www.nature.

com/npp

NEUROPSYCHOPHARMACOLOGY REVIEWS
Sleep in Parkinson’s disease
Ambra Stefani1 and Birgit Högl1

Sleep disturbances are common in Parkinson’s disease and comprise the entire spectrum of sleep disorders. On the one hand
regulation of sleep and wakefulness is affected in Parkinson’s disease, leading to the development of disorders, such as insomnia
and daytime sleepiness. While on the other hand control of motor activity during sleep is impaired, with subsequent manifestation
of parasomnias (mainly REM sleep behavior disorders, but also, albeit more rarely, sleepwalking, and overlap parasomnia). Restless
legs syndrome has been reported to be frequent in patients with Parkinson’s disease, although there is no consensus on whether it
is more frequent in Parkinson’s disease than in the general population. The same is true for sleep-related breathing disorders.
Regarding the diagnosis of sleep disorders in patients with Parkinson’s disease, one of the main challenges is correctly identifying
excessive daytime sleepiness as there are many potential confounding factors, for example it is necessary to distinguish sleep-
related breathing disorders from medication effects, and to distinguish restless legs syndrome from the concomitant presence of
potential mimics specific to Parkinson’s disease, such as akathisia, nocturnal leg cramps, nocturnal hypokinesia, early morning
dystonia, etc. The correct diagnosis of REM sleep behavior disorder is also not always easy, and video-polysomnography should be
performed in order to exclude mimic-like movements at the end of sleep apneas or violent periodic leg movements of sleep. These
aspects and specific considerations about diagnosis and treatment of sleep disorders in patients with Parkinson’s disease will be
reviewed.

Neuropsychopharmacology (2020) 45:121–128; https://doi.org/10.1038/s41386-019-0448-y

INTRODUCTION In patients with PD, both the sleep macrostructure (manifesting

Sleep and wakefulness regulation rely on a highly complex and for instance as sleep fragmentation and a relative increase in
integrated function of multiple brain areas and neurotransmitters, superficial sleep) [23, 24] and sleep microstructure, manifesting as
many of which have also been shown to be affected in patients disturbed integrity of certain sleep stages (e.g. disturbed sleep
with Parkinson disease (PD) [1–7]. With this pathophysiological spindles and K-complexes, or insufficient muscle atonia during
background, it is not surprising that disturbances of sleep and REM sleep) [25–32] are affected.
wakefulness are almost ubiquitous in patients with PD. An oft- The range of sleep disturbances in PD comprises the full
cited survey performed in 1988 found that among PD patients, spectrum of sleep disorder categories as outlined in the
98% had experienced disabilities at night or on waking since the International classification of sleep disorders 3rd edition (ICSD-3)
onset of their disease [8], and disturbed wakefulness regulation [33]. The categories of sleep disturbances apparent in patients
was shown to be a prominent feature in up to 30% of patients with PD thus comprise insomnia, disorders of daytime somno-
with PD [1, 2, 9–11]. lence, sleep-related breathing disorders, circadian disorders,
Beyond the PD-related impairments of brain and neurotrans- and sleep-related movement disorders, namely restless legs
mitter function there are other major contributing factors to syndrome (RLS), and parasomnias. This heterogeneity of sleep
disturbances of sleep and wakefulness in patients with PD, these phenotypes might reflect the well-known heterogeneity of PD
include dopaminergic drugs, which are known to influence motor phenotypes as well as the biologic (biomarker)
regulation of sleep and wakefulness, as well as other medications heterogeneity of PD.
used in this elderly and often multimorbid population, co-
morbidities, PD symptoms that impair patients' sleep, such as Insomnia and daytime sleepiness in patients with Parkinson’s
nocturnal akinesia, and genetic factors that predispose to certain disease
disturbances of sleep and wakefulness [2, 9, 12–14]. Moreover, As outlined above, patients with PD frequently experience
lifestyle factors and impulse control disorders, a frequent side insomnia, most often as a disorder of sleep maintenance, but
effect of dopaminergic drugs, can also play a role in the also as a disorder of sleep onset or early morning awakening. The
development and continuation of sleep disturbances in patients diagnosis of insomnia is always based on subjective symptoms.
with PD. Patients report difficulties falling asleep or maintaining sleep, early
An interesting, yet often neglected feature of PD concerns the awakening or non-restorative sleep, associated with subjective
interaction of sleep and motor function, with sleep benefit, i.e. concern or daytime impairment [1, 2, 9–11, 23]. Notably, there is
some patients experience an improvement of motor function sometimes a discrepancy between subjective complaints of
upon awakening [15–19], while others experience positive effects insomnia and only subtle disturbances of sleep structure in
of sleep deprivation on motor function [20–22]. otherwise healthy people, whereas in patients with PD, in addition

1
Department of Neurology, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
Correspondence: Ambra Stefani ([email protected])

Received: 4 March 2019 Revised: 26 May 2019 Accepted: 13 June 2019

Published online: 24 June 2019

© The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2019

 Sleep in Parkinson’s disease
A Stefani and B Högl
122
to the subjective complaints of insomnia, there is often a Daytime sleepiness in PD was first described many decades ago
significant manifest disruption of the integrity of sleep macro [1, 17, 40, 41], nonetheless it still remains an underappreciated
and microstructure. feature despite its relevance, especially, for example, following
Multiple studies have reported high prevalences of insomnia in reports of PD patients (taking dopamine agonists) falling asleep
patients with PD [10]. Gjerstad and co-workers investigated sleep while driving [42]. Driving safety in patients with PD has been
in a prospective longitudinal cohort of 231 patients with PD, and evaluated through driving simulators with studies reporting more
performed an 8-year follow-up in 89 of them. The authors total collisions in PD patients compared to controls [43, 44].
reported a large intraindividual variation in insomnia symptoms as Studies using the Epworth sleepiness scale to evaluate daytime
evaluated by questionnaires, but found that in the population- sleepiness in PD found varying abnormal scores (9.3% [45], 33%
averaged logistic regression model the presence of insomnia was [1], or 43.2%) [46], with 28.4% noting somnolence with
related to female sex (p = 0.001, OR 2.21, 95% CI 1.36–3.59), dopaminergic drug intake and 6.8% describing unintended sleep
disease duration (p = 0.009, OR 1.07, 95% CI 1.02–1.13) and to episodes [46].
depression as measured by the Montgomery and Aasberg However, the relationship between PD and daytime sleepiness
Depression Rating Scale (p = 0.03, OR 1.06, 95% CI 1.01–1.11) is controversial, and a large study using the Epworth sleepiness
[34]. However, PD-specific treatment, namely dopaminergic drugs, scale conducted by the Parkinson’s Progression Markers Initiative
can be responsible for these symptoms. Therefore, in another (PPMI) group on 423 PD patients, reported no difference in
study the same group examined the frequency, development, and prevalence of excessive sleepiness in de novo untreated PD
associated covariates for different types of insomnia complaints in patients compared with healthy controls [47]. A 3-year follow-up
a cohort of originally drug-naive patients with incident PD during in this cohort showed that daytime sleepiness increases sig-
the first 5 years of treatment after diagnosis of PD. Overall, in this nificantly over time in early PD, with a dose-dependent effect of
study they found that the prevalence of insomnia did not increase dopaminergic therapy, suggesting a relevant role of PD-specific
at the 5-year follow-up in these early PD patients, but, after the therapy more than underlying pathophysiological mechanisms for
initiation of dopaminergic medication, disorders of sleep main- excessive daytime sleepiness in PD [48].
tenance significantly increased over time, whereas disorders of
sleep onset decreased [35]. Sleep-related breathing disorders
1234567890();,:

In a Dutch 5-year, longitudinal cohort study of 421 PD patients Early reports showed large variability of sleep-related breathing
who were examined annually, Marinus and co-workers used a disorders in PD, with some studies showing more central, others
prospective cohort design to evaluate frequency, course, long- more obstructive, or no sleep-related breathing disorder at all, but
itudinal associations, and risk factors of insomnia. Linear mixed in early studies these differences may have been due to less
models were used to identify factors associated with longitudinal established methods of respiratory event recording during
changes in the SCOPA sleep scales. Presence of insomnia (defined polysomnography (PSG) and small sample sizes.
as a nighttime sleep section of the SCOPA-SLEEP questionnaire Even in patients without a confirmed diagnosis of manifest
score ≥7) was reported at baseline in 27% of the total of 412 PD sleep apnea a significant correlation between heavy snoring and
patients evaluated, and insomnia symptoms developed at some daytime sleepiness has been reported for PD [1, 49]. One study
point during the annual follow-up examinations in an additional showed that manifest or subclinical sleep breathing disorders are
33% of patients who did not have insomnia at baseline (n = 302). present in up to 50% of PD patients, but in contrast to non-PD
Once again female sex was associated with higher SCOPA sleep patients sleep structure in PD is not normalized with CPAP
disturbance scores as were depressive symptoms, more severe treatment [50].
motor complications (dyskinesias and motor fluctuations), higher However, other studies have reported variable prevalence and
antiparkinsonian medication doses and sleep medication use. In severity of sleep-related breathing disorders in PD. Diederich and
addition there was an association with higher disability, higher colleagues reported a 43% prevalence of sleep apnea syndrome in
autonomic dysfunction, presence of hallucinations, and postural PD, which was, however, mostly mild or moderate with little
instability gait difficulty phenotype [36]. decline of the minimal or mean oxygen saturation levels
Joy and co-workers evaluated newly diagnosed levodopa-naïve compared to an apnea–hypopnea index (AHI)-matched control
patients with PD and reported frequent and variable alteration of group [51]. Arnulf and co-workers found sleep apnea (defined
sleep macro-architecture in these patients [37]. However, Ferreira according to established criteria for moderate or severe obstruc-
and co-workers reported poor sleep quality and sleep architecture tive sleep apnea) in 20% of 54 PD patients treated with levodopa
changes in PD patients, which improved with levodopa following or a combination of levodopa and dopamine agonists referred for
improvement of motor symptoms (reduction of rigidity and tremor), sleepiness [52]. In another study the same group reported that
but dopamine did not reverse sleep architecture changes [38]. sleep apnea in PD was less frequent than in controls, when this
In a very large epidemiological dataset comprising 220,934 latter group was BMI-matched with hospitalized controls (27% vs.
participants, Gao and colleagues evaluated daytime napping and 40%), and only 10% of PD patients had severe sleep apnea [53].
nighttime sleeping durations in subsets of patients with estab- Similarly, Trotti and Bliwise reported no increased risk of
lished PD (n = 267), recent diagnosis of PD (n = 396), and in those obstructive sleep apnea in PD compared to normative
who were in the prediagnostic PD stage (n = 770) and who only population-based data from the Sleep Heart Health Study. In this
later converted. They reported that longer daytime napping was cohort, Epworth Sleepiness Scales scores, BMI, and snoring did not
associated with higher odds of PD in all three clinical stages. correlate with the AHI [54].
This association was strongest for established PD (long nappers, Further adding to the complexity of sleep disturbances in PD,
i.e. ≥ 1 h, versus non-nappers OR 3.9; 95% CI: 2.8, 5.6; p < 0.0001) these patients spend more time in the supine position and the
but also significant in the other cases (recent cases OR 2.2; 95% presence of severe obstructive sleep apnea syndrome in PD is
CI: 1.7, 3.0; p < 0.0001; prediagnostic cases OR 1.5; 95% CI: 1.2, 1.9; associated with a major reduction in position changes [55].
p = 0.0003). However, in nighttime sleep duration analysis, a At least one study has shown that PD patients with obstructive
U-shaped relation between hours of nighttime sleep and sleep apnea have worse cognitive functioning on cognitive
diagnosis of PD was observed for established cases, but was less screening measures than those without, but again, CPAP-
apparent for recent cases and disappeared for prediagnostic treatment may not result in overall cognitive improvement in
cases. The authors therefore showed that daytime sleepiness—as patients with PD [56].
expressed by daytime napping duration, but not nighttime sleep Based on these data, there is some discussion about whether
duration—is one of the early nonmotor symptoms of PD [39]. obstructive sleep apnea is a problem in patients with PD,

Neuropsychopharmacology (2020) 45:121 – 128

 Sleep in Parkinson’s disease
A Stefani and B Högl
123
especially as common symptoms associated with sleep apnea, e.g. patients with PD and this aspect was recently reviewed by Högl
sleepiness, cognitive impairment, nocturia, and snoring have been and Stefani [72].
reported to not be related with AHI in PD patients [53, 54]. These In the past three decades, multiple studies have attempted to
observations lead to questions about whether sleep apnea is a evaluate the frequency of RLS in patients with PD producing very
cause of sleepiness in PD patients and when is it clinically relevant discrepant results ranging from 0% to 52.3% [12, 13, 72–76].
[53, 57]. These concerns highlight the importance of a detailed Together with these discrepancies, some authors noted early on
sleep history and the need to perform adequate sleep studies in that RLS diagnosis may be confounded in patients with PD due to
PD in order to account for all sleep disturbances. Nevertheless, potential overlap of RLS symptoms with early morning dystonia,
even symptoms commonly associated with sleep apnea may not akathisia, painful neuropathy, nocturnal hypokinesia (which may
relate to AHI in PD; PD patients with relevant sleep apnea should be associated with a reported urge to move), biphasic dyskinesia,
be treated as a general rule due to probable long-term negative and nocturnal legs cramps [12, 75, 76].
cardiovascular outcomes, although long-term comparative follow- Interestingly, augmentation of RLS is present very rarely in
up studies investigating cardiovascular outcomes in PD patients patients with PD, probably because of a different underlying
with treated and untreated sleep-related breathing disorders, are alteration in dopaminergic circuits in RLS (dopamine dysfunction)
lacking [57]. and PD (dopamine deficit), and different responses of these
altered circuits to dopamine/dopaminergic therapy.
Circadian disturbances Frequency and causes of RLS in PD are still unclear. Angelini and
Regulation of sleep and wakefulness is a highly complex and co-workers investigated a series of 109 cognitively unimpaired de
integrated function involving multiple brain areas and neuro- novo PD and compared them to age-matched and sex-matched
transmitters, many of which are impaired in PD [1–7]. Dopamine controls. They found that there was no significant difference in
for example plays a key role in the circadian system, but its overall lifetime and current primary RLS between PD patients and
metabolism and activity are also strongly influenced by the controls, but discussed whether the frequent onset of RLS
circadian clock [6]. On this pathophysiological background it is not symptoms after diagnosis of PD could be related to dopaminergic
surprising that disturbances of sleep and wakefulness are almost therapy for PD [77]. This hypothesis is supported by the reports
ubiquitous in patients with PD. Moreover, impairment of circadian that even in subjects with PLMS the use of dopaminergic agents
function in PD is relevant not only for sleep–wake cycles but also might lead to the development of RLS [78].
for motor, autonomic, cognitive, and psychiatric symptoms in PD Verbaan and co-workers evaluated the frequency and clinical
patients [6]. profile of RLS in 269 non-demented PD patients and also reported
Interestingly, some components of the circadian system seem a similar prevalence of RLS as in the general population [79].
to be preserved in PD. In a rat PD model with unilateral 6-hydroxy- Gjerstad and co-workers performed a study in 200 drug-naïve
dopamine lesions, it was shown that circadian distribution of patients with early, untreated PD and 173 age-matched and
motor activity is intact [58]. Circadian distribution of temperature gender-matched control subjects. They clearly reported that
rhythms is also maintained in PD, which is not the case in multiple there was a three-fold higher risk of leg motor restlessness, but
system atrophy (MSA) [59]. However, increased sleepiness under not of true RLS, in patients with early PD. 40.5% of PD patients
treatment with dopamine agonists may also relate to an effect on and 17.9% of controls reported leg restlessness (p < 0.001), but
body temperature (as described in 1999) [60, 61]. only 15.5% of patients with PD and 9.2% of controls met criteria
Despite these reports of preserved circadian distribution of for full RLS (p = 0.07) [80]. Similar results were also reported by
motor activity pattern and temperature, on a clinical basis another group in a large sample of PD patients [81]. These data
circadian disturbances are frequent in patients with PD highlight the need for an accurate assessment of symptoms
[6, 7, 10, 62], and were noted as early as 1817 by James Parkinson when suspecting RLS in PD patients in order to exclude potential
[63]. It was later shown that circadian melatonin secretion rhythms mimics.
are blunted in PD, and amplitude of melatonin rhythm is reduced Only Cochen De Cock and colleagues evaluated the suggested
[64]. These alterations in PD patients may also relate to both immobilization test (SIT) in PD and reported that it is useful for
insufficient exposure to bright light [65–67] and phase advance of making a diagnosis of RLS in patients with PD in whom the
the sleep–wake cycle due to treatment with dopaminergic drugs diagnosis of RLS based on expert interview alone may be difficult.
[68, 69]. Moreover, it is conceivable that impulse control disorders, The most sensitive instrument was the sensory part of the SIT that
such as gambling, compulsive shopping, binge eating, compulsive clearly showed an increase of sensory leg discomfort over time
sexual behavior, and punding, take place mainly during the [82]. The PLM index was increased in patients with primary RLS
nighttime or favor loosing track of time and therefore accompany compared to controls, but did not differ between patients with PD,
circadian disruption or contribute to precipitating and perpetuat- with and without RLS [82].
ing sleep–wake cycle disturbances. In clinical cases, this may lead Nocturnal akinesia, a well-known motor manifestation of PD,
to the inversion of the day- and nighttime rhythm, with insomnia significantly diminishes the capacity to make comfort moves and
after midnight and increased daytime sleepiness [70]. can lead to sleep disruption [12]. Moreover, patients may report an
Interestingly, in a large case control study of Han Chinese urge to move due to nocturnal akinesia/hypokinesia. Lakke
patients, an association of single nucleotide polymorphisms in the and colleagues have shown that axial rotation is even more
clock genes ARNTL and PER1 was found in patients with PD, thus disturbed in the recumbent position than while standing, which
supporting the notion that genetic polymorphisms are present in may lead to increase of symptoms due to hypokinesia at rest or
these two circadian regulation genes [71]. during the night, mimicking RLS symptoms [83].
Published evidence highlights the complexity and multifactorial Impaired turning ability in bed has been associated with sleep
nature of circadian rhythm disturbances in PD, which implies that disturbances [84]. Louter and co-workers evaluated a PD cohort
an accurate clinical and instrumental (using e.g. actigraphy and prospectively and found that patients who subjectively reported
polysomnography) evaluation is needed in these patients to impaired bed mobility (i.e., nocturnal hypokinesia), indeed showed
identify the main cause or main problem in sleep–wake cycle fewer sleep-related body position changes than controls, and that
impairment and provide individualized treatment. polysomnographically evaluated sleep efficiency was diminished
in these patients [85]. This should be taken into account when
Sleep-related movement disorders treating motor symptoms in PD patients, as a study from Thailand
Among sleep-related movement disorders, RLS and periodic leg has shown that in PD patients with nocturnal hypokinesia/
movements of sleep (PLMS) have been particularly investigated in akinesia, nighttime apomorphine infusion improves the number of

Neuropsychopharmacology (2020) 45:121 – 128

 Sleep in Parkinson’s disease
A Stefani and B Högl
124
turns in bed, turning velocity, and the extension of turning as demonstrated that they could represent another prodromal sign
measured by actigraphy [86]. of RBD [100, 108].
Dream content was investigated in PD as early as 1992 [110].
RBD and other parasomnias Later on, Borek and colleagues investigated dream content in PD
In patients with PD, beyond the well-known and peculiar with and without RBD, showing that violent and aggressive
occurrence of REM sleep behavior disorder (RBD), non-REM-sleep dreams were more common in RBD patients, and that men with
parasomnias (e.g. sleepwalking) and parasomnia overlap disorder PD had more aggressive dreams than women with PD [111]. The
have also been described. same group further evaluated aggressive dream content in men
Bassetti and co-workers systematically investigated the pre- with PD and searched for a correlation with testosterone levels,
sence of sleepwalking in 165 consecutive PD patients. 3.6% (n = 6) which was not found [112].
reported adult-onset sleepwalking. In 4 out of 6 patients, RBD was Bugalho and Paiva characterized dream content in PD in detail
detected on video-polysomnography [87]. In another study, video- using the Hall and van de Castle system. They found more dreams
polysomnography (vPSG) was used to assess 30 patients with PD with animals, aggression/friendliness, physical aggression, befrien-
(10 of them with a history of sleepwalking, 10 with a history of der in PD compared to controls, and less aggressor and bodily
RBD and 10 without a history of parasomnia). Again, 8 out of 10 misfortunes features [113]. Valli and colleagues further analyzed
patients with a history of sleepwalking presented RBD on vPSG. dreams in patients with PD and RBD systematically, using
Sleepwalking in this cohort was associated with depression, higher spontaneous free-worded dream reports and a structured dream
disease severity, and functional disability. Due to the frequent questionnaire during vPSG. Those data could be linked to motor
occurrence of overlap parasomnia, the authors suggested that a behaviors on vPSG above chance level [114]. Interestingly, another
common underlying disturbance of motor control during sleep study by the same group assessed dream content analysis in PD
exists in PD [88]. with and without RBD and reported no major differences between
The diagnostic criteria for RBD comprise repeated episodes of these two groups regarding action-filledness, vividness, or threat
sleep-related vocalization and/or complex motor behaviors, and content. However, negative dreams were more frequent in PD
these behaviors need to be documented by PSG as occurring with RBD compared to PD without RBD [115].
during REM sleep, or, based on a clinical history of dreaming, are Dream content has also been investigated in the prodromal
presumed to occur during REM sleep. In addition, it is obligatory phase of RBD. Most patients with RBE can recall dream content,
that polysomnographic recording demonstrates REM sleep with- and report nonviolent, non-threatening dreams. RBE subjects who
out atonia [89]. Other sleep-related movement disorders that are at follow-up developed RBD reported more vivid and elaborate
frequent in PD (e.g. PLMS, sleep apnea) might produce similar dreams [109].
symptoms mimicking RBD by history and need to be excluded.
RBD affects up to 47% of patients with PD [90–93]. In the past Sleep benefit and positive effect of sleep deprivation in patients
RBD has received much attention due to the fact that it may with PD
precede PD by more than a decade [93–99], but there is also the The complex interaction of sleep and motor function is reflected
possibility that RBD onset is more or less simultaneous with PD in two interesting phenomena: sleep benefit, i.e. the experience of
onset or that RBD follows PD onset by several years [91, 100]. an improvement of motor function upon awakening [15–19], and
In fact, the remarkably high rate of conversion from isolated a positive effect of sleep deprivation on motor function [20–22].
RBD into alpha synuclein disease, namely PD, dementia with Lewy Sleep benefit was first described based on patients’ reports, and
bodies, or rarely MSA, has led several authors to suggest here that systematically evaluated in large cohorts of patients with PD with
RBD itself needs to be considered more than a REM-parasomnia, contrasting results. Some groups reported this phenomenon to be
as it represents an alpha synuclein disease or an early manifesta- common in a subgroup of PD patients with specific clinical
tion of alpha synuclein disease [94, 97, 101]. For clinical studies, characteristics, e.g. with longer disease duration [17] and younger
combinations of isolated RBD with other Parkinson/alpha-synu- age at onset of disease [19, 116]. This phenomenon has been
clein-related neurodegeneration risk markers is probably the most reported to be so relevant to allow PD patients with sleep benefit
useful approach. Multiple biomarkers of alpha synuclein-related to skip or delay medication [18]. A study systematic evaluating
neurodegeneration have been described [93], and may serve to motor state a night before sleep and in the morning upon
evaluate different aspects of neurodegeneration, and while some, awakening reported a slight motor improvement in the morning
such as olfactory dysfunction, are stable markers indicating a in patients with sleep benefit, without polysomnographic
higher risk of short-term conversion, others such as DAT-SPECT are differences between the two groups [15]. Another study using
progressive markers useful for monitoring disease progression PSG reported shorter total sleep times and longer sleep latencies
over time [93]. in PD patients reporting sleep benefit [117].
The International Parkinson and Movement Disorder Society has However, other groups found no actual improvement in motor
calculated that the PSG-confirmed likelihood ratio of more than functioning in PD patients reporting sleep benefit [118, 119], or
80% probability of suffering of prodromal PD is 130 in patients only in a small percentage of them [120, 121], or reported in those
with isolated (previously called “idiopathic“) RBD [102]. However, patients with PD experiencing sleep benefit no association with
this is true and has been extensively confirmed only for vPSG the previously reported clinical variables [122], maybe because of
confirmed RBD. In fact, likelihood ratio declines to 2.3 in case of methodological issues.
positive response to a screening test for RBD with documented Interestingly, in patients with PD it has also been described, for
specificity of 80–99% [102]. These is even more relevant the first time as early as 1987 [22], a motor improvement after
considering that an increasing amount of studies reported lower sleep deprivation. These observations have been later on
specificity of validated questionnaires for RBD outside the context replicated [20], but could not be confirmed in a controlled study.
of validation studies [103–107]. These latter results suggested that only a subgroup of PD patients
Interestingly, there is increasing evidence that there may be could benefit from partial sleep deprivation [21].
prodromal stages of RBD, which manifest as minor jerks
[91, 100, 108, 109] or REM sleep without atonia [101]. Mollenhauer Assessment of sleep disturbances in patients with PD
and co-workers found that even PD patients who did not yet meet In general, a comprehensive sleep history is often a very useful
the criteria for RBD had more movement during REM sleep [91], first step to narrow down the type of sleep disorders in patients
and Sixel-Döring and Trenkwalder denominated these seemingly with PD. It should start with the time when the patient goes to
purposeful movements “REM sleep behavioral events” (RBE) and bed and gets up and also include planned daytime naps. It should

Neuropsychopharmacology (2020) 45:121 – 128

 Sleep in Parkinson’s disease
A Stefani and B Högl
125
involve the perceived sleep latency, perceived awakenings However, in the evaluation of patients with abnormal daytime
(including prolonged wake phases during the nighttime and sleepiness, and with suspected RBD, vPSG evaluation is indis-
daytime dosing of/or fighting against sleepiness). The Epworth pensable. Also, if there is some treatment-refractory sleep
sleepiness scale or other scales can be used [123]. disturbance, or if one suspects multiple contributors and
Specifically, the evaluation of insomnia should rule out sleep comorbid sleep disorders, vPSG will help to narrow down the
hygiene or circadian disorders. Patients should be questioned differential diagnostic possibilities.
specifically about the presence of impulse control disorders and Due to the multifactorial aspects of sleep disorders in patients
nighttime activities, particularly in case of suspected circadian with PD, vPSG will often provide much more detailed, objective,
rhythm disturbances. If a circadian disorder, such as delayed or and quantifiable information about the underlying aspects of
advanced sleep phase syndrome or non-24-h sleep–wake disorder the sleep disorder in an individual patient, and at the same time
is suspected, assessments with actigraphy or dim light melatonin provide information about sleep integrity or fragmentation, the
onset may prove useful [124]. number of arousals or awakenings, the total sleep efficiency,
For patients with prominent daytime sleepiness, polysomno- respiration during sleep and respiratory events, and the quanti-
graphy should be used in every case (to rule out sleep disordered fication of motor activity during sleep, ranging from REM sleep
breathing), but a multiple sleep latency test (for instance to without atonia (RWA)/RBD to PLM, fragmentary myoclonus
demonstrate a narcolepsy-like phenotype and to quantify the [72, 134] and others. vPSG in patients with PD should in every
amount of daytime sleepiness) is also warranted [124]. case include not only the usual EMG channels of mental/
Respiration questioning should at least include snoring and submental muscles and tibial anterior muscles, but also of upper
witness apneas, positional dependence, breathing pauses, inten- extremity muscles (flexor digitorum superficialis from both arms).
sity of snoring, nocturnal hypertranspiration or nocturia. In specific This is not only recommended based on normative values
cases stridor (which is for patients relatively difficult to distinguish provided by the SINBAR group [135] but also provides more
from simple snoring) should also be assessed. If underlying sleep sensitivity and specificity than using EMG alone [136].
disordered breathing is suspected, cardiorespiratory polygraphy
or polysomnography should be performed [124]. Treatment of sleep disorders in patients with Parkinson’s disease
Every attempt should be made to assess the presence of RLS, From the manifold clinical manifestations and underlying
and distinguish it from other types of restlessness, specifically pathomechanisms of sleep disorders in patients with PD outlined
investigating possible mimics or confounders. Patients should be above, it is obvious that treatment needs to be tailored
asked about the ability to turn in bed. Polysomnography is not individually according to the predominant clinical symptomatol-
needed to make a diagnosis of RLS, and in patients with PD PLM ogy and underlying specific sleep-related diagnosis. However, a
are very frequent [72, 125]. In case of suspected RLS, an extensive major problem is the sparsity of randomized, controlled trials for
clinical history is fundamental to rule out possible mimics which sleep disorders in PD.
are very common in PD patients, these include nocturnal For treatment of insomnia in patients with PD, hypnotics are
hypokinesia/akinesia (sometimes associated with an urge to sometimes indicated, but the caveats of potential worsening of
move), akathisia, nocturnal leg cramps, early morning dystonia, daytime sleepiness or sleep-related breathing disorders should be
and painful neuropathy. In addition, medication-induced dyskine- kept in mind. Clinically, quetiapine is sometimes used, and in cases
sias could be mistaken for RLS-related PLM. of very severe insomnia clozapine—with the usual treatment
For patients with suspected RBD, vPSG is required, also if the caveats—have been used. Melatonin treatment is not specifically
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition indicated for insomnia in PD, but is often used for RBD (see
(DSM-5) [126], in contrast to the ICSD-3 [33], does not require below). Rotigotine has been reported to improve sleep quality and
polysomnographic demonstration of REM sleep without atonia if continuity in PD patients by promoting sleep stability and
there is a history suggestive of RBD in patients with an established increasing REM [137]. However, in general, there is insufficient
synucleinopathy diagnosis. However, it is likely that performance evidence on drugs to treat insomnia in PD patients, although
of vPSG would diagnose more patients with RBD, in whom history eszoplicone and melatonin are considered “possibly useful”. Some
taking alone was not sensitive [93, 127, 128] or also rule out authors maintain that cognitive behavioral treatment for insom-
mimics in subjects with an apparently “clear” history of RBD, such nia, as in patients without PD, may be useful [138]. To treat
as obstructive sleep apnea which may go along with violent daytime sleepiness in PD, caffeine [139, 140], and modafinil can
behavioral releases [129] and violent PLM [130]. be used.
Patients should be specifically investigated for altered dream Regarding treatment of sleep-related breathing disorders, there
content, dream enactment with movements or jerks, and is some controversy. If sleep apnea is moderate or severe, positive
vocalizations, specifically highly variable vocalizations for RBD airway pressure therapy for PD patients can be indicated [141].
[124]. In general, current treatment should be assessed due to However, the response to this treatment regarding improvement
potential side effects or influence on sleep disorders. of sleep structure or daytime sleepiness is less clear than in
Several questionnaires have been developed and validated for patients without PD [50]. Motor impairment often makes handling
patients with PD [123]. The International Movement Disorder of the CPAP device difficult for patients with PD. Intraoral devices
Society (MDS) task force recommends, for overall sleep distur- as an alternative treatment for certain patients with obstructive
bance, both the Parkinson’s Disease Sleep Scale (PDSS) [131] and sleep apnea may also be limited in those with abnormal salivation
Scales for Outcomes in PD Sleep (SCOPA sleep), as well as two or oro-facial dyskinesias.
generic scales, namely the Pittsburgh Sleep Quality Index (PSQI) For treatment of circadian disorders, light therapy shows
and the Epworth Sleepiness Scale [123, 132]. promising outcomes on sleep and alertness in PD, with beneficial
Specific questionnaires for specific sleep disorders, such as for effects on sleep, mood, and other non-motor symptoms in PD
RBD, have also been developed [93]. In general, they have the [66, 142–144].
advantage of being used to screen the general population or As prospective treatment studies for RLS co-existing with PD are
large samples of study populations without performing a vPSG. missing, most commonly used medications in the PD population
However, they cannot usually be used as diagnostic instruments are the same as in the general RLS population, namely dopamine
and e.g. for RBD questionnaires several limitations have agonists, calcium channel alpha-2-delta ligands, clonazepam, and
been demonstrated [93, 103–107, 127]. Actigraphy is also opioids [145–147]. As dopamine agonists and levodopa are
useful as a first screening method to potentially indicate already used to treat motor symptoms in PD, adjustments in
suspected RBD [133]. timing of intake depending on time of appearance of RLS

Neuropsychopharmacology (2020) 45:121 – 128

 Sleep in Parkinson’s disease
A Stefani and B Högl
126
symptoms may be beneficial. Iron supplementation should be 9. Poewe W, Hogl B. Parkinson’s disease and sleep. Curr Opin Neurol.
considered if ferritin levels are low [148]. Medication known to 2000;13:423–6.
exacerbate RLS (e.g. dopamine blockers, anti-cholinergic, and anti- 10. Chahine LM, Amara AW, Videnovic A. A systematic review of the literature on
histaminic agents) should be discontinued if possible. disorders of sleep and wakefulness in Parkinson’s disease from 2005 to 2015.
Sleep Med Rev. 2017;35:33–50.
Treatment of REM sleep behavior disorder should first include
11. Videnovic A, Comella CL. Sleep disorders in Parkinson’s disease. Handb Clin
safety measures to ensure maximum safety in the sleeping Neurol. 2011;99:997–1010.
environment. Such measures may include removing any objects 12. Poewe W, Högl B. Akathisia, restless legs and periodic limb movements in sleep
close to the bed that may cause injuries during dream enactment, in Parkinson’s disease. Neurology. 2004;63:S12–6.
or making adjustments by moving furniture or using pillows to 13. Peralta CM, Frauscher B, Seppi K, et al. Restless legs syndrome in Parkinson’s
cover furniture, walls, and the floor. Bed partners should be disease. Mov Disord. 2009;24:2076–80.
advised to sleep separately. Medications which potentially 14. Oertel W, Deuschl G, Poewe W. Parkinson-Syndrome und andere Bewegungs-
aggravate RBD (e.g. antidepressants) should be eliminated if störungen. Germany: Thieme Georg Verlag; 2011.
possible [149]. A bed alarm has been shown to be beneficial for 15. Hogl BE, Gomez-Arevalo G, Garcia S, et al. A clinical, pharmacologic, and poly-
somnographic study of sleep benefit in Parkinson’s disease. Neurology.
RBD in preliminary studies [150]. Rotigotine was also shown to
1998;50:1332–9.
improve RBD in a vPSG study [151]. A double-blind, crossover pilot 16. Hogl B, Gershanik O. Sleep benefit in Parkinson’s disease. J Neurol Neurosurg
trial in 12 patients reported a reduction in frequency of RBD Psychiatry. 2000;68:798–9.
episodes (as reported by diaries of bed partners) with rivastigmine 17. Tandberg E, Larsen JP, Karlsen K. Excessive daytime sleepiness and sleep benefit
[152]. Effective pharmacological treatment based on case reports in Parkinson’s disease: a community-based study. Mov Disord. 1999;14:922–7.
and series include clonazepam and melatonin, but double-blind, 18. Merello M, Hughes A, Colosimo C, Hoffman M, Starkstein S, Leiguarda R. Sleep
placebo-controlled trials are missing [93, 142, 147]. benefit in Parkinson’s disease. Mov Disord. 1997;12:506–8.
19. Currie LJ, Bennett JP Jr, Harrison MB, Trugman JM, Wooten GF. Clinical correlates
of sleep benefit in Parkinson’s disease. Neurology. 1997;48:1115–7.
20. Reist C, Sokolski KN, Chen CC, Coskinas E, Demet EM. The effect of sleep
FUTURE RESEARCH DIRECTIONS
deprivation on motor impairment and retinal adaptation in Parkinson’s disease.
Sleep and regulation of sleep and wakefulness are relevant Prog Neuro-Psychopharmacol Biol Psychiatry. 1995;19:445–54.
aspects in patients with Parkinson’s disease. Disorders of sleep and 21. Hogl B, Peralta C, Wetter TC, Gershanik O, Trenkwalder C. Effect of sleep
wakefulness in Parkinson’s disease are often reported, and deprivation on motor performance in patients with Parkinson’s disease. Mov
comprise the full spectrum of sleep disorder categories. However, Disord. 2001;16:616–21.
for most of them there are discordant data in the literature and 22. Bertolucci PH, Andrade LA, Lima JG, Carlini EA. Total sleep deprivation and
treatment studies specifically conducted on patients with Parkinson disease. Arq Neuro-Psiquiatr. 1987;45:224–30.
Parkinson’s disease are mostly missing. Therefore, these aspects 23. Pont-Sunyer C, Iranzo A, Gaig C, et al. Sleep disorders in Parkinsonian and
should be further clarified in future studies. Specifically, open nonParkinsonian LRRK2 mutation carriers. PLoS ONE. 2015;10:e0132368.
24. O’Dowd S, Galna B, Morris R, et al. Poor sleep quality and progression of gait
issues with discordant data such as relevance of restless legs
impairment in an incident Parkinson’s disease cohort. J Parkinson’s Dis.
syndrome and sleep apnea in Parkinson’s disease should be 2017;7:465–70.
disentangled. Moreover, disturbances of circadian rhythm are very 25. Emser W, Brenner M, Stober T, Schimrigk K. Changes in nocturnal sleep in
relevant in those patients and deserve more attention and Huntington’s and Parkinson’s disease. J Neurol. 1988;235:177–9.
investigations as their recognition and treatment might relevantly 26. Myslobodsky M, Mintz M, Ben-Mayor V, Radwan H. Unilateral dopamine deficit
improve quality of life of patients with Parkinson’s disease. Other and lateral eeg asymmetry: sleep abnormalities in hemi-Parkinson’s patients.
less understood aspects like sleep benefit and effect of sleep Electroencephalogr Clin Neurophysiol. 1982;54:227–31.
deprivation need to be further investigated. 27. Comella CL, Tanner CM, Ristanovic RK. Polysomnographic sleep measures in
Parkinson’s disease patients with treatment-induced hallucinations. Ann Neurol.
1993;34:710–4.
28. Puca FM, Bricolo A, Turella G. Effect of L-dopa or amantadine therapy on sleep
FUNDING AND DISCLOSURE spindles in Parkinsonism. Electroencephalogr Clin Neurophysiol.
The authors declare no competing interests. 1973;35:327–30.
29. Christensen JA, Nikolic M, Warby SC, et al. Sleep spindle alterations in patients
with Parkinson’s disease. Front Hum Neurosci. 2015;9:233.
ADDITIONAL INFORMATION 30. Kendel K, Saprianov G, Graf B. Wach-EEG und Schlaf-EEG beim Parkinson-
Syndrom. Akt Neurol. 1974;1:125–36.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims 31. Happe S, Anderer P, Pirker W, et al. Sleep microstructure and neurodegeneration
in published maps and institutional affiliations. as measured by [123I]beta-CIT SPECT in treated patients with Parkinson’s dis-
ease. J Neurol. 2004;251:1465–71.
32. Brunner H, Wetter TC, Hogl B, Yassouridis A, Trenkwalder C, Friess E. Micro-
REFERENCES structure of the non-rapid eye movement sleep electroencephalogram in
1. Hogl B, Seppi K, Brandauer E, et al. Increased daytime sleepiness in Parkinson’s patients with newly diagnosed Parkinson’s disease: effects of dopaminergic
disease: a questionnaire survey. Mov Disord. 2003;18:319–23. treatment. Mov Disord. 2002;17:928–33.
2. Trenkwalder C, Hogl B. Sleep in Parkinson syndromes. Handb Clin Neurol. 33. American Academy of Sleep Medicine. The international classification of sleep
2007;83:365–76. disorders: diagnostic & coding manual (ICSD-3). 3rd ed. Westchester, IL: Amer-
3. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. ican Academy of Sleep Medicine; 2014.
Nat Rev Neurosci. 2017;18:435–50. 34. Gjerstad MD, Wentzel-Larsen T, Aarsland D, Larsen JP. Insomnia in Parkinson’s
4. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: frequency and progression over time. J Neurol Neurosurg Psychiatry.
disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009; 2007;78:476–9.
8:464–74. 35. Tholfsen LK, Larsen JP, Schulz J, Tysnes OB, Gjerstad MD. Changes in insomnia
5. Freeman AAH. Neurochemistry of the sleep–wake cycle in Parkinson’s disease. subtypes in early Parkinson disease. Neurology. 2017;88:352–8.
In: Videnovic A, Högl B, editors. Disorders of sleep and circadian rhythms in 36. Zhu K, van Hilten JJ, Marinus J. The course of insomnia in Parkinson’s disease.
Parkinson’s disease. Vienna: Springer Vienna; 2015. p. 19–33. Parkinson Relat Disord. 2016;33:51–7.
6. Videnovic A, Lazar AS, Barker RA, Overeem S. ‘The clocks that time us’—circa- 37. Joy SP, Sinha S, Pal PK, Panda S, Philip M, Taly AB. Alterations in polysomno-
dian rhythms in neurodegenerative disorders. Nat Rev Neurol. 2014;10:683–93. graphic (PSG) profile in drug-naive Parkinson’s disease. Ann Indian Acad Neurol.
7. Videnovic A, Golombek D. Circadian and sleep disorders in Parkinson’s disease. 2014;17:287–91.
Exp Neurol. 2013;243:45–56. 38. Ferreira T, Prabhakar S, Kharbanda PS. Sleep disturbances in drug naive Par-
8. Lees AJ, Blackburn NA, Campbell VL. The nighttime problems of Parkinson’s kinson’s disease (PD) patients and effect of levodopa on sleep. Ann Indian Acad
disease. Clin Neuropharmacol. 1988;11:512–9. Neurol. 2014;17:416–9.

Neuropsychopharmacology (2020) 45:121 – 128

 Sleep in Parkinson’s disease
A Stefani and B Högl
127
39. Gao J, Huang X, Park Y, et al. Daytime napping, nighttime sleeping, and Par- 70. Djamshidian A, Poewe W, Hogl B. Impact of impulse control disorders on
kinson disease. Am J Epidemiol. 2011;173:1032–8. sleep–wake regulation in Parkinson’s disease. Parkinson’s Dis. 2015;2015:970862
40. Tandberg E, Larsen JP, Karlsen K. A community-based study of sleep disorders in 71. Gu Z, Wang B, Zhang YB, et al. Association of ARNTL and PER1 genes with
patients with Parkinson’s disease. Mov Disord. 1998;13:895–9. Parkinson’s disease: a case-control study of Han Chinese. Sci Rep. 2015;5:15891.
41. Factor SA, McAlarney T, Sanchez-Ramos JR, Weiner WJ. Sleep disorders and 72. Hogl B, Stefani A. Restless legs syndrome and periodic leg movements in
sleep effect in Parkinson’s disease. Mov Disord. 1990;5:280–5. patients with movement disorders: specific considerations. Mov Disord.
42. Frucht S, Rogers JD, Greene PE, Gordon MF, Fahn S. Falling asleep at the wheel: 2017;32:669–81.
motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology. 73. Nomura T, Inoue Y, Miyake M, Yasui K, Nakashima K. Prevalence and clinical
1999;52:1908–10. characteristics of restless legs syndrome in Japanese patients with Parkinson’s
43. Hauser RA, Gauger L, Anderson WM, Zesiewicz TA. Pramipexole-induced som- disease. Mov Disord. 2006;21:380–4.
nolence and episodes of daytime sleep. Mov Disord. 2000;15:658–63. 74. Nomura T, Inoue Y, Nakashima K. Clinical characteristics of restless legs syn-
44. Zesiewicz TA, Cimino CR, Malek AR, et al. Driving safety in Parkinson’s disease. drome in patients with Parkinson’s disease. J Neurol Sci. 2006;250:39–44.
Neurology. 2002;59:1787–8. 75. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between Parkinson
45. Ylikoski A, Martikainen K, Sarkanen T, Partinen M. Parkinson’s disease and disease and restless legs syndrome. Arch Neurol. 2002;59:421–4.
narcolepsy-like symptoms. Sleep Med. 2015;16:540–4. 76. Iranzo A, Comella CL, Santamaria J, Oertel W. Restless legs syndrome in Par-
46. Monaca C, Duhamel A, Jacquesson JM, et al. Vigilance troubles in Parkinson’s kinson’s disease and other neurodegenerative diseases of the central nervous
disease: a subjective and objective polysomnographic study. Sleep Med. system. Mov Disord. 2007;22(Suppl 18):S424–30.
2006;7:448–53. 77. Angelini M, Negrotti A, Marchesi E, Bonavina G, Calzetti S. A study of the pre-
47. Simuni T, Caspell-Garcia C, Coffey C, et al. Correlates of excessive daytime valence of restless legs syndrome in previously untreated Parkinson’s disease
sleepiness in de novo Parkinson’s disease: a case control study. Mov Disord. patients: absence of co-morbid association. J Neurol Sci. 2011;310:286–8.
2015;30:1371–81. 78. Santamaria J, Iranzo A, Tolosa E. Development of restless legs syndrome after
48. Amara AW, Chahine LM, Caspell-Garcia C, et al. Longitudinal assessment of dopaminergic treatment in a patient with periodic leg movements in sleep.
excessive daytime sleepiness in early Parkinson’s disease. J Neurol Neurosurg Sleep Med. 2003;4:153–5.
Psychiatry. 2017;88:653–62. 79. Verbaan D, van Rooden SM, van Hilten JJ, Rijsman RM. Prevalence and clinical
49. Braga-Neto P, da Silva-Junior FP, Sueli Monte F, de Bruin PF, de Bruin VM. profile of restless legs syndrome in Parkinson’s disease. Mov Disord.
Snoring and excessive daytime sleepiness in Parkinson’s disease. J Neurol Sci. 2010;25:2142–7.
2004;217:41–5. 80. Gjerstad MD, Tysnes OB, Larsen JP. Increased risk of leg motor restlessness but
50. Schäfer D. Schlafbezogene Atmungsstörungen bei Parkinsonsyndromen: Häu- not RLS in early Parkinson disease. Neurology. 2011;77:1941–6.
figkeit. Art Behandlätze. 2001;5:103–14. 81. Suzuki K, Okuma Y, Uchiyama T, et al. Characterizing restless legs syndrome and
51. Diederich NJ, Vaillant M, Leischen M, et al. Sleep apnea syndrome in Parkinson’s leg motor restlessness in patients with Parkinson’s disease: a multicenter case-
disease. A case-control study in 49 patients. Mov Disord. 2005;20:1413–8. controlled study. Parkinsonism Relat Disord. 2017;44:18–22.
52. Arnulf I, Konofal E, Merino-Andreu M, et al. Parkinson’s disease and sleepiness: 82. De Cock VC, Bayard S, Yu H, et al. Suggested immobilization test for diagnosis of
an integral part of PD. Neurology. 2002;58:1019–24. restless legs syndrome in Parkinson’s disease. Mov Disord. 2012;27:743–9.
53. Cochen De Cock V, Abouda M, Leu S, et al. Is obstructive sleep apnea a problem 83. Lakke JP, van Weerden TW, Staal-Schreinemachers A. Axial apraxia, a distinct
in Parkinson’s disease? Sleep Med. 2010;11:247–52. phenomenon. Clin Neurol Neurosurg. 1984;86:291–4.
54. Trotti LM, Bliwise DL. No increased risk of obstructive sleep apnea in Parkinson’s 84. Stack EL, Ashburn AM. Impaired bed mobility and disordered sleep in Parkin-
disease. Mov Disord. 2010;25:2246–9. son’s disease. Mov Disord. 2006;21:1340–2.
55. Cochen De Cock V, Benard-Serre N, Driss V, et al. Supine sleep and obstructive 85. Louter M, van Sloun RJ, Pevernagie DA, et al. Subjectively impaired bed mobility
sleep apnea syndrome in Parkinson’s disease. Sleep Med. 2015;16:1497–501. in Parkinson disease affects sleep efficiency. Sleep Med. 2013;14:668–74.
56. Harmell AL, Neikrug AB, Palmer BW, et al. Obstructive sleep apnea and cognition 86. Bhidayasiri R, Sringean J, Anan C, Boonpang K, Thanawattano C, Ray Chaudhuri
in Parkinson’s disease. Sleep Med. 2016;21:28–34. K. Quantitative demonstration of the efficacy of night-time apomorphine infu-
57. Hogl B. Sleep apnea in Parkinson’s disease: when is it significant? Sleep Med. sion to treat nocturnal hypokinesia in Parkinson’s disease using wearable sen-
2010;11:233–5. sors. Parkinsonism Relat Disord. 2016;33(Suppl 1):S36–s41.
58. Baier PC, Branisa P, Koch R, Schindehutte J, Paulus W, Trenkwalder C. Circadian 87. Poryazova R, Waldvogel D, Bassetti CL. Sleepwalking in patients with Parkinson
distribution of motor-activity in unilaterally 6-hydroxy-dopamine lesioned rats. disease. Arch Neurol. 2007;64:1524–7.
Exp Brain Res. 2006;169:283–8. 88. Di Fabio N, Poryazova R, Oberholzer M, Baumann CR, Bassetti CL. Sleepwalking,
59. Pierangeli G, Provini F, Maltoni P, et al. Nocturnal body core temperature falls in REM sleep behaviour disorder and overlap parasomnia in patients with Par-
Parkinson’s disease but not in multiple-system atrophy. Mov Disord. kinson’s disease. Eur Neurol. 2013;70:297–303.
2001;16:226–32. 89. American Academy of Sleep Medicine. The international classification of sleep
60. Boulay D, Depoortere R, Rostene W, Perrault G, Sanger DJ. Dopamine D3 disorders: diagnostic and coding manual. 3rd ed. Rev. ed. Darien, IL: American
receptor agonists produce similar decreases in body temperature and loco- Academy of Sleep Medicine; 2014.
motor activity in D3 knock-out and wild-type mice. Neuropharmacology. 90. Wetter TC, Trenkwalder C, Gershanik O, Högl B. Polysomnographic measures in
1999;38:555–65. Parkinson’s disease: a comparison between patients with and without REM
61. Boulay D, Depoortere R, Perrault G, Borrelli E, Sanger DJ. Dopamine D2 sleep disturbances. Wien Klin Wochenschr. 2001;113:249–53.
receptor knock-out mice are insensitive to the hypolocomotor and hypothermic 91. Mollenhauer B, Trautmann E, Sixel-Doring F, et al. Nonmotor and diagnostic
effects of dopamine D2/D3 receptor agonists. Neuropharmacology. findings in subjects with de novo Parkinson disease of the DeNoPa cohort.
1999;38:1389–96. Neurology. 2013;81:1226–34.
62. Videnovic A, Willis GL. Circadian system—a novel diagnostic and therapeutic 92. Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE. Association of REM sleep
target in Parkinson’s disease? Mov Disord. 2016;31:260–9. behavior disorder and neurodegenerative disease may reflect an underlying
63. Parkinson J. An essay on the shaking palsy. London: Whittingham and Rowland; synucleinopathy. Mov Disord. 2001;16:622–30.
1817. 93. Hogl B, Stefani A, Videnovic A. Idiopathic REM sleep behaviour disorder and
64. Videnovic A, Noble C, Reid KJ, et al. Circadian melatonin rhythm and excessive neurodegeneration—an update. Nat Rev Neurol. 2018;14:40–55.
daytime sleepiness in Parkinson disease. JAMA Neurol. 2014;71:463–9. 94. Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian
65. Martin JL, Ancoli-Israel S. Sleep disturbances in long-term care. Clin Geriatr Med. disorder or dementia in 81% of older men initially diagnosed with idiopathic
2008;24:39–50. rapid eye movement sleep behavior disorder: a 16-year update on a previously
66. Videnovic A, Klerman EB, Wang W, Marconi A, Kuhta T, Zee PC. Timed light reported series. Sleep Med. 2013;14:744–8.
therapy for sleep and daytime sleepiness associated with Parkinson disease: a 95. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian
randomized clinical trial. JAMA Neurol. 2017;74:411–8. disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye
67. Hogl B. Circadian rhythms and chronotherapeutics—underappreciated movement sleep behaviour disorder. Neurology. 1996;46:388–93.
approach to improving sleep and wakefulness in Parkinson disease. JAMA 96. Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Mon-
Neurol. 2017;74:387–8. tplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM
68. Garcia-Borreguero D, Larrosa O, Bravo M. Parkinson’s disease and sleep. Sleep sleep behavior disorder. Neurology. 2009;72:1296–300.
Med Rev. 2003;7:115–29. 97. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep beha-
69. Garcia-Borreguero D, Serrano C, Larrosa O, Granizo JJ. Circadian effects of viour disorder as an early marker for a neurodegenerative disorder: a descriptive
dopaminergic treatment in restless legs syndrome. Sleep Med. 2004;5:413–20. study. Lancet Neurol. 2006;5:572–7.

Neuropsychopharmacology (2020) 45:121 – 128

 Sleep in Parkinson’s disease
A Stefani and B Högl
128
98. Iranzo A, Tolosa E, Gelpi E, et al. Neurodegenerative disease status and post- 126. American Psychiatric Association. Diagnostic and statistical manual of mental
mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: disorders: DSM-5. 5th ed. American Psychiatric Association; 2013.
an observational cohort study. Lancet Neurol. 2013;12:443–53. 127. Stefani A, Frauscher B, Högl B. Diagnosis of REM sleep behavior disorder. In:
99. Galbiati A, Verga L, Giora E, Zucconi M, Ferini-Strambi L. The risk of neurode- Schenck CH, Högl B, Videnovic A, editors. Rapid-eye-movement sleep behavior
generation in REM sleep behavior disorder: a systematic review and meta- disorder. Springer; 2019.
analysis of longitudinal studies. Sleep Med Rev. 2019;43:37–46. 128. Fernandez-Arcos A, Iranzo A, Serradell M, Gaig C, Santamaria J. The clinical
100. Sixel-Doring F, Zimmermann J, Wegener A, Mollenhauer B, Trenkwalder C. The phenotype of idiopathic rapid eye movement sleep behavior disorder at pre-
evolution of REM sleep behavior disorder in early Parkinson disease. Sleep. sentation: a study in 203 consecutive patients. Sleep. 2016;39:121–32.
2016;39:1737–42. 129. Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea mimicking
101. Stefani A, Gabelia D, Hogl B, et al. Long-term follow-up investigation of isolated REM sleep behavior disorder. Sleep. 2005;28:203–6.
rapid eye movement sleep without atonia without rapid eye movement sleep 130. Gaig C, Iranzo A, Pujol M, Perez H, Santamaria J. Periodic limb movements
behavior disorder: a pilot study. J Clin Sleep Med. 2015;11:1273–9. during sleep mimicking REM sleep behavior disorder: a new form of periodic
102. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Par- limb movement disorder. Sleep. 2017;40.
kinson’s disease. Mov Disord. 2015;30:1600–11. 131. Trenkwalder C, Kohnen R, Högl B, et al. Parkinson’s Disease Sleep scale—vali-
103. Stefani A, Mahlknecht P, Seppi K, et al. Consistency of “Probable RBD” diagnosis dation of the revised version PDSS-2. Mov Disord. 2011;26:644–52.
with the RBD screening questionnaire: a follow-up study. Mov Disord Clin Pract. 132. Martinez-Martin P, Visser M, Rodriguez-Blazquez C, Marinus J, Chaudhuri KR, van
2017;4:403–5. Hilten JJ. SCOPA-sleep and PDSS: two scales for assessment of sleep disorder in
104. Stiasny-Kolster K, Sixel-Doring F, Trenkwalder C, et al. Diagnostic value of the Parkinson’s disease. Mov Disord. 2008;23:1681–8.
REM sleep behavior disorder screening questionnaire in Parkinson’s disease. 133. Stefani A, Heidbreder A, Brandauer E, et al. Screening for idiopathic REM sleep
Sleep Med. 2015;16:186–9. behavior disorder: usefulness of actigraphy. Sleep. 2018;41.
105. Halsband C, Zapf A, Sixel-Doring F, Trenkwalder C, Mollenhauer B. The REM 134. Nepozitek J, Dostalova S, Kemlink D, et al. Fragmentary myoclonus in idiopathic
sleep behavior disorder screening questionnaire is not valid in de novo Par- rapid eye movement sleep behaviour disorder. J Sleep Res. 2019:e12819.
kinson’s disease. Mov Disord Clin Pract. 2018;5:171–6. 135. Frauscher B, Iranzo A, Gaig C, et al. Normative EMG values during REM sleep for
106. Frauscher B, Mitterling T, Bode A, et al. A prospective questionnaire study in 100 the diagnosis of REM sleep behavior disorder. Sleep. 2012;35:835–47.
healthy sleepers: non-bothersome forms of recognizable sleep disorders are still 136. Fernandez-Arcos A, Iranzo A, Serradell M, et al. Diagnostic value of isolated
present. J Clin Sleep Med. 2014;10:623–9. mentalis versus mentalis plus upper limb electromyography in idiopathic REM
107. Pujol M, Pujol J, Alonso T, et al. Idiopathic REM sleep behavior disorder in the sleep behavior disorder patients eventually developing a neurodegenerative
elderly Spanish community: a primary care center study with a two-stage design syndrome. Sleep. 2017;40.
using video-polysomnography. Sleep Med. 2017;40:116–21. 137. Pierantozzi M, Placidi F, Liguori C, et al. Rotigotine may improve sleep archi-
108. Sixel-Doring F, Trautmann E, Mollenhauer B, Trenkwalder C. Rapid eye move- tecture in Parkinson’s disease: a double-blind, randomized, placebo-controlled
ment sleep behavioral events: a new marker for neurodegeneration in early polysomnographic study. Sleep Med. 2016;21:140–4.
Parkinson disease? Sleep. 2014;37:431–8. 138. Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor
109. Muntean ML, Trenkwalder C, Walters AS, Mollenhauer B, Sixel-Doring F. REM symptoms of Parkinson’s disease—an evidence-based medicine review. Mov
sleep behavioral events and dreaming. J Clin Sleep Med. 2015;11:537–41. Disord. 2019;34:180–98.
110. Cipolli C, Bolzani R, Massetani R, Murri L, Muratorio A. Dream structure in Par- 139. Postuma RB, Anang J, Pelletier A, et al. Caffeine as symptomatic treatment for
kinson’s patients. J Nerv Ment Dis. 1992;180:516–23. Parkinson disease (Cafe-PD): a randomized trial. Neurology. 2017;89:1795–803.
111. Borek LL, Kohn R, Friedman JH. Phenomenology of dreams in Parkinson’s dis- 140. Postuma RB, Lang AE, Munhoz RP, et al. Caffeine for treatment of Parkinson
ease. Mov Disord. 2007;22:198–202. disease: a randomized controlled trial. Neurology. 2012;79:651–8.
112. Chou KL, Moro-De-Casillas ML, Amick MM, Borek LL, Friedman JH. Testosterone 141. Neikrug AB, Liu L, Avanzino JA, et al. Continuous positive airway pressure
not associated with violent dreams or REM sleep behavior disorder in men with improves sleep and daytime sleepiness in patients with Parkinson disease and
Parkinson’s. Mov Disord. 2007;22:411–4. sleep apnea. Sleep. 2014;37:177–85.
113. Bugalho P, Paiva T. Dream features in the early stages of Parkinson’s disease. J 142. Videnovic A. Management of sleep disorders in Parkinson’s disease and multiple
Neural Transm. 2011;118:1613–9. system atrophy. Mov Disord. 2017;32:659–68.
114. Valli K, Frauscher B, Gschliesser V, et al. Can observers link dream content to 143. Rutten S, Vriend C, Smit JH, et al. Bright light therapy for depression in Parkinson
behaviours in rapid eye movement sleep behaviour disorder? A cross-sectional disease: a randomized controlled trial. Neurology. 2019;92:e1145–e1156.
experimental pilot study. J Sleep Res. 2012;21:21–9. 144. Videnovic A, Högl B. Toward disease modification trials in RBD: challenges and
115. Valli K, Frauscher B, Peltomaa T, Gschliesser V, Revonsuo A, Hogl B. Dreaming opportunities. In: Schenck CH, Högl B, Videnovic A, editors. Rapid-eye-
furiously? A sleep laboratory study on the dream content of people with Par- movement sleep behavior disorder. Springer; 2019.
kinson’s disease and with or without rapid eye movement sleep behavior dis- 145. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line
order. Sleep Med. 2015;16:419–27. treatment of restless legs syndrome/Willis–Ekbom disease, prevention and
116. Bateman DE, Levett K, Marsden CD. Sleep benefit in Parkinson’s disease. J treatment of dopaminergic augmentation: a combined task force of the IRLSSG,
Neurol Neurosurg Psychiatry. 1999;67:384–5. EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1–11.
117. Sherif E, Valko PO, Overeem S, Baumann CR. Sleep benefit in Parkinson’s disease 146. Winkelmann J, Allen RP, Högl B, et al. Treatment of restless legs syndrome:
is associated with short sleep times. Parkinsonism Relat Disorrd. 2014;20:116–8. evidence-based review and implications for clinical practice (Revised 2017). Mov
118. Van Gilst MM, van Mierlo P, Bloem BR, Overeem S. Quantitative motor perfor- Disord. 2018;33:1077–91.
mance and sleep benefit in Parkinson disease. Sleep. 2015;38:1567–73. 147. Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary:
119. Van Gilst MM, Bloem RR, Overeem S. Prospective assessment of subjective sleep treatment of restless legs syndrome in adults: report of the Guideline Devel-
benefit in Parkinson’s disease. BMC Neurol. 2015;15:2. opment, Dissemination, and Implementation Subcommittee of the American
120. Lee W, Evans AH, Williams DR. Objective measurement and characterization of Academy of Neurology. Neurology. 2016;87:2585–93.
sleep benefit in Parkinson’s disease. Mov Disord Clin Pract. 2017;4:590–6. 148. Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and consensus clinical
121. Lee W, Evans A, Williams DR. Subjective perception of sleep benefit in Parkin- practice guidelines for the iron treatment of restless legs syndrome/
son’s disease: valid or irrelevant? Parkinsonism Relat Disord. 2017;42:90–94. Willis–Ekbom disease in adults and children: an IRLSSG task force report. Sleep
122. Van Gilst MM, Cramer IC, Bloem BR, Overeem S, Faber MJ. A grounded theory Med. 2018;41:27–44.
study on the influence of sleep on Parkinson’s symptoms. BMC Res Notes. 149. Schenck CH, Högl B, Videnovic A, editors. Rapid-eye-movement sleep behavior
2016;9:299. disorder. Springer; 2019.
123. Hogl B, Arnulf I, Comella C, et al. Scales to assess sleep impairment in Parkin- 150. Howell MJ, Arneson PA, Schenck CH. A novel therapy for REM sleep behavior
son’s disease: critique and recommendations. Mov Disord. 2010;25:2704–16. disorder (RBD). J Clin Sleep Med. 2011;7:639–44A.
124. Hogl B, Wetter TC, Trenkwalder C. [Pathophysiology, clinical aspects and therapy 151. Wang Y, Yang Y, Wu H, Lan D, Chen Y, Zhao Z. Effects of rotigotine on REM sleep
of sleep disorders in Parkinson disease]. Nervenarzt. 2001;72:416–24. behavior disorder in Parkinson disease. J Clin Sleep Med. 2016;12:1403–9.
125. Wetter TC, Collado-Seidel V, Pollmacher T, Yassouridis A, Trenkwalder C. Sleep 152. Di Giacopo R, Fasano A, Quaranta D, Della Marca G, Bove F, Bentivoglio AR.
and periodic leg movement patterns in drug-free patients with Parkinson’s Rivastigmine as alternative treatment for refractory REM behavior disorder in
disease and multiple system atrophy. Sleep. 2000;23:361–7. Parkinson’s disease. Mov Disord. 2012;27:559–61.

Neuropsychopharmacology (2020) 45:121 – 128