevalence of RLS in drug-naïve patients with PD has varied from 5.5 to 16.5% [7, 12, 13]. There are differences between these two entities. PD is a chronic disease progressing slowly after onset over the life span, while it is unknown if RLS is a progressive condition or expressing different phenotypes during advancing age. The pathological hallmark of PD is synuclein aggregation to form Lewy neuritis and Lewy bodies associAri Ylikoski Vitalmed Research Center, Clinic of Neurology Hospital of Laakso Helsinki Sleep Clinic, Sitratori 3 FI–00420 Helsinki (Finland) E-Mail ari.ylikoski @ fimnet.fi
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Key Words Parkinson’s disease · Restless legs syndrome · Sleep disorders
Parkinson’s Disease and Restless Legs Syndrome
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
Subjects and Methods
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Altogether 1,500 patients with PD were randomly selected from the registry of the Finnish Parkinson Association including 5,373 PD patients from the total of 10,000–12,000 Finnish PD patients. The random sample was selected by random number generator, based on the registration number in the registry. This allowed us to have a representative sample of all subjects in the registry. After an initial selection, we found that forty-nine subjects were either deceased or hospitalized (unable to answer), two were relatives of Parkinson’s patients, one had dystonia without Parkinson’s disease and one was a healthy person. These persons were excluded and the remaining number of eligible patients was 1,447. A new questionnaire was sent to those participants who did not respond within three months. The patients were defined as having
PD, (a) if their diagnosis had been confirmed by a neurologist and (b) they used a typical antiparkinsonian medication. Due to the nature of a questionnaire study, most likely subjects with a cognitive dysfunction, for example, patients with Lewy body disease, were among non-responders. The structured questionnaire with 207 items included questions derived from the Basic Nordic Sleep Questionnaire [21]. The basic five alternatives for the responses were: (1) ‘never or less than once per month’, (2) ‘less than once per week’, (3) ‘on 1–2 days per week’, (4) ‘on 3–5 days per week’ and (5) ‘daily or almost daily’. The high likelihood for sleep apnea (hlSA) was asked separately with a question: ‘Have you had at least weekly breathing pauses (sleep apnea) at sleep (have other people noticed that you have at least weekly pauses in respiration when you sleep)?’. Daytime fatigue was asked as ‘Do you feel fatigued during daytime?’. Intense dreaming was defined as recalling dreams every night. RLS was defined using the international definition criteria [22]. We used six questions to define RLS: (1) ‘Do you have unpleasant sensations (tingling, burning sensations, pain, other unpleasant sensations) in your legs?’, (2) ‘Do you have an urge to move your legs?’, (3) ‘Do your symptoms of unpleasant sensations or urge to move become worse when you are sitting as compared to when you stand up?’, (4) ‘Do your symptoms of unpleasant sensations or urge to move become worse when you go to bed?’, (5) ‘If you have symptoms of unpleasant sensations and/or urge to move the limbs, do your symptoms get better when move your limbs or when you start to walk?’, (6) ‘Do your symptoms (as asked in the questions above) get worse in the evening or at night?’. The 5-point frequency scale for questions 1 and 2 is described earlier. Diagnosis of RLS was based on the commonly used criteria by Allen et al. [22]. In addition, we asked about the current unpleasantness for pain and urge to move limbs, circadian occurrence and, occurrence of RLS symptoms in the family, and frequency of the RLS symptoms. Alternatives to unpleasantness and urge were: (0) ‘not at all’, (1) ‘a little’, (2) ‘somewhat’, (3) ‘plenty’ and (4) ‘very much’. Discomfort of RLS symptoms was the sum of two questions (score 0–8). Disturbance level of RLS (DLRLS) was defined as 0 = none (score = 0), 1 = mild (1–2), 2 = moderate (3–4), 3 = severe (5–6) and 4 = very severe (7–8). Daytime sleepiness was ascertained with two validated instruments, the Epworth Sleepiness Scale (ESS) [23] and the Skogby Excessive Daytime Sleepiness Index (SEDS) [24]. In both cases, higher scores indicated greater sleepiness, with an 8-item ESSscore maximum of 24, and a 5-item SEDS-score maximum of 25. The REM Sleep Behaviour Disorder Screening Questionnaire (RBDSQ) [25] is a patient self-rating instrument with ten questions (yes/no) assessing the various aspects of sleep behavior. The RBDSQ has been validated as a screening tool for secondary RBD among PD patients (the cut-off value is 6 points, with a sensitivity of 0.842 and a specificity of 0.962) [26]. In the ICD-10 [27] criteria A–C must be met for Chronic Insomnia Disorder: (A) difficulties falling asleep, maintaining sleep or non-refreshing sleep. (B) symptoms occur at least 3 nights per week and for longer than one month. (C) the sleep problems cause marked personal distress or interference with personal functioning in daily living. In our study, persons were defined as having insomnia if criteria A–C were met:
ated with the destruction of dopaminergic DA neurons in the substantia nigra pars compacta region [14]. The precise pathophysiology of RLS is not known, but a decrease of brain iron seems to play an important role [1]. On the contrary, there are no shared neuronal degeneration nor Lewy Body deposition nor shared alpha-synuclein pathology with RLS and PD [15]. The CNS iron differs between the two entities. While abnormal accumulation of iron in the brain has been implicated in Parkinson’s disease, significant iron deficiency has been found in the neurons of substantia nigra in RLS patients [1, 16]. In the genetic studies of RLS, a gene has been associated with iron stores, but no genes have been related to dopamine or endogenous opioid systems, and no RLS-related variants have been found to be significantly shared with Parkinson’s disease [1, 17, 18]. Prolonged dopaminergic therapy in RLS patients may result in augmentation symptoms [19, 20]. In a community sample, more than 30 percent of patients on levodopa develop augmentation of RLS. Respective rates for ropinirole and pramipexole were around 24 and 11 percent [20]. It has been estimated that about 8 percent of RLS patients may develop augmentation each year up to about 8 years of treatment after which the rate of augmentation may start to decrease [20]. Augmentation of classical PD symptoms (tremor, rigidity, bradykinesia) is not known to occur after dopaminergic treatment, but patients with PD may develop dyskinesias and motor fluctuations after treatment with dopaminergic agents. The objective of this population study of randomly selected PD patients was to examine the prevalence of idiopathic and secondary RLS, before and after PD diagnosis, taking into account how each of these are related to other sleep disorders.
Results
The response rate was 59% (n = 854), and of these 68% returned fully answered questionnaires (n = 577). As compared to the non-responders, we did not find statisti214
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
cally significant differences in age, gender distribution or duration of PD. In this cohort, the median age of the responders was 67 years (mean 67.4 years, SD 8.7, range 43–89), and 52.2% of them were male. The median duration of PD was 5 years (mean 6.0 years, SD 5.1). One patient was treated with deep brain stimulation. Akineticrigid subtype of PD was found in 35.0% of the participants. Table 1 shows demographic and medication data in subjects with PD without RLS (PDw/oRLS) and PD with RLS. The latter group PD with RLS tended to have an earlier diagnosis of PD and a longer disease duration. Otherwise, both groups had similar ages, genders, educations, BMIs, manners with living, and medications. RLS (constellation of the four IRLSSG criteria) was found to occur in 20.3% (n = 117/577; 54% women, 46% men) of PD subjects. The frequency of RLS was 18.1% ‘never or less than once per month’, 24.1% ‘less than once per week’, 20.7% ‘on 1–2 days per week’, 18.1% ‘on 3–5 days per week’ and 19.0% ‘daily or almost daily’, respectively. DLRLS was none in 1.7% of participants with RLS, mild in 16.2%, moderate in 42.7%, severe in 23.9% and very severe in 15.4%, respectively. The frequency and severity of RLS were highly correlated (Chi square 172.6; p = 0.000). Frequency distribution of RLS symptoms and DLRLS, frequency distribution of RLS symptoms and proportion of patients are shown in the figure 1. The DLRLS (score 0–4) was 1.1 (95% CI 1.0–1.2) in PD without RLS and 2.4 (2.2–2.5) in PD with RLS (p < 0.001). Of the isolated symptoms of RLS, unpleasant sensations at least on three days per week were observed in 34.9% of the PD patients, and urge to move limbs (≥3 days/week) in 31%. Early onset of RLS occurred in 70.6% of women and in 29.4% of men. Among the late onset RLS patients (n = 65) 54% were women and 46% were men. The circadian rhythm differed between groups. The unpleasantness was found during 7.00–12.00 a.m. in 17.2% of PD-non-RLS group and in 14.5% of PD-RLS group (p = 0.492), during 1.00–6.00 p.m. in 22.9% and in 16.2% (p = 0.118), during 7.00–12.00 p.m. in 34.6% and in 68.4% (p < 0.000), and during 1.00–6.00 a.m. in 22.2% and in 54.7% (p < 0.000), respectively. A total of 39.3% of RLS patients (46/117) experienced RLS suffering (discomfort score DLRLS ≥3). Occurrence of hlSA was 76.5% in RLS-sufferers and 22.5% in RLSL-non-sufferers (OR 6.4, 95% CI 1.9–21.3, p = 0.002), depression 54.3 and 45.7% (2.3, 1.04–5.2, p = 0.041), respectively. Otherwise, no significant differences were found in RLS-sufferers compared to RLS-non-sufferers. Occurrence of akinetic-rigid subtype of PD was 35.0%, anosmia 67.0%, constipation 47.1% and nocturia 14.9%. Ylikoski/Martikainen/Partinen
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(A) they had at least one of the following symptoms (same items in ICD-10 [27] and DSM-IV-TR [28]: (a) difficulties falling asleep at least 3 nights per week (b) waking up too early at night without being able to sleep again on least 3 nights per week (c) waking up at least 3 times per night at least 3 nights per week (d) unrefreshing (non restorative) sleep during at least one month (B) they had suffered from insomnia at least for one month, and (C) the sleep disturbance affected negatively their social life, working life or leisure time. (Question: ‘If you suffer from sleep disturbance, exhaustion, and/or tiredness, do you think it gives trouble to your life when you have leisure time (rest, hobbies), or when you socialize with relatives or friends, or when you work (professionally, or with other daily activities)?’ (1) ‘no’, (2) ‘yes’.) Sleep maintenance insomnia (SMI; criterion A.c. of the ICD10) was evaluated asking two questions as ‘How often weekly have you awakened at night during the past three months?’ and ‘If you are used to waking up during night, how many times do you usually wake up during one night?’: (1) ‘usually I don’t wake up at night’, (2) ‘once’, (3) ‘2 times’, (4) ‘3–4 times’, (5) ‘at least 5 times’. SMI index is the sum of the two questions. SMI occurred when index was at least 8. Definition of anosmia was a subjective inability to perceive odor. Constipation was defined as infrequent bowel movements (≤3 times per week), and nocturia as frequent urgency to urinate during night (≥3 times a night). Patients were defined physically active (i.e., exercise >4 h weekly), if they reported to walk either 4 h or more in a week or walk at least 2 h and jog/ run at least 30–60 min in a week. The health-related quality of life was evaluated using the World Health Organization Well-Being Questionnaire (WHO5). The quality of life is considered poor if the standardized percentage score is less than 50 [29]. Depression was evaluated using an easy screening method for general practice, that is, the Short Form of the Beck Depression Inventory (SDI) (score 0–21), since it does not include any question about sleep. The limit for depression is 10 [30–32]. All statistical analyses were conducted using Stata 12.0 (Copyright 1985–2011 StataCorp LP). Quantitative values were expressed as medians, means, standard deviations and ranges. The normality of the distributions was tested with the Shapiro-Wilk normality test. For continuous variables parametric (Student’s ttest) or nonparametric methods (Mann-Whitney U test) were used depending of the distribution. Categorized values were expressed in numbers and percentages and analyzed by the Pearson’s Chisquare test and Fisher’s exact test. Values of p < 0.05 were considered statistically significant. Logistic regression analysis was used to compute odds ratios (OR) and their 95% confidence intervals (CI). The ethical permission was obtained from the local ethical committee and the study was conducted according to the declaration of Helsinki.
Table 1. Demographic and medication data in subjects with Parkinson’s disease without restless legs syndrome (PDw/oRLS) and Par-
kinson’s disease with restless legs syndrome (PD with RLS)
Age, years Sex, % male BMI, kg/m2 BMI at the age of 20 years BMI change1 Waist length, cm Male Female Education, % Primary Lower secondary Upper secondary Postsecondary Tertiary Exercise (>4 h weekly), % Alcohol (≥48 g weekly ), % Smoking, % Caffeine (≥200 mg daily), % PD duration, years Age of PD diagnosis, years Levodopa, % Agonists, % MAO-inhibitors, % DBS, %
All PD (n = 577)
PDw/oRLS (n = 460)
PD with RLS (n = 117)
p
67.4±8.7 52.2 26.5±4.5 21.9±2.5 4.5±4.5
67.6±8.6 53.8 26.3±4.4 21.9±2.5 4.3±4.4
66.3±9.2 45.7 27.2±4.8 22.0±2.8 5.2±4.7
0.14 0.12 0.07 0.81 0.08
100±10 88±12
100±11 88±12
101±8 92±13
0.55 0.04
39.7 22.2 21.0 2.1 15.0 54.0 18.2 6.2 27.3 6.0±5.1 61.2±9.1 75.3 75.5 49.7 1.6
39.6 22.7 21.3 2.0 14.4 55.2 19.3 6.6 26.5 5.6±4.1 61.7±8.8 73.9 76.9 49.9 1.7
40.2 20.5 19.7 2.6 17.1 49.6 14.3 4.5 30.6 7.4±7.9 59.1±9.9 81.0 69.8 49.1 0.9
0.92 0.28 0.24 0.39 0.40 0.005 0.006 0.11 0.11 0.88 0.49
BMI = Body mass index; DBS = deep brain stimulation. 1 BMI change from the age of 20 years to present time.
45
3.5
Proportion of patients (%)
2.5 2.0 1.5 1.0 0.5
a
35 30 25 20 15 10 5
45 years). Table 3 shows occurrences of different variables in subjects with PD and early onset RLS (PD with RLS onset ≤45 years) and PD and late onset RLS (PD with RLS onset >45 years). PD with RLS onset ≤45 216
Eur Neurol 2015;73:212–219 DOI: 10.1159/000375493
years was more hereditary than PD with RLS onset >45 years (64.7 vs. 22.4%; p < 0.001). The PD with RLS onset >45 years group used more often levodopa and MAO-inhibitors medication (Levodopa and MAO-inhibitors combined 17.6 vs. 46.1%; p = 0.033). Adjusted for age, sex, and disease duration, this difference in medication remained significant (OR 4.7; 95% CI 1.18– 19.0). From the subgroup of secondary RLS, an estimate of drug-naïve RLS prevalence was 5.4% (n = 22, 26.8% of 82 RLS patients; RLS symptoms onset before PD diagnosis). The prevalence of RLS in PD patients could have been the result from the confounding medication in 10.4% (n = 43, 52.4% of 82 RLS patients; RLS symptoms onset after PD diagnosis). In drug-naïve patients, RLS symptoms onset was 6.3 years (95% CI 9.6–3.1) before PD diagnosis compared to the latter group 4.6 years (3.0–6.3) after PD diagnosis. The duration of RLS symptoms was 11.0 years (7.7–14.3) and 5.1 years (1.9–8.2), respectively. In the analyses, drug-naïve RLS had a shorter duration of Parkinson’s disease (4.7 years; 95% CI 3.2–6.2) than secondary RLS with confounding medication group (9.7; 6.3–13.1) (p = 0.022). Otherwise, there were no significant differences between these groups. Ylikoski/Martikainen/Partinen
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1 Adjusted to age, sex and PD duration. RBD = REM sleep behavior disorder; hlSA = high likelihood of sleep apnea; ESS = Epworth sleepiness scale; SEDS = Skogby excessive daytime sleepiness index; SMI = sleep maintenance insomnia index; WHO5 = World Health Organization well-being index.
Table 3. Data in subjects with Parkinson’s disease and early onset RLS (onset ≤45 years) and Parkinson’s disease and late onset RLS
(onset >45 years)
Age, years1 Sex, % female Onset age of RLS, years1 Familial RLS, % RLS discomfort (score ≥5), % PD duration, years1 Age of PD diagnosis, years1 Levodopa, % MAO-inhibitors, % Levodopa and MAO-inhibitors, % Agonists, % Akinetic-rigid subtype of PD, % Anosmia, % Constipation, % Nocturia (≥3 times a night), % RBD, % OSAS, % ESS >10, % SEDS >15, % Fatigue, % Insomnia, % SMI (SMI index ≥8), % Intense dreaming, % Depression, % Poor quality of life (WHO5 45 years (n = 65)
p
64.2 (60.5–67.8) 70.6 27.8 (21.1–34.5) 64.7 41.2 5.2 (3.6–6.7) 59.0 (54.9–63.1) 70.6 35.3 17.6 82.4 55.2 62.5 47.1 17.6 50.0 5.9 23.5 58.8 64.7 40.0 47.1 31.2 25.0 41.2
67.5 (65.2–67.8) 53.8 60.5 (58.0–63.0) 22.4 44.6 8.0 (5.6–10.4) 59.5 (57.0–62.1) 84.6 53.8 46.1 64.6 35.0 68.7 46.9 17.2 49.1 21.9 38.5 54.8 56.9 59.0 40.0 25.4 29.2 58.5
0.170 0.214 0.001 0.799 0.195 0.836 0.183 0.173 0.033 0.162 0.122 0.633 0.989 0.964 0.951 0.131 0.252 0.770 0.562 0.184 0.599 0.636 0.737 0.202
1 Mean, 95% confidence interval. RBD = REM sleep behavior disorder; OSA = obstructive sleep apnea; ESS = Epworth sleepiness scale; SEDS = Skogby excessive daytime sleepiness index; SMI = sleep maintenance insomnia; WHO5 = World Health Organization well-being index.
The Onset of RLS The age of onset of RLS is known to vary widely from childhood to more than 80 years [15]. The prevalence of RLS in adults is around 3% in people aged 18–29 years and 10% in those aged 30–79 years [33]. In patients with PD, symptoms of RLS symptoms have been reported to follow PD diagnosis in 68–82% of PD patients [6, 23]. In our study (PD patients), the occurrence of early onset RLS was 4.2% and occurrence of late onset RLS was 16.1%. In this study, the onset of RLS symptoms followed PD diagnosis in 52.4% of all RLS patients and in 66.2% of the late onset RLS patients.
ever, due to a low number of subjects (n = 17) this difference was not statistically significant. In previous studies on PD patients, this typical gender distribution has not been described [7, 9, 12]. In accordance with these studies, we found no gender difference in the group of all RLS patients (n = 117; 54% women, 46% men) or in late onset RLS patients (n = 65; 54% women, 46% men). The RLS Genetics About 50 percent of people with primary RLS report a positive family history [35]. In PD patients, a familial trait seems to be more common if RLS onset happens ≤45 years [36]. These findings are consistent with our result. A familial occurrence of RLS was found in 64.7% of the early onset RLS.
The Gender Distribution Women are two times more likely than men to have RLS in the general population [34]. We found the same ratio in PD patients, as early onset of RLS occurred twice as often in women (70.6%) than in men (29.4%). How-
The Dopaminergic Medication Symptoms of RLS are known to respond to dopaminergic drugs in both idiopathic RLS and PD. Treating RLS patients, augmentation has been reported less frequently
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Discussion
with dopamine agonists 27% [37] than with levodopa 82% [38]. The more frequent symptoms of RLS in PD patients with longer dopaminergic could be the result of the same augmentation mechanisms, which are not fully known. Our finding of medication difference between early onset versus late onset of RLS groups contradicts the hypothesis that RLS and PD are two different entities that just happen to occur simultaneously, as there was no medication difference between secondary drug-naïve RLS group (RLS onset before PD diagnosis) and possible confounding medication RLS group (RLS onset after PD diagnosis). Since dopaminergic medication help RLS symptoms, the prevalence of secondary RLS in this study may be an underestimation. On the other hand, the prevalence of secondary RLS correlated positively with the use of levodopa, so augmentation could explain a part of the prevalence of RLS. Could it be that at least in some patients symptoms of RLS may be considered nonconventional symptoms of PD? If this is the case, it does not fit with the iron hypothesis of PD (accumulation of iron in the striatum) and RLS (lack of CNS iron). The Frequency and Severity of RLS Previous reports on the frequency and severity of symptoms of RLS in PD are rare. In a series of 29 PD patients with RLS, frequency of RLS was reported as 17% ‘at least once a year but less than once a month’, 24% ‘2 to 4 times a month’ and 10% ‘6 to 7 times a week’ [11]. The severity of RLS, measured with IRLSSG rating scale, was estimated as moderate in 19% of participants, severe in 19% and very severe in 4% [11]. In our series of 117 PD patients with RLS, the weekly frequency of RLS was 81.9%. The degree of difficulty was moderate in 42.7%, severe in 23.9% and very severe in 15.4%. All in all, the dopaminergic medication had no soothing effect on the frequency and severity of RLS in PD patients.
quality of life (WHO5 15), other sleep complaints and low
Disclosure Statement Ari Ylikoski has nothing to declare. Kirsti K. Martikainen has received lecture fees from Boehringer-Ingelheim, lecture and consultant fees from Orion Pharma, UCB Pharma, H. Lundbeck and NordicInfuCare.
Markku Partinen has received lecture fees from BoehringerIngelheim, GSK, MSD, Orion Pharma, lecture and consultant fees from Leiras-Nycomed, UCB, Cephalon, consultant fees from Servier, expert testimony fees from UCB, grants from Academy of Finland, Parkinson Foundation of Finland and Gyllenberg Foundation.
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