Parkinson Sleep Disorders

Disorders of Sleep and
Circadian Rhythms in
Parkinsons Disease
Aleksandar Videnovic
Birgit Hgl
Editors
123
Disorders of Sleep and Circadian Rhythms
in Parkinsons Disease
Aleksandar Videnovic Birgit Hgl
Editors
Disorders of Sleep
and Circadian Rhythms
Editors
Aleksandar Videnovic, MD, MSc Birgit Hgl, MD
Department of Neurology Department of Neurology
Massachusetts General Hospital Medical University of Innsbruck
Harvard Medical School Innsbruck
Boston, MA Austria
USA
ISBN 978-3-7091-1630-2 ISBN 978-3-7091-1631-9 (eBook)

DOI 10.1007/978-3-7091-1631-9
Library of Congress Control Number: 2015938763
Springer Wien Heidelberg New York Dordrecht London

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We dedicate this book
To our families, for their love and support,
To our patients, for their grace
and inspiration,
To our colleagues and mentors, for their
friendship and vision.
Birgit and Aleks

Foreword
Parkinsons disease holds a firm and prominent place in the Movement Disorder
section of all textbooks of Neurology. These discussions, however, usually focus on
the motor components of the disease with incomplete discussions of the plethora of
nonmotor disturbances. Nonmotor features of Parkinsons disease, however, have a
crucial impact on quality of life, and several of them may antedate the onset of clas-
sical motor signs. As such, nonmotor aspects of Parkinsons disease are emerging as
the earliest manifestations of the illness and ones that continue to provoke chal-
lenges throughout the course of the disease. Disorders of sleep and wakefulness are
a prominent example for these nonmotor elements of Parkinsons disease and rank
among the most prevalent and most problematic in overall burden across all stages
of the disease. Their multifaceted causes include Parkinsons disease itself but also
medications and comorbidities such as depression and agitation. Proper manage-
ment and comprehensive patient care require accurate identification, careful evalu-
ation, and precise treatment of sleep disruption and correction of circadian rhythms.
Because of this complexity, understanding, diagnosing, and treating sleepwake
disorders in Parkinsons disease require considerable expertise and attention to
detail. To this end, a key unmet need has been a comprehensive volume edited and
authored by internationally renowned movement disorder experts and sleep neu-
rologists to provide a thorough and up-to-date focus on sleep disorders and
Parkinsons disease.
In Disorders of Sleep and Circadian Rhythms in Parkinsons Disease, Aleksandar
Videnovic and Birgit Hgl have expertly accomplished this goal and have assem-
bled an outstanding group of international leaders to contribute state-ofthe-art
reviews on the pathophysiology, clinical manifestations, assessment, and treatment
of all major types of Parkinsons diseaseassociated disturbances of sleepwake
regulation. These chapters are preceded by a series of five outstanding reviews cov-
ering the neurobiology of sleep and wakefulness and the general approaches to the
evaluation of sleepwake function in Parkinsons disease. The topics covered in this
volume span the entire spectrum of sleep problems that clinicians encounter when
managing Parkinsons disease subjects, and the respective chapters are carefully
referenced and supplemented with informative tables and illustrations.
vii
viii Foreword
In filling this gap in the current landscape of available sources on both sleep
disorders and nonmotor symptoms of Parkinsons disease, this new volume is a
welcome source of reference for the expert clinician and health professional caring
for Parkinsons disease patients and for students and residents trying to understand
the mysteries of Parkinsons disease. Most importantly, with this text and the les-
sons learned, we hope that our Parkinsons disease patients will ultimately benefit
and be unburdened by the plight so well captured by William Shakespeare:
O sleep! O gentle sleep!

Natures soft nurse, how have I frighted thee,
That thou no more wilt weigh my eyelids down
And steep my senses in forgetfulness?
Innsbruck, Austria Werner Poewe

Chicago, IL, USA Christopher G. Goetz
Contents
Part I
1 Regulation of Sleep and Wake Homeostasis . . . . . . . . . . . . . . . . . . . . 3

Cathy A. Goldstein and Ronald D. Chervin
2 Neurochemistry of the Sleep-Wake Cycle
in Parkinsons Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Amanda A.H. Freeman
3 Impaired Sleep and Alertness in Parkinsons Disease:
What Did We Learn from Animal Models? . . . . . . . . . . . . . . . . . . 35
Pierre-Herv Luppi, Olivier Clment, Sara Valencia Garcia,
Frdric Brischoux, and Patrice Fort
4 Objective Measures of the SleepWake Cycle
Valrie Cochen De Cock
5 Subjective Assessment of Sleep and Sleepiness
Joan Santamaria
Part II
6 Insomnia in Parkinsons Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Margaret Park and Cynthia L. Comella
7 Sleep Disordered Breathing in Parkinsons Disease . . . . . . . . . . . . . . 93
Michael K. Scullin, Lynn Marie Trotti, and Donald L. Bliwise
8 Excessive Daytime Somnolence Associated
with Parkinsons Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
James Battista, Renee Monderer, and Michael Thorpy
9 Dysregulation of Circadian System in Parkinsons Disease. . . . . . . . 117
ix
x Contents
10 REM Sleep Behavior Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Michael J. Howell and Carlos H. Schenck
11 Quality Control for Diagnosis of REM Sleep Behavior Disorder:
Criteria, Questionnaires, Video, and Polysomnography . . . . . . . . . . 145
Birgit Frauscher and Birgit Hgl
12 Restless Legs Syndrome and Periodic Limb
Movements in Parkinsons Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
William G. Ondo
13 Fatigue and Sleepiness in Parkinsons Disease Patients . . . . . . . . . . . 173
Elisabeth Svensson
14 Cognition and the SleepWake Cycle in
Parkinsons Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Jean-Francois Gagnon, Ronald B. Postuma,
and Gabrielle Lyonnais-Lafond
15 Impact of Surgical Therapies on Sleep
and Alertness in Parkinsons Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 195
Amy W. Amara and Harrison C. Walker
16 Sleep Disorders in Atypical Parkinsonisms. . . . . . . . . . . . . . . . . . . . . 209
Alex Iranzo
Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Introduction: Sleep, Alertness, and Circadian
Rhythms in Parkinsons Disease
Parkinsons disease is the second most common neurodegenerative disorder. Named

after James Parkinson, an English surgeon, the disease was initially described in his
famous Essay on the Shaking Palsy, published in 1817. In this essay, Dr. Parkinson
writes about six patients with paralysis agitans or shaking palsy. His astute obser-
vations provided an excellent description of many aspects of this disease and testify
to the power of clinical observation in human medicine. On page 7, Dr. Parkinson
wrote In this stage, the sleep becomes much disturbed. The tremulous motion of
the limbs occur during sleep, and augment until they awaken the patient, and fre-
quently with much agitation and alarm. Dr. Parkinson recognized sleep dysfunc-
tion in his patients early on, two centuries ago. It is only over the past three decades
that disturbances of sleep and wake associated with Parkinsons disease (PD) have
attracted the attention of medical and scientific community.
Disorders of sleep and alertness are very common in PD, and likely to affect
every patient during the course of their disease. All described categories of sleep
disorders have been associated with PD. These disorders encompass insomnia,
sleep related breathing disorders, parasomnias, circadian rhythms disorders, and
sleep related movement disorders. Each of these disorders has unique characteris-
tics in PD, which likely reflect on interactions between neurodegenerative processes
of PD with sleep-wake regulation mechanisms.
Sleep disorders are commonly underreported by patients, and underdiagnosed/
misdiagnosed by health care professionals. Studies have reported that impaired
sleep and alertness affect quality of life of PD patients to a similar degree as motor
symptoms of the disease. Further, they predispose patient to significant safety chal-
lenges. It is therefore important to timely and accurately address sleep dysfunction
in PD patients, educate health professionals, and enhance public outreach related to
sleep health in PD.
Systematic study of sleep, alertness and circadian function PD is challenged by
many confounding factors that influence sleep-wake regulation in this population.
Examples include co-existent primary sleep disorders, psychiatric co-morbidities,
complex medication regimens, limited physical activity and light exposure. Further,
individual variability related to the PD phenotype poses additional challenges to the
study of sleep in PD. Specific expertise for the execution and interpretation of sleep
studies in PD may be limited, and the wide range of ascertainment methods and
associated costs may further limit the extent of sleep investigations in PD.
xi
xii Introduction: Sleep, Alertness, and Circadian Rhythms in Parkinsons Disease
Specific sleep disorders have emerged as important early manifestations of

synuclein related neurodegeneration specific for PD. The most robust support for
this hypothesis arises from investigations in patients with idiopathic REM sleep
behavior disorder (iRBD), as these patients confer a high risk for developing a
synucleinopathy. Therefore, patients with iRBD may be an ideal study population
for disease modifying therapies for PD, once these become available.
This book is dedicated to disorders of sleep, alertness, and circadian function in
PD. The book is composed of two parts. Part I is focused on the biology of sleep and
wake in general and in PD, as well as on the methods for the assessment of
sleep-wake cycles in PD. In Part II, specific sleep and circadian disorders associated
with PD are presented. Authors hope this book will serve as a valuable resource for
neurologists, movement disorders and sleep medicine specialists, trainees and other
allied health professionals.
Boston, USA
Birgit Hgl
Innsbruck, Austria
Part I
Regulation of Sleep and Wake
Homeostasis 1
Cathy A. Goldstein and Ronald D. Chervin
Contents
1.1 Introduction ..................................................................................................................... 4
1.2 History of Sleep Recording ............................................................................................. 4
1.3 NREM Sleep Anatomy and Physiology.......................................................................... 6
1.4 Slow-Wave Sleep, Slow-Wave Activity, and Their Dispersion over
the Course of a Normal Nocturnal Sleep Period ............................................................. 7
1.5 Slow-Wave Sleep and Slow-Wave Activity as a Function of Prior Wakefulness ........... 8
1.6 Topographic Organization of Slow-Wave Activity and Local,
Use-Dependent Changes ................................................................................................. 9
1.7 Sleep Homeostasis Across the Life Span........................................................................ 10
1.8 Genetic Contributions to Sleep Homeostasis .................................................................. 10
1.9 Clinical Manifestations of Sleep Homeostasis ............................................................... 11
Conclusion ............................................................................................................................... 12
References ................................................................................................................................ 13
Abstract
The interaction of two opposing processes, the circadian rhythm and homeostatic
sleep drive, governs sleep and wake. Circadian timing promotes alertness during
the environmental day and sleep during the environmental night, while the
homeostatic sleep drive grows with cumulative wakefulness independent of time.
Homeostatic sleep drive is measured by its electroencephalogram correlate,
slow-wave activity. Slow-wave activity increases not only in response to pro-
longed wakefulness, but also demonstrates spatial organization and increases in
a local, use-dependent pattern based on previous physical and mental activity.
These findings support the important hypothesis that sleep mediates homeostasis
C.A. Goldstein (*) R.D. Chervin

University of Michigan Health System Sleep Disorders Center, 1500 East Medical Center
Drive, Med Inn C728, Ann Arbor, MI 48109-5845, USA
e-mail: [email protected]; [email protected]
Springer-Verlag Wien 2015 3

A. Videnovic, B. Hgl (eds.), Disorders of Sleep and Circadian Rhythms
in Parkinsons Disease, DOI 10.1007/978-3-7091-1631-9_1
4 C.A. Goldstein and R.D. Chervin
of neuronal synapses. Therefore, the homeostatic control of sleep and wake has
implications that extend beyond alertness.
1.1 Introduction
Sleep is orchestrated by a two-process model comprised of the homeostatic sleep

drive (process S) and the circadian rhythm (process C) [1, 2]. Process S increases
with wakefulness and dissipates with sleep. Process C times human sleep such
that the highest propensity for sleep occurs during the environmental night, while
an increased alerting signal promotes wake during the environmental day [3].
These processes interact as follows. During daytime wakefulness, process S
increases sleep pressure. To counteract this, the circadian alerting signal increases
to a peak in the evening [4]. The net influence of these opposing forces allows
maintenance of wakefulness through bedtime [5]. At bedtime, the combination of
a sharp drop in the circadian alerting signal (coinciding with the onset of melato-
nin secretion) with the elevated homeostatic sleep drive facilitates sleep onset [6].
Despite dissipation of process S-mediated sleep pressure after sleep onset, sleep
continues due to a persistently low circadian alerting signal [7]. Together, these
processes typically allow for approximately 16 h of consolidated wakefulness and
8 h of continuous sleep (see Fig. 1.1). The circadian rhythm will be discussed
further in Chap. 9.
1.2 History of Sleep Recording
Homeostasis, as described by Cannon in 1932, is the need for organisms to achieve

a steady state [8]. In 1980, Borbly introduced the term sleep homeostasis, which can
be understood by its electrophysiological correlate, slow-wave activity [9].
Descriptions of brain wave activity during sleep began in the late 1930s after the
advent of the electroencephalogram (EEG) in 1928 [10]. Recordings demonstrated
the following EEG progression after sleep onset: drop out of alpha activity, appear-
ance of low-voltage activity, emergence of high-voltage, low-frequency (delta)
waves, followed by an increase in delta waves and the appearance of spindle activity.
Thus, delta waves were thought to represent real sleep [11, 12]. In addition, delta
activity was associated with an increased arousal threshold to auditory stimuli and,
therefore, was thought to parallel the depth of sleep [11, 13, 14]. The EEG pattern
described above was distinct from the activity recorded in rapid eye movement
(REM) sleep described initially by Aserinsky and Kleitman in 1953 [15]. In 1957,
Dement and Kleitman introduced a staging schema for EEG activity recorded during
sleep. They separated nonrapid eye movement (NREM) from rapid eye movement
(REM) sleep, and classified NREM sleep into stages 1, 2, 3, and 4 [16]. Stage 1 sleep
was described as low-voltage EEG activity that lacked spindle activity [16]. As sleep
continued, the EEG evolved with the development of slower activity, sleep spindles,
and K complexes that mark stage 2 sleep [16]. Stage 3 sleep was defined by epochs
containing at least two waves greater than 100 uV in amplitude with frequency less
1 Regulation of Sleep and Wake Homeostasis 5
Sleep Wake
2400
0200
0400
0600 Sleep offset
0800
1000
1200
1400
1600
1800
2000
2200
Sleep onset
2400
Least alert Most alert
Fig. 1.1 The two-process model of sleep. Green arrows denote the circadian alerting signal; the
longer the arrow, the greater the alerting signal. Purple arrows denote the homeostatic sleep drive.
The longer the arrow, the greater the homeostatic sleep drive. The blue vertical line divides wake
from sleep. The level of alertness is represented by the point at which the arrows meet, determined
by the net effect of circadian and homeostatic forces. Propensity for sleep is high when either the
magnitude of homeostatic sleep drive overcomes the circadian alerting signal, or the circadian alert-
ing signal is sufficiently low (e.g., at 04:0006:00). After sleep offset, homeostatic sleep drive accu-
mulates with wakefulness. However, the circadian alerting signal increases in an opposing fashion.
However, in the late afternoon the circadian alerting signal is not large enough to completely offset
the effect of growing sleep pressure on alertness. Therefore, sleepiness is high at this time, referred
to as the afternoon circadian dip. The circadian alerting signal is so high in the evening it overcomes
the homeostatic sleep drive. Alertness is high at this time, which is referred to as the forbidden zone
for sleep. The circadian alerting signal decreases about 2 h before habitual sleep onset and promotes
sleep due to the already elevated homeostatic sleep drive. The initial period of the sleep bout is
associated with dissipation of the homeostatic sleep need; however, sleep is maintained due to a
persistently low circadian alerting signal, which reaches a nadir around 04:00. Therefore, even when
the homeostatic sleep drive is less than the circadian alerting signal, if the circadian alerting signal
is low, sleep will continue (as seen during the early morning hours). The above model does not take
into account other factors outside of process C and process S mediating alertness
than 2 Hz [16]. During stage 4 sleep, the delta waves described above made up more
than 50 % of an epoch [16]. Current sleep scoring criteria consolidates stage 3 and 4
sleep into NREM 3 (N3) sleep [17]. In addition to measuring slow-wave sleep as
classically defined, the development of EEG spectral analysis allowed for the mea-
surement of slow-wave activity [18]. Slow-wave activity is defined as the EEG power
density in the 0.54.5 Hz range [18]. Although slow-wave sleep stages and slow-
wave activity show considerable overlap, they are distinct constructs and each can
generate different insight and opportunity in research and understanding of sleep
homeostasis.
1.3 NREM Sleep Anatomy and Physiology
Hyperpolarization of thalamic neurons and synchronization of cortical excitatory

and inhibitory postsynaptic potentials are responsible for the high-voltage, low-
frequency activity seen on EEG during NREM slow-wave sleep [19, 20]. The sleep-
active neurons reside in the ventrolateral preoptic nucleus (VLPO) and median
preoptic nucleus (MnPN) of the preoptic area (POA) in the hypothalamus [21, 22].
When active, the VLPO and MnPN inhibit wake-promoting centers via GABAergic
and galanergic projections [2327]. As the wake-promoting centers inhibit the
VLPO and MnPN, suppression of their activity releases inhibition of the VLPO and
MnPN. Neurons in the VLPO and MnPN demonstrate activity that is most pro-
nounced during NREM and REM sleep, and almost nonexistent during wake [28,
29]. Rates of neuronal discharge from the VLPO parallel the depth of NREM sleep
as measured by EEG slow-wave activity [28]. Therefore, this group of neurons may
play a significant role in the generation of slow-wave sleep. The inability for both
the arousal and sleep-promoting centers to be activated simultaneously underlies
the sleep-switch hypothesis [30]. This theory helps explain the stability of sleep
and wake states such that under normal conditions sleep does not intrude into wake-
fulness and vice versa [30]. The VLPO and MnPN are regulated by direct and indi-
rect connections from the master clock housed in the suprachiasmatic nucleus
(SCN), which facilitates the circadian control of sleep (discussed further in Chap.
9). Figure 1.2 depicts the nuclei responsible for NREM sleep.
As above, the SCN is responsible for timing activity of sleep-generating neurons
in the POA such that sleep demonstrates a circadian pattern. However, mechanisms
that mediate the homeostatic control of sleep are less clear, but likely involve sleep-
promoting neurochemicals (or somnogens) that act directly on the POA [31].
Prostaglandin D2 (PGD2) is a sleep-promoting hormone produced by the leptomen-
inges and choroid plexus [31]. PGD2 increases during sleep deprivation and acts
directly on receptors near the VLPO as well as indirectly by way of other somno-
gens to induce sleep [31, 32]. Cytokines are also known to elicit sleep and may be
most important in increasing NREM sleep during infection [31]. Growth-hormone
releasing hormone promotes sleep by its direct action on the POA, and increased
secretion of this hormone is seen in association with slow-wave sleep during the
initial portion of the sleep period [31]. However, adenosine may be the somnogen
most likely to mediate sleep homeostasis as it reflects brain energy levels. Adenosine
is produced when adenosine triphosphate (ATP) is broken down in metabolically
active tissues [31]. In addition, when cells are fatigued, phosphorylation of adenos-
ine to ATP is reduced [33]; therefore, the greater the neuronal activity, the greater is
the rise in adenosine. Animal experiments have demonstrated this with an increase
in basal forebrain adenosine levels during wakefulness and a decrease during sleep
[34]. Additionally, adenosine increases slow waves on EEG [35]. Adenosines
effects on sleep are mediated by inhibition of wake-active neurons, disinhibition of
sleep-active neurons, and stimulation of sleep-active neurons primarily by action on
A1 but also A2a receptors [31]. The alerting effect of caffeine occurs through ade-
nosine receptor antagonism [36].
LH
orexin
TMN
HA
GABA/Gal
VLPO MnPN
DR LC
5-HT NE
*
LDT/PPT
SCN Ach
Hypothalamic nuclei Pontine nuclei
Fig. 1.2 Nuclei responsible for the generation of NREM sleep. The orange ovals denote nuclei
that are wake promoting when active. Blue rectangles represent nuclei that promote sleep when
active. The purple circle is the suprachiasmatic nucleus (SCN) of the hypothalamus, which times
sleep and wake. *Projections from the SCN to the VLPO and LH are relayed via the SPZ and
DMH (not shown). Green dashed lines illustrate the GABAergic and galanergic pathways from the
VLPO/MnPN that inhibit the wake-promoting centers, allowing for sleep. The red dashed lines
represent inhibitory efferents to the VLPO/MnPN. With inhibition of the GABA-producing neu-
rons in the VLPO/MnPN by ACh, 5-HT, NE, Gal, and GABA (from the SPZ and DMH), wake-
promoting nuclei are disinhibited, which results in alertness. The TMN inhibits the VLPO/MnPN
through GABA and Gal opposed to HA, the wake-promoting transmitter of the TMN. VLPO ven-
trolateral preoptic nucleus, MnPN median preoptic nucleus, LH lateral hypothalamus, TMN tuber-
omamillary nucleus, DR dorsal raphe, LC locus coeruleus, LDT/PPT lateral dorsal tegmentum/
pedunculopontine nucleus, SPZ subparaventricular zone, DMH dorsomedial hypothalamic
nucleus, Ach acetylcholine, 5-HT serotonin, NE norepinephrine, Gal galanin, GABA gamma-
amino butyric acid [2129]
1.4 Slow-Wave Sleep, Slow-Wave Activity, and Their

Dispersion over the Course of a Normal Nocturnal Sleep
Period
The early work of Dement and Kleitman demonstrated a cyclical variation of the
sleep stages that occurred every 90100 min [16]. Notably, nearly all high-voltage
delta frequency activity took place during the first 3 h of sleep. After the second
sleep cycle, stages 3 and 4 sleep were not seen [16]. NREM slow-wave sleep is
now well known to decline over the course of subsequent sleep cycles through the
night [37]. Apart from slow-wave sleep, slow-wave activity, the density of EEG
activity in the 0.54.5 Hz range as measured by spectral analysis, demonstrates a

similar pattern. Slow-wave activity displays a gradual buildup during the first
NREM-REM cycle and an exponential decline from cycle 1 to cycle 3 [18].
Notably, the pattern of slow-wave sleep and slow-wave activity decay described
above persists in the nonentrained state, suggesting autonomy from circadian con-
tributions [38, 39].
1.5 Slow-Wave Sleep and Slow-Wave Activity as a Function

of Prior Wakefulness
During experiments that evaluated sleep stages during naps taken in the morning,
afternoon, and evening, a progressive increase was seen in the amount of slow-wave
sleep recorded over the course of the day [40, 41]. This finding does not eliminate
the possibility of a circadian effect. However, when healthy volunteers slept during
nap opportunities at 10:00, 12:00, 14:00, 16:00, 18:00, 20:00, and 04:00, EEG
power density in the delta and theta range increased in proportion to the duration of
prior wakefulness [42]. Conversely, latency to sleep onset was shortest at the 16:00
and 04:00 naps, consistent with the known bimodal distribution of sleep propensity
[5, 42]. In addition, when nocturnal sleep was recorded after napping, there was a
significant reduction of slow-wave sleep and slow-wave activity compared to base-
line nocturnal sleep that did not follow a nap [4345].
Studies that used total sleep deprivation protocols of 4064 h or sleep restric-
tion to 3 h per night showed a significant increase in the amount of slow-wave
sleep recorded during the recovery sleep period. In addition, shorter latency to
slow-wave sleep was seen during recovery sleep [14, 19, 37, 46]. EEG spectral
analysis demonstrated similar findings for slow-wave activity, with increases in
delta and theta EEG power during recovery sleep [19, 39, 4749]. The increase
in lower frequency EEG activity was not confined to stages 3 and 4 sleep but
also seen during stage 2 and REM sleep. The enhancement of the delta and theta
band activity was maximal during the first NREM-REM cycle and the rate of
build-up of slow-wave activity in this cycle was increased [19]. These findings
were attenuated during subsequent cycles and on recovery day two [19]. Slow-
wave activity during recovery sleep was independent of circadian timing [47].
However, slow-wave sleep did not demonstrate the same autonomy, with a
reduction in the expected amounted of slow-wave sleep when the recovery
period was placed at 07:00 [47]. The authors postulated that this finding was due
to the higher circadian propensity for stage REM sleep at that time, such that
REM sleep occurred at the expense of NREM sleep. Therefore, visually scored
epochs of slow-wave sleep were not increased as expected, as opposed to slow-
wave activity which was elevated in proportion to the degree of sleep depriva-
tion [47]. As prior wakefulness does, selective deprivation of slow-wave sleep
without decreasing total sleep time also increases slow-wave sleep and slow-
wave activity in later portions of the sleep period and during subsequent recov-
ery sleep periods [42, 50, 51].
In summary, slow-wave activity declines over the course of the sleep period, is
dependent on prior wakefulness, rebounds when selectively suppressed, and is inde-
pendent from the circadian control of alertness. Taken together, these findings
strongly suggest that slow-wave activity is a useful EEG marker that reflects sleep
homeostasis.
1.6 Topographic Organization of Slow-Wave Activity

and Local, Use-Dependent Changes
Slow-wave activity has a topographical organization in the cerebral cortex, with an

anterior-posterior gradient such that slow-wave activity is more prominent in frontal
than occipital areas [52, 53]. This frontal predilection is most pronounced during
the initial NREM sleep period and then declines over subsequent cycles [52, 53].
The anterior-posterior gradient is enhanced during recovery sleep following total
sleep and selective slow-wave sleep deprivation [51, 53, 54]. These findings suggest
a specific role for frontal brain regions in sleep homeostasis.
In addition to amount of prior wakefulness, the magnitude of activity during
wake may affect the homeostatic process occurring during sleep. Physical exercise,
novel mental activity, and structured social interactions all increase slow-wave sleep
[5557]. Furthermore, activation during wakefulness of specific brain regions has
consequences during sleep. For example, a study by Kattler demonstrated that
vibratory stimulation of the right hand during wakefulness increased delta power in
the left somatosensory cortex during the first hour of sleep that followed [58]. As
sensory stimulation is known to increase cerebral metabolism and blood flow in the
corresponding cortical area, this finding suggests that the homeostatic process dur-
ing sleep may be use dependent [58]. In contrast, among subjects subjected to arm
immobilization, slow-wave activity in the contralateral sensorimotor cortex
decreased during subsequent sleep [59]. The region-specific decrease in slow-wave
activity was proportional to next-day deterioration of motor performance in the
same limb [59]. In addition to sensorimotor manipulations, an experiment that used
a cognitive task that involved specific cortical areas also resulted in locally enhanced
slow-wave activity during the sleep that followed [60]. This local, use-dependent
increase in slow-wave activity decayed over the course of the night. When subjects
were retested, performance of the task was superior among those whose learning
occurred prior to sleep; furthermore, performance correlated with the increase in
slow-wave activity in the corresponding brain region [60].
Demonstration of local, use-dependent EEG changes, particularly in the setting
of learning, has contributed to a synaptic homeostasis hypothesis, to explain a fun-
damental purpose of sleep, as advanced by Tononi and Cirelli [61, 62]. This hypoth-
esis is based on the following premises. During wakefulness, neuronal plasticity
allows the brain to strengthen and increase synapses as the individual navigates new
experiences. However, synaptic potentiation comes at a high cost due to the large
amount of physiological resources it requires, and therefore is not sustainable.
Synaptic pruning, the selection of which synapses should remain, must occur to
conserve energy and allow for future learning. The synaptic homeostasis hypothesis
proposes that the purpose of sleep is to mediate this process, and that the footprint
of this function within sleep is slow-wave activity [61, 62].
1.7 Sleep Homeostasis Across the Life Span
The homeostatic regulation of sleep may differ with age. Slow-wave sleep and
slow-wave activity decline steeply during adolescence, particularly during sleep in
the first NREM sleep cycle [6370]. This pattern indicates that children, in compari-
son to adolescents, have a more rapid buildup of sleep pressure and need a greater
amount of recovery to restore homeostasis [70]. These findings may reflect increased
synaptic density in children, and provide further support for the synaptic homeosta-
sis theory [61, 62, 70].
The changes continue throughout the life span, with decreased slow-wave sleep
and slow-wave activity in older persons [71]. However, as reviewed comprehen-
sively by Bliwise in 1993, studies that have used sleep deprivation protocols have
demonstrated similar recovery sleep in elderly and younger subjects. Interestingly,
changes in sleep stages after sleep deprivation are seen only in the first recovery
night of older subjects, as opposed to the first and second nights in younger indi-
viduals. This suggests that aging does not necessarily impair the homeostatic pro-
cess regulating sleep loss [71]. In fact, older adults in comparison to younger
persons may be less affected by sleep loss, with the caveat that differences in base-
line sleep among young and old subjects could in part generate these impressions
[7275]. A recent investigation demonstrated that slow-wave activity not only
declines in the elderly, but that this decrement is associated with prefrontal gray
matter loss and deterioration in memory consolidation [76]. These findings further
support the role of slow-wave sleep and slow-wave activity in cognition.
1.8 Genetic Contributions to Sleep Homeostasis
In addition to age, genetics may affect the homeostatic regulation of sleep and wake.
A polymorphism in the adenosine deaminase (ADA) gene (G > A transition at posi-
tion 22 of the genes coding region) is associated with increased amounts of slow-
wave sleep and greater slow-wave activity [7779]. The same polymorphism is
associated with increased sleepiness and reduced vigilance in the setting of sleep
deprivation [78]. A functional polymorphism in the brain-derived neurotrophic fac-
tor (BDNF) gene also affects slow-wave sleep and slow-wave activity in both the
baseline and sleep-deprived states [80].
In addition, genes traditionally thought to modify circadian aspects of sleep are
now known to participate in homeostatic mechanisms. Animal models with dele-
tions or mutations of the circadian genes Bmal1, Cyc, Clock, Npas2, and Cry show
impaired sleep homeostasis [8185]. Additionally, the clock genes Per1 and Per2
have increased expression in animals undergoing sleep loss [83, 86]. In humans,
Per3 polymorphisms are involved in sleep homeostasis [87]. Subjects who are
homozygous for the five repeat variable number tandem repeat (VNTR) polymor-
phism (Per3 5/5), in comparison to subjects with the four repeat VNTR polymor-
phism (Per3 4/4), show shorter sleep latencies, higher initial amounts of slow-wave
activity, and more rapid slow-wave decline over the course of the night [87].
Additionally, when sleep deprived for 40 h, Per3 5/5 subjects have increased slow
rolling eye movements and greater deterioration in performance measures [87].
Interestingly, a previous study had demonstrated that the longer repeat polymor-
phism was associated with a morning circadian phenotype, while the shorter repeat
polymorphism was more frequent in evening types and those with delayed sleep
phase disorder [88].
Another gene that modifies circadian rhythms, hDEC2, has gained considerable
attention [89]. A point mutation in this gene was found in a mother and daughter
who both display short sleeper syndrome [89]. Individuals with this condition
require shorter sleep durations, have faster buildup of slow-wave activity, and thus
may function under a higher NREM sleep pressure [49]. Mice genetically modified
to contain the same proline to arginine substitution found in this family also demon-
strate longer active periods than mice without the mutation [89]. Therefore, hDEC2
is not only implicated in sleep timing but also modifies sleep duration requirements
[89]. These findings suggest that the same molecular machinery influences both
process C and process S, functions traditionally thought to oscillate autonomously.
1.9 Clinical Manifestations of Sleep Homeostasis
The homeostatic regulation of sleep has important implications in many different

clinical settings. Chronic partial sleep loss is ubiquitous, as almost 40 % of American
adults report sleep durations of less than 7 h on workday nights [90]. Sleep pressure
builds when sleep is chronically restricted and results in reduced daytime alertness
and impaired performance [91]. Shift work, as experienced by about 10 % of the US
workforce, can exacerbate sleep deprivation. For example, nightshift workers average
6.1 h of sleep per 24-h period [92]. Increased homeostatic sleep pressure amplifies
circadian fluctuations in performance [93, 94]. The greatest functional impairment is
seen during the circadian night and is more pronounced during chronic partial sleep
loss than during acute sleep deprivation [93, 94]. Repercussions can be grave among
nightshift workers who undergo recurrent sleep restriction and attempt wakefulness at
the circadian nadir of alertness. Naps may provide an important opportunity to miti-
gate the effects of increased sleep pressure on alertness and performance [9599].
Impairment of the sleep homeostatic process may play an important role in cer-
tain sleep disorders. In idiopathic hypersomnia, excessive daytime sleepiness occurs
despite adequate sleep duration and the absence of observable underlying sleep
disruption. This disorder lacks the REM intrusion phenomena seen in narcolepsy.
In a study that monitored 24-h EEG in 75 patients with idiopathic hypersomnia,
slow-wave sleep persisted later in the night than in normal controls [100]. This obser-
vation was more prominent among patients who had idiopathic hypersomnia with
long sleep time than it was among patients who had idiopathic hypersomnia without
long sleep time [100]. In addition, daytime sleep episodes contained percentages of
slow-wave sleep that exceed those recorded from controls [100]. Although the
pathophysiology of idiopathic hypersomnia remains unknown, differences in slow-
wave sleep between these patients and controls suggest involvement of the homeo-
static regulation of sleep.
In patients with delayed sleep phase disorder, sleep onset and offset occurs later
than desired [101]. Typical sleep onset is 2:00 AM to 6:00 AM and sleep offset is
10:00 AM to 2:00 PM [102]. The condition usually has been attributed to an abnor-
mality in circadian timing, but a contribution from homeostatic factors also may be
present. In comparison to controls, patients with delayed sleep phase disorder can
demonstrate a prolonged time interval between the time of highest circadian propen-
sity for sleep and sleep offset (abnormal phase angle) [103105]. Additionally, these
patients have increased amounts of slow-wave sleep in the latter portion of the sleep
period, longer sleep durations, and impaired ability to recover during sleep depriva-
tion [104, 106, 107]. Similar observations also have been made among sighted indi-
viduals with free-running circadian rhythm sleep disorder [108, 109]. Investigators
hypothesize that difficulty accruing and dissipating homeostatic sleep pressure may
be involved in the pathogenesis of delayed sleep phase disorder and free-running
disorder in sighted individuals [106, 110]. The differences in homeostatic sleep regu-
lation between morning and evening circadian phenotypes and the Per3 polymor-
phism discussed previously may further support this hypothesis. Furthermore,
morning types (individuals who prefer earlier sleep wake times) demonstrate a larger
buildup of slow-wave activity in response to increased sleep pressure and show a
faster decline over the course of the night compared to evening types (individuals
who prefer later sleep wake times) [111115]. However, some studies of phase angle
and sleep duration have not found differences between patients with delayed sleep
phase disorder and normal controls [116]. Therefore, further research is needed to
delineate the role of sleep homeostasis in circadian rhythm sleep disorders.
Conclusion
In summary, sleep is regulated by a dual process model. Process S, the homeostatic
sleep drive, increases with prior wakefulness and dissipates with sleep. The circa-
dian rhythm, or process C, gates sleep pressure so that wakefulness is sustained
throughout the environmental day and sleep occurs at night. The electrophysiologi-
cal correlate of sleep homeostasis, slow-wave activity, is a marker of sleep need
that also demonstrates local, use-dependent changes. This finding may have sig-
nificant implications for the role of sleep in memory and cognition. In addition,
clock genes originally found to modify circadian phase have now shown involve-
ment in sleep and wake homeostasis. This realization, combined with data that
suggest altered sleep homeostasis in different circadian phenotypes, underlines the
complexity of interactions between homeostatic and circadian control of sleep and
wakefulness. A better understanding of these processes and their interactions could
eventually have fundamental impact on clinical care and public health.
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phase syndrome. J Biol Rhythms. 2009;24(4):31321.
Neurochemistry of the Sleep-Wake Cycle
in Parkinsons Disease 2
Amanda A.H. Freeman
Contents
2.1 Introduction ..................................................................................................................... 20
2.2 Wake-Promoting Circuits ................................................................................................ 20
2.2.1 Dopamine ............................................................................................................ 20
2.2.2 Acetylcholine ...................................................................................................... 22
2.2.3 Hypocretin/Orexin .............................................................................................. 24
2.2.4 Serotonin ............................................................................................................. 25
2.2.5 Norepinephrine ................................................................................................... 26
2.2.6 Histamine ............................................................................................................ 27
2.3 Sleep-Promoting Circuit ................................................................................................. 28
2.3.1 Melanin-Concentrating Hormone ....................................................................... 28
Conclusion ............................................................................................................................... 28
References ................................................................................................................................ 29
Abstract
Many Parkinsons disease (PD) patients struggle with excessive daytime sleepi-
ness independent of their poor nocturnal sleep quality. Unexplained by comorbid
conditions, these symptoms are inherent to the underlying neuropathology of the
disease. Widespread neurodegeneration in PD affects multiple neurotransmitter
systems critical for regulating the sleep-wake cycle including: dopamine, acetyl-
choline, hypocretin/orexin, serotonin, norepinephrine, and melanin-concentrating
hormone. Disruptions in these interconnected signaling pathways reduce arousal
through both direct and indirect (i.e., positive and negative feedback loops)
A.A.H. Freeman, PhD

Department of Neurology, Emory University School of Medicine,
101 Woodruff Circle, WMRB, Suite 6000, Atlanta, GA 30322, USA
e-mail: [email protected]

20 A.A.H. Freeman
mechanisms. This chapter reviews the role of each of these neurotransmitter sys-
tems in sleep-wake regulation and how degeneration of these nuclei may contrib-
ute to deficits in the sleep-wake cycle of PD patients.
2.1 Introduction
Disruptions of the sleep-wake cycle in Parkinsons disease (PD) are evident in both
daytime functioning and nighttime sleep. Between 30 and 60 % of PD patients
report excessive daytime sleepiness (EDS) as indicated by scores >10 on the
Epworth Sleepiness Scale [1, 2], which is predictive of unintended sleep attacks [3].
Employing the multiple sleep latency test (MSLT) as an objective measure, patho-
logical sleepiness has been observed in 2050 % of PD patients (mean sleep latency
<5 min). The presence of rapid eye movement (REM) sleep along with the short
sleep latency, indicating a narcolepsy-like phenotype, has been documented in
1539 % [4, 5].
Impairments in daytime arousal are independent of the nocturnal sleep disrup-
tions in PD, which include sleep fragmentation, decreased slow-wave sleep,
decreased REM sleep, increased REM latency, and loss of sleep spindles [4, 5]. In
fact, contrary to what one might predict, poorer nocturnal sleep was associated with
greater, rather than lesser, degrees of daytime alertness [5]. While daytime sleepi-
ness correlates with disease severity [2], it cannot be explained by comorbid condi-
tions including insomnia, periodic leg movements, or sleep apnea [4, 5]. These
findings indicate that the sleep-wake disruptions are intrinsic to the neuropathology
underlying the disorder rather than a secondary effect of poor sleep quality.
Progressive loss of dopaminergic neurons is the hallmark of PD, and animal
models targeting dopaminergic disruption replicate some aspects of the sleepiness
phenotype observed in PD patients. However, significant neuronal loss correlating
with disease severity extends to additional neurotransmitter systems known to regu-
late arousal (e.g., acetylcholine, norepinephrine, serotonin, and hypocretin/orexin).
This chapter reviews deficits in wake-promoting neurotransmitter systems, which
may contribute to the disruptions in the sleep-wake cycles of Parkinsons disease
patients.
2.2 Wake-Promoting Circuits
2.2.1 Dopamine
Multiple lines of converging evidence, from pharmacological interventions to

genetic manipulations to targeted lesions, demonstrate that dopamine plays an
essential role in the sleep-wake cycle. Drugs that increase the synaptic availability
of dopamine, through stimulating release or inhibiting reuptake (e.g., amphetamine
or cocaine), have long been appreciated to increase arousal. Mice [6] and flies [7]
2 Neurochemistry of the Sleep-Wake Cycle in Parkinsons Disease 21
that lack functional dopamine transporters, thereby leading to increased synaptic

dopamine by preventing synaptic reuptake of dopamine, demonstrate a 20 %
increase in wakefulness and a >50 % decrease in rest, respectively. Administration
of a selective dopamine D1 receptor agonist (SKF 38393 or A68930) increases
wakefulness and decreases REM sleep and simultaneous blockade of the D1 recep-
tor (SCH 23390) prevents the increase in arousal [8]. During their subjective day,
rats spend less time awake and exhibit inappropriate REM sleep intrusions follow-
ing destruction of ascending dopamine pathways from the ventral tegmental area
(VTA) [9]. Lesions targeting presumptive wake-active, dopaminergic neurons in the
ventral periaqueductal gray of rats increase sleep by ~20 % [10]. Sleepiness and
REM intrusion into daytime naps, recapitulating the narcolepsy-like phenotype of
some PD patients, is observed in a methyl,4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)-induced model of parkinsonism in nonhuman primates [11]. Administration
of the dopamine precursor L-DOPA or the dopamine reuptake blocker bupropion
reverses these effects [11] presumably through activation of intact mesocorticolim-
bic circuits that are less vulnerable to MPTP. The specificity of dopamines role in
the regulation of the sleep-wake cycle, as opposed to maintenance of circadian
rhythm, is emphasized by the general preservation of circadian body temperature in
parkinsonian MPTP nonhuman primates [12].
Despite the evidence that dopamine promotes arousal, it has not traditionally
been considered a member of the ascending reticular activating system (ARAS)
because the firing rate of dopaminergic neurons does not vary across behavioral
state [13]. The average firing rate, however, does not take into account that these
neurons have either tonic or burst firing patterns. Extracellular dopamine concentra-
tions increase following burst firing compared to tonic firing even when the average
firing rate of the two conditions is kept constant [14]. The firing pattern of substantia
nigra pars compacta (SNpc) neurons can be modulated by gluatmatergic inputs via
an NMDA-receptor-dependent mechanism [15] or cholinergic inputs [16]. In the
context of the sleep-wake cycle, this latter mechanism is particularly relevant con-
sidering the projections from the wake-promoting pedunculopontine tegmental
nucleus to the SNpc [17].
The number of dopaminergic neurons of the SNpc decreases 5086 % prior to
clinical manifestation of symptoms [1821], resulting in a 7080 % decrease in
dopamine concentrations at striatal nerve terminals [18]. In addition, 4248 % of
the dopaminergic neurons in the VTA degenerate, while the ventral periaqueductal
gray is relatively spared (3 % loss) [19, 20]. Both, a direct and an indirect mecha-
nism may contribute to the sleepiness observed in PD following this loss of mid-
brain dopaminergic neurons. The SNpc neurons project directly to thalamocortical
circuits critical for promoting wakefulness including the midline, intralaminar, and
reticular nuclei of the thalamus [22]. These nigrothalamic projections are, in fact,
collaterals of the more well-known nigrostriatal pathway, therefore both degenerate
simultaneously in PD [22]. In a manner similar to that seen elsewhere throughout
the ARAS, the dopamine neurons within the SNpc, VTA, and ventral periaqueduc-
tal gray are known to feedback to the ARAS nuclei including the cortex, basal
forebrain, dorsal and median raphe, locus coeruleus, pedunculopontine tegmentum,
22 A.A.H. Freeman
Fig. 2.1 Degree of Parkinsons disease related degeneration in sleep-wake regulating nuclei as
measured by cell counts. The healthy brain depicts the nuclei, and corresponding neurotransmitter
or neuropeptide, known to regulate the sleep-wake cycle. The degree of neurodegeneration is
depicted by increasingly lighter shading in the Parkinsons disease brain. The percentage indicates
the decreased number of neurons in Parkinsons disease compared to controls
and laterodorsal tegmentum [10, 23, 24]. Loss of an excitatory dopaminergic input
to these wake-promoting nuclei may be an indirect route through which sleepiness
arises from dopamine loss.
Degeneration in PD, however, is not restricted to dopaminergic neurons and the
lack of strong correlation between sleepiness and the motor manifestations of the
disease or the decreased nocturnal sleep efficiency suggests that deficits within
other nuclei are likely to contribute to impairments in thalamocortical arousal states.
Extensive neuronal cell loss occurs in multiple nondopaminergic sleep-wake-related
neurotransmitter systems including acetylcholine, hypocretin/orexin, serotonin,
norepinephrine, histamine, and melanin-concentrating hormone, which may con-
tribute to these arousal deficits. Like the loss of dopamine, alterations in these sig-
naling pathways likely have direct effects on arousal and indirect effects mediated
by feedback loops to other sleep-wake regulatory nuclei (Fig. 2.1).
2.2.2 Acetylcholine
There are two primary cholinergic projection systems recognized to contribute to

sleep-wake regulation: the basal forebrain and the pedunculopontine tegmental
nucleus-lateral dorsal tegmental nucleus complex (PPN/LDT) in the brainstem. The
primary cholinergic input to the cortex arises from the basal forebrain which
includes three subpopulations: the medial septal nucleus, the diagonal band of
Broca, and, in particular, the nucleus basalis of Meynert (NbM). In the brainstem,
the PPN/LDT provide the major cholinergic input to the thalamus and the basal
ganglia (including the SNpc) and send descending projections to the pontine reticu-
lar formation including the subcoeruleus, and the gigantocellular nucleus of the
medulla [17, 25, 26].
The PPN/LDT neurons have either an equally high firing rate during both wake
and REM sleep (Wake-ON) or they have significantly higher activity during REM
than wake or non-REM sleep (REM-ON) [27]. Increases in activity occur 2060 s
in advance of state change [27]. This shift in firing rate prior to arousal demonstrates
PPN/LDTs critical role in driving the cortical desynchronization associated with
wakefulness and REM sleep.
Dysfunction within the cholinergic system occurs early in the progression of PD
and can be extensive. According to the Braak PD staging criteria, Lewy neurites
begin to appear simultaneously in the basal forebrain and SNpc in stage 3, prior to
dramatic cell loss in the SNpc [28]. Eventually, 3246 % of the NbM neurons
degenerate in PD [29, 30]. Degree of NbM loss does not correlate with disease dura-
tion [30], but in PD with dementia the magnitude can rival that observed in
Alzheimers disease [29]. Mapping acetylcholinesterase activity in vivo with posi-
tron emission tomography indicates that the resultant decrease in cortical innerva-
tion is only 15 %; however, this can be more extensive than the deficit observed in
Alzheimers patients (9.1 %) [31]. Postmortem examinations of parkinsonian brains
indicate that 46 % of PPN neurons degenerate, particularly in the pars compacta
component located in the caudal portion of the nucleus [32]. This degree of neuro-
nal loss correlates with disease severity [32]. While positron emission tomography
measures of AChE indicate that Alzheimers disease patients have no deficits in
cholinergic thalamic innervation, there is a 12.8 % decrease in PD and a 19.8 %
reduction in PD with dementia [33] indicative of PPN degeneration.
Deep brain stimulation (DBS) therapies reinforce the role that cholinergic brain-
stem nuclei play in sleep-wake regulation, and the impact that their degeneration
plays in PD. Originally, the PPN was selected as a DBS target to address the pos-
tural instability and gait disturbances in PD [34]. Patients also report improvements
in daytime sleepiness equivalent to a >50 % improvement on the Epworth Sleepiness
Scale following bilateral PPN stimulation in comparison to STN alone [35].
Objective polysomnographic measures indicate increased sleep efficiency, a 70 %
decrease in number of awakenings, and an almost twofold increase in time spent in
REM sleep [35, 36]. The wake-promoting effects of PPN stimulation occur at lower
stimulating frequencies (1025 Hz), whereas high-frequency stimulation (80 Hz)
can trigger sleep episodes [37]. Presumably, the higher frequency inhibits the wake-
promoting thalamic projections from the PPN.
REM sleep behavioral disorder (RBD) diagnosis often precedes the clinical mani-
festation of PD and is considered an early manifestation of -synucleinopathies
including PD, dementia with Lewy bodies, and multiple system atrophy. Longitudinal
studies of patients diagnosed with idiopathic RBD report that approximately 80 % of
patients will subsequently be diagnosed with a parkinsonian disorder or dementia
1214 years after the original onset of RBD [38, 39]. RBD is characterized by a loss
of muscle atonia during REM sleep, which is traditionally maintained by a complex
brainstem circuit including: PPN/LDT, locus coeruleus, subcoeruleus, medullary
24 A.A.H. Freeman
magnocellular reticular formation, and the ventrolateral reticulospinal tract (reviewed

in [40]). Despite the strong comorbidity of RBD and PD, the severity of RBD symp-
toms is not correlated with impaired dopamine transporter binding as measured by
positron emission tomography [41]. This suggests that the genuine pathology under-
lying RBD in the setting of parkinsonism involves degeneration of nondopaminergic
circuits. Acetylcholine is an obvious candidate considering the early pathology in
cholinergic circuits along with the prominent role of the PPN/LDT in the brainstem
circuitry regulating atonia in rapid eye movement sleep. In PD patients, positron
emission tomography reveals a significant correlation between the presence of RBD
symptoms and decreased acetylcholinesterase in cortex and thalamus, but no signifi-
cant relationship with either dopamine or serotonin measures [42]. Since these
regions of cholinergic innervation have two different origins, the basal forebrain and
the PPN/LDT, these results indicate concurrent degeneration of both pathways. PPN
DBS does not reduce the increased muscle tone during REM observed in RBD
patients [36]. Therefore, the decreased cholinergic innervation from the PPN is only
part of the disrupted pathophysiology that underlies RBD in PD.
2.2.3 Hypocretin/Orexin
Owing to their axonal projection patterns [43] and their generally excitatory effects
upon wake promoting neurons [44], the role of hypocretin/orexin (Hcrt/OX) neu-
rons in regulating the sleep-wake cycle has long been appreciated [45, 46]. The
Hcrt/OX-producing cell bodies are localized within the dorsomedial and lateral
hypothalamus, including the perifornical area, and innervate histaminergic neurons
in the nearby tuberomamillary nucleus and additional widespread ascending and
descending projections to disparate brain regions [43]. Targets include the cortex,
basal forebrain, amygdala, thalamus, SNpc, locus coeruleus, dorsal raphe, PPN/
LDT, pontine reticular formation, gigantocellular nucleus of the medulla, and the
spinal cord, in particular the intermediolateral cell column [43, 47]. Reciprocal
innervation from these targets to the dorsomedial hypothalamus positions Hcrt/OX
neurons to influence, and to be influenced by, circadian rhythms [48]. Regardless of
which receptor they are binding (i.e., Hcrt1/OX1 or Hcrt2/Ox2), both Hcrt/OX pep-
tides have excitatory downstream effects [45]. Additionally, many Hcrt/OX neurons
have been found to corelease glutamate that may contribute to some of their effects
on downstream targets [49].
In vivo electrophysiological investigations reveal that activation of the Hcrt/OX
system is critical to orchestrating the transition between non-REM or REM sleep
and wakefulness. Hcrt/OX neurons are most active during wake, particularly active
waking, whereas their firing rate decreases during non-REM sleep and ceases dur-
ing tonic REM sleep with a slight increase in activity during phasic REM [50, 51].
When applied experimentally, Hcrt/OX increases the firing rate of wake-promoting
nuclei including: cholinergic neurons in the basal forebrain [52] and brainstem
(LDT) [53], locus coeruleus [44], dorsal raphe [54], tuberomammillary nucleus
[55], and the VTA [56]. Local application of Hcrt/OX into the basal forebrain [57],
the locus coeruleus [58], or the LDT [59] increase wakefulness and decrease REM
sleep. Optogenetic activation of the Hcrt/OX neurons triggers a transition from
sleep to wakefulness, albeit with a delay between stimulation and arousal [60]. The
interconnection of the multiple wake-promoting nuclei is emphasized by activation
in downstream histaminergic neurons of the tuberomammillary nucleus and norad-
renergic neurons of the locus coeruleus following optogenetic stimulation of the
Hcrt/OX neurons [61]. Following sleep deprivation, sleep pressure overrides the
effects of Hcrt/OX activation and the probability of arousal decreases and the down-
stream nuclei are not activated [61]. The increased firing rate of Hcrt/OX neurons
throughout waking supports their hypothesized role in stabilizing the wake state,
but occurrence of the highest firing rate during active wake may indicate additional
roles in wake-related behaviors.
The number of Hcrt/OX neurons decreases by 2362 % progressively over the
course of PD [62]. Since the number of Hcrt/OX cells is dramatically reduced in
narcolepsy [63], one might expect that the narcoleptic-like sleepiness observed in
some PD patients (i.e., excessive daytime sleepiness and REM intrusions into day-
time naps) would be explained by the loss of Hcrt/OX, along with the decreased
dopaminergic signaling. Despite the dramatic degeneration of Hcrt/OX neurons, the
level of hypocretin-1 in the CSF is not significantly reduced and does not correlate
with sleep disruptions [64]. Experimental lesions in rats demonstrate that a 73 %
decrease in the number of Hcrt/OX neurons is required for a concomitant 50 %
reduction of Hcrt-1 in the CSF and increase in REM sleep [65]. Therefore, it seems
that the remaining, viable Hcrt/OX neurons are able to compensate sufficiently to
prevent significant decreases in CSF concentrations. However, the loss of excitatory
drive on downstream wake-promoting nuclei still seems like a parsimonious expla-
nation for some of the sleep-wake disturbances in PD patients. That being said,
because of neuropathological heterogeneity and multiple additional factors (e.g.,
medications or comorbid disease) that influence sleep-wake state, it is difficult to
pinpoint with certainty which parkinsonian-related sleep disturbance is attributable
to the Hcrt/OX system degeneration.
2.2.4 Serotonin
Serotonin is produced in cell groups along the midline from the midbrain to the pons.
The rostral potion of the serotonergic neurons in the pons and midbrain, including
the dorsal raphe and median raphe, can be differentiated from the caudal portion
based upon chemo- and cyto-architecture [66]. The neuroanatomical projections
allow the dorsal and median raphe to be distinguished; although they project to simi-
lar areas, the terminal fields are distinct [67]. Targets of the dorsal raphe projections
include the cortex, basal forebrain, thalamus, dorsomedial hypothalamus, SNpc,
median raphe, locus coeruleus, PPN, subcoeruleus, and the sleep-promoting VLPO
[24, 26, 68, 69]. Similarly, targets of the median raphe efferents include the cortex,
basal forebrain, thalamus, dorsomedial hypothalamus, SCN, SNpc, VTA, locus coe-
ruleus, dorsal raphe, PPN/LDT, and the subcoeruleus [26, 67].
26 A.A.H. Freeman
Of the multiple serotonergic nuclei, the dorsal raphe primarily regulates sleep-
wake cycles while the median raphe is integral to regulation of circadian rhythm
[7072]. The majority of serotonergic neurons within the dorsal raphe are type I,
which demonstrate alterations in firing rate across behavioral state. Activity is high-
est during active waking, particularly when orienting to a stimulus, and decreases
progressively across quiet waking and non-REM sleep [70, 72]. During REM sleep
serotonergic neurons are silent, but resume wake-related levels of activity prior to
the end of the episode [70, 72]. These findings indicate the dorsal raphe plays a key
role in initiating the transition between stages.
In PD, decreased numbers of neurons are observed in both the dorsal raphe
(37.2 %) [21] and the median raphe (56 %) [73]. Degeneration in each of these
neurons may contribute separately to the sleep-wake disturbances observed in
PD. Loss of the wake-promoting neurons in the dorsal raphe may contribute to the
excessive sleepiness. Meanwhile, loss of circadian regulating median raphe neurons
may contribute, in part, to the increased arousals at night and daytime sleepiness.
2.2.5 Norepinephrine
The locus coeruleus is the primary norepinephrine-producing nucleus in the

brain. Targets of widespread noradrenergic efferents include the cortex, basal
forebrain, thalamus, Hcrt/OX, dorsal raphe, PPN/LDT, subcoeruleus, and the
sleep-promoting VLPO [26, 68, 74, 75]. Whether norepinephrine has excitatory
or inhibitory influences on these downstream nuclei depends on the subtype of
adrenergic receptors present. In the basal forebrain and dorsal raphe, excitatory
effects are due to the presence of the 1- or -adrenoceptors [76]. The VLPO and
Hcrt/OX neurons express 2-adrenoceptors resulting in inhibitory responses
[75]. In the PPN/LDT, the wake-ON neurons express 1-adrenoceptors and the
REM-on neurons express 2-adrenoceptors allowing the effects of norepineph-
rine modulate state [77].
Activity of noradrenergic neurons is closely related to arousal. The neurons of
the locus coeruleus are most active during wakefulness, decrease their activity dur-
ing non-REM sleep, and are virtually silent during REM sleep [78]. Alterations in
firing rate precede the EEG transitions to the corresponding arousal level [78].
Norepinephrine provides such a strong alerting signal that acute optogenetic stimu-
lation results in immediate transition to wakefulness and long-term stimulation
increases wakefulness and decreases non-REM sleep times [79]. Optogenetic inhi-
bition of the locus coeruleus increases the number of sleep onsets and decreases the
duration of wake episodes, but does not prolong the duration of sleep episodes [79].
However, arousals still occur during optogenetic inhibition of the locus coeruleus,
indicating that this activity is not necessary and other components of the sleep-wake
regulatory network can compensate in its absence [79].
In PD, 6378 % of the neurons within the locus coeruleus degenerate [21, 80].
The extensive loss of this signaling pathway likely contributes to excessive daytime
sleepiness in PD patients; the specific contributions, however, are difficult to
disentangle from the effects of the degeneration in the other wake-promoting neu-
rotransmitter systems.
2.2.6 Histamine
Histamine is produced in large cell bodies of the tuberomammillary nucleus located

in the posterior hypothalamus. Widespread projections from histaminergic neurons
innervate the cortex, thalamus, SNpc, VTA, locus coeruleus, dorsal raphe, LDT,
pontine reticular formation, and the gigantocellular nucleus of the medulla [81].
The area of densest innervation is observed in the hypothalamus, including the Hcrt/
OX cell bodies, and the basal forebrain [55, 81]. Afferents also target the sleep-
promoting VLPO [68]. Four metabotropic histamine receptors have been identified
(H1R-H4R); however, H4R is primarily expressed in the periphery. Signaling
through both the H1R and H2R is excitatory, while H3R primarily functions as a
presynaptic autoreceptor or heteroreceptor (reviewed in [82]).
Electrophysiological recordings of histaminergic neurons in freely moving mice
across sleep-wake states reveal the highest firing rate during attentive or active
wakefulness [83]. Activity decreases during quiet waking, ceases prior to the onset
of sleep, and remains silent throughout non-REM and REM sleep [83]. Histaminergic
neurons resume firing only when the animal is completely awakened, indicating that
this signaling pathway is critical in the maintenance of wakefulness rather than
initiating the transition from sleep to wake [83].
In contrast to all other wake-promoting nuclei, the histaminergic neurons of the
tuberomammillary nucleus do not degenerate in PD [84]. In fact, the concentration
of histamine is significantly increased in the SNpc (201 %) and other areas of the
basal ganglia (159234 %) [85]. In the SNpc, histaminergic innervation increases
and the terminal fields are particularly dense surrounding remaining dopamine neu-
rons [86]. This juxtaposition suggests that histamine may be important for promot-
ing neuronal survival through stimulated release of interleukin-6 from astrocytes,
which, in turn, triggers synthesis and secretion of nerve growth factor [86]. In the
putamen, the concentration of the primary histamine metabolite tele-methylhistamine
is the same in control and PD brains, indicating that the metabolism of histamine is
unaltered despite the increased availability [85].
Pitolisant is an H3R antagonist/inverse agonist that is being developed to treat
excessive daytime sleepiness. When administered to a parkinsonian feline MPTP
model exhibiting daytime sleepiness, time spent awake is increased [87]. In clinical
trials of PD patients, pitolisant reduced subjective sleepiness and resulted in a five-
point decrease on the Epworth sleepiness scale [87].
It is difficult to know the role of increased histaminergic innervation of SNpc in
general, let alone in the context of the disrupted sleep-wake cycle in PD considering
the lack of information available regarding histaminergic innervation of other wake-
promoting nuclei. However, the evidence indicating that histaminergic metabolism
is preserved suggests that any loss of wake-promoting effect in histamine circuits
would be due to degeneration of downstream targets.
28 A.A.H. Freeman
2.3 Sleep-Promoting Circuit
2.3.1 Melanin-Concentrating Hormone
Melanin-concentrating hormone (MCH) neurons are intermixed with the Hcrt/OX

neurons in the dorsomedial, lateral hypothalamus, but they are a distinct neuronal
population [43]. Ascending and descending projections of the MCH neurons are
extensive, but the relevant nuclei for sleep-wake regulation include: basal forebrain,
thalamus, tuberomammillary nucleus, SNpc, VTA, PPN/LDT, dorsal and medial
raphe, locus coeruleus, and the pontine reticular formation [88]. There are also
reciprocal projections between the MCH neurons and the Hcrt/OX neurons [89].
MCH is an inhibitory neuropeptide, and >80 % of MCH neurons also corelease
GABA [90] thereby increasing the potential inhibitory effects.
Evidence suggests that the primary role of the MCH neurons in sleep-wake regu-
lation is to promote REM sleep. Electrophysiologically, the MCH neurons are max-
imally active during REM sleep and virtually silent during non-REM sleep and
wakefulness [50]. Intracerebroventricular administration of MCH increases REM
sleep amounts in a dose-dependent manner [91]. Optogenetic activation of MCH
neurons during non-REM sleep increases the likelihood of transition to REM sleep,
while activation during REM sleep increases the duration of the episode without
altering the EEG power spectrum or muscle tone [90]. The extension of REM sleep
duration is observed even in mice lacking the MCH receptor indicating that this
effect may be mediated by the coreleased GABA rather than the MCH itself [90].
Due to the diffuse projections, it is conceivable that MCH promotion of REM sleep
may occur through inhibitory projections to wake-promoting Hcrt/OX, histaminer-
gic or basal forebrain cholinergic neurons, or by driving the REM-OFF neurons in
the brainstem ARAS to cease firing. However, some evidence suggests that the
MCH-histaminergic TMN or MCH-cholinergic basal forebrain circuits play key
roles in mediating this effect [90].
In PD, the number of MCH neurons decreases by 74 % [62]. Loss of this signal-
ing pathway may explain, at least in part, some of the nocturnal REM sleep deficits
in PD patients. However, MCH is relatively unstudied in the context of PD and little
is known about the specific impact of this deficit.
Conclusion
The neurodegeneration in PD extends beyond the hallmark nigrostriatal system
and encompasses many other nuclei critical for the regulation of the sleep-wake
cycle.
Due to the redundant projections and feedback loops, both negative and posi-
tive, throughout these nuclei, it is difficult to isolate the sleep-wake disruptions
resulting from the loss of an individual neurotransmitter. This network must be
considered to function as a unit and altered activity in one or more components
impacts the output of the remaining members. The sleep-wake disruptions of PD
patients reflect the integrated degeneration of multiple arousal related nuclei
throughout the brain. While excessive daytime sleepiness and disrupted nocturnal
sleep are inherent to the disorder itself, one cannot discount the secondary con-
tributions of nocturnal movement disturbances or pharmacological therapies that
may further worsen these symptoms.
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Impaired Sleep and Alertness
in Parkinsons Disease: What Did 3
We Learn from Animal Models?
Pierre-Herv Luppi, Olivier Clment, Sara Valencia Garcia,

Frdric Brischoux, and Patrice Fort
Contents
3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.2 Populations of Neurons Responsible for Waking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.3 Mechanisms Involved in Non-REM (Slow-Wave Sleep, SWS) Sleep . . . . . . . . . . . . . . 37
3.4 Summary: The Neuronal Network Responsible for SWS (Non-REM) Sleep . . . . . . . . 38
3.5 Mechanisms Involved in Paradoxical (REM) Sleep Genesis . . . . . . . . . . . . . . . . . . . . . 38
3.5.1 The Localization of the Neurons Generating PS
in the Pontine Reticular Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.5.2 Mechanisms Responsible for SLD PS-On Neurons
Activation During PS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.5.3 Neurons Inhibiting the GABAergic and Monoaminergic
PS-Off Neurons at the Onset and During PS . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
P.-H. Luppi (*)

SLEEP team, INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center,
Team Physiopathologie des rseaux neuronaux du cycle veille-sommeil,
7 Rue Guillaume Paradin, F-69372 Lyon, France
University of Lyon, F-69000 Lyon, France
University Claude Bernard Lyon 1, F-69000 Lyon, France
Facult de Mdecine RTH Laennec, UMR5167 CNRS,
7 Rue Guillaume Paradin, Lyon 69372, France
O. Clment S. Valencia Garcia F. Brischoux P. Fort
SLEEP team, INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center,
Team Physiopathologie des rseaux neuronaux du cycle veille-sommeil,
7 Rue Guillaume Paradin, F-69372 Lyon, France
University of Lyon, F-69000 Lyon, France
University Claude Bernard Lyon 1, F-69000 Lyon, France

36 P.-H. Luppi et al.
3.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.6.1 A Network Model for PS Onset and Maintenance . . . . . . . . . . . . . . . . . . . . . . . 41
3.6.2 Role of Dopamine in the Sleep-Waking Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.6.3 Sleep in MPTP Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.6.4 REM Sleep Behavior Disorder Models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.6.5 Animal Models of RBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
3.6.6 Mechanisms Responsible for Phasic Motor Activation in RBD Patients . . . . . . 45
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Abstract
The aim of this review is to try to provide a conceptual framework on the
mechanisms potentially responsible for sleep alteration in Parkinsons disease
(PD) based on data obtained in animals. We first provide state-of-the-art
hypotheses on the mechanisms responsible for the succession of the three
vigilance states, namely waking, non-rapid eye movement (non-REM) also
called slow-wave sleep (SWS) and REM sleep also called paradoxical sleep
(PS). We then review our knowledge on the role of dopamine in sleep-waking
regulation. We pursue by discussing the results obtained on sleep in MPTP
animal model of PD. We complete our review by providing hypotheses on the
mechanisms responsible for REM sleep behavior disorder known to occur in half
of the Parkinsons patients based on studies of RBD animal models.
3.1 Introduction
Sleep disturbances, excessive daytime sleepiness, and rapid eye movement sleep
behavior disorder (RBD) are among the most frequent and disabling manifestations
of PD [13]. They often precede the motor features of the disease by years and may
serve as early biomarkers of the premotor phase of PD [36]. The pathophysiology
of these sleep alterations is still not comprehended. In particular, it is still discussed
as to whether the underlying mechanisms of sleep disturbances in PD are due to
dopamine (DA) deficiency. In the following, we review our current knowledge on
the neuronal networks responsible for the sleep-waking cycle and on the animal
models available to provide possible mechanisms at the origin of sleep disturbances
in PD.
3.2 Populations of Neurons Responsible for Waking
In most mammals, there are three vigilance states, which are characterized by clear
differences in electroencephalogram (EEG), electromyogram (EMG) and electro-
oculogram (EOG) recordings. The waking state is characterized by high-frequency,
low-amplitude (desynchronized) activity on the EEG, sustained EMG activity and
ocular movements; non-rapid eye movement (non-REM), also named slow-wave
3 Sleep in Parkinson Animal Models 37
sleep (SWS) (synchronized), is characterized by low-frequency, high-amplitude

delta oscillations on the EEG, low muscular activity on the EMG, and no ocular
movement; and rapid eye movement (REM), also called paradoxical sleep (PS), is
characterized by an activated low-amplitude EEG similar to the waking EEG, but
with complete disappearance of postural muscle tone and the occurrence of rapid
eye movements and muscle twitches.
The activation of the cortex during waking is induced by the activity of multiple
neurochemical systems. These neurochemical systems include the serotonergic
neurons, which are mainly localized in the dorsal raphe nucleus, noradrenergic neu-
rons in the locus coeruleus, the histaminergic neurons localized in the tuberomam-
millary nucleus, and the orexin (hypocretin) neurons localized in the tuberal
hypothalamus [7]. In addition, the cholinergic neurons in the pontine brainstem and
the basal forebrain are implicated both in cortical activation during waking and
paradoxical sleep. Altogether, these systems induce waking characterized by high-
frequency, low-amplitude cortical activation [8] by means of their extensive projec-
tion to the thalamus and/or the neocortex.
3.3 Mechanisms Involved in Non-REM

(Slow-Wave Sleep, SWS) Sleep
During sleep, it is believed that the waking-inducing systems are all inhibited by
gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the
brain [9, 10]. When the waking systems are inactivated, the thalamocortical
network oscillates in the delta range (i.e., the slow-wave mode of activity typical of
SWS) [7].
SWS-active neurons were localized by using expression of the immediate early
gene Fos as a marker of neuronal activation in rats that had slept for a long
period before sacrifice [11]. These neurons are distributed diffusely in the POA but
are more densely packed in the median preoptic nucleus (MnPn) and the ventrolat-
eral preoptic nucleus (VLPO). Studies showed that the number of Fos-
immunoreactive neurons in the VLPO and MnPn positively correlated with sleep
quantity and sleep consolidation during the last hour preceding sacrifice [11, 12]. It
was later demonstrated that VLPO and the suprachiasmatic nucleus (SCN), a criti-
cal site in circadian rhythm network, have synchronized activity [13]. Considering
that both areas are interconnected and receive inputs from the retinal ganglion cells,
it is, thus, possible that circadian- and photic-linked information may be conveyed
to modulate VLPO activity [7].
Electrophysiology experiments in behaving rats have shown that neurons
recorded in the VLPO and MnPn are active during SWS, generally anticipating its
onset by several seconds. Functionally, bilateral neurotoxic destruction of VLPO is
followed by a profound and long-lasting insomnia in rats [14]. Retrograde and
anterograde tract-tracing studies indicate that VLPO and MnPn neurons are recipro-
cally connected with wake-active neurons such as those containing histamine in the
tuberomammillary nucleus (TMN), hypocretin in the perifornical hypothalamic
area (PeF), serotonin in the dorsal raphe nuclei (DRN), noradrenaline in the locus
coeruleus (LC), and acetylcholine in the pontine (LDT/PPT) and basal forebrain
nuclei. In these wake-promoting areas, extracellular levels of GABA increase dur-
ing SWS compared to W.
Electrophysiological recordings of VLPO neurons in rat brain slices showed that
it contains a homogeneous neuronal group with specific intrinsic membrane proper-
ties, a clear-cut chemo-morphology, and an inhibitory response to the major waking
neurotransmitters [15]. These neurons are inhibited by noradrenaline (NA), via
postsynaptic alpha2-adrenoceptors, acetylcholine, through muscarinic postsynaptic
and nicotinic presynaptic actions on noradrenergic terminals. In contrast, histamine
and hypocretin do not modulate VLPO neurons [15, 16]. Finally, serotonin showed
complex effects inducing either inhibition (50%, Type 1) or excitation (50%, Type
2) of the VLPO neurons [7, 17]. Further, application of an adenosine A2A receptor
(A2AR) agonist evoked direct excitatory effects specifically in Type 2 VLPO neu-
rons [7, 17]. A number of studies also showed that adenosine A1 receptors (A1R)
promote sleep through inhibition of the wake-promoting neurons, in particular cho-
linergic and hypocretin neurons [18, 19]. However, transgenic mice that lack A1R
exhibit normal homeostatic regulation of sleep. In contrast, the lack of A2AR pre-
vents normal sleep regulation and blocks the wake-inducing effect of caffeine, sug-
gesting that the activation of A2AR is crucial in SWS [2022].
3.4 Summary: The Neuronal Network Responsible

for SWS (Non-REM) Sleep
Both the VLPO and the MnPn contain neurons responsible for sleep onset and
maintenance. These neurons are inhibited by noradrenergic and cholinergic inputs
during waking. The majority of them start firing at sleep onset (drowsiness) in
response to excitatory, homeostatic (adenosine and serotonin), and circadian drives
(suprachiasmatic input). Conversely, the slow removal of excitatory influences
would result in a progressive firing decrease in VLPO neurons and, therefore, an
activation of the wake-promoting systems inducing awakening [17, 23].
3.5 Mechanisms Involved in Paradoxical

(REM) Sleep Genesis
3.5.1 The Localization of the Neurons Generating

PS in the Pontine Reticular Formation
It was first shown that a state characterized by muscle atonia and REM persists fol-
lowing decortication, cerebellar ablation, or brain stem transections rostral to the
pons and in the pontine cat, a preparation in which all the structures rostral to the
pons have been removed [24]. These results indicated that brainstem structures are
necessary and sufficient to trigger and maintain the state of PS. Electrolytic and
chemical lesions showed that the dorsal part of pontis oralis (PnO) and caudalis
(PnC) nuclei, also named peri-locus coeruleus (peri-LC), pontine inhibitory area
(PIA), and subcoeruleus nucleus (SubC) contain the neurons responsible for PS
onset [24]. In addition, the PnO and PnC contain many neurons that show a tonic
firing selective to PS (called PS-on neurons) [25, 26]. More recently, a corre-
sponding area has been identified in rats, and named sublaterodorsal tegmental
nucleus (SLD). We demonstrated that most of the Fos-labeled neurons localized in
the SLD after PS recovery express the vesicular glutamate transporter 2 (vGlut2)
[27] and are therefore glutamatergic.
A number of recent results further suggest that PS-on glutamatergic neurons
located in the SLD generate muscle atonia via descending projections to PS-on
GABA/glycinergic premotoneurons located at medullary level. First, by means of
intracellular recordings during PS, it has been shown that trigeminal, hypoglossal,
and spinal motoneurons are tonically hyperpolarized by large inhibitory postsynap-
tic potentials (IPSPs) during PS. Further, when these recordings were combined
with local iontophoretic application of strychnine (a specific antagonist of the inhib-
itory neurotransmitter, glycine), motoneurons hyperpolarization was strongly
decreased, indicating that they are tonically inhibited by glycinergic neurons during
PS [2830]. It has then been shown that the levels of glycine but also that of GABA
increase within hypoglossal and spinal motor pools during PS-like atonia [31].
Further, it was recently shown that combined microdialysis of bicuculline, strych-
nine, and phaclophen (a GABA-B antagonist) in the trigeminal nucleus is necessary
to restore jaw muscle tone during PS [32]. Finally, mice with impaired glycinergic
and GABAergic transmissions display PS without atonia [33]. In addition, it has
been shown that the SLD sends direct efferent projections to GABA/glycinergic
neurons located in the nucleus raphe magnus (RMg) and the ventral (GiV), alpha
(Gia) gigantocellular and lateral paragigantocellular (LPGi) reticular nuclei [34,
35]. Further, GABA/glycinergic neurons of the Gia, GiV, LPGi, and RMg express
c-Fos after PS hypersomnia [34, 36].
It has also been shown that a subpopulation of SLD PS-on neurons project to the
intralaminar thalamic nuclei, the posterior hypothalamus, and the basal forebrain. In
addition to the SLD, it has also been shown that cholinergic neurons located in the
pedunculopontine and laterodorsal tegmental nuclei and glutamatergic neurons
located in the reticular formation active both during waking and PS and projecting
rostrally contribute to cortical activation during PS [7, 34].
3.5.2 Mechanisms Responsible for SLD PS-On

Neurons Activation During PS
A long-lasting PS-like hypersomnia can be pharmacologically induced with a short

latency in head-restrained unanesthetized rats by iontophoretic application into the
SLD of bicuculline or gabazine, two GABA-A receptor antagonists [34]. Further,
application of kynurenate, a glutamate antagonist, reverses the PS-like state induced
by bicuculline [34]. In the head restrained rat, we also recorded neurons within the
SLD specifically active during PS and excited following bicuculline or gabazine

iontophoresis [37]. Taken together, these data indicate that the activation of SLD
PS-on neurons is mainly due to the removal during PS of a tonic GABAergic tone
present during W and SWS combined with the continuous presence of a glutamater-
gic input. Combining retrograde tracing with cholera toxin b subunit (CTb) injected
in SLD and glutamate decarboxylase 67 (GAD67) immunohistochemistry or Fos
immunohistochemistry with GAD67mRNA in situ hybridization after 72 h of PS
deprivation, we recently demonstrated that the ventrolateral part of the periaqueduc-
tal gray (vlPAG) and the adjacent dorsal part of the deep mesencephalic nucleus
(dDPMe) are the only ponto-medullary structures containing a large number of
GABAergic neurons activated during PS deprivation projecting to the SLD [36].
Further, injection of muscimol in the vlPAG and/or the dDpMe induces strong
increases in PS quantities in cats [38] and rats [36]. Finally, neurochemical lesion of
these two structures induces a profound increase in PS quantities [39]. These con-
gruent experimental data led us to propose that PS-off GABAergic neurons within
the vlPAG and the dDpMe gate PS by tonically inhibiting PS-on neurons of the SLD
during W and SWS.
3.5.3 Neurons Inhibiting the GABAergic and Monoaminergic

PS-Off Neurons at the Onset and During PS
Bicuculline application on serotonergic and noradrenergic neurons during SWS or

PS restores a tonic firing pattern [9, 10, 40]. These results strongly suggest that an
increased GABA release is responsible for the PS-selective inactivation of mono-
aminergic neurons. This hypothesis is well supported by microdialysis experiments
in cats, which measured a significant increase in GABA release in the DRN and LC
during PS as compared to W and SWS [41, 42]. By combining retrograde tracing
with CTb and GAD immunohistochemistry in rats, the vlPAG and the dorsal para-
gigantocellular nucleus (DPGi) [10, 43] contained numerous GABAergic neurons
projecting both to the DRN and LC. We then demonstrated by combining c-Fos and
retrograde labeling that both nuclei contain numerous LC-projecting neurons selec-
tively activated during PS rebound following PS deprivation [44, 45]. Further, the
DPGi contains numerous PS-on neurons that increase their activity specifically dur-
ing PS [46]. In summary, a large body of data indicate that GABAergic PS-on neu-
rons localized in the vlPAG and the DPGi hyperpolarize the monoaminergic neurons
during PS.
We first proposed that these neurons might be also responsible for the inhibition
of the dDPMe/vlPAG PS-off GABAergic neurons during PS. To test this hypothe-
sis, we recently localized the neurons active during PS hypersomnia projecting to
the dDPMe/vlPAG PS-off GABAergic neurons [47]. The lateral hypothalamic area
(LH) is the only brain structure containing a very large number of neurons activated
during PS hypersomnia and projecting to the VLPAG/dDpMe. Forty-four percent of
these neurons express the neuropeptide melanin concentrating hormone (MCH).
These results indicate that LH hypothalamic neurons might play a crucial role in PS
onset and maintenance by means of descending projections to the vlPAG/dDPMe

PS-off GABAergic neurons.
Supporting this claim, rats receiving intracerebroventricular (icv) administration
of MCH showed a strong dose-dependent increase in PS and, to a minor extent,
SWS quantities, due to an increased number of PS bouts [48]. Further, subcutaneous
injection of an MCH antagonist decreases SWS and PS quantities [49] and mice
with genetically inactivated MCH signaling exhibit altered vigilance state architec-
ture and sleep homeostasis [50, 51]. Finally, it was recently shown that optogenetic
stimulation of MCH neurons induces PS [52, 53].
To determine the function of the LH MCH+/GABA+ and MCH-/GABA+ neu-
rons in PS control, we inactivated all LH neurons with muscimol (a GABA-A ago-
nist) or only those bearing alpha-2 adrenergic receptors using clonidine. Muscimol
and to a lesser degree clonidine bilateral injections in the LH induce an inhibition of
PS with or without an increase in SWS quantities, respectively. Our results suggest
that MCH/GABAergic PS-on neurons of the LH control PS onset and maintenance
by means of a direct inhibitory projection to vlPAG/dDpMe PS-off GABAergic
neurons. From our results, it can be proposed that MCH/GABAergic neurons of the
LH constitute a master generator of PS, which controls a slave generator located in
the brainstem.
The cessation of activity of the MCH/GABAergic PS-on neurons and more
largely of all the PS-on neurons at the end of PS episodes is certainly due to a com-
pletely different mechanism than the entrance into the state. Indeed, animals are
entering PS slowly from SWS, while in contrast they exit from it abruptly by a
microarousal [54]. This indicates that the end of PS is induced by the activation of
the W systems like the monoaminergic, hypocretin or the histaminergic neurons.
The mechanisms responsible for their activation remain to be identified.
3.6 Conclusion
3.6.1 A Network Model for PS Onset and Maintenance
The onset of PS would be due to the activation by intrinsic and extrinsic factors of
PS-on MCH/GABAergic neurons localized in the lateral hypothalamic area (LH).
These neurons would inhibit at the onset and during PS the PS-off GABAergic neu-
rons localized in the vlPAG and the dDpMe tonically inhibiting during W and SWS
the glutamatergic PS-on neurons from the SLD. The disinhibited ascending gluta-
matergic SLD PS-on neurons would in turn induce cortical activation via their pro-
jections to intralaminar thalamic relay neurons in collaboration with W/PS-on
cholinergic and glutamatergic neurons from the LDT and PPT, mesencephalic and
pontine reticular nuclei and the basal forebrain. Descending glutamatergic PS-on
SLD neurons would induce muscle atonia via their excitatory projections to GABA/
glycinergic premotoneurons localized in the raphe magnus, alpha and ventral gigan-
tocellular reticular nuclei. PS-on GABAergic neurons localized in the LH, DPGi,
and vlPAG would also inactivate the PS-off orexin (hypocretin) and aminergic
neurons during PS. The exit from PS would be due to the activation of waking
systems since PS episodes are almost always terminated by an arousal. The waking
systems would reciprocally inhibit the GABAergic PS-on neurons localized in the
LH, vlPAG and DPGi. Since the duration of PS is negatively coupled with the
metabolic rate, we propose that the activity of the waking systems is triggered to
end PS to restore crucial physiological parameters like thermoregulation.
3.6.2 Role of Dopamine in the Sleep-Waking Cycle
Early electrophysiological studies in rats and cats showed that the firing rate of
dopaminergic neurons of the substantia nigra (SNC) and the ventral tegmental area
(VTA) is not influenced by the sleep-wake cycle [55, 56]. More recently, it was
shown that dopamine neurons of the VTA display during paradoxical sleep (PS) a
prominent bursting pattern [57]. The burst pattern observed during PS is similar to
the activity measured during the consumption of palatable food known to induce
large synaptic dopamine release. Besides, it has been shown that c-Fos expression
is increased in a few or nearly no dopamine cells during a rebound of PS [58, 59].
Finally, a microdialysis study found out that extracellular levels of dopamine in
nucleus accumbens and prefrontal cortex are higher both during W and PS com-
pared to SWS [60].
Lesioning of the DA-containing neurons located in the SNC and the VTA of the
cat induces no change in the quantities of each vigilance state. Waking state is
characterized by akinesia, hypertonus, and a lack of behavioral arousal [61]. Wisor
et al. [62] quantified sleep and W in dopamine transporter (DAT) knockout mice.
These hyperdopaminergic mice show a significant increase of wake quantities and a
reduction of SWS during the light phase compared with wild-type mice. It has also
been shown that behavioral arousal is impaired in DA D1 receptor knockout mice
[63]. Further, systemic administration of a selective DA D1 agonist induces desyn-
chronization of the EEG and behavioral arousal, together with an increase of W and
a reduction of SWS and PS. In contrast, injection of a DA D1 antagonist tends to
produce sedation and to reduce W, whereas SWS and PS are increased [63]. Mice
with inactivation of the D2 receptor show reduced levels of spontaneous locomotor
activity. Systemic administration of DA D2 agonists induces biphasic effects, such
that low doses reduce W and increase SWS and REMS, whereas large doses induce
the opposite effects. Drugs with DA D2 receptor blocking properties increase
NREMS and reduce W [63]. Altogether, these results suggest that DA neurons of
the VTA and SNC play a role in behavioral arousal and a still to be identified role
during PS.
3.6.3 Sleep in MPTP Models
Chronic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

is known to induce a destruction of dopaminergic neurons of the SN and
VTA. The first study showing the induction of a sleep effect of MPTP reported a
selective REM sleep suppression that lasted 69 days after the last administration of
the neurotoxin in cats [64]. Conversely, it was then shown that MPTP-treated mice
present changes in sleep architecture, with longer wakefulness and REM sleep
episodes and an increase in the amount of REM sleep [65].
The abrupt ablation of REM sleep was also observed in a subsequent study in
MPTP-treated monkeys [66]. They further showed that 2 weeks after cessation of
MPTP treatment, REM sleep was still dramatically reduced and the animals also
displayed progressive sleep deterioration and fragmentation with increased
frequency and duration of wake after sleep onset and reduced sleep efficacy. The
animals further showed increased daytime sleepiness [66] Interestingly, 90 days
after the last MPTP injection, partial progressive but significance reemergence of
REM sleep was observed (8% vs. 16% in control) [66]. Despite the general increase
in tonic muscle activity, REM sleep muscle atonia still occurred but with intermit-
tent bouts of REM sleep without atonia without occurrence of RBD.
From these results, it can be concluded that MPTP models only partly replicate
the symptoms of PD. Indeed, REM sleep quantities are not reduced in Parkinsons
patients, suggesting that the decrease in REM sleep quantities in MPTP models is
not induced by the loss of dopaminergic neurons but rather by an effect on other
types of neurons involved in PS inhibition like the serotoninergic or noradrenergic
systems. In contrast, the increased daytime sleepiness might well be due to the
disappearance of the dopaminergic neurons known to be involved in behavioral
waking.
3.6.4 REM Sleep Behavior Disorder Models
Rapid eye movement sleep behavior disorder (RBD) is characterized by the occur-
rence of vivid, intense, and violent movements during rapid eye movement sleep
(REM sleep, also named paradoxical sleep, PS). The patient can talk, yell, punch,
kick, sit, jump from bed, and grab during REM sleep. When the patient is awakened
or wakes up spontaneously during the acting, he can recall dreams that correspond
to the physical activity. RBD is usually seen in middle-aged to elderly men [67].
The disorder occurs in association with various degenerative neurological diseases
such as PD [68]. It has been reported that up to 65% of patients diagnosed with
RBD subsequently developed PD within an average time of 1213 years from the
onset of RBD symptoms. The prevalence of RBD in PD is of 4658% [68]. The
neuronal dysfunction at the origin of the disease is not known. A large number of
results suggest that RBD is not due to a dysfunction of the dopaminergic nigrostria-
tal system. The strongest arguments are that RBD does not occur in about half of the
PD patients, the use of dopaminergic agents usually does not improve RBD, and
RBD precedes for several years the onset of PD in many PD patients [68]. It is
therefore more likely that RBD is due to a degeneration of the neuronal system
generating muscle atonia during REM sleep. In the following, we consequently
review results in animal models of RBD.
3.6.5 Animal Models of RBD
It has recently been shown that mice with impaired glycinergic and GABAergic
transmissions display all features of RBD, that is, REM sleep without atonia, myo-
clonic jerks during NREM sleep, sleep fragmentation, and EEG slowing [33]. In
addition, it has been shown that inactivation of GABA and glycinergic transmis-
sions in the spinal cord induced the occurrence of small phasic movements during
REM sleep [69]. Further, an increased tonus is seen during REM sleep in cats with
GiV and Gia cytotoxic lesion [70, 71].
In addition, in cats and rats, electrolytic and neurochemical lesions of the SLD
eliminate muscle atonia and induce phasic muscle activity during REM sleep. The
phasic events include large limb twitches, locomotion, fear, attack, and defensive
behaviors [39, 7274]. Importantly, these lesions also induce a moderate to severe
decrease in the total quantities of REM sleep depending on their location and size
[24, 39, 75].
In neurodegenerative diseases where RBD is frequent, neuronal cell loss was
observed in the brainstem structures controlling REM sleep, like the locus sub-
coeruleus (corresponding to the SLD), the pedunculopontine nucleus (PPTg),
and the gigantocellular reticular nucleus (Gi), and also in their rostral afferents,
especially the amygdala [68]. Importantly, RBD patients display normal quanti-
ties of REM sleep [76]. It seems therefore unlikely that RBD is due to a degenera-
tion of a large proportion of the SLD REM-on glutamatergic neurons since large
SLD lesions in cats and rats induce a moderate to strong decrease in REM sleep
quantities [24, 39, 75]. One possibility is that in RBD patients, only the descend-
ing REM-on neurons of the SLD specifically responsible for muscle atonia
degenerated. It would imply that REM-on glutamatergic neurons of the SLD are
divided in at least two subpopulations, one descending responsible for muscle
atonia and the other one inducing the state of REM sleep itself and EEG activa-
tion. Data obtained in cats support the existence of two populations of SLD
REM-on cells (see above). However, these two populations have not yet been
identified in rats.
Another possibility is that the premotor PS-on GABA/glycinergic neurons of
the RMg, Gia, and GiV degenerate in RBD patients. Indeed, lesions of these
structures in cats induced PS without atonia and only a moderate decrease in
REM sleep quantities [70]. Further, the duration of REM sleep episodes but not
the total quantities of REM sleep was decreased in RBD mice with disrupted
GABA and glycinergic transmissions [33]. These results are in favor of the
hypothesis that RBD is due to a degeneration of GABA/glycinergic REM-on
neurons.
Finally, it should be mentioned that neurons located in the ventral
mesencephalic reticular formation could also be implicated in RBD since neu-
rochemical lesions of this area in cats increased muscle tone and phasic muscle
activity during REM sleep with or without inducing a decrease in REM sleep
quantities [77].
3.6.6 Mechanisms Responsible for Phasic

Motor Activation in RBD Patients
It has been shown in rats and cats that, during REM sleep, in addition to a tonic GABA/
glycinergic inhibition, the motoneurons receive during the muscle twitches phasic glu-
tamate excitatory and glycine/GABA inhibitory inputs [7880]. Is has been further
shown that the phasic glutamatergic inputs are responsible for the occurrence of mus-
cles twitches since the application of glutamate antagonists on motoneurons abolish
them [79]. The localization of the neurons at the origin of these phasic glutamatergic
inputs is not known. Glutamatergic neurons projecting to motoneurons are localized
in the motor cortex, the red nucleus, the lateral vestibular nucleus, and the reticular
formation [81]. Voluntary movements are induced by the phasic depolarization of
motoneurons by direct and indirect (through the above structures) excitatory projec-
tions arising from the glutamatergic pyramidal cells of the motor cortex [82]. We
propose that this pathway is also responsible for the muscle twitches occurring during
REM sleep and the movements in RBD patients since pyramidal tract motor cortex
neuronal activity, which mediates limb movements, is as high during REM sleep as it
is during active wake [83, 84]. Further supporting this hypothesis, it has been shown
that RBD patients can recall dreams that correspond to their physical activity [85]. In
addition, it has been shown that, compared with wake movements, RBD movements
in Parkinsons patients are faster and more often repeated, jerky, and pseudohallucina-
tory, not self-centered, never associated with tremor, and rarely involved the environ-
ment in an appropriate manner. From these results, it has been proposed that in RBD
patients the motor cortex drives the movements during REM sleep without involving
the basal ganglia [86]. In summary, although additional experiments are necessary to
confirm such hypothesis, we propose that the motor cortex is at the origin of the
twitches of REM sleep and the movements of RBD patients.
Acknowledgments This work was supported by CNRS, Fondation France Parkinson and
University Claude Bernard of Lyon.
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Objective Measures of the SleepWake
Cycle in Parkinsons Disease 4
Valrie Cochen De Cock
Contents
4.1 Introduction ..................................................................................................................... 52
4.2 Videopolysomnographic Recordings .............................................................................. 52
4.2.1 Periodic Limb Movements.................................................................................. 53
4.2.2 Sleep Disordered Breathing ................................................................................ 53
4.2.3 REM Sleep Behavior Disorder ........................................................................... 54
4.2.4 Dystonia and Dyskinesia .................................................................................... 55
4.3 Suggested Immobilization Test (SIT) ............................................................................. 55
4.4 Multiple Sleep Latency Test (MSLT) ............................................................................. 56
4.5 Maintenance of Wakefulness Test (MWT) ..................................................................... 57
4.6 Ambulatory Polysomnography ....................................................................................... 57
4.7 Actigraphy....................................................................................................................... 58
Conclusion ............................................................................................................................... 58
References ................................................................................................................................ 58
Abstract
Complaints about sleepwake cycle are frequent in patients with Parkinsons
disease (PD). Nocturnal sleep in PD may be impaired by several factors: motor
phenomena related to the disease such as nocturnal bradykinesia/akinesia, rigid-
ity, tremor or nocturia, and comorbid sleep disorders such as insomnia, restless
legs syndrome (RLS), periodic limb movements (PLMs), circadian rhythm alter-
ation, sleep disordered breathing, and rapid-eye-movement (REM) sleep behav-
ior disorder (RBD). Moreover, daytime sleepiness and sleep attacks are frequently
reported in patients with PD. Numerous studies evaluating sleep in PD have
V. Cochen De Cock
Service des pathologies du sommeil, Clinique Beau Soleil,
119 avenue de Lodve, 34070 Montpellier, France

52 V. Cochen De Cock
pressed that not only the illness but also dopaminergic treatments may play an
important role in these sleep disorders.
Questionnaires have been developed to identify sleep disorders in the context
of PD, but objective measures are needed to confirm diagnoses and inform treat-
ments to the patients.
Videopolysomnographic recording is the gold standard to explore sleep and to
diagnose PLMs, sleep disordered breathing, and RBD. Suggested immobilization
test is a useful measure to explore RLS especially in patients with PD. Excessive
daytime sleepiness is usually explored as in central hypersomnia by multiple
sleep latency test (MSLT) but actigraphy or 24-h ambulatory polysomnography
could be interesting tools to evaluate sleepiness at home, in a more naturalistic
way. Maintenance of wakefulness test (MWT) is interesting to evaluate vigilance
and though the efficacy of the different treatments used to improve sleepiness.
4.1 Introduction
Sleep disorders are frequently reported in patients with Parkinsons disease (PD)
[13]. Sleep questionnaires may allow the detection of most of these disorders, but
objective measures are needed to explore sleep quality and to diagnose most of the
sleep disorders associated with PD such as restless legs syndrome (RLS), periodic
limb movements (PLMs), circadian rhythm alteration, sleep disordered breathing,
REM sleep behavior disorder (RBD), and daytime sleepiness. Videopolysomnographic
recordings, suggested immobilization test (SIT), multiple sleep latency test (MSLT),
actigraphy, and maintenance of wakefulness test (MWT) are the most useful objec-
tive methods to explore sleep disorders, sleepiness, and the efficacy of treatments
for sleepwake disturbances in PD.
4.2 Videopolysomnographic Recordings
Videopolysomnography is the gold standard to explore sleep. It allows quantifying

total sleep time, sleep efficiency, sleep latency, sleep architecture, sleep fragmenta-
tion, PLM, respiratory events, and RBD [4].
Videopolysomnography associates multiple channels electroencephalogram,
electrooculogram, chin electromyogram (EMG), leg EMG, airflow parameters,
respiratory effort parameters, oxygen saturation, position, sound and video record-
ings. Sleep stages, and microarousals, are scored through visual inspection of
30 epochs according to standard criteria [4].
Night sleep recordings in large studies with treated and untreated patients with
PD have demonstrated decreased sleep efficiency, increased wake time after sleep
onset, and sleep fragmentation [5]. Changes in slow wave sleep and REM sleep
duration are inconsistent from one study to another. Impaired sleep continuity may
be due to the neurodegenerative process itself, or may be associated with nocturnal
bradykinesia and rigidity, medication, psychiatric complications, nocturia, and
4 Objective Measures of the SleepWake Cycle in Parkinsons Disease 53
impaired circadian rhythm. Finally, PLMs sleep disordered breathing, or RBD may
also disrupt sleep in PD.
4.2.1 Periodic Limb Movements
PLMs are disruptive leg movements or sometimes only muscles contractions without
movement occurring mostly during sleep (for more details please refer Chap. 12).
Surface EMG from the left and right anterior tibialis muscles are used to quantify
leg movements. PLMs are scored according to American Academy of Sleep Medicine
(AASM) scoring manual [4], as all events lasting between 0.5 and 10 s, with a mini-
mum amplitude increase of 8 V from the resting EMG voltage, separated by inter-
vals of 590 s and arising in series of at least four consecutive movements [4].
Patients with PD exhibit significantly higher PLM indices both during wakeful-
ness and sleep compared to age and sex match controls [6]. PLMs are more frequent
during sleep stage 1 and 2 in patients with PD as it has been reported in patients with
idiopathic RLS and PLM disorder [7], but PLM index in PD is also high during
REM sleep probably because of an abnormal disinhibition of the motor system dur-
ing REM sleep in this extrapyramidal disorder [6]. Moreover, PLMs are also present
in drug-free patients with PD showing that this movement disorder may not result
from dopaminergic treatment [6].
4.2.2 Sleep Disordered Breathing
According to the AASM scoring manual [4], an apnea event is defined as a decrease of
at least 90 % of the peak thermal sensor excursion lasting at least 10 s. An hypopnea
event is defined as a 30 % decrease in nasal pressure signal excursions lasting at least
10 s with a 4 % decrease in SpO2 from the preceding baseline value, or as a 50 %
decrease in nasal pressure signal excursions lasting at least 10 s with a 3 % decrease
in SpO2 from the preceding baseline value. The apnea hypopnea index (AHI) is calcu-
lated as the total number of apnea and hypopnea events per hour of sleep. The pres-
ence of sleep apnea is defined as an apnea/hypopnea index greater than 5, and
classified as mild (AHI greater than or equal to 5 and lower than or equal to 15),
moderate (AHI greater than 15 and lower than or equal to 30), and severe (greater
than 30) sleep apnea. Sleep apnea episodes are typically classified as obstructive sleep
apnea, central sleep apnea, and mixed sleep apnea. The criterion differentiating these
categories is the presence or absence of concomitant respiratory efforts [4].
When the cutoff for the AHI is set at 15 events per hour, the prevalence of
obstructive sleep apnea (OSA) syndrome is estimated at about 20 % of the general
population of the United States [8]. Different studies have shown that the prevalence
of OSA in patients with PD ranges from 14.5 to 22.4 %, using the same cutoff value
for AHI [912], suggesting that this disorder has a similar prevalence in the PD
population as in the general population and indicating that the clinical significance
of OSA as a contributor to daytime sleepiness in PD is probably low [912]. For
more details please refer Chap. 7.
Sleep disordered breathing can also be explored by respiratory polygraphy, but

in the context of PD where sleep fragmentation is important it may induce diagnos-
tic errors (by excess or defect) and polysomnography should be preferred.
Strider, an inspiratory high pitched sound secondary to a laryngeal dysfunction
is a harbinger for multiple systeme atrophy but it has also recently been described
as a side effect of deep brain stimulation as in PD [13].
4.2.3 REM Sleep Behavior Disorder
Rapid-eye-movement (REM) sleep behavior disorder (RBD) is characterized by

abnormal and often harmful motor behaviors associated with dream mentation that
causes sleep disruption and/or injuries to the patient or the bed partner [14]. The
behaviors during RBD include mostly jerks and minor movements of the limbs,
gesturing, grabbing, slapping, punching, kicking, sitting up and leaping from bed,
but rarely standing up and walking [15]. Nonviolent elaborate behaviors (eating,
smoking, bicycling, kissing) may also occur during RBD [16].
RBD is accompanied by polysomnographic (PSG) abnormalities in REM sleep.
Normally, muscle atonia and EEG desynchronization are present throughout the
REM period and constitute tonic features of REM sleep in humans. Phasic events
occur intermittently during REM sleep and include bursts of rapid eye movements,
and facial and limb muscle twitches. In patients with RBD, both tonic and phasic
components of REM sleep are altered. Partial or complete loss of tonic chin EMG
atonia (REM sleep without atonia or RSWA) and increase of chin and limb phasic
EMG activities are characteristic features in patients with RBD [17].
According to AASM manual [4], each 30-s epoch should be scored as tonic if chin
EMG activity (EMG amplitude greater than the minimum amplitude than in non-REM
sleep) is present for more than 50 % of the epoch duration. Phasic chin EMG density
is scored from the submental EMG activity and represents the percentage of 3-s mini-
epochs containing EMG events lasting 0.15 s, with an amplitude exceeding four
times the amplitude of background EMG activity. A tonic chin EMG density greater
than 30 % and a phasic chin EMG density greater than 15 % allows for the correctly
classification of 86 % of 80 patients with idiopathic RBD vs. 80 age- and sex-matched
controls [17]. Sleep monitoring allows differentiating REM sleep behavior disorders
from the complex movements sometimes observed during sleep apnea [18].
Simultaneous recording of the mentalis, flexor digitorum superficialis, and extensor
digitorum brevis muscles provides the highest rates of REM sleep phasic EMG activ-
ity in subjects with RBD so that they should be explored [19]. RBD is present in more
than 50% of the patients with PD [20, 21]. Supprisingly patients with PD have an
improvement of the quality of their movement during RBD [20].
4.2.3.1 Bruxism
It has recently been shown that bruxism could also be associated with
RBD. Exploration of temporalis and masseter muscles tone could also be interest-
ing in patients complaining of noisy or painful contractions of the jaw during sleep
in order to evaluate if this contraction also appears during REM sleep [22].
4.2.4 Dystonia and Dyskinesia
In order to identify abnormal movements of the neck or the trunk, other muscles can
be explored during sleep such as sternocleidomastoid, splenius, and thoraco-lumbar
paraspinal muscles. Usually in PD, abnormal dyskinetic movements disappear dur-
ing sleep but they can delay sleep onset and increase wakefulness during sleep.
4.3 Suggested Immobilization Test (SIT)
The SIT is a tool developed recently to objectively assess primary RLS. It assesses
both subjective leg discomfort and objective leg movements during a 1-h period of
immobility prior to bedtime [23].
The diagnosis of RLS is based on four clinical criteria: (1) an urge to move the
legs, usually accompanied or caused by uncomfortable and unpleasant sensations in
the legs; (2) symptoms begin or worsen during periods of rest or inactivity; (3)
symptoms are partially or totally relieved by movement, such as walking or stretch-
ing; and (4) the urge to move or unpleasant sensations are worse in the evening or
night than during the day [24]. Patients with PD frequently complain about leg
discomfort and the clinical overlap between RLS, wearing-off related lower limb
discomfort, cramps, and lower pain thresholds in PD is an important diagnostic
confound [25]. Polysomnography recordings (PSG) reveal the presence of PLMs
during sleep in 80 % of the patients with idiopathic RLS but PLMs during PSG are
frequently reported in PD regardless of RLS status [6].
SIT is administered in the evening and lasts for 1 h. During the SIT, the patients
remain in bed reclined at 45 angle with their legs outstretched. They are instructed
to avoid moving voluntarily for the entire duration of the test. Surface EMG from
the left and right anterior tibialis muscles is used to quantify periodic leg move-
ments. The latter is scored according to the criteria defined by Michaud et al. [26]
(i.e., all movements lasting between 0.5 and 10 s, separated by intervals of 490 s,
and arising in series of at least four consecutive movements). The SIT periodic leg
movements index represents the number of periodic leg movements per hour of
immobility. Patients report severity of leg discomfort on a visual analogue scale
(VAS) ranging from 0 (no discomfort) to 100 (extreme discomfort) every 10 min
during the SIT. The mean leg discomfort score is assessed using the average of the
7 values, as well as the discomfort severity at the end of the test (time 60 min). In
patients with PD, the usual schedule of the dopaminergic treatment is not changed
before the test.
We recently demonstrated that the mean leg discomfort score in SIT is increased
in patients with PD and RLS compared to patients with PD without RLS [27]. Leg
discomfort is significantly higher at the end of the test in patients with RLS compared
to patients without RLS (Fig. 4.1). Using a mean leg discomfort cut-off of 11, we
showed sensitivity of 91 % and specificity of 72 % for RLS diagnosis in PD during
symptomatic time intervals. PLM index during SIT and during sleep did not differ
between PD patients with and without RLS so that PLMs index cannot be used as
Patient with Parkinsons disease Patient with Parkinsons disease

without restless legs syndrome and restless legs syndrome
20 h 10' 20' 30' 40' 50' 21 h
100 100
90 90
80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
Fig. 4.1 Examples of reports of severity of leg discomfort on the visual analogue scale in a patient
with PD without (left) and a patient with (right) RLS during the SIT
indirect diagnosis criteria of RLS in PD. The mean leg discomfort and the increase
of leg discomfort during the 1 h of the SIT may be useful in diagnosing RLS in PD.
4.4 Multiple Sleep Latency Test (MSLT)
Since initial description of sleep attacks at the wheel in patients with PD treated
with dopamine agonists [28], many reports have focused on excessive daytime
sleepiness (EDS) in patients with PD but the best method to explore EDS in PD
remains unclear. The subjective nature of EDS complaint, the definition used, the
different populations targeted, the potential confounding factors, and the various
methodological tools used to evaluate sleepiness explain most of the discrepancies
between studies on EDS prevalence and risk factors in PD.
Multiple sleep latency test (MSLT) is the gold standard to objectively explore
sleepiness in central hypersomnia [29]. Several studies have recorded nighttime sleep
and MSLT to objectively measure hypersomnia in patients with PD [3034].
Surprisingly, none of the controlled studies found significant differences on the mean
sleep latency on MSLT between unselected patients and controls [30, 32, 33]. A nar-
coleptic-like phenotype was also reported in unselected patients with PD [30, 31, 33];
this propensity increased when patients were selected for sleepiness reaching 39 %
[31] or hallucinations 60 % [36].
MSLT is an objective measure of daytime sleepiness. Patients receive the instruc-
tion not to fight against sleep. According to the AASM manual [4], the MSLT con-
sists in five nap opportunities, scheduled at 2-h intervals, starting 2 h after
awakening. Psychotropic drugs must be discontinued at least 2 weeks (depending
on the half-life) before the recording. Each test is terminated after a 15-min sleep
period or after 20 min if the patient does not fall asleep. Both sleep and REM sleep
latencies are measured. Mean sleep latency below 8 min confirms the EDS. Latency
below 5 min indicates severe sleepiness. Latency over 10 min is considered as nor-
mal. Between eight and ten, the interpretation depends on the clinical status of the
patient. A sleep onset REM period (SOREM) defined as the occurrence of REM
sleep within 15 min after sleep onset is also screened, with a narcoleptic phenotype
defined as the presence of at least two SOREM on the MSLT.
As the sensitivity of MSLT to identify PD patients with disabling sleepiness
remains questionable, further studies are required to validate the best methods to
screen and objective hypersomnia in PD. Alternative methods to assess daytime
sleepiness should be monitored in future in PD that may include the maintenance of
wakefulness test or even more a prolonged 24-h continuous sleep recording in stan-
dardized conditions.
4.5 Maintenance of Wakefulness Test (MWT)
MWT is an objective measure of daytime wakefulness. It measures the ability to

remain awake.
MWT consists in four 40 min tests, scheduled at 2-h intervals, starting 2 h after
awakening. During the MWT the room is dimly illuminated and the subject lies in a
semi-reclining position with the instruction to resist sleep [35, 36]. Subjects are not
allowed to maintain wakefulness by using extraordinary measures such as slapping
the face or singing. Recordings are monitored by a trained technologist. Each trial is
terminated at the first onset of sleep (sleep onset) or, if sleep onset is not achieved,
after a maximum in-bed duration of 40 min. Mean sleep latency below 11 min con-
firms the sleepiness [35, 36].
The MWT has clinical usefulness in evaluating response to treatment of sleepi-
ness. In PD, a significant, but small, relationship between subjective (ESS) and
objective (MWT) measures of daytime alertness hasbeen observed [37]. Interestingly,
using MWT, Bliwise et al. have shown that relative to unmediated patients, all
classes of dopaminergic medications were associated with reduced daytime alert-
ness, and this effect was not mediated by disease duration or disease severity.
Further, the results showed that increasing dosages of dopamine agonists were asso-
ciated with less daytime alertness, whereas higher levels of levodopa were associ-
ated with higher levels of alertness [37].
4.6 Ambulatory Polysomnography
PSG recording of wake and sleep activities at home or in the sleep laboratory is
another way to explore sleepiness during the day in patients with PD. It allows
observing sleep attacks and sleeping episodes during the day in naturalistic condi-
tions. Only one study to our knowledge has evaluated sleep and wake cycle in PD
using this method [38]. This study allowed them to show that sleep attacks are an
extreme manifestation of increased daytime sleepiness.
4.7 Actigraphy
Actigraphy is a noninvasive method for monitoring human restactivity cycles.

A small accelerometer unit is worn on the wrist by the patient to measure motor
activity. Absence of movement, measured by actigraphy, has proved to be a good
proxy of nighttime sleep quality and correlates with PSG and subjective sleep mea-
sures [39]. It has recently been shown that actigraphy correlates to sleep measures
by PSG even in patients with PD where akinesia could have been misleading [40].
Conclusion
Objective measures to explore sleepwake cycle and sleep disorders in PD
encompass videopolysomnography, suggested immobilization test, and
MSLT. Other methods such as MWT, 24-h ambulatory PSG, and actigraphy have
also been recently used, mainly to explore sleepiness. Even if these methods are
not specific to PD, they allow good identification of most sleep disorders.
However, limits such as the absence of specific criteria for sleep stages identifi-
cation in a disease where EEG is frequently impaired because of neurodegenera-
tion and the low sensibility of MSLT to objectively measure sleepiness suggest
that more accurate methods should be developed for the assessment of sleep and
alertness in PD.
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Subjective Assessment of Sleep
and Sleepiness in Parkinsons Disease 5
Joan Santamaria
Contents
5.1 How to Take a Sleep History .......................................................................................... 62
5.2 Sleep Scales .................................................................................................................... 65
5.2.1 Brief Description of the Scales ........................................................................... 66
5.2.2 Problems with Sleep Scales ................................................................................ 70
5.3 When to Use Sleep Scales and Which to Use? ............................................................... 71
5.4 Scales to Evaluate RBD .................................................................................................. 72
References ................................................................................................................................ 75
Abstract
Sleep disturbances in Parkinsons disease (PD) are common and need appropri-
ate diagnosis and care. Sleep can be assessed in two ways: subjectively by asking
patients about their symptoms and objectively with the help of electrophysiologi-
cal sleep recordings. There are a number of validated scales to evaluate sleep in
PD as well as electrophysiological sleep recordings. No validated scale or sleep
test, however, can do the job of a thorough sleep history taken with the patient
and bed partner. This needs time and a systematic approach defining the prob-
lem, schedules, behavior before sleep, during sleep, presence and timing of mid-
night awakenings and their cause, snoring, breathing pauses, dreaming, and
abnormal movements during sleep and excessive sleepiness. Several scales can
be used to screen sleep disorders, complementing not replacing the clinical
sleep history. There is not yet an ideal scale for assessment of the whole spectrum
J. Santamaria, MD
Neurology Service and Multidisciplinary Sleep Disorders Unit, Hospital Clnic of Barcelona,
University of Barcelona Medical School, Villarroel 170, 08036 Barcelona, Spain

62 J. Santamaria
of sleep problems in PD, although two have been developed specifically for use
in PD, namely, the Parkinsons disease sleep scale and the SCOPA-sleep.
Sleep disturbances are frequent in Parkinsons disease (PD) and need appropriate
diagnosis and care. Their evaluation is not easy, however, because the sleep com-
plaints may be multiple, from insomnia or hypersomnia to parasomnias, and often
need to be disentangled from the motor, sensory, and mood effects of the disease or
its treatments. Sleep can generally be assessed in two ways: subjectively by asking
patients about their symptoms and objectively with the help of electrophysiological
sleep recordings. These two ways are informative and complementary with discrep-
ancies sometimes in their results because they probably measure different aspects of
the phenomenon [1, 2]. Today, there are a number of validated scales to assess sleep
in PD, leaving perhaps the impression that by just using a sleep scale one can diag-
nose and measure the sleep problems of the patient. The same could be said about
sleep recordings. As a general rule, however, no valid scale or sleep test can do
the job of a thorough sleep history with the patient and bed partner.
In this chapter, an overview of the subjective assessment of sleep and sleepiness
in PD focusing first on the clinical history and then on sleep scales is presented.
A detailed clinical sleep history is particularly necessary when a patient reports
sleep complaints, either spontaneously or after questioning by the physician. One
may start the interview by simply asking the patient and bed partner about their
satisfaction with the quality of nocturnal sleep and the presence of problematic day-
time sleepiness. In the absence of complaints, for routine clinical practice there is
no need to ask anything else or to administer any sleep scale. One has to bear in
mind, however, that sleep symptoms in patients with PD are often underreported [3]
or even neglected, probably because they are considered normal in the context of
parkinsonism, which logically attracts the attention of patients and caregivers.
Therefore, when there are complaints about sleep or doubts about their presence a
more detailed approach is mandatory, particularly in patients who sleep alone, or
whose bed partner is unavailable.
5.1 How to Take a Sleep History
Taking a sleep history needs time and a systematic approach that can be summa-
rized in the following seven steps.
First: Defining the problem. The first step is to clarify what specific problem is
bothering the patient. The basic symptoms of sleep disorders are essentially three,
which may appear alone or in combination: (a) inability to sleep as desired, (b)
excessive daytime sleepiness, and (c) abnormal phenomena or behaviors during or
around the sleep period. Each of these symptoms has many possible causes and with
the clinical sleep history we have to look for the clues to identify them.
5 Subjective Assessment of Sleep and Sleepiness in Parkinsons Disease 63
Second: Sleepwake schedule. We always need to establish the characteristics of

the major sleep episode, usually corresponding to nocturnal sleep, going over the
sleep schedule on weekdays and weekends. A consistently shorter sleep duration
during weekdays than in weekends or holidays is an indirect proof of the presence
of sleep deprivation. A disorganized sleepwake schedule will very likely be a
source of problems for the patient.
Third: Behavior before sleep. It is useful to inquire about the routine before fall-
ing asleep. Patients may report reading, listening to an arousing radio program or
watching TV, eating, etc. Important aspects are usual time to go to bed, latency to
fall asleep, and presence of physically disturbing symptoms. Questions regarding
restless legs syndrome are essential since RLS may produce important sleep onset
difficulties . The main characteristics are an urge to move, usually accompanied by
an unpleasant sensation in the legs, which appears at night or in the afternoon, par-
ticularly during rest and that improves, at least transiently, with movement [4].
Finding a comfortable body position in bed to fall asleep is an almost impossible
task for those patients. The RLS symptoms usually decrease in intensity gradually
during the night and disappear by early morning. In PD, however, the presentation
and characteristics of RLS may be partially modified or masked by the dopaminer-
gic agents used for the treatment of parkinsonism. Another cause of potentially
troublesome sleep onset insomnia is the presence of either dyskinesia or off peri-
ods at the time of going to sleep. For these reasons, a detailed scrutiny of the type
and schedule of antiparkinsonian agents is essential to understand the sleep prob-
lems of the patient, given that excessive amounts of dopaminergic agents or selegi-
line which is converted to amphetamine [5] may be associated with sleep-onset
insomnia. The intake of caffeine, other stimulants, alcohol, or other drugs should be
actively questioned. In general, patients with PD report no more difficulties in fall-
ing asleep than healthy age-matched controls, in contrast to the problems in main-
taining sleep continuity which are much more often perceived [6, 7].
Fourth: Behavior during sleep and final awakening. A detailed interrogatory of
the patients behavior during sleep is essential and the cooperation of the bed part-
ner here is fundamental, and should include the number, duration and time of noc-
turnal awakenings, type of activities during the awakenings (staying in bed, walking,
going to bathroom, eating, etc.), time needed to fall asleep again after these awaken-
ings, and time and type (spontaneous or induced) of the final awakening in the
morning. One particularly frustrating symptom is awakening in the middle of the
night, without any more sleepiness left. Awakening may be spontaneous or induced
by snoring, arousals from sleep apnea, sudden limb jerks, pain, inability to turn in
the bed, or the feeling of full bladder. Getting up at night to pass urine is one of the
most common events that patients with PD report, and needs to be specifically scru-
tinized because it breaks sleep continuity (Table 5.2) and undermines the quality of
sleep. Appearance of motor symptoms tremor, rigidity during the night is an
indirect demonstration that sleep is broken given that the typical parkinsonian
symptoms, as a rule, decrease in intensity or disappear with sleep, reappearing with
arousals.
64 J. Santamaria
Questions about snoring or stridor, breathing pauses, and gasps during sleep
should be asked to the patient and bed partner. A good imitation of the sounds by the
physician may help the bed partner to identify the sounds. Also, the behavior during
arousals or awakenings, presence of talking, shouting, screaming, crying or laugh-
ing, limb or other body movements such as hitting, punching, kicking involuntarily
the bed partner, or falling out of bed are important points to clarify. Some of these
behaviors may look to an observer as if the patients were enacting their dreams,
fighting with an imaginary aggressor, and are typical of REM sleep behavior disor-
der (RBD). It is not always easy, however, to differentiate by clinical history the
movements associated with arousals at the end of severe obstructive apneas from
the dream enacting movements of RBD [9]. Also, large or brisk periodic leg move-
ments during sleep may be confused by the bed partner with dream-enacting move-
ments. Contusions or lacerations that are discovered at awakening by a patient that
sleeps alone may give an important diagnostic clue regarding the presence of a
parasomnia. Finally, the patient should be asked if after awakening in the morning
he/she had enough sleep and feels refreshed or would continue sleeping more time
if undisturbed and if he finds that the motor symptoms are better after sleep (sleep-
effect) [10].
Fifth: Dreaming and hallucinations. Dream content has different patterns,
depending upon the associated sleep disorder. Patients with obstructive sleep apnea
may report anxious or frustrating dreams such as arriving late at an interview, miss-
ing an essential piece in a job, problems with the car engine, etc., and this usually
improves after continuous positive airway pressure (CPAP) treatment [11]. Patients
with NREM parasomnias (confusion arousals, somnambulism, or nocturnal terrors)
may recall dreams, where they (or their loved ones) are in great danger and need to
escape (flight). Patients with REM sleep behavior disorder (RBD), in contrast, typi-
cally dream that they are threatened by other people or animals and they react
against the aggressor [12]. However, not every patient with dream enacting behavior
recalls dreaming, even when awakened immediately after the episode, and some-
times aggressive dreams can also be reported by obstructive sleep apnea patients
[9]. Abnormal dreaming in PD was reported in the old literature, before the discov-
ery of RBD, as a side effect of levodopa [13], but it is now difficult to disentangle
the possible role of this parasomnia in those cases.
Nocturnal hallucinations in PD should not be confused with dreams, but differ-
entiation is difficult and both phenomena may occasionally occur in the same
patient. A rule of thumb is that dreaming occurs with the eyes closed, even in dream
enactment episodes of REM sleep behavior disorder (RBD); whereas, hallucina-
tions occur with the patient being awake and the eyes open.
Sixth: Daytime behavior and excessive daytime sleepiness. It is important to ask
how the sleep problems affect the daytime activities of the patient and not focus
only in their nighttime symptoms. Patients with insomnia, for example, feel fatigued,
unable to concentrate, with a subjective decrease in their performance, but are rarely
sleepy. People with sleep onset or sleep maintenance insomnia often have stressful
daytime routines that make them unable to disconnect easily before going to bed.
The other main symptom, excessive daytime sleepiness (EDS), may cause clinically
significant problems in PD, including unintended episodes of sleep [14]. From the
practical standpoint, because sleepiness is a subjective feeling, the best way to mea-
sure it is asking the patient if he/she has problematic daytime sleepiness or a family
member when the patient is cognitively impaired. Sleepiness is sometimes confused
with tiredness or fatigue [15], another symptom that can also occur in PD. Tiredness,
generally, improves with rest whereas sleepiness is worsened with relaxation. It is
important to determine if sleepiness appears only in passive, relaxed situations or if
it occurs even in active tasks, and to clarify if the patient feels the sleepiness before
falling asleep, or, in contrast, falls asleep without feeling sleepy before. Most
patients are able to feel the sleepiness and take preventive maneuvers to avoid acci-
dents. Others, however, report that they suddenly discover they have fallen asleep
without remembering any preceding sleepiness, what is called a sleep attack.
Unintended sleep episodes (or sleep attacks) usually occur in a background of
continuous sleepiness, especially in situations of minimal or moderate physical
activity [16].
Seventh: Other symptoms. Questions about cataplexy, sleep paralysis, or hypna-
gogic hallucinations are sometimes very difficult to understand and may be con-
fused with other problems. It is helpful to ask the patients to describe these
symptoms using their own words rather than simply answering yes or no. Cataplexy
has not been reported yet in a patient with PD, even in patients with important
daytime sleepiness, although there are reports of patients with long-term narco-
lepsy who later in life develop PD [17]. Cataplexy is usually induced by positive
emotions, rarely by negative ones, may have different intensities, is not associated
with loss of consciousness (although the patient often has the eyes closed), disap-
pears in seconds to minutes unless another triggering emotion occurs. Knee buck-
ling, sagging of the jaw, and dropping of the head are the most common presentations
but full-blown attacks can result in complete muscle paralysis with postural
collapse.
Elaboration of the diagnostic hypothesis. Once all the information is available,
hypothesis of what could cause the sleep problems has to be made and then decide
whether any diagnostic test is needed before starting the treatment, as in any other
medical situation.
5.2 Sleep Scales
To make a diagnosis of a sleep disorder problem in PD there is no better option than

taking a clinical history with the patient and bed partner. However, for screening
purposes, to rate specific symptoms in research studies and to complement the clini-
cal interview, there are sleep scales. In the last 25 years, several scales designed to
evaluate sleep symptoms in the general population are available, such as the
Pittsburgh sleep quality index (PSQI) [18], the Epworth sleepiness scale (ESS) [19],
the Stanford sleepiness scale (SSS) [20], and more focused scales for the assess-
ment of RBD or RLS. In addition, a few scales have been specifically developed for
assessment of sleep or sleepiness in PD, including the Parkinsons disease sleep
66 J. Santamaria
scale (PDSS) version I [21] and II [8], the SCOPA-sleep [22], and the inappropriate
sleep composite score [23]. Sleep scales differ in the type of problem evaluated
(daytime sleepiness, nocturnal sleep, RBD, etc.), in the period of time assessed (cur-
rent moment, past week, past month, recent times), and in how are the questions
answered (the patient alone, by himself, alone but with the help of the physician or
health-assistant or together with the bed partner or caregiver). The quality of the
information obtained with sleep scales is entirely dependent upon the patients abil-
ity to perceive their sleep problems, like in a traditional clinical interview. This fact
becomes critical in the case of patients who sleep alone, are cognitively impaired, or
are not fully aware of the severity of their problem, as it occurs in excessive daytime
sleepiness or parasomnias. In PD, the information of a bed partner or caregiver,
therefore, will improve the results of sleep scales particularly when the disease
advances. For a variety of reasons, however, some scales were designed to be
answered without the help of a bed partner.
5.2.1 Brief Description of the Scales
The Parkinsons disease sleep scale (PDSS) is a self-rated scale designed to measure
nocturnal problems, sleep disturbance, and, in the first but not the second version,
excessive daytime sleepiness in PD over the previous week [8, 21]. The PDSS can be
used to screen daytime sleepiness and can also be used to ascertain the prevalence of
general sleep disturbance in PD. The scale consists of 15 questions, addressing
commonly reported nocturnal symptoms occurring in patients with PD. Several of the
items in the PDSS are only related with nocturnal disability. In the first version, each
item was rated on a visual analogue scale from 0 (severe and always present) to 10
(not present). In the second version, each item is scored from 0 (never) to 3 (very
often). The scale has been extensively used in PD population, and is credited for mak-
ing an attempt to address the multidimensional nature of sleep problems in PD.
The Pittsburgh sleep quality index (PSQI) is a self-rating questionnaire designed
to evaluate sleep quality, sleep habits, and disturbances during the previous month.
It consists of 19 questions that are combined to form seven component scores (sub-
jective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep
disturbances, use of sleeping medication, and daytime dysfunction), scored from 0
(no difficulty) to 3 (severe difficulty). Five other questions are available to be
answered by the bed partner or roommate, and provide clinical information but do
not contribute to the final score.
The SCOPA-sleep [7] is a short, self-rating scale evaluating nocturnal sleep quality
and daytime sleepiness specifically in patients with PD. The SCOPA includes a night-
time scale (NS), a single question about the quality of sleep with seven optional
answers, not counted in the final score, and a daytime sleepiness scale (DS). In the NS,
subjects indicate the extent to which their sleep was disturbed during the previous
month on a scale of 0 (not at all) to 3 (very much). There are five items that include
sleep initiation, sleep fragmentation, sleep efficiency, sleep duration, and early waken-
ing. The maximum score of this scale is 15, with higher scores reflecting more severe
sleep problems. The DS subscale evaluates daytime sleepiness in the past month and
subjects indicate how often they fell asleep unexpectedly, fell asleep in particular
everyday situations, how often they had difficulty staying awake, and whether falling
asleep in the daytime was considered a problem. There are six items with four response
options, ranging from 0 (never) to 3 (often) and the maximum score is 18, with higher
scores reflecting more severe sleepiness. An interesting point is that a single question,
not used in the sum scores of the scale, the overall sleep quality question is probably
as good to get a clinically relevant impression as the whole scale.
The Epworth sleepiness scale (ESS) [19] and the Stanford sleepiness scale (SSS)
[20] are self-administered scales designed to measure sleepiness either in recent
times (ESS) or right at the moment of doing the test (SSS). In the ESS, the patient
has to tell how likely has been for him in recent times to fall asleep in eight routine
activities, from watching TV to talking. In the SSS, the subject must choose from
descriptions of different sleepiness levels (from fully awake to fully asleep) the level
that best defines his/her current state, giving an instant picture only of that particular
moment, which is really not much relevant clinically during routine visits or follow-
up by patients. Despite their limitations, both scales, and particularly the ESS, have
been used frequently in PD [24] to identify, for example, the excessive levels of
sleepiness of patients with PD compared with controls [25] or to document that
unintended sleep episodes occur more often in patients with abnormally high ESS
[23]. A variation of the ESS is the ICSS [23], where the patients should describe the
possibility of falling asleep suddenly (sleep attacks) in the eight situations of the
ESS and four additional active ones (driving, working, etc.).
The Stavanger sleepiness scale [26] assesses sleepiness in a simple way, and
needs to be answered by the caregiver, who will tell how much time the patient
sleeps during daytime. Three possibilities are offered: no daytime sleepiness, mild
sleepiness, and excessive daytime sleepiness corresponding to different levels of
sleeping time during the day and the number of times falling asleep. The scale has
the advantage that it can be used in patients with advanced stages of the disease, that
have impaired mobility and do not make several of the activities asked for in the
ESS or ICSS. A multicenter study group in Europe [16] used it in the evaluation of
MSA and patients with PD.
A Movement Disorder Society Task force reviewed in 2010 the available sleep
scales and gave recommendations for their use in PD [27]. The Task force considered
that the PDSS, the PSQI, the SCOPA-sleep and the ESS could be recommended for
use in PD because they had been applied to PD populations. Other groups beyond the
original developing group had published data of these scales and their clinical use
and there were psychometrical studies showing that these scales are valid and reli-
able. They concluded that the ISCS and the SSS did not meet the criteria for recom-
mendation, although the Task force suggested their possible use as a complement to
the other scales and did not recommend the Stavanger scale because only the same
group that developed the scale had used it, although this has now changed [16]. It
was also mentioned that none of the reviewed scales was sufficient or appropriate to
diagnose specific sleep disorders and that a scale could not replace a full sleep history
with the patient and caregiver. For an overview of these scales, see Table 5.1.
Table 5.1 Summary of sleep scales for evaluation of PD
68
Range of
scores
Type of disorder Bed partner/ Period Number of (cut-off
Scale assessed informant assessed Population studied questions value) Comments
PDSS-2 Nocturnal Not required, allowed Previous Specific for PD 15 060 A previous version
disturbance to help week PDSS-1 exist with
several changes
PSQI Sleep quality, Required Previous Many populations, 19, 7 components 021 (5) It gives quantitative
both nocturnal month used also in PD information about
sleep and diurnal number of sleep
sleepiness hours, sleep latencies,
etc. Complex scoring
system
SCOPA-sleep Sleep quality, May or may not Previous Designed for PD 12 012 Easy to administer,
both nocturnal participate month (5/6) appears to have
sleep and diurnal selected questions
sleepiness from the PSQI and
ESS
ESS Daytime Not required Recent General, but used 8 024 Widely used, not
sleepiness times in PD several (>10) designed for PD but
times used in many studies
J. Santamaria
5
ISCS Sudden onset of Not required Not specified PD 6 1 Good to investigate

sleep risk of unintended
sleep episodes
(sleep attacks)
SSS Current daytime Not required Current General, but used 1 Instantaneous
sleepiness moment in PD several measure of
times sleepiness, not
appropriate for
routine follow-up of
patients
Stavanger Daytime Required Not specified Specifically 1 03 (2) It is particularly
sleepiness designed for PD useful in patients
with advanced PD
disease
Modified from Hgl et al. [27]
Subjective Assessment of Sleep and Sleepiness in Parkinsons Disease
69
70 J. Santamaria
5.2.2 Problems with Sleep Scales
Many sleep scales have been validated, a term that people automatically equals to
ready for clinical use without questioning anything else. However, the fact that a
sleep scale has been validated simply says that it asks about things related to sleep
problems (face validity), with more or less appropriate coverage of the sleep-related
problems (content validity), more or less appropriate relationship with other aspects
of the disease (construct validity), and with the items composing the scale having
some internal consistency [28]. These conditions, however, are apparently not very
difficult to achieve and other possible scales could be made with different questions
and very likely be successfully validated. Validation does not mean that all the ques-
tions of the scale have common sense or that they are all necessary. Two examples
of this the PDSS and the SCOPA-sleep scales are illustrative.
The PSDSS-1 and PDSS-2 have both been validated and yet have important
differences in their scoring system (a 10-cm visual analog scale from 0 = severe
and always present to 10 = not present, vs a numeric score) as well as in the items
asked (items 5, 9 and 15 of PDSS-1 are no longer present in PDSS-2 and items
4, 10 and 11 have different wording). In addition, there are items whose scores
were not significantly different in patients and controls (items 2, 1, 14) and a few
items are overrepresented, like items 4, 5, and 10, in which a patient with RLS
will very likely answer yes three times for the same problem. A lower number of
items would perhaps give similar relevant information and have similar clinimet-
ric properties than the 15-item scale (see Table 5.2). In fact, it is unclear why the
authors decided to make a 15-item scale.
The SCOPA-sleep scale is another validated scale, with repetitive questions. For
instance in the NS part, a positive response to item 2 (have woken too often), item 3
(lying awake too long at night), or item 4 (have woken up too early) implies very
likely a positive response to item 5 (had too little sleep at night) and the same hap-
pens in the Daytime sleepiness (DS) part where a positive answer to items 1, 2, 3, 4
implies very likely a positive answer to item 5. These repetitions will artificially
increase the difference between patients and controls. Finally, the construct validity
of the SCOPA-sleep was proved by showing a significant correlation with the ESS
and the PSQI. However, items 2, 3, and 4 in the DS-sleep part are very similar to
items 1, 2, 6 and probably 3 in the ESS, whereas items 1 and 3 of the NS-sleep part
are very similar to items 5a and 5b in the PSQI. It is not rare then that SCOPA-sleep
correlated well with ESS and PSQI.
Two other areas for improvement can be found. One is that in most sleep scales
the questions asked have not been extracted directly from the patients own way of
describing their complaints that is from how the patients describe their own prob-
lems rather from how their doctors (ESS, PDSS, SCOPA) interpret it. An extreme
case is the SCOPA, where the questions were chosen from the literature, and the
authors in fact did not see directly any of the patients or controls that participated in
the study, but only the written responses to their questionnaire.
The other is that all sleep scales have assessed their construct validity by calcu-
lating the correlation between the scores on the scale with those in other scales that
Table 5.2 Frequency of nocturnal sleep complaints

Score
(mean SD) Nocturnal problems
PDSS-2 (item number) ordered by (min: 0, reported by patients with Percent
frequency of positive response [8] max: 4) PD [3] (%)
Getting up at night to pass urine (item 8) 2.77 1.48 Need to visit lavatory 79
Difficulties staying asleep (item 3) 2.37 1.63 Inability to turn over in 65
bed
Bad sleep quality (item 1) 1.99 1.33 Painful leg cramps 55
Tired and sleepy after waking in the 1.69 1.62 Vivid dreams/nightmares 48
morning (item 14)
Uncomfortable/immobility at night 1.20 1.63 Cannot get out of bed 35
(item 9) unaided
Tremor on waking (item 13) 0.88 1.38 Limb/facial dystonia 34
Difficulties falling asleep (item 2) 0.84 1.41 Back pain 34
Restlessness, urge to move, pain or (Range of Jerks of legs 33
muscle cramps in ARMS or LEGS means in
(items 4, 5, 10, 11, very similar) the 4 items)
0.68
0.84 1.3
Distressing dreams at night (item 6) 0.58 1.13 Visual hallucinations 16
Snoring or difficulties in breathing (item 15) 0.36 0.86 None 4
Distressing hallucinations at night (item 7) 0.28 0.94 Told their doctors 45
Modified from Trenkwalder et al. [8], and from Lees et al. [3] from a list of complaints given by
patients with PD to a postal survey at the British PD association. The complaints in the PDSS and
in the list obtained from the patients have similarities but it is not the same. Remarkably, the most
disturbing sleep symptom in both lists is the need to visit the lavatory at night.
have addressed similar constructs, but not with objective sleep recordings.
Unfortunately, the older scales such as the ESS had limited or controversial cor-
relations with objective tests [1].
5.3 When to Use Sleep Scales and Which to Use?
Using scales has advantages and limitations. Advantages are the homogeneity of the
questions asked, which is ideal for multicenter studies or to always record the same
type of information. It may also help some patients to be aware of a sleep problem
that they did not consider relevant enough to tell their doctor. Limitations are inher-
ent to the methodology: homogeneity results in lack of flexibility in evaluating
symptoms that do not perfectly fit with the questions. They may also induce an
error, which is relying uniquely in a scale to diagnose or measure a sleep problem.
Given the availability of sleep scales, one logical question is when a neurolo-
gist caring for patients with PD should use a sleep scale and which ones to use.
There is no formal study addressing these issues. A comparative usefulness of
the PDSS-I and the SCOPA-sleep scales was performed by Martinez-Martn
72 J. Santamaria
et al. [22], reporting a relative good correlation between the two scales. The
authors suggested that the PDSS could be used to assess overall nocturnal sleep
quality and to obtain a profile about potential causes of bad sleep, but not to
assess daytime sleepiness. On the other hand, SCOPA-sleep assesses nocturnal
sleep disorders and daytime somnolence at a similar extent, but it does not
explore the potential causes.
In addition to these dedicated sleep scales, the revised version of the Unified
Parkinsons Disease Rating Scale (UPDRS) [29] and the new non-motor symptom
scale for PD [6] contain a few basic questions about nocturnal sleep and daytime
sleepiness, which are easier to administer and give probably similar information
than the more detailed sleep scales.
5.4 Scales to Evaluate RBD
In the last decade several scales (Table 5.3) have been described to screen for the
presence of RBD in the general population [30, 32, 33, 35] as well as in PD [31, 34].
All but one (Gjerstad) were elaborated taking into account the reports of RBD
patients (diagnosed with PSG) and bed partners and were applied to populations
with several sleep disorders, including patients with PD with and without RBD [32,
34], as well as in controls. The scales also had proper validation procedures. In
general, these instruments were rather sensitive to detect the parasomnia but not
specific, due to the misidentification of patients with other parasomnias, epilepsy or
sleep apnea. Two scales consist of only one question [31, 33], two of 13 [30, 32] and
one of 9 items [35]. In order to exclude the most common misdiagnosis (sleepwalk-
ing and sleep apnea), one questionnaire incorporates two specific questions for
these disorders [35].
A summary of the different scales can be found in Table 5.3. There are no formal
studies comparing the different scales. In terms of simplicity and reliability the
Mayo sleep questionnaire [33] is good, relies on the informant (and not on the
patient, which is often unaware of the problem) but it has not been applied specifi-
cally to a PD population. The rest of the scales have been used in PD [32, 34] and
shown to be sensitive to detect parasomnia. The Stavanger scale [31] is very simple
and has been used in follow up of population-based study of PD but did not have
formal PSG validation.
In conclusion, although there has been a lot of work in last decades trying to
elaborate scales and questionnaires to evaluate sleep disorders in the general
population and in specific groups such as in Parkinsons disease, there is still
room for improvement. Sleep scales are useful for screening purposes, to rate
specific symptoms in research studies, and to complement the clinical interview
with patient and bed partner, which will always give the final answer to the clini-
cal problem of the patient. Scales need to be created based directly on the com-
plaints of the patients and correlated with as many objective measurements of
sleep as possible.
5
Table 5.3 RBD screening scales

Range
of
scores
Author, year, Bed partner/ Period Number of (cut-off
type of scale Type of RBD n Control group n informant assessed questions value) Comments
Stiasny Narcolepsy 54 Patients with 160 Not required Not 13 013 6 questions need a bed
Kolster [30] (61 %); sleep specified (5) partner. All patients with
(screening) idiopathic disorders PD have 1 extra point
RBD (35 %), other than (item10). RBD patients
PD (4 %) RBD, referred who do not recall dreams
PSG confirmed to a sleep lab have 4 points less
Gjerstad PD 231 Age-matched 100 Required Not 1 03 (2) No questions about
et al. [31] No PSG healthy specified, dreams, only physical
(screening) recording elderly recent activity, asleep. No PSG
individuals times confirmation. Used for
implied follow-up in a large
population-based study
Li et al. [32] Idiopathic 107 Mostly 107 May or may not Lifetime 13 0100 Repeated questions about
(screening RBD (51), patients with participate and last (18/19) dreaming (aggressive
and rating of symptomatic other sleep year (item 4) or frightening
frequency) (29), RBD- disorders such (item 5). Dreams may
like disorder as OSAS and also be emotional
(27) insomnia (item 3) and
Subjective Assessment of Sleep and Sleepiness in Parkinsons Disease
nightmares (item 2).

Also items 10 and 11 are
very similar
Boeve Cognitively 176 Fundamental Not 5 05 (4) Patients without bed
et al. [33] impaired and/or specified partner cannot do it
(screening) parkinsonism
(continued)
73
74
Table 5.3 (continued)

Range
of
scores
Author, year, Bed partner/ Period Number of (cut-off
type of scale Type of RBD n Control group n informant assessed questions value) Comments
Nomura PDRBD (19); 45 PD Required Not 13 013 Same comments as that
et al. [34] PD without + 31 specified (6) for the RBDSQ, except
(screening) RBD (26); iRBD that the partner is
idiopathic RBD required to participate
(31)
PSG confirmed
Frauscher Idiopathic 30, 70 Consecutive 140 Available in most Last year 7 01 7 RBD questions and to
et al. [35] PD and sleep patients Ratio positive/ (0.25) exclude OSAS and
(screening alike 28; laboratory total responses sleepwalking. Frequency
and rating of narcolepsy 8, patients scores did not improve
frequency) drug-induced 4 without RBD discrimination. A single
PSG confirmed question compared well
with whole test
J. Santamaria
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Part II
Insomnia in Parkinsons Disease
6
Margaret Park and Cynthia L. Comella
Contents
6.1 Introduction ..................................................................................................................... 80
6.2 Definition ........................................................................................................................ 80
6.3 Pathophysiology and Sleep-Wake Systems .................................................................... 81
6.4 Evaluation ....................................................................................................................... 82
6.4.1 Evaluation Tools.................................................................................................. 83
6.5 Differential Diagnoses .................................................................................................... 84
6.5.1 Other Sleep Disorders ......................................................................................... 84
6.5.2 Circadian Rhythm Sleep Disorders ..................................................................... 84
6.6 Treatment ........................................................................................................................ 84
6.6.1 Behavioral Treatment .......................................................................................... 84
6.6.2 Pharmacological Treatment ................................................................................ 85
6.6.3 Deep Brain Stimulation (DBS) ........................................................................... 87
Conclusion ................................................................................................................................. 88
References .................................................................................................................................. 88
Abstract
Insomnia is the most common sleep disorder in Parkinsons disease (PD). Sleep
maintenance insomnia is the most common type of insomnia in this population.
The pathophysiology of insomnia is complex and not fully understood.
Contributing factors to insomnia in PD include complex medication regimens
M. Park, MD (*)
Rush University Medical Center, Sleep Disorders Service and Reacher Center,
710 S Paulina Street, Chicago, IL 60612, USA
C.L. Comella, MD, FAAN
Rush University Medical Center, Department of Neurological Sciences,
1725 West Harrison Street, Suite 755, Chicago, IL 60612, USA

80 M. Park and C.L. Comella
and comorbidities associated with the disease. A dedicated sleep interview that
includes patients bed partners or care givers is a necessary diagnostic step in the
management of insomnia. Treatment options include non-pharmacological and
pharmacological approaches.
6.1 Introduction
Sleep complaints are highly prevalent in patients with Parkinsons disease (PD). Up
to 88 % of PD patients report nighttime sleep fragmentation and early morning awak-
enings, [1] which are associated with decreased overall total sleep time, increased
wake periods in the middle of the night (wake after sleep onset periods, or WASO),
poor daytime function, and excessive daytime sleepiness (EDS). Up to 60 % of PD
patients specifically complain of insomnia [2], which objectively correlate with day-
time fatigue and sleepiness [3], impaired attention and executive functioning [4], and
caregiver burden [5, 6]. Subjectively, PD patients cite insomnia as a significant source
of distress [7, 8]. Insomnia is frequently the cause of low quality of life for both the
PD patient and their caregivers [6, 8]. Despite this, research investigating insomnia
in PD has been relatively sparse, possibly due to the complex, multifactorial nature
underlying the relationship between insomnia and PD.
This chapter is intended to provide a brief overview of insomnia, discuss the phe-
nomenon of insomnia in PD, provide suggestions regarding evaluation of insomnia
and its application in PD, and review potential treatment options for insomnia in PD.
6.2 Definition
The definition of insomnia has been a source of contention for several years. There are
debates regarding how to differentiate the symptom from the disorder, whether spe-
cific time thresholds should be included (e.g., how long it takes to fall asleep, duration
of WASO periods), and how to combine these sleep complaints with daytime, or
wake, complaints (e.g., fatigue or sleepiness) [9]. Generally, there is consensus that
the core symptoms of insomnia should involve at least one nighttime or sleep symp-
tom (e.g., difficulty initiating or maintaining sleep, early morning awakenings, non-
restorative sleep) and at least one daytime or wake symptom (e.g., fatigue, mood
issues, cognitive dysfunction, social or occupational impairment, EDS) [9, 10].
Diagnostic criteria for insomnia are included within the following three different
classification systems: the Diagnostic and Statistical Manual of Mental Disorders,
4th edition (DSM-V) [11]; the International Classification of Diseases, 10th revision
(ICD-10) [12]; and the International Classification of Sleep Disorders, 3rd edition
(ICSD-3) [10]. For this discussion, the ICSD-3 criteria for chronic insomnia disor-
der will be used which include difficulty initiating or maintaining sleep, early morn-
ing awakening, and patients complaints related to poor nighttime sleep.
For PD patients, risk factors for insomnia include having PD itself (e.g., motor
symptoms), treatment factors (e.g., medication side effects, wearing-off effects),
psychosocial disturbances (e.g., depression, anxiety), and comorbid medical disor-
ders. It is important to note that PD patients may have overlapping insomnia and
6 Insomnia in Parkinsons Disease 81
other sleep disorders. Below is a brief summary of each of these diagnoses as it may
pertain to PD.
Difficulty initiating or maintaining sleep may be considered a common symptom
of an underlying existing medical condition. For PD patients, motor symptoms can
be especially disruptive or disturbing at night [13]. For example, bradykinesia
causes difficulty turning in bed, requiring frequent readjustment of pillows and
blankets. Early morning dystonia is a common complaint, when dopamine levels
are low or are not supplemented by medications, leading to severe contractures that
disrupt sleep. Non-motor PD symptoms can also interfere with sleep, particularly
autonomic dysfunction. Urinary and gastrointestinal dysfunction during sleep is
known to significantly contribute to insomnia complaints [1416]. When these
PD-related symptoms lead to concern or distress to the point of causing loss of sleep
or prolonged WASO, this insomnia diagnosis should be considered.
The bidirectional relationship between insomnia and mood disorders, specifi-
cally depression and anxiety, has been well documented. Insomnia may be a symp-
tom of a variety of mental disorders, but patients also cite insomnia as a potential
trigger or exacerbator of their mood or mental disorder. In PD, depression is highly
prevalent [17, 18], possibly associated with dysfunction of dopaminergic transmis-
sion, a notion that is partially supported by improvement after dopamine agonist
administration [19]. Additionally, movement issues can increase anxiety and depres-
sion symptoms, which can also affect sleep quality. Mood disorders in PD must be
evaluated independently of motor symptoms, as depression can lead to maladaptive
behaviors that can worsen insomnia [10, 20].
Medications used to help PD-related motor symptoms may alternately cause
daytime sleepiness and nighttime hyperarousal [21]. Direct effects on the sleep
and wake systems may depend on dose and timing of the medications. For
example, levodopa 200 mg in the evening may improve subjective sleep quality
[22], but continuous dopaminergic therapy has been shown to worsen sleep
fragmentation [23]. Non-selective MAO-B-inhibitors have been reported to
cause both daytime sleepiness and sleep disruption, possibly due to an amphet-
amine-like metabolite [24] that has not been reported with selective MAO-B-
inhibitors [25].
Medications that may also help with non-motor symptoms can also exert delete-
rious effects on sleep and wake function. For example, antidepressants can have
either an alerting or sedating effect, so correct timing of these medications is impor-
tant. A thorough review of medications (including over-the-counter preparations),
side effects, dosage, and timing of administration is recommended.
6.3 Pathophysiology and Sleep-Wake Systems
PD pathology involves lesions in the upper brainstem and lower midbrain [15],
areas that are crucial in sleep and wake regulation. Alterations of brainstem cho-
linergic and noradrenergic neurons can result in altered REM sleep, while loss of
serotonin is associated with reduced slow wave sleep. It is important to remember
that PD pathology also affects wake systems [21]. As brainstem dopaminergic,
cholinergic, and serotoninergic neurons, along with forebrain acetylcholine and
histamine, are integral to the arousal system, PD-related neurodegeneration fun-

damentally alters the ability to sustain wakefulness. PD patients may also have
relative losses of orexinergic neurons in the lateral hypothalamic region, which
normally provides excitatory signals to these same arousal systems [26]. The
overall result is an altered arousal threshold, leading to increased susceptibility to
sleep (i.e., daytime napping), which can hinder the ability to initiate and consoli-
date nighttime sleep.
Early involvement of PD pathology within the brainstem regions [15] may
explain the high frequency of insomnia complaints even in the mild stages of PD,
suggesting that insomnia steadily worsens as PD progresses. On the contrary,
insomnia in PD has been shown to fluctuate over time [27]. Similarly, various imag-
ing techniques have failed to associate sleep disturbances with specific structural
abnormalities in PD [28] suggesting that PD-related insomnia is not solely attrib-
uted to brainstem neurodegeneration.
6.4 Evaluation
As with any medical disorder, evaluation of insomnia should begin with a thorough
history that includes frequency and duration of symptoms, exacerbating and reliev-
ing factors, average and range of bedtimes, perceived sleep latency, number of
arousals, duration of WASO, average and range of wake times, and perceived qual-
ity of sleep. Discussion regarding behavioral habits during the 24-h day may include
levels of activity during the day, daytime napping habits, use of non-sleep activities
while in bed such as use of electronics, and environmental factors (e.g., tempera-
ture, noise, pets). Medical and psychiatric history should be considered in the con-
text of the timing of symptoms, along with review of medications specifically
including medications attempted for treatment of sleep and wake symptoms (includ-
ing over-the-counter preparations) and a review of medications that can potentially
influence sleep and wake rhythms (e.g., antidepressants, steroids, antihistamines,
etc.) [29, 30].
Because of the complexity of insomnia in PD, evaluation and management of PD
is necessarily multifaceted. In addition to a thorough history and examination, clini-
cians are encouraged to reevaluate both the timing and dose of PD pharmacother-
apy, as this may help insomnia by either directly helping with nighttime sleep
consolidation (e.g., by reducing nocturnal akinesia or dyskinesia that may interfere
with sleep) or indirectly by reducing daytime sleepiness (i.e., increasing wake peri-
ods during the day, thereby helping with nighttime sleep latency and consolidation).
Concomitantly, consultation for associated comorbid medical issues (e.g., urologi-
cal issues) is recommended to reduce the potential interference of nighttime sleep
consolidation. Consistent reevaluation of psychiatric and psychological symptoms
is recommended to adequately address symptoms of depression, anxiety, hallucina-
tions, and panic from interfering with sleep and wake function. Finally, consultation
with a clinician who is experienced with the diagnosis and management of insomnia
is often helpful.
6.4.1 Evaluation Tools
For PD, six scales have been deemed to meet criteria as per the movement disor-
ders task force [31]: the Pittsburgh sleep quality index (PSQI), the Epworth sleep-
iness scale (ESS), the inappropriate sleep composite score (ISCS), the Stanford
sleepiness scale (SSS), the Parkinsons disease sleep scale (PDSS) [32], and the
scales for outcomes in Parkinsons disease (SCOPA-sleep) [33]. The first four
scales are generic sleep tools, generally limited in their ability to evaluate
PD-specific sleep symptoms, while the latter two scales have been developed to
be specific to PD. The PDSS is a visual analogue scale that includes PD-related
nocturnal symptoms including overall quality of nighttime sleep, sleep onset and
maintenance insomnia, nocturnal restlessness, nocturnal psychosis, nocturia, noc-
turnal motor symptoms, sleep refreshment, and daytime dozing. A modified ver-
sion, the PDSS-2, includes screening for sleep apnea, and is reported to have an
excellent level of validity and reliability. The SCOPA-sleep is a short, two-part
scale that assesses nighttime sleep and daytime sleepiness. Although this scale
has been validated, it does not incorporate other PD-specific problems such as
nocturnal hallucinations, motor symptoms, or nocturia. The PDSS and SCOPA-
sleep scales have been developed specifically for PD patients, with incorporation
of items to assess nocturnal sleep quality and impairment. However, while more
applicable to sleep symptoms in PD, neither scale has been evaluated specifically
for PD-related insomnia.
Available tools for insomnia assessment typically consist of sleep diary and
actigraphy measures. Sleep diaries are subjective tools that help identify pat-
terns of sleep [34]. Patients are typically asked to keep a prospective record of
their bed times, WASO, wake times, and sleep quantity and quality over a course
of a few weeks. Patients are usually instructed to record this information during
the morning times, using recall of the previous nights sleep to complete this
information. Using these records, parameters such as time-in-bed along with
subjective ratings of sleep and wake function can be estimated. Sleep diaries do
not necessarily correlate with objective measures of sleep, but this data can help
identify important factors related to the insomnia complaints. Further, sleep
diaries can be used to assess treatment response [35, 36]. Actigraphy is an accel-
erometer device that monitors motion and calculates activity counts, providing
objective information regarding sleep and wake patterns over several days or
weeks. It is considered a useful evaluative tool for insomnia [37, 38], particu-
larly in assessing whether certain patterns of sleep emerge or to evaluate the
implementation of behavioral methods such as sleep restriction on existing
patterns.
Although sleep studies (polysomnography, or PSG) are considered the gold-
standard assessment for most nocturnal sleep disorders, PSG is not recom-
mended for routine assessment of insomnia [39]. However, as comorbid sleep
disorders are highly prevalent in PD patients, PSG is often utilized to evaluate
potential sleep apnea, periodic limb movement disorder, and REM behavior
disorder.
6.5 Differential Diagnoses
6.5.1 Other Sleep Disorders
While discussion regarding other nocturnal sleep disorders is out of the scope of this
chapter, it is important to note that PD patients often have comorbid sleep disorders
including sleep apnea, restless leg syndrome (RLS), periodic limb movement disor-
der, and REM behavior disorder that contribute to sleep fragmentation, poor sleep
quality, and daytime dysfunction. Evaluation and treatment of these disorders may
improve the insomnia complaint, in which case an independent diagnosis of insom-
nia is excluded. However, it is also possible that insomnia is persistent and separate
from these other sleep disorders. Further, the existence of these sleep disorders may
potentially exacerbate insomnia symptoms and interfere with treatment of insomnia
[40]. For example, patients may be unable to adhere to relaxation techniques for
insomnia (CBT-I) if RLS symptoms are present. The symptoms of these sleep dis-
orders should be considered during the initial evaluation as well as during subse-
quent follow-up visits.
6.5.2 Circadian Rhythm Sleep Disorders
The circadian system is suspected to be affected in PD-related pathophysiology,

substantiated by reports of advanced sleep-wake schedules (i.e., early bedtimes and
early wake times) in PD patients. Though the suprachiasmatic nucleus of PD
patients is likely not involved, aberrant clock genes [41] and abnormalities in circa-
dian hormonal patterns [42, 43] are reported. Clinically, circadian involvement in
PD is partially supported by the beneficial effect of administering bright light in PD
patients [44]. However, it is yet unclear whether the clinical observation of circadian
misalignment in PD is mediated directly by alterations in the circadian system or via
other indirect pathways (e.g., age, depression). Evaluation of insomnia should
include a review of preferred versus habitual sleep and wake times to consider cir-
cadian rhythm disorders into the differential diagnosis.
6.6 Treatment
6.6.1 Behavioral Treatment
For movement issues, the comfort of the PD patient during the night can be improved
by simple measures. For example, PD patients may find relief by using sheets that
do not slip, wearing silk pajamas without buttons, and placing levodopa tablets and
a bottle of water on the bedside table. In advanced stages of the disease, the patients
spouse should be encouraged to sleep in a different bed or room as needed, as inad-
equate rest for the caregiver can make the patients sleep disturbance intolerable and
lead to early institutionalization.
Enhancing both daytime activities and assisting with calming nighttime

activities can provide insomnia relief. Increased activity during the day helps to
increase sleep pressure so that sleep latency at bedtime is reduced. Nighttime
measures may include stimulus control, proper sleep hygiene, and sleep restric-
tion. Stimulus control is a set of instructions to reinforce the association between
sleep and the bed/bedroom [45]. Examples include going to bed only when feeling
sleepy, avoiding activities other than sleep in the bed/bedroom (e.g., no reading or
watching TV), getting out of bed if sleep is not achieved in an acceptable amount
of time, keeping a routine sleep-wake schedule (e.g., same wake time regardless
of the amount of sleep perceived the night before), and avoidance of daytime
napping. Proper sleep hygiene habits are also advised. For example, use of eve-
ning caffeine may cause evening alertness as well as worsen PD-related urinary
processes. Restriction of daytime napping is also crucial in allowing for improved
nighttime sleep onset latency and nighttime sleep consolidation. Patients may also
be instructed to adjust environmental influences (e.g., light, noise, temperature)
that may promote or interfere with sleep [46]. Sleep restriction involves limiting
the amount of time-in-bed so as to reflect, as close as possible, the actual sleep
time. Sleep efficiency, which is the amount of time sleeping divided by the amount
of time in bed, is one outcome that helps guide treatment efficacy. Once accept-
able sleep efficiency is achieved, the time-in-bed is gradually increased. For the
PD patient, the caveat in implementing these particular behavioral techniques is
potential worsening of daytime sleepiness, so caution with risky behaviors during
the day such as driving (especially due to potential dopaminergic influence) need
to be considered.
Cognitive behavioral therapy for insomnia (CBT-I) combines several of these
behavioral techniques with a cognitive approach to help with insomnia symptoms.
For example, a patient may go to bed earlier than a natural sleep time to allow
for more sleep, even if sleep typically does not occur at that earlier time. This may
cause excessive worry to occur during this time in bed (e.g., if I cant sleep, I will
have poor work performance and get fired). CBT-I is used to reduce excessive wor-
rying about sleep and to help reframe beliefs regarding the association between
insomnia and daytime consequences [47, 48]. CBT-I is considered the first-line
treatment for insomnia [39, 49] but frequently requires a trained clinician for effec-
tive results. CBT-I [48] is a potential promising line of insomnia treatment for PD
patients. One study demonstrated possible benefit of using CBT-I in PD patients
[44]. This finding remains to be replicated, warranting further investigation.
6.6.2 Pharmacological Treatment
Despite clinical evidence that insomnia is widespread in PD patients, research evi-

dence is somewhat limited. As a result, most treatment recommendations are based
on small studies or on anecdotal reports. Generally, if pharmacotherapy for insom-
nia is considered necessary, medications should be used in conjunction with behav-
ioral treatments for insomnia.
Pharmacotherapy management should consider modification of dopaminergic

doses to address PD motor symptoms. Timing of dopaminergic doses may help to
identify gaps in dopaminergic stimulation over the 24-h period, but this needs to be
considered in the context of possibly causing alerting effects in the middle of the
night. While low doses of dopaminergic stimulation may result in sleepiness, higher
doses may induce wakefulness [21]. As a result, lower doses given during the day
may induce sleepiness but the additive effect at the end of the day may result in an
alerting effect [50]. Additionally, PD-related urinary symptoms often disrupt sleep.
Transitory blockade of nighttime polyuria with an evening intranasal dose of des-
mopressin may be effective in improving sleep consolidation [51].
Generally, medications for sleep are prescribed for acute onset insomnia rather
than for chronic insomnia, as the sedating effect of these medications tends to
decrease over time and/or side effects become more significant [52]. Potential side
effects include morning sedation, memory deficits, impaired balance, and poten-
tially sleep-related amnestic behaviors such as sleep walking. Contraindications of
benzodiazepine medications for sleep include use of other sedative drugs which
may lead to synergistic and additive side effects, substance use, sleep-disordered
breathing including sleep apnea, and hepatic failure. Additional long-term concerns
include rebound insomnia, withdrawal symptoms, and dependence [53]. In com-
parison, non-benzodiazepine hypnotics generally have shorter half-lives with less
impact on muscle relaxation.
In PD, eszopiclone was found to have favorable subjective improvement in
insomnia symptoms for a small group of PD patients [54] but objective data and
long-term evaluation have not been evaluated. If the PD patient has comorbid sleep
disorders requiring benzodiazepine medication (e.g., clonazepam for REM behav-
ior disorder), the PD patient and caregiver will need to be appraised of the particular
risks associated with these medications so as to take proper safety precautions. In
summary, sedative medications in general should be considered only when neces-
sary, as the peak effect of these medications may coincide with worsening motor
symptoms and wearing-off effects in the middle of the night and in the early morn-
ing period, combining to aggravate imbalance and cognitive deficits.
While other prescription medications often have sedative and hypnotic effects,
there is little evidence regarding their efficacy or safety in treatment of insomnia.
Trazodone is perhaps one of the most widely prescribed medications for sleep pos-
sibly because of its short half-life. However, morning sedation is a common side
effect [55] and the medication tends to lose its hypnotic effect after a short period of
time. Medications such as gabapentin or pregabalin are often used for chronic pain
conditions and have sedative qualities that may help with sleep latency, but have not
been formally studied for insomnia. Sedating antipsychotic medications (e.g., que-
tiapine, risperidone) are often used for sleep purposes [30]; however, these medica-
tions are not FDA-approved for insomnia and may not be advisable for insomnia
treatment due to concern regarding severe outcomes including metabolic syndrome
and sudden death.
For PD patients, sedative antidepressants and antipsychotics are often considered
to treat both insomnia symptoms along with comorbid psychiatric symptoms.
Clozapine and quetiapine [56] have been reported to improve subjective sleep qual-
ity but were not evaluated with objective sleep measures. Doxepin also appears to
be effective for insomnia in PD patients [44]. Consideration should be given regard-
ing the timeline of insomnia symptoms, as these medications can worsen symptoms
of restless leg syndrome, periodic limb movements, and REM behavior disorder.
Melatonin (N-acetyl-5-methoxytryptamine) is an herbal supplement, available
without a prescription in the United States. Melatonin receptor agonists (e.g.,
ramelteon) are available by prescription only, with properties similar to endogenous
melatonin. These medications may help with sleep latency and possibly sleep dura-
tion but have the additional benefit of potentially shifting circadian rhythms [57,
58]. Melatonin and its derivatives are typically less potent but also have fewer side
effects than hypnotic medications.
For PD patients, melatonin can have beneficial effects in subjective sleep quality
but only mild benefit in objective sleep parameters [59]. Long-term data are not
available to determine whether these sleep benefits are sustained chronically.
Generally, higher doses of melatonin (e.g., 50 mg) are not considered more effective
than lower doses of melatonin (e.g., melatonin dose 35 mg) in PD.
Sodium oxybate is a prescription medication that is FDA-approved for narco-
lepsy patients. It is derived as the sodium salt of gamma-hydroxybutyric acid.
Although the mechanism of action is officially unknown, it likely exerts its effect
via GABAergic pathways. Its heavy sedative effects allow for sleep consolidation,
improving next-day alertness.
Sodium oxybate was evaluated in an open-labeled study of PD patients and
found to have significant subjective improvement in sleep quality [60]. While objec-
tive sleep measures showed increased slow wave sleep and REM sleep, overall total
sleep time and sleep efficiency remained unchanged. Due to its heavy sedative
effect, this medication should be used only after evaluation for sleep apnea, should
not be taken with other sedative medications, or be used in patients who use alcohol.
Exacerbation of depressive symptoms with suicidality has been reported in trials of
sodium oxybate, requiring close monitoring of depressive symptoms when using
this medication in the PD patient.
Over-the-counter preparations often exert sedative effects via antihistaminergic
and anticholinergic pathways. Patients should be advised regarding the limited use
of over-the-counter preparations, particularly as there is limited data on the safety
and efficacy of these compounds when used routinely or chronically [53].
6.6.3 Deep Brain Stimulation (DBS)
Subthalamic nucleus stimulation may improve insomnia symptoms via increasing

sleep duration and/or reducing nocturnal awakenings [61]. It is unclear whether this
effect is mediated by sleep pathways or by improvement in motor symptoms.
However, DBS is also associated with emergence of restless leg symptoms and
periodic limb movements during the period of subthalamic stimulation. This sug-
gests that the improvement noted with DBS is mediated by pathways outside of the
basal ganglia. However, these DBS effects have only been observed in the advanced
stages of PD. As a result, it is unclear whether these benefits would be observed for
PD patients in the early stages of the disease and whether the effect would be
long-lasting.
Conclusion
Insomnia in Parkinsons disease is a complex phenomenon that integrates several
factors including PD pathology, age, depression, and medication effect, all of
which contribute to insomnia pathophysiology. Therefore, insomnia evaluation
necessitates consideration of multiple factors including adjustment of medica-
tions, behavioral adaptations to help with motor symptoms, addressing non-
motor issues such as psychiatric and urinary complaints, evaluation of underlying
sleep disorders such as sleep apnea and restless legs syndrome, and possibly
administering a combination of pharmacotherapy and behavioral treatments for
insomnia. Treatment of insomnia will likely involve a multidisciplinary team of
specialists including neurology, psychiatry, urology, and a sleep clinician who is
experienced with the diagnosis and management of insomnia.
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Sleep Disordered Breathing
Michael K. Scullin, Lynn Marie Trotti, and Donald L. Bliwise
Contents
7.1 An Introduction to Sleep Disordered Breathing ............................................................. 94
7.1.1 Definitions, Detection, and Diagnosis ................................................................ 94
7.1.2 Correlates of Sleep Disordered Breathing in the General Population ................ 95
7.2 Relevance of Sleep Disordered Breathing in Parkinsons Disease ................................. 95
7.3 Prevalence of Sleep Disordered Breathing in Parkinsons Disease ................................ 96
7.3.1 Questionnaires..................................................................................................... 96
7.3.2 Polysomnography................................................................................................ 96
7.4 Clinical Implications of Sleep Disordered Breathing ..................................................... 99
7.4.1 Excessive Daytime Sleepiness ............................................................................ 99
7.4.2 Cardiovascular Risk ............................................................................................ 99
7.4.3 Cognition and Memory Consolidation................................................................ 100
7.4.4 Motor Symptoms ................................................................................................ 101
7.5 Treatment Options........................................................................................................... 102
7.6 Future Directions ............................................................................................................ 102
References ................................................................................................................................ 104
Abstract
Sleep disordered breathing (SDB) is a serious medical condition in which there
are repeated reductions or cessations of breathing during sleep. Early research
suggested that because Parkinsons disease (PD) patients have pulmonary abnor-
malities while they are awake they may be at increased risk for developing sleep
disordered breathing. A large literature now demonstrates that sleep disordered
M.K. Scullin (*)

Department of Psychology and Neuroscience, Baylor University, Waco, TX, USA
L.M. Trotti D.L. Bliwise
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

94 M.K. Scullin et al.
breathing is common in Parkinsons disease patients, but no different than age-

matched controls from the general population. In the general population, sleep
disordered breathing often correlates with excessive daytime sleepiness, but this
correlation is not typically observed within Parkinsons disease patients.
However, sleep disordered breathing in Parkinsons disease has been preliminarily
linked to impaired sleep-dependent memory consolidation, blunted sympathetic
responses, and worsening motor function Unified Parkinsons Disease Rating
Scale (UPDRS). Parkinsons disease patients who have sleep disordered breath-
ing may benefit from positive airway pressure or mandibular advancement treat-
ments, and an exciting avenue for future research is determining whether such
treatment also positively affects disease progression and quality of life.
7.1 An Introduction to Sleep Disordered Breathing
Sleep disordered breathing (SDB) is a medical condition in which breathing repeat-

edly ceases (apnea) or is reduced (hypopnea) during sleep. This condition affects
more than 40 million Americans and approximately 75 % of severe cases are undi-
agnosed [1, 2]. In this chapter, we first discuss SDB in the context of individuals
without neurological disease. Then we turn our attention to why SDB might be
particularly relevant to Parkinsons disease (PD), and we evaluate the literature with
regard to two questions. First, is SDB more common in PD than in the general com-
munity? Second, in PD patients, what are the clinically relevant correlates of SDB?
7.1.1 Definitions, Detection, and Diagnosis
SDB is a general term that includes several distinguishable subtypes of poor breath-
ing during sleep. Obstructive sleep apnea is characterized by the cessation of breath-
ing due to an occluded upper airway. By contrast, in central sleep apnea there is an
unstable ventilatory control system, which results in periods of absent respiration
despite an open airway [3]. Complex sleep apnea syndrome is diagnosed when an
individual demonstrates both central and obstructive events.
A variety of questionnaires are used in the clinical assessment of SDB (e.g., Berlin
Questionnaire [4], STOP-BANG Questionnaire [5]). Some of the most important
screening questions involve the frequency of snoring and bed partner reports of the
patient gasping for air, because these signs indicate obstructed breathing. In addition,
SDB is more likely in obese individuals [6] and in those who have an enlarged neck
circumference, retrognathia, or other craniofacial morphologies that reduce airflow
[7]. The gold standard for detecting SDB, however, is nocturnal polysomnographic
recordings of electroencephalography, electrooculography, electromyography, respi-
ratory effort, airflow, and oxygen saturation levels. Apneas are scored when there is
a 90 % reduction in airflow for 10 s and hypopneas are scored when there is a
3090 % reduction in airflow for 10 s accompanied by a 4 % reduction in oxygen
saturation levels [8]. An apnea-hypopnea index (AHI), which is the total combined
7 Sleep Disordered Breathing in Parkinsons Disease 95
number of apneas and hypopneas per hour of sleep, is normal when less than 5; how-
ever, an AHI from 5 to 14.9 indicates mild SDB, an AHI from 15 to 29.9 indicates
moderate SDB, and an AHI greater than 30 indicates severe SDB.
7.1.2 Correlates of Sleep Disordered Breathing in the General

Population
In the general population, the prevalence of SDB increases with age and is more
prevalent in men than women [9]. Independent of these demographic factors, SDB
has been linked to several poor health outcomes. First, SDB can lead to daytime
sleepiness, moodiness, and poor vigilance. Such outcomes may have implications
for workplace performance and vehicle accidents [10]. Second, sleep apnea has
been implicated to cause poorer cognitive performance on executive control tasks
[11], and may increase risk for developing mild cognitive impairment or dementia
[12]. Third, SDB is strongly associated with hypertension [13], and may also pre-
dispose individuals to cardiac ischemia, congestive heart failure, cardiac arrhyth-
mias, and cerebrovascular disease [14]. Fourth, at least in rodent models, SDB has
been implicated in the loss of catecholamine neurons [15], with hypoxia contribut-
ing to a reduction in extracellular dopamine [16].
7.2 Relevance of Sleep Disordered Breathing in Parkinsons

Disease
There are several reasons why SDB might be particularly important in PD patients.
Mortality rates may be elevated in PD patients in the early morning hours relative to
other neurological diseases [17], and some have interpreted this result as evidence
for respiratory insufficiency during sleep [18]. Moreover, beyond neuropathology in
the nigrostriatal pathways, PD may also be associated with neurodegeneration in
other brainstem regions [19, 20], which may contribute to SDB by disrupting respi-
ratory and autonomic functions [21].
SDB is also implicated in PD because waking pulmonary function abnormalities
are associated with this disease [22]. Such abnormalities may be due to degenera-
tion of dopaminergic neurons or to medication side effects including dyskinesias or
wearing-off [23]. Pulmonary abnormalities may include upper airway obstruction
as well as chest wall rigidity and hypokinesia, each of which might be expected to
result in breathing abnormalities during sleep [2326].
Another reason why SDB might be particularly important in PD patients is that
one of the most common symptoms of SDB in the general populationexcessive
daytime sleepinessis also a major concern in PD patients. Hobson et al. [27]
found that excessive daytime sleepiness was present in 51 % of a sample of 638 PD
patients, even in patients who were living independently and still driving. Though
some of the excessive daytime sleepiness in PD patients may be attributable to the
usage of dopaminergic medications [28], the relationship between sleepiness and
medication class may be complex. Using the objective Maintenance of Wakefulness
Test (MWT) to determine alertness, Bliwise et al. [29] found that higher dosages of
dopamine agonists were associated with greater daytime sleepiness (lower alert-
ness) whereas higher dosages of levodopa were associated with lower daytime
sleepiness (higher alertness). Additional research has shown that daytime sleepiness
is not solely attributable to dopaminergic medications, but appears to be an integral
part of the disease [30, 31].
7.3 Prevalence of Sleep Disordered Breathing

Given the prevalence of symptoms of sleep apnea in PD patients (especially day-

time sleepiness) as well as possible mechanisms for its predisposition in PD (chest
wall rigidity), a pertinent question is whether SDB is more common in PD patients
relative to age-matched controls. There have been two approaches to address this
question: one relying on questionnaires and the other relying on in-laboratory
polysomnography.
7.3.1 Questionnaires
Chotinaiwattarakul et al. [32] found that high risk for SDB, as assessed by the
Berlin Questionnaire [4], was suggested in nearly 50 % of their 134 PD patients
whereas only approximately 35 % of non-blood relative controls. Similarly, Rongve
et al. [33] compared 39 patients with a diagnosis of PD dementia or Lewy body
dementias to 420 healthy controls using the Mayo Sleep Questionnaire. This ques-
tionnaire uses bed partner report of arrested respiratory episodes during sleep or the
reported use of continuous positive airway pressure to determine probable obstruc-
tive sleep apnea. Rongve et al. [33] observed a higher rate of probable obstructive
sleep apnea in their patient group (25.7 %) than in their healthy control group
(15.2 %). However, not all questionnaire studies have suggested differences in SDB
across PD and control groups. For example, using the Sleep Questionnaire and
Assessment of Wakefulness (SQAW [34]), Happe et al. [35] found a nominally
lower rate of SDB symptoms in the PD group than the control group.
7.3.2 Polysomnography
Polysomnographic studies have also yielded some variable findings for prevalence
rates. A summary of these studies is shown in Table 7.1. Prior to modern AHI crite-
ria, early research compared the number of apneic episodes in small samples of PD
patients and normal controls, with some findings suggesting greater apneic episodes
in PD patients than controls [18, 47], and other findings suggesting no differences
[48]. Using more contemporary AHI cutoff scores, 7 out of 12 studies have observed
high prevalence of SDB in PD patients. These studies generally observed AHIs
7
Table 7.1 Overview of polysomnographic studies that assessed the prevalence of sleep disordered breathing (SDB) in Parkinsons disease (PD)
Reference PSG PD No SDB Mild SDB Moderate Severe Authors
(chronological) nights group Control group (04.9) (515) SDB (15.130) SDB (>30) conclusion
Arnulf [30] 1 N = 54 None 50 % 27.8 % 11 % 9.3 % Higher rate in PD
Maria [36] 1 N = 15 Age-matched controls (n = 15) 33.3 % 60 % Higher rate in PD
Baumann [37] 1 N = 10 None 0% 80 % 10 % 10 % Higher rate in PD
Diederich [38] 1 N = 49 AHI-matched controls (n = 49) 57.1 % 20.4 % 8.2 % 14.3 % Lower rate in PD
Shpirer [39] 1 N = 46 Age-matched controls (n = 30) 78.3 %a 21.7 %a AHI was higher
in PD
Monaca [40] 1 N = 36 None 44.4 %a 44.4 %a 11.1 % No commentary
Sixel-Dring [41] 2 N = 20 Progressive supranuclear 45 % 55 % Common,
palsy (n = 20) undetected in PD
Norlinah [42] 1 N = 44 None 51 % 24.5 % 16.3 % 8.2 % High SDB
prevalence in PD
Cochen De Cock [43] 1 N = 100 In-hospital controls (n = 50) 73 % 6% 11 % 10 % Lower rate in PD
Trotti and Bliwise [44] 3 N = 55 Sleep Heart Health Study 56.3 % 29.1 % 10.9 % (11.7 %) 3.6 % (6.1 %) No difference
Sleep Disordered Breathing in Parkinsons Disease
(53.7 %) (28.6 %)
Yong [45] 1 N = 56 Age-matched controls (n = 68) 50.9 % 15.1 % 18.9 % (19.4 %) 15.1 % (9 %) No difference
(34.3 %) (37.3 %)
Nomura [46] 1 N = 107 Non-PD sleep apnea controls 77.6 % 22.4 % No difference or
(n = 31) milder in PD
Severity of SDB is determined by the apnea-hypopnea index (AHI; number in parentheses). References are listed in chronological order. When available, data
from control groups are presented in parentheses. Missing cells and collapsed cells reflect the manner in which data were reported in the original papers
Notes: aindicates that AHI cutoff was at 10 (rather than 5 and 15)
97
>5 in more than 50 % of their patient samples, and one study even observed an AHI
>5 in all of their PD patients. Though this might be considered to be strong evidence
for an increased prevalence of SDB in PD, there exist at least three important limita-
tions for these studies. One limitation is that these studies may have preferentially
selected PD patients for excessive daytime sleepiness or those who were referred to
the sleep center for clinical purposes. Either selection criteria could be expected to
bias diagnosis of SDB in the PD group. In addition, only one of these studies used
more than one night of polysomnographic assessment and two of these studies had
very small sample sizes (Ns 15). None of these seven studies included a sample
size that exceeded N = 54. Furthermore, scoring criteria for apneas and hypopneas
vary widely, which is a limitation for studies that did not test (healthy) control
groups with blinded scoring. Only two of the six studies that concluded an increased
prevalence of SDB in PD patients supported that conclusion by demonstrating sig-
nificantly greater AHI relative to an age-matched control group.
Several studies have failed to observe significantly higher SDB in PD patients
(Table 7.1). For example, Trotti and Bliwise [44] measured AHI in 55 idiopathic PD
patients across three nights of in-laboratory polysomnographic testing, and com-
pared prevalence rates against those observed in the Sleep Heart Health Study [13],
which is the largest epidemiological study of SDB in the general population. They
found no difference in the prevalence of mild, moderate, or severe sleep apnea in
their PD patients. Yong et al. [45] also observed no difference between 56 PD
patients and 68 age- and sex-matched controls in an Asian population. Our most
recent workthe Emory 48-h protocol [29]also suggests no increased risk of
SDB in PD patients. We had 84 idiopathic PD patients undergo at least one night of
polysomnographic testing (N = 74 completed two nights). Most patients (59.5 %)
showed a mean AHI <5, and 32.1 % of patients showed mild sleep apnea (AHI
514.9). Only 4.8 % and 3.6 % of patients showed moderate (AHI 1529.9) or
severe (AHI 30) signs of sleep apnea, respectively. When compared with preva-
lence estimates from the Sleep Heart Health Study [13], our results suggest that the
prevalence rate of AHI is similar for mild sleep apnea, and possibly lower for mod-
erate and severe sleep apnea, in PD patients than in the general population.
Three additional studies have suggested either lower rates, or less severe, SDB in
PD patients than in controls. Cochen De Cock et al. [43] found a lower prevalence
of mild or greater SDB in a sample of 100 PD patients (27 %) relative to 50 non-
neurological in-hospital control patients (40 %). Diederich et al. [38] conducted a
case-control study in which 49 idiopathic PD patients were matched to 49 controls
based on age, gender, and AHI. They observed fewer obstructive sleep apneas and
higher oxygen saturation levels in the PD patients than in the AHI-matched con-
trols. Most recently, Nomura et al. [46] concluded that SDB in their sample of 107
PD patients was very similar to that of the elderly general population; furthermore,
relative to a sample of 31 non-PD patients with obstructive sleep apnea, the PD
patients who showed an AHI 15 had a lower respiratory arousal index and a less
severe decrease in oxygen saturation.
In sum, though there are reports of a higher prevalence of SDB in PD patients
than the general population, several of these studies are based on small sample sizes
and may have been confounded by selection biases (referral for sleepiness). Our
interpretation of the literature is consistent with Peeraully et al.s [49] recent review
of case-control polysomnographic studies that there is no increased prevalence of
SDB in PD. Nevertheless, SDB is still common in PD patients and may have
important clinical implications for this population.
7.4 Clinical Implications of Sleep Disordered Breathing
One important clinical consideration for SDB in PD may be poorer quality of life
[32]. We next consider the clinical correlates of SDB that might explain why quality
of life is dampened in PD patients with probable sleep apnea.
7.4.1 Excessive Daytime Sleepiness
First, because excessive daytime sleepiness greatly affects quality of life in PD

patients [50], and because this is a primary symptom of SDB [51], one might expect
that some sleepiness in this patient group is due to SDB [37]. Some findings support
this association. For example, Shpirer et al. [39] found that PD patients who had an
Epworth Sleepiness Scale (ESS) score greater than 10 had a higher AHI than those
with scores below 10 (see also [42, 52]). However, when measured as continuous
variables, AHI and ESS did not correlate significantly [39]. Other studies have
reported no significant correlation between AHI and ESS [43, 44], and we did not
observe a correlation in our 48-h protocol [29].
When sleepiness has been measured objectively using the Mean Sleep Latency
Test, with few exceptions [53], there is typically no correlation between AHI and
mean sleep latency [30, 40]. In the 48-h protocol, we incorporated up to eight
Maintenance of Wakefulness Tests (MWTs) in which PD patients were instructed to
stay awake while lying in bed for 40 min [29]. In this study, we did not observe a
relationship between AHI and MWT scores. Therefore, the relationship between
SDB and quality of life in PD [32] does not appear to be mediated by excessive
daytime sleepiness. However, the causes of sleepiness are multifactorial (e.g., the
presence of dopaminergic medications), which may explain why SDB is a weaker
predictor of sleepiness in PD patients.
7.4.2 Cardiovascular Risk
As previously described, common correlates of SDB in healthy controls include

hypertension, cardiovascular events, and higher body mass index [13, 14]. Though
studies of SDB in PD are not as well powered as those in the general community, it
is still surprising that the typical (aforementioned) correlates of SDB have not been
observed in studies of PD patients [42, 43, 46]. Valko et al. [54] evaluated the asso-
ciation between heart rate variability and presence or absence of obstructive sleep
apnea syndrome in 62 PD patients and 62 age-matched controls. Their control group

demonstrated several significant associations between obstructive sleep apnea syn-
drome and heart rate variability, particularly for the low-frequency power band and
the low-frequency/high-frequency power band ratio. By contrast, heart rate vari-
ability did not correlate with SDB in the PD group. The authors suggested that there
is a blunted sympathetic response to sleep breathing events in PD.
7.4.3 Cognition and Memory Consolidation
SDB has also often been connected to the development of dementia, mild cognitive
impairment, or subtle cognitive effects in the general population [12]. It should be
noted, however, that this literature has produced variable results, and in the large-
scale, multicenter Apnea Positive Pressure Long-Term Efficacy Study (APPLES),
few associations were observed [11]. Few studies have examined SDB in relation to
cognition in idiopathic PD patients (though much work has been done for REM
sleep behavior disorder [55]). Cochen De Cock et al. [43] found no correlation
between SDB and Mini-Mental State Examination scores in PD patients. However,
more recently, Stavitsky et al. [56] observed a positive correlation between
actigraphy-defined sleep efficiency and an executive function composite. Though
not necessarily implicating SDB, it is possible that some of the actigraphy-defined
poor sleep efficiency might be due to breathing events due to breathing events or
periodic limb movements [57].
There is an important distinction to be made between impaired cognition as
assessed by neuropsychological testing (as a stable trait feature of PD), versus an
emerging memory consolidation literature that connects cognitive test perfor-
mance improvements to the sleep obtained between repeated cognitive tests (for
review, see [58]). In the 48-h protocol, we gave PD patients eight digit span back-
ward (executive function) tests across 2 days [59]. As illustrated in Fig. 7.1, PD
patients taking dopaminergic medications demonstrated significant digit span back-
ward improvements across the 48-h study. The improvement was not simply due to
practice effects because no performance improvements were observed across the
repeated daytime tests. Instead, performance improvements were localized to the
nocturnal sleep interval (Fig. 7.1). The degree of digit span backward improve-
ment was significantly associated with higher levels of slow-wave sleep and higher
oxygen saturation during the night that constituted the training interval, and not
during the pre-experimental night (laboratory adaptation night). PD patients who
demonstrated 5 or more minutes of oxygen saturation below 90 % during the train-
ing interval night did not show significant digit span improvements. Though this
(sleep) effect appears robust for repeated executive function testing, it has not been
observed for motor memory testing in PD patients [60, 61]. We suggest that correct-
ing SDB might improve the ability to acquire some new skills (as suggested by digit
span backward training), which could have a positive impact on PD patients quality
of life on a day-to-day basis (cf. [32]).
Fig. 7.1 Improvement on the 7

digit span backward test Nocturnal
across an interval that 6.5 Day 1 Day 2
Digit span backward score

sleep
included nocturnal sleep, but ns ** ns
not daytime wake, in 6
dopamine-treated Parkinsons
disease patients [59].
5.5
** indicates p < .01
5
4.5
4
Test 1 Test 4 Test 5 Test 8
7.4.4 Motor Symptoms
SDB might also be associated with poorer quality of life because nocturnal hypoxia
could potentially exacerbate certain aspects of PD neuropathology. Basic science
studies have shown experimentally that sleep apnea could cause the loss of cate-
cholamine neurons [15] or reduce extracellular dopamine [16]. Furthermore, oxida-
tive stress has been implicated in dopamine cell degeneration, mitochondrial
dysfunction, excitotoxicity, and inflammation in PD [62, 63]. Therefore, one might
expect that higher AHI or indices of nocturnal hypoxia would correlate with mea-
sures of disease severity in PD. Consistent with this idea, Efthimiou et al. [47]
observed more apneas in PD patients with more severe disease (Hoehn and Yahr
scale). Moreover, Maria et al. [36] found significant correlations between log-
transformed UPDRS motor scores and log-transformed AHI as well as median oxy-
gen saturation levels, even after controlling for age. Cochen De Cock et al. [43] also
observed a significant correlation between AHI and UPDRS motor scores, with
SDB being more frequent and severe in the most disabled PD patients. One addi-
tional study [32] observed a nonsignificant trend for higher SDB risk (Berlin
Questionnaire [4]) in PD patients at more severe disease stages, and another study
[42] observed significant correlations for greater sleep fragmentation and more
severe disease stages, but three studies have reported no significant correlations
between SDB variables and either UPDRS or Hoehn Yahr scores [41, 42, 64].
We contend that a limitation in prior studies of the clinical correlates of SDB
in PD patients is that most studies have examined polysomnography in relation to
disease severity in PD patients at a single time point in the course of disease. A
current direction of our research is examining the association between polysom-
nographic variables and change in motor disease severity over the course of dis-
ease. We recently evaluated whether change in motor disease severity (UPDRS
motor subscale) in 29 idiopathic PD patients was associated with SDB variables
[65]. The two time points (Time 1 [T1] and Time 2 [T2]) were separated by an
average interval of 265 days, and at T2 patients underwent 2 nights of
polysomnographic recording. Variables derived from overnight polysomnography

were not associated cross-sectionally with UPDRS motor scores at T1 or T2 in
our data. Similar absence of significant findings with cross-sectional analyses has
been observed previously [41, 64]. However, in our data poorer sleep was strongly
associated with declining function in UPDRS motor scores (i.e., from T1 to T2).
As illustrated in Fig. 7.2, there were strong correlations with mean oxygen satura-
tion levels (but not AHI), particularly during REM sleep. The UPDRS-change
correlations with mean oxygen saturation during REM sleep was not negated
when controlling for time between UPDRS assessments, overt dream enactment,
low REM sleep amounts, dopamine dosage, age, gender, education, years since
diagnosis, cognitive status, or mean oxygen saturation while awake. Thus, noctur-
nal oxygen saturation levels may represent an important biomarker of change in
disease severity.
7.5 Treatment Options
There are several treatment options for SDB in PD patients. First, breathing prob-
lems might be treated by normal antiparkinsonian medications to reduce rigidity
[66]. SDB may also be treated using positive airway pressure therapy (e.g., CPAP),
which is the most typical treatment for non-PD patients who have obstructive
sleep apnea. However, controversy exists over the efficacy of CPAP treatment in
PD patients, because some work has suggested that not all PD patients tolerate
CPAP [67]. CPAP tolerance might be a particular limitation in PD because these
patients often may not be amenable to the restrictive nature of the CPAP mask.
Despite these potential issues, at least in severe cases of SDB, CPAP must be
considered as a treatment option [68, 69]. In patients who are intolerant of CPAP
or have milder SBD, mandibular advancement devices may be a useful second
line of treatment [70].
7.6 Future Directions
We believe that an exciting avenue for future research will be in determining whether
relatively mild levels of nocturnal hypoxia are associated with motor and nonmotor
symptom progression. SDB is very common in PD (but the prevalence does not dif-
fer from the general population; Table 7.1), and nocturnal hypoxia might cause the
loss of dopamine [15, 16] and result in additional cellular dysfunction [62, 63]. It
therefore remains possible that even mild SDB could accelerate disease progression
[65], and, conversely, that ameliorating nocturnal hypoxia in PD patients might be a
viable target for improving longevity and quality of life.
a
Mean oxygen saturation in REM sleep (%) 98
rp=.69**
97
96
95
94
93
92
10 0 10 20
UPDRS change
b
98
Mean oxygen saturation in NREM sleep (%)
rp=.42*
96
94
92
90
10 0 10 20
UPDRS change
Fig. 7.2 Change in motor symptom severity across approximately 9 months (assessed as UPDRS
motor symptom score) correlates with level of oxygen saturation during REM sleep (a) and NREM
sleep (b) in idiopathic Parkinsons disease patients Positive numbers indicate worsening severity
of motor symptoms [65]. * indicates p < .05, ** indicates p < .01
Acknowledgments Preparation of this chapter was supported by funding from the National
Institute on Health (grant numbers 1P50NS071669 and F32AG041543). M.K.S. was partially
supported by an Emory University School of Medicine Cottrell Fellowship.
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Excessive Daytime Somnolence
Associated with Parkinsons Disease 8
James Battista, Renee Monderer, and Michael Thorpy
Contents
8.1 Introduction ..................................................................................................................... 108
8.2 Epidemiology of EDS in PD ........................................................................................... 108
8.3 Evaluations of Sleepiness in PD ..................................................................................... 109
8.4 Pathophysiology of EDS in PD....................................................................................... 110
8.5 Effects of PD Treatment on Sleep and Wakefulness....................................................... 111
8.6 Other Sleep Disturbances in PD as Contributors to EDS ............................................... 112
8.7 Treatment of EDS in PD ................................................................................................. 113
Conclusions .............................................................................................................................. 114
References ................................................................................................................................ 114
Abstract
Excessive daytime sleepiness (EDS) occurs in up to 50 % of patients with
Parkinsons disease (PD) and is characterized by an inability to maintain full
alertness in the daytime and undesirable lapses into sleep. Often overshadowed
by the motor symptoms of PD, EDS can contribute to home and automobile
accidents and have a negative impact on mood and overall quality of life. Sleep
disturbances and EDS can result from the medications used to treat PD, degen-
eration of neuronal systems involved in the control of the sleepwake system
that occurs as part of the PD disease process, and comorbid conditions including
specific sleep disorders and depression. The treatment of EDS in the PD patient
requires careful evaluation of the multiple contributing causes and instituting
recommendations that can consist of sleep hygiene and behavioral changes,
alterations in the dosing and timing of PD medications, treatment of comor-
J. Battista, MD R. Monderer, MD (*) M. Thorpy, MD

Department of Neurology, Montefiore Medical Center,
111 E. 210th St, Bronx, NY 10467, USA

108 J. Battista et al.
bid disorders, and the use of medications that affect nocturnal sleep quality and
daytime alertness.
8.1 Introduction
Sleep disturbances are increasingly recognized as impacting on the quality of life of

patients with Parkinsons disease (PD). Although the motor features are the most
evident aspects of PD, sleep disturbances and excessive daytime sleepiness (EDS)
are common manifestations. EDS is characterized by the inability to maintain alert-
ness during the day resulting in unwanted lapses into sleep. Other manifestations of
sleep disorders in PD include episodes of falling asleep without warning (sleep
attacks), sleep onset and sleep maintenance insomnia, and abnormal movements
during sleep. Sleep disturbances and EDS can result from the medications used to
treat PD, degeneration of neuronal systems involved in the control of the sleep
wake system that occurs as part of the PD disease process, and comorbid conditions
including specific sleep disorders and depression (Table 8.1). It is essential to rec-
ognize and evaluate the sleep disturbances and EDS in PD as interventions, both
pharmacologic and nonpharmacologic, can improve the patients general health,
mood, and quality of life.
8.2 Epidemiology of EDS in PD
The estimated prevalence of EDS in PD is 2949 % [1, 2]. In one study investigating
the prevalence of EDS and risk factors in a newly diagnosed PD cohort (n = 126), it
was found at 3-year follow-up that 49 % experienced EDS. Dopamine agonist treat-
ment and non-tremor dominant motor PD phenotype were most strongly associated
Table 8.1 Factors that Neuronal degeneration

contribute to daytime
Dopaminergic medications
sleepiness
Anticholinergic medications
MAOB inhibitor medications
Depression
Anxiety
Sleep apnea
Insomnia
Restless legs syndrome/periodic limb movements in sleep
REM sleep behavior disorder
Circadian rhythm disorders
Psychosis, hallucinations, nightmares
Motor symptomstremor, dystonia, akinesia, dyskinesias
Pain
Autonomic dysfunction
8 Excessive Daytime Somnolence Associated with Parkinsons Disease 109
with EDS [2]. Other studies have shown that male sex, reduced daily activities of
living, and a high daily levodopa equivalent dopaminergic dosage are associated
with EDS [1, 3]. In addition, the presence of anxiety and baseline postural instabil-
ity causing gait difficulty are other factors correlated with EDS in PD [3].
Longitudinal studies have shown an increasing trend between the prevalence of
EDS in PD and cognitive decline and disease progression [4].
The estimated prevalence of sleep attacks in PD is 14 %, and episodes of sud-
den sleep onset in PD are 742 % [5]. Sleep attacks are defined as abrupt episodes
of unexpected sleep that occur during normal activities. Patients may or may not
be aware of sleepiness prior to the onset of sleep attacks. Older age, male sex, lon-
ger disease duration, disturbed nighttime sleep, and dopaminergic medications have
been associated with sleep attacks [6]. In those treated with dopamine agonists, there
is a two- to threefold increase in sleep attacks when compared to those who are on
levodopa [5]. Genetic polymorphisms in the dopamine D2 receptor gene Taq1A and
preprohypocretin have also been significantly associated with sleep attacks in PD [7].
Due to the impairment of daytime sleepiness, an important issue for PD patients
is whether they should drive a motor vehicle. A study of 6,620 patients with PD
found that 15 % had been involved in and 11 % had caused at least one motor
vehicle accident in the past 5 years [8]. PD patients who felt moderately impaired
by PD, had an increased Epworth Sleepiness Scale (ESS) score or experienced
sudden onset sleeping while driving, had an increased risk of causing accidents.
Accidents tended to occur in easy driving situations [8]. Another study compared
patients with PD to controls on the ability to perform on a simulated driving test
[9]. Subjects with PD committed more errors during both baseline and distractions,
driving slower with higher speed variability during distraction. Declining driving
performance was associated with multiple symptoms including increased daytime
sleepiness [9].
8.3 Evaluations of Sleepiness in PD
Subjective questionnaires and objective tests have been designed to evaluate

EDS. The Epworth Sleepiness Scale (ESS) is a questionnaire that assesses how
likely patients are to doze off in eight everyday situations that vary in the levels of
stimulation, immobility, and relaxation. A score of 10 or above out of 24 is consid-
ered pathologic sleepiness.
Additional questionnaires that can be used to assess sleepiness in PD are the
UPDRS Part II, the Pittsburg Sleep Quality Index (PSQI), the Scales for Outcomes
in PD-Sleep Scale (SCOPA), the Parkinsons Disease Sleep Scale (PDSS) and its
second edition (PDSS-2). Questions address subjective sleep quality, sleep latency,
sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medica-
tions, and daytime dysfunction. Sleep disturbances are addressed as part of the over-
all picture of disease impact.
The first version of PDSS is a visual analogue scale that addresses 15 commonly
reported symptoms associated with sleep disturbances such as nighttime sleep
awakenings, movements in sleep, and daytime sleepiness. This has been further
extended in the PDSS-2, which has five categories and addresses other sleep distur-
bances such as restless legs syndrome, akinesia, pain, and sleep apnea.
The overnight polysomnogram (PSG) is useful to diagnose, or rule out, under-
lying sleep disorders including sleep apnea, periodic limb movement disorder
(PLMD), REM sleep behavior disorder (RBD), and parasomnias. These sleep dis-
orders, often found in PD patients [1012], can cause a fragmented nighttime sleep
resulting in daytime sleepiness. Studies have found deficiencies in total sleep time,
sleep latency, slow-wave sleep, REM sleep, and sleep efficiency in patients with PD
[13, 14].
The multiple sleep latency test (MSLT), which typically follows overnight pol-
somnography, assesses the ability or tendency to fall asleep. The MSLT measures
the speed at which a subject falls asleep when given the opportunity to sleep, and
whether a patient goes into REM sleep. It consists of five 20-min nap opportunities
2 h apart. Studies have shown pathologic sleepiness, defined as a mean sleep latency
<5 min, is prevalent in PD. A study of 27 PD patients found a mean sleep latency of
<5 min in 40 of the 134 nap opportunities during MSLTs [15].
Actigraphy is a noninvasive method of monitoring human rest/activity cycles.
One study of actigraphy demonstrated that PD patients had a 1.5-fold to twofold
lower daytime motor activity level than controls, which suggests daytime sleepiness
or limited physical activity [16]. Additionally, the study showed a 1.5-fold to two-
fold higher nighttime motor activity which represents the fragmented sleep often
reported in patients with PD.
8.4 Pathophysiology of EDS in PD
The cause of EDS in PD is often multifactorial with the most relevant effects com-
ing from dopaminergic medications and the disease process itself. The progressive
cell loss in the dopaminergic and non-dopaminergic neurons and networks that
modulate sleepwake mechanisms in PD is a major contributing factor to the etiol-
ogy of sleep disturbances in PD. In addition to the nigrostriatal pathway, PD affects
areas of the brainstem, such as the pedunculopontine nucleus, the ventrolateral teg-
mental area, the locus coeruleus, the dorsal raphe nucleus, and thalamic nuclei,
which are involved in maintaining alertness [17]. Circadian sleepwake dysrhyth-
mia in PD may reflect the central nervous system pathophysiology affecting the reti-
nohypothalamic tract and suprachiasmatic nucleus.
Hypocretin (orexin), which is known to be decreased in narcolepsy, is also
thought to be related to the EDS seen in PD; however, the data to support this has
varied. One study measuring ventricular cerebrospinal fluid levels found an almost
25 % reduction in PD patients [18]. Another study of 16 PD patients with symptoms
of narcolepsy found a correlation with increased objective sleepiness and decreased
cerebrospinal fluid (CSF) hypocretin. In addition, in two patients with severe disease
serial CSF hypocretin levels decreased over time. Overall, the study concluded that
dopamine deficiency correlated with poorer sleep quality and hypocretin signaling
related to EDS in PD patients [19]. However, not all studies have shown loss of
hypocretin in PD. A study measuring hypocretin levels in cerebrospinal fluid col-
lected by lumbar puncture in 62 patients with PD did not find a decreased level [20].
8.5 Effects of PD Treatment on Sleep and Wakefulness
Medications used to treat PD often lead to EDS both through direct pharmacologic
effects and/or by disturbing nighttime sleep. Dopaminergic agents, antidepres-
sants, and amantadine can all cause EDS by disturbing nighttime sleep. Withdrawal
from benzodiazepines and other sedatives can cause rebound insomnia resulting in
EDS. Anticholinergic agents, through M1 muscarinic receptors, increase REM latency
and suppress REM sleep and can cause sedating effects during the day. Trihexyphenidyl
increases nighttime wakefulness that can result in daytime sleepiness [21].
Levodopa and dopamine agonists can adversely affect nighttime sleep resulting
in EDS. A study of PD patients taking levodopa found that 74 % had a disruption of
nighttime sleep [22].
Studies have shown that dopamine agonists increase daytime sleepiness [2326].
Studies comparing dopamine agonists found that both ergot and nonergot dopamine
agonists caused EDS [2426]. Total dopamine dose, rather than the choice of dopa-
mine agonist, was the best predictor of EDS [26]. In one study of 15 patients evalu-
ated before and 8 months after starting dopaminergic medications, the ESS was
significantly increased and the mean sleep latency on MSLT was significantly
decreased after treatment [25].
Rotigotine resulted in a higher percentage of patients with improvement in all
items of the PDSS-2 except distressing dreams and distressing hallucinations at
night [27]. There were significant improvements compared with placebo in the cat-
egories of wake with painful limb posturing (increase of 25 % vs decrease by 95 %),
limb pain causing waking (decrease in 31 % vs decrease by 83 %), and cramps in
limbs causes waking (decrease by 47 % vs 78 %) [27]. Another study looking at
nocturnal sleep disturbances using the UPDRS Part III and PDSS-2 with an opti-
mized titration of rotigotine found significant improvement in scores on both scales
versus placebo [28].
Catechol O-methyltransferase inhibitors enhance dopaminergic activity, which
can lead to worsening of levodopa-induced adverse effects, including sleep disor-
ders and hallucinations [29]. Selegiline, which is metabolized to amphetamine, is
one of the most likely to cause sleep-onset insomnia that can lead to EDS [30].
Rasagiline is not metabolized to amphetamine metabolites; it may not have the
same degree of insomnia as selegiline [31].
Deep brain stimulation (DBS), used for treatment of Parkinsons disease refrac-
tory to medications, has also been shown to help improve sleep. DBS of the sub-
thalamic nucleus (STN) has been shown to improve nighttime sleep. In a study
of five patients 3 months after surgery, there was an increase in total sleep time
and slow-wave sleep as well as a reduction of wakefulness after sleep onset and at
1-year follow-up [17].
A similar improvement in sleep quality was found with DBS of the globus pallidus
internal (GPi) segment and the pedunculopontine tegmental nucleus (PPTg). However,
unlike STN-DBS, stimulation of the PPTg improved not only nighttime sleep but also
ameliorated excessive daytime sleepiness [32]. The ESS was reduced by more than
50 % with PPTg-DBS at 1-year follow up. This improvement was seen both with PPTg
stimulation only at night or on for 24 h/day. It is hypothesized that stimulation of the
PPTg, which is part of the reticular activating pathway, induces a recovery of the activ-
ity of this pathway and therefore improves sleep quality and daytime alertness [32].
8.6 Other Sleep Disturbances in PD as Contributors to EDS
In PD different types of insomnia, sleep related breathing disorders, circadian

rhythms disorders, parasomnias, RLS, and other sleep related movement disorders
have been reported. The associations and impact of each of these sleep disorders on
EDS have not been systematically studied and remain controversial. Clinical studies
have found controversial results as to whether sleep apnea is increased in
PD. Research studies in PD have shown an increased rate of snoring (71.8 %) [33]
and sleep apnea (20 %) [34]. Notably, no correlation was found between apnea/
hypopnea index (AHI) and the MSLT, and the authors concluded that sleep apnea
may not be a major factor contributing to the severity of sleepiness in most patients
with PD [34]. Two case reports of patients with PD and OSA found that CPAP
clearly restored more daytime activity [35].
Insomnia is found in 5460 % of PD patients [36]. Sleep fragmentation and early
awakenings are the most common types of insomnia symptoms reported with mini-
mal differences in sleep initiation. While insomnia may contribute to tiredness,
fatigue, and EDS in PD, several studies found inverse relationship between daytime
sleepiness and overnight sleep quality.
The prevalence of RLS has been shown to be significantly higher in the PD popu-
lation compared to sex-matched controls [37]. Daytime fatigue is commonly
reported in patients with RLS. There have been controversial results regarding the
incidence of periodic limb movement disorder (PLMD) in PD [38].
RBD is characterized by acting out of vivid dreams in vigorous and often violent
ways during REM sleep. RBD appeared to predict subsequent development of
dementia, as well as cognitive fluctuations and hallucinations [39].
Circadian rhythm sleep disorders result from the misalignment sleep patterns
and normal daytime activities. Excessive daytime sleepiness and nighttime sleep
disturbance often lead to irregular sleepwake patterns in PD.
In PD motor symptoms, depression and pain can affect sleep. Disruptive night-
time motor symptoms include tremor, nocturnal dystonia, and nocturnal akinesia.
Depression often adversely affects sleep in PD causing difficulty falling asleep,
staying asleep, and early morning awakenings. Pain is noted in about 50 % of
patients with PD [40], which may cause difficulty falling asleep and staying asleep.
Disruptive nighttime motor symptoms, depression, and pain all fragment nighttime
sleep leading to daytime fatigue and EDS.
Hallucinations can disrupt sleep and affect almost 33 % of patients with PD. PD
patients with hallucinations have increased awakenings, decreased sleep efficiency,
and more daytime sleepiness [41].
8.7 Treatment of EDS in PD
EDS in PD can be related to sleep disruption, sleep deprivation, medication side

effects, underlying sleep disorders, or from the primary disease. The clinician must
first determine which factors are involved in producing the EDS. Promoting good
sleep hygiene and emphasizing the importance of daytime light exposure and day-
time activity are crucial. Good sleep hygiene includes maintaining a regular sleep
wake schedule, spending an appropriate amount of time in bed (~8 h), and avoiding
caffeine and frequent naps during the day (Table 8.2). Adjusting doses of dopami-
nergic medication can help promote daytime alertness and increase quality of sleep
at night. The physician must determine if the patient has an underlying sleep disor-
der and treat as appropriate.
Recognition and treatment of primary sleep disorders in PD patients is essential.
CPAP has been shown to improve daytime functioning in those patients with
OSA. If insomnia is present, proper sleep hygiene and the possible use of an appro-
priate hypnotic medication are the main treatments. Levodopa or dopamine agonists
improve symptoms of RLS, especially with a nighttime dose of levodopa or dopa-
mine agonists. Gabapentin, opioids, or benzodiazepines are other options. If RBD
is present, clonazepam is the most effective treatment for RBD; however, this medi-
cation may contribute to daytime sleepiness because it is long-acting and sedating.
Melatonin is an alternative treatment for RBD. Melatonin is also useful in treating
circadian rhythm disorders.
Bupropion, an antidepressant that increases synaptic dopamine by blocking the
dopamine transporter, may be useful not only in improving depression in patients
with PD but also in improving daytime alertness [42]. Quetiapine, an antipsy-
chotic drug that has fewer extrapyramidal effects than older antipsychotics, is
effective for treating psychosis and hallucinations allowing more restful nocturnal
sleep [43].
Table 8.2 Sleep tips to Avoiding daytime naps

improve sleep and daytime
Exposure to bright lights or sunlight in the daytime
functioning in PD
Increasing daytime activity level
Obtaining adequate amount of time in bed at night
Avoiding caffeine or nicotine several hours before bedtime
Avoiding alcohol around bedtime that fragments sleep
Avoiding spicy, heavy, or sugary foods before bedtime
Limiting liquids after 8 pm to avoid nighttime urination
Maintaining a regular sleep schedule
Keeping the bedroom quiet, dark, and comfortable
Treatment with modafinil may be helpful for EDS in PD. Several studies have
shown that modafinil at doses of 100200 mg/day showed significant improvements
in the ESS and the clinical global impression of change without any major PD
symptom adverse effects [44]. Alternatively, one study found that treating patients
with modafinil was only partially helpful, and adding sodium oxybate or antihista-
mine receptor-3 drugs seem to be more activating [45]. However, results have varied
as larger study found no significant improvement in the ESS or MSLT with modafinil
(200400 mg/day) [45].
Cognitive behavior therapy has been helpful in those with PD. A recent study
found improved scores on the PDSS after cognitive behavior therapy [46].
Conclusions
Excessive daytime sleepiness is common in PD and multifactorial, resulting
from medications used to treat PD, mood or anxiety disorders, specific sleep
disorders, PD motor symptoms, and primary effects of the disease process of PD
on neuronal sleep wake centers. A systematic evaluation should be conducted to
assess for the presence of sleep disturbances and daytime sleepiness. Several
questionnaires have been developed to assess for the presence of daytime sleepi-
ness and sleep disruption including the ESS, PDSS-2, SCOPA, UPDRS Part II,
and the PSQI. These tools should be used to help guide treatment. Sleep studies
will determine if a sleep disorder such as obstructive sleep apnea, periodic limb
movements, or narcolepsy are contributing disorders.
If nocturnal sleep and daytime alertness are not well controlled, social inter-
actions, work performance, and quality of life can be affected and result in feel-
ings of insecurity, anxiety, and depression. Various therapeutic strategies are
available to help with nocturnal sleep including adjusting medications used to
treat motor symptoms, treating underlying sleep disorders, encouraging good
sleep hygiene, avoiding daytime naps, and increasing daytime activity and light
exposure. Alerting medications in the daytime and sedating medications at night
can be used when needed. Recognizing and addressing daytime sleepiness and
disturbed nocturnal sleep in PD will improve mood, activities of daily living, and
quality of life for the patient.
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Dysregulation of Circadian System
Contents
9.1 Introduction ..................................................................................................................... 118
9.2 Overview of the Human Circadian System..................................................................... 118
9.2.1 Neuroanatomy and Neurochemistry of the Circadian System ............................ 118
9.2.2 Genetic Regulation of the Circadian System ...................................................... 119
9.2.3 Circadian Entrainment and Markers of Circadian Rhythmicity ......................... 120
9.3 Dopamine in the Circadian Timing System .................................................................... 121
9.4 Circadian Rhythm Dysfunction in PD ............................................................................ 122
9.4.1 Diurnal Clinical Fluctuations in PD: Are they Driven
by Circadian Dysregulation? ............................................................................... 122
9.4.2 Circadian Markers in PD..................................................................................... 123
9.4.3 Light Exposure and Nonphotic Circadian Entrainment in PD............................ 125
9.4.4 Circadian Disruption in PD: Potential Mechanisms ........................................... 125
Conclusion ............................................................................................................................... 126
References ................................................................................................................................ 126
Abstract
Circadian rhythms are physiological and behavioral cycles with a periodicity of
approximately 24 h, generated by the endogenous biological clock, the suprachi-
asmatic nucleus (SCN). These rhythms influence most physiological processes,
including the sleepwake cycle. The exact pathophysiology of sleepwake dis-
turbances in Parkinsons disease (PD) remains largely unknown, but the etiol-
ogy is likely to be multifactorial, including influence of motor PD symptoms on
sleep, adverse effects of antiparkinsonian medications, and neurodegeneration of
A. Videnovic, MD, MSc

Department of Neurology, Neurological Clinical Research Institute,
Massachusetts General Hospital, Harvard Medical School,
165 Cambridge Street, Suite 600, Boston, MA 02114, USA

118 A. Videnovic
central sleep regulatory areas. The circadian system and its main central pace-
maker, the SCN, have a major influence on sleepwake homeostasis. A grow-
ing body of evidence points to significant alterations of the circadian system
in PD. Despite this, little is known about the role of the circadian system in the
regulation of sleepwake cycles in PD. In this chapter, we discuss the role of the
circadian system in the regulation of the sleepwake cycle and outline implica-
tions of circadian timekeeping in PD.
9.1 Introduction
The human circadian system regulates numerous biological rhythms. The daily
sleepwake cycle is the most notable human behavior that is regulated by the circa-
dian system. The two-process model of sleep regulation has been proposed to explain
the relationship between the circadian system and sleep. This model proposes a sleep
homeostatic process (process S) that interacts with the circadian process (process C),
which is independent of sleep. Thus, process S, which is described in detail in Chap.
1 of this book, represents an internal homeostatic requirement for sleep that increases
during wakefulness and decreases with sleep. The sleep homeostatic process regu-
lates the amount and depth of sleep. Although the precise mechanisms of circadian
regulation of sleep and alertness are not fully elucidated, it appears that the circadian
system functions to consolidate wakefulness and regulate the timing of sleep. In this
chapter, we discuss the role of the circadian system in the regulation of the sleep
wake cycle and outline implications of circadian timekeeping in PD.
9.2 Overview of the Human Circadian System
Nearly all physiological and behavioral processes in humans exhibit daily rhythms,
regulated by the endogenous circadian timing system. These rhythms recur with a
periodicity of approximately 24 h, under the governance of the suprachiasmatic
nucleus (SCN) located in the anterior hypothalamus [1]. The timing of human bio-
logical rhythms is synchronized to the rotation of earth and is under the influence of
numerous external and internal time clues. This synchronization may become dis-
rupted leading to misalignment or internal desynchronization. This loss of coordi-
nation of rhythms may have negative consequences on sleepwake cycles and
numerous other biological functions.
9.2.1 Neuroanatomy and Neurochemistry

of the Circadian System
The circadian timing system has three distinct components: a circadian pacemaker
SCN, afferent pathways for light and other stimuli that synchronize the pacemaker
to the environment, and efferent output rhythms that are regulated by the SCN.
9 Dysregulation of Circadian System in Parkinsons Disease 119
The SCN is composed of core and shell subnuclei. Each of the subnuclei has
distinct neurochemical properties [1]. Gamma-aminobutyric acid (GABA) is the
dominant neurotransmitter in the SCN, present in nearly all SCN neurons. The SCN
core contains high density of vasoactive intestinal polypeptide (VIP), gastrin-
releasing peptide (GRP), and bombesin-containing neurons. Somatostatin and neu-
rophysin are dominant neurochemicals within the SCN shell.
The main afferent pathways to the SCN emerge from the retina and reach the
SCN directly via the retinohypothalamic tract, or indirectly via retinogeniculate
pathways [2]. The melanopsin-containing retinal ganglion retinal cells are the pri-
mary photoreceptors for the circadian system. The SCN also receives nonphotic
information from the raphe nuclei, basal forebrain, pons, medulla, and posterior
hypothalamus.
The major efferents from the SCN project to the subparaventricular zone and the
paraventricular nucleus of the hypothalamus, dorsomedial hypothalamus, thalamus,
preoptic and retrochiasmatic areas, stria terminalis, lateral septum, and the interge-
niculate nucleus. In addition to these distinct neuroanatomical networks, the SCN
also communicates via diffusion of humoral signals such as transforming growth
factor (TGF)-, cardiotrophin-like cytokine (CLC), and prokineticin 2 (PK2).
The SCN represents the main clock of the circadian system. Almost all periph-
eral tissues as well as brain regions outside the SCN contain circadian clocks
influenced by the SCN in addition to their own distinct circadian synchronizers
[3] (Fig. 9.1).
9.2.2 Genetic Regulation of the Circadian System
Circadian rhythms are generated by a core set of clock genes, including three
Period genes (Per1, Per2, Per3), Clock, Bmal1, and two plant cryptochrome gene
homologues (Cry1 and Cry2) [4]. The proteins encoded by these genes interact to
create a self-sustaining negative transcriptiontranslation feedback loop that
drives the timing system. The intracellular levels of CLOCK remain steady during
the 24-h period. BMAL1 levels, which are high at the beginning of the day, pro-
mote the formation of BMAL1-CLOCK heterodimers. These proteins activate
transcription of the PER and CRY genes resulting in high levels of these tran-
scripts. As PER accumulates in the cytoplasm, it becomes phosphorylated and
degraded by ubiquitination. Cry accumulates in the cytoplasm late in the subjec-
tive day and translocates to the nucleus to inhibit Clock-Bmal1-mediated tran-
scription. During the night, the PER-CRY complex is degraded, and the cycle
starts again. This feedback loop ensures a high level of BMAL1 and low levels of
PER and CRY at the beginning of a new circadian day.
Circadian clock genes control a significant proportion of genome. It is estimated
that approximately 10 % of all expressed genes are under regulation of the clock
genes. Furthermore, peripheral tissues contain independent clocks. It is likely that
peripheral clocks are synchronized by an input directly from the SCN or SCN-
mediated messages. For a detailed overview of the molecular regulation of the cir-
cadian system, please see the excellent review by Dardente and Cermakian [2].
120 A. Videnovic
s
ue
ec
Tim
SCN
SCN peripheral
outputs
SCN central outputs

vior
eha
y and b Heart
og
siol Liver
Phy
Muscle
Sleep-wake cycles Kidney
cognitive performance .
. .
. .
.
Fig. 9.1 A simplified scheme of the circadian system. The environmental photic (light) and non-
photic (feeding schedules, physical activity) zeitgebers synchronize the central circadian pace-
maker (SCN) to daily lightdark and social rhythms. The SCN synchronizes other central and
peripheral clocks via neuronal and humoral efferents. This internal synchronization is important
for optimal physiologic function and behavior
9.2.3 Circadian Entrainment and Markers of Circadian

Rhythmicity
Circadian rhythms are synchronized with the solar day by daily adjustments in the
timing of the SCN, following the exposure to stimuli that signal the time of day.
These stimuli are known as zeitgebers (German for time-giver). Light is the
most important and potent zeitgeber. In addition to light, feeding schedules, activity,
and the hormone melatonin also influence the circadian timing [1].
Circadian rhythms can be described by their phase and amplitude. Circadian output
rhythms are used to estimate the time (the phase) of the clock [5]. In humans, timing of
the circadian core body temperature and hormonal rhythms are the most commonly
used phase markers. The hormone melatonin is one of the best understood output
rhythms of the SCN. The timing of melatonin secretion by the pineal gland is regulated
by the SCN, with the onset of secretion being approximately 2 h before natural sleep
time and being highest during the middle of the night [1]. Melatonin onset measured in
dim light melatonin onset (DLMO) is a stable marker of circadian phase and is used in
research as well as clinical practice to determine the timing of the endogenous circa-
dian rhythm. The amplitude of a circadian rhythm refers to the half-distance from the
maximum to the minimum of the observed rhythm. Plasma melatonin has been proven
reliable as a marker of the amplitude of the circadian clock [68]. Since markers of
circadian rhythms may be influenced by environmental stimuli and behavior (light
dark, restactivity, meals), the underlying endogenous circadian rhythms are best
assessed under the protocols that minimize exposure to stimuli that evoke responses in
the physiological variables being monitored. The constant routine and forced desyn-
chrony are prototypes of protocols used to assess endogenous circadian rhythms. The
detailed description of these protocols is beyond the scope of this chapter.
9.3 Dopamine in the Circadian Timing System
Dopaminergic neurotransmission has been implied at several levels in the circadian

system, starting with the photic afferent connection with the SCN. In the retina,
dopamine (DA) plays an important role in light adaptation [9], and regulates the
rhythmic expression of melanopsin, a photopigment of photosensitive retinal gan-
glion cells which has been implied in circadian entrainment [10]. Dopaminergic
retinal cells express circadian rhythms in core clock genes Per, Cry, Clock, and
Bmal1 [11]. In addition, DA modulates rhythms in retinal second messengers like
cAMP, therefore interacting directly with retinal physiology and sensitivity [12].
Dopamine also affects the phase and amplitude of specific clock genes presumably
through dopaminergic D1 receptors in the retina [13]. In the SCN, dopaminergic D1
receptors are present in both fetuses and adults [14, 15].
Several lines of evidence suggest that clock genes play a role in DA metabolism.
The clock gene regulates dopaminergic activity in the ventral tegmental area (VTA)
[16]. Several genes involved in dopaminergic signaling are differentially regulated
in the VTA of Clock mutant mice, which also exhibits altered circadian rhythmicity,
indicating a role of this gene in DA-related transcription in the VTA [16]. Circadian
fluctuations in extracellular DA levels have been reported in the striatum and nucleus
accumbens [17]. DA also regulates clock gene expression in the dorsal striatum [18,
19]. Promoter regions of the DA active transporter (DAT), D1A receptor, and tyro-
sine hydroxylase (TH) genes include an E-Box element, which is the target of the
canonical molecular clock.
Dopaminergic activity and metabolism can also be considered an output of the
circadian clock. DA and its metabolites and receptors exhibit daily fluctuations in
their levels in different brain regions [20]. In particular, DA metabolism exhibits a
diurnal rhythm in striatal regions, related to cyclic variations in the expression of
DAT, D1A receptors, and TH [21]. There is a clear interaction between DA and
melatonin, a well-known circadian output, which acts as a marker for both daily and
seasonal variations in physiology and behavior, in several areas of the central ner-
vous system [22]. Seasonal variations of DA have also been described in humans,
although its importance and consequences remain to be established [23].
In summary, DA exhibits a two-way interaction with the circadian system at
several levels. It has been hypothesized that diurnal and circadian changes in dopa-
minergic neurotransmission influence mood-related behavior [24] as well as
addiction-related behavior [21, 25].
122 A. Videnovic
9.4 Circadian Rhythm Dysfunction in PD
Circadian biology of PD has not been systematically studied. Exciting emerging

evidence suggests that circadian dysregulation plays an important role in
PD. Answers to the question Is PD affected by chronobiology? require a multidi-
rectional approach that includes a better understanding of common diurnal varia-
tions of symptoms and signs in PD as well as the assessment of physiologic and
molecular markers of circadian rhythmicity in the PD population. Further, our
understanding of circadian regulation in PD will be substantially enriched by exam-
ining the effects of potent modulators of the circadian system, such as light and
other nonphotic zeitgebers, on PD symptoms and disease progression.
9.4.1 Diurnal Clinical Fluctuations in PD: Are they Driven by

Circadian Dysregulation?
Diurnal rhythms of symptoms and signs associated with PD have been reported in
numerous studies. Examples include fluctuations in daily motor activity [2629],
autonomic function [3035], sleepwake cycles [3640], visual performance [41],
as well as responsiveness to dopaminergic treatments [26, 42]. These observations
are suggestive of possible circadian influences on the expression of clinical features
of PD.
Fluctuations of motor symptoms in PD are very common. An actigraph, a wrist-
worn monitor that detects movements, has been employed in numerous studies that
assessed restactivity rhythms in PD population. These actigraphy studies demon-
strate lower peak activity levels and lower amplitude of the restactivity cycle in PD
patients compared to healthy older adults [3640]. Increased levels of physical
activity and shorter periods of immobility during the night result in an almost flat
diurnal pattern of motor activity in PD [43, 44]. In addition, PD patients have a more
fragmented pattern of activity with transitions from high to low activity periods,
leading to less predictable restactivity rhythm [45]. Motor symptoms tend to be
more prominent in the afternoon and evening, both in stable patients and in those
with wearing off symptoms [26, 42]. This daily pattern appears to be independent
of the timing of dopaminergic medications and may be related to circadian regula-
tion of dopaminergic systems. Furthermore, responsiveness of PD motor symptoms
to dopaminergic treatments declines throughout the day, despite the absence of sig-
nificant changes in levodopa pharmacokinetics [26]. While the presence of motor
artifact in PD poses challenges to the interpretation of actigraphy studies in this
population, actigraphy can be used in conjunction with PD sleepwake diaries and
newer nonparametric circadian rhythm analysis in order to minimize shortcoming
of the actigraphy recordings of the restactivity cycles in the PD population.
Output rhythms of the autonomic nervous system are influenced by circadian
timekeeping. Alterations in the circadian regulation of the autonomic system in PD
have been reported. Twenty-four hour ambulatory blood pressure monitoring in
patients with PD demonstrates reversal of circadian rhythm of blood pressure,
increased diurnal blood pressure variability, postprandial hypotension, and a high

nocturnal blood pressure [32, 4648]. Holter electrocardiographic monitoring in PD
patients reveals a decrease of sympathetic activity during the day with a loss of the
circadian heart rate variability and a disappearance of the sympathetic morning
peak [31]. The spectral analysis of heart rate variability reveals a significant decrease
of the daytime low frequency power, decreased daytime lowhigh frequency ratio,
and decreased nighttime high frequency power [31, 35, 49, 50]. These abnormali-
ties, more prominent in advanced PD, are also present in untreated patients with
early PD [49]. The prognostic significance and pathophysiological mechanisms
leading to altered autonomic circadian variability in PD remain to be determined.
While observed abnormalities may arise within the peripheral autonomic ganglia,
the influence of central networks including hypothalamus may be significant as well
[5153].
Similarly to motor performance and autonomic function, circadian fluctuations
of sensory systems have been reported in PD. For example, visual performance,
measured by contrast sensitivity, is altered in PD [41]. Impairment of retinal DA,
which exhibits an endogenous circadian rhythm independent of lightdark cycles, is
most likely responsible for these changes [54]. Since circadian changes in contrast
sensitivity may occur independently of circadian oscillations in motor symptoms, it
is possible that various anatomical networks (retina, striatum, and cortex) may have
differential threshold to the circadian signaling of DA [55].
The sleepwake cycle is a prototype of a biological rhythm strongly influenced
by circadian system. Disruption of sleep and impaired daytime alertness are com-
mon manifestations of PD, affect majority of PD patients, and may emerge early in
the course of the disease. Sleep fragmentation and excessive daytime sleepiness are
the most common abnormalities of the sleepwake cycle in PD. While the etiology
of insomnia and hypersomnia associated with PD is multifactorial, circadian disrup-
tion should be considered as one of the contributing factors. Several lines of evi-
dence stemming from research on animal models of PD support this hypothesis.
Transgenic mice overexpressing human alpha-synuclein (Thy1-aSyn) exhibits dis-
rupted circadian behaviors including the temporal distribution of sleep and activity.
Furthermore, the firing rate of SCN neurons early in the progression of experimen-
tally induced parkinsonism in the Thy1-aSyn mice may result in impairments of
neural and hormonal output rhythms of the SCN.
9.4.2 Circadian Markers in PD
Physiologic and molecular markers of the circadian system may provide insight into
the function of circadian timekeeping in PD. Only a few studies attempted to charac-
terize profiles of circadian markers in PD. In a cohort of 26 PD patients, the ampli-
tude of melatonin rhythm was decreased, and the phase was advanced in treated
patients with and without motor complications compared to de novo patients [56].
These results suggest a trend toward advanced melatonin phase and amplitude reduc-
tion during the evolution of PD. Circadian rhythms of temperature and plasma
124 A. Videnovic
cortisol did not differ between the groups in this study. In a separate study, nine
patients with de novo PD had a preserved melatonin rhythm compared with healthy
controls [57]. In a study of 12 PD patients, 24-h mean cortisol production rate was
significantly higher and the mean secretory cortisol curve was flatter, leading to sig-
nificantly reduced diurnal variation in the PD group relative to controls [58]. Body
temperature is an excellent marker of endogenous circadian rhythmicity. While 24-h
rhythms of core body temperature remain similar in PD relative to healthy controls
[59], basal body temperature is significantly lower in parkinsonian patients [60]. PD
patients with coexistent depression have altered circadian rhythms of rectal tempera-
ture and lower amplitudes of core body temperature [61]. These circadian modifica-
tions of temperature regulation have been confirmed in the 6-hydroxydopamine
(6-OHDA) animal model of parkinsonism where a significant decrease of the mesor
and a phase advance of temperature rhythm have been reported [62]. Although these
investigations suggest modifications of circadian rhythmicity in PD, results are to be
interpreted with caution due to small sample sizes and study designs that reflect
influences of both endogenous circadian and exogenous (e.g., light exposure, physi-
cal activity, meals, social schedules) rhythms on PD. In a recent study of 20 patients
with mild to moderate PD and 12 age-matched controls that employed modified con-
stant routine experimental protocol that minimize exogenous influences on circadian
rhythms, significant blunting of circadian rhythm of melatonin secretion and reduced
amplitude of melatonin rhythm was observed [63]. PD patients with excessive day-
time somnolence had a more prominent reduction in the amplitude of their melatonin
rhythm compared to PD patients without EDS. Significant reductions in the ampli-
tude of melatonin secretion was also demonstrated in de novo PD patients [64]. In
contrast to these findings, Bolitho et al. recently reported a threefold increase in
melatonin secretion in a cohort of PD patients [65]. While further investigations are
needed, these observations provide a rationale for the role of circadian disruption in
excessive sleepiness associated with PD.
Several studies have demonstrated strong oscillatory expression patterns of
core clock genes in human whole blood and peripheral blood mononuclear cells
(PBMCs) [6668], demonstrating the feasibility of using clock gene expression
as a circadian marker. Time-related variations in the expression of circadian clock
genes have been recently reported in patients with PD [69]. In a study of 17 indi-
viduals with PD and 16 age-matched controls, the relative abundance of the clock
gene Bmal1 was significantly lower during the night in PD patients versus controls.
Expression levels of Bmal1 in PD patients correlated with PD severity as assessed
by the UPDRS [69]. A lack of time-dependent variation in Bmal1 expression in
PD patients was recently confirmed in another study [64]. Exciting emerging evi-
dence suggests alterations in molecular regulation of circadian timekeeping in ani-
mal models of PD. Depletion of striatal DA by 6-OHDA or blockade of D2 DA
receptors by raclopride blunts the circadian rhythm of striatal Per2. Furthermore,
timed daily activation of D2 DA receptors restores and entrains the Per2 rhythm in
DA-depleted striatum. These observations suggest a role of dopaminergic stimula-
tion of D2 DA receptors in the maintenance of circadian molecular oscillations in
the striatum.
9.4.3 Light Exposure and Nonphotic Circadian

Entrainment in PD
Light, the main synchronizer for the human circadian system, is increasingly applied
as therapy in a variety of sleep and neuropsychiatric conditions including circadian
rhythm disorders, seasonal affective disorder, and dementia [70]. Light therapy is
usually a well tolerated and easily applied nonpharmacological treatment modality.
Numerous studies have demonstrated beneficial effects of light therapy on sleep
quality, daytime sleepiness, mood, and quality of life in healthy elderly and in
patients with dementia. Several lines of evidence support the rationale for exploring
supplemental light exposure in PD. For example, DA is likely a mediator of light
signaling to the retinal circadian clock which provides direct input to the SCN [9].
Exposure to light facilitates the recovery of motor function in a chronic experimen-
tal model of PD [71]. Only a few exploratory studies, however, examined the effects
of bright light in patients affected by PD.
In a case series of 12 PD patients, daily exposure to supplemental bright light
of 1,0001,500 lux prior to habitual bedtime resulted in improved sleep quality
and mood [72]. Evening exposure to bright light was also associated with
improvements in bradykinesia and rigidity. Beneficial effects of supplemental
light exposure emerged several days after initiating the treatment. Similar benefi-
cial effects of supplemental bright light on sleep, mood anxiety, and motor per-
formance were reported in an open-label retrospective study of 129
levodopa-treated PD patients followed up to 8 years [73]. In another study, 36 PD
patients were randomized to receive treatment with bright light therapy of 7,500
lux (active arm) or 950 lux (placebo arm) in 30-min sessions every morning for
2 weeks [74]. Exposure to bright light of 7,500 lux was associated with improve-
ments in UPDRS part I, II, IV scores, and daytime sleepiness. While these stud-
ies demonstrated good feasibility and positive effects of bright light therapy on
nonmotor and motor manifestations of PD, further validation studies involving
larger cohorts and employing objective outcome measures are needed. The tim-
ing, duration, intensity, and spectral qualities of light therapy will need to be
optimized for use in the PD population.
9.4.4 Circadian Disruption in PD: Potential Mechanisms
Mechanisms underlying circadian dysregulation in PD are not fully elucidated.

Primary neurodegenerative processes of PD leading to progressive depletion of DA
likely have negative consequences on circadian timekeeping as dopaminergic trans-
mission is an integral part of circadian homeostasis. Fluctuations in DA metabo-
lism, overnight DA accumulation, or diurnal receptor downregulation may be in
part driving diurnal fluctuations of PD clinical features [7577]. Neuroanatomical
sites of circadian disruption in PD may be along the afferent pathways to the SCN,
within the SCN itself, or within the downstream peripheral efferents of the
SCN. Circadian entrainment may be compromised in the population as PD patients
126 A. Videnovic
tend to be less active and spend more time indoors. For example, reduced light
exposure and/or impaired light transmission, partly due to dopaminergic retinal
degeneration [78], may affect circadian timekeeping in the PD population. While
the structure and function of the SCN in PD has not been rigorously examined to
date, degeneration of this central circadian pacemaker may be yet another possible
mechanism of impaired circadian rhythmicity in PD. Hypothalamic dopaminergic
neurons, however, do not appear to be involved in the disease [79]. Finally, altera-
tions in SCN output may be primarily responsible for fluctuations in biological
rhythms and symptoms of PD.
Conclusion
Increasing evidence suggests disruptions of the circadian system in PD. Further,
systematic investigations directed at circadian timekeeping may provide addi-
tional insight into the pathogenesis of daytime sleepiness and sleep dysfunction,
and may possibly shed new insights into the neurodegenerative processes of PD
itself. Furthermore, better understanding of the circadian biology of Parkinsons
disease may lead to the development of novel, circadian-based treatment
approaches for motor and nonmotor manifestations of PD.
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REM Sleep Behavior Disorder
10
Michael J. Howell and Carlos H. Schenck
Contents
10.1 Historical Perspective ................................................................................................... 132
10.2 Clinical Presentation ..................................................................................................... 133
10.3 Epidemiology ................................................................................................................ 133
10.4 RBD and Early Features of Alpha-Synuclein Pathology .............................................. 134
10.4.1 RBD in PD....................................................................................................... 135
10.5 Pathophysiology ............................................................................................................ 135
10.6 Clinical Evaluation and Diagnosis ................................................................................ 136
10.6.1 History and Examination ................................................................................. 136
10.6.2 Polysomnography ............................................................................................ 137
10.7 Treatment ...................................................................................................................... 138
10.7.1 Clonazepam ..................................................................................................... 139
10.7.2 Melatonin......................................................................................................... 139
10.7.3 Pramipexole ..................................................................................................... 139
10.7.4 Rivastigmine .................................................................................................... 139
10.7.5 Other Medications ........................................................................................... 140
10.7.6 Deep Brain Stimulation ................................................................................... 140
10.7.7 Bed Alarm Therapy ......................................................................................... 140
10.8 Future Directions .......................................................................................................... 140
10.8.1 Possible Neuroprotection ................................................................................ 140
References ................................................................................................................................ 141
Abstract
REM sleep behavior disorder (RBD), a condition of dream enactment, often
predates Parkinsons disease (PD) and is the result of early neurodegenerative
M.J. Howell, MD (*)

Department of Neurology, University of Minnesota, Minneapolis, USA
C.H. Schenck, MD
Department of Psychiatry, University of Minnesota, Minneapolis, USA

132 M.J. Howell and C.H. Schenck
processes in the brainstem. Normally, REM sleep is characterized by vivid menta-

tion combined with skeletal muscle paralysis. This REM atonia is diminished or
absent in RBD, which enables patients to act out their dreams with violent, injuri-
ous nocturnal behaviors. Consistent with an impending neurodegenerative disorder,
patients with RBD demonstrate subtle motor, autonomic, and cognitive changes
frequently seen in synucleinopathies. These disorders include PD as well as mul-
tiple system atrophy (MSA) and dementia with Lewy bodies (DLB). In PD, RBD
is linked with the akineticrigid predominant subtype, gait freezing, and predicts
aggressive cognitive impairment. Clinical management is focused upon decreasing
the potential for sleep-related injuries (SRIs), treating comorbid sleep disorders,
and eliminating exacerbating agents. High-dose melatonin, low-dose clonazepam,
and combined melatoninclonazepam appear to be effective therapies.
10.1 Historical Perspective
In 1817, James Parkinson wrote An Essay on the Shaking Palsy [1]. This first
comprehensive description of the disorder that would later bear his name noted that
sleep becomes much disturbed in patients and hinted at a disorder of agitated
dream enactment.
His (Case VI) attendants observed, that of late the trembling would sometimes begin in his
sleep, and increase until it awakened him: when he always was in a state of agitation and
alarm.
when exhausted nature seizes a small portion of sleep, the motion becomes so violent
as not only to shake the bed-hangings, but even the floor and sashes of the room.
Prior to Parkinsons monograph, episodes of dream enactment suggestive of

RBD were reported as early by Hippocrates (circa 460370 BCE), Aristotle (384
322 BCE), and Galen (circa 129200) and later by Cervantes (15471616). By the
Renaissance, dream enactment was considered a window into subconscious psy-
chological conflict. In William Shakespeares Macbeth, the sleepwalking Lady
Macbeth admits to being a coconspirator in murder and reveals her subsequent
internal torment.
Out damned spot! Out, I say! What, will these hands never be clean?
Soon after Aserinsky and Kleitman discovered regularly occurring periods of eye
motility during sleep in 1953 [2], investigators began to explore the brainstem mecha-
nisms of REM sleep, including those leading to skeletal muscle paralysis. In 1965,
experimental lesions of pontine regions by Jouvet adjacent to the locus coeruleus in
cats caused an absence of the expected atonia. These cats demonstrated prominent
motor behaviors during REM sleep suspected to be dream mentation (oneirism) [3].
In 1982, Schenck and Mahowald evaluated a 67-year-old man who presented with
a history of violent dream-enactment behavior (DEB). A subsequent polysomnogram
10 REM Sleep Behavior Disorder 133
demonstrated REM sleep without atonia along with vigorous DEB. In 1986, they
published a series of patients and named the condition REM sleep behavior disor-
der. By 1996, 38 % of their original series of patients had developed a parkinsonian
syndrome and by 2013 the conversion rate reached 81 % [4].
10.2 Clinical Presentation
Prior to developing bradykinesia, cogwheel rigidity, and tremor, many Parkinsons

disease (PD) patients will describe a parasomnia or abnormal nocturnal behavior
emanating from sleep. The sleep-related movements appear purposeful as if the
patient is acting out some internal dream plot and when awoken, vivid dreams are
described. The condition typically presents in a middle-aged individual without a
history of sleepwalking or other parasomnia. The frequency of incidents ranges
from once every few months to multiple nightly episodes. Often, there is a pro-
longed prodrome lasting years with progressively more prominent nocturnal behav-
iors occurring over time [5, 6].
The spectrum of dream-enactment behavior (DEB) in RBD varies from small
hand movements to violent activities such as punching, kicking, or leaping out of
bed. Examples of sleep-related injuries include subdural hematoma, shoulder dislo-
cation, cervical fracture, as well as lacerations severing tendons, arteries, and nerves.
As bed partners are frequently the target of violent dream enactment, RBD may have
forensic implications, with patients wrongly in the criminal justice system [5, 6].
Patients manifest DEB more often during the second half of the night and sleep-
related injury (SRI) is more likely to occur in later REM periods. This is related to
the progressive increase in phasic activity, frequency, and duration of REM sleep
normally seen throughout a night of sleep.
Importantly, RBD patients may not have more violent dreams than normal indi-
viduals. Instead, they merely act them out. Sleep-related vocalizations may be loud
and frequently laden with expletives. This is most often discordant from waking
personality, and RBD patients do not demonstrate greater daytime aggressiveness.
Patients and families may adopt extraordinary measures to prevent SRI: placing
obstacles to hinder exiting the bed or sleeping on a floor mattress in a room devoid
of furniture. Prolonged diagnostic delay is common and some families deal with
these behaviors for decades prior to seeking medical attention.
Prior to the onset, and early in the course of PD, DEB progresses in frequency
and intensity. Then late in the disease state a moderation of RBD occurs, likely
secondary to diffuse motor circuit impairment [6].
10.3 Epidemiology
Surveys have revealed that some DEB is nearly universal with 98 % of college-aged
students reporting at least one episode of DEB [7]. The vast majority of these cases,
however, are transient and nondistressing. Various reports have suggested that the
prevalence of RBD is approximately 0.5 % in the general population [5], with

higher prevalence among patients with neurodegenerative disease, other sleep dis-
orders, or on antidepressant medications [5, 8]. Thus, there are approximately 35
million patients worldwide; however, the clinical symptoms are frequently dis-
missed and thus vast majority of cases remain undiagnosed for a long time.
As noted above, RBD is often a heralding manifestation of PD and is common
among other alpha-synuclein disorders. According to several studies, approximately
one-third to one-half of patients with PD have RBD [6, 9, 10]. Among similar
pathologies the frequency is even higher, with 5080 % of patients with DLB and
8095 % of patients with MSA [6, 11].
Similar to PD, RBD is associated with various environmental and behavioral risk
factors. In particular, RBD patients are more likely to smoke, have a history of trau-
matic brain injury, farming, pesticide exposure, and fewer years of education [12].
The majority of reported cases are males; however, female RBD is likely under-
reported. Women present with less injurious dream enactment and thus are less
likely to receive medical attention. Further, due to the gender difference in life
expectancy, elderly women are less likely to have bed partners than elderly men, and
thus less likely to have witnessed parasomnia behaviors [13, 14].
10.4 RBD and Early Features of Alpha-Synuclein Pathology
Patients with RBD demonstrate clinical and subclinical phenomena suggestive of an

impending alpha-synuclein CNS pathology. When fully developed, these disorders
manifest as either PD, MSA, DLB or rarely pure autonomic failure.
Motor testing in RBD demonstrates slight, often imperceptible parkinsonian
abnormalities. In particular, subtle changes are noted on the Purdue Peg Board,
alternate tap test, the Unified Parkinsons Disease Rating Scale (UPDRS), and timed
evaluation of standing and walking [15]. Further, in a survey of normal elderly indi-
viduals, the presence of RBD symptoms was associated with at least mild parkinso-
nian exam findings [6].
Patients with RBD also have subtle cognitive dysfunction. Studies have demon-
strated impairments in visuospatial skills as well as in color and facial expression
identification [15, 16]. Other investigations have revealed deficits in attention and
executive function [6]. Prospectively, the presence of RBD symptoms confers a
greater than twofold risk of developing mild cognitive impairment (MCI) over 4
years [17]. Conversely, among patients with MCI or dementia the presence of RBD
helps distinguish DLB from Alzheimers disease [6, 18].
As in PD, hyposmia/anosmia is frequently noted in RBD. Over half of RBD
patients have impairments in smell identification, compared to 1015 % in age-
matched controls [15, 19]. The most common deficit is an inability to identify paint
thinner [19]. RBD and hyposmia in combination with impaired color identification
place the patient at very high risk of impending PD [16].
In RBD, autonomic dysfunction is consistent with an evolving neurodegenera-
tive disorder. Comorbid enteric neuron pathology manifests as constipation [15] and
similar to hyposmia, when combined with impaired color vision predicts progres-
sion to PD [20]. Heart rate responses to both orthostasis and arousal are blunted
compared to controls and intermediate compared to PD [21]. Cardiac scintigraphy
has been used to predict a parkinsonian syndrome. Among RBD patients, reduced
uptake of (123) I-metaiodobenzylguanidine, indicating sympathetic denervation,
has been demonstrated in PD and DLB but not in MSA [6, 22].
10.4.1 RBD in PD
RBD is associated with the akinetic/rigid subtype of PD and a greater burden of dis-
ease. Removal of tremor scores from the UPDRS increases its sensitivity and specific-
ity in diagnosing early PD among RBD patients [23]. Further, RBD in PD is associated
with a higher Hoehn and Yahr stage (increased severity), greater motor fluctuations,
and increased levodopa dose [9]. Orthostatic hypotension and constipation are both
more common in PD with RBD compared to PD alone [9, 24]. In DLB, the presence
of RBD is associated with earlier onset of parkinsonism and visual hallucinations [25].
PD patients with RBD are also more likely to have freezing of gait (FOG) and a
higher frequency of falls [24]. Interestingly, many of the same brainstem regions
implicated in the pathophysiology of RBD mediate the pathogenesis of
FOG. Moreover, it was recently demonstrated that PD patients with FOG demon-
strate increased tonic REM EMG tone compared to PD patients without FOG [26].
The presence of RBD predicts greater cognitive dysfunction in PD. Neuropsy-
chological testing has demonstrated at least mild cognitive impairment in nearly all
(90 %) PD patients with RBD compared to less than half (38 %) of the patients with
PD alone [27]. Among PD patients who are without severe cognitive deficit, RBD
predicts dementia. In a 4-year prospective study, 48 % of PD patients with RBD
developed dementia compared to none of PD patients without RBD [28].
It has been reported that overnight RBD behaviors in PD lack the bradykinesia
and hypophonia that characterize daytime motor performance in PD. This phenom-
enon suggests that RBD motor activity may bypass the basal ganglia regulatory.
10.5 Pathophysiology
Prior to the hallmark destruction of dopamine-producing neurons in the substantia

nigra (SN), early alpha-synuclein degeneration occurs in the brainstem nuclei that
control REM sleep. Under physiological circumstances the suppression of motor
activity during REM is the cumulative result of multiple pathways that ultimately
terminate on spinal motor neurons, most notably via the magnocellular reticular
formation in the medulla. Multiple areas of the brainstem may influence muscle
tone including pontine REM-on (precoeruleus and sublateral dorsal) and REM-off
(ventral lateral portion of the periaqueductal gray matter and lateral pontine tegmen-
tum) nuclei [6]. Decreased neuronal fiber integrity is seen in these REM-regulating
regions among patients with RBD [29].
By the time PD motor abnormalities develop, the majority of dopaminergic cells

in the substantial nigra (SN) are dysfunctional. However, in RBD patients who have
not yet manifested parkinsonism, neuroimaging reveals a coincident and progres-
sive reduction in dopamine transporters and innervation [30, 31]. Further, transcra-
nial ultrasound hyperechogenicity of substantial nigra in RBD resembles
abnormalities seen in PD [32].
Cholinergic function is impaired in RBD and correlates with cognitive decline.
Among PD subjects with RBD compared to PD subjects without RBD positron
emission tomography reveals cholinergic denervation [33]. These findings are simi-
lar to those seen in transcranial magnetic stimulation studies that demonstrate
reduced short latency inhibition, indicating impaired cholinergic activity, in
RBD. These cholinergic deficits are linked with deficiencies in episodic verbal
memory, executive function, and visuospatial cognitive domains [27].
Cortical abnormalities, similar to those seen in PD and related disorders, are
noted in patients with RBD. Voxel-based morphology studies demonstrate gray
matter reductions that correlate with decreased regional cerebral blood flow (rCBF)
in the parieto-occipital and hippocampal regions [34, 35]. Also, an increase in hip-
pocampal rCBF is noted in RBD patients with MCI and predicts those who will
ultimately progress to either PD or DLB [36].
RBD is not associated only with alpha-synuclein neurodegenerative disorders.
Other etiologies include other forms of neurodegeneration, side effects of medica-
tions, structural CNS lesions, and narcolepsy linked to the orexin dysfunction. RBD
has been reported in tauopathy-related parkinsonian syndromes (progressive supra-
nuclear palsy, Guadeloupean parkinsonism, corticobasal degeneration), TDP-
43opathies (frontotemporal dementia, amyotrophic lateral sclerosis), trinucleotide
repeat disorders (SCA-3, Huntingtons disease), and rarely amyloidopathies
(Alzheimers disease) [6]. However, these disorders are not typically preceded by
RBD, but instead RBD develops after the onset of other neurological deficits.
Medications such as tricyclic antidepressants and serotonin-specific reuptake inhib-
itors can precipitate or exacerbate RBD [6, 37]. It is uncertain whether these medi-
cations cause a de-novo RBD or, unmask latent RBD. Occasionally, various
vascular, demyelinating, and traumatic etiologies are linked to development of RBD
[38]. In these cases, cranial imaging typically demonstrates pontine tegmentum
pathology. Finally, impaired orexin function can precipitate DEB, with up to 50 %
of narcolepsy patients having RBD symptoms. This association is strongest among
narcolepsy patients with cataplexy [39].
10.6 Clinical Evaluation and Diagnosis
10.6.1 History and Examination
A detailed review of the patients sleep and circadian rhythm, preferably with the
assistance of a bed partner is the first step in the evaluation of all parasomnia
behaviors. Recurrent, brief DEB occurring in the later half of the sleep period
followed by complete alertness and orientation upon awakening are features that
help to distinguish RBD from other similar disorders. This presentation contrasts
with sleepwalking where there is often a lifelong history of prolonged, complex,
nonviolent activities emanating from the first half of the sleep period with residual
confusion [5].
Validated screening surveys are available to help identify RBD and quantify dis-
ease burden. These include the RBD Questionnaire-Hong Kong (RBDQ-HK) and
the Innsbruck RBD inventory [40, 41]. In addition, two separate groups of investi-
gators have reported one-question instruments to detect RBD. The Mayo Sleep
Questionnaire (MSQ) is a comprehensive sleep health survey, filled out by bed part-
ners, that includes the following question: Have you ever seen the patient appear to
act out his/her dreams while sleeping (punched or flailed arms in the air, shouted
or screamed)? [6]. This question is very similar to the RBD Single-Question
Screen: Have you ever been told, or suspected yourself, that you seem to act out
your dreams while asleep (for example, punching, flailing your arms in the air,
making running movements, etc.)? [42].
It is important to inquire about alpha-synucleinopathies, when assessing a pos-
sible RBD. When chronic unexplained hyposmia and/or constipation coexist with
RBD, they are highly suggestive of impending neurodegeneration. Further, it is
important to assess early bradykinesia and rigidity. These phenomena are often
imperceptible and may be dismissed as routine aging. In particular, a question such
as Does a patient have difficulty turning over in bed, or bradykinesia during routine
activities such as eating and dressing, or do they have changes in handwriting? may
be very informative. FOG, commonly present in PD, and can be explored with the
question. Do your feet ever feel as if they are stuck to the floor?
Among patients with known PD inquiring about DEB is a critical part of a com-
prehensive evaluation. In the setting of PD falling out of bed during sleep is highly
suggestive of RBD and a risk factor for sleep-related injury. Both the Innsbruck
RBD inventory and RBDQ-HK are effective screens for RBD among patients with
Parkinsons disease.
On examination, careful scrutiny of subtle parkinsonism is essential for accurate
longitudinal clinical monitoring. Documentation should contain a patients affecta-
tion, blink rate, volume of voice, speed of articulation, as well as motor tone with
distracting maneuvers to elicit subtle cogwheeling rigidity. Important features on
gait testing include any freezing of movement, stride length, arm swing, and number
of steps to turn 180. Further, postural instability (loss of righting reflex with sudden
retropulsion) is a risk factor for falling and commonly noted in PD patients with
RBD. The UPDRS includes these examination features and can be used to prospec-
tively quantify the burden of disease.
10.6.2 Polysomnography
Polysomnography (PSG) with time-synchronized video is necessary for defini-

tive RBD diagnosis and to exclude other conditions [43]. Even when abnormal
behavior does not occur during a single night study, the PSG is helpful in docu-
menting the absence of REM atonia. The combination of REM without atonia,
a history of DEB, and absence of clinically significant sleep disordered breath-
ing can establish a diagnosis. When RBD behaviors do occur, they are often
distinguished from other nocturnal behaviors based on appearance alone. RBD
movements more typically appear purposeful, pseudohallucinatory, frequently
with hand babbling (limb wrist, flexed fingerslike a baby). Other REM
sleep phenomena are often present including snoring and in males, penile
tumescence [44].
The American Academy of Sleep Medicine has defined a PSG epoch as either
sustained elevation of chin EMG activity (greater than 50 % of the 30-s epoch)
or excessive bursts of transient muscle activity (at least half of all 3-s mini
epochs). Using this criteria to define RBD epochs, 30 % or greater appears to
reliably distinguish RBD from non-RBD patients. Subtle dream enactment
often involves only the hands and thus forearm EMG monitoring should be
included [6].
PSG is particularly helpful in ruling out conditions such as sleep-disordered
breathing, periodic limb movement disorder (PLMD), and nocturnal epilepsy as
a source of the reported behaviors. The REM sleep fragmentation of obstructive
sleep apnea (OSA) can lead to DEB, but typically resolves with CPAP therapy.
PLMD, primarily a NREM sleep phenomena, can be confused with RBD by
history if the leg movements are especially prominent, but is easily discern-
ible on PSG. Nocturnal seizures should be evaluated with an expanded EEG
montage especially if there is a history of stereotyped, abnormal, and repetitive
behaviors.
10.7 Treatment
Modifying the sleeping environment with a focus upon patient safety is the initial
step in RBD treatment. The patient should remove any bedside object or furniture
that could be injurious. In particular, firearms and windows should not be easily
accessible. Bed partners are advised to sleep separately until RBD is brought under
control. However, this advice is commonly disregarded as bed partners will describe
an ability to pacify DEB with a few firm, but calm words.
RBD inducing or aggravating medications should be eliminated and comorbid
sleep disorders treated. Most cases of medication-induced RBD are self-limited fol-
lowing discontinuation of offending medication. DEBs frequently seen in associa-
tion with OSA typically resolve with treatment of OSA.
When violent nocturnal behaviors persist despite these interventions or in situa-
tions with a high probability of injury, pharmacotherapy is appropriate [45]. The
most commonly prescribed medications include clonazepam and/or melatonin [6,
46, 47]. As large randomized placebo-controlled therapeutic trials have not yet been
performed, consensus treatment has arisen based upon case series and small clinical
trials [45, 48].
10.7.1 Clonazepam
Over the last 30 years, clonazepam has been the most widely prescribed agent for
RBD and approximately 90 % of patients initially respond well to low doses (0.5
1.0 mg) administered at bedtime [4, 49]. Clonazepam reduces phasic EMG activity
during REM sleep with minimal effect on tonic muscle activity. The agent also
appears to be effective in cases that have progressed to PD [4, 6].
Long-term follow-up studies revealed mixed results, ranging from sustained ben-
efit without dose escalation to frequent dose escalations and treatment failures [4,
5052]. In one series, 58 % of patients on clonazepam reported clinically significant
adverse effects with 50 % either stopping the medication or reducing the dose [52].
Also, clonazepam may be particularly problematic in the setting of advanced PD
where its prolonged duration of action can result in morning sedation, impaired gait,
and cognitive side effects [53].
10.7.2 Melatonin
Recently, several studies have suggested that melatonin may be an effective and safe
first-line treatment for RBD either in combination with clonazepam or as sole ther-
apy. By uncertain mechanisms, melatonin in high doses at bedtime (615 mg) aug-
ments REM atonia and improves RBD symptoms. Effects persist for weeks after the
agent is discontinued [6, 47].
Importantly, a recent direct comparison study noted that melatonin was equal to
clonazepam in treatment efficacy and superior in side effect profile. Patients on
melatonin reported fewer adverse effects, in particular less falls and injuries com-
pared to clonazepam [54]. In the setting of advanced PD, melatonin is a particularly
intriguing option as it is only mildly sedating.
10.7.3 Pramipexole
Pramipexole may be effective in mild cases of RBD, in particular those associated

with frequent PLMs. Compared to clonazepam responsive patients, pramipexole
responsive patients have milder disease at baseline as measured by REM atonia.
Similar to treating OSA in RBD, pramipexole may decrease nocturnal behaviors by
reversing a sleep fragmenting condition. Patients report a decrease in distressing
nocturnal behaviors along with a decrease in PLMs; however, pramipexole has no
effect upon REM atonia [55].
10.7.4 Rivastigmine
Cholinergic agents may be useful in RBD among patients who have failed con-
ventional therapy. One small placebo-controlled crossover trial noted that the
cholinesterase inhibitor rivastigmine reduced the number of DEB episodes as noted

by bed partners [56].
10.7.5 Other Medications
Various therapies have been reported at least once to be successful. These include
imipramine, carbamazepine, levodopa, donepezil, sodium oxybate, triazolam, zopi-
clone, quetiapine, and clozapine [45, 46, 52].
10.7.6 Deep Brain Stimulation
Deep brain stimulation (DBS) for PD has thus far not been therapeutic for comorbid
RBD. Three case series of PD patients with RBD undergoing DBS noted improve-
ments in subjective sleep quality and sleep architecture on PSG, however, with little
to no improvement in DEB or REM atonia [5759]. These findings were not unex-
pected as the target of DBS in these studies, the subthalamic nucleus, does not have
a known effect upon REM sleep. Other DBS targets for PD include the globus palli-
dus internus and the paramedian pontine nucleus. The PPN is an REM-modulating
nucleus and thus an intriguing target for future RBD investigations.
10.7.7 Bed Alarm Therapy
Medication refractory RBD is a daunting and potentially life-threatening condition.

Exiting the bed while acting out a dream is a particularly high-risk behavior and
may result in severe traumatic injury.
The low arousal threshold and rapid transition to alert wakefulness from REM
sleep offers a therapeutic window to halt behavior prior to SRI. Despite apparent
unconsciousness during REM sleep, the brain is readily responsive to complex
auditory sound processing. This contrasts with the high arousal threshold of NREM
sleep often demonstrated by the inability to redirect or wake up SW patients (a
NREM parasomnia). This phenomenon is often noted by bed partners who describe
an ability to calm RBD patients with a simple phrase such as, sweetheart, you are
having a dream go back to sleep. A customized bed alarm, delivering such a calm-
ing message when a patient attempts to leave the bed can halt potentially injurious
dream enactment [53].
10.8 Future Directions
10.8.1 Possible Neuroprotection
At this time, it is uncertain what measures may be taken to prevent or delay the
onset of a neurodegenerative disorder such as PD. However, as RBD may help
identify patients at high risk for developing PD, it may also be an important target
in studies of neuroprotective/disease-modifying therapies.
These preliminary investigations have begun to explore whether compounds can
slow, halt, or possibly even reverse alpha-synuclein neurodegeneration. Recently,
riluzole, an antiglutamate compound currently used as neuroprotection in amyo-
trophic lateral sclerosis, has been demonstrated to both prevent RBD and increase
the number of surviving dopamine neurons in the marmoset MPTP model of
Parkinsons disease [60]. Another intriguing agent, already in use among RBD
patients, is melatonin. Recently, melatonin has been demonstrated to have antioxi-
dant properties and to protect mitochondrial function, suggesting it has potential
as a neuroprotective agent [61]. Obviously, prospective randomized-controlled
trials are needed prior to concluding that any substance may prevent or slow
neurodegeneration.
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Quality Control for Diagnosis of REM
Sleep Behavior Disorder: Criteria, 11
Questionnaires, Video,
and Polysomnography
Birgit Frauscher and Birgit Hgl
Contents
11.1 Introduction .................................................................................................................. 146
11.2 RBD Screening Questionnaires ................................................................................... 146
11.3 Polysomnographic Criteria for REM Sleep Without Atonia ....................................... 148
11.3.1 Manual Quantification of REM Sleep Without Atonia .................................. 148
11.3.2 Computer-Assisted Scoring Algorithms for REM Sleep Without Atonia ..... 151
11.3.3 Manual Versus Computer-Assisted Scoring of REM Sleep Without Atonia . 151
11.3.4 Recommended Montage for RBD Detection ................................................. 153
11.3.5 Normative EMG Values for Detection of REM Sleep Without Atonia ......... 153
11.4 Conclusions and Outlook ............................................................................................. 154
References ............................................................................................................................... 155
Abstract
The diagnosis of REM sleep behavior disorder (RBD) is based on clinical crite-
ria, which include history and information from video/polysomnography. While
probable RBD can be diagnosed from questionnaires, for a definite diagnosis
polysomnography demonstrating REM sleep without atonia is necessary. Several
studies have provided cut-off values for excessive muscle activity during REM
sleep to make an objective and accurate diagnosis of RBD. Recent advances
include development of computerized softwares for the automatic quantification
of electromyographic (EMG) activity during REM sleep. An exact and accurate
quality control in the diagnosis of RBD is necessary to avoid wrong
classification.
B. Frauscher B. Hgl, MD (*)

Department of Neurology, Medical University of Innsbruck,
Anichstrasse 35, Innsbruck A-6020, Austria

146 B. Frauscher and B. Hgl
11.1 Introduction
REM sleep behavior disorder (RBD) has recently attracted major interest from
investigators due to the fact that approximately 80 % of those initially diagnosed
with idiopathic RBD (iRBD) will convert to a neurodegenerative disorder, mainly a
synucleinopathy (for more details please see Chap. 10). As a high-risk population
for neurodegeneration, patients with iRBD are candidates to benefit from preventive
or disease modification strategies. Early and safe detection of preclinical stages of
neurodegeneration, namely RBD, is therefore of paramount importance.
RBD has a prevalence of 0.52 % in the general population [13], but >50 % in
patients with Parkinson syndromes [4, 5]. Beyond the often-dramatic clinical pic-
ture with violent dream enactment, leading to potential injury to patients and their
bed partners, RBD has recently started to solicit increased attention and to become
a major target of neurodegeneration research due to its unique position as a highly
predictive indicator of an imminent synucleinopathy.
As outlined above, patients with iRBD have a very high risk of developing an
overt neurodegenerative disorder after a decade or more [6]. Belonging to a high-
risk population for imminent neurodegenerative disorders, it is expected that patients
with RBD would greatly benefit from neuroprotective treatments, once these
become available, and they will provide an adequate population for any randomized
double-blind controlled study of neuroprotective treatments. First recommendations
for such future studies have already been made by the International RBD Study
Group [7]. Evaluating potential disease-modifying strategies in such a high-risk
group will be more effective than testing an unselected population in which the
conversion rate is very low.
In contrast to the potentially outstanding role of iRBD for the development of
neuroprotective or curative treatments are the difficulties encountered in making an
accurate diagnosis of RBD. For a definite diagnosis of RBD, polysomnography is a
requirement (ICSD 3) [8]. However, polysomnography is cost-intensive and not
widely available for all patient groups, or in all countries of the world.
11.2 RBD Screening Questionnaires
In light of the difficulty in accessing full polysomnography, especially for screen-

ing and first clinical selection purposes, questionnaires have been developed to aid
screening for RBD (see also Table 11.1). Nevertheless, questionnaires can only
diagnose probable RBD. The first validation studies of these RBD questionnaires
have been performed with acceptable results [915]. Sensitivity ranged from 74.3
to 96 % and specificity from 56 to 92.9 %. Even single RBD screening questions
were initially reported to have a good sensitivity and specificity [13, 14]. Despite
these initially encouraging results in detecting probable RBD, more recent work
increasingly suggests that beyond the narrow context of a validation study, the
diagnostic value of questionnaires in detecting RBD may be lower than previously
thought.
11 Quality Control for Diagnosis of REM Sleep Behavior Disorder 147
Table 11.1 Characteristics and validation results for questionnaires to detect probable RBD
Sensitivity Specificity
Author Questionnaire Characteristics (%) (%)
Stiasny-Kolster RBD Screening 10 items with 13 questions 96 56
et al. [9] Questionnaire Yes/no answers
Max score =13
Li et al. [11] RBDQ-HK 13 questions 82 87
Assesses for life time and
recent (1 year) occurrence
Boeve et al. [12] Mayo Sleep Contains an introductory 98 74
Questionnaire question about RBD,
followed by 5 subsequent
questions about RBD
symptoms
Postuma et al. [14] Single question Single question 94 87
Screen for RBD
Frauscher et al. [13] Innsbruck RBD 5 questions 91 86
Inventory Yes/no/do not know
answers
Frauscher et al. [13] RBD summary Single question 74 93
question (from
Innsbruck RBD
Inventory)
For example, a recent study demonstrates that even in a Parkinsons disease popu-
lation, the validity of the RBD questionnaire clearly depends on the setting, and where
and how it is administered [16]. Even more importantly, 16 % false positives were
obtained with a validated RBD screening questionnaire in healthy sleepers in whom
RBD was later definitely excluded both by sleep expert interview and polysomnogra-
phy [17, 18]. An unexpectedly high rate of RBD screening questionnaire positives,
probably reflecting major false positive numbers, was also accumulated in a current
research initiative to detect Parkinsons disease progression markers in a Parkinsons
disease population versus a control population, in which 20 % of the healthy control
group exceeded the RBD cut-off score (http://www.ppmi-info.org). Therefore, using
a questionnaire alone must definitely be considered unreliable as a diagnostic instru-
ment, even more so in the context of iRBD without any already diagnosed synucle-
inopathy, and when they are administered outside a study or hospital setting, or by
untrained interviewers or as handouts only. Thus, the application of questionnaires
alone without polysomnography can carry a substantial risk to both over- and under-
estimating RBD. This is of particular relevance in RBD as the clinical differential
diagnosis is a challenging one. Patients with obstructive sleep apnea, a highly frequent
disorder in the elderly, often exhibit violent limb movements in the arousal at the end
of each apnea [19], and patients with RLS/PLM can have intense limb or whole body
jerks [20]. Sleep-related seizures, non-REM parasomnias, psychiatric disorders, and
drug-induced conditions are among the remaining differential diagnoses which are
very difficult, if not impossible, to disentangle without PSG.
11.3 Polysomnographic Criteria for REM Sleep Without

Atonia
The polysomnographic hallmark of RBD is the electromyographic demonstration

of REM sleep without atonia. Current ICSD-criteria require polysomnographic
evaluation as mandatory for a definite diagnosis of RBD [8]. It is defined qualita-
tively as the EMG finding of excessive amounts of sustained or intermittent eleva-
tion of submental EMG tone or excessive phasic submental or (upper or lower) limb
EMG twitching [8]. As the qualitative assessment of REM sleep without atonia is
dependent on the individual polysomnographic scorer, the current ICSD-3 criteria
cite a normative study reporting that a total of 27 % of 30 s epochs which are posi-
tive for any (tonic/phasic or both) EMG activity in the chin or phasic activity
detected in the bilateral flexor digitorum superficialis, reliably distinguish RBD
patients from controls [21]. Examples of a 30 s epoch of normal REM sleep and of
REM sleep without atonia are provided in Fig. 11.1.
11.3.1 Manual Quantification of REM Sleep Without Atonia
Manual quantification of EMG activity during REM sleep was first performed in
healthy normals in the mid-seventies and early eighties (for an overview, see [22])
REM sleep without atonia in the context of RBD was first systematically assessed
by Lapierre and Montplaisir in 1992 [23], who classified EMG activity as phasic
and tonic EMG activity within 2 s mini-epochs and 20 s epochs. Phasic EMG
activity was defined as EMG activity between 0.1 and 5 s with an amplitude exceed-
ing four times the background EMG, and tonic EMG activity was defined as the
presence of tonic EMG activity for at least 50 % of the total epoch. This classifica-
tion system is still the most widely used system for EMG quantification [21, 2428].
Minor modifications of the original scoring system introduced by the various inves-
tigators concern the duration of the evaluated mini-epochs (2 vs. 3 s) and epochs (20
vs. 30 s) depending on historical national differences in polysomnographic record-
ing paper speed, and the amplitude criterion with 4-times vs. 2-times the back-
ground EMG activity, as well as the duration of phasic EMG activity with 0.15 s
vs. 0.110 s (for details, see [22]). The latest modification concerns the new intro-
duction of the measure any in order to simplify the quantification of EMG activity
during REM sleep, as the differentiation between phasic and tonic EMG activity can
be challenging in clinical practice [21]. Any EMG activity is defined as presence
of any EMG activity exceeding 0.1 s with an amplitude of twice the background
EMG activity [21]. Apart from the Lapierre & Montplaisir scoring system, two dif-
ferent scoring approaches have been introduced [2932]. Eisensehr et al. differenti-
ated between short- and long-lasting EMG activity [29]: short-lasting EMG activity
is defined as a minimum of 10 bursts of EMG activity between 0.1 and 0.5 s during
a 10 s EEG epoch, and long-lasting EMG activity as >0.5 s activity for at least 1 s
of the 10 s epoch [29]. Bliwise et al. [30] investigated the phasic electromyographic
metric (PEM) which is defined as EMG activity exceeding 0.1 s with an identifiable
Fig. 11.1 Examples of normal REM sleep and REM sleep without atonia. (a) Thirty sepoch of
normal REM sleep. Note that few bursts of EMG activity are also present during normal REM
sleep. (b) Thirty sepoch of REM sleep without atonia. Note increased levels of phasic EMG activ-
ity in the chin and the extremities. In the chin, there is in addition an increase of tonic background
EMG activity
return to baseline during the respective 2.5 s mini-epochs. In a recent study, the
Mayo group introduced phasic burst duration as a new related measure [35]. Higher
levels of phasic muscle activity even in nights without behavioral abnormalities
have previously been described by Bliwise and Rye [33].
For further details see Table 11.2.

The most obvious advantage of the Lapierre & Montplaisir scoring system is that
it is a simple practical method as it does not assess absolute EMG events, but the
presence or absence of defined EMG activity in mini-epochs which can thus be
positive or negative [23].
Table 11.2 Overview of studies which manually quantified REM sleep-related EMG activity
EMG Evaluated Epoch
Authors measure Amplitude Duration (s) muscles duration (s)
Lapierre and Phasic 4 background 0.15 Submental 2
Montplaisir [23] Tonic N/A >50 % of epoch 20
Eisensehr et al. Short- 50 % >10 0.10.5 Mental, 10
[29] lasting amplitude submental, TA
increase
Long- 50 % >0.5 for >1
lasting amplitude
increase
Consens et al. Phasic >4 0.15 Chin 3
[24] background
Tonic >4 50 % of epoch 30
background
Bliwise et al. PEM >2 0.1, identifiable Mental, 2.5
[3032] background return to brachioradialis,
baseline in the TA
mini-epoch
AASM [34, 35] Phasic >4 0.15 (total >5) Chin, limbs 30
background
Tonic > the >50 % of epoch 30
minimum
NREM
amplitude
Zhang et al. [26] Phasic >4 0.15 Chin, extensor 3
background forearm, TA
Tonic >2 50 % of epoch 30
background
SINBAR Phasic >2 0.15 Mental, SCM, 3
(Frauscher et al. background deltoid, biceps,
[25]) FDS, APB, TL
paraspinal, RF,
GAS, TA, EDB
Montplaisir Phasic >4 0.110 Mental, TA 2
et al. [27] background
Tonic >2 >50 % of epoch 20
background or
10 V
SINBAR (Iranzo Phasic >2 0.15.0 s Mental, FDS, 3
et al. [28]) background EDB
Table 11.2 (continued)

EMG Evaluated Epoch
Authors measure Amplitude Duration (s) muscles duration (s)
SINBAR Phasic >2 0.15 Mental, SCM, 3
(Frauscher et al. background biceps, FDS,
[21] Tonic >2 >50 % of epoch TA, EDB 30
background
or 10 V
Any >2 0.1 3
background
McCarter et al. Phasic >4 0.1 Chin, limbs Single
[33] burst background counts
Phasic >4 0.114.9 s 3
background
Any >4 0.1 3
background
Tonic >2 >15 s 30
background
or 10 V
Legend: PEM phasic electromyographic metric, TA tibialis anterior, SCM sternocleidomastoid,
FDS flexor digitorum superficialis, APB abductor pollicis brevis, TL thoracolumbal, RF rectus
femoris, GAS gastrocnemius, EDB extensor digitorum brevis
11.3.2 Computer-Assisted Scoring Algorithms for REM Sleep

Without Atonia
Due to the time intensity of manual quantitative EMG scoring, six different
computer-assisted algorithms for the detection of REM sleep without atonia have
been developed [3644]. For an overview, see Table 11.3.
The best evidence exists for the REM atonia index [4143]. This index varies
between 0 (complete loss of REM atonia) to 1 (complete REM atonia). A score
below 0.8 was demonstrated to be highly suggestive for RBD [42, 43]. The REM
atonia index was validated against the manual gold standard, and showed a high
correlation with a Spearmans rho of at least 0.75. The remaining studies used dif-
ferent measures. A validation against manual quantification was performed by only
two of these studies [36, 44]. Of note, for all of the computer-assisted scoring algo-
rithms manual artifact detection and exclusion is necessary.
11.3.3 Manual Versus Computer-Assisted Scoring of REM Sleep

Without Atonia
Manual scoring of REM sleep without atonia is still the gold standard in current
RBD research, but is often not feasible in clinical practice due to the time required
for such a procedure. Therefore, a computer-assisted algorithm for quantitative
scoring of EMG activity seems a mandatory requirement for implementation of
Table 11.3 Overview of studies with computer-assisted quantification of REM sleep without
atonia
N
subjects
EMG Evaluated (patients/
Authors measure Definition muscle Validation controls)
Burns et al. STREAM Variance of Chin Manual scoring 17/6
[36] the EMG according to Lapierre
signal per 3 s & Montplaisir: sens
epochs 100 %, spec 71 %
Ferri et al. REM atonia Ratio Chin Manual scoring 31/34
[41] index between the according to Lapierre
percentage of & Montplaisir: high
EMG correlation (rho
mini-epochs >0.75)
with average
1 V and
the total
mini-epochs
Ferri et al. Index Validation against 49/35 + 5
[42] improvement manual scoring: sens OSAS
Ferri et al. 84 %, spec 81 % 74/75
[43]
Mayer Short-and Short: Chin Not validated against 48/25
et al. [37] long-lasting 0.10.5 s manual scoring
muscle Long: > 0.5 s
activity
Shokrollahi Quantitative Wavelet Chin Not validated against 4/4

et al. [38] EMG analysis manual scoring,
analysis accuracy of
classification 94.3 %
Kempfner Quantitative Signal Chin Validated against 6/6
et al. [39] EMG processing STREAM: sens
analysis and 100 %, spec 100 %
statistical
classifier
Kempfner Quantitative One-class Chin + further Not validated against 16/16 + 16
et al. [40] EMG support muscles manual scoring, ROC PLMD
analysis vector 0.993 for
machine combination of
classifier submentalis + anterior
tibialis
Frauscher SINBAR Tonic, Chin, FDS Validated against 20/60
et al. [44] phasic, any manual scoring; sens
89 %, spec 83 %,
Spearman rho 0.98.
Legend: FDS flexor digitorum superficialis muscle, PD Parkinson disease, ROC receiver operating
curve, sens sensitivity, SINBAR Sleep Innsbruck-Barcelona, spec specificity, STREAM supra-
threshold REM EMG activity metric
quantitative motor analysis in clinical routine. Such an algorithm will allow for a
rater-independent, easy and fast to apply quantification of absolute EMG events and
calculation of precise objective indices. Major criticisms of the published algo-
rithms and software focus on the fact that all of them use only the chin muscle activ-
ity, and not the extremities, which were shown to be predominantly associated with
movements related to RBD [28]. Moreover, none of the previous algorithms was
incorporated into the polysomnographic software, which is a mandatory prerequi-
site for manual artifact elimination. Both disadvantages were recently overcome by
a study validating software specifically developed and integrated with polysomnog-
raphy for RWA detection against the gold standard of manual RWA quantification.
The authors found both a high sensitivity and specificity for this software with fur-
ther improvement of the results when performing manual artifact correction [44].
This automatic scoring system has three major advantages: (1) This algorithm
does not only evaluate chin muscle tone as is the case with other algorithms. Chin
EMG tone is sensitive, but also highly susceptible to recording artifacts, and a good
signal might be difficult to obtain in less specialized clinical conditions. The con-
comitant recording of the flexor digitorum superficialis muscle, and quantification
of EMG activity in that muscle, provides an extra assurance against false positive
recordings. (2) The result of computer-based classification into tonic, any or phasic
activity in chin and phasic activity in the extremities is readily visible for each
epoch of the whole recording on the polysomnographic screen, and a validation and
artifact control is easy and feasible. (3) This is the first RWA quantification system
already integrated and built into a polysomnographic system, and therefore does not
require data export, data transformation, and separate handling, but the quantitative
values can be obtained during polysomnographic, similar to apnea indices [44].
11.3.4 Recommended Montage for RBD Detection
The mentalis muscle has been best investigated for RBD detection as it is part of the
routine polsomnographic evaluation. Studies on other additional muscles are com-
paratively scarce, but it has been demonstrated that adding extremity muscles
improves the detection of REM-related movements in RBD patients [21].
Furthermore, it has been shown that a combination between the chin and the flexor
digitorum superficialis muscles is most suitable for RBD detection [25].
11.3.5 Normative EMG Values for Detection of REM Sleep

Without Atonia
Objective polysomnographic demonstration of REM sleep without atonia is essen-

tial. However, also during normal REM sleep phasic EMG activity, especially in the
context of rapid eye movements can be present. As presence or absence of REM
sleep without atonia is therefore not exclusive, quantitative cut-off values are very
much needed and should be implemented for both clinical and research purposes.
Up till now, four groups have worked on normative EMG values for a correct diag-
nosis of RBD [17, 21, 27, 33, 4143]. Montplaisir et al. manually investigated pha-
sic and tonic chin EMG activity and leg movements in the tibialis anterior muscles
in 80 idiopathic RBD subjects and 80 sex- and age-matched normal controls.
Another study in 30 RBD patients and 30 controls investigated the area-under-the-
curves (AUC) in different muscles of the human body, namely the mentalis, sterno-
cleidomastoid, biceps, flexor digitorum superficialis, tibialis anterior, and extensor
digitorum brevis muscles on both sides. The authors demonstrated that although all
investigated muscles differentiated well between patients and controls, the chin and
muscles of the upper limbs had even better AUCs than the lower limbs which might
be explained by overlapping phenomena such as periodic leg movements in sleep or
fragmentary myoclonus. Moreover, the authors found that the measure of any
EMG activity which is a simplified version of phasic and tonic EMG activity dis-
criminates identically between cases and controls. In addition, the 30 s epoch scor-
ing approach as introduced by the AASM in 2007 was also found to be sufficient to
differentiate cases from controls [21]. Similar cut-off values were found by investi-
gating healthy normal sleepers between 18 and 80 years of age as well as patients
with sleep apnea syndrome [17, 33]. Ferri et al. established normative values for a
computer-assisted scoring algorithm for REM sleep without atonia [4143].
11.4 Conclusions and Outlook
Despite several questionnaires for RBD being available [915], and despite solid
validation studies with single questions [10, 13] it should be kept in mind that ques-
tionnaires can help find probable RBD but are not appropriate to make a definite
diagnosis of RBD and rule out the most relevant differential diagnosis. On the other
hand, criteria for the polysomnographic diagnosis of RBD are currently under re-
consideration and debate, and quantitative cut-off scores have been provided by a
few investigators [21, 27, 33, 41]. These cut-off scores await future replication in
adequately sized populations of normal sleepers. Whereas manual scoring is still
the gold standard, computer-assisted scoring algorithms will gain increasing impor-
tance when implementing the scoring of REM-related EMG activity in clinical rou-
tine, as traditional manual scoring is very time consuming. The current drawback of
the existing softwares is that no automatic artifact detection algorithm is included.
Therefore, manual artifact correction is crucial when applying one of the existing
computer softwares in order to avoid false positive RBD diagnoses. Ambulatory
screening instruments to apply to the general population to detect RBD would be a
necessary next step to further advance the field.
While diagnosis of RBD is still made on qualitative grounds or without polysom-
nography for clinical routine and even in many research settings, the authors think
that a stringent quality control for the diagnosis of RBD is necessary to provide a
good basis for further clinical and research applications. The evidence compiled in
this chapter indicates that suitable instruments have been developed to make an
objective, and quantitative accurate diagnosis.
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Restless Legs Syndrome and Periodic
Limb Movements in Parkinsons Disease 12
William G. Ondo
Contents
12.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
12.2 Restless Legs Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
12.3 Pathophysiology of RLS Compared to PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
12.4 Clinical RLS in Patients with PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
12.5 Prevalence of PD in RLS Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
12.6 Periodic Limb Movements of Sleep in RLS and PD . . . . . . . . . . . . . . . . . . . . . . . . . . 166
12.7 Treatment of RLS in PD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Abstract
The symptoms of Parkinsons disease (PD) commonly include a number of sleep
disorders, including restless legs syndrome (RLS) and periodic limb movements
of sleep (PLMS). RLS occurs in about 20 % of PD patients in most studies, but
idiopathic RLS does not seem to precede the development of PD. In fact there is
some evidence that idiopathic RLS may prevent the subsequent development of
PD. In cases of PD/RLS the PD usually presents first, and RLS may represent
one of many non-motor features associated with PD. Although common, RLS is
usually not a major contributor to sleep deprivation or functional impairment in
the PD population. PLMS are seen in many neurodegenerative disorders, as well
as idiopathic RLS. Most studies report higher rates of PLMS in PD, but polysom-
nography studies suggest relatively little impact of PLMS on other sleep mea-
sures. The response of both PD and RLS to dopaminergics is of great interest,
especially given the lack of overt dopamine pathology in RLS.
W.G. Ondo, MD
Department of Neurology, University of Texas Health Science Center-Houston,
Houston, TX, USA

160 W.G. Ondo
12.1 Introduction
Parkinsons disease (PD) is a complex neurodegenerative disorder. Although

clinically defined by rigidity, bradykinesia, and tremor, numerous sensory,
autonomic, sleep symptoms, and other non-motor symptoms are commonly
reported. Some of these symptoms likely result from dopamine cell loss, while
others do not.
Restless legs syndrome (RLS) and PD both respond to dopaminergic treat-
ments, both show some dopaminergic abnormalities on functional imaging, and
are both variably associated with periodic limb movements of sleep [1]. Therefore,
a relationship between the two conditions has long been sought. Earlier results,
however, were mixed. Prior to the development of current RLS criteria, some
studies [2, 3], but not others [4, 5], reported a higher prevalence of RLS in patients
with PD. Diagnostic inconsistency makes these reports difficult to interpret. Most
reports employing current criteria do suggest that PD patients have higher rates of
RLS than the general population; however, clear pathophysiological connections
are lacking.
12.2 Restless Legs Syndrome
A 2003 NIH consensus summit defined Restless legs syndrome by the simultaneous
presence of: (1) Desire to move the extremities, often associated with paresthesia/
dysesthesia; (2) worsening of symptoms at rest; (3) transient improvement with
movement; and (4) worsening of symptoms in the evening or night [6]. No widely
available biomarker or test corroborates the diagnosis, which is made exclusively
via interview. Patients, however, often have difficulty describing their sensory com-
ponent of their RLS. The descriptions are quite varied and tend to be suggestible
and education dependent. The limb sensation is always unpleasant but not necessar-
ily painful. It is usually deep within the legs. In one study of RLS patients, the most
common terms used, in descending order of frequency included: need to move,
crawling, tingling, restless, cramping, creeping, pulling, painful,
electric, tension, discomfort, and itching [7]. Patients usually deny any
burning or pins and needles sensations, commonly experienced in neuropathies
or nerve entrapments, although neuropathic pain and RLS can coexist. RLS differs
from akathisia, also reported in PD, in that (1) the urge to move is isolated in the
limbs, rather than the entire body, (2) there is more dramatic relief with ambulation,
and (3) there is a more robust worsening at night, with near complete cessation of
symptoms in the early morning.
RLS is extremely common, affecting about 10 % of Caucasian populations [8],
although it appears less common in Asian and African populations [9]. In roughly
60 % of cases, a family history of RLS can be found, although this is often not
initially reported by the patient. Multiple genes and additional loci have been
published [1014].
12 Restless Legs Syndrome and Periodic Limb Movements in Parkinsons Disease 161
12.3 Pathophysiology of RLS Compared to PD
The pathology of idiopathic RLS involves CNS iron homeostatic dysregulation.

CSF ferritin and other measures of iron are lower in RLS cases [15]. Specially
sequenced MRI studies and transcranial ultrasound show reduced iron stores in the
striatum and substantia nigra [16, 17]. Most importantly, pathologic data in RLS
autopsied brains show reduced ferritin staining, reduced iron staining, increased
transferrin stains, reduced iron regulatory protein-1 activity, and also reduced trans-
ferrin receptors [18, 19]. The transferrin receptor downregulation is particularly
telling, as a simple reduction of iron availability to the area would upregulate these
receptors. Therefore, it appears that primary RLS has reduced intracellular iron
indices secondary to a perturbation of homeostatic mechanisms that regulate iron
influx and/or efflux from the cell. In contrast, PD is associated with increased iron
in dopaminergic areas [16].
Two Korean studies have evaluated CNS iron, as measured by sonography, in
subjects with both PD and RLS, compared to PD without RLS and idiopathic RLS
[20, 21]. Both found that the PD/RLS group had increased CNS iron similar to PD
without RLS. Idiopathic RLS showed reduced CNS iron similar to other studies. It
should be noted that patient with PD/RLS generally had PD first and later developed
RLS. Similar studies on subjects with young onset RLS that later developed PD
have not been done.
CNS dopaminergic systems are implicated in RLS; however, pathophysiologic
understanding of this is lacking. Dopaminergic medications, especially dopamine
agonists robustly improve RLS, even at low doses. Normal circadian dopaminergic
variation is also augmented in patients with RLS [22]. Dopamine imaging studies in
RLS, however, have been inconsistent and difficult to interpret. PET studies mea-
suring levodopa/dopamine have been normal [23] or shown slight reductions [24,
25]. Imaging of dopamine transporter protein have been normal [2628] or shown
modest reductions [29]. Imaging of dopamine receptors show normal [28] or mod-
estly reduced availability of receptors [25, 26], suggesting either decreased recep-
tors or increased endogenous dopamine occupancy. Explanations for these
disparities include different severities of RLS subjects, the variable use of dopami-
nergic medications as treatments, different times of data acquisition (day vs. night),
different ligands, rapid turnover of DAT faster than the fidelity of slower acting
ligands, and other technical considerations. They are difficult to reconcile but may
be limited by only assessing nigrostriatal dopamine. Some models and theories
of RLS suggest that spinal dopaminergic areas are culpable [30]. These areas,
however, are too small to image.
Pathologic data does not suggest reduced dopamine in RLS. CSF studies and
human brain studies of the nigrostriatal system generally suggest normal or even
increased dopaminergic turnover [3133]. Specifically, substantia nigra dopaminer-
gic cells are not reduced in number, nor are there markers associated with neurode-
generative diseases, such as tau or alpha-synuclein abnormalities [19, 34]. PD, of
course, exhibits reduced dopamine cells and multiple neurodegenerative markers.
162 W.G. Ondo
In RLS, the relationship between reduced iron pathology and the effective treat-
ment with dopaminergics is not clearly understood, and beyond the scope of this
text. However, some evidence suggests that the bridge is Thy1. This cell adhesion
molecule, which is robustly expressed on dopaminergic neurons, is reduced in brain
homogenates in iron-deprived mice [35] and in brains of patients with RLS [36].
Thy1 regulates vesicular release of monoamines, including dopamine [37]. A lead-
ing theory suggests that reduced iron stores decrease Thy1, which is necessary for
the transmission of dopamine across the synapse. Thy1 status in PD has not been
explored.
Both conditions, especially RLS, have a genetic contribution. Genes associ-
ated with RLS do not seem to be risk factors for PD [38]. One large family with
PD caused by Parkin mutations included a large number of members with RLS,
both with and without concurrent PD [39]. The RLS inheritance pattern was con-
sistent with an autosomal dominant pattern; however, the authors did not find an
association between RLS and Parkin mutations within the family. In a South
Tyrolean population Parkin status did not independently predict onset or severity
of RLS but did synergistically interact with RLS4 to predict a younger age at RLS
onset [40].
In summary, there are no clear pathologic similarities between PD and idiopathic
RLS. Brain iron is decreased in RLS but increased in PD. Dopamine and dopamine
cells are overtly reduced in PD, but not reduced in RLS, where the dopaminergic
dysfunction is not clear. Nevertheless, most studies suggest that RLS is more com-
mon in subjects with PD than controls.
12.4 Clinical RLS in Patients with PD
Multiple surveys have queried the prevalence of RLS symptoms in PD populations

(Table 12.1). Symptoms of RLS in the PD population can overlap with general
akathisia and dystonia, both of which can occur when dopaminergic medications
wear off. RLS symptoms can also wax and wane, and of course can be treated with
PD medications. Therefore, the diagnosis of clinical RLS in PD can be particularly
problematic [53, 54]. Most studies were performed at tertiary centers but there is
little reason to suspect intrinsic bias. Some reports seek associations and/or include
a control group. In general, most studies suggest a higher rate of RLS in PD than
control populations or historic controls.
In a prospective survey of 303 consecutive PD patients, we found that 20.8 % of
all patients with PD met the diagnostic criteria for RLS [41]. Despite this high num-
ber of cases, there are several caveats that tended to lessen its clinical significance.
The RLS symptoms in PD patients are often ephemeral, usually not severe, and
might be confused with other PD symptoms such as wearing-off dystonia, akathisia,
or internal tremor. We specifically attempted to differentiate among these condi-
tions. Most patients in our group were not previously diagnosed with RLS and few
recognized that this was separate from other PD symptoms. Finally, the presence of
RLS did not affect Epworth scale scores of daytime sleepiness.
12
Table 12.1 Summary of RLS in PD studies

Study Population RLS in PD Risk factors Onset of RLS and PD Comment
Ondo et al. (2002) [41] USA 63/303 (20.8 %) Reduced serum ferritin PD first in 85 % Older age of onset and
less family history than
idiopathic RLS
Driver-Dunckly et al. (2006) [42] USAUndergoing 6/25 (24 %) NR NR Improved with STN DBS
STN DBS
Peralta et al. (2005) [43] Austria 28/113 (24 %) Younger age PD first in 83 % RLS symptoms during
Lower on H&Y wearing-off episodes
Simuni et al. (2000) [44] Abstract USA 42/200 (21 %) Tendency for PD first in 93 % RLS undiagnosed in 59 %
fluctuators (p = 0.14)
Braga-Neto et al. (2004) [45] Brazil 45/86 (49.9 %) Longer duration of PD, NR RLS not associated with
but not age daytime sleepiness
Chaudhuri et al. (2006) [46] USA and Europe 46/123a (37.4) NR Part of a non-motor survey
Controls (28.1)
Verbaan et al. (2010) [47] Holland 269 (11 %) Female NR RLS severity correlated
with PD severity
Loo et al. (2008) [48] Singapore 400 (3.0 % vs RLS correlated with RLS onset 61.7
0.5 %) H&Y and poor sleep
Kumar et al. (2002) [49] India 21/149 (14.1 %) NR NR RLS diagnosis based on a
Controls (0.9 %) single question
Krishman et al. (2003) [50] India 10/126 (7.9 %) Older age NR
Controls (1.3 %) Depression
Nomora et al. (2005) [51] Japan 20/165 (12 %) Younger age PD first in 95 % RLS worsened PSQI
Controls (2.3 %)
Restless Legs Syndrome and Periodic Limb Movements in Parkinsons Disease
Tan et al. (2002) [52] Singapore 1/135 (0.6 %) Motor restlessness in

Controls (0.1 %) 15.2 %
PSQI Pittsburg sleep quality index
163
a
A single written question, not full RLS criteria
164 W.G. Ondo
After determining the prevalence of RLS in PD, we next evaluated for factors
that could predict RLS in this population, and determined that only lower serum
ferritin levels predicted RLS symptoms in the PD population. RLS did not correlate
with duration of PD, age, H&Y, gender, dementia, use of levodopa, use of dopamine
agonists, history of pallidotomy, or history of deep brain stimulation (DBS). PD
symptoms preceded RLS symptoms in 35/41 (85.4 %), X2 = 20.5, p < 0.0001, of
cases in which patients confidently remembered the initial onset of both symptoms.
We next compared the PD/RLS group to patients with RLS not associated with PD
(idiopathic RLS). Only 20.2 % of all PD/RLS patients reported a positive family
history of RLS, compared to more than 60 % of our non-PD RLS population. The
serum ferritin was also lower in the PD/RLS group compared to the idiopathic RLS
group. In the cases with PD who did have a family history of RLS, the RLS symp-
toms usually preceded PD and generally resembled typical RLS. In short, our results
do not suggest that RLS is a forme fruste or a risk factor for the subsequent develop-
ment of PD, but rather that PD is a risk factor for RLS, which probably constitutes
a non-motor feature of PD.
Peralta reported that 28/113 (24 %) of Austrian PD patients met criteria for RLS
[43]. PD/RLS subjects were younger and had lower (less severe) on medicine PD
severity. PD preceded RLS in 83 %. Two other US studies reported that 24 and 21 %
of PD patients had RLS [42, 44]. A Dutch study reported that only 11 % of PD
subjects had RLS [47]. Female sex was the only specific predictor of RLS in this
population. PD severity did correlate with RLS severity. They did not report a non-
PD control group.
Studies done in Asian populations show lower absolute rates of RLS than
Caucasian studies but mostly show a relatively increased frequency of RLS in
PD. Krishnan et al. evaluated the prevalence of RLS in patients with PD compared
to normal controls in a population from India [50]. They found that 10 of 126 cases
of PD (7.9 %) versus only 1 of 128 controls ((0.8 %), p = 0.01) reported RLS. PD
patients with RLS were older and reported more depression. Another report from
India similarly found RLS in 14.1 % of PD patients vs. only 0.9 % in controls [49].
Although both prevalence are lower than U.S. reports, the absolute difference in
RLS prevalence between PD and controls is similar. This probably reflects baseline
epidemiology that suggests RLS is less common in non-Caucasian populations.
A Japanese survey reported similar results. RLS was seen in 12 % of PD subjects
compared to 2.3 % of controls [51]. They associated RLS with a younger age of PD
and associated it with poor sleep. PD almost always preceded RLS. The only study
that did not find any increased risk of RLS in PD was reported from Singapore. Tan,
in a mostly Chinese population, found only a single case of RLS out of 125 patients
presenting with PD [52]. The study also reported a very low RLS prevalence in the
general population [9].
In summary, studies done since modern RLS criteria were established, aside
from one Singapore study, report that the absolute differences in the rates of PD/
RLS is about 10 % greater (range: 6.614 %) than historic controls or actual con-
trols. All reports that queried symptom onset show that PD preceded RLS in the
majority.
12.5 Prevalence of PD in RLS Patients
Evaluating the prevalence of PD in populations presenting with RLS is prob-

lematic, since PD symptoms would usually be more overt and precipitate an
evaluation. Banno et al., however, reported that extrapyramidal disease or
movement disorders were previously diagnosed in 17.5 % of male RLS patients
vs. 0.2 % of male controls, and in 23.5 % of female patients vs. 0.2 % of female
controls (p < 0.05). They did not clarify whether they felt that these prior diag-
noses were correct or truly represented a different disease [3]. In an abstract,
Fazzini et al. reported that 19/29 RLS patients had PD symptoms [55]. In con-
trast Walters et al. reported no patients presenting with RLS who had PD [56].
As part of the Health Professional Follow-up Study, employing only written
questionnaires for RLS in men, Gao et al. reported a slight increased risk for PD
in mild (<15 days/months) RLS of 1.1 [95 % C.I.: 0.4, 3.0] and a stronger asso-
ciation with more severe (>15 days/month) RLS of 3.09 [95 % C.I.: 1.5, 6.2]; p
trend = 0.003 [57].
Over 15 years we collected 36 cases in which subjects developed RLS long
before PD, and/or had a family history of RLS in a first-degree relative and had
well-documented RLS before the onset of their PD. In this RLS/PD group, 13
were female, 18 had a positive family history of RLS, and 6 had a family history
of PD. We compared these to a control group of idiopathic PD without RLS:
N = 36, ten females, one with family history of RLS, nine with family history of
PD. The age at motor onset of RLS/PD was older (64.25 6.4 years vs.
56.8 10.7) than for patients with idiopathic PD (p 0.001). Patients with idio-
pathic PD developed dyskinesia more (21/36) than RLS/PD (4/32) at last fol-
low-up (p = 0.0001). PD phenotype and L-dopa dose were similar. We concluded
that idiopathic RLS may actually delay the onset of PD, reduce dyskinesia
occurrence, and possibly reduce progression of PD. This is potentially sup-
ported by aforementioned pathological studies that show increase dopamine
turnover in RLS, and reduced iron, as opposed to increased iron seen in
PD. Assessments of brain iron in this unique group (idiopathic RLS followed by
PD) have not been done.
Recently Wong et al., using a written RLS questionnaire without interview, eval-
uated for incident diagnosis of PD in 22,999 U.S. male health professionals age
4075 years enrolled in the Health Professionals Follow-up Study [58]. They found
a moderate increased rate of PD diagnosis within 4 years of RLS but not after
4 years. Since the pathologic process of PD begins years before the clinical diagno-
sis, they postulated that RLS may be an early feature of PD, preceding motor signs,
similar to REM behavioral disorder.
It is the authors opinion that the RLS phenotype is associated with PD but that
it derives from a different pathophysiology than idiopathic RLS, perhaps a conse-
quence of reduced CNS dopamine. There is no clear evidence of reduced dopami-
nergic tone in RLS, despite its robust response to dopaminergics. Therefore, PD is
a risk factor for RLS symptoms, but RLS pathophysiology and idiopathic RLS
symptoms are not risk factors for PD.
166 W.G. Ondo
12.6 Periodic Limb Movements of Sleep in RLS and PD
Periodic limb movements of sleep (PLMS) are defined by the American Academy
of Sleep Medicine as at least four periodic episodes of repetitive and highly stereo-
typed limb movements that occur during sleep. The incidence in the general popu-
lation increases with age and is reported to occur in as many as 57 % of elderly
people [59, 60]. Renal disease and a number of neurological conditions are associ-
ated with higher rates. Typically the movements involve various degrees of flexion
of the toes, ankles, knees, and hips (triple flexion response), although other patterns
are seen. The anterior tibialis is the most affected muscles and the one usually used
to assess electromyographic signals to quantify PLM. The physiology of PLM is
only partially understood but thought to result from disinhibition of the spinal cord
[61]. Autonomic lability with transient hypertension and tachycardia accompany
PLM and could be an argument to more aggressively treat the condition when it is
not thought to otherwise cause any clinical disability [62]. An expanding body of
research has epidemiologically associated PLM with cardiovascular disease [63,
64]. The term periodic limb movement disorder is appropriate when idiopathic
PLMS are thought to independently result in disability.
PLMS are strongly associated with RLS. One large study reported that 81 %
of RLS patients showed pathologic PLMS [65]. The prevalence increased to
87 % if two nights were recorded. Although PLMS accompany most cases of
RLS, data evaluating RLS prevalence in the setting of polysomnographically
documented PLMS found that only 9 of 53 (17.0 %) PLMS patients complained
of RLS symptoms [66]. Therefore, most people with RLS have PLMS but many
patients with isolated PLMS do not have RLS. Although the exact relationship
between the two phenotypes is unclear, genetic research suggests a strong bio-
logical association [11].
PD is also associated with higher rates of PLMS in most [1, 67, 68], but not all
reports [69, 70]. There is more compelling evidence that when present, PLMS cor-
relate with the severity of PD, both clinically and on imaging studies [68, 71]. The
clinical consequences of PLMS in PD are less clear. One study reported that
greater PLMS was associated with more subjective sleep disturbance, and
decreased Quality of Life Scales, but this was largely explained by an association
of PLMS with more advanced disease. The same study found and association of
PLM and REM behavioral disorder, which interestingly has also been seen in
patients presenting with RBD but without PD. Other objective measures of sleep,
including sleep efficiency, have not been associated with PLMS in PD [68].
Several other PSG studies, none of which primarily evaluated PLMS, have not
reported an association of PLMS with daytime sleepiness. One study that per-
formed PSG studies in PD subjects with and without RLS did find that PLMS were
more common in the PPD/RLS group [48]. In contrast another study segregating
PD based on the presence of PLMS did not find higher rates of RLS in the PLMS+
group [68].
The assessment of PLMS in PD is clearly confounded by dopaminergic treat-
ment, which improves PLMS in general, and does improve PLMS specifically in
PD in one prospective trial [72]. Another retrospective report in PD suggests benefit

of clonazepam for PLMS [73] but there has never been any controlled treatment
trial of PLMS in PD.
12.7 Treatment of RLS in PD
No formal study has ever prospectively assessed the treatment of RLS in the setting
of PD. Anti-cholinergic and anti-histaminergic drugs, including amitriptyline, mir-
tazapine, quetiapine, and many others used in PD, can exacerbate RLS in general
and should be discontinued if possible. One may consider checking serum ferritin
and supplementing this if low; however, it is not known whether this could affect the
PD course. Dopamine agonists and levodopa improve RLS as well as PD, so adjust-
ment of these medications may improve RLS. A PSG study found that PD patients
already treated with clonazepam had fewer PLM and less daytime sleepiness than
those not treated with clonazepam [73].
Interestingly, several reports suggest that CNS surgeries for PD may affect RLS
in the PD/RLS population. Rye first reported a single case of RLS symptoms
improving in a PD patient following pallidotomy [74]. Driver-Dunkley et al. found
RLS in 6/25 PD subjects prior to undergoing bilateral DBS of the subthalamic
nucleus (STN) [42]. All six had some improvement in RLS at 324 months after
DBS. Three had complete resolution and the mean International RLS rating scale
improved by 84 %. PD medications were lowered by 56 % and the UPDRS off
motor scores improved by 63 %, suggesting an excellent clinical response to the
DBS. As part of a larger assessment of STN DBS in sleep, Chahine et al. reported
improved IRLS scales in six subjects with PD/RLS [75]. In contrast, Kedia et al.
reported the emergence of RLS after STN DBS postoperatively in 11 of 195 patients.
The mean reduction in antiparkinsonian medication was 74 %, which they felt may
have unmasked the RLS symptoms [76]. Parra et al. also reported a case of RLS
emergence after DBS [77]. We recently performed a bilateral GPi DBS in a patient
with idiopathic RLS without PD. She demonstrated moderate benefit [78].
Conclusions
The majority of studies suggest that RLS is more common in PD than in the
general population. Most studies of predominately Caucasian populations
demonstrate a >2 rate of RLS in PD compared to the normal population. PD/
RLS rates in Asian surveys are less, as are the baseline rates of RLS but still
greater than control populations. Reported risk factors for RLS in the PD popu-
lation include reduced serum iron stores, older age, younger age, depression,
and worse PD. RLS symptoms severity is less than those seeking treatment for
idiopathic RLS but may be similar to the idiopathic RLS population in entirety.
Although the data is mixed, the overall effect of RLS on daytime sleepiness
and quality of life in PD is probably modest. Importantly, there is no good
evidence to suggest that RLS is a forme fruste of PD, and in fact the patho-
physiologies are markedly different, despite similar responses to dopaminergic
168 W.G. Ondo
medications. Therefore, it appears that RLS is one of many non-motor features

intrinsic to PD, presumably secondary to dopaminergic loss, although this is
not actually known.
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Fatigue and Sleepiness in Parkinsons
Disease Patients 13
Elisabeth Svensson
Contents
13.1 Introduction ................................................................................................................... 174
13.2 Defining Fatigue............................................................................................................ 174
13.3 Measuring Fatigue ........................................................................................................ 175
13.4 The Epidemiology of Fatigue in PD Patients................................................................ 176
13.5 Factors Associated with Fatigue in PD Patients ........................................................... 177
13.5.1 Fatigue and Sleepiness .................................................................................... 177
13.5.2 Fatigue and Depression ................................................................................... 177
13.6 Pathophysiology ............................................................................................................ 177
13.7 Treatment ...................................................................................................................... 178
13.7.1 Pharmacologic Interventions ........................................................................... 178
13.7.2 Non-pharmacologic Interventions ................................................................... 178
Conclusion ............................................................................................................................... 179
References ................................................................................................................................ 179
Abstract
The main focus of this chapter is fatigue in Parkinsons disease (PD) patients,
with particular emphasis on defining and measuring fatigue, describing the epi-
demiology of fatigue and associated factors, including a brief discussion of the
interface between fatigue and sleepiness. Fatigue is a common non-motor symp-
tom in PD patients, but is also a common complaint in the general population. To
facilitate research of fatigue in PD it is important to clearly define the concept of
fatigue and to use fatigue scales with good psychometric properties. Additionally,
it is important to disentangle the effects of fatigue from the effects of other
comorbid symptoms in the PD patients, such as depression and sleep problems.
Fatigue and sleepiness are two distinct entities; thus, it is important to separate
E. Svensson, PhD
Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark

174 E. Svensson
excessive daytime sleepiness from fatigue. Because of scant knowledge on

pathophysiology and treatment, these sections are discussed briefly.
13.1 Introduction
Fatigue and sleepiness are commonly seen both in the general and clinical popula-
tions, such as Parkinsons disease (PD) patients. Such non-motor symptoms are
often under-recognized clinically [1], despite being of uttermost importance for the
patients and significantly associated with worse quality of life [24]. For many
patients and clinicians, the distinction between fatigue and sleepiness is unclear, as
there is no clear definition of these concepts, and no consensus on what is normal or
pathological. Terms such as fatigued, tired, and sleepy are used interchangeably;
while fatigue can be described as an individuals feeling of abnormal tiredness,
sleepiness is defined as a tendency to fall asleep. Sleepiness and fatigue frequently
co-occur in PD patients; however, it is suggested that they should be regarded as
distinct symptoms that must be understood and managed separately [5]. The main
focus of this chapter is fatigue, with particular emphasis on defining and measuring
fatigue, describing the epidemiology of fatigue and associated factors, including a
brief discussion of the interface between fatigue and sleepiness. Finally, the patho-
physiology and treatment of fatigue in PD patients are briefly discussed.
13.2 Defining Fatigue
There are two types of fatigue, peripheral fatigue (fatigability) and central fatigue.
Fatigability is objectively measured and involves lack of energy associated with
repetitive muscular movements. The main focus of this chapter will be on central
fatigue, which is a subjective feeling, and thus, objectively immeasurable. There is
no universally accepted definition of this type of fatigue, and the division between
pathological and normal fatigue is unclear [6]. Focus groups of PD patients opera-
tionalized fatigue as abnormal tiredness [7], interfering with normal function. The
fatigue experienced by the PD patient is different from the fatigue experienced
before developing the disease [7].
Fatigue can be described as physical or mental fatigue [6]. Physical fatigue is
the subjective feeling of being exhausted and lacking energy, including muscle
weakness, despite being able to perform the tasks. Mental fatigue is the subjective
feeling of being mentally exhausted, including difficulty concentrating and lack
of mental clarity during and after periods of cognitive strain. It is suggested that
mental and physical fatigue are independent of each other [8], as they are not corre-
lated. If the fatigue is persistent over 6 months, it can be defined as chronic fatigue
[9]. In patient populations with stable diseases, the concept of chronic fatigue is
useful, as it helps to separate acute and transient fatigue from fatigue that is stable
over time.
13 Fatigue and Sleepiness in Parkinsons Disease Patients 175
Fatigue can be categorized as primary or secondary fatigue. Primary fatigue is

related to the neurologic disease itself, while secondary fatigue is caused by other
factors such as infections, anemia, endocrine dysfunction, depression, sleep distur-
bance, or side effects of the medications. It may be difficult to disentangle these two
issues; during a clinical investigation, it is important to rule out fatigue from sec-
ondary causes. In research, it is important to define what type of fatigue one seeks
to measure.
13.3 Measuring Fatigue
A variety of questionnaires have been developed to measure fatigue and assess its
severity, both for clinical and research purposes [10]. These questionnaires encom-
pass different properties, such as being one- or multidimensional, and generic ver-
sus disease-specific. A one-dimensional fatigue scale condenses a range of
symptoms into a single score. A multidimensional scale incorporates several aspects
of fatigue [11]; for example, being able to distinguish between mental and physical
fatigue [12]. A generic scale can be used to assess fatigue within the general popula-
tion, while the use of a disease-specific instrument may better reflect the conse-
quences of disease, such as PD.
As the questionnaires have varying properties, it may be that measurements from
different questionnaires yield prevalence estimates that vary. In fact, a comparison
between the Fatigue Severity Scale (FSS) and the Functional Assessment of Chronic
Illness TherapyFatigue scale (FACIT-F)concludes that they do not appear to
measure identical aspects of fatigue [13].
The International Movement Disorder Society has rated all instruments used to
measure fatigue in PD [14]. For screening purposes, recommended scales include
the FSS, FACIT-F, and the Parkinson Fatigue Scale (PFS) [14]. The Committee sug-
gested further examinations of psychometric properties of the scales, including sen-
sitivity and specificity.
An example of a generic unidimensional scale is the FSS [15], which is probably
the most widely used fatigue instrument. The FSS does not distinguish between dif-
ferent aspects of fatigue; and what aspect of fatigue measured is not defined. The
FSS is a nine-item instrument; each statement is rated on a scale of 17. The indi-
vidual score is the mean of the numerical responses. A cutoff of four is used to
distinguish between fatigued and non-fatigued, but other cutoffs have also been
suggested. The psychometric properties of the FSS in PD are good [14].
The Parkinson Fatigue Scale is a PD-specific scale, developed to assess fatigue
in PD patients [7]. The scale is unidimensional, encompassing physical fatigue. The
focus of the instrument is to distinguish between PD patients who report having
fatigue versus not, and between problematic and non-problematic levels of fatigue
[7]. Its psychometric properties, including reliability, are good [14].
The FACIT-F scale is another widely used instrument, available in many lan-
guages and freely available (http://www.facit.org). While it does not define the type
of fatigue it aims to assess, it covers both the experience and impact of fatigue. It
176 E. Svensson
consists of 13 items, with 5 response categories, yielding a sum between 0 and 52.
The FACIT-F is reported to have good psychometric properties, including data qual-
ity, validity, and reliability [14].
One questionnaire not included in the rating by the International Movement
Disorder Society is the Fatigue Questionnaire (FQ). The FQ is widely used in can-
cer research [7], and is an example of a multidimensional fatigue questionnaire that
distinguishes between mental and physical fatigue [12]. The FQ also contains two
additional items about the duration and extent/impact of disease, enabling the iden-
tification of cases with chronic fatigue. The FQ was originally validated in primary
care, and has demonstrated good face-and discriminate validity, as well as stable
psychometric properties across populations [12].
13.4 The Epidemiology of Fatigue in PD Patients
The prevalence of fatigue in PD patients is found to range between 32 and 70 %,

depending on the population examined, the definition of fatigue and the instrument
used to measure fatigue (reviewed in [16]). Most of these studies involved small
clinical cohorts. Using a population-based cohort approach, two studies have esti-
mated the prevalence of fatigue of 28 % (chronic fatigue, FQ) [17] and 44 % (mea-
sured by Nottingham health profile) [18]. This prevalence is likely an underestimation,
since studies have not included PD patients who are unable to utilize self-report
instruments.
Many of the studies mentioned above have examined whether PD patients expe-
rience higher levels of fatigue than those without PD, often using clinical popula-
tions. Comparison between PD patients and patients without PD is important as
fatigue is common in the general population; one estimation is that 18 % of general
population over the age of 65 years experience fatigue (measured as chronic fatigue)
[19]. However, clinical populations may have even higher levels of fatigue than the
general population, resulting in an underestimation of the importance of fatigue in
PD compared with disease-free individuals. Available population-based studies that
compared fatigue in the PD population with the general population found signifi-
cantly higher prevalence of fatigue among PD patients [17, 18].
Women usually report higher levels of fatigue than men in the general population
[19]. Examining gender-specific differences, therefore, may be of importance. Few
studies have investigated gender differences in PD [16], and results have been incon-
sistent. One recent study found no evidence of gender differences in fatigue [20],
while two earlier studies found a trend towards significantly higher levels of fatigue
in women [21] and a significantly higher prevalence of fatigue in women [17].
Most cross-sectional studies reported an association between PD severity and
progression and fatigue [17, 20, 22], while others did not confirm these associations
[8, 18]. Data from a longitudinal study of a community-based PD cohort reported an
increasing lifetime prevalence of fatigue over time [23], and fatigue being related to
disease severity. Persistence of fatigue has also been shown to vary, with half of all
PD patients experiencing persistent fatigue.
13.5 Factors Associated with Fatigue in PD Patients
Some PD patients have fatigue only, with the absence of other non-motor symptoms
[23]. Among patients without sleep problems, depression, and dementia, 43.5 %
reported fatigue. Comorbid non-motor symptoms are, however, very common.
Among 100 patients who reported the presence of sleep disturbance, depression,
anxiety, fatigue or sensory symptoms, 59 % had two or more symptoms, 23 % had
four or more, and 11 % had all five symptoms [22]. Thus, it is important to disen-
tangle the effects of the different non-motor symptoms in PD patients, as they are
associated and may contribute to secondary fatigue. Here, we focus on sleepiness
and depression.
13.5.1 Fatigue and Sleepiness
There has been some focus on the overlap of fatigue and sleep problems, such as
sleepiness (or daytime somnolence) in PD patients. Interestingly, while sleep prob-
lems overall, as measured by the unidimensional disease-specific Parkinsons
Disease Sleep Scale, are significantly associated with fatigue [24, 25], studies
assessing daytime sleepiness (using Epworth Sleepiness Scale ) generally have not
found an association with fatigue [20, 21, 26]. This suggests that fatigue is a distinct
entity from sleepiness, as measured by the ESS. Additionally, there are differences
in the way fatigue and sleepiness are correlated with other factors such as dopami-
nergic treatment and depression [27]. This is further underlined by the finding that
modaphenil has an effect in treating sleepiness (reviewed in [28]), but not fatigue
(reviewed in [29]). Thus, it is important to separate excessive daytime sleepiness
from fatigue.
13.5.2 Fatigue and Depression
The presence of fatigue is one of the criteria for diagnosing depression. Thus, in any
study of fatigue in PD patients, depression must be taken into account [11].
Accordingly, there are several reports of the association between fatigue and depres-
sion. However, nondepressed patients are also fatigued [23], and patients success-
fully treated for depressive mood may still continue to have fatigue.
13.6 Pathophysiology
The physiological causes of fatigue in PD patients are largely unknown. Evidence

is emerging that fatigue is present in early stages of disease, rather than as the
result of PD progression. Fatigue is present in 40 % of recently diagnosed PD
patients in a representative cohort of patients with incident PD [21]. In a study of
levodopa-nave PD patients, fatigued and nonfatigued PD patients have similar
178 E. Svensson
dopamine transporter uptake, while the fatigued patients had more severe
Parkinsonism [30]. Although an association between dopamine drugs and fatigue
has been observed, there is no evidence of a dose response [20]. Thus, it seems
unlikely that the nigrostriatal dopaminergic pathology plays a role for fatigue in
PD patients [20].
Fatigue is common not only in other neurologic diseases such as multiple sclero-
sis but also other somatic diseases such as cancer and rheumatologic conditions, as
well as psychiatric disorders such as major depression and chronic fatigue syn-
drome. The pathophysiology of fatigue in all these states is also largely unknown. It
is possible that there are common underlying factors for all of these disease states.
While there are several hypotheses implicating immune, metabolic, and endocrine
processes, there is little evidence to support them [16].
Further research is necessary to clarify the pathophysiology of fatigue in
PD. Investigations must disentangle the effects of the different non-motor symp-
toms in order to elucidate the effects of primary versus secondary fatigue.
13.7 Treatment
The treatment of subjective fatigue in PD is a challenge, as there is scant knowledge

of the pathophysiology. However, treatment of secondary fatigue, such as fatigue
due to depression, may lead to improvement in mental and physical dimensions of
central fatigue [31]. If pathophysiological studies find a common underlying factor
for fatigue across disorders [20], this may result in the development of therapies
beneficial for fatigue in PD patients as well.
Treatment of fatigue can broadly be divided into pharmacologic and non-
pharmacologic interventions.
13.7.1 Pharmacologic Interventions
There are few studies investigating the efficacy of pharmacological treatments of

fatigue in PD patients. A 6-week randomized controlled trial of 36 patients showed
methylphenidate (compared to placebo) to significantly reduce FSS and FSI scores
[32]. These results have not been replicated. As previously mentioned, modafinil
has been reported not to reduce fatigue, but these studies were small (reviewed in
[29]). The Movement Disorder Societys evidence-based medicine review update
on treatments for non-motor symptoms of PD concluded that there is insufficient
evidence of methylphenidate and modafinil for the treatment of fatigue [33].
13.7.2 Non-pharmacologic Interventions
Non-pharmacologic interventions include patient and caregiver education, psycho-

logical approaches and physical exercise [34]. This section will focus on exercise.
To date, there has been no randomized controlled trial of exercise for fatigue in
PD. However, higher levels of exercise may be associated with lower levels of
fatigue in observational studies [35, 36]; in addition to improving fatigue in PD
patients, depression may also decrease. The potential effects of exercise in PD
patients have been reviewed by Speelman and colleagues [37].
The benefits of exercise as a treatment for fatigue for patients with several medi-
cal conditions such as depression, cancer, and multiple sclerosis may extend to PD
as well [5]. The difficulties of getting patients, especially those with severe motor
dysfunction, to exercise at appropriate levels may be a challenge. However, as there
are several benefits of physical activity, exercise programs for patients with PD are
warranted [38].
Conclusion
Fatigue is a common non-motor symptom in PD patients as well as a common
complaint in the general population. Further research on pathophysiology and
treatment is warranted: Improving our knowledge is important to develop
effective prevention strategies and treatment for this non-motor symptom of
PD. To facilitate further research of fatigue in PD patients, it is of importance
to clearly define the concept of fatigue under investigation. Additionally, it is
important to disentangle the effects of fatigue from the effects of other comor-
bid symptoms of PD, such as depression and sleep problems, as these represent
distinct entities.
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Cognition and the SleepWake Cycle
Jean-Francois Gagnon, Ronald B. Postuma,
and Gabrielle Lyonnais-Lafond
Contents
14.1 Introduction ................................................................................................................... 184
14.2 Cognition in Parkinsons Disease ................................................................................. 184
14.3 Sleep and Cognition in Aging ....................................................................................... 185
14.4 Sleep and Cognition in Parkinsons Disease ................................................................. 186
14.4.1 Rapid-Eye-Movement Sleep Behavior Disorder ............................................. 186
14.4.2 Sleep-Disordered Breathing and Excessive Daytime Sleepiness .................... 188
14.4.3 Insomnia, Sleep Quality, and Alterations in Sleep Architecture ..................... 189
14.5 Conclusions and Future Directions ............................................................................... 191
References ................................................................................................................................ 191
Abstract
Non-motor symptoms of Parkinsons disease (PD) have received increas-
ing attention in the past decade, particularly cognitive and sleep dysfunctions.
Moreover, a growing body of evidence suggests an association between sleep
and cognition in aging. This chapter outlines the role of sleep in the mainte-
nance of cognition and learning and the high prevalence of cognitive impairment
J.-F. Gagnon, PhD (*) G. Lyonnais-Lafond, BSc candidate

Department of Psychology, Universit du Qubec Montral, Montreal, QC, Canada
Centre dtudes Avances en Mdecine du Sommeil, Hpital du Sacr-Cur de Montral,
5400 boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
R.B. Postuma, MD, MSc
Centre dtudes Avances en Mdecine du Sommeil, Hpital du Sacr-Cur de Montral,
5400 boul. Gouin Ouest, Montreal, QC H4J 1C5, Canada
Department of Neurology, McGill University,
Montreal General Hospital, Montreal, QC, Canada

184 J.-F. Gagnon et al.
in PD. We then summarize the evidence for and against associations between
rapid-eye-movement (REM) sleep behavior disorder (RBD), excessive daytime
sleepiness (EDS), sleep-disordered breathing (SDB), insomnia, sleep quality,
sleep architecture abnormalities, and cognitive impairment in PD. Three major
sleep outcomes, RBD, EDS, and reduced sleep spindles, are correlated to cogni-
tive impairment in PD, whereas insomnia, sleep quality, and SDB show modest
or no correlation. Further longitudinal studies are needed to determine the role
of RBD, EDS, and sleep spindle abnormalities as potential markers of cognitive
decline in PD.
14.1 Introduction
The non-motor features of Parkinsons disease (PD) have been well identified by
clinicians and researchers in the last decade. Two of the most devastating for patients
and their caregivers are sleep disorders and cognitive impairment, which affect
nearly all patients with PD over the course of the disease. Indeed, patients with PD
frequently develop symptoms such as insomnia, rapid-eye-movement (REM) sleep
behavior disorder (RBD), sleep-disordered breathing (SDB), excessive daytime
sleepiness (EDS), mild cognitive impairment (MCI), and/or dementia. Moreover,
sleep and cognition are strongly related: (1) some memory and learning process
appear to be mediated by cerebral plasticity mechanisms that occur in part during
the sleepwake cycle and (2) several sleep disorders are associated with varying
degrees of cognitive deficits. Both sleep and cognition present age-related changes,
which are amplified in pathological aging, such as neurodegenerative diseases.
Recent studies suggest that some of these PD-related sleep disorders are associated
with an increased risk for cognitive impairment. This chapter reviews the evidence
for an association between sleep and cognition in PD.
14.2 Cognition in Parkinsons Disease
Cognitive impairment is a frequent non-motor symptom of PD, and can occur early in
the course of the disease [1, 2]. The cognitive profile of patients with PD is heteroge-
neous and varies widely with the disease stage [1, 2]. The most consistently reported
impaired cognitive domains in PD are attention, executive functions, episodic mem-
ory, and visuospatial abilities [1, 2]. The severity of the cognitive impairment also
differs widely between patients: some patients remain cognitively intact for a long
period of time, whereas others develop MCI or dementia early in the disease course.
MCI is defined as significant cognitive decline compared to age- and education-
equivalent individuals, without major impact on activities of daily living. It is now
a well-recognized feature of PD [1]. Cross-sectional studies using various defini-
tions of PD-MCI have reported MCI in 1938 % of patients with PD [1]. New crite-
ria for PD-MCI have been proposed by a Movement Disorder Society Task Force [1].
14 Cognition and the SleepWake Cycle in Parkinsons Disease 185
However, the validity of these criteria remains to be determined. MCI is a risk factor
for a more severe cognitive decline in PD [1, 3], which is not surprising, given that
MCI is often an intermediate stage between normal aging and dementia in the
general population [4].
Dementia is one of the most devastating non-motor features of PD. The point
prevalence of dementia in PD has been estimated at from 8 to 48 % in cross-sectional
studies [2]. This wide range is mainly due to between-study variability in methodol-
ogy (i.e., population selection, dementia criteria, and population heterogeneity).
A point prevalence of 30 % is suggested [2, 5]. The Movement Disorder Society
Task Force has also proposed criteria for dementia in PD [2]. Whereas the cross-
sectional prevalence is moderately high, prospective long-term studies have reported
that most patients with PD eventually develop dementia [2, 5].
There is considerable variation between the time of dementia onset and the time
of PD onset [2]. Some demographic and clinical risk factors for dementia in PD
have been identified, namely older age, depression, more severe parkinsonism with
rigidity, akinetic-rigid subtype, freezing, postural instability, and gait disturbance
[2, 5]. In addition, hallucinations, MCI, and apathy increase the risk for dementia in
PD, mainly because they are early symptoms of cognitive impairment [1, 2, 5].
Various candidate biomarkers for cognitive decline in PD are currently being inves-
tigated, including waking EEG and structural and functional neuroimaging abnor-
malities, biomarkers in cerebrospinal fluid, and genetic polymorphisms [5]. This
chapter focuses on sleep abnormalities as potential risk factors for and markers of
dementia in PD.
14.3 Sleep and Cognition in Aging
Sleep is a complex physiological state characterized by coordinated cyclic changes

in the activity of diverse neuronal systems. Thus, major changes in neuronal molec-
ular, electrophysiological, and neurochemical activity occur throughout the sleep
wake cycle [6, 7]. Although the specific roles of these physiological events have not
been determined, growing evidence suggests that sleep has a significant impact on
cognition, particularly memory consolidation and cerebral plasticity [68].
In normal aging, age-related changes in sleep are common, and are characterized
by increased wake after sleep onset (WASO), reduced duration of slow-wave sleep
(SWS), and increased time spent in stage 1 sleep [9, 10]. Consequently, there are
more awakenings and sleep quality is poor. Although stage 2 sleep remains relatively
unchanged, the EEG features of stage 2 sleep are less pronounced, with reduced fre-
quency of sleep spindles and lower amplitude of K complexes. The REM sleep per-
centage remains constant, with only a small decrease in older age. Circadian phase
advances, characterized by a shift in the sleepwake cycle toward morningness,
have also been reported. Recent studies suggest that age-related changes in sleep
parameters are associated with age-related cognitive decline [11, 12].
In addition to sleep-related architecture changes, aging is associated with
increased prevalence of sleep disorders such as SDB, EDS, insomnia, and
RBD. These disorders can also impact cognition. In older adults with SDB,
impaired vigilance, attention, executive functions, and learning have been reported
[13, 14]. In a prospective study in older women, SDB was identified as a risk fac-
tor for developing MCI or dementia [15]. However, the mechanism of this effect is
unclear (i.e., hypoxia, disrupted sleep, comorbidities such as cerebrovascular dis-
ease). Idiopathic RBD is also associated with cognitive impairment, characterized
by reduced performance in attention, executive functions, learning, and visuospatial
tasks and increased risk for MCI. This is almost certainly due to the fact that RBD
is a well-recognized risk factor for dementia with Lewy bodies and PD [16, 17].
Moreover, alterations in the sleepwake cycle (insomnia, EDS, WASO, and poor
sleep quality and duration) may be associated with altered cognitive performance
and cognitive decline in the elderly population, although this relationship remains
controversial [1821].
All of these sleep abnormalities are associated with PD, which is characterized
by widespread degeneration of the neurons of the reticular activating system and the
diverse brain stem structures involved in sleep regulation [9, 10]. This suggests that
in pathological aging such as PD: (1) sleep alterations may impact the cerebral
plasticity-related mechanisms underlying certain cognitive functions; and/or (2)
sleep alterations may indicate more widespread and severe neurodegeneration, par-
ticularly in the brain stem, the thalamus and the cortex (thalamo-cortical loop),
which indirectly impacts neurobiological systems related to cognitive functions.
14.4 Sleep and Cognition in Parkinsons Disease
As reported in other chapters of this book, sleep complaints and sleep disorders are
major non-motor symptoms in PD [9, 10]. The most frequently reported sleep dis-
orders in PD are RBD, EDS, SDB, and insomnia. What are the relationships between
these disorders and cognition in PD?
14.4.1 Rapid-Eye-Movement Sleep Behavior Disorder
In studies using polysomnography (PSG) for diagnosis, RBD affects approximately

3045 % of patients with PD [22, 23]. RBD has been related to disturbances of the
brain stem neural networks underlying REM sleep muscle atonia and motor control
[24]. These brain stem regions are known to be disrupted in PD [24]. Given that
RBD affects only a subgroup of patients with PD, those with concomitant RBD
could have a more severe form of PD characterized by more diffuse neurodegenera-
tion, leading to functional impairments such as cognitive deficits.
From 2006 to 2009, some studies reported decreased cognitive performance in
patients with PD with RBD. Sinforiani et al. showed altered executive functions
performance in patients with PD with clinical RBD compared to patients with PD
without RBD [25]. Compared to normative values, patients with PD without RBD
did not present any cognitive deficits. A 2-year follow-up of these cohorts confirmed
executive dysfunction in patients with PD with RBD, particularly in older individu-

als at risk for more rapid progression of motor symptoms and hallucinations [26].
Moreover, patients with PD without RBD remained cognitively intact. In 2007, our
group performed complete neuropsychological assessments to compare two groups
of patients with PD, with and without RBD, to a group of healthy subjects [27]. We
found decreased performance on cognitive tests measuring attention, executive func-
tions, verbal learning and memory, and visuospatial abilities in patients with PD with
RBD. patients with PD without RBD showed equivalent performance to healthy sub-
jects on all cognitive measures. These results were confirmed in a larger sample drawn
from the same cohort in 2009 [28], showing additionally that the presence of MCI in
PD is strongly related to RBD. Thus, MCI was present in 73 % of patients with PD
with RBD compared to 11 % of patients with PD without RBD and 8 % of controls
[28]. Some subsequent studies have confirmed the association between RBD and cog-
nitive dysfunction in PD [2932] whereas others have not [3338]. Two recent studies
assessed cognition in treatment-nave newly diagnosed patients with PD [39, 40]. The
first reported equivalent cognitive performance and MCI frequency in patients with
PD with and without RBD [39]. The second showed no difference in cognitive profile
between patients with PD with and without REM sleep behavior events [40]. These
two studies suggest that PD duration and the use of dopaminergic medication may
modulate cognitive impairment in patients with PD with RBD. Indeed, higher age
and more advanced duration of PD are two well recognized risk factors for cogni-
tive decline in PD [41]. Moreover, although still unclear, dopaminergic medication
seems to modulate cognition in patients with PD but the positive or negative impact
varies according to the type of treatment and concentration used [5]. Note that most
previous studies on the impact of RBD in PD have been cross-sectional with certain
methodological limitations. Many used screening cognitive tests only, which have
poor sensitivity to detect cognitive impairment in PD [31, 34, 36, 38]. Moreover, RBD
diagnostic criteria varied, with some studies using clinical criteria without PSG confir-
mation or nonstandard PSG criteria, which may affect the accuracy of RBD classifica-
tion, falsely reducing differences between groups [25, 26, 3032, 3438, 40]. Others
have not included a healthy control group, which limits the interpretation of the results
[25, 26, 3039]. Furthermore, studies of the highest quality, which used PSG criteria
for RBD and standard cognitive batteries, were performed on relatively small samples
of patients with PD, reducing the statistical power [2729, 33, 39]. Hence, further
longitudinal studies in larger samples are needed, including PSG to confirm RBD, a
healthy control group, and complete neuropsychological assessments, in order to bet-
ter understand the association between RBD and cognition in PD.
The association between RBD and the development of dementia in PD has also
been investigated. Marion et al. reported higher prevalence of clinical RBD in PD
with dementia and faster cognitive decline in PD with RBD [42]. In a prospective
study over a mean 4-year follow-up, we found that 48 % of patients with PD with
RBD at baseline developed dementia, whereas no patients with PD without RBD
converted to dementia [43]. This finding was confirmed by Nomura et al., who
observed faster occurrence of dementia in PD with RBD compared to PD with nor-
mal REM sleep features [44]. Taken together, these studies suggest that RBD in
patients with PD may be associated with more rapid cognitive decline, and that
RBD could be a clinical risk factor for dementia in PD.
Other studies have found functional and structural impairments specific to RBD
in PD, which can explain to some degree the higher risk of cognitive deficits in
patients with PD with RBD. A distinct clinical profile, often associated with the
presence of cognitive impairment in PD, has been identified in patients with PD
with RBD, with autonomic dysfunction, higher incidence of visual hallucinations,
more freezing and falls, a non-tremor dominant subtype, and symmetric disease
[4550]. Other studies have demonstrated abnormalities in quantitative waking
EEG and event-related potentials, mainly in posterior cortical areas, in patients with
PD with RBD [51, 52]. Another study using positron emission tomography ([11C]
methylpiperidyl propionate acetylcholinesterase) reported relative neocortical, lim-
bic cortical, and thalamic cholinergic denervation in patients with PD with clinical
RBD [53]. A further study using diffusion tensor imaging and voxel-based mor-
phometry (VBM) identified subtle (in uncorrected analyses) reductions in cortical
gray matter volume (parietal and temporal lobes) and widespread white matter
microstructural abnormalities in patients with PD with clinical RBD [54]. Taken
together, these studies provide functional and anatomical support, which could
explain the higher prevalence of cognitive impairment in PD associated with RBD.
14.4.2 Sleep-Disordered Breathing and Excessive Daytime

Sleepiness
Unlike the relatively clear relationship with RBD, the role of SDB in cognition in
PD is much less clear. SDB is commonly present in PD, with prevalence varying
from 22 to 66 % depending on the apnea-hypopnea index (AHI) cut-off used [55].
However, studies with control subjects have not found increased SDB prevalence in
PD compared to healthy age-matched individuals [55]. Despite the high incidence
of SDB in PD and its deleterious effects on health reported in the general popula-
tion, the impact of SDB on motor and non-motor symptoms in PD appears to be
minimal. Only a few studies have investigated the impact of SDB on cognition in
PD. Cochen de Cock et al. found no significant effect of sleep apnea on nocturia,
sleepiness, depression, cardiovascular events, or cognitive impairment in PD [56].
However, they used the standardized mini-mental state examination to measure cog-
nitive functioning, a screening test that is insensitive to cognitive impairment in PD
[57]. Our group recently studied 92 patients with PD who underwent PSG, an exten-
sive neurological exam, including several non-motor measures, and a complete neu-
ropsychological assessment [58]. The prevalence of SDB in our cohort, depending
on the AHI cut-off, was 11 % (with AHI >15), 21 % (AHI >10), and 33 % (AHI >5).
We found no significant differences in motor and non-motor symptoms between
apneic and non-apneic patients with PD, regardless of the AHI cut-off. Of note, the
two PD groups did not differ on any cognitive measures (attention, executive func-
tions, learning and memory, or visuospatial abilities) or in the proportion of patients
with MCI. These results confirm the absence of a strong relationship between SDB
and most major outcomes in PD, including cognitive decline.
EDS is another frequent non-motor symptom in PD. Although EDS has been
related to cognitive dysfunction in PD [59, 60], several factors may confound this
relationship, and other studies have not confirmed it [6163]. In fact, only a few
studies have formally examined the relationship between EDS and cognition in
PD. Gjerstad et al. reported that patients with PD with EDS more often had demen-
tia at baseline and showed faster progression of cognitive impairment and disability
after a 4-year follow-up [64]. In a subsequent 4-year follow-up on their cohort,
the association between cognitive impairment and EDS was confirmed by univari-
ate analysis, but not by multivariate analysis [65]. In another study, Compta et al.
reported no significant difference on the Epworth sleepiness scale (ESS) scores
between patients with PD with and without dementia [66]. However, the EDS prev-
alence (ESS > 10) was higher in patients with PD with dementia. Goldman et al.
compared EDS symptoms between cognitively intact patients with PD, patients
with PD with MCI, and patients with PD with dementia [37]. They found higher
ESS scores and higher EDS prevalence in patients with PD with dementia compared
to the two other groups. ESS scores correlated with several cognitive measures.
However, patients with PD with and without MCI were equivalent on the ESS. In
non-demented patients with PD, a significant correlation between EDS and slowed
processing speed has been reported, with no differences in other cognitive measures
[30]. We recently compared daytime sleepiness symptom severity in 16 patients with
PD with MCI, 20 cognitively intact patients with PD, and 36 healthy subjects [67].
All groups were equivalent on sociodemographic variables, and the two PD groups
did not differ on clinical signs of PD, including dopaminergic medication dosage.
We found no difference on the ESS scores between patients with PD with MCI
(mean = 9.60) and patients with PD with normal cognition (mean = 9.55). However,
the two PD groups scored higher on the ESS than healthy subjects (mean = 6.42). Of
note, EDS in PD may be heterogeneous: in early stages, medication side effects may
play a prominent role, whereas EDS becomes less dependent on medication doses
as the disease progresses (i.e., it is mostly a primary disease manifestation). Using
structural neuroimaging and VBM, Kato et al. found that patients with PD with
EDS had marked gray matter atrophy in several brain regions compared to patients
with PD without EDS and healthy subjects, whereas patients with PD without EDS
showed no gray matter atrophy compared to controls [68]. Taken together, these
results suggest that in PD: (1) EDS is a common feature regardless of the presence
of cognitive impairment; (2) the severity of EDS increases with cognitive decline
and the symptoms are more manifest in patients with dementia; and (3) EDS is
associated with more severe neurodegeneration. This suggests that EDS may be a
risk factor for dementia in PD, although this hypothesis needs further validation.
14.4.3 Insomnia, Sleep Quality, and Alterations in Sleep

Architecture
Insomnia, characterized by difficulty maintaining sleep, and reduced sleep quality

are major complaints in PD, affecting the majority of patients [9, 10]. Here again,
the association between these symptoms and cognition in PD remains unclear. Erro
et al. compared sleep non-motor symptoms between patients with PD with and
without cognitive impairment [32]. They found a relationship between sleep non-
motor symptoms and cognitive dysfunctions, where insomnia was associated with
lower scores on several cognitive tests. Lee et al. also found sleep complaints on the
Neuropsychiatric Inventory in 54 % of patients with PD with dementia [69].
However, no patients with PD without dementia or healthy subjects were included
as controls. We recently compared insomnia severity complaints on the Insomnia
Severity Index (ISI) between patients with PD with MCI, cognitively intact patients
with PD, and healthy subjects [67]. We found no difference on the ISI scores
between patients with PD with MCI (mean = 9.63) and patients with PD with nor-
mal cognition (mean = 10.95). However, the two PD groups scored higher on the ISI
than healthy subjects (mean = 5.15), suggesting that insomnia is a core characteristic
of PD, independent of cognitive status. Other groups found no association between
either insomnia or sleep quality and cognition in PD [37, 63, 70].
Very few studies have investigated the relationships between sleep architecture
parameters and cognition in PD. Stavitsky et al. performed a complete neuropsy-
chological assessment and used actigraphy to record sleep in non-demented patients
with PD and controls. They found that poorer attention and executive functioning
was correlated to poor sleep quality in both groups. Attention and executive func-
tions performance was predicted by sleep efficiency in patients with PD, whereas
memory and psychomotor function were not [71]. Recently, we prospectively fol-
lowed 68 patients with PD and 47 healthy individuals [72]. All participants under-
went a comprehensive neuropsychological assessment and PSG recordings in the
laboratory. Slow waves (>75 V and <4 Hz) and sleep spindles (1215 Hz) were
automatically detected by artifact-free non-REM sleep electroencephalography. At
follow-up (mean: 4.5 years later), 18 patients with PD developed dementia and 50
remained dementia-free. At baseline, sleep spindle density and amplitude were
reduced in patients with PD who converted to dementia compared to both healthy
controls and patients who remained dementia-free, mostly in posterior cortical
regions. Dementia-free patients with PD were intermediate between control sub-
jects and patients with dementia, with lower baseline sleep spindle density in all
cortical areas compared to healthy subjects. Although slow-wave amplitude was
lower in patients with PD compared to controls, no difference was observed between
those who developed or did not develop dementia. These results suggest that sleep
spindle activity are particularly impaired in patients with PD who developed demen-
tia, with a more posterior topographical pattern. Thus, sleep spindle alterations are
associated with later development of dementia in patients with PD, and conse-
quently may serve as an additional marker of cognitive decline in these patients.
Preliminary research also suggests that sleep improves cognitive performance in
PD. Scullin et al. found that performance on a simple working memory task (back-
ward digit span) improved following a nocturnal sleep interval in patients with PD on
dopaminergic medication, but not in medication-free patients [73]. The amount of that
patients with PD on dopaminergic medication obtained between training sessions was
correlated with improvement on the working memory task. Although their results sug-
gest that improved sleep quality may enhance working memory capacity in patients
with PD, further studies are needed to better understand the underlying mechanisms
and to generalize this observation to other cognitive domains that are affected in PD.
14.5 Conclusions and Future Directions
In conclusion, good-quality sleep is key for maintaining neurological health. The

degenerative process of PD causes numerous sleep abnormalities. Three major
sleep outcomes, RBD, EDS, and sleep spindle alterations, are related to decreased
cognition in PD, whereas insomnia and SDB have modest or no association.
Although much of this relationship is correlative and related to underlying degen-
eration of sleepwake structures, some cognitive deficits could also be caused by
sleep disturbances. Further research into the associations between sleep and cogni-
tion in PD could provide insight into the mechanisms and heterogeneity of the dis-
ease, identify new potential risk factors for or markers of cognitive decline, and
ultimately enable improving the cognition of patients affected by PD.
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Impact of Surgical Therapies on Sleep
and Alertness in Parkinsons Disease 15
Amy W. Amara and Harrison C. Walker
Contents
15.1 Historical Overview of Surgical Therapies for Parkinsons Disease ............................ 196
15.2 Deep Brain Stimulation of the Subthalamic Nucleus ................................................... 197
15.3 Deep Brain Stimulation of the Globus Pallidus Internal Segment................................ 199
15.4 Deep Brain Stimulation of the Ventral Intermediate Nucleus
of the Thalamus (VIM) ................................................................................................. 200
15.5 Deep Brain Stimulation of the Pedunculopontine Nucleus (PPN) ............................... 200
15.6 Lesional Therapies for Parkinsons Disease ................................................................. 202
15.7 Other Surgical Therapies for Parkinsons Disease ........................................................ 203
Conclusion ............................................................................................................................... 204
References ................................................................................................................................ 204
Abstract
Surgical therapies for Parkinsons disease (PD) play an increasingly important
role in the treatment of motor symptoms that are refractory to medical man-
agement. These therapies include deep brain stimulation, lesional/ablation sur-
gery of brain structures, and placement of an intrajejunal tube to administer
continuous drug delivery of levodopa/carbidopa intestinal gel (LCIG). Sleep
dysfunction and excessive daytime sleepiness are very common among patients
with Parkinsons disease and negatively impact quality of life. For this reason,
A.W. Amara (*)

Division of Movement Disorders, Department of Neurology,
UAB Sleep/Wake Disorders Center,
University of Alabama at Birmingham, Birmingham, AL, USA
H.C. Walker
Division of Movement Disorders, Department of Neurology,
University of Alabama at Birmingham, Birmingham, AL, USA

196 A.W. Amara and H.C. Walker
understanding the impact of surgical therapies on these symptoms can provide

additional insights into strategies for optimizing outcomes and provide a better
understanding of the pathophysiology of sleep disorders in PD patients. In this
chapter, we review the available data on the effects of surgical therapies on sleep
architecture, sleep quality, and daytime vigilance and discuss the need for further
study to fully understand the mechanisms underlying changes in sleep following
surgical intervention.
15.1 Historical Overview of Surgical Therapies

for Parkinsons Disease
Surgical therapy for movement disorders was introduced as early as 1912 with bilat-
eral cervical rhizotomy for treatment of a patient with Parkinsons disease (PD) in
France. Later, other groups performed surgical lesioning of the motor, premotor,
and supplementary motor cortices or the corticospinal tract (for an excellent review,
see [1]). Lesions of the basal ganglia for Parkinsonism and tremor were explored by
Dr. Russell Myers (University of Iowa) and others in the 1940s and 1950s through
open surgical approaches excising the head of the caudate, anterior limb of internal
capsule, pallidofugal fibers, or globus pallidus interna/ansa lenticularis. Other inter-
ventions included ligation of the anterior choroidal artery by Dr. Irving S. Cooper in
1953. These procedures resulted in some relief of Parkinsonian symptoms, but at
high risk of mortality and morbidity. As stereotactic techniques advanced, palli-
dotomy and thalamotomy were introduced and were used frequently prior to the
advent of levodopa. The Austrian Ernest Spiegel and his student Henry Wycis at
Temple University pioneered many of these techniques, as did Drs. Cooper in Spain
and Rolf Hassler in Germany. These ablative surgeries gained favor again as some
of the long-term side effects of levodopa were recognized in the 1970s [1].
Stimulation of subcortical brain structures occurred as early as 1947 at Temple
University and in these early days stimulation was used for a range of psychiatric
and neurological disorders (reviewed in [2]). Most often, electrical stimulation was
used to optimize targeting for ultimate ablation surgery. In France, Dr. Alim-Louis
Benabid and colleagues introduced modern deep brain stimulation in 1987, with
stimulation of the ventral intermediate nucleus (VIM) of the thalamus (contralateral
to thalamotomy) for tremor. In 1990, Dr. Hagai Bergman and colleagues demon-
strated that pharmacologic lesioning of the subthalamic nucleus (STN) in MPTP-
treated monkeys improved Parkinsonian symptoms [3], leading to interest in the
STN as a stimulation target. In humans, Dr. Pierre Pollak and colleagues in France
first reported the use of high frequency STN DBS for Parkinsons disease in 1993
[4]. Since that time, the body of literature on the effects of deep brain stimulation
(DBS) on motor and non-motor symptoms of Parkinsons disease has grown expo-
nentially. While VIM DBS is very effective for tremor, stimulation of the STN and
globus pallidus internal segment (GPi) have become the preferred surgical thera-
peutic targets due to their beneficial effects on bradykinesia, rigidity, and motor
15 Impact of Surgical Therapies on Sleep and Alertness in Parkinsons Disease 197
Fig. 15.1 Coronal human Weigert stain (myelin stains black) brain slice with schematic depiction
of common anatomic structures targeted for movement disorders surgical therapy, including the
subthalamic nucleus (STN), globus pallidus interna (GPi), and ventral intermediate thalamus
(VIM). Also depicted are neighboring structures such as the posterior limb of the internal capsule
(IC) and optic tract (OT)
fluctuations in addition to tremor (Fig. 15.1). Potential adverse events of DBS for
treatment of PD include mood changes, cognitive dysfunction, speech changes,
intracranial hemorrhage, and infection [5]. In this chapter, we summarize the motor
effects of surgical therapies for Parkinsons disease and also review the available
data on how these therapies impact sleep and vigilance in this patient population.
15.2 Deep Brain Stimulation of the Subthalamic Nucleus
Deep brain stimulation of the bilateral STN provides greater improvement in motor
symptoms, motor fluctuations, and quality of life than best medical therapy in
patients with PD. However, the surgical therapy does have an increased risk of
adverse events [68]. Unilateral STN DBS also improves motor symptoms and
quality of life in these patients [911]. Because of the growing recognition of the
prevalence and severity of non-motor symptoms of Parkinsons disease, investiga-
tors have increasingly evaluated the effects of STN DBS on sleep and other non-
motor symptoms.
Several studies report changes in sleep quality and sleep architecture following
bilateral STN DBS. Arnulf and colleagues evaluated 10 subjects 36 months after
STN DBS with 2 nights of polysomnography (PSG): 1 night with the stimulator on
and 1 night with the stimulator off [12]. Compared to the night with DBS off, sub-
jects had a 47 % increase in total sleep time and a 36 % increase in sleep efficiency
when DBS was on. In this study, periods of prolonged wakefulness on the DBS-off
night coincided with akinesia and dystonia, which were not present during the
DBS-on night. Iranzo and colleagues evaluated 11 subjects pre-surgically and 6

months following bilateral STN DBS and showed post-surgical improvement in
subjective sleep quality [13]. Polysomnography showed increased nocturnal mobil-
ity, fewer arousals, and an increase in the longest period of uninterrupted sleep. In
this study, however, there was no improvement in sleep efficiency and no significant
difference in other measures of sleep architecture. Monaca et al. studied 10 subjects
with PSG pre-surgically and 3 months after bilateral STN DBS (1 night with DBS
on and 1 night with DBS off) [14]. Compared to their pre-surgical evaluation, sub-
jects reported improved sleep quality following STN DBS and post-surgical PSG
showed increased sleep duration and sleep efficiency but no change in sleep archi-
tecture based on sleep stage percentage. There were no significant differences
between the pre-surgical PSG night and the post-surgical DBS off night; therefore,
the authors concluded that the lesional/subthalamotomy effect associated with elec-
trode placement was not sufficient to improve sleep in these subjects [14]. However,
Merlino and colleagues reported that microsubthalamotomy improved both objec-
tive and subjective sleep in 15 subjects who underwent PSG and questionnaire eval-
uation 1 week before and 1 week after STN DBS before the stimulator was turned
on [15]. Cicolin and colleagues investigated polysomnographic changes before and
3 months after bilateral STN DBS in five patients with Parkinsons disease [16].
They found a significant increase in sleep efficiency and a significant reduction in
latency to rapid-eye-movement (REM) sleep. They also reported trends toward
increased total sleep time and time spent in slow wave sleep and REM sleep, but
these did not reach significance. In each of these studies evaluating sleep architec-
ture with PSG, there were no changes in REM Sleep Behavior Disorder or periodic
limb movements of sleep before and after STN DBS [12, 16, 13, 14]. However, a
recent study by Nishida and colleagues found a reduction in REM sleep without
atonia [17]. They evaluated ten subjects (two with unilateral and eight with bilateral
STN DBS) 1 week pre-surgically and 1 week after initial DBS programming. In
addition to improvement in subjective sleep quality, PSG showed reduced wake
after sleep onset, increased time spent in REM, and an increase in normal REM
(atonic REM). Of the four subjects who met criteria for REM without atonia pre-
surgically, three had restoration of REM atonia following surgery.
Additional studies have evaluated subjective sleep quality before and after STN
DBS. Hjort and colleagues evaluated changes in subjective sleep quality using the
Parkinsons disease sleep scale (PDSS) in 10 subjects 1 month before and 3 months
after bilateral STN DBS compared to changes in sleep quality in 10 control subjects
who were on the waiting list for DBS [18]. The subjects who underwent surgery had
a significant improvement in sleep quality post-surgically while the control group
had no significant change in sleep quality over the 4-month evaluation period, and
the STN DBS group had significantly better sleep quality than the control group at
the conclusion of the study. Lyons and colleagues evaluated 89 subjects before and
6 months after bilateral STN DBS and followed 83 of these subjects to 12 months
and 43 of the subjects to 24 months post-operatively with 2 days of patient diaries
at each time point [19]. This analysis showed an improvement in subjective total
sleep time following surgery that persisted at 24 months. There was no change in
daytime sleepiness post-surgically compared to baseline. Zibetti et al. evaluated 36
subjects with the UPDRS part IV at baseline and 12 and 24 months after bilateral
STN DBS and reported an improvement in subjective sleep quality at both time-
points based on item 41 of the questionnaire [20].
Unilateral STN DBS also improves subjective sleep quality. Our group evaluated
53 patients with the Pittsburgh Sleep Quality Index at baseline and 6 months after
unilateral STN DBS and showed a significant improvement in subjective sleep qual-
ity over time [21]. Subjects who underwent right STN DBS had more improvement
in sleep quality than subjects who underwent surgery on the left. Chahine and col-
leagues evaluated 17 subjects (12 with unilateral STN DBS and 5 with bilateral
STN DBS) [22]. A combined analysis of all subjects showed improved subjective
sleep quality and daytime sleepiness 4 weeks post-operatively that was sustained at
6 months. The 6 subjects in this group who had restless legs syndrome pre-
operatively showed subjective improvement in symptoms at 4 weeks and 6 months
compared to baseline.
The cause of the improvement in sleep quality and sleep architecture following
STN DBS is likely multifactorial, related to improvements in PD motor symptoms,
reduction of medications, improved quality of life, and possible stimulation-induced
changes in sleep physiology. Further objective study with polysomnography in
larger groups of subjects may help to further clarify how STN DBS alters sleep.
Despite the multiple reports of improvement in sleep following STN DBS, a
single case report describes onset of severe insomnia following bilateral STN
DBS [23]. The patient had continued right-sided motor symptoms and the left
STN DBS electrode was determined to be positioned in the extreme external and
anterior STN and was therefore repositioned. Following repositioning, the
patients insomnia resolved, with average total sleep time changing from approxi-
mately 4 h per night prior to repositioning to 8 h per night afterwards. The authors
postulate that the malpositioned electrode disrupted inhibitory connections
between the anterior hypothalamus and the upper reticular formation. This report
supports the idea that DBS may directly alter sleep architecture in some
circumstances.
15.3 Deep Brain Stimulation of the Globus Pallidus Internal

Segment
Bilateral DBS of the GPi is also superior to best medical therapy for treatment of
Parkinsons disease based on data from a prospective randomized trial [6].
Stimulation at this target is reported to be comparable to STN DBS in terms of
motor outcomes up to 36 months post-operatively [24, 25]. Although some studies
have shown more motor improvement and more adverse events in subjects undergo-
ing STN versus GPi DBS, as reviewed: [26], a recent randomized study showed
greater motor improvement with STN DBS with no difference between the targets
in a composite outcome of cognitive and behavioral function [27]. While STN DBS
was the preferred target for Parkinsons disease surgical therapy for a number of
years, these findings have renewed interest in the use of GPi as a target for treatment
of patients with moderate to advanced PD.
Despite the increased interest in GPi DBS for PD, relatively few studies have
evaluated the effects of this stimulation site on sleep. One study reported pre- and
post-operative quality of life assessments (Parkinsons Disease Questionnaire-39)
in 11 subjects who underwent GPi DBS (7 bilateral and 4 unilateral). In this study,
6 of 11 subjects reported an improvement in daytime sleepiness following GPi DBS
[28]. Volkmann and colleagues evaluated 20 subjects before surgery and at 6 and 36
months following bilateral GPi DBS with the Sickness Impact Profile as a measure
of health related quality of life [29]. They reported a significant improvement in the
Sleep and Rest subdomain of the scale at 6 months post-operatively that was not
sustained at 36 months. To our knowledge, there are no published reports of poly-
somnographic outcomes in PD patients with GPi DBS. Future studies evaluating
PSG and subjective sleep quality in these patients is important, particularly consid-
ering the increasing use of this therapy in PD patients.
15.4 Deep Brain Stimulation of the Ventral Intermediate

Nucleus of the Thalamus (VIM)
DBS of the VIM was explored as an alternative to thalamotomy for the treatment of
tremor in patients with Parkinsons disease. While it is effective for tremor control
in patients with PD and essential tremor, VIM DBS does not provide marked
improvement in bradykinesia, rigidity, or dyskinesias in Parkinsons disease [30].
Therefore, with the exception of select patients with tremor predominant Parkinsons
disease, thalamic stimulation has largely been abandoned in favor of use of STN or
GPi DBS. The proximity of the VIM to the reticular nucleus of the thalamus, where
sleep spindles are generated, prompted Arnulf and colleagues to investigate for
changes in sleep architecture following VIM DBS in six subjects (four with
Parkinsons disease and two with essential tremor) [31]. They evaluated subjects
36 months post-operatively with 2 nights of PSG, 1 night with the stimulator at
therapeutic settings and 1 night with the stimulator off. At high frequency stimula-
tion (135185 Hz), there were no changes in sleep architecture or sleep spindles
compared to DBS off. In an unsuccessful attempt to induce sleep, the authors also
evaluated subjects while awake during low frequency VIM stimulation (1 s bursts of
15 Hz or 30 s trains of 5 Hz) [31].
15.5 Deep Brain Stimulation of the Pedunculopontine

Nucleus (PPN)
Due to its role in locomotion, the PPN has been explored as a DBS target in
patients with Parkinsons disease who have significant gait disorder refractory to
other therapies. Initial studies demonstrated that stereotactic placement of PPN
electrodes is safe and that there may be some improvement in gait with bilateral
PPN stimulation [32, 33]. Subsequent studies have shown mixed results and have
not definitively demonstrated improvement in motor outcomes from stimulation
of this novel target. Stefani and colleagues reported motor outcomes in six
subjects with bilateral STN and PPN DBS [34], and simultaneous stimulation of
PPN and STN produced some degree of additive motor improvement, but was not
significantly better than STN DBS alone. Because PPN stimulation was not supe-
rior to STN DBS in this group of patients, the authors recommend PPN DBS only
as a supplemental therapy to STN DBS [34]. In contrast, Moro and colleagues
evaluated six subjects with unilateral PPN DBS and found no significant change
in the UPDRS part III. Subjects did report a subjective improvement in falls in the
open label phase of the study [35]. Ferraye and colleagues studied six subjects
who had previously undergone bilateral STN DBS and evaluated the effects of
bilateral PPN DBS. They reported a reduction in falls related to freezing in the
off-medication state without significant changes in other gait measures [36]. Khan
and colleagues studied seven subjects who underwent bilateral caudal zona incerta
(cZI) and PPN DBS with evaluations prior to surgery and 1 year post-operatively
[37]. In the on medication state, PPN DBS alone, cZI stimulation alone, or simul-
taneous stimulation of both targets resulted in statistically significant improve-
ment in motor outcomes compared to baseline, and the combination stimulation
was significantly more effective than either target alone [37]. In summary, pub-
lished reports suggest that PPN DBS may improve balance when used in combi-
nation with STN stimulation in the on medication state. However, PPN studies to
date have evaluated small numbers of subjects with different surgical approaches
(unilateral versus bilateral) and in the context of parallel stimulation at other tar-
gets. Further study is needed to determine the benefit of this therapy for gait dys-
function in PD.
In addition to its function in locomotion, the PPN plays a critical role in regula-
tion of behavioral state and sleep. For this reason, several groups have investigated
the impact of PPN DBS on sleep in patients with PD. Romigi and colleagues
reported polysomnography in one subject before surgery and after bilateral STN
and PPN DBS [38]. PSG was performed post-operatively with STN DBS alone and
PPN DBS alone. STN stimulation improved sleep efficiency compared to the pre-
surgical PSG, but did not alter REM sleep. In contrast, PPN DBS increased the
percentage of REM sleep and reduced REM latency. Sleep questionnaires from this
patient and four others with bilateral PPN and STN DBS [39] in multiple conditions
(PPN and STN on; PPN off and STN on; and PPN-cyclic on (on at night) and STN
on) were evaluated at 3 months and 1 year post-operatively. At 3 months, the sub-
jects had improvement in sleep quality based on the Parkinsons disease sleep scale
(PDSS) in all three stimulation conditions. Evaluation of individual items from the
PDSS suggested more improvement in insomnia when PPN stimulation (either con-
tinuous or cyclic) compared to STN stimulation alone. PPN cyclic on also caused
further improvement in nocturnal restlessness and daytime dozing compared to the
other two stimulation conditions. At 1-year follow-up, the improvement in sleep
quality was maintained and subjects also had improvement in daytime sleepiness as
measured by the Epworth sleepiness scale [39]. The authors also reported PSG
recordings in two of these five subjects (one previously reported [38]) and found
reduced REM latency and increase REM sleep [39].
Lim and colleagues investigated the effect of unilateral PPN DBS on sleep in five
subjects (three with Parkinsons disease and two with progressive supranuclear
palsy) [40]. Polysomnography was performed with PPN DBS on during the first
night and with DBS off during the second night. PPN DBS resulted in higher per-
centage of REM sleep (14 %) compared to DBS off (8 %). REM time was also
higher during the PPN DBS on night. PPN DBS did not induce any significant
change in total sleep time, non-REM sleep, or wake after sleep onset. Interestingly,
two of the five subjects had REM Sleep Behavior Disorder, and REM without atonia
was unchanged with PPN DBS on versus off in these subjects [40].
In addition to these reports on the nocturnal effects of PPN DBS on sleep, another
group has observed profound effects of PPN DBS on wake-time vigilance. Arnulf
and colleagues initiated an investigation using a cross-over, double-blind design
after observing that two patients with STN and PPN DBS fell asleep during routine
programming of the PPN stimulator when high-frequency stimulation was applied
[41]. During the daytime, the two subjects were evaluated with polysomnography
for at least 5 min at each parameter: stimulation off, right, left, or bilateral at high
frequency or low frequency with 3-min washout between each setting. At low fre-
quency stimulation bilaterally or on either side, both subjects remained alert, but at
high frequency stimulation, both subjects reported drowsiness and entered non-
REM sleep, predominantly stage N1 and rarely stage N2. Interestingly, in one of the
two subjects, abrupt cessation of low frequency PPN stimulation induced REM
sleep on five different occasions [41].
In summary, DBS of the PPN likely alters arousal and sleep in complex ways and
thus provides a unique opportunity to investigate the effects of stimulation at this
site on sleep architecture. The distinct outcomes from high and low frequency PPN
stimulation observed in these case reports suggests that altering the stimulation pat-
tern in the PPN region can yield markedly different behavioral states. Further inves-
tigation may provide additional clues to the role of the PPN and its connections in
both normal sleep architecture and sleep dysfunction in patients with Parkinsons
disease.
15.6 Lesional Therapies for Parkinsons Disease
Deep brain stimulation became preferred over lesional therapies for Parkinsons dis-
ease because it is reversible, adjustable, and less likely to be associated with speech and
bulbar dysfunction when performed bilaterally [42]. Despite this, lesion therapy is still
performed commonly worldwide, and there is new interest in focused ultrasound for
movement disorders [43]. In this context, review of the available literature on the
effects of lesion therapies on sleep and vigilance may provide insights into sleep dys-
function in this patient population. An early case report documented induction of pro-
found insomnia following bilateral thalamotomy for Parkinsons disease. The subject
had baseline insomnia that was relieved by initial left thalamotomy. However, 2 years
later following subsequent right thalamotomy, he developed severe insomnia and was
observed in the hospital with no sleep for more than 96 h. Although he eventually was
able to sleep again, he continued to have difficulty with insomnia after discharge [44].
A more recent case report documented a similar outcome following simultaneous left
VIM DBS and right VIM radiofrequency ablation. The patient developed severe
insomnia following surgery that was not relieved by turning DBS off or by adjusting
DBS parameters. The sleep changes were therefore attributed to lesion effects. The
patient reported improvement in insomnia over time, but PSG recording 16 months
post-operatively showed continued poor sleep efficiency, prolonged sleep latency,
reduced sleep time, and abnormal sleep architecture [45]. Interestingly, the report by
Bricolo also mentions anecdotal experience by the author that other patients undergo-
ing bilateral thalamotomy often experience sleep disruption in the immediate post-
operative period, but that these symptoms usually resolve quickly [44].
Roth and colleagues investigated the effects of bilateral stereotactic pallido-thalamic
tractotomy in three subjects with Parkinsons disease with PSG before and after the
surgery. The patients had a significant increase in total sleep time and sleep efficiency
and a reduction in latency to REM sleep [46]. The authors propose that the alterations
in sleep could be related to improved motor symptoms or post-surgical reduction of
medications. Favre and colleagues reported subjective changes in motor and non-motor
symptoms based on questionnaires before and after unilateral or simultaneous bilateral
pallidotomy in 44 patients [47]. One of the parameters evaluated was sleep, with 59 %
of patients reporting improvement in sleep following unilateral pallidotomy and 47 %
of patients reporting improvement in sleep following simultaneous bilateral pallidot-
omy. It is unclear if these changes were related to improvement in motor symptoms,
altered medications, or lesional effects on sleep architecture.
15.7 Other Surgical Therapies for Parkinsons Disease
In addition to DBS and lesional therapies for Parkinsons disease, another surgical
therapy includes placement of an intrajejunal tube to administer continuous drug
delivery with levodopa/carbidopa intestinal gel (LCIG) [48]. In addition to its influ-
ence on motor symptoms, the effects of this therapy on sleep quality and other non-
motor symptoms have also been investigated. In an open label assessment, 22
subjects who received levodopa/carbidopa intrajejunal infusion were evaluated at
baseline and after 6 months with the non-motor symptoms scale (NMSS) as the
primary outcome measure. Additionally, 13 subjects were evaluated with the
Parkinsons disease sleep scale (PDSS). The results showed a significant improve-
ment in several domains of NMSS, including the sleep/fatigue domain and a signifi-
cant improvement in the PDSS [49]. In another open label evaluation, 14 subjects
were evaluated with the NMSS and the PDSS at baseline and at an average of 24
months after beginning therapy with LCIG. This study also showed a significant
improvement in PDSS and a trend toward improvement in the sleep/fatigue domain
of the NMSS [50]. Zibetti and colleagues report an additional open label evaluation
of 12 subjects at baseline and 24 months after initiation of LCIG [51]. They report
a 30 % improvement in subjective sleep symptoms and a 31 % improvement in
subjective daytime sleepiness. The improvement in subjective sleep quality in these
three studies is likely multifactorial, related to improved motor symptoms, altered
dopaminergic medications, placebo effect, or other causes. As more patients
undergo this therapy, controlled trials with more subjects and with objective PSG
evaluation of sleep architecture should help to further elucidate these changes.
Conclusion
Surgical therapies play a key role in the treatment of motor symptoms of
Parkinsons disease and provide a unique opportunity to investigate the impact of
these therapies on sleep dysfunction in PD patients. To date, most studies have
been case reports and small case series. Further objective study in larger patient
samples with controls and blinding are required to gain a better understanding of
the impact of these therapies on sleep [52]. Additionally, more mechanistic stud-
ies are needed to determine the etiology of sleep improvement. The change in
sleep is likely multifactorial, related to increased nocturnal mobility due to motor
improvement, medication adjustment, changes in mood, placebo effect, or direct
effects of the surgical therapy on sleep architecture. Many questions remain to be
answered [52]: Is there an influence of laterality of DBS or lesional therapy on
sleep outcomes? Are there effects from stimulation of other structures in ana-
tomical proximity to the DBS target? Are there other stimulation settings that are
more beneficial for sleep than the conventional settings? Surgical therapies are
an important treatment option for PD, and more knowledge about how these
therapies alter wakefulness and sleep will provide information to tailor therapies
that optimize outcomes for individual patients.
Acknowledgments This work was supported in part by the Francis and Ingeborg Heide
Schumann Fellowship in Parkinsons Disease Research (AA) and the Sartain Lanier Family
Foundation (HW), and grant funding from the NIH NINDS K23NS080912 (AW) and NIH NINDS
K23NS067053 (HW), and the American Sleep Medicine Foundation (AW). We would also like to
sincerely thank Anthony Nicholas for contributing the content of Fig. 15.1.
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Sleep Disorders in Atypical
Parkinsonisms 16
Alex Iranzo
Contents
16.1 Dementia with Lewy Bodies (DLB). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
16.1.1 Studies Evaluating Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
16.1.2 REM Sleep Behavior Disorder (RBD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
16.2 Multiple System Atrophy (MSA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
16.2.1 Sleep Fragmentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
16.2.2 Excessive Daytime Sleepiness (EDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
16.2.3 Restless Legs Syndrome (RLS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
16.2.4 Periodic Leg Movements in Sleep (PLMS) . . . . . . . . . . . . . . . . . . . . . . . . . . 215
16.2.5 REM Sleep Behavior Disorder (RBD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
16.2.6 Sleep Disordered Breathing and Stridor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
16.3 Progressive Supranuclear Palsy (PSP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Abstract
Atypical parkinsonism includes dementia with Lewy bodies (DLB), multiple
system atrophy (MSA), and progressive supranuclear palsy (PSP). In DLB, insom-
nia, circadian rhythm changes, frequent daytime napping, confusional awakenings,
and REM sleep behavior disorder (RBD) are frequent. Severity of dementia is
linked to abnormal sleep architecture even in the forms of ambiguous sleep and
status dissociatus. In DLB, RBD may be the presenting symptom and is considered
a red flag of the disease. About 70 % of the MSA patients report sleep problems
such as insufficient and fragmented sleep, hypersomnia, RBD, and stridor. RBD
A. Iranzo, MD, PhD

Neurology Service, Hospital Clnic de Barcelona
and Institut dInvestigaci Biomdiques August Pi i Sunyer (IDIBAPS),
C/Villarroel 170, Barcelona 08036, Spain

210 A. Iranzo
and stridor are considered red flags of MSA and may be their initial manifestation.
Death during sleep is not infrequent in MSA subjects with untreated stridor. Nasal
continuous positive airway pressure and tracheostomy abolish stridor in MSA. PSP
patients complain of insomnia and have reduced and abnormal sleep architecture
on polysomnography. RBD occurs in PSP but is much less frequent than in DLB
and MSA. The cause of sleep disorders in atypical parkinsonisms are multifactorial
and they include the degenerative process itself; parkinsonism leading to immobil-
ity; coexistent disturbances such as depression, dementia, and anxiety; and the
effect of some medications. Treatment should be individualized.
Atypical parkinsonisms are neurological conditions where parkinsonism (defined

as the combination of bradykinesia, rigidity, and tremor) is present with the
exception of idiopathic Parkinsons disease (PD). These conditions include DLB,
MSA, PSP, corticobasal degeneration, and others. Besides parkinsonism, other
symptoms occur such as ataxia, oculomotor abnormalities, dysautonomic features,
dementia, and sleep problems. Disorders of sleep in atypical parkinsonisms include
insomnia, excessive daytime sleepiness (EDS), RBD, restless legs syndrome (RLS),
and sleep-disordered breathing (SDB). This chapter reviews the sleep disorders
occurring in DLB, MSA, and PSP, as three most common of neurodegenerative
atypical parkinsonian disorders (Tables 16.1 and 16.2).
Table 16.1 Main sleep 1. Dementia with Lewy bodies

disturbances in the atypical
1.1. Insomnia
parkinsonisms dementia with
Lewy bodies, multiple system 1.2. Circadian rhythmic dysregulation
atrophy, and progressive 1.3. Excessive daytime sleepiness
supranuclear palsy 1.4. Confusional awakenings
1.5. Nocturnal wandering
1.6. Ambiguous sleep and status dissociatus
1.7. Periodic leg movements in sleep
1.8. REM sleep behavior disorder
2. Multiple system atrophy
2.1. Insomnia
2.2. Excessive daytime sleepiness
2.3. Periodic and aperiodic limb movements in non-REM
sleep
2.4. REM sleep behavior disorder
2.5. Central hypoventilation
2.6. Central sleep apnea
2.7. Obstructive sleep apnea
2.8. Stridor due to vocal cord obstruction at the larynx
3. Progressive supranuclear palsy
3.1. Insomnia
3.2. Subclinical REM sleep without atonia
3.3. Mild form of REM sleep behavior disorder
16 Sleep Disorders in Atypical Parkinsonisms 211
Table 16.2 Main sleep 1. Corticobasal degeneration

disturbances in other atypical
1.1. Insomnia
parkinsonisms
1.2. Anecdotal descriptions of REM sleep behavior disorder
2. Autosomal dominant spinocerebellar ataxias
2.1. Restless legs syndrome (SCA 3 and less frequently in
SCA 1, SCA 2, and SCA 6)
2.2. Periodic leg movements in sleep (SCA 1,2,3, and 6)
2.3. Subclinical REM sleep without atonia (SCA 2)
2.4. REM sleep behavior disorder (SCA 3 and not in SCA 1
and in SCA 2)
2.5. Anecdotal descriptions of stridor due to vocal cord
abductor paralysis in SCA 3
3. Huntington disease
3.1. Insomnia
3.2. Circadian rhythmic dysregulation
3.3. Excessive daytime sleepiness
3.4. Mild form of restless legs syndrome
3.5. Subclinical periodic leg movements in sleep
3.6. Mild form of REM sleep behavior disorder
16.1 Dementia with Lewy Bodies (DLB)
DLB is the second most common cause of neurodegenerative dementia after

Alzheimers disease (AD). It is characterized by parkinsonism, recurrent visual
hallucinations, and fluctuations in cognition and alertness. DLB is diagnosed if
dementia precedes or appears within 1 year before onset of parkinsonism.
Neuronal loss and Lewy bodies are found in the brainstem, limbic system, and
neocortex [1].
16.1.1 Studies Evaluating Sleep Disorders
Overall, insomnia, circadian rhythm disorder with early awakening, EDS due to
frequent napping, nocturnal hallucinations, and confusional nocturnal wandering
are frequent. In contrast, SDB and RLS seem to be no more common than in the
general population of similar age. RBD is very common and may antedate the onset
of dementia by several years. Detection of RBD in a patient with dementia point
toward DLB because this parasomnia is rare in other forms of dementia including
AD, frontotemporal dementia, and PSP.
In a large multicenter study, Bliwise et al. [2] compared nocturnal sleep disturbance
between 339 patients with DLB and 4,192 with AD. Sleep problems were estimated
by the informant report through the Neuropsychiatric Inventory Questionnaire
(NPI-Q) item Does the patient awaken you at night, rise too early in the morning,
or takes excessive naps during the day? Nocturnal sleep disturbance was more
frequent in DLB (63 %) than in AD (27 %) and was not linked to more advanced
disease, depressive symptoms, apathy, hallucinations, delusions, or agitation.
212 A. Iranzo
In a retrospective study, Pao et al. [3] reviewed the polysomnographic (PSG)

findings of 78 DLB patients (71 male, mean age 71 years) with sleep-related
complaints. Seventy-five (96 %) patients had histories of dream-enactment behav-
iors with 65 (83 %) showing confirmation of RBD during PSG. The remaining 13
subjects did not attain any REM sleep, and hence RBD could not be confirmed by
PSG. Mean respiratory disturbance index (RDI, number of apneas and hypopneas
per hour of sleep) was 12, and this was greater than 5 in 60 % and greater than
10 in 36 %. The mean periodic leg movements in sleep (PLMS) index (number of
PLMS per hour of sleep) associated with arousals was 6. Sleep efficiency was less
than 80 % in 72 % of the subjects, and about 75 % of the sample had isolated
arousals. Among the six patients who underwent multiple sleep latency test
(MSLT) two showed a sleep latency onset of less than 5 min and none showed
REM sleep.
Terzaghi et al. [4] evaluated the clinical and video-PSG findings of 29 consecu-
tive DLB patients. Patients were taking levodopa but no dopamine agonists, benzo-
diazepines, cholinergics, neuroleptics, or antidepressants. Patients were 21 males,
their mean age was 75 years and mean disease duration was 3 years. Eleven (38 %)
patients reported insomnia, 17 (59 %) EDS, 1 (3 %) had RLS, 3 (10 %) nightmares,
23 (79 %) hallucinations at night, 19 (65 %) episodes suggestive of confusional
arousals, and 18 (62 %) episodes suggestive of RBD. Video-PSG showed a mean
sleep efficiency of 55 %, mean RDI of 6, and mean PLMS index of 50. REM sleep
without atonia was found in 46 %, RDI greater than 5 in 35 % and PLMS index
greater than 15 in 61 %. Dissociated or ambiguous sleep was found in six patients
who had severe dementia. Disruptive motor behaviors during sleep were found in
70 % and consisted in RBD in 11 subjects, confusional episodes from NREM sleep
in 7 cases, and arousal-related episodes from REM or NREM sleep mimicking RBD
in 2. Of note, these REM and NREM sleep enactment behaviors have also been
described to occur in PD associated with dementia [5].
16.1.2 REM Sleep Behavior Disorder (RBD)
The most studied sleep disturbance in DLB is RBD. Available data indicate that in
subjects with DLB, RBD is common, may be the first symptom of the disease, is
associated with less AD pathology in the brain, and can be considered a red flag of
the disease. RBD is very rare in AD and other forms of dementia with the exception
of PD associated with dementia. Current diagnostic criteria of DLB consider RBD
as a suggestive feature of the disease because it has been demonstrated to be more
frequent than in other dementing disorders [1]. This statement was initially based
on a single retrospective study involving 37 consecutive patients with dementia plus
RBD [6]. Thirty-four of these patients (92 %) were male. In 35 (96 %) RBD symp-
toms preceded or occurred simultaneously with the cognitive complaints. Of the 37
patients, 23 fulfilled the 1996-consensus criteria for probable DLB (dementia plus
at least two of the following: parkinsonism, visual hallucinations, and fluctuations),
and all fulfilled criteria for possible DLB (dementia plus one of the following:
parkinsonism, visual hallucinations, and fluctuations) [7]. The diagnosis of DLB

was confirmed in the three patients that underwent autopsy and supported the notion
that the combination of dementia and RBD most often reflects DLB. This is in
agreement with neuropathological studies in patients with antemortem diagnosis of
DLB plus RBD showing cell loss and Lewy bodies in the brainstem, limbic system,
and neocortex [8, 9]. In a cohort of 234 autopsy-confirmed dementia patients fol-
lowed longitudinally, a history of definite or probable RBD was present in 76 % of
98 with autopsy confirmed DLB, indicating that RBD is a common feature of
DLB. In contrast, only 6 of the 136 patients without autopsy-confirmed DLB exhib-
ited RBD [9]. Thus, inclusion of RBD improves the diagnostic accuracy of DLB
[9]. Dugger et al. [10] compared the clinical characteristics of 71 DLB patients with
RBD and 19 without RBD. Those with RBD were predominantly male, had shorter
duration of dementia, earlier onset of parkinsonism and visual hallucinations, and
less AD-related pathology on autopsy. In 54 of the 71 (76 %) RBD patients this
parasomnia coincided or developed before dementia onset. This group of patients in
whom RBD developed before cognitive impairment were characterized by earlier
onset of visual hallucinations and parkinsonism, more severe baseline parkinsonism
and shorter duration of dementia.
On the other hand, patients initially diagnosed with idiopathic RBD frequently
are diagnosed with DLB and other synucleinopathies (mainly PD and less fre-
quently MSA) with time. We reported that in a cohort of 44 IRBD subjects, 36
(82 %) were eventually diagnosed with a defined neurodegenerative syndrome: 14
with DLB, 16 with PD, 1 with MSA and 5 with mild cognitive impairment [11]. All
14 subjects diagnosed with DLB were men. In these subjects with DLB, recurrent
visual hallucinations occurred in 13 (93 %), parkinsonism in 11 (79 %), and fluctu-
ating cognition in 9 (65 %). Dementia was preceded by a recognized period of mild
cognitive impairment characterized by executive, visuospatial and memory dys-
function. The median interval between the diagnosis of mild cognitive impairment
and the diagnosis of DLB was 2 years. Median age at DLB diagnosis was 76 years,
median RBD duration at the time of the diagnosis of DLB was 12 years, and the
median interval between diagnosis of RBD with PSG and clinical diagnosis of DLB
was 7 years.
16.2 Multiple System Atrophy (MSA)
MSA is a progressive neurodegenerative disorder characterized by a combination

of parkinsonism, cerebellar syndrome, and autonomic failure [12]. Neuropathology
shows neuronal loss and alpha-synuclein positive glial cytoplasmic inclusions in
many brain structures. About 70 % of the MSA patients, regardless of the parkin-
sonian or cerebellar clinical subtype, report sleep problems. Insufficient and frag-
mented sleep, EDS, RBD, nocturnal stridor, and SDB are common in MSA. RBD
and stridor are considered red flags of the disease and may be initial manifesta-
tion. Death during sleep is not infrequent and may be related to laryngeal
narrowing.
214 A. Iranzo
16.2.1 Sleep Fragmentation
Sleep onset insomnia and interrupted sleep are common complains. PSG studies
have consistently found low sleep efficiency between 40 and 60 %, increased sleep
latency and excessive sleep fragmentation, with relatively long periods of wakeful-
ness throughout the night, sometimes without a clear cause [1322]. However, there
is a small subgroup of patients that report no sleep problems despite PSG shows
dramatic fragmented sleep, severe PLMS and intense RBD. In MSA, many causes
may contribute to sleep fragmentation and these include urinary incontinence, anxi-
ety, depression, PLMS, inability to change body position in the bed because of
parkinsonism, and the use of several medications. Abnormal nighttime sleep
increases with progression of the disease. It is unclear, though, if interrupted sleep
contributes to EDS in MSA.
16.2.2 Excessive Daytime Sleepiness (EDS)
EDS is frequent but in most of the cases is not a major complaint. Many variables
may induce EDS in MSA but studies have not found consistent clues of which are
the most relevant. Moreno-Lpez et al. [21] evaluated EDS in 86 European MSA
subjects (73 with the parkinsonian and 13 with the cerebellar subtypes) with the
Epworth sleepiness scale (ESS). Mean EES score was higher (more indicative of
hypersomnia) in MSA than in healthy subjects (7.72 versus 4.5). EDS (defined as an
ESS greater than 10) was present in 28 % of the patients and in 2 % of the healthy
subjects. EDS was associated with SDB and low sleep efficiency, and not with dis-
ease duration and dopaminergic therapy. Shimohata et al. [22] evaluated EDS in 25
Japanese patients (21 with the cerebellar and 4 with the parkinsonian subtypes) and
found that the mean ESS was 6.2 and that the score was greater than 10 in 24 %.
PSG detected SDB in 96 % and PLMS in 44 % but these variables were not linked
to ESS score. Guo et al. [19] found a mean EES score of 8.2 in a sample of 37 sub-
jects from China. In one small study [23] in which MSLT was performed in five
MSA patients, the sleep latency was normal in four, despite poor nocturnal sleep
quality. Hypocretin neurons have been found to be moderately decreased in the
brain of patients with MSA [24] but hypocretin-1 levels in the cerebrospinal fluid
were normal [23]. Sleep attacks induced by the introduction of levodopa have been
reported in a few MSA patients with the parkinsonian subtype.
16.2.3 Restless Legs Syndrome (RLS)
There are only a few studies addressing whether RLS is common in the backdrop of
MSA and they have shown different results. An optimal strategy would be to study
untreated MSA patients and to exclude other conditions with symptoms that may
resemble RLS. None of the published studies, however, have excluded other forms
of sensory and motor problems that are common in MSA and that may mimic the
symptoms of RLS (e.g., rigidity, stiffness, central pain, dystonia, etc.). Most of
these studies evaluated the presence of RLS in subjects already treated for parkin-
sonism with dopaminergic agents, a therapy that may mask the symptoms of true
RLS. Thus, the prevalence of RLS given in these studies may have been either
underestimated or overestimated. Moreno et al. [21] found RLS in 24 (28 %) of 86
subjects, 23 with the parkinsonian subtype and 1 with the cerebellar subtype, and
RLS was unrelated to the amount of dopaminergic therapy. Other studies reported
RLS in 3 % [20] and 12 % [16, 22] of the patients.
16.2.4 Periodic Leg Movements in Sleep (PLMS)
It is not clear whether PLMS are more frequent in MSA than in the general popula-
tion of similar age. One small study comparing PLMS in untreated ten MSA
patients, ten PD patients, and ten matched controls found an increase in PLMS in
PD only [25]. Compared to controls, MSA patients had more PLMS (mean PLMS
index of 34 versus 14), but the difference did not reach the level of significance.
Overall, PSG studies commonly disclose PLMS in untreated and dopaminergic-
treated patients with MSA, both with the predominantly parkinsonian and cerebel-
lar presentations [15, 19, 20, 22]. Most patients with MSA who experience PLMS
are unaware of these leg movements probably because they are generally not associ-
ated with arousals. Therefore, PLMS in MSA do not appear to be a main contribut-
ing factor for developing sleep fragmentation and EDS. In MSA, it is common to
find aperiodic leg and upper limb movements in non-REM sleep which in some
cases resemble visually those typical jerky and brisk movements seen in RBD dur-
ing REM sleep.
16.2.5 REM Sleep Behavior Disorder (RBD)
A majority of patients with MSA have RBD with a prevalence of 70100 % [13, 15,
20, 2628]. The finding that in MSA brainstem cell loss is consistently widespread
and severe may explain the high prevalence of RBD in this disease. In one study, 21
consecutive MSA patients without sleep behavioral complaints underwent video-
PSG that demonstrated RBD in 19 (90.5 %) [27]. In another study, video-PSG
showed RBD in 35 out of 37 (95 %) consecutive patients [13]. In our experience, all
78 MSA patients who were referred to our sleep center from April 1997 to October
2013 for different reasons (suspected RBD, stridor, or sleep fragmentation) had
RBD on video-PSG. Taken together, we think that in a patient with suspected MSA,
the absence of RBD (particularly if it is formally excluded by video-PSG) should
seriously question the diagnosis of this disease. RBD is currently considered a red
flag for the diagnosis of MSA [12].
Self-awareness of abnormal sleep behaviors and unpleasant dream recall is vari-
able among MSA subjects with RBD. In one study, 27 of 39 (69 %) consecutive
MSA patients with RBD or their relatives reported dream-enacting behaviors.
216 A. Iranzo
Interestingly, most of the 12 patients that did not report dream-enacting behaviors
were sleeping alone at their home [13]. In another study, only 7 of 21 (33 %) MSA
patients with RBD recalled vivid dreams [27]. In our first published case series
comprising 26 consecutive MSA cases with RBD free of psychoactive drugs, 77 %
of the patients were unaware of their abnormal behaviors, which were only noticed
by bed partners. Recall of unpleasant dreams was absent in 35 % of the patients
[26]. Bed partners report that RBD-related movements are faster, stronger, and
smother than during wakefulness [28].
The strong male predominance seen in idiopathic RBD, and in those RBD forms
associated with PD and DLB is much less evident in MSA, where 3361 % of the
patients are men [13, 2628]. This may be explained by the simple fact that most, if
not all, patients with MSA have RBD. The male/female ratio of RBD in MSA
reflects the roughly 1:1 male/female ratio of the disease. RBD in MSA is unrelated
to age, disease severity, disease duration, clinical subtype (parkinsonian or cerebel-
lar), or to any other demographic or clinical feature [26].
RBD may be the first symptom of MSA. In one study of 27 RBD patients
aware of their dream-enacting behaviors, RBD preceded the waking motor symp-
toms in 12 (44 %) [26]. In another study with 19 patients, RBD features were
reported by the patients or their relatives as the first manifestation of the disease
in 3, concomitant with other symptoms in 9, and developed after the onset of wak-
ing symptoms in the remaining 7 [15]. In our series, RBD onset antedated parkin-
sonian, cerebellar and dysautonomic onset in 35 of 67 (52 %) patients by a mean
of 7 years (range, 138 years). MSA is eventually diagnosed in only a few sub-
jects with the initial diagnosis of idiopathic RBD (most of them are diagnosed
with PD and DLB), probably because in the general population MSA is much
more rare than PD and DLB [11]. We reported a patient presenting with dysauto-
nomia, stridor during sleep and RBD without parkinsonism or cerebellar syn-
drome in whom brain pathology disclosed MSA after sudden death during
wakefulness [29].
16.2.6 Sleep Disordered Breathing and Stridor
Breathing problems in MSA may be of central and peripheral (obstructive) origin.

During wakefulness intermittent involuntary gasping, abnormal hypoxic ventilatory
responses, cluster breathing, irregular breathing, abnormal hypoxic and hypercap-
nic respiratory responses, periodic breathing in the erect posture, respiratory failure
and laryngeal stridor have been described. These disturbances during wakefulness
have mainly a central origin due to neurodegeneration of the respiratory center in
the lower brainstem. Breathing problems during sleep include central apneas,
obstructive apneas/hypopneas, Cheyne-Stokes breathing pattern, apneustic breath-
ing, snoring and stridor, either alone or combined with other sleep breathing abnor-
malities. These abnormalities occurring during sleep may be of either central or
peripheral (upper airway, particularly in the larynx involving the vocal cords)
origin.
One of the most relevant sleep related symptoms of MSA is nocturnal stridor.
In clinical series, stridor is considered a relatively common finding in MSA occur-
ring in about 19 % of the patients [16]. Its frequency increases when patients are
formally studied with video-PSG where stridor of variable intensity is found in
3042 % [1418]. Stridor is considered one of the red flags that should raise suspi-
cion of MSA in a patient with parkinsonism [12]. Stridor may occur in all stages of
the disease, it may rarely be the first symptom of the disease [30], and is not related
to MSA clinical subtype. The presence of stridor indicates obstruction of the airway
at the level of the larynx. As the disease advances, nocturnal stridor progresses into
wakefulness due to an increasing reduction in the glottic aperture. Stridor (as a sign
of obstruction in the larynx) and snoring (as a sign of obstruction in the oropharynx)
may coexist in the same MSA patient.
MSA patients, particularly those with stridor, may have typical obstructive sleep
apnea episodes with oxyhemoglobin desaturations [15, 17, 18]. Stridor during
wakefulness indicates severe obstruction of the glottic aperture and this may lead in
some cases to subacute episodes of respiratory failure and death [30]. In the major-
ity of patients with nocturnal stridor the clinical exam of the vocal cords during
wakefulness with laryngoscopy is very useful showing unilateral or bilateral partial
or complete vocal cord abduction restriction, paradoxical vocal cord movements,
flickering of the vocal cords, and floppy epiglottis [18, 31]. In almost all MSA
patients with stridor during wakefulness, laryngoscopy shows severe laryngeal
narrowing.
The presence of stridor in MSA has been linked to decreased survival and sudden
death during sleep. MSA patients with stridor treated with tracheostomy and nasal
continuous positive airway pressure (CPAP) show similar survival trends than
patients without stridor. Sudden death, however, may occur in patients already
treated with tracheostomy and CPAP. It has been reported that tracheostomy may
increase fatal central sleep apneas [32], emphasizing the idea that respiratory
impairment in MSA is complex and occurs at multiple levels. However, the clinical
relevance of these central apneas, which are usually not related to severe oxyhemo-
globin desaturations, is not clear. Nevertheless it can be speculated that the associa-
tion of impaired central hypoxic ventilatory response with upper airway obstruction
during sleep and with physiological decreased ventilatory response during sleep,
particularly during REM sleep, may render MSA patients at risk of sudden death
during sleep.
The cause of stridor in MSA is not completely understood. There are currently
two opposed views suggesting completely different mechanisms with different
treatment implications. One view suggests that stridor occurs as a result of a dys-
tonic contraction of the thyroarytenoid (TA) muscles, in essence, the muscles that
adduct the vocal cords [33]. An alternative view suggests that stridor is due to paral-
ysis of the posterior cricoarytenoid (PCA) muscles, the only muscles that abduct the
vocal cords, probably as a result of degeneration of the nucleus ambiguus neurons
and/or the nerve fibers innervating them [31]. There are findings supporting both
views and it cannot be excluded that stridor may be produced by different mecha-
nisms in different patients. An alternative explanation that fits better the available
218 A. Iranzo
data comes from a study by Isono et al. [34] who performed a very detailed study of
MSA patients with stridor during sleep under general anesthesia. They suggested
that stridor during sleep is the result of a reflex contraction of the abductors (PCA)
combined with a reflex contraction of the adductors (TA). This reflex co-contraction
is a normal response of all the muscles of the larynx to an increase in airway
resistance in order to protect the patency of the upper airway. In patients with MSA,
however, the selective weakness of the abductors makes that the net result of this
reflex contraction is the narrowing of the glottic aperture, due to the predominance
of the adductors, resulting in stridor. There are many causes of increased upper
airway resistance in MSA, particularly the weakness of the vocal cord abductors as
well as the presence of decreased oropharyngeal space. This may explain why
relatively low pressures of CPAP are able, by decreasing upper airway resistance, to
diminish this adductor reflex response of the TA and subsequently to eliminate
stridor.
Nocturnal stridor should alert the clinician about the possibility of respiratory
complications during sleep including sudden death. It is reasonable to confirm its
presence by video-PSG recording, although a simple audio home recording may be
useful. In cases where stridor occurs only during sleep, treatment with CPAP should
be first offered, given that in most cases stridor and obstructive sleep apneic events
can be completely eliminated, the reasonable tolerance, improved nocturnal sleep of
the patient and their family as well as the reported increase in survival [18].
Laryngoscopy during spontaneous sleep (sleep not induced by drugs) in a MSA
subject with stridor documented inspiratory adduction of the vocal cords with
downward displacement of the larynx. Application of CPAP resulted in improve-
ment of stridor, distension of the hypopharynx, separation of the vocal cords and
reduction of the downward displacement of the larynx [35]. During CPAP titration
central sleep apneic event may appear, but its clinical relevance is not known. When
CPAP does not fully eliminate stridor, cannot be tolerated and especially as soon as
stridor appears during wakefulness, thracheostomy needs to be considered.
Botulinum toxin has been reported to relieve stridor in three patients with diurnal
stridor [33] but there is not enough information available to recommend it in patients
with stridor. Unilateral cordectomy and laser arytenoidectony have also been
proposed, but again there are not enough studies to determine when and how it
should be used. It is important to realize that the vocal cord weakness induced by
botulinum toxin or the persistent glottic aperture produced by surgery may render
MSA patients more prone to bronchial aspiration, a frequent cause of death in MSA.
16.3 Progressive Supranuclear Palsy (PSP)
PSP is a neurodegenerative disease clinically characterized by dementia, parkinson-

ism, falls, and vertical gaze palsy. PSP is a tauopathy involving the brainstem, basal
ganglia, frontal lobe and several other brain areas [36]. PSG studies show decreased
REM sleep percentage and features also seen in other neurodegenerative diseases
such as decreased total sleep time and reduction in sleep spindles and K complexes.
These abnormalities are mainly due to neurodegeneration of the sleep structures
that regulate and modulate the sleep-wake cycle. Sleep complains include insomnia
and sometimes symptoms suggestive of RBD. In some patients, RBD-like symp-
toms may reflect true nocturnal wandering and confusional awakenings which are
frequent in patients with any type of dementia. Sleep disorder breathing, EDS,
PLMS, and RLS are not major concerns in PSP.
RBD in PSP occurs but is less frequent than in the synucleinopathies PD, DLB,
and MSA. In PSP, the subclinical form of RBD (asymptomatic REM sleep with-
out atonia) is more frequent than full-blown RBD with dream-enacting behaviors
and nightmares. There are no reported cases from sleep centers of patients with
idiopathic RBD who were later diagnosed with PSP. The first reported case of
RBD linked to PSP was a 70-year-old woman presenting with inhibition of speech
during wakefulness and intelligible somniloquy at night due to RBD. In this
patient, parkinsonism developed 1 year before the onset of RBD [37]. In a series
of 15 PSP patients who underwent PSG, 2 had clinical RBD and 4 exhibited
asymptomatic REM sleep without atonia. Clinical manifestations of RBD were
severe in one patient, but none of the patients were aware of their abnormal sleep
behaviors [38]. Nomura et al. [39] evaluated PSG in 20 PSP patients and 93 sub-
jects with PD. When compared with PD, PSP group had lower sleep efficiency,
lower total sleep time and a small number of subjects showing subclinical REM
sleep without atonia (20 % in PSP versus 60 % in PD). None of the PSP patients
experienced RBD symptoms in contrast to 32 % with PD. In another study,
Sixel-Dring et al. [40] evaluated sleep in 20 PSP and 20 PD subjects. On PSG,
PSP patients had significantly lower sleep efficiency (43 %) compared to PD
patients (62 %). Seventeen PSP patients and 19 PD patients had asymptomatic
REM sleep without atonia. Seven PSP patients and 13 PD patients had clinical
RBD. The finding that RBD may be found in a tauopathy such as PSP argues
against RBD as an exclusive feature of the synucleinopathies (PD, DLB, and
MSA), and implies that RBD may be explained by dysfunction of the brainstem
structures that regulate REM sleep.
Conclusion
Sleep disorders are common in the atypical parkinsonisms DLB, MSA, and
PSP. They mainly include insomnia, hypersomnia, sleep disordered breathing of
either central or peripheral origin, and RBD. In DLB and MSA, RBD may be the
initial symptom of the disease and it is considered a red flag. Stridor during sleep
in MSA is linked to sudden death and may be eliminated with CPAP and
tracheostomy. Origins of sleep disorders in the atypical parkinsonism are multi-
factorial and associated with degeneration of the brain structures that regulate
sleep and coexistent clinical features such as immobility, dementia, nocturia,
depression, and anxiety.
220 A. Iranzo
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Future Directions
Aleksandar Videnovic and Birgit Hgl
Clinical observations and research performed on sleep and alertness issues in PD

have attracted the attention of the medical and scientific PD community. This
provides a unique opportunity to further examine interactions between sleep and
circadian regulation and PD outcomes. Numerous avenues for future investigations
need to be considered. Given the complexities of sleep and circadian research, these
efforts will require a collaborative and multidisciplinary approach of clinicians and
investigators involved in various aspects of PD.
Better understanding of the natural history of sleep and circadian disorders in the
PD population will require multicenter longitudinal studies. Optimization of the
existing methods and tools, as well as the development of new instruments for
the ascertainment of PD-specific sleep and alertness problems and issues related to
the circadian dysregulation, will be critical for further advancements. Further, an
educational outreach is needed to implement best practices and appropriate use of
methodologies currently available to assess various aspects of sleep-wake cycle in
the PD population.
New screening instruments will need to be developed in order to facilitate timely
and cost-effective diagnosis of sleep disorders in PD as well as to enable early
detection and sharpen the profile of sleep-specific pre-motor forms of PD. The latter
is of utmost importance in the field, as it will provide means to identify individuals
at risk for development of synuclein-related neurodegeneration, as well as allow for
timely testing of therapies that may modify the progression of the disease.
Systematic study of sleep in genetically homogeneous PD cohorts will help
overcome obstacles related to sleep research within quite heterogeneous phenotypic
expression profiles of PD. This will further facilitate our understanding how
A. Videnovic, MD, MSc ()

Department of Neurology, Massachusetts General Hospital
Harvard Medical School, Boston, MA, USA
B. Hgl, MD
Department of Neurology, Medical University of Innsbruck,
Innsbruck, Austria

in Parkinsons Disease, DOI 10.1007/978-3-7091-1631-9
224 Future Directions
sleep-wake regulation in this disease affects its motor, cognitive, neuropsychiatric

and autonomic features.
Circadian dysregulation has started to emerge as an important component of
sleep-wake disruption in neurodegenerative disorders. Further exploration of
bidirectional relationship between circadian disruption and sleep problems on one
side, and between neurodegenerative disease process and circadian function on the
other side, will position circadian system as a potential novel diagnostic and
therapeutic target in PD.
Despite the wide range of sleep disturbance in PD and its major clinical impact,
almost no systematic treatment studies have been performed. This is a strong impe-
tus to focus efforts on design and execution of clinical treatment studies that will
lead to optimized and new treatments for the various aspects of sleep, wakefulness
and circadian disturbances in PD.
Index
A D
Acetylcholine, 2223, 38 Daytime sleepiness (DS), 70
Actigraphy, 58, 83, 110, 122 Deep brain stimulation (DBS), 8788
Apnea-hypopnea index (AHI), 94, 188 EDS, 111
Ascending reticular activating system GPi, 199200
(ARAS), 21 PPN, 200202
Atypical parkinsonisms RBD, 140
autosomal dominant spinocerebellar STN, 197199
ataxias, 210, 211 VIM, 200
corticobasal degeneration, 210, 211 Dementia with Lewy bodies (DLB), 134, 135
DLB (see Dementia with lewy bodies RBD, 212213
(DLB)) sleep disturbances, 210, 211
Huntington disease, 210, 211 Dim light melatonin onset (DLMO), 120
MSA (see Multiple system atrophy (MSA)) Dopamine, 111
PSP, 210, 218219 ARAS, 21
in circadian timing system, 121122
MPTP, 21
B neurodegeneration, 22
Bed alarm therapy, 140 oxidative stress, 101
role of, 20
sleep-waking cycle, role of, 42
C SNpc neurons, 21
Circadian dysregulation, 224 ventral tegmental area, 21
Circadian rhythm sleep disorders, 82 Dream, 64, 112, 132, 215216
Circadian system. See Human circadian system Dream-enactment behavior (DEB), 132
Cognition, 100
in aging, 185186
cognitive profile, 184 E
dementia, 185 EDS. See Excessive daytime sleepiness (EDS)
EDS, 189 Epworth Sleepiness Scale (ESS), 65, 109, 177
insomnia, 189190 Eszopiclone, 86
MCI, 184185 Excessive daytime sleepiness (EDS), 64
RBD anticholinergic agents, 111
SDB, 188 catechol O-methyltransferase inhibitors, 111
sleep quality, 190 circadian rhythms disorders, 112
sleep spindle alterations, 190 cognition, 189
Cognitive behavioral therapy for insomnia DBS, 111
(CBT-I), 85 epidemiology, 108109
Cognitive behavior therapy (CBT), 114 evaluations, 109110

in Parkinsons Disease, DOI 10.1007/978-3-7091-1631-9
226 Index
Excessive daytime sleepiness (EDS) (cont.) diurnal clinical fluctuations, 122123

factors, 108 light exposure, 125
GPi segment and PPTg, 112 mechanisms, 125126
insomnia, 112 nonphotic circadian entrainment, 125
levodopa and dopamine agonists, 111 physiologic and molecular markers,
MSA, 214 123124
parasomnias, 112 dopamine, 121
pathophysiology, 110111 genetic regulation, 119
rotigotine, 111 neuroanatomy and neurochemistry,
SDB, 99 119, 120
selegiline, 111 Huntington disease, 210, 211
sleep related breathing disorders, 112 Hypocretin/orexin, 2425
sleepwake cycle, 189
treatment, 113114
trihexyphenidyl, 111 I
Insomnia, 37, 64, 112, 201, 202, 214, 219
behavioral treatment, 8485
F bradykinesia, 81
Fatigue, 203 cognition, 189190
central fatigue, 174 deep brain stimulation, 8788
depression, 177 definition, 80
epidemiology, 176 diagnostic criteria, 80
measurement differential diagnoses, 84
FACIT-F, 175176 medications, 81
FQ, 176 and mood disorders, 81
FSS, 175 MSA, 210
generic scale, 175 pathophysiology and sleepwake systems,
multidimensional scale, 175 8182
one-dimensional fatigue scale, 175 PDSS, 83
PFS, 175 pharmacological treatment, 8587
mental fatigue, 174 PSQI, 83
pathophysiology, 177178 risk factors, 80
peripheral fatigue, 174 SCOPA-sleep, 83
physical fatigue, 174 sleepwake cycle, 189190
primary/secondary fatigue, 175 Insomnia Severity Index (ISI), 190
and sleepiness, 177
treatment
non-pharmacologic interventions, L
178179 Levodopa/carbidopa intestinal gel (LCIG), 203
pharmacologic interventions, 178
Fatigue Questionnaire (FQ), 176
Fatigue Severity Scale (FSS), 175 M
Maintenance of wakefulness test (MWT), 57
Melanin-concentrating hormone (MCH), 28
G Melatonin, 87
Globus pallidus internal (GPi) segment, 112, Methyl,4-phenyl-1,2,3,6-tetrahydropyridine
199200 (MPTP), 21
MSA. See Multiple system atrophy (MSA)
Multiple sleep latency test (MSLT),
H 5657, 110
Hallucinations, 64, 83, 111, 113, 213 Multiple system atrophy (MSA)
Histamine, 27, 37, 38 breathing problems, 216
Human circadian system central hypoventilation, 210
circadian entrainment and markers, central sleep apnea, 210
120121 EDS, 210, 214
circadian rhythm dysfunction insomnia, 210
Index 227
obstructive sleep apnea, 210 PLMS. See Periodic limb movements of sleep
PLMS, 210, 215 (PLMS)
RBD, 210, 215216 Polysomnography (PSG), 9698, 110,
RLS, 214215 137138
sleep fragmentation, 214 Progressive supranuclear palsy (PSP),
stridor, 210, 217218 218219
N R
Non-motor symptoms scale (NMSS), 203 Rapid eye movement (REM)
Non-rapid eye movement (non-REM), MPTP, 43
3738 polysomnographic criteria
Norepinephrine, 2627 automatic scoring system, 153
computer-assisted scoring algorithms,
151153
O Lapierre & Montplaisir scoring system,
Obstructive sleep apnea (OSA) syndrome, 53, 150151
112, 113 manual scoring, 151
mentalis muscle, 153
normative EMG values, 153154
P PEM, 148149
Parkinson Fatigue Scale (PFS), 175 phasic and tonic activity, 148, 149
Parkinsons disease (PD) RBD
circadian system (see Human circadian animal models, 44
system) phasic motor activation, 45
cognition (see Cognition) prevalence, 43
EDS (see Excessive daytime sleepiness sleep deterioration and
(EDS)) fragmentation, 43
fatigue (see Fatigue) sleep muscle atonia, 43
insomnia (see Insomnia) Rapid eye movement sleep behavior disorder
PLMS (see Periodic limb movements of (RBD)
sleep (PLMS)) alpha-synuclein pathology, 134135
RLS (see Restless legs syndrome (RLS)) animal models, 44
SDB (See Sleep disordered breathing bruxism, 54
(SDB)) clinical evaluation and diagnosis
Sleepwake cycle (see Sleepwake cycle) examination, 137
surgical therapy history, 136137
Parkinsons disease sleep scale (PDSS), 66, PSG, 137138
109110, 203 clinical presentation, 133
Pedunculopontine nucleus (PPN), 200202 cognition and sleepwake cycle
Pedunculopontine tegmental nucleus diagnosis
(PPTg), 112 polysomnography, REM sleep without
Periodic limb movement disorder atonia, 148154
(PLMD), 112 screening questionnaires, 146147
Periodic limb movements (PLM), 53 DLB, 212213
Periodic limb movements of sleep (PLMS) dystonia and dyskinesia, 55
assessment of, 166167 EMG activity, 54
autonomic lability, 166 epidemiology, 133134
definition, 166 historical perspective, 132133
incidence, 166 MSA, 215216
MSA, 215 neurodegenerative disorder, 140141
physiology, 166 pathophysiology, 135136
Phasic electromyographic metric (PEM), phasic motor activation, 45
148149 polysomnographic (PSG)
Pittsburg Sleep Quality Index (PSQI), 65, 66, abnormalities, 54
68, 109 prevalence, 43, 146
228 Index
Rapid eye movement sleep behavior disorder STOP-BANG Questionnaire, 94

(RBD) (cont.) treatment options, 102
treatment cognition, 188
bed alarm therapy, 140 sleepwake cycle, 188
carbamazepine, 140 Sleep homeostasis
clonazepam, 139 circadian alerting signal, 5
clozapine, 140 clinical manifestations, 1112
DBS, 140 definition, 4
donepezil, 140 delta wave activity, 4
imipramine, 140 EEG progression, 4
levodopa, 140 genetic contributions, 1011
melatonin, 139 homeostatic sleep drive, 5
pramipexole, 139 NREM sleep anatomy and physiology, 67
quetiapine, 140 slow-wave activity
rivastigmine, 139140 definition, 5, 78
sodium oxybate, 140 EEG, 5, 78
triazolam, 140 recovery sleep, 8
zopiclone, 140 sleep deprivation, 8
RBD. See Rapid eye movement sleep behavior topographic organization, 910
disorder (RBD) slow-wave sleep
Restless legs syndrome (RLS) EEG spectral analysis, 5
MSA, 214215 NREM, 78
pathophysiology, 161162 Sleep questionnaire and assessment of
PLMS, 166167 wakefulness (SQAW), 96
prevalence, 112, 165 Sleep scales
treatment, 167 advantages and limitations, 7172
RLS. See Restless legs syndrome (RLS) ESS, 65, 67, 68
PDSS, 66
PDSS-2, 68
S PSQI, 65, 66, 68
SCOPA-sleep scale, 6668 RBD, 7274
Serotonin, 2526 SCOPA-sleep, 6668
Sleep disordered breathing (SDB) SSS, 65
apnea-hypopnea index, 94 Stavanger sleepiness scale, 67, 69
catecholamine neurons, 95 Sleepwake cycle
clinical assessment, 94 acetylcholine, 2223
clinical implications actigraphy, 58
cardiovascular risk, 99100 in aging, 185186
cognition, 100 ambulatory polysomnography, 57
excessive daytime sleepiness, 99 dopamine
memory consolidation, 100 ARAS, 21
motor symptoms, 101103 MPTP, 21
definition, 94 neurodegeneration, 22
detection, 94 SNpc neurons, 21
future aspects, 102 ventral tegmental area, 21
hypertension, 95 EDS, 189
mortality rates, 95 histamine, 27
polysomnography, 9698 hypocretin/orexin, 2425
prevalence of, 95 insomnia, 189190
pulmonary abnormalities, 95 multiple sleep latency test, 5657
SQAW, 96 norepinephrine, 2627
Index 229
RBD U
SDB, 188 Unified Parkinsons Disease Rating Scale
serotonin, 2526 (UPDRS), 72
sleep quality, 190
sleep spindle alterations, 190
videopolysomnographic recordings V
periodic limb movements, 53 Videopolysomnographic recordings
REM sleep behavior disorder, 5455 periodic limb movements, 53
sleep disordered breathing, 5354 REM sleep behavior disorder, 5455
wakefulness test, maintenance of, 57 sleep disordered breathing, 5354
Sodium oxybate, 87
Stanford sleepiness scale (SSS), 65, 67
STOP-BANG Questionnaire, 94 Z
Suggested immobilization test (SIT), 5556 Zeitgebers, 120

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What are some of the sleep disorders discussed in the document?

What are some of the sleep disorders discussed in the document?

What are some of the assessment tools mentioned for evaluating sleep disorders?

What are some of the assessment tools mentioned for evaluating sleep disorders?

Disorders of Sleep and

ISBN 978-3-7091-1630-2 ISBN 978-3-7091-1631-9 (eBook)

Library of Congress Control Number: 2015938763

Springer Wien Heidelberg New York Dordrecht London

Printed on acid-free paper

Springer-Verlag GmbH Wien is part of Springer Science+Business Media (www.springer.com)

Birgit and Aleks

O sleep! O gentle sleep!

Innsbruck, Austria Werner Poewe

1 Regulation of Sleep and Wake Homeostasis . . . . . . . . . . . . . . . . . . . . 3

6 Insomnia in Parkinsons Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

10 REM Sleep Behavior Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

Parkinsons disease is the second most common neurodegenerative disorder. Named

Specific sleep disorders have emerged as important early manifestations of

C.A. Goldstein (*) R.D. Chervin

Springer-Verlag Wien 2015 3

Sleep is orchestrated by a two-process model comprised of the homeostatic sleep

1.2 History of Sleep Recording

Homeostasis, as described by Cannon in 1932, is the need for organisms to achieve

Least alert Most alert

1.3 NREM Sleep Anatomy and Physiology

Hyperpolarization of thalamic neurons and synchronization of cortical excitatory

Hypothalamic nuclei Pontine nuclei

1.4 Slow-Wave Sleep, Slow-Wave Activity, and Their

activity in the 0.54.5 Hz range as measured by spectral analysis, demonstrates a

1.5 Slow-Wave Sleep and Slow-Wave Activity as a Function

1.6 Topographic Organization of Slow-Wave Activity

Slow-wave activity has a topographical organization in the cerebral cortex, with an

1.7 Sleep Homeostasis Across the Life Span

1.8 Genetic Contributions to Sleep Homeostasis

1.9 Clinical Manifestations of Sleep Homeostasis

The homeostatic regulation of sleep has important implications in many different

A.A.H. Freeman, PhD

Springer-Verlag Wien 2015 19

2.2 Wake-Promoting Circuits

Multiple lines of converging evidence, from pharmacological interventions to

that lack functional dopamine transporters, thereby leading to increased synaptic

There are two primary cholinergic projection systems recognized to contribute to

magnocellular reticular formation, and the ventrolateral reticulospinal tract (reviewed

The locus coeruleus is the primary norepinephrine-producing nucleus in the

Histamine is produced in large cell bodies of the tuberomammillary nucleus located

2.3 Sleep-Promoting Circuit

2.3.1 Melanin-Concentrating Hormone

Melanin-concentrating hormone (MCH) neurons are intermixed with the Hcrt/OX

Pierre-Herv Luppi, Olivier Clment, Sara Valencia Garcia,

P.-H. Luppi (*)

Springer-Verlag Wien 2015 35

3.2 Populations of Neurons Responsible for Waking

sleep (SWS) (synchronized), is characterized by low-frequency, high-amplitude

3.3 Mechanisms Involved in Non-REM

3.4 Summary: The Neuronal Network Responsible

3.5 Mechanisms Involved in Paradoxical

3.5.1 The Localization of the Neurons Generating

3.5.2 Mechanisms Responsible for SLD PS-On

A long-lasting PS-like hypersomnia can be pharmacologically induced with a short