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Journal of Parkinson’s Disease 4 (2014) 223–236 DOI 10.3233/JPD-130280 IOS Press

Review

Nocturnal Manifestations of Atypical Parkinsonian Disorders Roongroj Bhidayasiria,b,∗ , Onanong Jitkritsadakula and Carlo Colosimoc a Chulalongkorn

Center of Excellence on Parkinson’s Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand b Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA c Dipartimento di Scienze Neurologiche, Sapienza Universit´ a di Roma, Rome, Italy

Abstract. Although nocturnal disturbances are increasingly recognized as an integral part of the continuum of daytime manifestations of Parkinson’s disease (PD), there is still little evidence in the medical literature to support the occurrence of these complex phenomena in patients with atypical parkinsonian disorders (APDs). Based on the anatomical substrates in APDs, which are considered to be more extensive outside the basal ganglia than in PD, we might expect that patients with APDs encounter the whole range of nocturnal disturbances, including motor, sleep disorders, autonomic dysfunctions, and neuropsychiatric manifestations at a similar, or even greater, frequency than in PD. This article is a review of the current literature on the problems at nighttime of patients with progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and dementia with Lewy bodies. MEDLINE, life science journals and online books were searched by querying appropriate key words. Reports were included if the studies were related to nocturnal manifestations in APDs. Forty articles fulfilled the selection criteria. Differences between these symptoms in APDs and PD are highlighted, given the evidence available about each manifestation. This analysis of nocturnal manifestations of APDs suggests the need for future studies to address these issues to improve the quality of life not only of patients with APDs but the caregivers who encounter the challenges of supporting these patients on a daily basis. Keywords: Atypical parkinsonian disorders, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, dementia with lewy body, nocturnal manifestations, REM behavioral disorder, nocturia, nocturnal akinesia, hallucinations

Although nocturnal disturbances are increasingly recognized as being a part of the continuum of daytime manifestations of Parkinson’s disease (PD), there is still little evidence in the medical literature to support the occurrence of these complex phenomena in patients with atypical parkinsonian disorders (APDs) [1–4]. Since the degeneration in APDs is considered ∗ Correspondence

to: Roongroj Bhidayasiri, MD, FRCP, FRCPI, Chulalongkorn Center of Excellence on Parkinson’s Disease & Related Disorders, Chulalongkorn University Hospital, 1873 Rama 4 Road, Bangkok 10330, Thailand. Tel.: +66 2 256 4627; Fax: +66 2 256 4630; E-mail: [email protected].

to be more severe and involves the anatomical structures outside the basal ganglia (not limited to sleep regulatory center), it might be expected that there are multiple nocturnal manifestations in these patients, including motor-related symptoms, sleep disturbances, autonomic dysfunction, and neuropsychiatric disorders (Table 1). This article reviews the current evidence on the nocturnal manifestations of APDs with reference to those occurring in PD, with comparisons of the similarities and differences between the two groups. While this recognition of certain manifestations may be useful in the clinical differentiation of APDs from

ISSN 1877-7171/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

N/A N/A N/A N/A 84.6% [44] 19% [108] 10% [108] N/A 17% [108] 37% [36] 47.2% [112], 69% [113] 84% [108] N/A 83% [108] N/A N/A Uncommon [22], 5.5% [108] Common [44]

44.44% [44], 15–34% [103] 54–60% [106], 45.7% [107] 21.9% [109], 41.7% [107] 15% [110] 50.2% [111] 20% [110] Uncommon [36] 60% [114] 36–65% [114], 32.43% [107] Common [115], 55.8% [107] 79% [1], 61.9% [107] 40% [115] 16% [1], 22.2% [119] 33.9% [107]

MSA

34% [1] Common [102] 55% [1] 65% [1]

PD

Uncommon [29] Uncommon [22] N/A

N/A N/A Common [104] Common [29]

20% [44], 27% [103] Common [29] Uncommon [29] Uncommon [29] N/A N/A N/A

Common [29] N/A N/A Common [29]

PSP

Uncommon [117] Uncommon [22] Uncommon [31]

N/A N/A N/A N/A

5% [44], 0% [31] Common [31] 80% [31] 80% [31] 0% [31] 40% [31] N/A

N/A N/A Uncommon (14) N/A

CBD N/A N/A N/A N/A

DLB

Common [118] 58% [118] Common [120]

N/A N/A Common [116] N/A

67.5% [44], Common [104, 105] N/A N/A N/A Common [104] N/A N/A

PD: Parkinson’s disease; MSA: multiple system atrophy; PSP: progressive supranuclear palsy; CBD: corticobasal degeneration; DLB: dementia with Lewy body.

Nocturnal motor manifestation • Nocturnal akinesia and dystonia • Early-morning akinesia and dystonia • Nocturnal painful cramps • Difficulty turning in bed Sleep-related disorders • REM behavioral disorders • Insomnia • Restless leg syndromes • PLMS • Excessive daytime sleepiness • Sleep apnea • Nocturnal stridor Autonomic dysfunction • Erectile dysfunction • Sexual dysfunction • Urinary symptoms – Nocturia Neuropsychiatric manifestation • Psychosis • Hallucination (visual) • Vivid dreams

Categories

Table 1 The frequency of nocturnal manifestations of atypical parkinsonian disorders in comparison to Parkinson’s disease

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PD, it is of equal importance to be aware of critical nighttime conditions (e.g. breathing disorders), which can be life-threatening, and require immediate intervention. APDs are characterized by rapidly evolving parkinsonisms that usually have a poor or transient response to dopaminergic therapy and are often associated with one or more atypical features [5]. The common forms that are included in this review are multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). APD is a mirror image of typical parkinsonisms with a spectrum of manifestations that constitute the syndrome of atypical parkinsonism that rapidly becomes severe and characteristically involves the axis of the body. When other signs are prominent, they tend to leave parkinsonisms in the background. Within the context of nocturnal manifestations, these clinical features may contribute to a range of motor, sleep, autonomic, and neuropsychiatric symptoms and some of them may also extend to occur during the daytime (Table 1). For example axial rigidity can lead to nocturnal akinesia and an

Fig. 1. The drawing of the human brainstem and its nuclei. The figure illustrates the area of the degeneration of the brainstem in each parkinsonian disorder. PD: Parkinson’s disease; MSA: Multiple system atrophy; PSP: Progressive supranuclear palsy; CBD: Corticobasal degeneration; DLB: Dementia with Lewy body. BF: Basal forebrain/nucleus basalis of Meynert; LHA: Lateral hypothalamic area; TMN: Tuberomammillary nucleus; VTA: Ventral tegmental area; LDT: Laterodorsal tegmental nucleus; PPT: Pedunculopontine nucleus; LC: Locus coeruleus; Raphe: Raphe nuclei; DN: Dentate nucleus; DV: Dorsal motor nucleus of vagus nerve; OL: Inferior olivary nucleus.

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impairment of the respiratory center may result in sleep-disordered breathing, hypoventilation that may result in acute/chronic hypoxemia, and excessive daytime sleepiness. For the purpose of clarity, we perform systematic review of the published literature relating to nocturnal clinical features in APDs by separating them into four sections as outlined in Table 1. ANATOMICAL SUBSTRATES LINKED TO NOCTURNAL MANIFESTATIONS Although nocturnal disturbances in APDs can be assigned to different categories as shown in Table 1, these areas can overlap and any one of the symptoms may influence and be responsible for the others. This suggests that the etiology is most likely multifactorial and in part due to neurodegenerative processes affecting centers that regulate sleep and wakefulness [6, 7]. These changes impact the individual susceptibility, the efficacy of the pharmacologic therapy, and the interindividual dynamics. The degenerative process in most APDs is multifocal involving specific central nervous system neurons and peripheral autonomic nervous system neurons [7]. Thus, a particular set of affected neurons determines nocturnal clinical presentations (Fig. 1). In addition to striatal and nigral involvement, which may underpin a range of motor-related manifestations, a number of neuropathological studies, mostly in PD and other neurodegenerative disorders have given additional insights that include the possibility that a complex anatomical framework involving multiple brainstem nuclei and neurotransmitters (not limited to dopamine) is responsible for abnormal sleeprelated behaviors in these patients (Table 2) [7–14]. By utilizing PD as a disease model to determine the patho-anatomic correlate for most sleep disturbances, the existing data indicate that not only dopaminergic neuronal loss, but noradrenergic neurons in the locus coeruleus, serotonergic neurons in the raphe, cholinergic neurons in the basal forebrain, orexin/hypocretin neurons in the hypothalamus, and perhaps also the cells that secrete melanin concentrating hormone are involved in the pathogenesis of the respective behaviors (Table 2) [15–17]. For dopamine, there is an apparent paradox that the loss of endogenous dopamine in PD contributes to sleepiness, whereas sleepiness has also been associated with administration of exogenous dopamine in the forms of dopamine agonists or levodopa [18]. This evidence further supports the possibility that dopamine-mediated arousal functions are independent of the nigrostriatal dopaminergic system (likely to involve the mesocorticolimbic dopaminergic

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Table 2 Comparison of the pattern of degeneration that occurs in PD and atypical parkinsonian disorders with a reference to a sleep regulating center Region Cortex Frontal • Motor cortex • Premotor cortex • Sensory cortex • Superior frontal gyrus Parietal Occipital Temporal • Entorhinal Limbic system • Amygdala • Hippocampus • Cingulate • Thalamus • Hypothalamus (including tuberomamillary nucleus) Basal ganglia Striatum (caudate and putamen) Globus pallidus Subthalamic nucleus Brainstem Substantia nigra Basal nucleus of Meynert Red nucleus Oculomotor nuclei Midbrain tectum Midbrain tegmentum Locus ceruleus Cerebellar peduncle Pontine tegmentum (including pedunculopontine, laterodorsal tegmental, and raphe nuclei) Pontine nuclei (including pontocerebellar fibers) Medullary tegmentum (including dorsal motor nucleus of the vagus) Inferior olive (including olivocerebellar fibers) Dentate nucleus Cerebellar white matter

Sleep regulating center

∗

∗

∗ ∗ ∗

PD

MSA

PSP

CBD

DLB

+ + + + + 0

++ N/A 0 0 0 0

+++ +++ 0 ++ 0 0

+++ + +++ +++ +++ 0

++ ++ N/A N/A ++ +

++

0

0

0

+++

+++ ++ ++ 0 ++

0 0 + + +

0 0 0 +++ +++

0 0 N/A + N/A

+++ +++ +++ N/A N/A

+ 0 0

+++ ++ 0

+++ +++ +++

+ ++ +

+++ N/A N/A

+++ +++ 0 + 0 ++ +++ 0 +++

+++ + N/A 0 0 0 + +++ (middle & inferior) +

+++ +++ ++ +++ +++ +++ +++ +++ (superior) +++

+ +++ + 0 0 0 + 0 +(PPT)

++ ++ N/A N/A N/A N/A ++ N/A N/A

0 +++

+++ +++

++ +++

0 0

N/A ++

0 0 0

+++ +++ +++

++ ++ 0

0 + 0

N/A N/A N/A

0 = spared, + = mild, ++ = moderate, +++ = severe, N/A = no data, ∗ = affected area. PD = Parkinson’s disease, MSA = multiple system atrophy, PSP = progressive supranuclear palsy, CBD = corticobasal degeneration, DLB = dementia with Lewy bodies, PPT = pedunculopontine nuclei.

circuit). These neurons are mainly located in the reticular formation which is a heterogeneous region that runs through the core of the brainstem from the medulla up to the midbrain and into the posterior hypothalamus (Fig. 1). In particular, the rostral reticular formation receives inputs from a number of sensory systems and promotes wakefulness via excitatory projections to the thalamus, hypothalamus and basal forebrain [19]. Braak’s hypothesis of ascending brainstem degeneration proposes that degeneration of several other non-dopaminergic brainstem nuclei (the cholinergic pedunculopontine nucleus, the noradrenergic locus coeruleus, the serotonergic tegmental area, and the nucleus magnocellularis) occur before the degener-

ation of the dopaminergic neurons in the substantia nigra (SN), supporting the frequent occurrence of REM behavioral disorder (RBD) during the preclinical stage of PD [10]. The varying degree of synuclein pathology depicts a temporal sequence of clinical symptomatology in which some of them have been classified as preclinical manifestations that develop before the clinical signs of parkinsonism [4, 20]. However, in APDs, there is a paucity of clinicopathological data to determine the progression of degeneration in each stage of the diseases but it seems very likely that these brainstem nuclei are affected at the early disease stage (Table 2). Therefore, we can predict that patients with APDs may experience sleep disturbances as well as other nocturnal-related disorders at a similar, or even at

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greater, frequency than patients with PD. The pathological heterogeneity among different forms of APDs may account for varying clinical presentations that occur at nighttime. This statement is supported by a recent PRIAMO study which indicated that approximately 70% of patients with APD (except CBD) experienced similar or even more sleep disturbances than PD patients [21]. Similarly, the frequency of urinary symptoms which include nocturia, frequency, and urgency were reported in up to 90% of MSA patients in comparison to 58% of PD patients. Visual hallucinations and psychoses may occur as part of the nocturnal manifestations in patients with parkinsonisms but the presence of persistent visual hallucinations is usually indicative of underlying Lewy body pathology (PD and DLB) [22, 23]. The predicted anatomical substrates for visual hallucinations have been confirmed using functional imaging techniques. Most data derived mainly from PD literature reported changes consistently seen in the temporal, parietal, and occipital lobes, particularly in the ventral visual processing pathways while amygdala is considered to be the final processing center in this ventral stream of the cortical visual system [24].

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3) The study was available in full length in English and published before the 31st December 2013. Review articles, editorials, case reports, and clinical commentaries are excluded from the review process. Selection process (Fig. 2) The selection process was performed in three stages: 1) Titles and abstracts were identified from database searches and chosen if the study population was MSA, PSP, DLB, and CBD patients. 2) The chosen articles were retrieved as full-length articles, and only studies fulfilling the selection criteria were included. 3) The reference lists of the selected articles were searched, and relevant articles identified were taken through stage 2 until no further articles were found. Steps 1 and 2 were performed independently by two of the authors (R.B., O.J.), and any disagreement was resolved jointly by discussion. Statistical analysis or meta-analysis was not attempted because of significant variability in study methodologies.

METHODS RESULTS Data source and search MEDLINE, life science journals, and online books were searched by querying the key words: (progressive supranuclear palsy OR multiple system atrophy OR dementia with Lewy bodies OR corticobasal degeneration) AND (sleep OR nocturnal OR polysomnography OR nocturia OR insomnia OR daytime somnolence OR excessive daytime sleepiness OR nocturnal akinesia OR nocturnal hypokinesia OR stridor OR autonomic OR supine hypertension OR loss of blood pressure fall OR nocturnal psychosis OR sleep fragmentation). Study selection The study was included on fulfillment of the following selection criteria: 1) The study was conducted in patients with APDs, which include PSP, MSA, CBD, and DLB, with or without control subjects. 2) The study contained data related to nocturnal manifestations, which are under the scope of four symptom domains, including motor, sleep, autonomic and neuropsychiatric symptoms that mainly manifest at night.

We screened 1,326 titles and abstracts, from which 51 full-length articles were selected for further review. Of these, 40 articles fulfilled the selection criteria (Supplementary data). NOCTURNAL MOTOR-RELATED MANIFESTATIONS IN APDs In one of the original studies on nighttime problems in PD, 98% of patients from a national survey reported experiencing disabilities at night or upon waking [1]. Inability to turn over in bed was rated as the most troublesome symptom and affected two-thirds of patients. The symptoms may last throughout the night and extend to the early morning on waking to include the difficulty in getting out of bed unaided, severe tremor, foot dystonia, and painful leg cramps [3, 25]. Patients with PD change their position in bed less frequently than do their spouses [26]. Moreover, nocturnal hypokinesia negatively affects sleep quality in these patients [27, 28]. Although the evidence on impaired nocturnal mobility is limited in APDs, it is likely that nocturnal hypokinesia is one of the factors contributing to sleep disturbances in these patients. In

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Fig. 2. Summary of the search results.

a study of 11 patients with PSP (Steele-RichardsonOlzewski syndrome), immobility in bed and difficulty with transfers as documented by clinical assessments and a structured sleep questionnaire contributed to sleep disturbances significantly more frequently than in normal controls [29]. However, polysomnography was not performed in this study due to the severity of the underlying disability in the subjects. As most APD patients had predominant akineticrigid syndrome with rapid involvement of axial structures, we can expect that their mobility in bed would be significantly impaired due to general movement difficulties, pain, stiffness, dystonia, or weakness. It can be difficult for these patients to find a comfortable position in which to sleep and to get out of bed. Due to the severity of axial rigidity and stiffness, turning in bed can be very difficult and may be considered a risk factor for pressure sores in this patient group [26]. Flexed posture, axial rigidity, and a lack of coordination of contractions of the upper airway and chest wall muscles may limit chest wall expansion, leading to restrictive ventilation and hypoxemia at night [30]. Unlike PD, many APD patients are probably unable to use turning strategies such as hip hitching or sitting up (like in PD patients) as a result of their akinetic rigid state [27]. In addition to nocturnal hypokinesia, painful dystonia (usually localized in the legs) may occur at any

time during the night or typically in the early morning as a result of dystonic spasms and postures. While this phenomenon is well recognized among PD patients as one of many manifestations of motor complications, the occurrence of this symptom has not been specifically explored in APD patients. One small case series involving five CBD patients rated this problem as being uncommon [31]. SLEEP-RELATED DISORDERS IN APDs Sleep disorders are common and well documented in patients with PD. In a community-based survey, nearly two thirds of PD patients reported sleep disorders, significantly more than among patients with diabetes (46%) and healthy control subjects (33%) [32]. Moreover, about a third of PD patients rated their overall nighttime problem as moderate to severe. The most common sleep disturbances reported by PD patients were frequent and early awakening. In order to determine the extent of sleep problems in PD, different scales have been developed and critiqued by a panel of experts of the Movement Disorders Society [33]. Some of these scales have been utilized in studies involving patients with APDs. Although the evidence on sleep-related disorders is much less in APDs, mostly in the forms of small case series and small controlled trials, a recent PRIAMO study found

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a higher prevalence of nonmotor symptoms (NMS) in patients with APDs compared with patients with PD [21]. Specifically, sleep disturbances were reported in 67.7% of MSA patients, 76.7% of PSP patients, 78.6% of DLB patients, and 36.4% of CBD patients while 65% of PD patients experienced sleep problems. Urinary symptoms in the forms of urgency, frequency, and nocturia were most frequent in MSA (90.9%), followed by DLB (78.6%), and about half of patients with PSP, CBD and PD were affected. Another separate study, which utilized the Nonmotor Symptom Scale, identified sleep/fatigue symptoms domain significantly correlated with mood/cognitive symptoms in MSA patients [34]. Importantly, these nocturnal symptoms contributed to the worsening quality of life in patients with APDs [21, 34]. For practical purposes in this review, we group sleep disturbances into five main categories; sleep structure, REM sleep behavioral disorder, sleep-related breathing disorder, restless legs syndrome, and excessive daytime sleepiness. Sleep structure While PD patients typically complain of insomnia, fragmented sleep with frequent awakening, leg cramps, jerks, and nocturia, the full spectrum of sleep disturbances in patients with APDs is not well described in the literature. Although the PRIAMO study specifically evaluated sleep symptoms in 89 patients with APDs in four domains, including RBD, insomnia, excessive daytime sleepiness, and restless legs, the details were not presented in the study except a discussion on the common occurrence of RBD in MSA [21]. Based on the severe involvement of degeneration of sleep regulation center in various brainstem nuclei in APDs noted above (except CBD) (Fig. 1), we hypothesize that most patients with APDs are likely to experience similar, or even worse, sleep disturbances than patients with PD. When matched for age, sex, and disease duration, one study identified a higher prevalence of sleep disorders in MSA patients (70%) than PD subjects (51%) [35]. Sleep fragmentation is the most frequent complaint and is reported in 53% of MSA patients, followed by early waking (33%), and insomnia. These subjective complaints were confirmed by polysomnographic (PSG) studies showing reduced total sleep time, low sleep efficiency, and reduction of both REM sleep and slow wave sleep in MSA patients [36, 37]. Moreover, poor response to levodopa, pain, nocturia, and periodic limb movements (PLMs) may partly account for sleep fragmentation and for PSG abnormalities [36, 38].

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Most patients with PSP also complain of insomnia, which appears to be worse than PD and Alzheimer’s disease (AD) [39]. PSG studies reported a significant reduction of sleep quality, and total sleep time as well as an increased sleep fragmentation early in the course of the disease [39–41]. With the progression of disease, REM sleep is dramatically reduced [40]. Indeed, the number of awakenings increased with greater motor impairment, and the total sleep time declined as dementia worsened [39]. In DLB, one study indicated that 70% of patients had sleep efficiency well below 80% with arousals attributable to disordered breathing, PLMs, and spontaneous arousals [42]. In one small case series involving five CBD patients, all patients reported to have insomnia with four displayed PLMs during sleep and/or RLS [31]. REM behavioral disorder (RBD) RBD is a parasomnia characterized by vigorous dream-enacting behaviors associated with nightmares and abnormal increased phasic and/or tonic electromyographic activity during REM sleep [43]. A number of PSG studies in APDs have focused on the association of RBD and synucleinopathy. To establish the diagnosis of RBD, PSG with audiovisual recording is essential to detect increased EMG activity and abnormal behaviors during REM sleep and to exclude other sleep disorders that can resemble RBD [43]. In a study involving the review of clinical records of 398 patients with parkinsonism, patients with MSA, PD, or DLB were more likely to have probable (p < 0.01) or PSG-confirmed (p < 0.01) RBD compared with subjects with the nonsynucleinopathies (PSP, CBD, AD and other dementing illnesses) [44]. Moreover, in 10 cases who had clinical diagnosis of RBD, neuropathological studies confirmed the diagnosis of Lewy body disease in nine and MSA in one. The positive predictive values for RBD indicating a synucleinopathy from PSG and neuropathological confirmations were 91.7% and 100% respectively. This high value indicates that if RBD is present in a patient with a parkinsonian disorder, there is a high likelihood that a synucleinopathy is present [45]. Indeed, the prevalence of RBD in MSA was reported to be as high as 90.5–100% [46–48] and RBD is currently considered a red flag for the diagnosis of MSA [49]. Many experts also believe that most if not all patients with MSA have RBD, which may explain less male predominance of RBD in this disorder. In DLB, the prevalence was reported to be at least 50% and RBD is included as one of the criteria for the diagnosis of probable DLB (plus at least one of

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the three core features including parkinsonism, visual hallucinations, and fluctuations) [42, 50, 51]. Although there are recent reports of RBD in patients with PSP and CBD, pathological confirmation of the underlying diagnosis is often unavailable and many of them had REM sleep without atonia or clinical RBD [52–55]. In small case series, one-third (7 out of 20) of PSP patients and none (0 out of 5) of CBD patients had clinical RBD [31, 55]. RBD patients display abnormal motor and vocal behaviors during REM sleep that have different degrees of severity on different nights [56]. Motor behaviors are more frequent, ranging from mild limb jerking, punching and kicking to jumping out of bed. These behaviors may result in injuries to both patients and bed partners. Recalled dreams often have a negative emotional content associated with nightmares of being frightened or being attacked by animals. Indeed, the types of unpleasant dreams, motor, and vocal expressions of RBD are similar among subjects with idiopathic RBD, PD, and MSA [46]. Moreover, the RBD-synucleinopathy association is particularly high when RBD precedes the onset of cognitive impairment, parkinsonism, or autonomic dysfunction [36, 47, 56–58]. This period can be as long as 10–12 years (range 1–61 years) according to the most recent large clinicopathological study [57]. Sleep talk, frequently accompanied by various craniofacial movements, has been reported as an early clinical manifestation of REM sleep without atonia in MSA [48] and this feature may be useful in the clinical discrimination of DLB from other types of dementia [59]. Clinically, many patients with both MSA and DLB were often not aware of their abnormal behaviors and unpleasant dreams which were only noticed by bed partners. RBD in MSA is unrelated to age, disease severity, disease duration, or clinical subtype (parkinsonism or cerebellar) [46]. Recently, the term ‘sleep enactment behaviors (SEBs)’ has been introduced to include RBD and arousalsrelated episodes from NREM or REM sleep and they are reported to be more frequent in DLB patients with associated risk factors including advanced stage of disease and a high degree of cognitive impairment [60].

dor. Among those reported, nocturnal stridor and OSA are the most common with reported frequencies of 13 to 69% and 15 to 27% respectively [36, 47]. Stridor was found to be associated with other sleep-related respiratory and motor disorders suggesting an impairment of homeostatic brainstem integration in MSA [63]. The presence of nocturnal akinesia of the upper airway and the prolonged supine position during sleep may predispose MSA patients to SDB. Clinically, stridor can easily be recognized by caregivers as harsh and strained high-pitched sound but laryngeal examination of the glottis is often necessary to evaluate the degree of narrowing of the upper airway as well as the position of the vocal cords [62]. Debates continue whether the stridor occurs as a result of dystonic vocal cord or bilateral vocal fold paresis [63–65]. However, false negative findings may be obtained from this examination, requiring the examination under anesthesia and/or esophageal pressure monitoring in highly suspected cases [61, 66, 67]. Prompt intervention of SDBs is essential since they may underlie the mechanism of sudden death in these patients. While upper airway resistance syndrome, OSA, and central apnea syndrome were also identified in DLB patients, these problems were not considered a major cause of poor sleep efficiency in DLB [42].

Sleep disordered breathing (SDB)

EDS is described as inappropriate and undesirable sleepiness during waking hours and is a common nonmotor symptom in PD, affecting up to 50% of patients [75–77]. Many factors, including nocturnal disturbances, dopaminergic medications (particularly dopamine agonists), and even the severity of the disease itself, may contribute to EDS [78]. EDS is probably frequent in non-PD parkinsonism as well. In

The frequent occurrences of SDBs in MSA patients have received significant attention owing to their severity and life-threatening potential [61–63]. During sleep in MSA, SDB may manifest as obstructive sleep apnea (OSA), central sleep apnea, irregular and apneustic breathing, Cheyne-Stokes breathing pattern, and stri-

Restless legs syndrome (RLS) RLS is primarily a sensory disorder characterized by an abnormal urge to move the limbs that occurs during rest and improves with voluntary movement of the affected limb [68]. While the prevalence of RLS in PD ranging from 0.5% to 19.5% [69–71], very few studies have evaluated the association of RLS in APD patients [72–74]. Among those reports, RLS was found to be very low in patients PSP (1 in 27 patients), and DLB (none in 5 patients), but conflicting results were obtained for MSA (4.7% vs. 28%) [72, 74]. Another study reported two out of five (40%) CBD patients suffering from RLS [31]. Excessive daytime sleepiness (EDS)

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one multicenter survey of EDS in patients with MSA in Europe, EDS was present in 28% of patients with MSA, 29% of patients with PD, and 2% of control subjects [74]. Similar rate of EDS (24%) was also identified in Japanese populations with MSA [79]. While disease severity was correlated with EDS in MSA and PD, the amount of dopaminergic treatment was correlated with EDS in only PD, but not MSA [74]. In a single study involving 15 PSP patients, one-third had a latency of less than 8 minutes on multiple sleep latency test, which is considered as a marker of EDS, but no narcolepsy-like pattern was observed [54]. Those with EDS had longer nocturnal sleep than those with normal alertness, suggesting that sleepiness was probably caused by a primary central hypersomnia. AUTONOMIC DYSFUNCTION AT NIGHT IN APDs Autonomic dysfunction has been designated as a core criterion for the diagnosis of probable and possible MSA according to the second consensus statement for the diagnosis of MSA [80]. Premotor signs of MSA have been recognized to include the combination of autonomic failure, sleep problems, and respiratory disturbances when they are present before the onset of ataxia or parkinsonism [81–83]. The manifestations of autonomic dysfunction in MSA encompasses the whole spectrum of orthostatic hypotension, urinary symptoms, sexual dysfunction, constipation, and SDB which are well described in the medical literature and are not included in this review. Nocturia and orthostatic hypotension can be troublesome especially at night when pathological blood pressure increase is often observed [21, 84]. Moreover, severe supine hypertension may be dangerous in patients with MSA when they are supine at night leading to intracerebral hemorrhage [85]. Continuous leakage of urine due to frequent involuntary bladder emptying is also another characteristic urinary symptom in MSA which may result in a frequent urge for patients to get out of bed to go to the toilet at night [86]. Although excluded in the second consensus for the diagnosis, erectile dysfunction has been observed in almost all MSA patients and may be the first symptom in one-third of the patients [82, 86]. It is also likely that urinary symptoms in MSA are present throughout the course of the illness since there is a close relationship between urine storage dysfunction and life-threatening breathing disorders [87, 88]. The occurrence of autonomic dysfunction is not limited to MSA. Autonomic dysfunction is common among DLB patients, in the intermediate range

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between PD and MSA [89]. While these features are considered as supportive criteria for a clinical diagnosis, its presence negates survival in patients with DLB [90]. The majority of confirmed DLB patients reported urinary incontinence and constipation as the most frequent symptoms while almost one-third of these patients experienced episodic hypotension associated with syncopal episodes [91]. Compared to PD, the frequency of orthostatic intolerance which can occur at night was greater in DLB but was comparable to MSA [89]. The pattern of sweat loss in DLB is predominantly distal, similar to PD [89]. In PSP, no major autonomic features have been reported and if present, should be an exclusion criterion for PSP [92]. Nocturia and urgency were found to be common urinary symptoms in patients with CBD, appearing 1–3 years after the onset of the disease and were more common in patients with longer disease duration (>5 years) [93].

NOCTURNAL NEUROPSYCHIATRIC MANIFESTATIONS IN APDs In a national survey of nocturnal symptoms among 220 PD patients, vivid dreams/nightmares and visual hallucinations were reported in 48% and 16% of patients respectively [1]. Among APDs, DLB probably represents the most common disorder with neuropsychiatric symptoms experienced by 60–70% of patients [94]. The observation that visual hallucinations may be specific to Lewy body pathology probably reflects a greater vulnerability of the visual systems to PD and DLB. Typically, patients with DLB have recurrent images of people, animals, or objects which may occur several times a day, but most commonly in the evening or night, probably related to darkness or reduced daylight. Hallucinations are usually not frightening or threatening, although may become so in more severely demented patients or when accompanied by delusions [95]. Even though less recognized, these associated symptoms may be more disturbing for the spouses than the patients themselves, including anxiety, depression, apathy, diminished initiative, motivation, and affect [94, 96]. Most clinical and pathological studies report a low frequency of visual hallucinations and psychosis in non-Lewy body forms of parkinsonisms [97, 98]. PSP is associated with high rates of apathy and disinhibition but low rates of hallucinations, even in the context of dopaminergic medications [99]. Only 5–9% of patients with MSA and CBD patients rarely reported hallucinations [100].

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CONCLUSIONS Nocturnal manifestations are certainly not limited to PD. Supported by anatomical substrates subserving sleep regulation, movements, and visual processing systems, patients with APDs encounter a whole range of nocturnal symptoms with some differences depending on the topographic distribution of degeneration in each syndrome. In PD, neurologists failed to identify nocturnal disturbances in over 40% of routine consultations [101] and just over half of PD patients found their nocturnal symptoms sufficiently troublesome to mention them to their physicians, although 39% claimed that the doctor did not try to help [1]. We estimate that a similar situation or even worse occurs in patients with APDs. Therefore, this review article serves as a platform highlighting the importance of nocturnal manifestations in APDs and documents the lack of evidence of these issues of how to manage nighttime disturbances of APDs in clinical practice. It is clear that these nocturnal problems can be disturbing to patients, but even more for the caregivers who encounter these patients on a daily basis. More prospective studies are needed to address specific issues of nocturnal symptoms in each syndrome which will lead to improving the quality of life in both those directly affected and their caregivers.

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ACKNOWLEDGMENTS [11]

The study was supported by a Rachadapiseksompoj faculty grant, research unit grant of Chulalongkorn University to Chulalongkorn Center of Excellence of Parkinson’s Disease & Related Disorders, and CUCLUSTER fund no. H-34-94-53. CONFLICTS OF INTEREST

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The authors have no conflicts of interest. [15]

SUPPLEMENTARY MATERIAL

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Supplementary tables are available in the electronic version of this article: http://dx.doi.org/10.3233/JPD130280.

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