Sleep and Parkinson’s Disease

Thomas Freedom, MD
Introduction
Sleep is common to most living organisms. For most of history it was
thought of as a passive state. It was not until the middle of the 20th
century with the discovery of rapid eye movement (REM) sleep and
subsequent demonstration of pertinent brain processes that the active
nature of sleep was appreciated. These processes involve many areas of
the central nervous system.1
Sleep disturbances are wide-spread.2 Patients with Parkinson’s disease
(PD) are prone to sleep disturbances and disorders. This predisposition
can be due to cellular and biochemical disturbances, medications, age,
and comorbidities.3 Certain regions of the central nervous system
involved in sleep processes are impaired in PD.4

Basics of Sleep
Although sleep is familiar to most observers, the processes that occur
during sleep require special equipment to record. Sleep has been catego-
rized by stages for purposes of study and treatment. The scoring of sleep
stages depends on three parameters: electroencephalography (EEG),
electooculography (EOG), and electromyography (EMG). Based on these
parameters, REM (rapid eye movement) and nonREM (NREM) sleep are
recognized. NREM sleep is further divided into four stages. Stages 1 and
2 are considered “lighter,” whereas stages 3 and 4 —also known as delta
or slow wave sleep (SWS) based on the EEG pattern of high amplitude
slow waves—are considered “deeper” stages of NREM sleep.5
Sleep follows a pattern of cycles throughout the night in normal
children and adults (Fig 1). NREM and REM sleep alternate in approx-
imately 90-minute cycles. Stages of SWS predominate early in the night.
REM episodes grow longer in duration in successive cycles; the duration
SWS decreases and it may not be present in the last cycles.

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FIG 1. Typical progression of sleep stages during an episode of nocturnal sleep.

Tests of Sleep and Sleepiness

The nocturnal polysomnogram (PSG), or overnight sleep study, is the
most widely used tool for diagnosing sleep disorders. This consists of
continuous measurements of EEG, EOG, EMG, respiratory flow, respi-
ratory effort, electrocardiography, and arterial oximetry during sleep.6
Daytime polysomnography studies include the multiple sleep latency
test (MSLT), in which the patient is given four to five opportunities to nap
throughout the day at 2-hour intervals; this measures daytime sleepiness.7
The maintenance of wakefulness test (MWT) is similar to the MSLT, but
is conducted in a manner to measure the ability to stay awake.8
Validated questionnaires such as the Epworth sleepiness scale
(ESS)9 or the Parkinson’s disease sleepiness scale (PDSS)10 can be
completed by the patient or caregiver. ISCS (Inappropriate Sleep
Composite Scale) (Appendix 1)11 is a modified ESS and may be useful
in assessing risk of driving. A sleep log recording sleep and wake
habits can be obtained through the National Sleep Foundation.13
Sleep and Aging
Sleep patterns evolve from the beginning to the end of life. At birth,
there is approximately equal time spent in waking, REM (active) sleep,
and nonREM (quiet) sleep. Sleep cycles are roughly 50 minutes in
duration. In infancy, the cycle begins with REM sleep. By early
childhood, the normal pattern of cycles beginning with nonREM sleep is
achieved. Through childhood into early adulthood, the proportion of
wakefulness increases and slow wave sleep decreases. This continues
through life until old age in which there may be little or no slow wave
sleep. The percentage of REM sleep remains relatively constant in
adulthood with slight decrease in the elderly.13 Studies have not been
consistent regarding sleep and aging. A meta-analysis of 65 articles
published over 43 years including 3577 children and adults was con-
ducted. These articles met strict criteria. Results included that aging is
associated with increases in sleep latency (time to sleep onset after lights
out), sleep stages 1 and 2, and wake time after sleep onset. Decreases in
276 DM, May 2007
TABLE 1. Causes of poor sleep in aging18
Problem Examples
Behavioral Retirement reducing need for regular wake time
Napping
Medical illness Chronic cardiac or pulmonary disease
Any disease causing chronic pain (arthritis)
Chronic renal failure
Medications Diuretics (nocturnal wakes)
Psychiatric illness Depression
Primary sleep diseases Sleep-disordered breathing
Periodic limb movements of sleep

sleep efficiency (percentage of time asleep during the sleep period),

percentage of REM sleep, and percentage of SWS were also noted.14
Causes of poor sleep in normal aging include increased arousals and
awakenings, nocturia, phase advance (shift of the circadian rhythm to
earlier time with subsequent early sleep and wake times), and decreased
amplitude of circadian rhythm parameters, ie, temperature, hormonal
secretion. In addition, menopause may have a major impact on sleep.15
Sleep complaints are common in the aged. Among a rural population of
older subjects, as many as 40% reported loud snoring, 36.7% had
difficulty falling asleep, and 18.9% had uncontrollable daytime somno-
lence.16 Restless legs are also common.17
Other causes of poor sleep are noted in Table 1.18

Sleep Dysfunction in Parkinson’s Disease

In addition to those associated with aging, abnormalities of sleep occur
more frequently in Parkinson’s disease. These include excessive daytime
sleepiness, insomnia, and a host of intrinsic sleep disorders. The treatment
of Parkinson’s disease may also be contributory to sleep dysfunction.3
Sundowning19 is a common occurrence. A total of 82% of patients with
PD responding to a community survey had complaints of sleep distur-
bance or sleepiness.20 And a prevalence of sleep complaints as high as
98% has been reported.21
In addition to its role in motor and behavior activity, dopamine has
effects on the sleep/wake patterns. Dysfunction in dopaminergic systems
involved in sleep, in parallel to that in motor systems, may contribute to
sleep disruption and disorder.4 Psychological problems and stress are
reported to be present in 2/3 of PD patients and may have a negative
impact on sleep.22
DM, May 2007 277
Excessive Daytime Sleepiness
Fifteen percent of PD patients may exhibit excessive daytime sleepiness
(EDS), and of those, features of narcolepsy may occur in 39%. Sleepiness
can be independent of nocturnal disturbances, age, duration of disease,
treatment, or motor disability.23 On the other hand, this has been shown
to worsen over time. A group of PD patients with a 7.7% prevalence of
sleepiness had an increase to 28.9% after 4 years.24 In PD patients, 19.9%
had EDS versus 9.8% of age-matched controls, and sleep attacks (rapid
onset of sleep without warning or without adequate time to react)
occurred in 13.9% versus 1.9% of controls.25 One study showed that
length of disease, male gender, and use of dopamine agononists are
associated with EDS.26 However, severity of disease may not have an
impact on level of sleep disturbance.27 Whereas mild daytime sleepiness
in PD may be similar to normal controls (10%), EDS has been shown to
be more common in PD patients (15.5%) than those with diabetes mellitus
(4%) or healthy controls (1%).28
Patients may not be aware of sleepiness. A total of 38% of 47 patients
did not perceive falling asleep in at least 1 of 5 naps on an MSLT. Six
percent of those patients had been involved in an automobile accident.29
On the other hand, sleep without warning has been shown to be infrequent
and can be predicted by screening for EDS.11
Sleep attacks, which are unintended sleep episodes occurring without
warning in conditions associated with EDS, have also been reported in as
many as 20% of patients with Parkinson disease.30 Sleep attacks, and
MSLTs demonstrating REM onset episodes are suggestive of narcolepsy-
like symptoms; isolated muscle atonia on daytime testing and patient
reports of falls associated with negative emotion lead to speculation that
some falls may be possible cataplectic attacks.31 Sleep attacks occur in
PD patients with excessive sleepiness,32 and some authors have argued
that sleep attacks do not occur in the absence of EDS.33 However, PSG
evidence of rapid transition from stable wakefulness to stage 2 sleep
without intervening drowsiness has been demonstrated.34
EDS may be exacerbated by other underlying medical disorders,
disturbance in sleep or the sleep cycle, or due to medication effects.20

Disorders of Initiation or Maintenance of Sleep

The elderly have difficulty with insomnia. Given the age of Parkinson’s
patients, there is some overlap. However, PD patients have difficulties
independent of aging. There are more sleep disruptions compared with
age-matched controls.35 Some causes include problems turning in bed,
278 DM, May 2007
pain, medications, dystonia, disruption of circadian rhythm, and sleep
disorders.36
Intrinsic Sleep Disorders
Intrinsic sleep disorders also occur in PD and may include Sleep Apnea
Syndromes, REM Sleep Behavior Disorder (RBD), Restless Legs Syn-
drome (RLS), and periodic limb movement disorder (PLMD).3
Sleep-Related Breathing Disorder
Apnea during sleep consists of cessation of air flow with (obstructive)
or without (central) respiratory effort.
Criteria used to diagnose obstructive sleep apnea syndrome include:
excessive daytime sleepiness or insomnia; frequent episodes of obstructed
breathing during sleep; associated features such as loud snoring, morning
headaches, dry mouth upon awakening, and chest retraction in children
during sleep; polysomnography demonstrating obstructive apneas, arousals,
bradytachycardia, and arterial oxygen desaturations; and MSLT showing
increased daytime sleepiness. Not all of these need to be present.37
Central sleep apnea can include: insomnia or excessive sleepiness; shallow
or absent breathing during sleep; gasps, grunts, or choking during sleep;
frequent body movements; cyanosis; polysomnography demonstration of
central apneas with arousals, bradytachycardia, or oxygen desaturations.38
Snoring is associated with excessive daytime sleepiness.39 Obstructive
sleep apnea is more common and related to disease severity in PD.
Central sleep apnea has a slightly increased prevalence in PD and in
general is milder than obstructive disease.40

REM Sleep Behavior Disorder and Hallucinations

Normally during REM sleep there is muscle atonia except for extraocular
muscles and the diaphragm. Structures in the pons and medulla are involved
in REM sleep.41,42 There are circumstances in which this mechanism does
not function. These structures can be impaired in PD.4 Loss of REM atonia
was shown to occur in 58% of patients with PD, and 33% of patients had a
condition known as REM sleep behavior disorder (RDB).43
RBD is characterized by the intermittent loss of EMG atonia during
REM sleep and the appearance of elaborate motor activity associated with
dream mentation.44 This was first described in human beings in the
1980s.45 It often presents in the sixth or seventh decade and appears more
commonly in males. It is uncertain as to the role of heredity. There is
often a prodrome of talking, yelling, or limb movements prior to the full
manifestation of disease.44
DM, May 2007 279
 The minimal criteria of RBD are limb or body movement associated
with dream mentation and at least one of the following: harmful or
potentially harmful sleep behaviors; dreams that appear to be “acted out”;
or sleep behavior that disrupts sleep continuity.44 Sleep-related injury is
a significant problem with 33% of PD patients who have RBD causing
injury to themselves or to caregivers compared with 6% of non-RBD
patients.46
One series has shown that 38% of males who presented with RBD
developed PD. This occurred within a mean of 3.7 years after diagnosis
of RBD and 12.7 years after the onset of REM sleep symptoms.47
A total of 126 PD patients were studied for sleep fragmentation, altered
dream phenomena, and hallucinations or illusions. Eighty-two percent of the
patients with hallucinations/illusions experienced some form of sleep disor-
der, 15% with sleep fragmentation only, 12% with altered dream phenomena
only, and 55% with both sleep fragmentation and altered dream phenomena.
A total of 22% of patients experienced none of these symptoms.48 Halluci-
nations are not limited to visual phenomena and may progress over time.49
Hallucinations have been associated with vivid night dreams, or daytime
nonREM sleep.50 Ten of 14 patients with hallucinations had loss of atonia in
REM sleep, and the 3 patients who underwent an MSLT had 2 or more sleep
onset REM episodes (as in narcolepsy), but mean sleep latencies greater than
10 minutes (normal range). Two of 8 PD patients without hallucinations had
atonia in REM sleep. Clonazepam was effective in reducing hallucinations in
5 of 8 patients.51
Restless Legs Syndrome
In the 1940s, Ekbom described patients with extremity discomfort,
which he named the Restless Legs Syndrome (RLS); he summarized his
experience with 175 patients in 1960.52
Criteria for RLS based on an NIH workshop in collaboration with the
International Restless Legs Syndrome Study Group include:
1. Desire to move the limbs usually associated with paresthesias/
dysesthesias.
2. Symptoms begin or worsen during inactivity or rest (ie, lying, sitting).
3. Symptoms partially or totally relieved by movement (walking or
stretching).
4. Symptoms are worse in the evening or night.53
RLS has been reported to occur with a prevalence of 20.7% in patients
with PD; a greater prevalence is present compared with healthy nor-
mals.54,55 Not all studies show this increased prevalence.56
280 DM, May 2007
 RLS can be related to low ferritin level57 and this has also been shown
in PD.55 RLS is responsive to levodopa and dopamine agonists.58
Symptoms may be exacerbated by antihistamines, antipsychotics, anti-
emetics, tricyclics, SSRIs, and other antidepressants.59
Periodic Limb Movement Disorder
Periodic limb movements in sleep have been found to be more common in
PD and Multiple System Atrophy (MSA) than in controls.60 Periodic limb
movements were not increased in treated patients compared with normal
controls, but increased in a group of patients taken off l-dopa therapy for 2
weeks from 11 to 55/hour. They respond to medications used for RLS.61
Diagnostic criteria include: 1) insomnia or excessive sleepiness, occasion-
ally patients are asymptomatic and movements are noted by an observer; 2)
repetitive highly stereotyped muscle movements (in the lower extremity
extension of the big toe with partial flexion of the ankle, knee, and sometimes
hip); 3) polysomnogram demonstrates repetitive episodes of muscle contrac-
tion, and arousal or awakenings may occur. Symptoms should not be
explained by another medical or psychological disorder.62
Complications of Treatment
Medications used to treat PD can have an impact on sleep. For example,
EDS and sleep attacks have been reported with dopamine agonists63 and
L-dopa.64 No difference has been demonstrated between ergot and
nonergot drugs.65 Levodopa has also been shown to be associated with
sleepiness. There may be a dose-dependent effect. Impaired driving has
been reported with the use of medications.66 The effect of l-dopa may be
less severe than that of dopamine agonists.67
Although deep brain stimulation (DBS) is generally beneficial for
sleep,68,69 restless legs occurred in 11 of 195 advanced PD patients
undergoing subthalamic nucleus DBS. This was thought to be due to
unmasking of symptoms due to lowering of levodopa.70
Evaluation of Sleep Disorders in
Parkinson’s Disease
Vigilance on the part of the primary care provider regarding sleep
complaints in patients with PD is crucial. If sleep disturbance is
suspected, the ESS10 or PDSS11 can be completed by the patient or
caregiver. The ISCS may be useful in assessing risk of driving. A sleep
log is often helpful.12
Evaluation starts by inquiring about sleep disturbance or sleepiness. If
there is a positive response, one can investigate regarding daytime
DM, May 2007 281
sleepiness, automobile accidents, difficulty initiating and/or maintaining
sleep, factors disrupting sleep, snoring/witnessed apneas, abnormal be-
haviors during sleep, lower extremity discomfort at rest, and leg move-
ments during sleep.
Polysomnography71 and sleep medicine consultation,72 particularly in
suspected REM sleep behavior disorder, may be needed.
MLST7 or MWT8 may be helpful following nocturnal PSG for patients
with EDS.

Treatment
Management is focused on the particular sleep disturbance. In the case
of excessive sleepiness determining the underlying etiology is needed to
determine treatment. Maximizing sleep by optimizing sleep habits (sleep
hygiene), adjustment of medications (both to optimize sleep and minimize
daytime sleepiness), and treating underlying sleep disorders is recom-
mended.73 Driving should be restricted in sleepy patients.74
Modafinil was safe and effective in 15 PD patients who had daytime
sleepiness.75 In addition to modest efficacy,76 modafinil may allow higher
doses of medication antiparkinsonian to be tolerated.77
Management of insomnia includes sleep hygiene, cognitive behavioral therapy,
and limited use of hypnotics.78 In disorders of circadian rhythm, treatment with
chronotherapy (progress change of sleep times) or melatonin is generally
not effective. The use of bright light exposure at specific times has been
shown to be efficacious in resetting the circadian rhythm.79
REM sleep behavior disorder responds to clonazepam in nearly 90% of
patients.80 For those unable to tolerate clonazepam or in whom it is
ineffective, melatonin can be considered.81 Dopamine agonists may be
helpful, but limited experience with these medications in RBD requires
further study.82 L-dopa has also been shown to improve symptoms in
patients with RBD preceding PD.83
For restless legs, avoidance or decreased dosages of medications that
may precipitate or worsen symptoms may be helpful.59 Levodopa or
dopamine agonists are effective. Gabapentin is the most effective of the
anticonvulsants. Opiates are used when patients refractory to or cannot
tolerate other medications.58 These medications may also be effective for
periodic limb movements. A recent study showed that cabergoline84 was
efficacious for periodic limb movements. Iron supplements can be
effective in patients with low (less than 50 mcg/l) Ferritin.57
Augmentation, which is defined as earlier onset of symptoms in RLS
may occur with the use of levodopa or dopamine agonists. Other features
include increase of symptoms with increasing medication dose, shorter
282 DM, May 2007
latency to symptom onset when at rest, expansion of symptoms to
additional body parts, shorter duration of treatment effects, and onset or
worsening of periodic limb movements while awake.85 Decreasing dose
or changing to a new medication may be required.58
Positive airway pressure (PAP) is the most effective therapy of
obstructive sleep apnea syndrome.86 Surgery87 and oral appliances88 are
not as effective, but can be considered in patients with mild disease and
those who cannot tolerate PAP.
Central sleep apnea can be treated with medications, with bi-level PAP
or noninvasive positive pressure ventilation.89

Deep Brain Stimulation

Deep brain stimulation (DBS) of the subthalamic nucleus has been
reported to improve overall measures of sleep; nocturia and daytime
sleepiness did not improve.68 Nocturnal sleep was worsened by turning
DBS off without affecting REM sleep behavior disorder.69

Driving
Driving with cognitive and motor deficits is a major issue. The
discussion here shall be limited, however, to sleepiness and driving.
Abnormalities on simulated driving have been shown in PD patients.90
Severity of disease and dopamine “load” are risks of falling asleep while
driving.91 Dose reduction of medications may improve sleepiness and
allow for safe driving.92 Although not specifically studied in driving, the
addition of modafinil can increase daytime alertness and could be
considered.75-77 As previously noted, ISCS and ESS may be useful in
assessment and may lead to the need to restrict driving.

Summary
Sleep is impaired in Parkinson’s disease more than would be expected
by effects of age. Sleep disorders, treatment, and behavior account for
some of this. Sleep impairment is also likely due to the underlying
processes affecting centers of the brain involved in sleep. Intrinsic sleep
disorders can occur more frequently in patients with PD.
Diagnosis can be made by using various surveys, or by formal
polysomnography. Treatment is focused on underlying disease, sleep
disorders, or behavioral management. Many of these problems can be
treated by the primary care physician. More complicated problems may
require a sleep medicine consultation.
The following questionnaire will help you measure your general level of
daytime sleepiness. Answers are rated on a reliable scale called the
DM, May 2007 283
Epworth Sleepiness Scale (ESS), the same assessment tool used by sleep
experts worldwide.
Each item describes a routine daytime situation. Use the scale below to
rate the likelihood that you would doze off or fall asleep (in contrast to
just feeling tired) during that activity. If you haven’t done some of these
things recently, consider how you think they would affect you.
Please note that this scale should not be used to make your own
diagnosis. It is intended as a tool to help you identify your own level of
daytime sleepiness, which can be a symptom of a sleep disorder.
Appendix 1
The Inappropriate Sleepiness Composite Scale (ISCS) is
the Total Added Score of Responses to Questions 6 and
8 Through 12 of the Modified ESS11
Modified Epworth Sleepiness Scale.
The modified score is the standard Epworth score plus 4 questions
designed to detect falling asleep in inappropriate situations. Patients were
asked to complete each of 3 versions of the questionnaire.
Version 1: Dozing off.
Patients were given the question, “How likely are you to doze or fall
asleep in the following situations (in contrast to just feeling tired)?
This refers to your usual present way of life. Even if you have not
done some of these things recently, try to recall whether they may
have occurred previously.” Patients were instructed to use the
following scale to choose the most appropriate number for each
situation: 0 ⫽ would never doze; 1 ⫽ slight chance of dozing; 2 ⫽
moderate chance of dozing; 3 ⫽ high chance of dozing.
Version 2: Sudden onset of sleep.
Patients were given the question, “If you were likely to doze or fall
asleep in any of the following situations, was the episode ever
sudden or unpredictable?” Patients were instructed to use the
following scale to choose the most appropriate number for each
situation: 0 ⫽ never; 1 ⫽ occasional but usually gradual or with
warning; 2 ⫽ often unpredictable; 3 ⫽ always sudden and unpre-
dictable.
Version 3: Blank spells.
Patients were given the question, “Have you ever had any episodes of
sudden ‘blank spells,’occurring without warning, during which you
were unaware of your surroundings in any of the following
situations? By sudden blank spells we mean sudden unexpected
284 DM, May 2007
 episodes during which you have had a loss of awareness of what was
going on around you without being asleep.” Patients were instructed
to use the following scale to choose the most appropriate number for
each situation: 0 ⫽ never; 1 ⫽ infrequently (once per month or
less); 2 ⫽ occasionally (up to once per week); 3 ⫽ frequently (more
than once per week).
Situation
Chance of Event at Present (Score, 0-3)
Epworth Sleepiness Scale (ESS)

1 Sitting and reading

2. Watching television
3. Sitting, inactive, in a public place (eg, theater or a meeting)
4. As a passenger in a car for 1 hour without a break
5. Lying down to rest in afternoon when circumstances permit
6. Sitting and talking to someone
7. Sitting quietly after lunch without alcohol
8. In car, when stopped for a few minutes in traffic
Modified Epworth Sleepiness Scale/additional situations
9. While driving
10. While eating a meal
11. While attending to work
12. While attending to routine household activities
*Questions 1-8 of version 1 of the questionnaire comprise the full
original Epworth Sleepiness Scale and were self-administered by the
patient (as per the validation of the Epworth Scale 7) while all other
questions in version 1 and all questions in versions 2 and 3 of the
questionnaire were administered by clinic staff.

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