Curr Neurol Neurosci Rep (2015) 15:8 DOI 10.1007/s11910-015-0525-5

SLEEP (M THORPY, M BILLIARD, SECTION EDITORS)

Parkinson’s Disease and Sleep/Wake Disturbances Keisuke Suzuki & Masayuki Miyamoto & Tomoyuki Miyamoto & Koichi Hirata

# Springer Science+Business Media New York 2015

Abstract Sleep disturbances are a common non-motor feature in patients with Parkinson’s disease (PD). Early diagnosis and appropriate management are imperative for enhancing patient quality of life. Sleep disturbances can be caused by multiple factors in addition to age-related changes in sleep, such as nocturnal motor symptoms (rigidity, resting tremor, akinesia, tardive dyskinesia, and the “wearing off” phenomenon), nonmotor symptoms (pain, hallucination, and psychosis), nocturia, and medication. Disease-related pathology involving the brainstem and changes in the neurotransmitter systems (norepinephrine, serotonin, and acetylcholine) responsible for regulating sleep structure and the sleep/wake cycle play a role in emerging excessive daytime sleepiness and sleep disturbances. Additionally, screening for sleep apnea syndrome, rapid eye movement sleep behavior disorder, and restless legs syndrome is clinically important. Questionnaire-based assessment utilizing the PD Sleep Scale-2 is useful for screening PD-related nocturnal symptoms. In this review, we focus on the current understanding and management of sleep disturbances in PD. Keywords Parkinson’s disease . Insomnia . Excessive daytime sleepiness . Restless legs syndrome . Rapid eye movement sleep behavior disorder . Sleep apnea syndrome This article is part of the Topical Collection on Sleep K. Suzuki (*) : K. Hirata Department of Neurology, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan e-mail: [email protected] M. Miyamoto School of Nursing & Department of Neurology, Dokkyo Medical University, Tochigi, Japan T. Miyamoto Department of Neurology, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan

Introduction Sleep disturbances are common disabling non-motor features of Parkinson’s disease (PD) that have a detrimental effect on health-related quality of life [1, 2•]. The cause of sleep disturbances in PD is multifactorial and overlapping (Table 1). The reported prevalence of sleep disturbances in PD varies depending on differences in the study population and methodology, with values ranging from approximately 40 to 90 % [3–6]. The frequency of sleep disturbances increases in parallel with disease progression, reflecting the impact of nocturnal motor and non-motor symptoms on sleep; however, sleep disturbances can occur at any time during the course of PD and even in the early stages. The presence of sleep disorders may predict the presence of more comorbid non-motor symptoms and reduced quality of life [7, 8]. Sleep disturbances are also associated with reduced quality of life in early-stage PD patients [2•]. Surprisingly, in a multicenter international study examining non-motor symptoms, sleep problems, such as insomnia and daytime sleepiness, were undeclared by approximately half of PD patients [9]. Some PD patients show motor improvement upon awakening in the morning and prior to taking medication. This phenomenon is called sleep benefit and is reported in 33–55 % of PD patients; however, the underlying mechanism and associated factors remain unclear [10]. Thus, comprehensively assessing sleep disturbances in PD patients and investigating possible causes are imperative for improving the quality of life of patients. In this review, we address sleep disturbances related to PD and present new information on comorbid primary sleep disorders in PD, such as rapid eye movement sleep behavior disorder (RBD), restless legs syndrome (RLS), and obstructive sleep apnea syndrome (OSAS).

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Table 1 Causes of sleep disturbances in Parkinson’s disease (adapted from Suzuki et al. [11]) 1. PD-related pathological changes Impairment of sleep architecture (REM and non-REM sleep) Impairment of the arousal system (orexin, serotonin, noradrenalin, acetylcholine, and dopamine) Impairment of the sleep-wake cycle, circadian rhythm sleep disorder, sundown syndrome 2. Nocturnal motor symptoms Wearing off phenomenon, rigidity, akinesia, tremor, medication-related dyskinesia, and dystonia 3. Nocturnal non-motor symptoms Neuropsychiatric symptoms (depression, psychosis, cognitive impairment) Sensory symptoms (pain, dysesthesia, restlessness of the arms or legs) Hallucinations Nightmares and vivid dreams Nocturia 4. Medication use Dopaminergic drugs, antipsychotics 5. Comorbid primary sleep disorders Sleep apnea syndrome REM sleep behavior disorder Restless legs syndrome, periodic limb movements

The Cause of Sleep Disturbances in PD Multiple factors and conditions related to PD are implicated in sleep disturbances in patients with PD (Table 1) [11]. Diseaserelated pathological changes include impairment in thalamocortical arousal and the degeneration of the brainstem regulatory centers for sleep/wakefulness maintenance and REM sleep, resulting in excessive daytime sleepiness and insomnia [12]. Additionally, sleep architecture may be altered in PD due to disease-related changes in the brainstem; the degeneration of cholinergic neurons in the basal forebrain and brainstem, including the pedunculopontine nucleus and noradrenergic neurons in the locus coeruleus, results in a reduction in REM sleep and RBD. A loss of serotonergic neurons in the raphe nucleus is associated with a decreased percentage of slow wave sleep [13]. Sleep disturbances also result from nocturnal motor symptoms, psychiatric symptoms, dementia, medication use, circadian rhythm sleep disorders, and comorbid primary sleep disorders such as SAS, RLS, and RBD. There are no firmly established treatments for PD-related sleep disturbances. Sleep problems other than nocturnal motor symptoms, insomnia, nightmares, and dopamine dysregulation syndrome may not respond well to dopaminergic treatment; however, increased severity in nocturnal motor symptoms, such as rigidity, bradykinesia, and resting tremor, may benefit from increasing the bedtime dose of dopaminergic treatment or introducing dopaminergic treatment at bedtime.

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In contrast, nocturnal psychiatric symptoms including hallucinations and psychosis can be effectively treated by reducing the bedtime dose of dopaminergic treatment or adding antipsychotics. Table 2 shows treatments for sleep disturbances in patients with PD [11]. Readers may also refer to a recent review regarding the treatment of sleep disorders in PD [14].

Sleep Disturbances and Their Relationship with the Disease Course in PD Sleep disturbances increase as the disease progresses, resulting in severe nocturnal motor and non-motor symptoms. In PD patients, reduced total sleep time and sleep efficiency, increased stage 1 and 2 sleep, and decreased slow wave sleep are expected in the presence of various nocturnal motor and non-motor problems and disease-related changes involving sleep architecture. However, many studies report conflicting results of sleep architecture changes; these discrepancies are probably due to individual night-to-night variations, medication effects (dopaminergic drugs, antidepressants, and hypnotics), and differences in patient selection (disease severity). A recent review found no significant difference in sleep stage 1, 2, or slow wave sleep between PD patients and controls [15•]. Lees et al. [3] found that 98 % of 220 PD patients reported at least one sleep problem. The common problems were nocturia (79 %), inability to turn over in bed (65 %), painful leg cramps (55 %), and vivid dreams/nightmares (48 %). The most troublesome problem was inability to turn over in bed (39 %). In a community-based sleep study, sleep-onset insomnia, sleep maintenance insomnia, and early awakening were observed in 31.8, 38.9, and 23.4 % of PD patients compared with 22, 12, and 11 % of healthy controls, respectively [6]. Self-reported sleep problems occurred more frequently in patients with PD (60 %) than healthy controls (33 %) and patients with diabetes mellitus (45 %). Sleep maintenance insomnia is more common than sleep-onset insomnia in PD patients relative to healthy controls [16, 17], likely due to nocturnal motor symptoms (akinesia, tremor, rigidity, and wearing off) and non-motor symptoms (psychosis, depression, hallucination, and pain). Therefore, sleep problems are not surprisingly more common in patients in the more advanced stages than those in the early stages of PD. In contrast, in early, drug-naïve patients with PD, nocturia, nighttime cramps, dystonia, tremor, and daytime sleepiness are the most important nocturnal disabilities [18]. In another study, the Epworth Sleepiness Scale (ESS) score was abnormally high in one patient (out of 20), while short mean sleep latency was found in three other patients (out of 15), and REM sleep without atonia was a common finding; RBD was rare in early untreated PD patients [19]. Several tools are recommended for assessing sleep problems in patients with PD [20]. The PD Sleep Scale-2 (PDSS-

Curr Neurol Neurosci Rep (2015) 15:8 Table 2

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Management of sleep problems in patients with Parkinson’s disease (modified with permission from Suzuki et al. [11])

Type of insomnia

Cause

Treatment

Difficulty initiating sleep

Unknown cause

Difficulty maintaining sleep/early morning awakening

Drug-related (alerting effect) Unknown cause Wearing off, resting tremor, rigidity, akinesia

Hypnotics (short-acting type; eszopiclone, zolpidem, zopiclone, brotizolam) Remove or reduce dose of causative drug Hypnotics (intermediate type; flunitrazepam) Increase frequency of levodopa administration, add dopamine agonist, or switch to a different type of dopamine agonist Increase frequency of levodopa and reduce dose of levodopa administration, add dopamine agonist Antidepressant (SSRI, SNRI, tricyclic antidepressant) Antianxiety drug Dopamine agonist (D3 R) Oxybutynin, flavoxate Dopamine agonist (D1 R) Daytime rehabilitation Remove or reduce dose of causative drug (including dopamine agonist) Modafinil, caffeine Reduce dopaminergic drugs, consider Yi-Gan Sana and atypical antipsychotics Hazard avoidance (remove potentially dangerous objects from the bedroom and place a mattress on the floor), consider clonazepam and Yi-Gan Sana Continuous positive airway pressure therapy (severe case) Adjustment of dopaminergic treatment, use dopamine agonist and/or clonazepam prior to bedtime, consider iron supplement (if serum ferritin levels are below 50 μg/L) Gabapentin, pregabalin, gabapentin enacarbil, or opioids may be alternatively used

Drug-induced dyskinesia Depression, anxiety

Nocturia Excessive daytime sleepiness

Unknown cause Drug-related (sedative effect) Refractory

Hallucinations, delusions, delirium REM sleep behavior disorder

Sleep apnea syndrome Restless legs syndrome, periodic limb movements

a

Yi-Gan San is an herbal medicine that is used in Asia but that has not been approved by the FDA or EMA for use in the USA or Europe, respectively

2), consisting of 15 questions concerning various sleep and nocturnal disturbances and rated by the patients using one of five categories from 0 (never) to 4 (very frequent), can be used in outpatient clinics or at the bedside and is a useful screening tool for addressing PD-related sleep disturbances [21•]. The total score ranges from 0 (no disturbance) to 60 (maximum nocturnal disturbance). The PDSS-2 has been validated and translated into Japanese, and the PDSS-2 total score correlates with daytime sleepiness, depressive symptoms, quality of life, and motor scores [22]. The PDSS-2 could also be suitable for evaluating responses to dopaminergic treatment [23].

Excessive Daytime Sleepiness Excessive daytime sleepiness (EDS) is a common sleep problem observed in PD and affects 15 to 50 % of patients [24–26]. EDS can be caused by PD-related motor and non-motor nocturnal problems and disease-related changes in arousal

systems, including the cholinergic, serotoninergic, and noradrenergic systems, as well as the orexin system. Risk factors for EDS in PD have been reported to include male gender, longer disease duration, disease severity, and dopaminergic medication [24, 25, 27]. Genetic susceptibility to sleepiness in PD was considered; however, the effect of the COMT genotype on sleepiness was not confirmed in a subsequent study [28]. Cerebrospinal fluid (CSF) levels of orexin are decreased in patients with narcolepsy, a sleep disorder characterized by daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. The multiple sleep latency test (MSLT) shows shorter sleep latency and emergence of REM sleep within 15 min after sleep onset, called the sleeponset REM period. Using the MSLT, a narcolepsy-like phenotype (≥2 sleep-onset REM periods) was demonstrated in a subset of patients in a study on 54 PD patients with sleepiness. Decreased orexin levels in the hypothalamus and a loss of orexin neurons have been observed in PD patients in correlation with disease progression [29, 30]. However, orexin levels

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in the cerebrospinal fluid of PD patients with EDS remain controversial [31–33]. In a prospective study including 232 PD patients, the EDS frequency increased from 5.6 % at baseline to 22.5 % at the 4year follow-up and to 40.8 % at the 8-year follow-up. EDS was related to age, gender, and the use of dopamine agonists in a logistic regression model, whereas in patients who had never used dopamine agonists, EDS was associated with the Hoehn and Yahr stage only, suggesting that disease-related changes in sleep-wake regulation and dopamine agonists contribute to EDS [34]. Additionally, daytime sleepiness measured using both the ESS and MSLT did not differ between drug-naïve PD patients and healthy controls, and increased daytime sleepiness emerged on both the ESS and MSLT after the introduction of dopaminergic treatment in PD patients [19, 35]; these studies support the dopaminergic medication effect on sleepiness in PD. In contrast, in a study of 134 patients with PD using ESS and MSLT, no difference was observed in type and dose of dopaminergic medication, disease severity, depression, insomnia, and nighttime sleep evaluation between the EDS and non-EDS groups, but pain complaint was more frequent and body mass index was higher in the EDS group than in the non-EDS group [36]. In animal studies, the effects of dopaminergic treatment on sleep are complicated by biphasic effects, i.e., a presynaptic sedative effect at low doses and a post-synaptic alerting effect at high doses [37]; however, in the clinic, all dopaminergic drugs have sedative effects on patients with PD. In contrast, Arnulf et al. [38] found a negative correlation between a daily dose of levodopa and the severity of sleepiness in PD patients. Divergent dosedependent effects of drug class on alertness in PD were reported; increasing dosages of dopamine agonists were associated with less daytime alertness, whereas higher levels of levodopa were associated with higher levels of alertness [39]. In PD patients, dopaminergic drugs are associated with EDS as a class effect, and the association between the specific type of dopamine agonist and EDS is unclear [40]. Sudden-onset sleep episodes while driving have been reported in 3.8–22.8 % of PD patients [24, 27, 41]. In patients with a higher ESS score (≥10), the frequency of sudden-onset sleep episodes is increased [25, 27]; therefore, screening for sudden-onset sleep episodes in patients with EDS is important. However, one should be aware that sudden-onset sleep episodes are sometimes unrecognized by patients.

Rapid Eye Movement Sleep Behavior Disorder Idiopathic RBD and PD-Related Diseases RBD was first described by Schenck in 1986 [42] and is characterized by a loss of normal muscle atonia during REM sleep and dream-enacting behavior. The clinical manifestation

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includes vocalizations, such as talking and shouting, and violent, aggressive complex behavior during REM sleep in association with vivid, unpleasant, and violent dreams that can cause sleep-related injury to the patient or bed partner [43]. The prevalence of RBD in the general population is reported to be 0.5 % [44]. A link between RBD and neurodegenerative diseases has been suggested due to a novel observation by Schenck et al. [45], which demonstrated that 38 % of 29 male patients with idiopathic RBD developed PD 12.7±7.3 years after the onset of RBD. A 16-year-update from the initial study provided a conversion rate of 81 % of idiopathic RBD to neurodegenerative diseases (13 PD; 3 dementia with Lewy bodies (DLB); 2 multiple system atrophy (MSA); 1 dementia; and 2 Alzheimer’s disease (AD) with Lewy pathology) [46]. These intriguing findings have been reproduced by other investigators. Iranzo et al. [47] also found that 82 % of 44 patients with RBD developed neurodegenerative diseases over a 12-year follow-up (16 PD, 14 DLB, 1 MSA, and 5 mild cognitive impairment). Postuma et al. [48] reported that 28 % of 93 patients with idiopathic RBD developed neurodegenerative diseases (14 PD; 7 DLB; 4 AD; and 1 MSA) over a mean of 5.2 years of follow-up. The estimated risk for neurodegenerative diseases in RBD subjects was 17.7 % at 5 years of followup, 40.6 % at 10 years of follow-up, and 52.4 % at 12 years of follow-up. Furthermore, when including mild cognitive impairment, the risk of neurodegenerative diseases in RBD patients was 33.1 % at 5 years, 75.7 % at 10 years, and 90.9 % at 14 years [49]. In a clinicopathological study including 172 patients with or without coexisting neurological diseases, the neuropathological diagnoses were Lewy body disease (n= 77), combined Lewy body disease and AD (n=59), MSA (n=19), AD (n=6), progressive supranuclear palsy (n=2), and others (n = 9), demonstrating a high percentage of synucleinopathies (94 %) among RBD patients associated with neurodegenerative diseases (n=170) [50••]. Taken together, these longitudinal studies suggest that idiopathic RBD carries a substantial risk for developing synucleinopathies, particularly Lewy body-related diseases such as PD and DLB. Concomitant AD pathology has frequently been reported in patients with DLB. A study including pathologically confirmed DLB patients found a robust correlation between RBD and DLB pathology; the primary finding indicated that the presence of RBD was associated with a higher likelihood of DLB and less severe AD-related pathology in the medial temporal lobes, whereas the absence of RBD was associated with AD-like atrophy patterns on MRI and an increased phospho-tau burden [51••]. A recent multicenter international study showed that idiopathic RBD subjects have a positive family history of dreamenacting behavior [52], and the potential risk factors of idiopathic RBD include comorbid depression and antidepressant

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use, ischemic heart disease [53], smoking, head injury, pesticide exposure, and farming [54]. Thus, whether antidepressant use causes secondary RBD or induces disease in subjects who are already susceptible to RBD remains unclear. The involvement of cholinergic and monoaminergic brainstem nuclei, including the pedunculopontine nuclei, laterodorsal tegmental nucleus, sublaterodorsal nuclei, and locus coeruleus as well as neuronal networks involving the limbic system and neocortex are thought to contribute to the occurrence of RBD [55]. The diagnosis of RBD in the latest version of the international classification of sleep disorders 3rd edition (ICSD-3) states the following [56]: “Criteria A-D must be met; A. Repeated episodes of sleep-related vocalization and/or complex motor behaviors; B. These behaviors are documented by polysomnography to occur during REM sleep or, based on clinical history of dream enactment, are presumed to occur during REM sleep; C. Polysomnographic recording demonstrates REM sleep without atonia (RWA); D. The disturbance is not better explained by another sleep disorder, mental disorder, medication, or substance use.” Antidepressants, such as tricyclics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, as well as narcolepsy and brain lesions affecting the regulation of REM sleep, can cause secondary RBD. For the definition of RWA, see the AASM Manual [57]. When patients with a typical clinical history of dream-enacting behaviors also exhibit typical dream-enacting behaviors during vPSG but do not demonstrate sufficient RWA, RBD may be provisionally diagnosed. Because polysomnography (PSG) cannot be routinely performed, several screening tools for RBD have been reported to be useful in clinical practice. These include the RBD screening questionnaire [58, 59], Mayo sleep questionnaire [60], RBD questionnaire-Hong Kong [61], and Innsbruck RBD inventory [62]. RBD patients are able to recall the content of their dreams upon awakening at the time of the abnormal behavior, although details may be forgotten by noon of the following day [55]. Also of note, in patients with severe sleep apnea syndrome, apnea-induced arousals can mimic the symptoms of RBD [63]. Idiopathic RBD patients show clinical features and abnormal test results, including olfactory impairment; visual color impairment; subtle motor signs; increased systolic blood pressure drop after standing [64]; cognitive impairments, such as deficits in attention, executive functions, learning capacities, and visuospatial abilities [65]; cardiac autonomic dysfunction, including reductions in beat-to-beat RR variability [66] and u pt a ke o f c a r d i a c M I B G s ci n t i g r ap h y [ 67 ] ; a n d hyperechogenicity of the substantia nigra on transcranial sonography [68]. These features are also observed in Lewy body-related diseases, such as PD and DLB, supporting RBD as a forme fruste of Lewy body-related diseases. Therefore, identifying RBD subjects who are susceptible to the later

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development of neurodegenerative disease is of clinical importance for possible future disease-modifying therapy. Postuma et al. [69] reported that in idiopathic RBD subjects, increased tonic chin EMG activity during REM sleep on baseline PSG findings could predict the future development of PD. In a follow-up positron emission tomography study of a patient with idiopathic RBD, nigrostriatal presynaptic dopaminergic function was almost normal except for a slight decrease in the left posterior putamen at 1 year after the onset of RBD symptoms but was decreased by 4–6 % per year at 3.5 years after the RBD onset [70]. In a 2.5-year follow-up study of 43 idiopathic RBD subjects, of all of the subjects with reduced striatal dopamine transporter uptake and/or substantia nigra hyperechogenicity at baseline, 8 subjects developed neurodegenerative diseases (5 PD, 2 DLB, and 1 MSA), while the idiopathic RBD subjects with normal neuroimaging results at baseline remained disease-free [71]. Prior to the onset of clinically evident parkinsonism in idiopathic RBD, a Unified PD Rating Scale motor score >4 can predict prodromal parkinsonism with 88 % sensitivity and 94 % specificity 2 years prior to PD diagnosis, and other quantitative motor examinations can detect parkinsonism earlier [72]. Subtle gait changes, increased stride-to-stride variability, and decreased rhythmicity and velocity have been detected in idiopathic RBD patients in a cross-sectional study [73], which may be early signs predicting parkinsonism. Parkinson’s Disease and RBD The frequency of RBD in PD patients has been reported to be 15–60 % [43, 74] with RBD symptoms varying over time [75]. Generally, RBD frequency increases when diagnosed using PSG compared with diagnosis using clinical history without PSG because PSG can detect mild forms of RBD and abnormal behavior, which the patient does not remember upon awakening. Bolitho et al. [76] used different questionnaires to compare RWA on PSG findings in PD patients and found that PD patients who were positive for RBD on questionnaires specific to dream enactment (and not the total scores of these questionnaires) were correctly identified with higher degrees of RWA, improving the diagnostic accuracy of the questionnaires. RBD preceded the motor manifestation of PD in up to half of PD patients [77]. Gong et al. [78] reported that among PD patients with RBD, clinical features did not differ between the RBD-preceding and RBD non-preceding group. However, Gong et al. found that the RBD non-preceding subgroup had a significantly higher Unified PD Rating Scale part I score, lower quality of life score, and a lower apnea-hypopnea index during REM than PD patients in the non-RBD group. Nihei et al. [79] found that the RBD-preceding group had a higher onset age of PD, shorter PD duration, and lower levodopa equivalent dose compared with the RBD-non-preceding

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group. RBD comorbidity in PD patients has been associated with distinct characteristics of PD, including an akinetic rigid phenotype, increased fall frequency, poor responses to dopaminergic medications, orthostatic hypotension, and impaired color vision [80, 81]. However, the clinical motor subtype of PD associated with RBD remains controversial; several studies failed to find a clinical motor subtype that differs between PD patients with and without RBD [82, 83]. Gagnon et al. reported that mild cognitive impairment was found in 50 % of idiopathic RBD patients and 73 % of PD patients with RBD, while mild cognitive impairment was observed in 11 % of PD patients without RBD and 8 % of control subjects with mild cognitive impairment. These results showed an increased presence of mild cognitive impairment in idiopathic RBD patients and PD patients with RBD [84]. RBD was associated with mild cognitive impairment among drug-naïve patients with PD [85]. In contrast, in another study, 30 % of 57 newly diagnosed patients with PD had PSG-confirmed RBD, and non-RBD patients and RBD patients did not differ with respect to age, gender, disease duration, motor symptom subtype, and severity or cognitive performance [86]. A 4-year prospective study found that RBD at baseline was associated with increased risks of hallucination, cognitive fluctuations, and dementia in patients with PD [87]. A decreased uptake of cardiac MIBG scintigraphy was reported in PD patients with RBD compared with those without RBD [88, 89]. Among PD patients, the frequency of RBD was significantly higher in patients with older PD onset (>40 years) than the younger onset group (≤40 years) (24.8 vs. 7.8 %). PD patients with RBD had a more advanced stage, poorer sleep quality, and more frequent daytime sleepiness than those without RBD [90]. The presence of RBD in PD patients was also associated with a poorer quality of life [8, 80, 83] and increased frequencies of non-motor symptoms such as depression, fatigue, and sleep disturbances [91]. A study using neuromelanin-sensitive, structural and diffusion magnetic resonance imaging revealed a reduced signal intensity in the locus coeruleus/ subcoeruleus area, involved in the control of atonia during REM sleep, in PD patients with RBD compared with those without RBD and healthy volunteers [92].

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specific to patients with PD. The relationship between RLS and PD has been investigated due to the dopaminergic dysfunction and the favorable response to dopaminergic agents observed in both diseases. However, the results of dopamine imaging studies in the brain are inconsistent. A transcranial sonography study revealed that the substantia nigra echogenicity was low in idiopathic RLS but high in PD patients [94]. Severe RLS symptoms (>15 times/month) in men were associated with the development of PD [95]. However, in approximately 70–95 % of PD patients, RLS develops after the onset of PD [96–98], and there is currently no evidence suggesting RLS as a risk for developing PD [99, 100]. Several studies have reported increased RLS comorbidity in PD patients [98, 100], but the reported prevalence of RLS in PD varies, ranging from 0 to 50 %, possibly depending on the method and patient selection used [101]. PD patients with comorbid RLS are reported to have less family history of RLS, older RLS onset [97], longer PD duration, more severe disability, and longer dopaminergic treatment duration [102, 103]. Older age [104] and younger age of PD onset [96, 98] were both related to RLS comorbidity. Additionally, Peralta et al. [98] reported that symptoms relating to the urge to move the legs and unpleasant sensations were associated with wearing off in 61 % of RLS-positive patients with PD. Many PD patients suffer from motor restlessness and sensory symptoms related to parkinsonism; these symptoms may mimic RLS, and dopaminergic treatment for PD may unmask subclinical RLS [101]. To eliminate confounding factors related to dopaminergic treatment in PD, several studies have assessed RLS prevalence in untreated PD patients; two studies (a clinical case–control study [105] and a population-based incident cohort study [106]) found no significant increase in RLS prevalence in PD patients. Shin et al. [107] reported increased RLS prevalence in drug-naïve PD patients (16.5 %) compared with that in the general population, but no controls were included in this study. Although RLS may not be prevalent, leg motor restlessness that does not fulfill the RLS criteria may be more common in untreated patients with PD than in controls [106].

Sleep Apnea Syndrome Restless Legs Syndrome RLS is a sensorimotor disorder characterized by unpleasant sensations in the legs [93]. Four essential criteria include an urge to move the legs, symptoms beginning or worsening during periods of rest or inactivity, relief by movement, and predominant occurrence in the evening or night rather than during the day. Additionally, the impact of RLS on daytime functioning and sleep problems were added to the latest ICSD-3 [56]. However, these RLS criteria pertain to the general population, and there are currently no RLS criteria

Young et al. [108] reported that habitual snorers with an apnea–hypopnea index (AHI) 5) was less frequent in 100 PD patients (50 unselected patients and 50 patients referred for sleepiness) compared with 50 in-hospital controls (27 vs. 40 %). Additionally, in the PD group, sleep apnea was not associated with daytime sleepiness, nocturia, depression, cognitive impairment, or cardiovascular events. Trotti and Bliwise [112] examined the frequency and severity of OSA in 55 PD patients compared with a large sample of normative data from the Sleep Heart Health Study (n=6,132) and found no increased risk of OSA in PD patients (AHI 5–14.9, PD 29.1 % vs. controls 28.6 %; AHI 15–29.9, 10.9 vs. 11.7 %; AHI ≥30, 3.6 vs. 6.1 %). Milder nocturnal desaturation was observed in PD with OSA patients compared with OSA controls [113–115], as was a blunted sympathetic response to OSA [116]; this may suggest that these autonomic disturbances could protect PD patients from cardiovascular diseases. Disease severity is not universally associated with OSA severity [110, 117]. These findings imply that OSA may not be a relevant issue in PD; however, a randomized, placebo-controlled, crossover study showed that in PD patients with an AHI ≥10, continuous positive airway pressure therapy improved not only sleep apnea but also daytime sleepiness, as measured using the multiple sleep latency test [118]. Therefore, OSA patients with PD, particularly in severe cases, are recommended to receive appropriate treatment [36].

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References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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Conclusion We here review the current understanding of sleep problems in PD patients. Management should consider the impacts of sleep problems on motor and non-motor symptoms as well as quality of life. Compliance with Ethics Guidelines

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Conflict of Interest Keisuke Suzuki, Masayuki Miyamoto, Tomoyuki Miyamoto, and Koichi Hirata declare that they have no conflict of interest.

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Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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