Is obstructive sleep apnea a problem in Parkinson’s disease?

Sleep Medicine 11 (2010) 247–252

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Original Article

Is obstructive sleep apnea a problem in Parkinson’s disease? Valérie Cochen De Cock a,b, Maher Abouda a, Smaranda Leu a,b, Delphine Oudiette a,d, Emmanuel Roze b, Marie Vidailhet b,d, Thomas Similowski c, Isabelle Arnulf a,d,* a

Sleep Disorders Unit, Pitié-Salpêtrière Hospital, APHP, Paris, France Neurology Department, Pitié-Salpêtrière Hospital, APHP, Paris, France c Department of Respiratory and Intensive Care Medicine, Pitié-Salpêtrière Hospital, APHP, Paris 6 university, ER10upmc, France d CRICM UMR975 and Paris 6 University, Paris, France b

a r t i c l e

i n f o

Article history: Received 17 February 2009 Received in revised form 14 May 2009 Accepted 18 May 2009 Available online 22 July 2009 Keywords: Obstructive sleep apnea Sleepiness REM sleep behavior disorder Stridor Hypoventilation Parkinson’s disease

a b s t r a c t Background: Parkinson’s disease (PD) is associated with sleep disorders and daytime sleepiness. Upper airway dysfunction in PD may promote obstructive sleep apnea. However, the frequency and clinical relevance of sleep-disordered breathing in PD remains unclear. Methods: Sleep apnea symptoms, cardiovascular events and treatment were collected in 100 patients with PD (50 unselected, consecutive patients matched for age, sex and body mass index with 50 patients referred for sleepiness) and 50 in-hospital controls. The motor and cognitive status was evaluated in patients with PD. The 150 subjects underwent a video-polysomnography. Results: Sleep apnea (defined as an apnea–hypopnea index greater than 5) was less frequent in the PD group (27% patients, including 6% with mild, 11% with moderate and 10% with severe sleep apnea) than in the control group (40% in-hospital controls, p < 0.002). Sleep apnea was not associated with increased sleepiness, nocturia, depression, cognitive impairment and cardiovascular events in patients with PD. Sleep apnea was more frequent and severe in the most disabled patients. Patients with PD did not display sleep hypoventilation, stridor and abnormal central sleep apnea. In patients with REM sleep behavior disorders, snoring and obstructive sleep apnea occurred during REM sleep, although the chin muscle tone was maintained. Conclusion: Obstructive sleep apnea does not seem to be a clinically relevant issue in PD. Daytime sleepiness, nocturia and cognitive impairment are mostly caused by other, non-apneic mechanisms. The maintenance of chin muscle tone during REM sleep behavior disorder has no influence on the frequency of apneic events. Ó 2009 Elsevier B.V. All rights reserved.

1. Introduction Parkinson’s disease (PD), the consequence of a major loss of dopamine neurons in the basal ganglia, is the most common serious movement disorder. It occurs in 1–2% of adults older than 60 years [1]. Patients suffer a progressive motor disability, with rare and slow movements, muscle rigidity and resting tremor. They can also exhibit respiratory abnormalities of a restrictive and obstructive nature [2,3]. Upper airway dysfunction is frequent (one-third of patients), impeding airflow in a dopamine-reversible manner [2–5]. Daytime sleepiness is common in PD patients [6], and many of them snore. In a series of 86 consecutive patients, 72% of them snored [7]. In the perspective of the PD-associated upper airway dysfunction, these observations lend relevance to the question of

* Corresponding author. Address: Unité des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Tel.: +33 1 42 16 77 04; fax: +33 1 42 16 77 00. E-mail address: [email protected] (I. Arnulf). 1389-9457/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2009.05.008

obstructive sleep apnea in this population. In two series of 15 and 49 patients, 43–73% of PD patients had an apnea/hypopnea index greater than 5 [8,9]. It is unclear whether these patients would meet the accepted definition of the obstructive sleep apnea syndrome, namely the association of an abnormal apnea/hypopnea index with symptoms otherwise unexplained [10]. Of note, only 6–14% of the patients described in the above two series had an apnea/hypopnea index greater than 30, a relatively low figure. Yet, up to 60% of PD patients exhibit REM sleep behavior disorders, which are characterized by the abnormal persistence of muscle tone during REM sleep, including chin muscle tone [11,12]. Upper airway muscle atonia during REM sleep promotes obstructive apnea [13]. Its absence during REM sleep behavior disorders could contribute to prevent upper airway closure. We hypothesized that in PD patients with REM sleep behavior disorders, the lack of REM sleep related upper airway atonia would counterbalance the putative obstructive apnea promoting effect of the PD-related upper airway dysfunction. To test this hypothesis, we first assessed the frequency of sleep-related breathing disorders, related symptoms, and cardiovascular events in a cohort of

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50 consecutive unselected patients with PD who were compared to 50 sex-, age- and body mass index- (BMI) matched in-hospital controls without neurological disorders and also compared to 50 sex-, age-, and BMI-matched patients with PD complaining of daytime sleepiness. We then compared these disorders according to the presence or absence of chin muscle tone during REM sleep. 2. Methods 2.1. Subjects Fifty consecutive, unselected PD patients followed in the Neurology Department were recruited to take part in the study. Patients met the standard criteria for definite idiopathic PD [14]. They had a score at the Mini-Mental State Examination greater than 21. There were no other criteria of selection. No patient had a previous diagnosis of a sleep disorder. Fifty other PD patients were extracted from a different group of 115 patients referred for excessive daytime sleepiness, who also had a score at the Mini-Mental State Examination greater than 21. They were selected to match with the previous group for age, sex and body mass index. Fifty age-, sex- and BMI-matched controls with no neurological disease and no sleep complaint were selected among control subjects (in- and out-subjects with suspicion of venous thromboembolism, later not confirmed) of another study aimed at evaluating the association between sleep apnea and venous thromboembolism (PHRC 03-602). The controls had a dyspnea (35%), a chest pain (18%) or a painful leg when consulting. A venous thromboembolism was suspected because they had risk factors for it, including cancer (n = 6), history of deep vein thrombosis or pulmonary embolism (n = 11), leg venous varices (n = 10), chronic venous insufficiency (n = 4), coronary heart disease or cardiac insufficiency (n = 8), a history of stroke (n = 2), chronic obstructive pulmonary disorder (n = 9), recent surgery (n = 6) traumatism (n = 1), and immobilization (n = 4). They were monitored three months after the initial event which led to suspected pulmonary embolism. The demographical and clinical characteristics of these three groups are summarized in Table 1. This study and the studies from which the controls were drawn were approved by the appropriate legal and ethical French authorities. All the participants gave written consent.

Table 1 Demographical and clinical characteristics of patients with Parkinson’s disease (PD), unselected and referred for sleepiness, and matched controls. Patients

Controls

Unselected PD

Sleepy PD

No. Age, y Sex, % men Body mass index, kg/m2 Disease course, y Motor disability while treated,* score/ 108 Use of dopamine agonists, % Dopaminergic treatment, mg/day Use of benzodiazepine, % Use of antidepressant at bedtime, % Mini-Mental State Examination, score/30 Epworth sleepiness scale, score/24 % sleepy patients, with score > 10 Cardiovascular events,  % patients with

50 62.4 ± 13.8 70 24.7 ± 4.6 NA NA

50 62.1 ± 9.8 70 24.5 ± 3.2 6.8 ± 4.0 16.8 ± 10.1

50 62.7 ± 8.5 70 24.8 ± 4.5 8.2 ± 5.1 27.6 ± 16.0b

NA NA 10 4à NA 5.8 ± 4.0à 12à 39

56.0 583 ± 367 26 28 28.2 ± 2.4 9.2 ± 4.7 36 10

60.0 793 ± 423§ 28 24 27.7 ± 2.2 13.2 ± 4.7§ 66§ 38§

b

p < 0.02 for a difference between unselected and sleepy patient. Motor disability is measured using the Unified Parkinson’s Disease Rating Scale part III.   Cardiovascular events include hypertension, coronary heart disease and stroke. à p < 0.02 for a difference between controls and PD. § p < 0.02 for a difference between unselected and sleepy PD. *

2.2. Study design As part of a standardized research protocol, each patient underwent a medical interview on cardiovascular risk events (history of hypertension, stroke, coronary heart disease), sleep disorders [15], use of benzodiazepines, sleep apnea symptoms including snoring, nocturia (defined as more than one micturition per night), symptoms of depression (defined by the need for antidepressants), Epworth sleepiness scale [16], a neurological evaluation of the motor parkinsonian disability using part III of the Unified Parkinson’s Disease Rating Scale [17], cognitive test using the Mini-Mental State Examination [18], and an overnight video-polysomnography. The controls only had the sleep interview and polysomnography. The sleep recordings included three electroencephalogram (Fp1/Cz, O2/Cz, C3/A2), bilateral electrooculogram, electromyogram of the chin and leg muscles, airflow via nasal pressure transducer, tracheal sounds through a microphone, thoracic and abdominal belts, body position, electrocardiogram, finger pulse oximetry, EEG-synchronized infra-red videography and ambiance microphone. The sleep stages [19], arousals [20], periodic leg movements [21] and respiratory events [10] were scored visually according to international criteria. Hypopnea was defined as a more than 50% airflow decrease associated with a 3% oxygen desaturation or an arousal. The presence of sleep apnea was defined as an apnea/hypopnea index greater than 5, and classified as mild (apnea/hypopnea index greater than or equal to 5 and lower than or equal to 15), moderate (apnea/hypopnea index greater than 15 and lower than or equal to 30), and severe (greater than 30) sleep apnea [10]. In order to compare the apnea/hypopnea indexes during REM sleep in patients with and without enhanced chin muscle tone, we measured the percentage of REM sleep without atonia as previously described and set the abnormal threshold as more than 20% of REM sleep without atonia [12]. 2.3. Data analysis The analysis of variance was used to compare continuous measures between groups (PD vs. controls, sleepy vs. unselected PD, PD with vs. without REM sleep atonia, PD with vs. without sleep apnea). The chi-square test was used for non-continuous measures. The correlations between continuous measures were assessed using Spearman test. Oxygen saturation was logarithmically transformed. Results were reported as mean ± SD. The threshold of p < 0.02 was chosen as significant in order to avoid type I error. Statistics were performed using JMP 7.0 software (SAS Institute, Cary, NC, USA).

3. Results 3.1. Clinical interview and examination The main clinical characteristics of each group are summarized in Table 1. By definition, the age, sex and body mass index were not different in the three groups. The sleepy patients with PD had a more severe motor form of PD than the unselected patients, as shown by higher disability scores and a need for higher dosages of dopaminergic agents, despite a similar disease course. In contrast, they had a similar level of cognitive impairment. The patients with PD were sleepier than the controls, whether they were selected for this symptom or not. 3.2. Night-time sleep Compared to the controls, the patients with PD had reduced total sleep time, and increased duration of wakefulness after sleep onset, but sleep latencies, sleep architecture, arousal and periodic

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V. Cochen De Cock et al. / Sleep Medicine 11 (2010) 247–252 Table 2 Sleep measures in patients with Parkinson’s disease (unselected and referred for sleepiness) and matched controls. Sleep measures

Controls

Unselected PD

Sleepy PD

No. Night-time sleep, min Total sleep period Total sleep time Wakefulness after sleep onset

50

50

50

450 ± 105 376 ± 77* 90 ± 61*

507 ± 93 347 ± 108 161 ± 88

449 ± 69  336 ± 85 117 ± 73 

30 ± 33 100 ± 54

52 ± 52 146 ± 111

13 ± 16  116 ± 84

7±7 54 ± 15 21 ± 13 17 ± 8

4±5 59 ± 14 18 ± 10 19 ± 10

12 ± 14  49 ± 15  27 ± 11  12 ± 7 

25 ± 20 7 ± 17 40 23 ± 23* 10 ± 15 67 ± 36 23 ± 33 84 ± 8*

15 ± 11 12 ± 17 20 6 ± 11 4±9 73 ± 41 18 ± 31 88 ± 8

25 ± 20  10 ± 21 34 17 ± 16  8 ± 12 80 ± 31 9 ± 17 85 ± 6

Latency to, min Sleep onset REM sleep onset Sleep stages, % total sleep time Stage 1 Stage 2 Stage 3–4 REM sleep Sleep fragmentation with Arousals/hr Periodic legs movements/hr Patients with OSA, % Apnea–hypopnea/hr Apnea/hr Obstructive, % Central and mixed, % Minimum oxygen saturation *  

p < 0.02 for a difference between controls and PD. p < 0.02 for a difference between unselected and sleepy PD.

for sleepiness had no more respiratory events than the controls, but they had higher apnea–hypopnea indexes (and non-different apnea indexes) than the unselected PD patients. There was no period of hypoventilation or stridor in the PD patients, whether during REM or non-REM sleep. In the PD group, 27 patients had sleep apnea (Table 3). They did not differ from the 73 PD patients without sleep apnea in terms of demography (age, male sex), body mass index, cardiovascular risk factors (although p = 0.07), use of benzodiazepines, and symptoms associated with sleep apnea syndrome (snoring, nocturia, daytime sleepiness, depression as assessed by the need for antidepressant therapy, cognitive impairment). Patients with sleep apnea had a more severe PD as shown by a greater motor disability than patients without sleep apnea. Furthermore there was a weak but significant correlation between the motor disability score and the apnea index (r = 0.25, p = 0.0014). The minimum oxygen saturation did not correlate with cognitive impairment, motor disability and the dose of dopaminergic treatment. There was no correlation between the apnea/hypopnea indexes and age, sex, body mass index, disease course, use of antidepressants or benzodiazepines, daily dose of dopaminergic treatment, Epworth sleepiness score, cognitive score, frequency of snoring, nocturia and cardiovascular events. 3.4. Effect of muscle tone on apnea/hypopnea index during REM sleep

leg movement indexes were not different (Table 2). In the group of patients with PD, the sleepy patients had better sleep quality, as indicated by a shorter total sleep period, reduced wakefulness after sleep onset, shorter sleep onset latency, and increase of sleep stage 3–4 (but not when slow wave sleep was expressed in minutes), compared to the unselected patients. However, they had more frequent arousals. 3.3. Sleep-disordered breathing In the PD group (n = 100) 27% of patients had sleep apnea, including 6% with mild, 11% with moderate and 10% with severe sleep apnea. Surprisingly, the PD patients had less frequent sleep apnea than the controls (40%, p < 0.002), lower apnea–hypopnea indexes and higher minimum oxygen saturation (Table 2). The percent of central and mixed apnea were similar in the controls and in the patients with PD. The frequency of sleep apnea was not different in the unselected PD patients (20.4%) than in the PD patients referred for sleepiness (34%, p = 0.18). The PD patients referred

Contrary to our expectations, the patients with abnormal persistence of chin muscle tone during REM sleep tended to have higher apnea/hypopnea index during REM sleep (18.2 ± 15.9) than the patients with normal atonia during this stage (6.8 ± 10.7, p = 0.05). The PD patients with enhanced muscle tone during REM sleep still had obstructive apnea and snoring. An example of a series of obstructive apnea during REM sleep without atonia in a patient with PD is shown in Fig. 1. We occasionally observed patients snoring while they simultaneously exhibit complex behaviors such as kicking, fighting or conducting a concert (Video 1). In contrast, the patients did not snore while they sleep-talked. We also noticed that some patients would move lips as if speaking without any sound emission. 4. Discussion Only 27% of patients with PD have sleep apnea vs. 40% of the in-hospital controls. Furthermore, only 10% of all patients with PD have severe sleep apnea. These frequencies are obtained in a large

Table 3 Risk factors and symptoms in 100 patients with Parkinson’s disease according to their apnea–hypopnea indexes. Apnea–hypopnea index

No. Age, y Sex, % men Body mass index, kg/m2 Disease course, y Motor disability, score/104 Dopaminergic treatment, mg/day Use of antidepressant, % Use of benzodiazepine, % Mini-Mental State Examination, score/30 Snoring, % Epworth sleepiness scale, score/24 Nocturia, % Cardiovascular events*, %

Normal (30)

73 62 ± 9 68 25 ± 4 8±5 20 ± 14  656 ± 409 22 25 28 ± 3 92 11 ± 5 17 13à

27 63 ± 10 74 25 ± 5 7±3 28 ± 14 744 ± 392 22 26 28 ± 2 100 12 ± 6 18 33

6 62 ± 10 100 27 ± 6 8±4 27 ± 16 729 ± 533 33 33 28 ± 2 100 11 ± 6 20 40

11 62 ± 8 64 24 ± 4 7±3 30 ± 13 677 ± 345 18 27 27 ± 1 100 13 ± 5 17 29

10 65 ± 12 70 24 ± 5 7±4 31 ± 16 862 ± 338 20 20 28 ± 2 100 11 ± 7 17 33

*Hypertension, coronary heart disease, stroke.   p < 0.02 àp < 0.07 for normal vs. abnormal apnea–hypopnea index. The samples were too small in mild, moderate and severe subgroups to perform between-subgroup statistics.

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Fig. 1. A sequence of REM sleep without atonia in a patient with Parkinson’s disease. Repeated obstructive apneas occur in spite of subnormal chin muscle tone (chin EMG), with further muscle enhancement when the apneas resume. LOC-A1 and ROC-A1: eye movements via left and right ocular canthus; C3-A2 EEG: central electroencephalogram; L and R leg EMG: left and right leg EMG; Airflow via nasal pressure; phono: tracheal audio monitor; RC: Rib cage and ABD: abdomen respiratory movements. SaO2: transcutaneous oxygen saturation.

group of 100 patients with PD followed in a tertiary care Movement Disorders Unit. They are lower than those obtained in three smaller series, showing that 10/15 patients [8], 21/49 patients [9] and 7/9 sleepy patients [22] had sleep apnea. These series, however, include patients specifically referred for sleep monitoring while our 50 unselected patients are consecutively recruited without selection bias. Patients with PD tend to have lower weights than age-matched healthy controls [23]. This could have been a confounding factor, but our PD patients were matched with the controls for BMI. One may be surprised by the relatively high (40%) proportion of in-hospital controls, who have more than 5 apnea–hypopneas per hour. During the last decade, however, the use of nasal pressure instead of thermistor has largely increased the sensitivity to detect sleep hypopnea in the sleep community, as shown by the high (59%) prevalence of ‘‘healthy” employees with apnea–hypopnea indexes greater than 5 in systematic monitoring in Japan [24]. Hence, we need to be cautious before attributing a problem (e.g., sleepiness) to an abnormal apnea–hypopnea index in a patient. We have not directly compared the prevalence of sleep apnea in patients with PD to sex-, age-, and BMI-matched healthy controls, which is a limitation, even if the prevalence of sleep apnea found in our control group is close to the sleep apnea frequency obtained in these healthy controls in Japan. But the comparison of patients with PD to other patients (or to subjects with a symptom) is meaningful to determine if PD can cause a given sleep disorder per se, or if it has to do with the burden of any chronic disease, as shown for insomnia prevalence in PD when compared to diabetes mellitus [25]. What is the clinical relevance of sleep apnea found in patients with PD? Symptoms usually associated with the sleep apnea syndrome include excessive daytime sleepiness, snoring, nocturia, cognitive impairment and depressive mood. Most of these symptoms can be observed in PD patients irrespective of the presence of sleep apnea. Indeed, in our group of patients with PD, these symptoms are equally present in patients with and without sleep apnea. Furthermore, the severity of sleepiness and cognitive impairment and the frequency of nocturia, snoring and depressive mood are not related with the apnea/hypopnea index. The specific role of sleep apnea as a cause of excessive daytime sleepiness is therefore not supported here. Yet establishing the cause of excessive daytime sleepiness in PD is particularly important, as illustrated by the re-

cent reports of driving accidents caused by sleep attacks in treated PD patients [26]. Daytime sleepiness can have many other causes in patients with PD, including frequent sleep deprivation and fragmentation, hypersomnia of central origin with narcolepsy-like disorder (found in up to 40% patients), and sedation as a side effect of dopaminergic agents [27]. Increased cardiovascular risk is the main long term consequence of obstructive sleep apnea. We have not monitored the arterial pressure or autonomic variations after the respiratory event. Yet, our apneic patients have no more hypertension, stroke and coronary heart disease than patients without sleep apnea. Furthermore, the apnea/hypopnea index does not correlate with increased cardiovascular events. Eventually, patients with PD had no more arousals during the night than controls. All in all, sleep apnea does not seem to be clinically relevant in patients with PD. Sleep apnea should therefore not be the first suspected diagnosis in a PD patient with sleepiness and snoring, for example. Whether PD patients with sleep apnea would benefit from continuous positive airway pressure also remains to be demonstrated. Particularly, the question of whether the hypoxia associated with sleep apnea is deleterious for their vulnerable brains is still open. In our study, the motor disability is indeed more severe in patients with than without sleep apnea and correlates with the apnea/hypopnea index. One may interpret this association in two opposite directions. First, the most disabled patients have more frequent swallowing and speaking problems, indicating a more severe upper airway dysfunction, and possibly a greater vulnerability to obstructive sleep apnea. As upper airway obstruction signs are reversible with levodopa intake during pulmonary function tests [3,28], levodopa at night could improve obstructive sleep apnea. Unfortunately, this treatment has a short half-life and is not efficient all night long [29]. On the other hand, the intermittent hypoxia associated with sleep apnea may increase the loss of dopaminergic neurons, thereby worsening motor disability. Dopamine pathways are vulnerable to ischemic-anoxic insult [30]. In a rat model of intermittent hypoxia, the expression patterns of proteins involved in dopamine signalling (dopamine and vesicular monoamine transporters, tyrosine hydroxylase, and dopamine-type 1 receptors) suggest that the deficient dopaminergic transmission in nigrostriatal motor pathway is due to a sequestration (but not a neuronal loss) of dopamine in the presynaptic neurons [30]. The evaluation of motor status before and after sleep apnea treatment should be

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assessed in patients with PD to support a rationale for treating sleep apnea. Here, the evaluation of motor status was performed in the on-dopa state, which is less sensitive to evaluate the severity of dopamine denervation than an evaluation in the off-dopa state, after 12 h levodopa withdrawal. Although PD is a disease of central origin, patients with PD have no more central apnea than controls, no central alveolar hypoventilation, and no stridor. These results suggest that the central control of ventilation during sleep, the CO2 chemosensitivity and the vocal cord control during sleep are unaltered in PD. Idiopathic PD is indeed distinct from the exceptional, fatal parkinsonism associated with central alveolar hypoventilation [31] and from the multiple system atrophy with nocturnal stridor [32]. Stridor and hypoventilation are life-threatening features of atypical parkinsonism, which is a different issue from the rarely clinically relevant obstructive sleep apnea in idiopathic PD. The loss of tone in upper airway muscles contributes to obstructive sleep apnea. The muscle atonia during REM sleep compromises pharyngeal patency in vulnerable patients [13]. REM sleep behavior disorder, a condition with increased muscle tone during REM sleep, provides an interesting model to evaluate the contribution of atonia to upper airway obstruction. Surprisingly, patients with REM sleep without atonia still have obstructive apnea despite subnormal chin muscle activity. The upper airway muscle tone may be only partially restored, however, as some patients move their lips without producing sounds during REM sleep behavior disorders. In addition, other mechanisms of sleep apnea such as REM-induced nasal congestion (a mechanism similar to penile erection) may contribute to sleep apnea during REM sleep without atonia [31]. On the other hand, one may observe phasic movements at the time of apnea-associated arousals, but it is yet unclear if these movements have to do with confusional arousals for REM sleep [32] or if they belong to the RBD spectrum. 5. Conclusions In idiopathic PD, obstructive sleep apnea does not seem to be abnormally frequent. It also does not seem to be explicative of an excessive daytime sleepiness when present or associated with abnormally frequent clinical events. In practice, this means that sleepiness in a PD patient (a common condition) should not be assigned too hastily to sleep apnea even if there are signs of upper airway dysfunction or snoring. Other mechanisms of sleepiness should be considered. The possibility that control of nocturnal hypoxemia with continuous positive airway pressure in PD patients with documented obstructive sleep apnea, which could interfere with the progression of the disease, remains to be documented. Conflict of interest statement VCDC, MA, SL, DO, MV, TS and IA do not have a financial relationship with a commercial entity that has an interest in the subject of the manuscript. Acknowledgments Work performed at the Unité des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. The Clinical Investigation Center of Saint Antoine Hospital in Paris took part in the study coordination and data collection. Financial support: The study was supported by grants from the French Health Ministry [PHRC 03-602], France Parkinson, and Lilly Foundation.

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