European Journal of Neurology 2008, 15 (Suppl.

1): 14–20

Non-motor symptoms in ParkinsonÕs disease

W. Poewe
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria

Keywords: Although still considered a paradigmatic movement disorder, ParkinsonÕs disease

autonomic dysfunction,
dementia, depression,
ParkinsonÕs disease,
psychosis, sleep disorders
Received 29 November 2007
Accepted 10 December 2007
(PD) is associated with a broad spectrum of non-motor symptoms. These include
disorders of mood and affect with apathy, anhedonia and depression, cognitive dys-
function and hallucinosis, as well as complex behavioural disorders. Sensory dys-
function with hyposmia or pain is almost universal, as are disturbances of sleep–wake
cycle regulation. Autonomic dysfunction including orthostatic hypotension, urogeni-
tal dysfunction and constipation is also present to some degree in a majority of
patients. Whilst overall non-motor symptoms become increasingly prevalent with
advancing disease, many of them can also antedate the first occurrence of motor signs
– most notably depression, hyposmia or rapid eye movement sleep behaviour disorder
(RBD). Although exact clinicopathological correlations for most of these non-motor
features are still poorly understood, the occurrence of constipation, RBD or hyposmia
prior to the onset of clinically overt motor dysfunction would appear consistent with
the ascending hypothesis of PD pathology proposed by Braak and colleagues.
Screening these early non-motor features might, therefore, be one approach towards
early ÔpreclinicalÕ diagnosis of PD. This review article provides an overview of the
clinical spectrum of non-motor symptoms in PD together with a brief review of
treatment options.

side effects such as orthostatic hypotension, hallucina-

Introduction
Idiopathic ParkinsonÕs disease (PD) is generally con-
sidered a paradigmatic movement disorder, as most
patients present with one or more of the cardinal motor
features. Current treatment strategies focus on dopa-
mine replacement to correct at least partially the dis-
turbances of movement caused by striatal dopamine
deficiency. However, it has long been recognized that
the neuropathology underlying PD involves many brain
areas beyond the dopaminergic nigrostriatal system,
including areas that are not directly involved in motor
control such as the locus coeruleus, the dorsal vagal
nucleus, the raphe nuclei of the brainstem, the hypo-
thalamus, the olfactory tubercle and large parts of the
limbic cortex and the neocortex [1, 2]. Pathology also
extends into the peripheral autonomic nervous system
involving sympathetic ganglia, cardiac sympathetic
efferents and the myenteric plexus of the gut [2]. It is,
therefore, not surprising that the majority of patients
with PD, if not all of them, reveal a variety of non-
motor symptoms, either as spontaneous complaint or
upon specific questioning [3,4]. In addition, drugs used
to treat motor symptoms frequently induce non-motor
Correspondence: Prof. W. Poewe, Department of Neurology, Medical
University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
(tel.: +43 512 504 23850; fax: +43 512 504 23852; e-mail: werner.
poewe@i-med.ac.at).
tions, somnolence, insomnia or leg oedema, adding to
the overall burden of the non-motor spectrum of par-
kinsonian morbidity. Recently, it has also become
clearer that in PD, non-motor dysfunction may actually
antedate overt signs and symptoms of motor distur-
bance [5]. A recent hypothesis about neuropathological
stages of PD suggests that Lewy body pathology in the
nigrostiatal system only develops after lower brainstem
areas and the olfactory system have become affected [1].
This has led to clinical studies assessing olfactory dys-
function or rapid eye movement (REM) sleep beha-
viour disorder (RBD) as potential risk factors for later
development of PD in otherwise asymptomatic indi-
viduals [6,7]. Independent of their role as early or
ÔpreclinicalÕ markers, the non-motor symptoms of PD
become increasingly prevalent and obvious over the
course of the illness and are a major determinant of
quality of life, progression of overall disability and
nursing home placement [8].
Spectrum of non-motor symptoms in PD
Non-motor symptoms in PD involve a multitude of
functions including sleep–wake cycle regulation, cog-
nitive function, regulation of mood and hedonistic tone,
autonomic nervous system function as well as sensory
function and pain perception (see Table 1). In their
various combinations, they may eventually become the

Ó 2008 The Author

Journal compilation Ó 2008 EFNS 14

Table 1 Non-motor features of ParkinsonÕs disease
Neuropsychiatric dysfunction
Mood disorders
Apathy and anhedonia
Frontal executive dysfunction
Dementia and psychosis
Sleep disorders
Sleep fragmentation and insomnia
RBD
PLMS/RLS
Excessive daytime somnolence
Autonomic dysfunction
Orthostatic hypotension
Urogenital dysfunction
Constipation
Sensory symptoms and pain
Olfactory dysfunction
Abnormal sensations
Pain
RBD, rapid eye movement sleep behaviour disorder; PLMS, periodic
limb movements in sleep; RLS, restless legs syndrome.
chief complaints and therapeutic challenges in
advanced stages of PD.
Sensory symptoms and pain
Painful sensations not explained by osteoarthritic con-
ditions, neuropathy or other causes of pain commonly
observed in elderly populations have been reported in
40–50% of patients with PD in different series [9–12].
PD-related pain may be a presenting symptom when
patients complain of aching shoulder pain on the side
initially affected by rigidity and loss of dexterity, not
uncommonly leading to orthopaedic referrals and
occasionally even shoulder surgery for suspected
impingement or lesions to the rotator cuff. Sensory
symptoms and pain are also prominent in fluctuating
PD, where tingling or burning sensations, neuralgic
pain or diffuse pain have been described as common
ÔoffÕ-period phenomena in one study [12] (see Table 2).
The pathophysiology underlying painful sensations in
PD are poorly understood, but may include alterations
in central pain-processing pathways, as suggested by
one recent study describing decreased heat pain
thresholds in PD patients [13], which were more marked
on the side initially and more severely affected by the
disease.
Defective odour detection and discrimination is a
sensory abnormality which appears to affect some 90%
of patients with PD [14] and has been related to neu-
ropathology affecting the olfactory bulbs [15]. Hypos-
mia is generally marked when formally tested, although
many patients do not spontaneously complain of it.
Within the spectrum of parkinsonism, hyposmia is not
Ó 2008 The Author
Journal compilation Ó 2008 EFNS European Journal of Neurology, 15 (Suppl. 1), 14–20
Non-motor symptoms in ParkinsonÕs disease 15
Table 2 Non-motor symptoms during wearing-off in patients with
fluctuating ParkinsonÕs disease (from Witjas et al. [12])
Frequency during
Non-motor fluctuation Frequency (%) ÔoffÕ state (%)
Anxiety 66 88
Drenching sweats 64 59
Slowness of thinking 58 83
Fatigue 56 75
Akathisia 54 63
Irritability 52 88
Hallucinations 49 25
specific to PD, but has also been reported in multiple
system atrophy (MSA) patients, although it appears to
differentiate between vascular parkinsonism and PD
and has also been absent in parkin disease [16,17].
Hyposmia does not appear to progress over the course
of PD, but is present from the start of the illness.
Recent data suggest that idiopathic hyposmia in
asymptomatic first-degree relatives of PD patients is
associated with an increased risk to develop overt PD
and may thus be an early preclinical sign or even a risk
marker for the general population [6].
Autonomic dysfunction
Autonomic dysfunction is an almost universal feature
of PD and includes orthostatic hypotension, urinary
and sexual dysfunction as well as constipation [3].
Orthostatic hypotension
Retrospective chart reviews in a large series of 135 cases
of pathologically proven PD found evidence for
symptomatic orthostatic hypotension in life in 30% of
cases, bladder dysfunction in 32% and constipation in
36% [4]. Senard et al. [18], when studying 91 patients
with idiopathic PD in a cardiovascular laboratory with
tilt table examinations, found systolic blood pressure
drops of >20 mmHg in 58% of their patients. In 20%
of cases, orthostatic hypotension was symptomatic, and
symptomatic orthostatic hypotension correlated with
dopaminergic medication dose on the one hand and
duration and severity of PD on the other hand [18].
Compared with MSA, symptomatic orthostatic hypo-
tension is a late feature in PD. Wenning et al. [19], in a
small series of postmortem-confirmed cases of PD and
MSA, found mean latencies to symptomatic orthostatic
hypotension of 24 months in 15 patients with MSA,
compared with 166 months in 11 patients with PD.
Mechanisms of orthostatic hypotension may differ
between MSA and PD: whilst the central autonomic
nervous system bears the brunt of pathology related to
16 W. Poewe

autonomic failure in MSA, peripheral sympathetic Management of autonomic failure in PD is largely

cardiovascular denervation is prominent in PD, as based on pragmatic recommendations without firm
shown in multiple studies of cardiac MIBG (metaiod- evidence for efficacy from controlled clinical trials. The
obenzylguanidine) scintigraphy in both disorders [20]. measures most commonly used are summarized in
Autonomic failure is also prominent in patients with Table 3.
pathologically proven dementia with Lewy bodies
(DLB). Dysautonomia was found in 28 of 29 patients
Neuropsychiatric dysfunction
with pathologically proven DLB [21]. A recent study
has provided evidence that orthostatic hypotension is Contrary to James ParkinsonÕs original descriptions
more pronounced in PD patients with dementia than in about Ôthe senses and intellect being uninjuredÕ, PD is
PD patients without dementia. In a small cardiovas- clearly associated with a variety of alterations in mood,
cular function study, Peralta et al. [22] found systolic initiative, hedonistic tone and cognitive functioning (see
blood pressure drops upon head-up tilt in 50% of Table 4).
patients with PD and dementia as compared with only
7% of patients without clinically defined dementia.
Depression
These observations in PD dementia and DLB suggest a
potential link with the spread of Lewy body pathology Loss of initiative and assertiveness as well as anhedonia
to neocortical and limbic structures and parts of the and anxiety are common complaints and findings in
peripheral autonomic nervous system. patients with PD. The reported prevalence of major
depression in PD ranges from a low of 4% to a high of
70% with a mean of about 40% [29,30]. This figure has
Constipation
been confirmed by more recent studies showing the
Lewy body pathology in the peripheral autonomic presence of depressive symptoms in 36–50% of patients
nervous system in PD also includes the myenteric with PD [31]. It has been suggested that the majority of
plexus with subsequent colonic sympathetic denerva- depressed PD patients meet criteria for major depres-
tion [23]. Clinically, this is associated with a high sion according to DSM-IV [32], whilst more recent
prevalence of prolonged intestinal transit time and series suggest that this percentage may actually be much
constipation in PD. Several case–control studies have
reported increased prevalence of constipation in PD of
between 28% and 61% as compared with controls Table 3 Practical management of autonomic dysfunction in
(6–33%) [24–26] and one series even found either con- ParkinsonÕs disease
stipation or prolonged intestinal transit time in 80% of
Orthostatic hypotension
patients with PD [27]. Importantly, constipation has
Elastic stockings
been reported as a prominent complaint before onset of High salt intake
overt motor symptoms in about half of the patients in Head-up tilt
one series [25]. In line with such observations, a large Fludrocortisone 0.1–0.3 mg/day
prospective follow-up study in 6790 male participants in Midodrine 2.5–10 mg/day
Etilefrine 15–25 mg/day
the Honolulu Heart Programme found evidence for a
Neurogenic bladder symptoms
2.7–4.5 fold increase in relative risk for PD in males Detrusor hyperreflexia
with <1 bowel movement per day as compared with Oxybutynine 5–15 mg/day
subjects with one, two or more movements per day [28]. Tolterodine 2–4 mg/day
Similar to hyposmia, constipation may, therefore, turn Trospium chloride 20–40 mg/day
Retention
out to be one of the earliest symptoms of Lewy body
Bethanechol chloride 25–75 mg/day
degeneration in PD. Intermittent SC
Nocturnal polyuria
Desmopressin spray 10–40 lg/night
Urogenital dysfunction Erectile dysfunction
50 mg sildenafil (caveat: orthostatic hypotension)
Urogenital dysfunction in PD includes erectile and
10 mg vardenafil
ejaculatory failure, urinary frequency and urgency, 20 mg tadalafil
incomplete bladder emptying, double micturition and 3 mg sublingual apomorphine
urge incontinence. Similar to orthostatic hypotension, Constipation
urogenital failure is a late feature of PD, with mean Stop anticholinergics
Ensure adequate fluid
latencies of 144 vs. 12 months in MSA in one post-
Add laxatives (macrogol)
mortem case series [19].

Ó 2008 The Author

Journal compilation Ó 2008 EFNS European Journal of Neurology, 15 (Suppl. 1), 14–20

Table 4 Neuropsychiatric features of ParkinsonÕs disease
Mood disorder
Anhedonia, apathy
Anxiety
Depression
Cognitive dysfunction
Dysexecutive syndrome
Visuospatial dysfunction
Dementia
Psychosis
Complex behavioural disorders
DA dysregulation syndrome (hedonistic homeostatic
dysregulation) punding
DA, dopamine.
lower, with the majority of patients presenting with
symptoms of Ôminor depressionÕ or Ôdysthymic disorderÕ
[33]. Patients with PD and depressive symptoms gen-
erally show less self-blame, guilt and sense of failure
and fewer self-destructive thoughts than patients with
primary major depression, and they rarely commit
suicide [30]. On the other hand, features of anxiety and
panic attacks are frequently encountered, as is loss of
interest and initiative, fatigue, indecisiveness and
anhedonia. Depressive episodes or panic attacks have
been found to precede the onset of motor symptoms in
up to 30% of patients with PD [5].
Whilst some of the depressive symptoms in PD may
actually occur as a reaction at the time of first diag-
nosis, there is general consensus that PD-specific
pathology with multiple transmitter deficiencies in
mesocortical monoaminergic systems play a major role,
including the mesocorticolimbic dopamine projection
as well as the mesocortical noradrenergic and seroto-
nergic projections.
Cognitive dysfunction and dementia
Subtle cognitive deficits are almost universally identified
even in early PD upon detailed neuropsychological
testing [34]. They relate to frontal executive dysfunction
with impaired problem-solving and defective planning
and organization of goal-directed behaviour, as well as
difficulties with set shifting, visuospatial deficits and
some impairment of learning and memory [35]. Com-
munity-based studies have suggested that some 30–40%
of patients with PD will develop clinically defined
dementia. A recent meta-analysis of prevalence studies
on dementia in PD has estimated that 31% of PD
patients fulfil the diagnostic criteria for dementia and
that PD dementia accounts for around 4% of degen-
erative dementias and may have a population-based
prevalence of between 0.2% and 0.5% in people
>65 years of age [36].
Ó 2008 The Author
Journal compilation Ó 2008 EFNS European Journal of Neurology, 15 (Suppl. 1), 14–20
Non-motor symptoms in ParkinsonÕs disease 17
The development of dementia has a significant
impact on the natural history of PD and has been
shown to be associated with more rapid progression
of disability, increased risk for nursing home place-
ment and increased mortality [37–39]. The underlying
pathology may include Alzheimer-type changes, cor-
tical Lewy body degeneration and vascular lesions,
but Lewy body degeneration has been suggested to be
the major driving factor for the development of
dementia in PD [36]. The clinical profile of PD
dementia includes aspects of psychomotor slowing,
apathy and bradyphrenia, deficits in memory
retrieval, impaired set-shifting, problem-solving, poor
visuospatial function, fluctuations in attention and
cognition, as well as prominent mood and personality
disorders, hallucinosis and psychosis, whilst language
and praxis remain largely intact [40]. Recently, one
large and several small-scale randomized, placebo-
controlled trials have suggested efficacy of cholines-
terase inhibition in improving cognitive function, as
well as erratic and psychotic behaviour in patients
with PD dementia [41,42]. Whether or not DLB is a
distinct clinical entity from PD dementia is currently
a subject of debate.
Psychosis
Hallucinosis and psychotic episodes are amongst the
most challenging of the parkinsonian non-motor
symptoms. Although there are few systematic and
prospective studies of incidence and risk factors for
psychosis in PD, recent drug trials in early PD have
found incidences of hallucinosis and psychosis in up
to 17% of patients [43], and cross-sectional surveys in
outpatient clinic populations have reported a 40%
prevalence of hallucinations in PD [44]. Psychosis has
been identified as a major risk factor for nursing
home placement in PD [38], and early psychotic
reactions to dopaminergic replacement in PD have
been correlated with subsequent development of
cognitive decline and dementia [45]. Drug-induced
psychosis in PD is more common in elderly patients
than those with cognitive impairment. Hallucinosis
and psychosis can be triggered by all major classes of
antiparkinsonian agents including dopamine agonists,
levodopa, monoamine oxidase B inhibitors, amanta-
dine and anticholinergics. Several randomized con-
trolled studies suggest that dopamine agonists are
more probably to induce hallucinosis than levodopa
[43,46]. The clinical spectrum of psychosis in PD
includes visual illusions, visual hallucinations with
retained insight, as well as florid paranoid hallucina-
tory psychosis and delusions. Visual phenomena are
the predominant type of hallucinations in PD and
18 W. Poewe
they are usually well formed, colourful and rich in
detail. Acoustic and tactile hallucinations are less
common and, if present, usually occur in association
with visual hallucinations [47]. Currently, clozapine
remains the only drug with proven antipsychotic effi-
cacy without motor worsening, as shown by placebo-
controlled, randomized trials in PD. Quetiapine may
be a safer option, but its efficacy has not been
established in placebo-controlled studies. Olanzapine
has been shown to induce marked motor worsening
without evidence of efficacy in several randomized
controlled studies. Cholinesterase inhibitors may be an
important management alternative in PD dementia.
Sleep disorders
Sleep disorders are amongst the most frequent non-
motor problems of PD [48]. They include difficulties
falling asleep, frequent awakenings, nocturnal cramp-
ing, painful dystonia, or nocturnal motor symptoms
with difficulties turning in bed, motor restlessness or
clear-cut restless legs syndrome (RLS), night-time
incontinence, nocturnal confusion, hallucinosis and
daytime sleepiness. The awareness of the clinical
implications of these disturbances has only increased in
recent years, prompting new research.
Multiple contributing factors and clinical manifesta-
tions are involved. The motor abnormalities of par-
kinsonism, e.g. nocturnal tremor, nocturnal akinesia,
ÔoffÕ-period dystonia, and RLS or periodic limb move-
ments in sleep (PLMS) are possible causes. PD-related
neurodegeneration impacts the sleep structure. This
induces sleep fragmentation, reduced sleep efficiency,
reduced slow-wave sleep, reduced REM sleep and
RBD. Respiratory disturbances and autonomic distur-
bances are other possible mechanisms.
An RBD is a pathological sleep structure character-
ized by loss of REM sleep muscle atonia with phasic or
tonic activity in the chin and extremity electromyogra-
phy. It is associated with jerking and sometimes very
violent limb and body movements which seem to be
related to dream content. Several studies have found
incidences of RBD between 15% and 40%, and a recent
study has suggested RBD as a preclinical marker for
PD [7,49].
Excessive daytime sleepiness (EDS) was found in up
to 51% of patients with PD [50]. The frequency of
sudden onset of sleep varies amongst studies from 3.8%
to 30%. Case reports and series suggest no difference
between ergot and non-ergot agonists with regard to
EDS or sudden onset of sleep. There appears to be a
significant correlation between the dose of dopaminer-
gic medication and Epworth Sleepiness Scale Scores,
EDS or sudden onset of sleep [51].
Journal compilation Ó 2008 EFNS European Journal of Neurology, 15 (Suppl. 1), 14–20
Management of sleep disorders in PD is complex and
have to target underlying mechanisms. Dopamine
agonists may be helpful in sleep fragmentation because
of nocturnal motor disability or RLS/PLMS.
Clonazepam may be considered in RBD, and continu-
ous positive airway pressure in some patients. Atypical
neuroleptics or cholinesterase inhibitors may improve
sleep in patients with nocturnal episodes of confusion
or hallucinosis. Modafinil has some success in patients
with EDS. Usually, mechanisms are multiple and
treatment multimodal. Overall, sleep problems in PD
remain a major therapeutic challenge.
Conclusions
Non-motor symptoms are universal features of idio-
pathic PD and involve dysfunction in the neuropsy-
chiatric, sensory and autonomic domains. In sum,
they add significantly to the overall disability caused
by PD and are critical determinants of health-related
quality of life. In the era of effective symptomatic
therapies for the motor symptoms of PD, non-motor
dysfunction has developed into a major prognostic
factor for overall disease burden and everyday func-
tion in PD. In addition, there is increasing evidence
that non-motor dysfunction antedates clinical mani-
festations of the motor symptoms of PD by years or
even decades and may thus turn out to be a critical
target for early diagnosis paradigms and identification
of at-risk populations. Besides defining predictive
values of certain types of non-motor dysfunction
including hyposmia, RBD or autonomic dysfunction,
future research must focus on the development of
effective symptomatic therapies for PD non-motor
symptoms.
Conflicts of interest
WP declares no conflicts of interest.
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