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Management of non-motor symptoms in advanced Parkinson disease
Daniel D. Truong a,⁎, Roongroj Bhidayasiri a,b,c , Erik Wolters d
a
The Parkinson's and Movement Disorder Institute, 9940 Talbert Avenue, Fountain Valley, CA 92708, USA
Department of Neurology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Chulalongkorn Comprehensive Movement Disorders Center, Division of Neurology, Chulalongkorn University Hospital, Bangkok, Thailand
d
VU University Medical Center, Amsterdam, The Netherlands
b
c
Abstract
Progress in pharmacology has markedly improved the treatment of early Parkinson's disease. The management of advanced Parkinson's
symptoms, however, remains a challenge. These symptoms are divided into motor and non-motor symptoms. Non-motor symptoms may
appear early or late in the disease and sometimes even before the onset of the first motor symptoms confirming the diagnosis. The spectrum
of non-motor symptoms encompasses autonomic dysfunctions, sleep disorders, mood disorders, impulse control disorders, cognitive
dysfunction, dementia, paranoia and hallucinations. They are often less appreciated than motor symptoms but are important sources of
disability for many PD patients. This review describes these non-motor symptoms and their managements.
© 2007 Published by Elsevier B.V.
Keywords: Parkinson's disease; Non-motor complications; On-off fluctuation; Pathological gambling; Dopamine dysregulation syndrome; Levodopa;
Compulsive shopping
1. Introduction
Recently, a number of non-motor manifestations of PD
have attracted the attention of physicians and researchers
(Table 1). Often, these non-motor symptoms can be more
disabling than the motor dysfunctions, and they are not responsive to dopaminergic therapy. Several lines of evidence
suggest that in addition to the dopamine system, other neurotransmitters can be affected in PD, for example serotonergic, noradrenergic and cholinergic systems [1]. Using 123I2β-carboxymethoxy-3β-(4-iodophenyl) tropane (β-CIT)
single photon emission computed tomography (SPECT),
for instance, revealed reduced striatal binding ratios (reflecting regional dopamine transporter densities) associated with
motor symptoms, and dorsal midbrain binding ratios
(reflecting regional serotonin transporter densities) correlated
with alterations of mentation, behavior, and mood [1]. Also,
PET studies with serotonergic and noradrenergic receptor
⁎ Corresponding author. Tel.: +1 714 378 5062; fax: +1 714 378 5061.
E-mail address: [email protected] (D.D. Truong).
ligands have established the involvement of these transmitter
systems in PD [2,3], whereas significant cholinergic
denervation in PD was elegantly shown by Bohnen et al.
[4]. Furthermore, Lewy bodies within cortical and subcortical
structures also may add to the non-motor profiles in PD.
These findings provide more evidence that degeneration of
the nigrostriatal dopaminergic neurons, dysfunctional serotoninergic raphe, adrenergic locus coeruleus and cholinergic
basal nucleus systems contribute differentially to motor
deficits and non-motor symptoms in PD.
Non-motor manifestations comprise autonomic dysfunction, sleep disorders and above all neuropsychiatric (behavioral and psychological) symptoms [5]. More than 60% of PD
patients report one or more neuropsychiatric symptoms,
initially mostly depression and anxiety, symptoms which may
antedate motor symptoms by several years [6,7]; later, apathy,
impulse control disorders, cognitive impairment, dementia
and psychosis may emerge. Dopamine therapy, used for the
treatment of motor symptoms, may improve some of these
symptoms, but it has not consistently been shown to be
effective. In contrast, neuropsychiatric complications frequently occur related to anti-parkinsonian treatments and
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Table 1
Major non-motor symptoms of Parkinson disease
1) Autonomic dysfunction
– Constipation
– Urinary incontinence
– Orthostatic or postprandial light-headedness
– Heat or cold intolerance
– Orthostatic hypotension
– Sexual dysfunction
– Abnormal sweating, either hypo- or hyperhidrosis
2) Sleep disorders
– Sleep fragmentation
– Insomnia
– Excessive daytime sleepiness
– Sleep attacks
– REM behavior disorder
3) Neuropsychiatric disorders
– Depression and anxiety
– Impulse control disorders
– Cognitive dysfunction
– Psychosis
4) Others
– Pain
– Fatigue etc.
may limit therapeutic control of motor symptoms in up to 10%
of patients even at initial monotherapy. These complications
include vivid dreams, nightmares, and visual hallucinations
with or without intact reality testing, delusional disorder,
manic psychosis, and delirium. In addition, hypersexuality and
dopamine dysregulation syndrome can occur as complications
of dopaminergic medication [8]. Furthermore, fluctuations in
motor performance on anti-parkinsonian medications can be
associated with neuropsychiatric symptoms, particularly acute
depression with anxiety and panic attacks, but also pain,
suicidal ideation, hallucinations and delusions. While research
evidence indicates that non-dopaminergic neurotransmitter
systems (i.e., serotonergic, noradrenergic, and cholinergic) are
disrupted in PD and may contribute to neuropsychiatric
disturbances, double-blind, placebo-controlled studies on the
treatment of these symptoms are few, and treatment recommendations are generally based on studies in non-PD patients.
Before deciding on a management approach to an individual
patient with advanced PD, it is necessary to ascertain if the
symptoms are induced by dopaminomimetic medication, related
to disease state, or a combination of both. In contrast to many
other conditions where the dosage of medications is increased to
alleviate patient symptoms, many patients with advanced PD are
sensitive to small changes in plasma levodopa levels and may
suffer adverse reactions to anti-parkinsonian drugs. Therefore,
the management of patients with advanced PD should be
individualized and directed toward decreasing the dose of the
offending drug while raising the dose of or initiating an alternative medication, with the goal of maintaining symptom control.
2. Autonomic dysfunction
Autonomic dysfunction in PD has been recognized since
the original description of the disease by James Parkinson in
1817. The manifestations are protean, and include gastrointestinal, urogenital, cardiovascular, sudomotor, and thermoregulatory system dysfunctions, depending on which component
of the autonomic nervous system is affected, enteric,
parasympathetic cholinergic, sympathetic cholinergic, sympathetic noradrenergic, and adrenomedullary hormone [9]. For
example, parasympathetic cholinergic failure presents as constipation, dry mouth, a constant pulse rate, urinary retention and
erectile dysfunction in men. Sympathetic cholinergic failure
results in decreased sweating. Sympathetic noradrenergic
failure presents as orthostatic intolerance and orthostatic hypotension. The overall prevalence of autonomic features varies
considerably from 2% for urinary incontinence to 72% for
constipation, in part related to disease duration, severity or use
of anti-parkinsonian medications [10]. However, common
symptoms of autonomic failure in PD include constipation,
urinary incontinence, orthostatic or postprandial light-headedness, heat or cold intolerance, and orthostatic hypotension.
Hence, in PD there seems to be failure or dysregulation of
more than one component of the autonomic nervous system.
Unlike pure autonomic failure and multiple system
atrophy (MSA) where lesions are located in the peripheral
(postganglionic) and central autonomic nervous systems
(preganglionic) respectively, it is not entirely clear if autonomic dysfunction in PD results from pathology at a single
anatomical site or at a combination of sites. However, evidence indicates abnormalities in both peripheral and central
nervous systems, with early involvement of the parasympathetic system in the course of the disease. Lewy bodies
sometimes associated with neuronal loss can be found in
central and peripheral autonomic regulation [11–13]. Loss of
sympathetic nerves and subsequent failure of baroreflex can
explain orthostatic hypotension in PD. In clinicopathological
retrospective studies, earlier and more severe orthostatic
hypotension has been reported in patients with MSA,
compared with patients with PD (15–20%) [14,15]. However impairment of both sympathetic and parasympathetic
functions, consistent with an autonomic neuronopathy in
these patients have been demonstrated in PD patients who
had no clinical evidence of orthostatic hypotension [16].
Hypotension during standing or after a large meal can worsen
during treatment with levodopa, dopamine agonists, or any
vasodilator. Blood pressure seems to fluctuate with motor
impairment in PD patients with wearing-off [17]. This
fluctuation may represent autonomic dysfunction caused by
the PD process itself, the effect of PD medication, or both. In
PD, cardiac sympathetic denervation also occurs, manifesting
clinically as shortness of breath during exercise and a
tendency to fatigue.
The prevalence of urinary disturbance was found to be
27% to 39% using validated questionnaires and greater than
40% using a non-validated questionnaire [18–20]. In PD,
urinary frequency, urgency and nocturia are frequently reported [19,21]. Furthermore, urge incontinence can compound a bladder disorder by poor mobility. The major
abnormality of bladder dysfunction appears to be detrusor
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hyperreflexia, which results in bladder contractions at
bladder volumes that under normal circumstances would
not trigger detrusor activity [22].
Anticholinergics such as oxybutinin chloride, tolterodine
tartrate, and trospium chloride and possibly also solifenacin
can be used to treated neurogenic bladder symptoms [23]. As
tolterodine is less lipophilic, it may be more suitable for
patients with cognitive impairment [24]. There are no studies
available addressing the issue of possible worsening of
cognitive impairment using anticholinergics in patients with
PD. High frequency stimulation of the subthalamic nucleus
(STN) improves bladder capacity and increases the volume
at first desire to void, but does not influence bladder emptying [25,26]. Patients also report significant decrease of
overactive bladder symptoms after stimulation of the STN
[27].
Furthermore, sweating disturbances, either hypohidrosis or
in particular hyperhidrosis, were reported in 64% of PD
patients, compared to 12.5% of controls in one study [28]. The
patterns of sweating abnormalities were often localized and
asymmetric, correlating with other symptoms of autonomic
dysfunction, but not with disease severity. Sweating problems
tended to occur predominantly in ‘off’ periods and in ‘on’
periods with dyskinesia. Drenching sweats should be
considered part of the spectrum of off-period fluctuations in
Parkinson's disease. Sage and Mark reported with serial
plasma levodopa levels and simultaneous clinical examinations subtherapeutic levodopa levels during severe sweating
episodes [29]. Sweating fluctuates in conjunction with
wearing-off phenomena [17]. Patients' sweating responds
favorably to agonist therapy [29].
Sexual dysfunction is relatively common in patients with
PD, with 81% of men and 43% of women with PD reporting
reduced sexual activity [30]. In another study, 60% of men
with PD had sexual dysfunction, compared to 37% of healthy
age-matched control subjects [30]. Some PD patients develop
hypersexuality (see impulse control disorders). Furthermore,
the effects of psychiatric morbidity, marital strain, psychosocial stress, and medications on sexual difficulties in PD
patients remain unclear.
2.1. Treatment of autonomic dysfunction
A mismatch between therapeutic need and available
evidence from randomized trials in patients with PD is seen
in the area of autonomic dysfunction. No single trial studying
the effect of any antihypotensive agent in a homogeneous
population with PD has been conducted. Randomized
controlled trials in patients with neurogenic orthostatic
hypotension, some of whom have PD, support the use of
midodrine [31,32]. Others have assessed the efficacy of
dihydroergotamine, etilefrine, fludrocortisone, and L-ThreoDOPS. Furthermore, there is no safety data specifically in
PD patients. Although these drugs could be options to treat
orthostatic hypotension in PD patients, such use should be
considered as investigational.
3
The same is true for constipation and neurogenic bladder
disturbances. While trials assessing the efficacy of oxybutynin
and tolterodine in neurogenic bladder dysfunction exist,
subjects in the study were not homogeneous in their
underlying disorders and the study did not specifically include
PD patients. Only one randomized, double-blind, placebocontrolled study with sildenafil has been conducted in a
relatively small number of PD patients with sexual dysfunction
[33]. The results indicated that sildenafil was efficacious in
both PD and MSA patients with erectile dysfunction.
3. Sleep disturbances
Sleep disturbances and daytime sleepiness are well-known
phenomena in PD and were reported in the original description
by James Parkinson. Sleep disorders have a complex etiology
related not only to the underlying neurodegenerative process,
but also to the motor and non-motor features of PD and to
dopaminergic therapy. A community-based study revealed
that nearly two-thirds of PD patients reported sleep disturbances, which is significantly more frequently than patient
with diabetes and healthy control subjects [34]. Furthermore,
about a third of PD patients rated their overall nighttime
problems as moderate to severe. Virtually all patients with PD
suffer from various levels of nocturnal disability causing sleep
disruption. Subjectively, nocturnal symptoms in PD can be
classified into insomnia, motor, urinary, and neuropsychiatric,
associated with daytime somnolence.
Sleep disturbances may take the form of difficulty falling
asleep or more commonly fragmentation of nocturnal sleep,
with frequent and prolonged awakening. Patients awaken
after 2 to 3 h of sleep and feel relatively refreshed. However,
they are unable to return to sleep except for short periods.
This may be due to PD-specific motor phenomena, such as
nocturnal immobility, resting tremor, dyskinesias, or nocturia
as well as coexisting sleep disorders, such as restless leg
syndrome, periodic limb movements in sleep or sleep disordered breathing. In addition, sleep disorders in PD patients
may also include rapid eye movement (REM) sleep behavior
disorder, which has a strong association with PD and is
characterized by excessive nocturnal motor activity that
usually represents attempted enactment of vivid, actionfilled, and violent dreams [35]. Other factors such as dementia and depression can also affect sleep in PD patients.
Insomnia, hypersomnia, and parasomnia may all occur in
PD and contribute to excessive daytime sleepiness (EDS).
Daytime sleepiness has been reported in almost 50% of PD
patients who were also found to be sleepier than normal
controls [36]. During the day, they take frequent naps, and the
total period of sleep in a 24-hour day is relatively normal.
Daytime sleepiness was found in patients on levodopa monotherapy as well as on dopamine agonists [37,38], though in
a study of 386 consecutive non-demented non-depressed PD
patients, dopamine dosage was significantly higher in
patients with abnormal Epworth Sleepiness Scale values
[38]. In addition to EDS, sudden sleep episodes (‘sleep
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attacks’) with subsequent automobile accidents were reported
in PD patients on dopaminergic treatment [39]. Although it
was attributed to nocturnal sleep fragmentation in earlier
reports, it is now considered to be associated with
dopaminergic therapy [40].
The primary neurodegenerative process of PD can lead to
sleep abnormalities, particularly by affecting the mesocorticolimbic dopaminergic neurons associated with ascending
reticular activating system, as well as degeneration of pathways
from the dorsal raphe and locus coeruleus [41]. In addition,
drugs used in the treatment of PD, particularly dopamine
agonists, are associated with drowsiness. Similar problems have
been reported with amantadine and anticholinergics. Levodopa
and all dopamine agonists can cause EDS and sleep attacks
[39,41]. However, levodopa monotherapy carried the lowest
risk for sleep attacks, followed by dopamine agonist monotherapy and then by a combination of levodopa and dopamine
agonists [42]. No significant differences in the risk for sleep
attacks were found among dopamine agonists and concomitant
sleep disorders do not seem to predispose for sleep attacks. The
characteristics of sleep attacks in patients on levodopa
monotherapy are not different from those occurring in patients
on combination therapy with dopamine agonist. In contrast,
selegiline may have an awakening effect because of its
amphetamine-like effects. Current driving recommendations
are that patients taking dopaminergic therapy for PD should be
warned of the risk for sleepiness and sleep episodes and should
be advised not to drive if they experience such events or to stop
driving if they are feeling sleepy [41].
3.1. Treatment of sleep disturbances
PD patients tend to fall within the age range at which sleep
disturbances in the general population are common. Therefore,
it is important to consider alternative diagnoses, such as sleep
apnea or restless leg syndrome. Nocturia should be investigated
to exclude urinary tract infection, detrusor hyperactivity or
prostatism in men. Once these possibilities have been excluded,
the first step is to employ simple strategies, such as sleep
hygiene. Simple sleep hygiene, such as regular bedtime, regular
meals, and appropriate bedroom environment are basic measures that should not be overlooked. A review of medication is
also important. Selegiline should be scheduled in the morning
as a single daily dose. Tricyclic antidepressants should be given
in the evening. Sedative drugs should be avoided during the
day. In addition, a review of dopaminergic therapy is important
and a preference should be given to simplification. Each PD
patient should be evaluated individually with regard to
advantages and disadvantages of modification of their
dopaminergic therapy. If daytime somnolence still persists
despite the above measures, modafinil may be considered [43].
In addition to the above measures, certain specific
situations may warrant changes in the dose, drug, or timing.
Treatment strategies that provide sustained anti-parkinsonian
effects have been shown to have beneficial impact on motor
symptoms in sleep. These strategies include use of sustained
dopaminergic therapy with controlled release levodopa or
evening dosing of the long-acting dopamine agonist, cabergoline, use of overnight sustained subcutaneous apomorphine
infusion, or subthalamic nucleus stimulation. Transdermal
rotigotine, a lipid-soluble, non-ergot, D3, D2, D1 dopamine
receptor agonist that has demonstrated efficacy as an
alternative therapeutic option in advanced Parkinson's disease
may also be used [44]. In some situations, atypical neuroleptics
(such as quetiapine or clozapine) or sedatives are required to
treat the symptoms that may be aggravated by dopaminergic
therapy. Parasomnias, including REM behavior disorder are
associated with PD and may respond to clonazepam or
additional dopaminergic therapy.
4. Mood disorders
The prevalence of depression in PD is estimated to be
40%, with reported prevalence rates ranging from 4% to 70%
depending on diagnostic criteria and selection of the study
population [45–50]. While the majority of cases meet
classification criteria for minor depression, only 4 to 6% of
PD patients suffer from major depression according to DSMIV criteria, with higher rates in patients with associated
dementia [51]. This finding indicates that depression in PD is
mostly of mild to moderate severity. Anxiety disorders,
including generalized anxiety disorders, agoraphobia, panic
disorder and social phobia, have been reported in 20 to 40%
of patients with PD and frequently co-occur with depression
[6,52,53]. Subthreshold depression is reported to present in
21% of PD patients [54].
The profile of depressive symptoms in PD is not identical
to that reported in patients with primary depression.
Distinctive features of depression in PD include elevated
levels of dysphoria, irritability, little guilt or feeling of failure,
and a low suicidal rate despite a high frequency of suicidal
ideation [55]. Even though one might assume a relationship
between motor symptoms and depression, there is no clear
relationship to age at onset or duration of PD, family history
of mood disorders, or a personal history of previous depressive episodes [51,56–60]. Although depression does contribute significantly to disability in patients with PD [56,61],
it is unlikely that depression occurs as a secondary reaction to
motor deficits in PD. Retrospective studies indicate that
affective symptoms may manifest as the first symptom of PD
many years before motor signs [7,62,63].
In addition to dopamine, a number of studies suggest that
serotonin is mainly involved in the pathogenesis of depression in PD [45,64]. Neurochemical studies showed reduced
peripheral and central serotonin metabolites, improved
depressive symptoms following serotonin reuptake inhibitors, and decreased platelet imipramine binding in depressed
PD patients [65,66]. Furthermore, imaging studies reported
reduced metabolism in the frontal lobes, particularly on the
left [67,68]. PD patients with depression have been found to
have reduced cortical 5HT1A receptor binding compared
with non-depressed patients with PD [69].
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4.1. Treatment strategies in PD-related depression
Psychosocial support, counseling, and psychotherapy all
play an important part in the management of depression and
PD, particularly when it is related to depressive reactions at the
time of diagnosis. Since depression in PD is associated with
neurotransmitter changes and is thus not a reaction to the
disease process, specific pharmacological treatment is usually
needed. Unfortunately, only a few randomized, controlled,
double-blind studies on antidepressant treatment in PD are
available and no placebo-controlled randomized studies have
specifically targeted depression in a PD population. Therefore,
the evidence provided below is based on open-label studies
involving a small number of PD patients or extrapolates from
studies and experience in non-PD patients with depression.
Two aspects of medications should be considered in the
treatment of motor and depressive symptoms in PD: 1) effects
of anti-parkinsonian medication on motor symptoms and
depression; and 2) effects of antidepressant therapy on
depression and motor symptoms. Mood swings with severe
depression and suicidal ideation accompanying ‘off’ periods in
fluctuating PD are a well-recognized phenomenon and
illustrate a role for dopamine in mood regulation. Furthermore,
anxiety and depression can increase during off periods and can
even precede akinetic states. In this situation, dopamine
replacement with levodopa is considered as first line treatment.
Although dopamine replacement, either with levodopa or a
dopamine agonist can exert significant effect in improving
motor functions, the two medications alone or together do not
provide consistent antidepressive effects and have been
suspected to cause or worsen depression in some PD patients.
While the MAO-B inhibitor, selegiline, was originally
developed as an antidepressant, its antidepressant effect in
PD patients is unclear [70–72]. MAO-A inhibitors should not
be co-prescribed with levodopa because of the potential risk of
hypertension, nor with serotonin reuptake inhibitors or tricyclic
antidepressants because of a potential serotonin syndrome.
The affinity of ropinirole and pramipexole for corticofrontal D2 and in particular D3 receptors seems to play a
significant role for their antidepressant properties. While
laboratory-based studies suggest anxiolytic effects of ropinirole, antidepressive and antianhedonic effects have been
reported with pramipexole in various animal models, there
are only a few open and controlled studies [73–76].
Selective serotonin reuptake inhibitors (SSRIs) appear to
have a similar efficacy compared to tricyclic antidepressant
(TCAs). Together with TCAs, SSRIs are currently the most
widely used class of drugs to treat depression in PD.
Imipramine, nortriptyline, and desipramine are shown to be
effective in treating depression in PD in randomized controlled,
double-blind studies and they may even reduce some motor
symptoms. However, treatment with TCAs is often limited by
adverse effects. While numerous open-label and case reports
are supportive of the effectiveness of SSRIs, no controlled trials
assessing their efficacy and safety are available [77,78]. The
effects of sertraline on motor and depressive symptoms with
5
minor and major depression were confirmed by the Beck
Depression Inventory, showing significant improvement from
baseline to the final visit in a 7-week period [79]. Additionally,
two open-label studies on paroxetine for depression yielded
similar results [77,80]. Although data from about 500 patients
in retrospective and open studies showed that worsening of
motor symptoms during SSRI therapy is a rare phenomenon, a
recent study showed a faster increase in anti-parkinsonian drug
prescription after initiation of SSRI in PD patients [81,82]. The
‘new antidepressants’, such as reboxetine, mirtazapine,
nefazodone, and venlafaxine, are different from SSRIs and
TCAs in their mechanism of action. Venlafaxine and nefazodone are serotonergic/noradrenergic reuptake inhibitors while
nefazodone is a weaker serotonin and norepinephrine reuptake
inhibitor, but a potent serotonin 5-HT2 receptor antagonist.
Mirtazapine is a potent antagonist of central alpha2 adrenergic
autoreceptors and antagonist of serotonin 5-HT2 and 5-HT3
receptors resulting in increase of both noradrenergic and specific serotonergic transmission. Because of these new aspects
of the pharmacological profile, the ‘new antidepressants’ seem
to be a plausible approach to the treatment of depression in PD.
However, clinical trials are clearly needed to determine the
efficacy of the ‘new antidepressants’ in PD patients.
In severe refractory cases, electroconvulsive therapy
(ECT), which can also improve psychosis and temporarily
parkinsonism, may be an effective and less invasive treatment
for depression than high doses of medication [83]. Although
the exact mechanism of ECT is still unclear, the effectiveness
of ECT may be related to increases of brain norepinephrine,
serotonin, or dopamine together with down regulation of
beta-adrenergic and possibly presynaptic alpha adrenergic
receptors as well as changes in cerebral blood flow and
glucose metabolism. Following ECT, dyskinesias can
transiently increase in severity and confusional states may
be more common than in non-PD patients with depression.
4.2. Impulse control disorders
Impulse control disorders (ICDs) are now recognized to
occur in a subset of patients with Parkinson's disease. This
spectrum of disorders, characterized by excessive or poorly
controlled preoccupations, urges, or behaviors, includes not
only punding, pathologic gambling and hypersexuality, but
also compulsive shopping and binge eating. In a small percentage of patients, these behavioral abnormalities are associated with overuse of dopamine replacement therapy (DRT)
and are referred to as a homeostatic hedonistic dysregulation
called dopamine dysregulation syndrome (DDS) [8,84].
4.3. Punding
The term punding was coined to describe a distinctive form
of motor stereotypy seen in amphetamine addicts [85]. The first
case of L-dopa-induced punding was described by Friedman in
1994 and followed by three other cases in 1999 [86]. Punding
behavior, a stereotypical motor behavioral response elicited by
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repeated exposure to levodopa induced by behavioral sensitization, is observed in a minority of PD patients. The punding
prevalence of 1.4% is reported in unselected PD population and
14% in patients taking high dose of levodopa [87,88]. Punding
is characterized by intense fascination with the repetitive
manipulation, examination, cataloguing, and endless sorting of
objects of common use. Patients may pick at themselves or take
apart watches and radios or sort and arrange common objects,
such as pebbles, rocks, or other small objects [88]. There are
clear similarities between punding and obsessive–compulsive
disorder (OCD) such as purposeless, influence of gender and
life history and the feeling of calm after performing of the
stereotypies [88–90]. Punding however is not associated with
obsessionality. Although the patients acknowledge its disruptiveness, inappropriateness and unproductiveness, forcible
attempts by family to interrupt the behavior lead to irritability
and dysphoria [88]. Patients that engage in punding use higher
doses of dopamine replacement therapy and have more severe
dyskinesia than patients who do not pund [91]. There is no
identifiable pattern to the dopamine receptor stimulation profile
of the medications used by the punders compared with the nonpunders [88]. Currently punding is underdiagnosed, and
attention should be given to patients who require large doses
of dopamine replacement therapy, frequent rescue doses, rescue
medications overnight and have disabling severe dyskinesia.
All improve with reduction of anti-PD medications.
4.6. Compulsive shopping
4.4. Pathological gambling
4.8. Dopamine dysregulation syndrome (DDS)
Although some studies have suggested an association of
certain dopamine agonists [92,93] with the development of
gambling, others have failed to find a difference between the
agonists [94]. In a UK study 4.4% of treated patients and 8% of
dopamine agonist-treated patient exhibited pathological gambling [95]. A recent Canadian study reported a lifetime
prevalence of 3.4% in Parkinson's disease and 7.2% in patients
using dopamine agonists [94]. Pathological gambling is
associated with earlier PD onset, higher novelty seeking traits,
personal or family history of alcoholism, and with dopamine
agonists as adjunctive therapy but not monotherapy [94,96].
Reduction or stopping dopamine agonists may improve the
pathological gambling behavior [93].
DDS is characterized by severe dopamine addiction where
patients, supposedly due to increasing tolerance to the
beneficial motor effects of L-dopa, continuously ask for
more medication. Indeed, patients suffering this syndrome
report ‘wanting’ but not ‘liking’ levodopa. They eventually
also experience a diminishing degree of pleasure by tolerance
to the pleasurable effects of levodopa. In DDS patients, an
increased occurrence of punding is reported, correlating
positively with drug-induced enhancement of DA levels in
the ventral striatum. Other attributes of human addiction might
also be seen, including an increased reaction to monetary
reward, hypersexuality and compulsive gambling [8]. Curiously, novelty- and fun-seeking personalities, normally
predicting addictive potential for the development of DDS in
PD, were not found to correlate with L-dopa-induced
enhancement of DA levels, suggesting a different mechanism
by which they predispose PD patients to develop DDS [101].
4.5. Hypersexuality
Hypersexuality with nymphomania or satyriasis may
occur during treatment with dopamine agonists [97], but is
also described during high frequency subthalamic deep brain
stimulation [98]. As soon as this condition disrupts accepted
normal behavioral and/or marital life, treatment is required.
Hypersexuality, however, is rather refractory and therefore
difficult to treat. In some cases, it will resolve after stopping
the dopamine agonist, in others after treatment with olanzapine or quetiapine in combination with a reduction of the
agonists. In our hands, treatment with the antihormone cyproteron seems to be very effective.
A compulsive buying disorder is characterized by
excessive or poorly controlled preoccupations, urges, or
behaviors regarding shopping and spending that lead to
subjective distress or impaired functioning [99]. Compulsive
buying disorder is estimated to have a lifetime prevalence of
5.8% in the United States general adult population; mostly
occurring in women (approximately 80%), and it tends to run
in families with mood disorders and substance abuse. In
Parkinson's disease this behavior is occasionally seen in
patients treated with dopamine agonists or with high frequency
deep brain stimulation of the subthalamic nucleus. When
stopping of the agonists and/or deep brain stimulation is not an
option, group cognitive-behavioral models, psychopharmacologic treatment and/or financial counseling might be helpful.
4.7. Binge eating
Binge eating, also an impulse control disorder, is occasionally seen in PD patients, supposedly induced by treatment
with dopamine agonists. It is defined by both eating an amount
of food that is definitely larger than most people would eat
during the same period of time under similar circumstances
and a lack of control over eating (the feeling that one cannot
stop eating or control what or how much one is eating) [100].
5. Cognitive dysfunction
The cognitive deficits in PD may present to varying magnitudes early in the course of the disease and are
multifactorial in origin, involving subcortical-frontal dopaminergic system as well as extrastriatal systems [102,103].
Subtle cognitive impairment, in the form of slowness in
thinking (bradyphrenia), word finding difficulty, impairment
of planning initiation, and monitoring of goal-directed
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behaviors, is frequent in PD, even at early stages [104]. This
is usually not a significant problem for these patients since it
does not interfere with day-to-day activities and responsibilities. On the other hand, dementia refers to cognitive
impairment of sufficient magnitude to affect daily activities
as well as diminishing the quality of life. It is a syndrome of
global decline of intellect, memory, and personality.
Dementia is reported in approximately 20% to 44% of PD
patients but there is a high degree of variability ranging
between 10% and 90% [105,106]. A prevalence as high as
90% can be found among PD patients in nursing homes [107].
One community-based prevalence study reported a prevalence of dementia in 27.7% among PD patients, which is a
two- to three-fold higher risk of dementia, compared to the
general population [108]. Parkinson's patients with dementia
have worse UPDRS scores and dementia scores than
Parkinson's patients without dementia [109]. Heterogenous
factors may contribute to pathology of dementia in
Parkinson's disease using IM-SPECT [109].
Particular risk factors for the development of dementia in
PD include older age at onset (after 65 years), presence of
hallucinations, lower mini mental scores at baseline, dementia
in other family members, more severe disease (such as early
appearance of bilateral motor involvement), and the early
development of confusional states or psychotic symptoms
with levodopa administration [110]. The dementia in PD
usually becomes apparent several years after the onset of motor
symptoms. The type of dementia seen in PD overlaps with that
of dementia with Lewy bodies and represents a combination of
cortical and subcortical neuropsychological impairments with
dysexecutive, attentional, and visuospatial deficits, and often
prominent behavioral disturbances. The memory deficit is
typically an impairment of retrieval with relatively preserved
mnemonic function. Other cognitive disturbances, such as
apraxia, aphasia or agnosia, are often absent. Furthermore, the
development of dementia is frequently complicated by
confusion and psychosis, limiting the use of anti-parkinsonian
medications. These features are different from patients with
Lewy body dementia (DLB), who tend to present with
pronounced fluctuations in vigilance, frequent collapsing, and
distinctive psychiatric symptoms, such as complicated scenic
hallucinations, a clear sensitivity to the use of atypical
neuroleptics, and the rapid progression of dementing syndrome. As a result, the development of dementia in PD is a
poor prognostic factor, with a greater risk of admission to a
nursing home, and an increased mortality compared to PD
patients without dementia [111,112].
Dementia in PD appears to be heterogeneous with a
spectrum of pathological changes. Cognitive decline in PD
has been linked to neuronal loss in the substantia nigra, and
in cortical and limbic structures, particularly with cholinergic, but also noradrenergic, dopaminergic, and serotonergic
dysfunction, and to the number and distribution of cortical
Lewy bodies (LBs), which are abundant in DLB [113–115].
There is considerable overlap between the pathological and
the clinical features of PD with dementia and DLB, with no
7
clear correlation between the presence of cognitive impairment and the extent of cortical LBs [116,117]. These cortical
LBs are smaller and more irregular than midbrain LBs. In
necropsy studies, a high density of cortical LBs is commonly
associated with the dementia. Cognitive decline can develop
in the presence of mild PD, and widespread cortical
pathology does not always lead to cognitive decline [118].
E. and H. Braak demonstrated extracellular amyloid deposit
in all areas of the cortex, where neurofibrillary tangles are
missing [118]. Other elements that are considered essential
for the development of dementia include the decline of
cholinergic neurons in the Nucleus basalis of Meynert and
distinct changes in the entorhinal cortex, whereas only minor
abnormalities are observed in the hippocampal regions. In
addition, serotonergic neurons are lost in the nucleus raphe
and noradrenergic neurons in the locus coeruleus. The
pattern of ascending pathology from brainstem to limbic and
neocortical areas may provide an explanation into why
cognitive changes appear relatively late in classical PD
[119].
5.1. Treatment of cognitive dysfunction
Despite optimistic reports in the early years of levodopa
therapy, it became apparent in subsequent studies that
levodopa has a limited effect on cognitive impairment in PD
patients [120]. Furthermore, the use of levodopa or
dopamine agonists in demented patients is complicated by
the development of confusion and psychosis [121]. Since
there is strong evidence for the involvement of cholinergic
deficits in PD patients with dementia, cholinesterase
inhibitors have then been tried in these patients, with the
first report of favorable effects in six patients with PD and
dementia [122]. Tacrine improved cognitive and behavioral
symptoms, notably apathy and hallucinations, without
detrimental effects on motor function. Subsequent small
studies tested the effects of donepezil in patients with DLB
and reported favorable effects on confusion, psychosis and
cognition, without any deterioration in motor symptoms
[114]. Donepezil was also tested in another small, but
randomized, placebo-controlled study with a positive result
in the improvement of memory subscales and a trend
towards improvement on a psychomotor speed and attention
[123]. In another small open study, galantamine was reported
to improve cognitive functions, hallucinations and parkinsonism in about half of PD patients [124]. Rivastigmine has
shown benefits in patients with dementia with Lewy bodies
with regards to hallucinations, anxiety, apathy, and delusions
[125]. It also showed in double-blind study moderate but
significant improvements in global ratings of dementia,
cognition (including measures of executive functions and
attention), and behavioral symptoms among patients with
dementia associated with Parkinson's disease [126]. Parkinsonian symptoms were reported as adverse events more
frequently in the rivastigmine group and were most
commonly manifested as tremors. They were severe enough
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to cause withdrawal from the study of only 1.7% of patients
in the rivastigmine group and none of the patients in the
placebo group. In a follow-up open study patients treated
with rivastigmine continued to show improvement above
baseline. Placebo patients switching to rivastigmine for the
active treatment extension experienced an improvement
similar to that of the original rivastigmine group during the
double-blind trial. Tremors were the most common adverse
events [127].
Although limited by their open design and small sample
size, the results of previous published studies suggest that
cholinesterase inhibitors (tacrine, donepezil, rivastigmine,
and galantamine) might be beneficial in the treatment of
dementia in PD [128].
6. Psychosis in Parkinson's disease
Psychosis affects nearly one-third of patients with PD,
mainly during cognitive deterioration, and is a major
precipitant of nursing home placement. The occurrence of
psychosis usually manifests as vivid dreams, hallucinations,
delusions, and confusional psychosis. When hallucinations
occur, they usually involve one of two situations [129]. First, a
medical illness can superimpose on PD with resultant
hallucinations that are part of the complications of infection,
dehydration, or drug toxicity. These patients are usually
confused and agitated in the midst of their hallucinations.
Alternatively, chronic PD patients on dopaminergic therapy
can gradually develop hallucinations that are generally visual
in content and without marked agitation or confusion.
Sanchez-Ramos et al. [130] evaluated various patient
characteristics to determine potential risk factors for the
occurrence of psychosis in PD. Psychosis often occurred in
elderly patients with longer disease duration, cognitive
impairment, history of depression and sleep disturbances.
The duration of disease and the total daily dose of levodopa
were not significant risk factors. The relationship between the
use of anti-parkinsonian drugs and visual hallucinations is
complicated but most anti-parkinsonian medications are
capable of inducing visual hallucinations. The ‘continuum
hypothesis’ proposes that medication-induced psychiatric
symptoms in PD begin with drug-induced sleep disturbances,
followed by vivid dreams, with progression to hallucinatory
and delusional experiences have been challenged [131]. In
some patients, visual hallucinations may represent intrusion of
REM sleep-related imagery into wakefulness. Frequently,
hallucinations occur in low light situations (sundowning), and
when the individual is going from one state of consciousness to
another, such as waking from sleep. Some patients report
‘seeing’ a relative in the bedroom upon wakening, but then
realize that the person is not really present. Other examples
include seeing something in the corner of the eye or crawling
bugs in patterned wall covering or floor ties. Seeing small
people (Lilliputian figures), children and animals is also
common. While uncommon, insight into the unreality of the
perception is lost if hallucinations become more vivid.
6.1. Treatment of psychosis in Parkinson's disease
The management of psychosis in PD should be based on
careful assessment and amelioration of the contributing and
triggering factors in each patient. Medical conditions, such
as pneumonia and urinary tract infections can trigger
psychosis and should be aggressively treated. The strategy
should also focus on reductions of polypharmacy with antiparkinsonian medications and other centrally active drugs
whenever possible. Although all anti-parkinsonian medications can cause psychiatric side effects, some are more prone
to these side effects than others [5]. Anticholinergics are
more likely to cause confusion and psychosis, followed by
selegiline and amantadine. Dopamine agonists and COMTinhibitors are less common agents to cause psychosis although the incidence of psychosis increases with rapid
titration and the age of patients. Standard levodopa may be
better tolerated than controlled release preparations. Therefore, when reducing and simplifying anti-parkinsonian therapy, drugs with high risk–benefit ratios regarding cognitive
side effects versus anti-parkinsonian efficacy should be
tapered first, for example anticholinergics and amantadine
before dopamine agonists and levodopa. As cognitive deterioration is a major psychotogenic factor and often precedes
psychosis, a treatment with cholinesterase inhibitors might
be helpful in preventing or treating this condition. Cholinesterase inhibitors, such as donepezil or rivastigmine have
been reported not only to improve cognitive function, but
also to improve behavioral and psychiatric symptoms in PD
patients [132,133].
Generally, a compromise has to be reached between motor
function and mental state, but the balance can be improved by
the use of atypical antipsychotics. In the past, typical low
potency neuroleptics such as thioridazine and haloperidol
were used in small doses in an effort to improve psychosis.
However, they usually worsen parkinsonism because of their
strong binding to D2 receptors and the use of typical
antipsychotics is currently not recommended. New atypical
antipsychotics, including clozapine, risperidone, remoxipride, zotepine, olanzapine, and quetiapine have been used
with mixed success [134–138]. Of these, clozapine (D4
antagonist) is the only antipsychotic that has been shown to
improve psychosis without worsening motor symptoms at
effective antipsychotic doses. The reason may be related to its
regional selectivity for action at dopamine receptors in the
mesolimbic area, rather than the nigrostriatal system. The
Movement Disorders Task Force reviewed the evidence for
its efficacy and safety and concluded that clozapine is
‘efficacious’ in the short term (b 4 weeks), but has ‘insufficient’ evidence on the long-term efficacy [139]. In general,
over 80% of patients respond with complete or partial
resolution of psychosis. Despite its effectiveness, a potential
fatal side effect of agranulocytosis can occur, which requires
regular supervision of treatment, including weekly blood
count for the first six months, followed by two weekly
thereafter. Other adverse events include postural hypotension
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and sedation. Clozapine was considered by the Movement
Disorders Task Force to have ‘acceptable risk with specialized monitoring' at doses of less than 50 mg/day [139].
Although quetiapine is considered an alternative to
clozapine, a recent study did not show any beneficial effects
of quetiapine for the treatment of psychosis in Parkinson's
disease [140,141]. The evidence of quetiapine's efficacy as
well as safety has been considered as ‘insufficient’ [139].
Olanzapine has been shown to be associated with worsening
motor symptoms in PD patients in a controlled study comparing clozapine and olanzapine in the treatment of
psychosis in PD [142]. The Movement Disorders Task
Force considered olanzapine to have ‘insufficient’ evidence
for its efficacy and ‘unacceptable risk’ of motor deterioration
[139]. Olanzapine is generally not recommended in the
treatment of psychosis in PD.
All atypical antipsychotics should be initiated at low doses,
as PD patients typically respond to very low doses and are
sensitive to side effects. Any change in medications should be
taken cautiously, starting at low doses and titrating up or down
slowly as patients are often sensitive to side effects or
deterioration of Parkinsonism. Akinetic crisis or a malignant
neuroleptic syndrome may occur and can be fatal. Therefore,
sudden discontinuation or ‘drug holidays’ should be avoided.
6.2. Pain
Painful sensory complaints have long been described in
Parkinson's disease [143,144]. Indeed, in his original
description of ‘the shaking palsy’ in 1817, James Parkinson's
patients often described pain or ‘rheumatism’ as a symptom
of the disorder [145]. Muscle cramps or tightness, typically
in the neck, paraspinal or calf muscles are the most common
pain reported. Other etiologies are painful dystonias,
radicular or neuritic pain, joint pain, and only 2% diffuse
generalized pain [146]. Pain may be related to motor
fluctuations, early morning dystonia, or secondary causes
such as musculoskeletal pain. Recently Djaldetti et al. report
increased evoked pain sensitivity in subjects with Parkinson
disease (PD) compared with control subjects, especially in
those patients who previously described spontaneous pain
[147]. Furthermore, increases in thermal pain sensitivity in
patients with PD with spontaneous pain make it plausible
that the experimental pain and spontaneous pain share
mechanisms. Pain thresholds are significantly lower in the
more affected limb regardless of the presence or absence of
pain. In their study, no differences in the sensory threshold
were noted between “off” and “on” periods in patients with
response fluctuations [147]. Rarely a burning oral and
genital pain syndrome may occur, which can be abolished or
reduced by levodopa [148]. Levodopa raised the objective
pain threshold in pain-free Parkinson's disease patients but
not in healthy subjects [149]. When the pain fluctuates in
parallel with the motor changes, this pain may respond to
modifications in anti-parkinsonian therapy, which can be far
more effective than conventional analgesic treatments [150].
9
6.3. Fatigue
Fatigue is “a sense of tiredness, lack of energy or total
body give out” [151]. Fatigue is reported to occur in 33% to
58% [152,153]. Fatigue has been shown to be correlated with
anxiety and activities of daily life but not sleep, gender, age,
or depression. There appears to be no correlation with motor
dysfunction [153] or depression [154]. In the Norwegian PD
cohort first reported in 1996, fatigue, as measured by the
Nottingham Health Profile (NHP) at baseline, increased
later. While 35.7% were fatigued initially, this number went
up to 42.9% then 55.7%. Fatigue was persistent in 56% of
those affected, whereas the other 44% only suffered from
fatigue intermittently. Fatigue was related to disease severity,
and excessive daytime somnolence (EDS) [152]. It is poorly
understood, generally under-recognized, and has no known
treatment.
7. Conclusions
Levodopa and other dopaminergic medications drastically
improve the motor symptoms and quality of life of patients
with PD in the early stages of the disease. However, once the
‘honeymoon’ period has waned, usually after a few years of
dopaminergic therapy, patients become progressively disabled despite an ever more complex combination of available
anti-parkinsonian treatments. Sooner or later, they suffer
from ‘dopa-resistant’ motor symptoms (speech impairment,
abnormal posture and balance), ‘dopa-resistant’ non-motor
signs (cognitive and neuropsychiatric impairment, autonomic
dysfunction, sleep disorders), and/or drug-related side effects
(psychosis, motor fluctuations, dyskinesias). In addition to
novel therapies to treat dopa-resistant motor symptoms,
evidence suggests the need to routinely screen for non-motor
symptoms in PD and to develop a new, comprehensive
assessment measure that is more balanced in weighing motor
and non-motor aspects of the disease. Treatment studies of
non-motor symptoms should also incorporate functional
outcome measures. Parkinson's disease is now considered
not only a motor disorder, but a neuropsychiatric, autonomic,
and sleep disorder with important non-motor aspects. Consequently there has been a shift of treatment focus to reduce
disability, instead of merely reducing symptom severity.
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