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A review of normal sleep and its disturbances in Parkinson’s disease
P.K. Pal*, S. Calne, Ali Samii, J.A.E. Fleming
1
Neurodegenerative Disorders Centre, University of British Columbia, 2221, Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5
Received 14 December 1998; received in revised form 10 February 1999; accepted 10 February 1999
Abstract
Patients with Parkinson’s disease frequently report sleep disturbances which include difficulty initiating or maintaining sleep, parasomnias
or excessive daytime sleepiness. The underlying causes include: normal aging, motor symptoms of the disease, antiparkinson drugs,
comorbid psychiatric conditions, and concurrent illnesses. An accurate history from the patient and care-giver regarding previous sleep
patterns and how they have changed, and the degree of impact these sleep disturbances have on patient’s daily life is crucial for successful
management. Apart from drug therapy, appropriate counselling and nonpharmacologic treatments have major roles in the overall manage-
ment. This review summarizes the current concepts of (i) the pattern and function of normal sleep, and (ii) the nature, pathogenesis and
management of sleep disturbances in Parkinson’s disease. q1999 Elsevier Science Ltd. All rights reserved.
Keywords: Parkinson’s disease; Sleep; Insomnia; Parasomnia; Daytime sleepiness; Sleep benefit; Treatment
1. Introduction
Sleep has a restorative function not only for the body but
particularly for the mind. It is not just a passive phenomenon
or the absence of waking; rather it is ‘‘a special activity of
the brain, controlled by elaborate and precise mechanisms’’
[1]. The sleep duration depends on many factors with age
being the most important. As people age and succumb to
age-related illnesses sleep patterns change from the
‘‘normal sleep’’ of youth. Parkinson’s disease (PD) is
most common in the elderly, so it is not surprising that
patients have already experienced changes in their sleep
pattern prior to diagnosis. In addition to this, the underlying
neurochemical changes, pathophysiological alterations in
the central nervous system, motor problems, coexisting
depression and other psychiatric disturbances, together
with anti-parkinsonian medications can all interfere with
sleep.
2. Normal sleep and dreaming
Normal sleep is composed of a recurring succession of
indentifiable stages. Two seperate states of sleep have been
defined based on physiologic measures: (i) non-rapid eye
movement (NREM), and (ii) rapid eye movement (REM)
sleep. NREM sleep consists of 4 successive stages and these
roughly parallel a ‘‘depth of sleep’’ continuum. The arousal
threshold is generally lower in stage 1 and higher in stage 4
sleep [2]. Stages 3 and 4 are also known as slow wave sleep
(SWS) because of the high amount of delta waves in this
stage. During NREM sleep the muscles are relaxed and a
normal person makes a major postural adjustment approxi-
mately once every 20 min. Subjects are not easily aroused
during REM sleep, but spontaneous awakening is most
frequent in this stage [3].
Dreaming is common and it occurs at all ages in regular
cycles several times every night. On average, there is a
correlation of approximately 85% between the subjective
experience of dreaming and that of REM sleep [4]. The
remaining 15% of dreaming, which is said to occur in
NREM sleep, probably occurs when the underlying
neuronal activity approximates that seen in a full-blown
REM sleep episode but has not quite reached sufficient
intensity to register in the human EEG as REM sleep [4].
The probability of recalling a dream is greater if it occurs
during REM sleep but falls to zero 8 minutes after a NREM
sleep cycle begins [3]. Thus we tend to remember only early
morning dreams. In an analysis of over 10 000 dreams of
normal people, Hall and Castle [5] found that approximately
64% of the dreams were associated with sadness, apprehen-
sion, or anger, and only 18% were happy or exciting. In
contrast NREM sleep dreams are more pleasant, less vivid
and visual, less emotional and poorly recalled [3].
Parkinsonism and Related Disorders 5 (1999) 1–17
Parkinsonism &
Related Disorders
PRD 149
1353-8020/99/$ - see front matter q1999 Elsevier Science Ltd. All rights reserved.
PII: S1353-8020(99)00011-5
* Corresponding author. Tel.: 604-822-7763; fax: 604-822-7866.
1
Associate Professor in Psychiatry, Co-director, Sleep Program, Univer-
sity Hospital, Vancouver, BC, Canada.
2.1. Sleep patterns
2.1.1. Sleep in the young adult
Most young adults report sleeping 7.5 h on weekday
nights and about 8.5 h on weekend nights, though there is
a large variability of these figures from person to person and
from night to night [2]. Normal sleep begins with NREM
sleep, and REM sleep does not occur for up to 80 min or
longer. Thereafter NREM and REM sleep alternate cycli-
cally. SWS predominates in the first third of sleep and REM
sleep in the last third. NREM sleep constitutes about 75–
80% of the total sleep, REM sleep accounts for 20–25%,
occurring in 4–6 discrete episodes and wakefulness
accounts for ,5% of the night [2].
2.1.2. Sleep in the elderly
In the elderly there is more interindividual variability in
sleep performance [6]. There are quantitative and qualita-
tive changes of sleep with age. The nocturnal sleep length
decreases and the SWS is most affected. The amount of
SWS gradually decreases and it may be absent at the age
of 60 years. Women appear to maintain SWS later into life
than men [2]. The percentage of REM sleep is well main-
tained, though the latency of the first REM sleep shortens.
Arousals—both extended and transient, are frequent. Peri-
odic limb movements and sleep related respiratory distur-
bances are common in the elderly and these are partly
responsible for the arousals [7]. The strong monophasic
circadian rhythm (only nocturnal sleep) of youth is replaced
by polyphasic rhythm characterized by increased daytime
naps. There is also a phase advance of sleep, with a tendency
to go to sleep earlier and awake earlier [8,9].
2.2. Functions of sleep
Sleep has a restorative value, conserves energy and helps
to consolidate recent learning. Whole brain energy metabo-
lism is reduced by 25–30% in NREM sleep compared to the
waking state in both monkeys [10,11] and humans [12].
During sleep there is an increase in the secretion of anabolic
hormones [13–15], a decrease in the levels of catabolic
hormones [16] and the brain’s energy resources are diverted
to protein synthesis for the restoration of cell structure and
function [17]. Nakanishi et al. [18] reported widely distrib-
uted increases in rates of cerebral protein synthesis in natu-
rally occurring deep sleep (stage 3–4) in comparison to light
sleep (stage 1–2) in adult rhesus monkeys and Ramm and
Smith [19] observed a positive correlation between
weighted time in deep sleep and intracerebral protein synth-
esis in REM-sleep deprived rats. These results support the
hypothesis that deep sleep has a restorative function. Based
on the observation that deep sleep increases during recovery
from sleep deprivation, it has also been suggested that it
reverses the effects of prolonged wakefulness [20,21].
Since memory consolidation requires sleep and inhibitors
of protein synthesis block long-term memory [22], it is
possible that cerebral protein synthesis in deep sleep is
related to consolidation of memory.
The exact role of REM sleep is still not known. The need
for it decreases with age: 50% of the total sleep of a
newborn to only 25% by 10 years of age [3]. Its ontogenic
pattern roughly parallels cerebral myelinization and it has
been claimed that REM sleep becomes vital only in the
critical stages of development of the central nervous system
[23]. REM sleep may be a later phylogenetic process related
to warm blooded animals, is genetically programmed and
helps in organizing the neuronal circuits in controlling
instinctive behavioral sequences [24]. In animal experi-
ments it has been conclusively proved that REM sleep is
essential for consolidation of recent learning and memory
[25]. Though the results of the experiments in humans
usually yielded negative results, there are researchers who
believe that REM sleep is particularly important for proce-
dural learning [26]. According to the ‘neural network
theory’ of Crick and Mitchison [27], during REM sleep
the information networks are organized by selective erasure
of nonvital information, through the process of dreaming,
thus preventing ‘jam’ in the memory banks. Finally, REM
sleep is believed to allow a smooth and rapid transition from
sleep to wakefulness [28,29].
2.3. Mechanism of normal sleep and dreaming
Sleep is a process involving the entire central nervous
system. Sleep is actively produced by sleep promoting
substances acting mainly on sleep-inducing neurons located
in the brainstem. The rostral reticular formation (RF)
contains a subset of neurons that maintain wakefulness
and the caudal brainstem contains neurons that induce
sleep. Serotonergic neurons originating in the dorsal raphe
nuclei (DRN), noradrenergic neurons originating in the
locus ceruleus (LC) and cholinergic neurons of the pedun-
culopontine nucleus (PPN) are implicated in the control and
regulation of sleep, and the latter specifically in control of
REM sleep. PPN has strong connections with both the
REM-atonia circuitry and the REM-phasic generator circui-
try and a strong reciprocal connection with the substantia
nigra (SN). The pacemaker for the sleep–wake cycle is
probably in the suprachiasmatic nucleus of hypothalamus
[30,31]. SN is strongly connected to the REM-phasic
generator circuitry and probably plays an important role in
the generation of ponto-geniculo-occipital spikes (PGOs).
REM sleep has been shown to be linked to PGOs. These
waves are generated in the pontine RF [32], propagate
rostrally through the brachium conjunctivum [33,34] and
project through the lateral geniculate bodies and other thala-
mic nuclei [35] to the cortex. It has been shown that the
serotonergic neurons of DRN and the monoaminergic
neurons of the LC normally suppress these PGO waves.
Hobson et al. [36] proposed the reciprocal roles of ACh in
REM sleep and the monoamines in SWS. The cholino-
ceptive cells in the gigantocellular tegmental fields fire
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–172
rapidly and in a phasic manner throughout REM sleep. This
firing pattern is correlated with PGOs, rapid eye movements
and muscle twitches.
The biological events of REM sleep and the subjective
experience of dreaming are tightly linked. REM sleep has
two components: (i) tonic (EMG suppression, low voltage
desynchronized EEG), and (ii) phasic (rapid eye move-
ments, middle ear muscle activity, somatic muscle-limb
twitches, variability of autonomic activity and PGO spikes).
It is not known whether dreaming occurs in phasic or tonic
REM sleep.
3. Sleep in PD patients
Sleep disturbances are common in PD; however its exact
prevalence is difficult to ascertain due to the heterogeneity
of patients and different criteria used to categorize sleep
disturbances. Nausieda et al. [37] and van Hilten et al.
[38] reported prevalence to be as high as 74–81%, and in
another study [39] 98% of patients had ‘disabilities at night
or on waking’.
There is a paucity of data on the role of gender in sleep
disturbances. In a study of 153 patients and their spouses,
Smith et al. [40] reported sleep disturbances occured more
frequently in females (PD: 41%, spouse: 48%) than in men
(25 and 27% respectively). van Hilten et al. [38] reported
that although there was no sex difference for difficulty initi-
ating sleep, female patients experienced more disturbed
sleep maintenance (87.5%) and excessive dreaming
(68.4%) than the males (64 and 31.6% respectively).
3.1. Types of sleep disturbances
In PD there may be different combinations of sleep distur-
bances [37–39,41–45] which can be broadly divided into
three major categories (Table 1): (i) insomnias; (ii) para-
somnias; and (iii) excessive daytime sleepiness (EDS).
3.1.1. Insomnias
Insomnias are disorders of initiating (initial insomnia) or
maintaining sleep (sleep maintenance insomnia or sleep
fragmentation). Sleep fragmentation is the most consistent
and often the earliest sleep disturbance in PD, characterized
by frequent awakenings in the night with often 30–40% of
the time spent awake. In one study more than 80% of PD
patients complained of difficulty maintaining sleep and most
awakened 2–5 times/night [39]. This may be due to noctur-
nal problems related to age, PD or complications of treat-
ment. Problems include: nocturia, inability to turn over in
bed, painful leg cramps, vivid dreams/nightmares, pain,
stiffness, anxiety, jerks, etc. [38,39,43].
Initial insomnia is a common problem in the normal
population and is often related to anxiety and agitated
depression. In PD, the amphetamine-like effect of levodopa
that disappears with time [45], severity of illness [46], rest-
less legs and akathisia may contribute further, though in
controlled studies the prevalence of initial insomnia is
found to be similar to elderly controls.
3.1.2. Parasomnias
These are undesirable behaviors that occur exclusively
during sleep or are exaggerated by sleep [47] and include
a number of phenomena such as vivid dreams, altered dream
content, nightmares, night terrors, nocturnal vocalizations,
REM Sleep Behavior Disorder (RBD), nocturnal hallucino-
sis, sleeptalking, somnambulism, and panic attacks.
Accurate evaluation of these disorders may need polysom-
nography in addition to a detailed clinical history from the
patient’s bed-partner.
Sharf et al. [48] reported a high incidence (30.7%) of
chronic levodopa related ‘new dream experiences’ in PD
patients which were absent prior to levodopa therapy.
These included vivid dreams (22.7%), night terrors with
nocturnal vocalizations (6.8%) and nightmares (5.7%).
Their incidence of first occurrence and prevalence corre-
lated with the duration of levodopa therapy but not with
the age, stage of disease, disability, concurrent medications
or family history of psychosis. A similar higher incidence of
‘altered dream experience’ (more intense, unpleasant, frigh-
tening or recurring dreams) in PD patients (24%) when
compared to controls (1.6%) was reported by van Hilten
et al. [38], but there was no correlation with any of the
clinical or medication variables. This discrepancy could
have been due to the mean higher dose of levodopa, more
severe stage of illness and inclusion of patients with mild to
moderate dementia in Sharf’s study [38]. The prevalence of
hallucinations is also reported to be high (21.8–29.5%)
[39,48] in patients experiencing altered dreams. Since
there is also a high incidence of altered dreaming (59–
61.3%) in hallucinating patients [39,49], a common under-
lying pathogenetic mechanism is possible. Psychiatric
effects of chronic dopaminergic therapy may be a part of
a progressive syndrome with sleep disruption and vivid
dreams as an initial manifestation [37,49]. Moskovitz et al.
[49] proposed a kindling mechanism such that there is a
progressive development of dopamine receptor hypersensi-
tivity in the mesolimbic system with chronic dopaminergic
stimulation and altered dreaming might be a first step in a
progressive cascade of events leading to drug-induced
psychosis.
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–17 3
Table 1
Types of sleep disturbances in Parkinson’s disease
1. Insomnias:
(a) Sleep maintenance insomnia (sleep fragmentation)
(b) Initial insomnia
2. Parasomnias:
Vivid dreams, altered dream content, nightmares, night
terrors, nocturnal vocalizations, REM Sleep Behavior
Disorder, nocturnal hallucinosis, sleep talking,
somnambulism and panic attacks.
3. Excessive daytime sleepiness
In our experience, a subset of patients with long standing
PD and impaired cognition, on chronic dopaminergic ther-
apy, are most susceptible to vivid dreams and visual hallu-
cinations. Dopamine agonists are more likely to cause
altered dreaming than levodopa.
Some of the above parasomnias have been reported to
precede the development of full-blown RBD [50]. Night-
mares, induced by chronic dopaminergic medications,
may be a precursor of dementia, or may be idiopathic
[51]. There is no alteration of sleep architecture in patients
with night terrors [52] whereas patients with nocturnal
hallucinations have fragmented sleep that is similar to
RBD [53]. Though rare, panic attacks can manifest noctur-
nally in PD, typically during the off phase in depressed
patients taking levodopa but not dopamine agonists [54].
3.1.2.1. REM sleep behavior disorder (RBD). Wakefulness
is associated with consciousness and muscle tone, and REM
sleep with dreaming and muscle atonia. Abnormal
combinations of wakefulness, REM sleep and NREM
sleep may result in RBD, manifesting as wakeful
automatic behavior during REM sleep. RBD is
characterized by vigorous and injurious behavior that
usually represents attempted enactment of vivid, action-
filled, and violent dreams [55,56]. These occur at least
90 min after sleep onset and during REM episodes. The
patients may injure themselves or their bed-partners. Most
patients complain of sleep injury but not sleep disruption
and they are usually awakened by their partner. These
violent nocturnal behaviors are completely discordant with
their waking personality. Polysomnography is essential for
the diagnosis and is characterized by EMG evidence of loss
of generalized muscle atonia of REM sleep, or prominent
phasic muscle twitching in REM sleep, or both [57]. RBD
usually affects older men and may be idiopathic or limited to
other disorders (60%) [57]. The exact incidence of RBD in
PD is not known. Comella et al. [53] evaluated 10 non-
depressed, non-demented PD patients on dopaminergic
medications polysomnographically, and reported RBD in
five. PD patients with dopaminergic drug induced
hallucinations had significantly greater REM sleep
disturbances, with RBD in four out of five patients.
Uchiyama et al. [58] reported incidental Lewy Body
Disease (LBD) at autopsy in an 84-year-old patient with a
20 year history of RBD. Histopathological examination
revealed LBD with a marked decrease of pigmented neurons
in the LC and SN. These changes were almost identical to
those seen in PD, though this patient did not have clinical
parkinsonism. Subsequently, Negro and Faber [59] reported
a patient with RBD who developed parkinsonism and
dementia (thus fitting into the clinical criteria of DLBD)
after 13 years. A similar case was also reported by Turner
et al. [60]. Schenck et al. [57], followed 29 male patients
(.50 years of age) with RBD. Eleven of them (38.1%) were
eventually diagnosed to have a parkinsonian disorder
(presumably PD) at a mean interval of 3.7 ^1.4 years
after the diagnosis of RBD. This subset of patients was
distinguished from the patients with idiopathic RBD by a
significantly elevated hourly index of periodic leg move-
ments of NREM sleep and an elevated percentage of
REM sleep. Thus RBD, especially in older males, may
precede a progressive neurodegenerative disorder such as
PD, DLBD or multiple system atrophy (MSA), or it can
be one of their early clinical manifestations. In PD, a
confounding factor is the effect of anti-parkinsonian drugs
on REM sleep (discussed below).
3.1.3. Excessive daytime sleepiness (EDS)
EDS is an inappropriate and undesirable sleepiness
during waking hours. A direct, objective measurement of
EDS is the Multiple Sleep Latency Test (MSLT) [61].
However this test is cumbersome, time-consuming and
expensive. An alternative reliable measurement is the
Epworth Sleepiness Scale (ESS), a set of eight questions,
validated by correlation with MSLT and has the ability to
distinguish persons with sleep apnea, narcolepsy, and idio-
pathic hypersomnia from persons without sleep disorders
[62–64].
The circadian rhythm of sleep is biphasic in the elderly
and thus they have more pronounced normal afternoon
drowsiness. Surveys of the general population have shown
that between 0.5 and 5% complained of EDS [65]. However,
in a recent cross-sectional study of 4578 non-institutiona-
lized elderly persons (65 years or more) from Medicare
enrollees in four US communities, approximately 20%
reported ‘usually sleepy in the daytime’ [66]. In the latter
study daytime sleepiness correlated independently with
frequent nocturnal awakeninngs, loud snoring, depression,
and limitation of daily activities. EDS can also be a cardinal
sign of many diseases including sleep apnea, narcolepsy,
nocturnal periodic movements, circadian rhythm disorders,
affective disorders (depression), excessive drug or alcohol
use, or idiopathic hypersomnolence [61,66,67].
EDS is common in PD [37–39]. However, in one study
[38] no significant difference was found in its prevalence
between PD patients (44.4%) and controls (31%). The diur-
nal pattern was similar, with a peak in the early afternoon.
The authors concluded that no relationship exists between
PD and EDS and that EDS is probably a consequence of
aging, as previously reported by Morewitz [68] and Carska-
don [69]. Factor et al. [39] observed that though the preva-
lence of daytime napping might be similar in PD and the
normal elderly controls, spontaneous dozing is more
common in PD. It is likely that EDS is equally common
in both groups, but more severe in PD as a result of more
fragmented nocturnal sleep.
EDS should be differentiated from two other apparently
similar conditions which may be found in patients with PD:
(i) ‘sleepy all day’, and (ii) excessive daytime fatigue
(EDF). In the former condition though the subject feels
sleepy, there are no distinct episodes of inappropriate
sleep and is often due to an unrelated systemic disorder
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–174
(electrolyte imbalance, endocrine disease, megaloblastic
anaemia, iron deficiency anaemia) or depression [45].
EDF is severe physical tiredeness and lack of energy,
distinct from sadness, sleepiness, and impaired motor func-
tion secondary to PD symptoms (weakness, stiffness and
tremor). EDF was reported in 43% of patients with PD
[38]. No relationship was found between fatigue and the
patients’ clinical characteristics or the use of PD medica-
tions, and most of the patients associated fatigue with physi-
cal exertion. It was exacerbated by high and low ambient
temperature. Unlike previous studies [70,71], van Hilten et
al. [38] did not find any association between EDF and any
circadian factor, and EDF was not subject to a typical diur-
nal pattern. In our experience, unusual fatiguability is
common in PD and often it does not respond to an increase
in dopaminergic medications, even though these improve
rigidity and bradykinesia. Underlying depression often
contributes to EDF and patients may benefit from antide-
pressants.
3.2. Causes of sleep disturbances in PD patients
3.2.1. Effects of Parkinson’s disease
Disturbance in sleep–wake regulation may result from
the disease process involving neuronal loss of LC, SN,
retrorubral nucleus and PPN [72]. The severity of parkinso-
nian symptoms influences the degree of sleep disturbances.
Sleep onset latency and the number of awakenings tend to
increase in proportion to the severity of waking parkinso-
nian symptoms [46]. When asleep, patients with rigidity
have less REM sleep than patients with normal tone.
[73,74].
The severity of tremor during the night has a significant
impact on the quality of sleep. Tremor disappears at the
onset of stage 1 sleep, in some cases before alpha EEG
activity is entirely gone [75–77]. Tremor may reappear in
stages 1 and 2 and with awakenings, arousals, and body
movements [78]. It may also be present for a few seconds
during sleep stage changes, during bursts of REM, shortly
before or after a REM period and at other times without any
obvious correlation [75,77]. Tremor is rarely present during
stages 3 and 4 sleep and is not associated with sleep spindles
or K complexes [41]. The amplitude of tremor varies
considerably during sleep and is usually less than 50% of
the waking amplitude [76]. The alternating pattern of tremor
disappears during sleep, and both agonist and antagonist
muscles oscillate independently in a non-alternating pattern;
non-alternating tremor persists during all stages of NREM
sleep at a subclinical level and disappears during REM sleep
[79]. Often tremor improves or is absent for 1–2 h after
awakening [41].
3.2.2. Sleep disruption due to abnormal nocturnal motor
activities commonly seen in PD
Abnormal simple and complex movements are common
during sleep in PD [41] and these may result in sleep
disruption from frequent awakenings. Simple movements
include repeated blinking at the onset of sleep, rapid eye
movements during NREM sleep, blepharospasm at the onset
of REM sleep and prolonged tonic limb muscle contraction
during NREM sleep [73,74,80,81]. The more complex
movements are as follows.
3.2.2.1. Fragmentary nocturnal myoclonus. Fragmentary
irregular myoclonic jerks of the extremities may occur
mainly during light NREM sleep. This may be related to
chronic dopaminergic therapy [82,83] and occur more
frequently in those with levodopa-induced dyskinesias
[82]. Improvement by discontinuing levodopa and by
serotonergic antagonists suggests that this phenomenon
may be due to levodopa-induced upregulation of
serotonergic transmission [82].
3.2.2.2. Periodic leg movements of sleep (PLMS) and
Restless leg syndrome (RLS). PLMS is described as
rhythmic extensions of the big toe and dorsiflexion of the
ankle with occasional flexion of the knee and hip, each
movement lasting 0.5–5 s with a frequency of one every
20–40 s [84]. In contrast to myoclonus, PLMS are more
often unilateral, prolonged and spaced at regular intervals
[54]. The PLMS are more numerous in the first half of the
night and they may awaken the patient. The prevalence of
PLMS is correlated with age. Although it has been reported
to occur in nearly one-third of PD patients [41], this
prevalence may not be greater than that found in a general
population over the age of 65 [85]. PLMS may result from a
deficit in central dopaminergic transmission [86] for it
repsonds well to dopaminergic drugs.
RLS is best described as difficult to describe creeping
sensations deep in the lower limbs accompanied by the
compulsion to move which relieves the discomfort tempora-
rily. Occasionally the upper limbs are also affected [84].
Symptoms are worse in the evening or when the patient
attempts to rest and are relieved by aggressive motor activ-
ity and walking. These patients have either difficulty falling
asleep due to dysesthesias or they may fall asleep but wake
up later with paresthesias [84]. The distinction between
PLMS and RLS is somewhat artificial and the two
frequently coexist in PD [54]. Approximately 50% of
patients with RLS have associated PLMS [87].
3.2.2.3. Nocturnal Akathisia (NA). NA is a subjective
sensation of restlessness that may or may not be
accompanied by repetitive stereotyped movements due to
difficulty remaining still [88]. Often described by the patient
as ‘inner restlessness’, it lacks the characteristic feature of
RLS of being typically relieved by movement or pacing
[54]. It tends to occur more commonly in PD patients
with bradykinesia and ‘stiffness’ [89] or it may occur
unrelated to either motor or mental state or time of day [88].
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–17 5
3.2.3. Age related sleep changes
It has been a matter of debate as to whether sleep distur-
bances in PD could be entirely due to normal aging. In a
study comparing PD patients with age-matched controls,
high rates of sleep disturbances were found in both groups
(81 and 92%, respectively) [38]. There were no statistically
significant differences between the two groups in the preva-
lence of impaired sleep initiation, sleep maintenance, exces-
sive dreaming, problems with waking up, and excessive
daytime sleepiness (EDS). However PD patients had greater
severity of disturbed sleep maintenance with more frequent
awakenings due to nocturia, pain, stiffness, and problems
turning over in bed. In a later study [90] this difference in the
degree of disturbed sleep maintenance has been correlated
with a significantly elevated motor activity level in the PD
patients. Similarly, though prevalence of EDS and excessive
dreaming were not different in the two groups, the PD
patients had more spontaneous dozing during the day [39],
altered dreaming [38], nocturnal vocalizations and halluci-
nations [39]. Thus, though PD patients and normal elderly
may have similar prevalence of sleep disturbances, qualita-
tive and quantitative differences do exist.
3.2.4. Coexisting medical and psychiatric conditions
3.2.4.1. Medical illnesses. PD patients are susceptible to
other age-related problems such as joint pain, prostatic
hypertrophy, and dyspnoea. All these can result in sleep
disturbances, the most common of which is frequent
awakening. Goetz et al. [91] found pain to be a frequent
accompanying feature in chronic PD (mean Hoehn–Yahr
score: 3.3), occurring in 46% of patients. Most subjects
(74%) experienced muscle cramps or tightness, typically
in the neck, paraspinal, or calf muscles; also included
were painful dystonias (28%), radicular or neuritic pain
(14%) and joint pain (14%). Though the overall incidence
of depression and sleep disturbances was not statistically
different in those with pain (63 and 31%) compared to
those without (57 and 22%), the severity of sleep disruption
correlated with the severity of pain. Patients with pain had
more difficulty maintaining sleep and more nightmares than
patients without. The association between depression and
sleep disturbances was significantly greater in those with
pain than in those without.
Sleep fragmentation has been reported to occur due to
nocturnal respiratory disturbances in some PD patients
[41]. Patients with moderate to severe PD can have impaired
waking pulmonary functions as a result of one or more of
the following: (i) obstructive ventilatory deficit, probably
due in part to abnormal tone in upper airway muscles, and
respiratory muscle incoordination with decreased effective
muscle strength [92]; (ii) intermittent airway closure due to
abnormal movements of glottic and supraglottic structures
caused either by disease or by dopaminergic medications
[93]; (iii) swallowing disturbances [94]; and (iv) abnormal-
ities of respiratory drive [95,96]. The above factors lead to
impaired nocturnal respiration including central and
obstructive sleep apneas and episodes of hypoventilation
[97,98]. The severity of these respiratory disturbances was
found to be greater in patients with autonomic disturbance
[97].
3.2.4.2. Psychiatric illnesses. Patients with anxiety
disorders complain of difficulty falling asleep but less
frequently of nocturnal awakenings. Patients with
depression have either insomnia (middle and terminal
insomnia are more common) or less frequently
hypersomnia. Moreover depressed mood is a significant
contributing factor to the prevalence of EDS in the
general population, and the elderly in particular [66,99–
101]. The depressed patients obtain less SWS. Though
total REM sleep is not curtailed, severely depressed
patients enter REM sleep shortly after sleep onset [102].
Anxiety is extremely common in PD [103,104] and
depression is reported in 30–90% of the patients [105].
Though depression in PD may be reactive, particularly in
young onset patients, it is most often endogenous [106]. PD
patients can have a variety of sleep disturbances as outlined
above, as a result of coexisting anxiety and/or depression
[44,91,107,108]. Kostic et al. [107] found that depressed PD
patients had a decreased latency of REM sleep when
compared to non-depressed PD patients, but other sleep
variables did not differ between the two groups. In a later
study involving 99 patients with PD and 47 controls, Menza
and Rosen [44] found that depression correlated with the
frequency of restless legs and non-restorative sleep. There
was also a significant correlation between anxiety, nighttime
awakenings and feeling unrefreshed, and the presence of on-
off phenomenon and high levodopa dosage.
3.2.5. Adverse effects of medications
3.2.5.1. Dopaminomimetic drugs. Dopaminergic projec-
tions from the ventral tegmental area to the cerebral cortex,
where the predominant receptor is D1, are associated with
arousal [109]. D1 agonists produce arousal and suppress
REM sleep, while antagonists produce sedation and increase
REM sleep [110–113]. High doses of dopamine receptor
agonists such as apomorphine reduce total sleep time as
well as REM sleep, while low doses induce sleep and
increase the amount of SWS [114,115]. Thus levodopa
and dopamine agonists influence sleep through their effects
on mesocortical dopaminergic pathways.
In healthy adults dopaminomimetic drugs lengthen
daytime sleep latencies, improve attention, and increase
wakefulness during nocturnal sleep. Though higher doses
decrease the duration of REM sleep, this is entirely due to
wakefulness. Latencies of REM sleep and ratios of REM
sleep to NREM sleep are not altered [116]. The exact effect
of dopaminomimetic drugs on PD patients is still controver-
sial. Levodopa has been reported to have decreased,
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–176
increased or even have no effect on REM sleep [80,117–
123].
Askenasy and Yahr [124] reported reversal of the light
fragmented sleep pattern and normalization of muscle activ-
ity during sleep occuring after clinical improvement with
dopaminergic drugs in five PD patients. There was a strong
association between the improvement in sleep pattern and
clinical improvement during wakefulness. Improvement in
nocturnal sleep is possibly related to improved daytime
wakefulness because of the arousal effect of dopamine
and the normalization of sleep muscle activity produced
by dopaminergic agents [124]. Improvement of sleep scores
and reduction of spontaneous movements with levodopa or
its controlled release preparations, taken shortly before
going to bed, has also been reported in other studies
[125– 127]. Sleep maintenance has been reported to improve
with an increasing daily dose of levodopa within the range
of 50–1625 mg levodopa/day [38].
However, these beneficial effects of levodopa on sleep
have not been substantiated in other studies. Sleep distur-
bances have been reported after long-term levodopa therapy
[128,129] and their prevalence has been found to parallel the
duration of levodopa therapy rather than the duration of PD
[37]. In a study involving 220 patients with PD, Lees et al.
[43] failed to observe any correlation between the occur-
rence of nocturnal symptoms and the timing of the last daily
dose of antiparkinsonian therapy. Recently, van Hilten et al.
[90], using continuous activity monitoring, evaluated 89
non-depressed PD patients for sleep disruption. A higher
daily dose of levodopa was associated with higher nocturnal
activity levels, an increased proportion of time with move-
ment and a more disturbed sleep. The daily dose of levodopa
or dopamine agonists, rather than disease severity, proved to
be the best predictor of nocturnal activity and thus sleep
disturbance. The authors postulated that in mild to moderate
PD, dopaminergic medications cause sleep-disruption by
their effects on sleep regulation and arousal effect. However
in more seriously affected patients, the beneficial effects of
these drugs on the nocturnal disabilities outweigh the
adverse effects on sleep, and thus sleep benefit occurs.
3.2.5.2. Commonly used drugs that can cause
insomnia. Antihypertensives (clonidine, beta-blockers
such as propranolol, atenolol, pindolol), bronchodilators
(terbutaline, albuterol, salmeterol, metaproterenol), xan-
thine derivatives (theophylline), decongestants (phenyl-
prpanolamine, pseudoephedrine), hormones (thyroid
preperations, cortisone, progesterone), anticholinergics,
phenytoin, nicotine, caffeine and quinidine [130,131].
3.2.5.3. Drugs causing alteration of sleep architec-
ture. Patients with PD may often take the following
drugs, which may cause adverse effect on sleep: (i) Benzo-
diazepines: Though these drugs are the cornerstone for
treating sleep disorders, they change the architercture of
normal sleep by producing alterations in the duration of
the various sleep stages. While stage 2 sleep is prolonged,
the duration of both SWS and REM sleep may be consider-
ably reduced probably due to an unselective depression of
the activity in arousal systems and in the brainstem and
pontine mechanisms which promote SWS and REM sleep
[132]. Excessive daytime sedation can also result from
chronic usage of these drugs. (ii) Antidepressants: Tricyclic
antidepressants (TCA) and monoamine oxidase inhibitors
(MAOI) suppress REM sleep [133]. Some of these
compounds increase the level of motor activity during
sleep which leads to agitated REM sleep or cause an
increased incidence of periodic movements during sleep
[2]. (iii) Antipsychotics: Many antipsychotic drugs have
sedative/hypnotic properties and increase both SWS and
REM sleep [134]. The increase in REM sleep may be partly
due to the dopamine receptor antagonism [132]. (iv) Anti-
cholinergics: These may contribute to existing autonomic
dysfunction and may worsen prostate problems. They may
have an adverse effect on respiratory activity during sleep,
and may also suppress REM sleep [135,136]. The with-
drawal of drugs that selectively suppress a stage of sleep
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–17 7
Table 2
Causes of sleep disturbances in Parkinson’s disease
1. Age related sleep changes
2. Effects of Parkinson’s disease (PD):
(a) Disturbance in sleep-wake regulation by the disease process
involving neuronal loss of locus ceruleus, substantia nigra, retrorubral
nucleus and pedunculopontine nucleus
(b) Sleep disruption and arousal attributable to the effects of
Parkinsonian motor symptoms including tremor, rigidity, bradykinesia
and motor fluctuations (e.g. dyskinesias, freezing, unpredictable off
periods)
3. Abnormal nocturnal motor activities commonly seen in PD:
(a) Simple motor activities:
Repeated blinking at sleep onset, rapid eye movements during NREM
sleep, prolonged tonic limb muscle contraction during NREM sleep,
blepharospasm at onset of REM sleep.
(b) Complex motor activities:
Fragmentary nocturnal myoclonus, periodic leg movements of sleep,
restless leg syndrome, nocturnal akathisia, movements related to
parasomnias.
4. Coexisting medical and psychiatric conditions
5. Adverse effects of medications:
(a) Dopaminomimetic medications:
May cause arousals, myoclonic movements, disruption of the circadian
rhythm, vivid dreams and nightmares.
(b) Commonly used drugs known to cause insomnia:
Antihypertensives (clonidine, beta-blockers such as propranolol,
atenolol, pindolol), bronchodilators (terbutaline, albuterol, salmeterol,
metaproterenol), xanthine derivatives (theophylline), decongestants
(phenylprpanolamine, pseudoephedrine), hormones (thyroid
preperations, cortisone, progesterone), anticholinergics, phenytoin,
nicotine, cagffeine and quinidine.
(c) Drugs causing alteration of sleep architecture:
Benzodiazepines: Prolong stage 2 sleep, reduce stages 3 and 4 and REM
sleep; excessive daytime sleepiness.
Antidepressants: Suppress REM sleep; may increase level of motor
activity in sleep.
Antipsychotics: May increase stages 3 and 4 and REM sleep.
Anticholinergics: May suppress REM sleep.
tends to be associated with a rebound of that stage of sleep.
Thus a detailed history of drug intake or recent withdrawal
needs to be obtained in order not to misdiagnose an organic
sleep disorder.
The causes of sleep disturbances in PD patients are
summarized in Table 2.
3.3. Sleep disturbances in spouses of PD patients
Caregivers, especially the spouses of PD patients are also
prone to develop frequent sleep disturbances though their
importance is often overshadowed by the problems of the
patient. Very often the decision to hospitalize a PD patient is
the direct consequence of repetitive night sleep disturbances
caused by the patient to the caregiver. Recently Smith et al.
[40] evaluated sleep in 153 PD patients and their spouses
using a nationwide survey. Subjectively rated sleep distur-
bances were found to be as frequent in the spouses of PD
patients as in the patients themselves. Females in both
groups were more affected than males. In both groups, the
major predictor of sleep disturbance was depression and in
addition, the spouses had to wake up during the night to
assist the patients. ‘Psychological’ and ‘somatic’ symptoms
of depression were assessed by the Zung Self-rating Depres-
sion Scale [137]. Interestingly, ‘somatic depression’ was the
best predictor of poor sleep for male spouses whereas
‘psychological depression’ or stress ratings, was for female
care-givers.
3.4. Effect of sleep on Parkinson’s disease: ‘‘Sleep Benefit’’
Sleep benefit (SB) is defined as a period of lessened
disability, or feeling ‘on’ upon awakening from sleep
[138]. The incidence of SB has been reported to vary
from 10–55% [39,138–142]. The mechanism underlying
SB is not known though several hypotheses have been
proposed [39,140,143–145].
Factor et al. [39] did not find any difference in age, stage
and duration of disease, predominant signs and symptoms,
or antiparkinsonian medications between the morning-
better (43.6%) and morning-worse (37.2%) groups. Both
groups had substantial difficulty with sleep initiation and
maintenance. The morning-same group (19.2%) had more
recent onset, less severe disease and required fewer anti-
parkinsonian medications.
Comella et al. [139] reported SB, lasting from 30 min to
more than 3 h in 25% of 117 PD patients. Compared to PD
patients without SB, these patients were younger, had
shorter duration of disease, lower Hoehn and Yahr stage,
and took less levodopa per day. In contrast the patients with
SB in another study [138] had longer durations of PD,
longer duration of treatment with levodopa and were taking
a higher total daily dose of levodopa than those without SB.
The latter findings argue against the hypothesis that SB
occurs only in patients with milder PD. Higher residual
tissue levels of levodopa each morning in those on higher
doses of levodopa, or sensitization to levodopa in patients
on levodopa for longer duration, may play a role in pro-
ducing SB [138]. Similarly, Merello et al. [141] reported
SB in 55% of the 312 patients. These patients were also
significantly older, had longer disease duration, and were
more often men than those without SB.. However there were
no significant differences between the two groups with
respect to the frequency of motor fluctuations, duration of
levodopa treatment and the type of levodopa preparation
taken at bedtime. Although the frequency of using sleep
medications, hours of sleep, sleep latency or sleep problems
(nightmares or somnambulism) were similar in the two
groups, more patients with SB tended to wake up during
the night than did patients without. The duration of SB in
patients in this study was 85.4 ^67 min and about 50% of
them were able to postpone the morning levodopa dose.
This apparent paradox of a positive correlation between
SB and disease duration but not with the duration of levo-
dopa therapy might be due to the delay in starting levodopa
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–178
Table 3
Management of sleep disturbances in Parkinson’s disease
1. Nonpharmacologic management:
Good sleep hygiene, behavioral therapies.
2. Treatment of coexisting medical illnesses.
3. Treatment of coexisting psychiatric illnesses:
Anxiety: Short acting Benzodiazepines
Depression: Amitryptiline, fluoxetine, venlafaxine
Psychosis: Clozapine, olanzapine, ondasetron.
4. Adjustment of dopaminomimetic medications:
(a) Sleep-onset insomnia/nocturnal hallucinations/nightmares/
delirium/dyskinesias/ nocturnal myoclonus:
(i) Reduce evening doses of dopaminiomimetic drugs,
(ii) Prepone the drugs, (iii) If possible stop selegiline and
amantadine.
(b) Sleep-maintenance insomnia due to Parkinsonian motor
symptoms:
(i) Small bedtime dose of levodopa-carbidopa (e.g. Sinemet
100/25) with a second similar dose at 2 or 3 A.M. if patient
awakens,
(ii) Controlled release levodopa-carbidopa (e.g. Sinemet CR
200/50) at bedtime.
5. Treatment of specific disorders:
REM Sleep Behaviour Disorder:
Clonazepam
Nocturnal myoclonus:
(i) Reduction of nightime dose of dopaminomimetics,
(ii) Benzodiazepine shortly before bedtime
Periodic leg movements of sleep/restless leg syndrome:
(i) Benzodiazepines (e.g. clonazepam, temazepam,
nitrazepam),
(ii) Dopaminomimetic drugs, (iii) Opioids (e.g. oxycodone,
propoxyphene), (iv) Carbamazepine, (v) Clonidine,
(vi) Lioresal
Leg cramps:
(i) Evening dose of controlled release levodopa/carbidopa,
(ii) Quinine,
(iii) Anticholinergics, (iv) Lioresal
6. Use of sedatives/ hypnotics:
(i) Benzodiazepines, (ii) Zolpidem, (iii) Zopiclone
by those who had SB early in the course of their disease
[141].
In conclusion, it is evident that a subset of PD patients do
experience SB, but it is still uncertain whether age, duration
and stage of illness, or antiparkinsonian medications modify
the beneficial effect of sleep.
4. Management of sleep problems in PD patients
4.1. Establishing a diagnosis
It is important to take a detailed history from both the
patient and the bed-partner/caregiver, regarding the
patient’s routine night sleep behaviour. The following
items need to be addressed and explored: (i) did sleep distur-
bances preceed or follow the symptoms of PD? (ii) a review
of all medications and schedule of administration; (iii)
daytime sleeping/naps; (iv) evidence of depression and/or
anxiety; (v) coexisting medical illnesses; (vi) family history
of sleep disorder; (vii) a sleep record over one month; (viii)
a complete clinical examination with special attention to the
possibility of multisystem atrophy and dementia.
Sleep loss of one or more nights will lead to prolongation
and deepening of SWS on subsequent nights. REM sleep
usually tends to recover only after the restoration SWS.
However, if there is deprivation specifically of REM or
SWS sleep, a preferential rebound of that stage of sleep
may occur. In contrast, chronic restriction of nocturnal
sleep, an irregular sleep schedule or frequent disturbances
of sleep can result in premature REM sleep (sleep onset
REM episodes) which can be associated with hypnagogic
hallucinations, sleep paralysis or an increased incidence of
hypnic myoclonia in individuals with no organic sleep
disorder [2].
Polysomnographic evaluation reveals a variety of
abnormalities which may include: (i) increase in stage 1
and decrease in stages 3, 4 and REM sleep [146]; (ii) a
decrease in the number of sleep spindles in SWS [147];
(iii) presence of alpha activity during REM sleep [73];
and (iv) disturbed normal cycling between NREM and
REM sleep [81]. REM sleep and total sleep time are often
markedly decreased in patients with nocturnal hallucina-
tions [148]. Polysomnography can be helpful in patients
suspected of having sleep apnea, RLS-PLMS, RBD and
EDS. MSLT is helpful to quantify the severity of EDS. It
may be difficult to perform a clean scoring in polysomno-
graphy of a PD patient due to muscle artefacts. A detailed
description of polysomnography and MSLT is beyond the
scope of this review.
4.2. Treatment
The initial step should be to identify the nature of the
disturbed sleep and assess any concurrent medical, psycho-
logical, or psychosocial factors contributing to it. Counsel-
ling the patient and the caregiver with special emphasis on
normal age-related changes in sleep pattern is important.
Further management of sleep problems falls into two cate-
gories: (a) nonpharmacologic management that focuses on
practicing good sleep hygiene and behavioral therapy; and
(b) pharmacologic management of insomnia and of specific
problems leading to disturbed sleep in PD (cf. Table 3).
4.2.1. Nonpharmacologic management
Sleep hygiene refers to a number of simple recommenda-
tions often suggested to help people with insomnia change
behavior that is adversely affecting sleep [149]. Good sleep
hygiene is the cornerstone of effective management of any
sleep disorder. For a review on this topic, the reader is
referred to Zarcone [150]. Behavioral programmes for
insomnia [151,152] include stimulus control therapy
[151], sleep restriction therapy [153], relaxation therapies
[149], cognitive therapy [154], chronotherapy [155] and
bright light therapy [156]. These therapies need to be
tailored according to the underlying causes of sleep distur-
bances and coexisting medical illnesses. In PD patients, we
recommended the following:
(i) The bedroom should be well ventilated with a comfor-
table temperature, night light, low, adjustable bed with
firm non-slippery mattress, easily accessible nighttime
medications and a drink. There should be an unobstructed
well-lit path to the bathroom.
(ii) A bedside commode, urinal or condom catheter may
be necessary if the patient has increased frequency of
micturation.
(iii) When there is excessive bradykinesia and rigidity,
devices to help the patient get in and out of bed are help-
ful. A rehabilitation specialist can advise on appropriate
aides for individual needs.
(iv) The following are helpful: regular exercise (avoid
strenuous exercise in the evening), relaxation therapy,
and avoiding caffeinated drinks, smoking, heavy meals
and alcoholic beverages.
(v) Patients with urinary frequency at night should limit
fluid intake after 4 P.M.
(vi) It is often helpful to have a warm bath 2 h before
bedtime, a glass of warm milk and a light bedtime snack.
(vii) Reading before lights-out may help patients to over-
come initial insomnia.
(viii) The patient may find it easier to fall asleep in a
comfortable reclining arm-chair, rather than in a bed.
However they must be able to adjust the chair themselves.
(ix) A flexible sleep schedule is recommended rather than
going to bed at a fixed time—otherwise missing the set
time leads to anxiety and further insomnia. However, to
promote re-regulation of the circadian rhythm it is impor-
tant to get up at the same time each morning.
(x) If the patient wakes up during the night, simple self-
hypnosis and relaxation exercises are helpful rather than
concentrating on returning to sleep. A rehabilitation
therapist can teach relaxation techniques.
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–17 9
(xi) Early morning waking, unless due to depression, is
often best managed by getting out of bed and getting on
with normal daily activities, if the symptoms permit.
(xii) Adequate exposure to morning sunlight helps in
maintaining the circadian rhythm. The use of sunglasses
should be discouraged.
(xiii) Many patients find short daytime naps to be bene-
ficial. These should not be of concern unless they are very
frequent or associated with vivid dreams (due to sleep
onset REMs). A biphasic sleep pattern is not unusual in
the elderly and afternoon sleep may be restorative. If a
patient is continually napping during the day it can be
helpful to establish one or two regular nap times, taken
on the bed with the telephone off, lasting for a pre-deter-
mined length of time.
The caregiver also needs sleep. The patient and the care-
giver may sleep better (at least sometimes) in separate
bedrooms. Alternatively patients may do well with two
beds in the same room—this prevents the partner being
disturbed by the patient’s movements in bed.
4.2.2. Pharmacologic management
4.2.2.1. General guidelines
Adjustment of dopaminomimetic medications. High
evening doses of dopaminomimetic medications is an
important cause of sleep-onset insomnia and parasomnias.
This problem should be judiciously managed by either
taking the drugs earlier in the evening or reducing the
bedtime dose. Selegiline can also cause insomnia due to
its amphetamine metabolites. It should always be taken
before noon and if it still causes insomnia, it should be
stopped. Amantadine can have stimulatory effects and if
possible it should be stopped in patients with difficulty in
sleeping. Patients with insomnia due to dyskinetic nocturnal
movements may also respond to a reduction in the evening
dose of dopaminomimetic drugs.
Patients with frequent awakenings resulting from poorly
controlled parkinsonian motor symptoms at night but with-
out nocturnal hallucinations, bad dreams or vocalizations
may benefit from a small bedtime dose of levodopa-carbi-
dopa (e.g. Sinemet 100/25) with a second similar dose at 2
or 3 A.M. if the patient awakens [41]. Alternatively a
controlled release (CR) Sinemet 200/50 at bedtime may
be helpful. Recently Stocchi et al. [157] reported the selec-
tive beneficial effect of a single bedtime dose of Sinemet CR
on nocturnal akinesia and length of sleep, but not on
problems of sleep initiation and mainenance. Dopamine
agonists are not usually as effective as levodopa [124,158].
Gabapentin, a gamma-amino butyric acid analogue,
primarily used as an anticonvulsant, has been shown to
improve rigidity, bradykinesia, and tremor [159,160] as
well as reduce painful dystonia, dyskinesia and motor fluc-
tuations [161] in PD. Moreover it has been reported to
increase sleep stages 3 and 4 in healthy subjects [162] and
thus may be beneficial in PD patients with both motor fluc-
tuations and sleep disturbances.
Use of sedatives and hypnotics. Though long-term use
of sedative-hypnotics is not desirable, in our experience
majority of the PD patients with sleep disturbances will
ultimately need these medications at some time during
their illness. Kupfer and Reynolds [163] have summarized
the five basic principles of pharmacotherapy for chronic
insomnia: (i) use the lowest effective dose; (ii) use
intermittent dosing (2–4 times weekly); (iii) prescribe
medication for short-term use (i.e. regular use for no more
than 3–4 weeks); (iv) discontinue the medication gradually;
and (v) be alert for rebound insomnia following
discontinuation.
Benzodiazepines are the most commonly used drugs.
All carry risk of causing daytime sedation, motor
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–1710
Table 4
Commonly used benzodiazepines
a
Generic name (Trade name) Formulations Half-life (hours) Clinical indication Dose (mg/day)
Alprazolam (Xanax) Tablet: 0.25, 0.5, 1, 2 mg Short (7–15) Anxiety, panic attacks 0.75–4 (in 3 divided doses)
Lorazepam (Ativan) Tablet: 0.5, 1, 2 mg Short (8–15) Anxiety, panic attacks 1–6 (in 2–3 divided doses)
Oxazepam (Serax) Tablet: 15 mg Capsule: 10,
15, 30 mg. Short (5–15) Anxiety 30–120 (in 3–4 divided doses)
Clonazepam (Rivotril) Tablet: 0.5, 2 mg Long (20–40) Anxiety, panic attacks,
RBD, PLMS, RLS 1–3 (in 3 divided doses)
Diazepam (Valium) Tablet: 2, 5, 10 mg Long (20–50) Anxiety 5–40 (in 2-4 divided doses)
Clorazepate (Tranxene) Tablet: 3.75, 7.5, 15 mg
Capsule: 3.75, 7.5, 15 mg Long (30–100) Anxiety 15–60 (in 3 divided doses)
Prazepam (Centrax) Tablet: 5, 10 mg Capsule: 5,
10, 20 mg Long (30–100) Anxiety 20–60
Triazolam (Halcion) Tablet: 0.125, 0.25, 0.5 mg Ultrashort (1.5–5.5) Hypnotic 0.125–0.25
Temazepam (Restoril) Capsule: 7.5, 15, 30 mg Short (9–12) Hypnotic, PLMS, RLS 15–30
Estazolam (Prosom) Tablet: 1, 2 mg Intermediate (10–24) Hypnotic 1–4
Quazepam (Doral) Capsule: 7.5, 15 mg Long (39) Hypnotic 7.5–15
Flurazepam (Dalmane) Capsule: 15, 30 mg Long (47–100) Hypnotic 15–30
a
RBD: REM sleep behavior disorder; PLMS: Periodic leg movements of sleep; RLS: Restless leg syndrome.
incoordination, and cognitive impairments such as antero-
grade amnesia [164]. These side effects are more frequent in
the elderly and those with underlying cognitive dysfunction.
Moreover physical dependence, withdrawal and rebound
insomnia may occur if used continuously [165]. Benzodia-
zepines have been classified into different groups according
to their onset of action, duration of effects, and clinical uses
(anxiolytics or hypnotics). While these drugs are effective
for the treatment of acute insomnia, their role in the
management of chronic insomnia remains unclear [166].
There are no convincing data available to indicate that
one particular drug is more efficacious than the other. The
choice of a drug is based on the desired duration of action
needed to treat a particular type of insomnia, and is also
dictated by the availability and cost. Table 4 lists the avail-
able hypnotics with their therapeutic doses.
The efficacy of zolpidem, a short acting imidazopyridine
hypnotic, has been found to be similar to that of benzodia-
zepines in studies of acute and chronic insomnia [167–169].
The dose recommended is 5 mg in elderly patients and 5–
10 mg in younger patients [170]. It may be less likely than
benzodiazepines to disturb the architecture of sleep and
cause cognitive and psychomotor side effects [171–173].
Zolpidem is useful in restoring a normal sleep pattern in
elderly patients with dementia [174], but in a recent review
of literature, Lobo and Greene [175] did not find any distinct
advantage of zolpidem over triazolam.
Zopiclone, a short/medium acting cyclopyrrolone hypno-
tic is as effective as benzodiazepines in the short-term treat-
ment of chronic insomnia. The standard dose is 7.5 mg
(3.75 mg in the elderly) [176]. It causes less ‘morning-
after’ drowsiness and psychomotor impairment, so it is a
useful alternative to the longer acting benzodiazepines
[177]; moreover it may have advantages over benzodiaze-
pines in terms of dependence and abuse [176]. It may cause
a bad taste in the mouth and patients should be warned of
this.
Sedative effects of some tricyclic antidepressants such as
amitriptyline (10–75 mg) can often be very useful to treat
initial insomnia in patients with or without clinical evidence
of depression.
Diphenhydramine (25–50 mg) has both sedative antihis-
taminic as well as anticholinergic properties and is often
useful in some PD patients.
4.2.2.2. Treatment of specific disorders
Anxiety and depression. Anxiety often causes sleep-
onset insomnia and depression results in sleep maintenance
insomnia (especially early morning awakening), unusual
fatiguability and sleepiness throughout the day, and some-
times initial insomnia (related to agitated depression).
Management of these problems often requires guidance
from a psychiatrist. The ideal management of anxiety
should be correction of the underlying factor(s) causing
anxiety, which, unfortunately is not possible in most
instances. Some patients develop severe anxiety during
prolonged ‘off’ states and in these patients treatment should
be directed to reduce motor fluctuations. Non-medical treat-
ment like relaxation therapy is often beneficial in those PD
patients where motor disabilities are not limiting factors.
Finally if the above mangement strategies fail, benzodiaze-
pines are the drugs of choice. The dosage ranges of the
anxiolytic benzodiazepines are listed in Table 4. Rapidly
acting benzodiazepines with short duration of action (such
as alprazolam and lorazepam) are helpful in preventing
anticipated episodes of anxiety or panic attacks and can be
taken on an ‘as needed’ basis 30–45 min before an event
likely to precipitate such an attack. Patients with sustained
anxiety due to recurring or non-recurring stresses and medi-
cal illnesses will need anxiolytics for longer periods. In
these patients the longer acting benzodiazepines (such as
diazepam, clorazepate, prazepam) may be more helpful.
The drugs are given in 2–3 divided doses, gradually
increased to the minimum effective dose, and continued
for at least few weeks before trying to gradually withdraw
them. Buspirone (Buspar), a serotonergic anxiolytic, is also
helpful in treating anxiety in patients who do not response
adequately to benzodiazepines or have side effects like
cognitive dysfunction. It should be initiated at 5 mg twice
daily, gradually increased to 20–40 mg daily [178]. It could
take 5–10 days, or as much as 2–4 weeks of treatment
before clinical anxiolytic effect is felt [179]. Finally, it
should be mentined that several antidepressants, like imipra-
mine (50 mg daily), also exert major antianxiety effects.
Most parkinsonian patients who are depressed do not
have severe depression [180] and most often depression
and dysphoria are mixed with anxiety. Sometimes reassur-
ance with or without supplementary psychotherapy is suffi-
cient, but most often antidepressant medications are needed
[106]. Antidepressant medications include: (i) tricyclic anti-
depressants (amitriptyline, nortriptyline), (ii) monoamine
oxidase (MAO) inhibitors (phenelzine, tranylcypromine),
(iii) selective serotonin reuptake inibitors (SSRIs) (fluoxe-
tine, sertraline, and paroxetine), (iv) others: bupropion,
trazodone, nefazodone, and venlafaxine. For an excellent
review on these drugs the reader is referred to Cohen
[181]. For PD patients with insomnia and depression we
start amitriptyline (which has sedative properties) at an
initial dose of 10 mg/day to be taken in the evening. The
dose is gradually built up over next few weeks to a total dose
of 50–75 mg/day, depending on the response. The patient is
warned about the anticholinergic side effects especially
postural hypotension. It can be lessened if the drug is
given 12 h before the patient gets up in the morning or at
least 3 h before bedtime. The patient should have an 8-oz
glass of liquid to take first thing in the morning before
arising, to counter volume depletion [182]. There is an
early beneficial effect on sleep though it takes 2–3 weeks
for the antidepressant effects. In patients with significant
postural hypotension or those unresponsive to amitriptyline
we recommend venlafaxine or fluoxetine. Most patients
respond to a dose range of 75–225 mg daily, though
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–17 11
severely depressed patients may require dosages closer to
the maximum dosage of 375 mg daily in divided doses
[183]. Venlafaxine is usually started at a low dose of
18.75 mg twice daily and then increased by 18.75 mg
every 3 days to 37.5 mg twice daily [183]. It is also avail-
able as 75 mg extended release formulation and can be
given once daily. Fluoxetine is usually given at a dose of
20 mg daily. Some patients with severe depression refrac-
tory to drug therapy often benefit from electroconvulsive
therapy [184,185].
RBD. Clonazepam is highly effective (nearly 90%) in
the treatment of RBD, with little evidence of tolerance or
abuse [186] It may be started at of 0.5 mg and increased to
2.0 mg, up to 2 h before bedtime in patients with sleep onset
insomnia, prominent limb jerking shortly after sleep onset,
or excessive morning sedation [50]. Nocturnal vocalizations
have also been found to respond to clonazepam [41].
Nocturnal hallucinations, nightmares and delirium. Th-
ese are common in PD patients on chronic dopaminomi-
metic therapy and especially in those with underlying
dementia. In sudden-onset psychosis with PD, possible trig-
gering factors should be investigated. These include urinary
and pulmonary infections, metabolic encephalopathy and
cerebrovascular events [187]. If the psychosis begins during
a hospital admission it may be because the drugs are only
now being given as ordered: the patient may have been
chronically underdosing at home (personal observation).
In addition, the use of the following simple check list with
the spouse or caregiver can be very helpful: (i) incorrect use
of antiparkinson drugs over the previous few days; (ii)
possible side effects from or interactions with drugs ordered
for another condition (particularly meperidine); (iii) the
addition of non formulary health ‘‘food’’ products; (iv) a
recent general anesthetic; (v) recent travel with time and
dosing changes; (vi) dehydration and/or constipation. If no
precipitating factors are found, adjunctive therapy such as
selegiline, dopamine agonists, anticholinergics, and aman-
tadine should be stopped [188]. Patients unresponsive to
these measures may need a reduction in the dose of levo-
dopa, especially at night. However, if this leads to worsen-
ing of motor symptoms, one of the following drugs may be
needed:
(i) Low doses of clozapine, an atypical neuroleptic,
reduce hallucinations with minimal or no exacerbation
of parkinsonian symptoms [189–194]. It is started at a
dose of 6.25 mg qhs. Clozapine can cause agranulocyto-
sis (weekly monitoring of white blood cell counts is
necessary), postural hypotension, and sedation [187]. In
our experience 12.5 mg bid is usually sufficient for
parkinsonian patients and higher doses may lead to exces-
sive somnolence and, if patients fail to maintain their
fluid intake, dehydration.
(ii) Olanzapine is an atypical antipsychotic with a high
affinity for dopamine and serotonin receptors. It has a
clinical profile comparable to that of clozapine [195]
but with much less risk of granulocytopenia [196]. In a
recent study on 15 nondemented PD patients with drug-
induced psychosis, there was a significant reduction of the
psychotic symptoms using a dose of 5–15 mg/day, with-
out worsening of extrapyramidal symptoms [197]. Olan-
zapine significantly increased total sleep time. In our
clinic experience 1.25 mg bid may be sufficient and
more may be too sedating. Therefore the 5 mg tablet
has to be cut in quarters. Once cut, the tablet must be
kept in a dark bottle and used within 7 days. Olanzapine
seems to exacerbate PD more than clozapine, but less
than other neuroleptics.
(iii) Ondansetron, a 5-HT3 receptor antagonist, is an
effective treatment for psychotic symptoms such as visual
hallucinations, paranoid delusions and confusion in
advanced PD [198–200]. The dose is increased by 4–
8 mg/week up to a total daily maintenance level of 12
to 24 mg/day. Side effects include constipation and occa-
sional mild headaches. It does not worsen motor features
of PD or interfere with efficacy of levodopa [198]. The
use of this drug is limited by its high cost.
(iv) Risperidone (0.5–2.0 mg qhs) can worsen parkinso-
nian symptoms [201]. In our experience, this drug, used
in a dose high enough to control psychosis, usually
exacerbates parkinsonism.
Nocturnal myoclonus. Reassurence that this is an
exageration of normal myclonus in sleep may be all that
is required. Reduction in the nighttime dose of dopamine
agonist may also be beneficial. Other options include
addition of a benzodiazepine shortly before bedtime [54].
PLMS and RLS. Beneficial effects of varying degrees
have been noted with the following drugs in the treatment of
PLMS and/or RLS: (i) benzodiazepines such as
clonazepam, temazepam, or nitrazepam [202–207]; (ii)
dopaminomimetic drugs [87,208]; (iii) opioids such as
oxycodone or propoxyphene [54,209,210]; (iv)
carbamazepine [211]; (v) clonidine [212,213]; (vi) lioresal
[214].
Tricyclic antidepressants can worsen RLS and PLMS [51].
Leg cramps. Early morning leg cramps often cause
great discomfort. While electrolyte imbalance,
hypothyroidism or ischaemia should be excluded, the
usual cause is a focal dystonia. The early morning cramps
may respond to an increased evening dose of a controlled
release preparation of levodopa.
Treatment options for nocturnal cramps include: an
evening dose of quinine (300 mg), anticholinergic drugs,
or lioresal (10–40 mg) [45]. Sometimes patients improve
considerably if the dose of levodopa is reduced, and the
intake of a dopamine agonist is increased.
5. Conclusions
Sleep disturbances are common in PD, the most frequent
being insomnia. Other problems include vivid dreams, rapid
P.K. Pal et al. / Parkinsonism and Related Disorders 5 (1999) 1–1712
eye movement sleep behavior disorder, abnormal nocturnal
movements, excessive daytime sleepiness and fatigue. PD,
antiparkinsonian drugs, dementia, anxiety, and depression
all contribute in varying ways to sleep disturbances. The
beneficial effect of sleep on the symptoms of PD has been
correlated with the stage of disease and duration of treat-
ment. A correct diagnosis of the kind of sleep disorder is
obtained from history given by both the patient and the
caregiver, a schedule of current medications, prior sleep
history, psychiatric assessment and often polysomnographic
evaluation. Management includes counselling both the
patient and the caregiver towards a realistic expectation of
the quality and quantity of sleep required, treatment of coex-
istent psychiatric problems, and common sense. It is often
helpful to readjust the dose and timing of antiparkinsonian
drugs, with the judicious use of hypnotics, anxiolytics, and
antidepressants. Sleep disturbances in the caregivers may
also need treatment.
Acknowledgements
We wish to thank the Parkinson Foundation of Canada,
the National Parkinson Foundation, Miami, the Medical
Research Council of Canada, and the Pacific Parkinson
Research Institute, Vancouver, for their support.
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