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Nonmotor Symptoms in Parkinson's Disease: The Dark

Side of the Moon
Roberto Ceravolo, Carlo Rossi, Lorenzo Kiferle, Ubaldo Bonuccelli
Future Neurology. 2010;5(6):851-871.

Abstract and Introduction

Abstract

Nonmotor symptoms may appear during the course of Parkinson's disease, complicating the advanced
phase in particular, but are also common in the premotor phase of Parkinson's disease. The appearance
of nonmotor manifestations represents a milestone, determining a worse prognosis and lower quality of
life; however, they are often misdiagnosed and untreated. The spectrum of nonmotor symptoms
encompasses mood disorders, psychosis, dementia, sleep disorders, impulse-control disorders and
autonomic dysfunctions. This article describes these nonmotor symptoms and their management.

Introduction

Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder,
characterized by the progressive loss of substantia nigra pars compacta dopamine neurons and the
consequent decrease in the neurotransmitter dopamine. Patients exhibit a range of clinical symptoms,
with the most common affecting motor function and including resting tremor, rigidity, akinesia,
bradykinesia and postural instability. Nonmotor symptoms (NMSs) are often an integral part of the
disease and some of them, such as depression, anxiety and hyposmia, can precede the onset of
Parkinsonism. Other NMSs, such as psychosis, dementia, impulse-control disorders (ICDs), somnolence
and autonomic dysfunctions, are almost invariably present in advanced disease and in various
combinations they may represent the principal complaints and therapeutic challenges. If untreated, they
may impair quality of life and represent a major cause of hospitalization and institutionalization.[1] In this
article, we briefly summarize the principal NMSs of PD, focusing on their clinical and therapeutic
management.

Depression
Depression is a common NMS in PD with prevalence rate ranging from 7 to 76%.[2] A recent review of 104
prevalence studies of depression in PD reported a weighted prevalence of major depression of 17% and
a prevalence of minor depression and dysthymia of 22 and 13%, respectively. [3] Depressive disorders
may represent the first manifestation of PD years before the onset of motor symptoms. [4] Although
common, depression is underdiagnosed and not often treated. Almost two-thirds of subjects meeting the
criteria for depression are not treated,[5] with a clear impact on disability and on the increased need for
symptomatic therapy of PD.[6] Depression is often under-recognized as it may be masked by motor
symptoms (i.e., bradykinesia and hypomimia) and frequently co-occurs with other neuropsychiatric
conditions (i.e., cognitive impairment and anxiety). In 2006 the National Institute of Neurological Disorders
and Stroke (NINDS)/National Institute of Mental Health (NIMH) workgroup on depression and PD
recommended changes to the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic
criteria for depression to be applied in PD patients.[7]

The symptom profile of depression in PD patients is different in comparison with patients without PD: they
have higher rates of anxiety, pessimism, irrationality, suicidal ideation without suicidal behavior, and less
guilt and self approach.[8–10] A combination of dysfunction of dopaminergic and norepineprinergic systems
has been implicated in the pathogenesis of depression in PD.[11] A PET study evidenced that PD patients
with depression had a lower [11C]RTI-32 binding, a tracer for both dopamine and noradrenaline
transporter, in the locus coeruleus and in several regions of the limbic system, such as the amygdala,
anterior cingulated cortex, thalamus and ventral striatum.[11] Furthermore, the involvement of
serotoninergic system in the pathogenesis has been proposed, as the loss of raphe serotoninergic
neurons has been associated with the occurrence of depression in a postmortem study. [12] A preliminary
PET study with [11C]DASB, a selective radiotracer for the serotonin transporter-linked promoter region
(5HTTLPR), evidenced that depressive symptom ratings were related to a higher DASB uptake in the
orbitofrontal and cingulated cortex, insula and putamen.[13] The relationship between depression and other
PD symptoms has been evaluated by several studies. Depression has been associated with a worse
motor progression,[14,15] even if other studies did not replicate these results.[6] A higher frequency of major
depression in patients with akinetic-rigid subtype when compared with a tremor-dominant phenotype has
been reported.[16] Anxiety and depression may fluctuate during the day. It is still controversial whether they
are related to motor fluctuations. Clinical and pharmacological studies found an improvement of mood in
the passage from an 'off' to an 'on' motor state,[17,18] whereas Richard and colleagues evidenced a lack of
association between mood and motor changes.[19]

Among other NMSs, the association of depression with dementia is more evident. Major depression is a
risk factor of developing dementia, and in addition, PD patients with cognitive impairment have a higher
risk of developing dementia.[20,21] Depression often occurs with other neuropsychiatric aspects of the
disease: in a study of Nuti and colleagues general anxiety and panic disorders were present in 11 and
30% of depressed PD patients, respectively.[22] Apathy, which is common in PD, with a frequency that
ranges from 17 to 33%,[23–25] rarely occurs alone and is associated more frequently with depression and
dementia.[26,27]

The diagnosis of depression in PD is clinical, even if rating scales such as the Beck Depression Inventory
(BDI)[28] and the Hamilton Depression Rating Scale (HAMD)[29] are often used to assess its severity and
progression. In the treatment of depression, the antidepressant effect of PD therapy has to be evaluated
before adding specific antidepressive therapy. The use of levodopa, even if it has been associated with
mood changes in patients with mood fluctuations, as discussed earlier, generally does not alleviate
depressive symptoms in PD patients.[30] Dopamine agonists may reduce depression in PD. While the
action of dopamine agonists on motor symptoms is mediated by the D2 receptors of the nigrostriatal
pathway, the stimulation of D3 receptors of the mesolimbic pathway may explain the antidepressive
properties of some dopamine agonists. In fact, in a prospective, randomized trial that compared the
effects of pergolide (a D1/D2 agonist) and pramipexole (a D2/D3 agonist) in depressed nondemented PD
patients, there was a significant decrease in the average Montgomery and Asberg Depression Rating
Scale score in patients treated with pramipexole but not in the pergolide group.[31] Pramipexole has been
demonstrated to have the same efficacy of selective serotonin reuptake inhibitors (SSRI) for major
depression in patients with or without PD.[32] A recent meta-analysis of seven randomized controlled trials
evidenced that pramipexole has a beneficial effect on mood and motivational symptoms in PD patients
without depression.[33] Recently, a multicentric randomized, double-blind placebo controlled trial
conducted in 323 patients with mild-to-moderate PD showed a significant improvement of depressive
symptoms in patients treated with pramipexole, when compared with placebo.[34] Ropinirole in extended-
release preparation has been demonstrated to reduce the BDI score in a randomized placebo controlled
trial.[35] Monoamine oxidase (MAO)-B inhibitors have weak antidepressant properties.[8] Tricyclic
antidepressants (TCAs), such as amitriptyline, imipramine, nortriptyline and trazodone, are efficient in PD,
but generally they are not well tolerated as they may aggravate orthostatic hypotension and worsen
cognitive impairment, constipation and dry mouth. Because of the lack of anticholinergic and sedative
side effects, SSRIs are generally preferred in clinical practice to TCAs, as they are better tolerated.
However, a recent placebo controlled trial by Menza and colleagues evidenced the efficacy of nortriptyline
in the treatment of depression, without a significant efficacy of paroxetine. [36] The use of SSRIs in PD has
been associated with a worsening of motor signs, as they may increase the serotonin-mediated inhibition
from the raphe nucleus and decrease dopamine release from the nigrostriatal pathway. [37,38] However,
recent studies evidenced that paroxetine, sertraline, fluvoxamine and citalopram have improved
depression in PD without worsening motor function.[39–42]

Few studies compared the antidepressant efficacy of SSRIs and dopamine agonists. The antidepressant
effect of sertraline when compared with pramipexole was evaluated in 67 patients in an open-label
randomized trial, which demonstrated a higher reduction of HAMD score in patients treated with
pramipexole compared with sertraline.[43] The combination of SSRI with MAO-B inhibitors, such as
selegiline and rasagiline, may result in the development of the potentially fatal serotonin syndrome,
representing another concern in the use of SSRI in PD, even if the occurrence of the syndrome is very
rare and the co-administration of MAO-Bs and antidepressants is common in clinical practice. Serotonin
syndrome is the result of overstimulation of 5HT1A receptors by SSRIs, TCAs, MAO inhibitors or other
serotoninergic agents and is characterized by a triad of mental, autonomic and neurological disorders
with a sudden onset less than 24 h after the beginning of serotoninergic treatment or an overdose. [44]

The selective serotonin and norepinephrine inhibitors have not yet been systematically studied for the
treatment of depression associated with PD. They may offer certain advantages over existing TCAs and
SSRIs.

Another treatment available and commonly used in depression in PD is mirtazapine, a presynaptic α2-
antagonist, which also has a role demonstrated in reducing Parkinsonian tremor. [45] In refractory cases,
noninvasive brain stimulation (transcranial magnetic stimulation, electroconvulsive treatment [ECT]) may
represent effective treatment options.[46–49] In particular, although structured studies are lacking, the
efficacy of ECT on depression and motor signs in PD patients with severe depression has been reported
since the 1970s.[50]

Anxiety
Anxiety is frequent in the course of PD; however, studies examining this symptom in PD are limited.
Anxiety affects nearly 40% of patients with PD.[22,51,52] Like depression, it can be an off-period related
phenomena and can respond to antiParkinsonian medication[53] but can also predate motor symptoms by
several years. Outside off-periods, a relationship between anxiety and severity of motor symptoms or
dementia has not been found, whereas it has been related to an underlying depressive disorder. [54] The
most common anxiety disorders in PD are panic attacks (especially during off-periods), generalized
anxiety disorder, and simple and social phobias. In a recent prospective study of 114 consecutive PD
patients, the prevalence of anxiety was 25%. Panic disorders were observed in 19% of patients, social
phobias in 13%, generalized anxiety disorder in 3% and comorbid depression was observed in 14%. The
risk factors associated were disease severity, the presence of postural instability or freezing of gait,
dyskinesias and on/off fluctuations, whereas tremor-dominant phenotype, levodopa dosage and
lateralization were not related to anxiety.[55]

If the anxiety occurs solely in off periods, adjustment of anti-Parkinsonian medication to improve/resolve
motor fluctuations is usually successful. There has been no assessment of anxiolytic treatment in PD.
Benzodiazepines should be used cautiously because they may increase adverse effects, such as
confusion or autonomic disorders. Buspirone, an anxiolytic drug whose pharmacological profile includes
dopaminergic effects, is well tolerated by PD patients at conventional anti-anxiety doses of 10–40
mg.[56] There is no evidence indicating the usefulness of trazodone in anxiety treatment in PD patients.
SSRIs are useful for the treatment of anxiety disorders but their therapeutic efficacy is yet to be
demonstrated in PD.

Psychosis
The most common type of psychotic symptoms in PD are hallucinations and illusions. With a prevalence
in treated PD patients of 15–40%,[57,58] hallucinations may represent one of the strongest negative factors
affecting the quality of life of both patients and caregivers. They have been associated with a worse
prognosis of PD and a higher risk of dementia, nursing home placement and mortality. [57,59,60] Delusions
occur in up to 10% of patients, usually in addition to hallucinations and usually involve jealously,
persecution and abandonment.[61]

A hallucination is a "sensory perception without external stimulation of the relevant sensory organ" and in
PD they are mostly in the visual modality[57,52–64] even if auditory.[65] Tactile and olfactory hallucinations
have been described as well.[65–67] In most cases visual hallucinations are rather simple and not
threatening images of people or animals, occurring more frequently at night-time.[57,60] Generally, patients
become familiar with hallucinations, as they are repetitive and stereotypical, with a short duration. Most
patients have retained insight of hallucinations, which is frequently lost as cognitive impairment
occurs.[68] Before the presentation of formed visual hallucinations, patients generally report the occurrence
of illusions or visual misperceptions. They can be represented by the misperception of unanimated
objects as living beings, by the vision of a shadow passing in the periphery of the visual field or by the
feeling of the presence of somebody behind them.[57] Generally, once present, hallucinations tend to
persist over time without a therapeutical change.[69]

The pathogenesis of hallucinations has to be considered as multifactorial. Traditionally, visual

hallucinations have been considered as an overstimulation of mesolimbic D3 and D4 dopamine receptors,
due to dopaminergic treatment in PD.[70] Hallucinations may be triggered by a introduction or a dose
increment of almost all the anti-Parkinsonian agents and they improve with the decrease of dopaminergic
treatment.[71,72] Among dopaminergic drugs, dopamine is more involved than levodopa in developing these
side effects.[73] Few studies have compared the risk of different dopamine agonists to induce psychosis. In
a cross-sectional retrospective study, Ecker et al. evidenced a positive correlation between the overall
number of drugs used per patient and the risk of developing psychotic symptoms and found that different
dopaminergic drugs were associated with different risks of psychotic symptoms. [74] In particular, pergolide
was associated with higher risk of developing psychosis, followed by ropinirole, pramipexole and
cabergoline. By contrast, in a meta-analysis relative to placebo, pramipexole had a significantly higher
risk of hallucinations than ropinirole.[75] Between other anti-Parkinsonian agents, selegiline, amantadine,
anticholinergic agents and catecholamine-O-methyl transferase inhibitors can worsen or even precipitate
psychosis in PD.[76]
Even if dopaminergic load plays an important role in visual hallucinations, other elements have to be
considered as cofactors in the development of these psychiatric disorders, as they were also reported in
the pre-levodopa era[77] and they may occur in patients who have never taken any medication for
PD.[78] However, when the hallucinations occur early in the course of the disease, especially without any
dopaminergic treatment, a diagnosis of levy body disease should be considered. Peripheral ocular and
retinal dysfunction may be responsible for visual hallucinations. [79,80] Moreover, central visual dysfunction
of visual processing may contribute to visual hallucinations. Visual hallucinations have also been
interpreted as intrusions of rapid eye movements (REM) sleep into wakefulness. The role of sleep
disorders in the pathogenesis of visual hallucinations have been highlighted by the frequent association
between REM behavior disorder (RBD) and visual hallucinations.[81,82] The relationship between
hallucinations and dementia is clear, as dementia is a risk factor for hallucinations [83] and the presence of
hallucinations is associated with increased risk of dementia. [84] Genetic studies evidenced that different
dopamine receptor genotypes and polymorphic variants of serotonin transporter and 5HT2A receptor
genes do not represent risk factors for developing visual hallucinations. [85,86]

Considering that dopaminergic treatment may induce psychosis in PD, interventions are primarily based
on reduction or withdrawal of the offending drugs and, if necessary, atypical antipsychotics should be
added.[72] The treatment of mild hallucinations is still a challenge, as a possible worsening of motor
symptoms may occur with the reduction of dopaminergic treatment or the introduction of
antipsychotics.[87] Clinical practice suggests reducing the dose or the number of drugs, and the initial
withdrawal of those drugs with less efficacy on motor symptoms and higher risk of inducing psychosis.
Anticholinergic drugs, MAO inhibitors, amantadine and then dopamine agonists should be withdrawn in
this order prior to reducing the levodopa dosage. As discussed earlier, hallucinations with retained insight
(so-called 'benign') tend to persist if not treated and worsen over time.[88] Whether to treat benign
hallucinations with antipsychotics is still debated. Goetz and colleagues have reported that early
treatment of benign hallucinations with antipsychotic agents resolved hallucinations, not only in the short
term, but also positively influenced the long-term progression of hallucinations, whereas the reduction of
dopaminergic treatment did not prevent the long-term progression of hallucinations.[89]

Among antipsychotics, clozapine is the only atypical antipsychotic fully recommended for the treatment of
psychosis in PD.[90] In fact, clozapine may reduce or resolve hallucinations in PD without a worsening of
motor symptoms, as evidenced by two well-designed, randomized placebo controlled trials.[91] The long-
term efficacy of clozapine has been demonstrated for up to 5 years.[92] However, other antipsychotics are
generally preferred to clozapine in clinical practice because of the side effect of agranulocytosis, which
requires frequent blood testing.[93]

Quetiapine represents the most commonly used antipsychotic treatment in PD patients. Quetiapine is well
tolerated and has been indicated as the first drug of choice for treating psychosis in PD by the American
Academy of Neurology's task force in 2006.[94] Open trials conducted on small numbers of patients
demonstrated a similar efficacy of quetiapine to clozapine,[95–99] even if three double-blind placebo
controlled studies found no significant efficacy of quetiapine in treating hallucinations. [100–102] Despite the
negative double-blind studies, clinicians usually prefer this medication to treat psychotic PD patients
instead of using clozapine because of concerns regarding clozapine-induced agranulocytosis. Other
drugs, such as olanzapine and risperidone, were demonstrated to be less effective and with a significant
motor worsening compared with clozapine.[103–109] Recent studies reported the use of novel antipsychotics,
such as ziprasidone and aripiprazole, in the treatment of psychosis in PD.
In a small case series, ziprasidone has been demonstrated to be effective in controlling psychosis, even if
is rarely used in the elderly as it has been associated with a prolonged QT interval. The majority of
studies report that ziprasidone is not associated with a worsening of motor signs,[110,111] even if, when
compared with the other atypical antipsychotics, it has been associated with a significant increase of
extrapiramidal side effects on non-PD patients.[112] Two small open-label trials with
aripiprazole[113,114] reported a lack of improvement in psychosis or worsening of Parkinsonism. In elderly
people with dementia, antipsychotics are associated with an increased risk of cerebrovascular incidents
and mortality, as well as worsening of cognition.[115] Melperone, a butyrophenone with atypical
antipsychotic properties, has been proposed to treat psychosis in PD, as psychotic symptoms improved
significantly in 30 subjects without motor worsening,[116] even if a recent multicenter, double-blinded
placebo controlled trial in the USA did not find the drug helpful on psychosis.[117] Thus, current research is
focused on developing new pharmacological strategies to treat psychosis. Cholinesterase inhibitors have
been evaluated in a small series of PD demented patients, with variable evidence of efficacy of
donepezil[118,119] and galantamine.[120] A large double-blind placebo controlled trial using rivastigmine, the
only cholinesterase inhibitor that is US FDA-approved for the treatment of dementia in PD, demonstrated
an improvement in neuropsychiatric symptoms in PD patients with dementia, including psychosis.
Moreover, the greatest benefit from the treatment was found in patients who presented visual
hallucinations at baseline.[121]

As the efficacy of clozapine for PD psychosis has been attributed to the serotonin 5HT2A receptor
blockade, Phase III clinical trials are evaluating the efficacy of pimavanserin, a serotonin 2A receptor
inverse agonist, in treating psychosis in PD. From the first reports, pimavanserin showed significantly
greater improvement in some but not all measures of psychosis at a dose that did not worsen motor
function, supporting a possible novel treatment for psychosis in PD. [122] However, the larger double-blind
placebo controlled Phase III trial evidenced a lack of statistically significant benefits of pimavanserin on
psychosis.[123]

Dementia
Patients with PD have a higher risk of developing dementia when compared with healthy controls; [124–
126]
the prevalence of PD with dementia (PD–D) has been estimated between 30 and 40% in clinic-based
surveys[127–134] representing the 3–4% of cases in a general dementia population.[129] A prospective study of
249 patients with PD showed a link between cognitive impairment and age in PD, with a 65% risk of
dementia by the age of 85 years.[135] The incidence of dementia has been calculated as 10% in PD
patients, four- to six-times greater than in subjects without PD.[124,129] The mean duration of PD before
diagnosis of dementia is approximately 10 years.[19,127] Recently, Hely and colleagues demonstrated that
83% of patients develop dementia after 20 years from disease onset. Interestingly, dementia occurred in
almost every patient, even in those with a younger onset of disease.[136] Indeed, even in early PD and in
the early stages, subtle cognitive deficits can be identified, with patients exhibiting difficulty with frontal
executive functioning.[137]

PD–D has been associated with reduced quality of life,[138] shortened survival[139] and increased caregiver
distress compared with PD without cognitive impairment.[140] Risk factors for PD–D include advanced
current age, visual hallucinations and more severe motor symptoms, in particular a predominance of
rigidity, postural instability and gait disturbances.[133,141] Age of PD onset and the effect of apolipoprotein E
genotypes remain controversial potential risk factors.[129,142–144]
The neuropathophysiological basis for dementia in PD is a subject of continued debate. While Alzheimer's
disease (AD) pathology may contribute to PD–D in some cases,[145] recent evidences suggest that the
neural substrate of most cases of PD–D is Lewy body-synuclein pathology.[146,147] Therefore, PD–D
appears to be distinct in terms of its clinical profile and neuropathology. [148] Nevertheless, both PD–D and
AD are associated with marked cholinergic deficits (to a greater extent in PD–D than in AD)[149,150] and it is
these deficits that underlie the rationale for cholinesterase inhibitor therapy in both conditions. Formal
neuropsychological examination reveals that the clinical features of PD–D include an insidious onset and
slowly progressive course of cognitive impairment, characterized by a'dysexecutive' syndrome, with a
prominent impairment in attention, executive and visuospatial functions. [151,152] Regarding executive
functions the verbal fluency impairments, both phonemic and semantic, are typical in patients with PD–D
at least in the early and moderate stages.[153–154] Unlike AD, primary memory is often less affected and the
language functions are usually preserved. Hallucinations, delusions, apathy and mood changes are often
associated behavioral features. Dopaminergic therapy may cause delirium and further cognitive
impairment in PD–D patients. However few recent reports found an improvement in some cognitive
functions, such as prospective memory[155] and attention.[156]

The most commonly used scales in the screening of cognitive impairment in PD during the clinical routine
are the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). MoCA
has been recently demonstrated to be superior to the MMSE in detecting the mild cognitive impairment in
PD.[157]

The relationship of dementia with Lewy bodies (DLB) to PD–D is unresolved and the topic of current
research efforts.[158] The predominant presenting clinical feature – dementia in DLB and Parkinsonism in
PD–D – is the major distinction between DLB and PD–D. Several studies have now shown that with most
diagnostic measures, there are few significant differences between DLB and PD–D.[159–160] More executive
dysfunction and more frequent psychoses have been found in DLB than in PD–D,[153] as well as
differences in the pattern and severity of Parkinsonism and levodopa responsivity. [161] In clinical practice,
the discriminate element is constituted by the timing of dementia onset. PD–D refers to dementia that
develops many years after the diagnosis of PD, while in DLB cognitive impairment occurs within 1 year of
the onset of motor symptoms.[162,163]

Management of dementia in PD involves the systematic assessment of features suggesting other

diseases as the cause of mental impairment, because their presence precludes a reliable diagnosis of
PD–D. When there is acute confusion because of systemic illness, intoxication or adverse reactions to
drugs, diagnosing PD–D must be deferred until these problems are resolved and the patient returns to a
stable medical state. Likewise, if the patient has major depression, PD–D evaluation must be deferred
until a proper attempt to treat depression is made. Anticholinergics, amantadine and benzodiazepines
should be avoided because of their relationship with a reduction in cognitive performances. Dopamine
agonists should be used cautiously since visual hallucinations are firmly associated with cognitive
impairment. Cholinesterase inhibitors have been demonstrated to improve cognitive impairment and other
behavioral symptoms, such as visual hallucinations and apathy. Some suggested that cholinergic side
effects and worsening of Parkinsonian symptoms may represent a limitation of this
therapy.[119,164] However, both donepezil (5–10 mg per day) and rivastigmine have been demonstrated to
significantly improve cognitive scales (MMSE and AD Assessment Scale, cognitive sub-scale [ADAS]-cog
scores), with only a mild worsening of motor symptoms (i.e., tremor) compared with placebo. [165–167] A
review of 487 patients with PD–D treated with rivastigmine showed an improvement in attention
domain.[168] Finally, the use of memantine, a NMDA inhibitor, in moderate PD–D patients revealed an
improvement of cognitive symptoms, even if its triggering effect on psychosis may limit the use in clinical
practice.[169]

Sleep Dysfunction
Sleep dysfunction is considered an intrinsic part of PD and the prevalence rates range from 75 to 98% in
the PD population.[170,171] The primary neurodegenerative process of PD plays a role in the genesis of
sleep disorders. The neurodegenerative process affecting brainstem cholinergic, serotoninergic and
noradrenergic regions, such as the pedunculopontine, locus coeruleus, and reticular-activating system,
may be responsible for RBD or excessive daytime sleepiness (EDS) in PD. [172] Based on Braak's
hypothesis, early involvement of these structures in the PD neurodegenerative process can explain the
presence of EDS relatively early in the course of the disease.

Disorders of sleep initiation and maintenance are more prevalent in PD groups compared with the healthy
population and are characterized by either a reduction in the stages III/IV of sleep or a decrease in REM
sleep.[173,174] Sleep fragmentation, the most common manifestation of sleep dysfunction (prevalence:
38.9%),[175] could be due to motor manifestations of PD, such as off period, dystonic movements and
cramps,[176] and to bladder dysfunction, such as nocturia.[170] Restless-legs syndrome (RLS) is more
prevalent in PD patients. Most authors consider RLS in PD as the effect of local iron deficiency in the
substantia nigra that leads to a dopaminergic dysfunction,[177,178] even if the evidence regarding the link
between iron and RLS is still inconclusive. Sleep apnea, either of obstructive or central type, has been
inconsistently associated with PD and the estimated prevalence is 20% of patients. [179] Moreover there is
no clear relationship between the prevalence of obstructive sleep apnea (OSA) in PD and disease
duration, severity or drug therapy.

Treatment should include counseling on good sleep hygiene. Improved control of motor symptoms of PD
may result in improved sleep efficiency. Comorbid conditions, such as OSA and RLS should be identified
by means of polysomnography and treated with continuous positive airway pressure and dopaminergic
agents, respectively. When present, depression and psychosis may be appropriately treated with the
result of a consolidation of the sleep/wake cycle. Control of nocturia also may improve sleep quality.

Hypnotic agents should be used only when previous measures are not sufficient and must be prescribed
with caution with close monitoring for potential side effects, specifically confusion and daytime sleepiness.
There are no controlled data on any specific hypnotic agent in PD.

Excessive daytime sleepiness is very common among patients with PD, and affects up to 50% of PD
patients, compared with 11% of the general population.[180,181] Factors that contribute to EDS in PD include
PD motor disability, impact of PD and other medications on alertness, presence of depression and
dementia, and concurrent medical illnesses.[182] The severity of EDS does not correlate with the degree of
nocturnal sleep impairment in PD.[179,183] However, the incidence of EDS increases with the progression of
the disease.

Long-term controlled studies comparing dopamine agonists and levodopa have shown a higher
prevalence of somnolence in patients treated with ropinirole,[184] pramipexole[185] and
pergolide[186] compared with those treated with levodopa. Sleep attack (SA), controversially defined as an
'event of overwhelming sleepiness that occurs without warning', was observed in PD in 1999. [187] SA was
described in patients receiving dopamine agonists and also with levodopa monotherapy. [188–190] The
concept of SA has been disputed by several authors, speculating that these episodes are an exaggerated
daytime sedation: dopaminergic drugs provoke excessive daytime sedation, making patients susceptible
to falling asleep in unintended situations. Patients may be unaware of prodromal sleepiness due to the
amnesic effect of the subsequent period of sleep and these sleep episodes should be more correctly
called 'unintended sleep episodes'.[191]

Many large-scale studies have consistently found a high prevalence of abnormal somnolence in treated
PD patients. The incidence of SA or unintended sleep episodes is less common, being higher or the
same as controls, but represents a concern as these episodes may occur while driving. The precise
relationship of the dopamine-agonists to EDS and SA remains to be determined. As a class, all the
dopamine agonists have a sedating, probably dose-related effect, but although single case reports and
studies comparing treated and untreated PD patients[192] before or after dopaminergic therapy,[193] suggest
a clear relationship between EDS, SA and the dopaminergic agent, large-scale studies[180,194–209] have
shown no univocal results and it has also not been definitely established whether or not nonergot
dopamine-agonists have more propensity than ergot derivatives to provoke EDS and SA. [205,208] Finally, it
should be mentioned that a genetic susceptibility to SA is possible, as different genetic polymorphisms
have been reported to be associated with higher risk of developing SA.[210–212]

Concomitant sedative medication should be avoided; reducing the dose or substituting with another
dopamine agonist could alleviate EDS and/or SA. Patients who experience sudden-onset sleep episodes
should be advised not to drive until the issue is resolved. The effect of modafinil in patients with EDS is
controversial.[213,214] Modafinil is generally well tolerated and does not affect motor function in PD patients
and some authors demonstrated an improvement of sleep disturbance.[213,214] Otherwise a recent double-
blind, placebo-controlled trial did not find any beneficial effects. [215] The stimulants in the treatment of EDS
are characterized by side effects, including difficulty falling asleep, inability to get comfortable,
constipation, dizziness, diarrhea and increased blood pressure (BP). Melatonin failed to improve objective
measures of sleep and motor function despite subjective improvement reported by the
patients.[216] Ramelteon, a new hypnotic agent approved for sleep initiation insomnia, which is a ligand of
melatonin receptors, may be useful in PD, but no data are currently available.

Rapid eye movements behavior disorder consists of tonic/phasic muscle activity during REM-sleep
atonia, coupled with vivid and usually frightening dreams. [217] Patients normally present violent
nonstereotyped complex movements that may cause self or partner injury. [218] Its prevalence in PD
patients ranges between 33 and 60%, with the variability being a result of different methods of patient
selection and disorder ascertainment.[219,220] In several studies RBD has been demonstrated to be more
frequent in the male than female gender, but the reasons for this male predominance are not yet
known.[221] It is now recognized that RBD may not only be associated with PD but can be a preclinical
marker of an evolving Parkinsonian disorder.[222] Although RBD is currently treated with clonazepam in
small doses (0.25–1 mg), the pathophysiology underlying RBD in same cases may involve a
dopaminergic deficiency, given its association with PD. The development of EDS with the use of
clonazepam should be considered and its use should be avoided in patients who present with OSA. RBD
has been positively treated with dopaminergic agents (pramipexole and levodopa), donepezil, and
gabapentin in anecdotic reports.[223,224] Melatonin was reported to be effective at doses of 3–12 mg.[225]

Behavioral Disorders
Impulse-control disorderss are characterized by the failure to resist an impulse, drive or temptation to
perform an act that is harmful to the person or to others. It is important that ICDs are recognized because
they may cause considerable distress to patients and caregivers, disastrous personal, financial and
socio–familial consequences, and they appear to be significantly under-reported owing to the patients'
embarrassment to admit them.[226–231] The prevalence rates reported for ICDs are quite variable ranging
from 6 to 25% and this heterogeneity might be due to methodological differences such as the measures
used for screening.[232–241] Nevertheless, considering just the report with the lowest prevalence rate
observed, this rate is higher than that reported in the general population. Pathological gambling (PG) is
the most extensively studied ICD in PD and it is the only one with formal diagnostic criteria included in
DSM-IV. PG has been defined as an ICD in which the patient fails to resist gambling impulses despite
severe personal, family or occupational consequences. The prevalence (either current or anytime during
PD) estimates for pathological or problem gambling is between 2.0 and 10.0%. [232–236] Hypersexuality is
common as well in PD patients (prevalence estimated 7.2%).[242] It usually manifests itself as an increase
of libido but sometimes it could involve exhibitionism, excessive use of sex phone-in lines, prostitution
services and sex shops. A recent very large cross-sectional study of 3090 patients has demonstrated a
prevalence of 13.6% for ICD (5.0% for PG, 3.5% for compulsive sexual behavior, 5.7% for compulsive
buying, 4.3% for binge-eating disorder) and found that 3.9% of PD patients presented two or more
ICDs.[243]

Patients who develop ICDs and mainly PG are usually males, have younger age at PD onset, longer
duration, early disease onset, have a personal or immediate family history of alcohol-use disorders or a
prior history of ICDs.[235,236,243–249] In addition, the psychological profile may play a role as a risk factor since
PD subjects with ICDs have higher novelty-seeking trait scores, as well as impaired planning on an
impulsivity scale.[237] Depressive mood is considered as a powerful risk factor and a low performance in
cognitive tasks exploring frontal function has been recently reported in association with
PG.[249,250] However the strongest risk factor is the exposure to dopaminergic drugs.[232–236] In an exhaustive
analysis of published case series, Gallagher et al. found no significant difference in risk factors for PG
between ergot and nonergot derivatives,[245] as well as between pramipexole and ropinirole.[243] Most cases
reported in the literature were in combination therapy (dopamine plus levodopa), suggesting a cross-
sensitization phenomenon of brain system mediating reward.[245] The role of dopamine doses in increasing
the risk of developing ICDs is controversial.[245,251] A possible explanation for the association between
dopamine agonists and ICDs is represented by the selective stimulation of these drugs on dopamine
receptors. D2 and D1 receptors are in fact abundant in dorsal striatum and probably mediate the motor
effect of dopamine agonists, whereas D3 receptors are more represented in ventral striatum, which is
associated with both behavioral addiction and substance use disorders. Most dopamine agonists and
paricularly pramipexole and ropinirole demonstrate a selectivity for D3 receptors and this characteristic
may be responsible for ICD susceptibility.[230,252]

Management of ICDs consists of patient and caregiver education, modification of dopamine replacement
therapy (DRT), and in some cases psychoactive drugs. It is essential to identify individuals with active
ICDs by an active screen. Clinicians should always involve the spouse or other family members and
ensure medical compliance including guarding against hoarding and overuse of medications. All patients
with ICDs should be thoroughly assessed for comorbid neuropsychiatric problems. For those patients
whose ICD occurs in the context of DRT, the behaviors often resolve or improve with dopamine agonist
reduction, switching to a different agonist or discontinuing agonist treatment entirely. [253,254] If tolerated, the
initial treatment of choice should be the downtitration of medication to the lowest effective daily dose of
DRT. Clinicians should discourage patients from taking nocturnal or 'rescue' doses of short-acting
dopaminergic agents. When a reduced DRT dosage causes worsening motor function, there is little
evidence and no prospective data to guide subsequent medication adjustments. Agonist reduction can be
offset by increases in levodopa treatment.[254] However, this intervention is not always successful; some
patients are reluctant to discontinue or decrease dopamine agonist treatment owing to the motor or
nonmotor benefits they experience when on the medication, and not all ICDs occur in the context of DRT.
When the aforementioned measures are not tolerated or prove ineffective, psychoactive drugs and
psychotherapy provides a secondary course of treatment. Counseling and cognitive-behavioral therapy
can be useful as an adjunctive approach, but several reports describe disappointing results. [232,255] Limiting
a patient's access to money or the internet may help in reducing PG and compulsive buying when such
controls are feasible. ICDs may improve with treatment of concomitant depression.[235] SSRIs, although
effective in obsessive compulsive disorders, are of questionable benefit in DRT, [256,257] since they may
facilitate dopaminergic transmission and could worsen ICDs. Atypical neuroleptics
clozapine,[258] risperidone[259] and quetiapine[260] have been reported to help control ICDs; however, one
controlled study of olanzapine has produced negative results. [261] In addition valproate and lithium have
been reported to help individual patients with ICDs.[242]

Punding is a complex stereotyped behavior characterized by an intense fascination with repetitive

manipulations of technical equipment, the continual handling, examining and sorting of common objects,
and this engagement is usually devoid of content. The prevalence of punding was reported in an initial
study as 14%[262] and was then reported as 1.4%.[263] Punding and walkabout are characterized by
repetitive behaviors and poor impulse control, but the behaviors are typically nonpleasurable or low in
risk–reward characteristics when compared with ICD behaviors.[264]

Dopamine dysregulation syndrome (DDS) is a neuropsychiatric behavioral syndrome associated with

substance misuse and behavioral disturbances that can resemble a hypomanic state or disturbances in
the impulse control system, resulting in an uncontrolled urge or drive to perform certain acts. DDS is
characterized by the use of dopaminergic drugs in excessive doses than those required to treat motor
symptoms despite the development of disabling dyskinesias.[260] The prevalence of DDS was reported at
between 3.4[265] and 14%.[244] Patients with PD who develop DDS are usually early-onset PD patients,
males, with past heavy alcohol consumption and past illegal drug use. They may have a previous mood
disorder and social isolation may exacerbate the syndrome. Any dopaminergic treatment has been
associated with described DDS, with a higher prevalence of levodopa and apomorphine. [260,265–267] The
management of DDS is not easy. The best management of hypomanic and psychotic episodes consists
in a reduction of DRT, to be performed in hospital, and a low dose of an atypical antipsychotic drug can
be effective in controlling the acute psychosis. Antidepressant drugs are helpful in treating the mood
disorder as well as psychotherapy in selected cases. Positive reinforcement helps to make patients aware
of their daily DRT requirements and booster doses of medication should be avoided. At discharge,
patients should receive their medication under supervision. Finally the patient's spouse, a family member,
carer or local pharmacist are useful surrogates to control the daily administration of the medication.

Autonomic Dysfunction
Dysautonomia is a common occurrence in PD and is probably due to the neurodegenerative disease
process itself, taking place inside either the CNS or peripheral postganglionic neurons. [268–270] Its
prevalence ranges between 14 and 80%, with variability attributed to the design and methodology of the
studies.[271] Symptoms such as constipation, nocturia and orthostatic hypotension significantly impair
quality-of-life scores for PD patients.[1]

Moreover, a dysfunction of the autonomic nervous system can be induced as a side effect of drug
treatment interacting. When dysautonomia is prominent or compared early in the clinical course of
disease, other Parkinsonisms, such as multisystemic atrophy, should be considered.
The PD-related autonomic symptoms include cardiovascular, gastrointestinal, urogenital and
thermoregulatory dysfunction.[272]

Cardiovascular Dysfunction

The involvement of the cardiovascular autonomic system in PD is of high importance, as many patients
suffer from orthostatic hypotension. Its prevalence varies widely, from 30–58%.[273] Almost all patients with
PD and orthostatic hypotension have significantly reduced sympathetic noradrenergic innervation of left
ventricular myocardium, as evaluated with single-photon emission computed tomography and 123I-
metaiodobenzylguanidine, which is in contrast with those in multisystem atrophy with orthostatic
hypotension.[274,275]

Interestingly, a subgroup of patients with orthostatic hypotension additionally present with supine
hypertension;[276,277] daytime to night-time BP normally fluctuates with BP values rising in the daytime and
falling after night-time. Schmidt et al., with a 24-h ambulatory BP monitoring, demonstrated an altered
nocturnal 24-h BP profile in most of PD patients similar to those patients with essential and secondary
hypertension.[277] This phenomenon is highly clinically relevant, because it has been associated with an
increased prevalence of hypertensive target-organ damage, as well as cerebrovascular and
cardiovascular events in hypertensive patients.[278]

Finally it has been suggested that PD patients have higher BP at the off-stage than at on-stage[279,280] and
that patients with the on–off type of motor fluctuation have higher resting heart rate, greater orthostatic BP
fall and lower responses to the Valsalva maneuver and cold pressor stimuli at the off-stage than healthy
control subjects.[281]

Early diagnosis and symptomatic treatment of orthostatic hypotension can greatly improve quality of life
and, in the case of pathologically elevated BP values, probably improve cardiovascular mortality of the
patients affected.[282] Considering that this symptom may be a consequence of dopaminergic treatment, a
reduction of dopamine agonists is often necessary. Domperidone, a peripheral dopamine-blocking agent,
could be useful for treatment of PD-related orthostatic hypotension.[283] Nonpharmacological measures for
orthostatic hypotension treatment include elevation of the head of the bed by 10–30°, increase in salt and
fluid intake and the use of waist-high compression stockings. Pharmacological treatments include
reduction of antihypertensive in patients who are treated for hypertension and use of agents that increase
BP including α-adrenergic agents such as midodrine or salt-retaining mineralcorticoids (e.g.,
fludrocortisone). Pyridostigmine was reported to be effective in neurogenic orthostatic hypotension but
has not been specifically tested in PD.[284]

Gastrointestinal Symptoms

Constipation is one of the most common complaints among PD patients, [285] with a reported prevalence of
58%.[286] Constipation in PD is thought to result from a combination of neurodegenerative process
affecting gastrointestinal motility coupled with the effects of dopaminergic medications. Constipation is
even considered to be a potential premotor marker of PD and it has been correlated with the presence of
incidental Lewy bodies in the bowel in a population without PD. [287] As an adjunctive feature in PD, an
abdominopelvic dyssynergia has been demonstrated and should be differentiated from colonic problems.

Treatment of constipation should include exercise, dietary modifications, increases in fluid intake and
ultimately judicial use of laxatives. Indeed, the coexistent abdominopelvic dyssynergia could be worsened
by the use of laxatives. Psyllium, polyethylene glycol, bisacodyl, magnesium sulphate,[288] lubiprostone
and macrogol have all been demonstrated to improve constipation in PD.[288–290] In recalcitrant constipation
alternatives are neostigmine, symbiotic yogurt containing components, subcutaneous methylnaltrexone,
botulinum toxin injections and sacral nerve stimulation. [291]

Delayed gastric emptying is another symptom that is present in PD with a prevalence of nearly 70%. It
could be due to or be exacerbated by PD treatment and, vice versa, it could determine an alteration in the
pharmacokinetic of dopaminergic medications. Patients should be counseled on the negative impact of
high-protein diets on the absorption of levodopa.

Dysphagia is often asymptomatic and could determine an impairment in quality of life only in the
advanced stages. When suspected it must be treated due to the risk of food inhalation. The insertion of
gastric tube in severe cases is controversial. In a recent meta-analysis on patients with advanced
dementia there was no evidence of increased survival in patients receiving enteral tube feeding. [292]

Nausea is common as well and is often due to DRT. It is usually treated with adjustment of the timing of
levodopa therapy in relation to food and the use of domperidone.

Hypersalivation is another frequent symptom referred to in the course of PD, caused by a reduced ability
to swallow rather than overproduction of saliva. Anticholinergics and injection of botulinum toxin into the
salivary glands are therapeutic options.[293]

Urinary & Sexual Dysfunction

Bladder dysfunction is another common symptom in PD. Patients usually develop detrusor muscle
hyperactivity, which causes urinary urgency, frequency and nocturia. Hypoactive detrusor has also been
described with delayed bladder emptying, difficulty with initiation of urination and recurrent urinary
infections. Urological evaluation and formal urodynamic testing are indicated for accurate diagnosis of the
nature of the problem. Oxybutynin and tolterodine can be used, although no controlled clinical trials in PD
populations have been performed[294] and possible side effects, such as memory loss and constipation,
must be taken into consideration. Botulinum toxin injections into the bladder wall may improve storage
urine capacity and control.[295,296]

Sexual dysfunction, such as male erectile dysfunction, is reported by more than 60% of PD
patients.[286] Depression, physical disability and autonomic dysfunction may contribute to the increased
prevalence of erectile dysfunction in PD patients. Sildenafil citrate has been found to be safe and effective
in the treatment of erectile dysfunction in PD.

Hyperhydrosis

Hyperhydrosis is another manifestation of dysautonomia in PD. The cause of hyperhydrosis may be

related to hypothalamic dysfunction. Sweating problems occur predominantly in off-periods and in on-
periods with dyskinesias.[173,297] Treatment options for hyperhydrosis are limited. Patients with motor
fluctuations may improve with adjustment of PD medications. Propranolol has been helpful in some
cases.

Sensory Dysfunction
Hyposmia

Olfactory dysfunction is strongly associated with PD with a prevalence ranging from 70 to 100%, with a
loss of smell frequently predating the onset of motor symptoms. The early onset of anosmia in PD
correlates with Braak's hypothesis, which demonstrates that deposition of α-synuclein in the anterior
olfactory structures appears in the earliest stages of development of PD pathology. [268,298,299]

Visual Disturbances

A combination of retinal dopaminergic dysfunction and involvement of the visual cortex has also been
postulated in the preclinical phase of PD and abnormalities of color perception and visual contrast
sensitivity have been demonstrated. Innervation around the fovea is largely dopaminergic and
pathological studies in patients with untreated PD show that retinal dopamine concentration is decreased
compared with treated patients.[300,301] Visual symptoms, with advancing disease, become clinically
apparent and contribute to disability, compromising patient safety.[302]

Pain

Among the NMSs of PD, painful symptoms are frequently under-recognized and seldom treated. Pain is
an important source of distress and disability for PD patients. A recent cross-sectional survey in a regional
population in Norway reported that over 80% of patients with PD endure painful symptoms during the
day.[303] A recent Italian multicenter survey conducted in 1072 consecutive patients demonstrated that pain
symptoms are frequent and have an high impact on quality of life.[304] Four different types of pain have
been categorized in PD:[305] muscoloskeletal (due to Parkinsonian rigidity, reumatologic disease or skeletal
deformity), dystonic, radicular-neuropathic (due to a root lesion, focal or peripheral neuropathy) and
central pain.

Among them, musculoskeletal and dystonic are the most frequently reported by patients, with a
prevalence of 70 and 40%, respectively. Dystonic pain is the one more frequently associated with motor
fluctuations and the effects of dopaminergic drugs.[303] Central pain is defined as a painful, burning,
stabbing, aching, itching or tingling sensations in undefined and peculiar body regions or a vague overall
sensation of tension and discomfort that responds poorly to dopaminergic treatment. It has been
demonstrated that PD patients have generally a lower heat-pain threshold when compared with controls,
and that PD patients with pain have lower heat-pain threshold, than pain-free patients.[306] Controversies
exist regarding whether the heat-pain threshold may be responsive to dopaminergic
treatment.[306,307] Neurotransmitters other than dopamine, such as serotonin and noradrenaline, may be
involved in the pathogenesis of central pain in PD. Serotoninergic and noradrenergic neurons have been
implicated in the mediation of inhibitory mechanisms of endogenous pain via the descending inhibitory
pathways in the brain.[308] At the very early stage of disease, serotoninergic nuclei (i.e., raphe nuclei) and
noradrenergic nuclei (i.e., locus coeruleus) are involved in the neurodegenerative process[309] and their
degeneration may be related to the pathological modulation of pain in PD. On this purpose, Djaldetti and
colleagues studied the effects of duloxetine, a serotonin and norepinephrine inhibitor, on modulating
primary pain in 23 PD patients, and found evidence of a significant beneficial effect on pain perceived by
the patients.[310] In conclusion, pain is a common and undervaluated NMS in PD, that may be responsive
to treatment if diagnosed and correctly identified. Consensus criteria for pain in PD are urgently needed
for a better evaluation of this frequent and hidden aspect of the disease.

Future Perspective
Recognition and treatment of these mostly under-recognized and under-treated symptoms represent a
new challenge in PD management, as they can be an important source of disability. Since both motor
symptoms (e.g., dyskinesias) and nonmotor symptoms (e.g., panic attacks, EDS, SA, ICDs and punding)
are related to the pulsatility of dopaminergic stimulation, pharmacologic and surgical approaches
attempting to generate a continuous stimulation should be preferred. Regarding symptoms, such as mood
disorders, hyposmia and RBD, they may precede the motor symptoms onset, and the scenario in the
future could be to use disease-modifying drugs as soon as possible in order to prevent the full clinical
conversion into PD. Finally, PD involving several neurotransmitter systems should not be considered as a
strictly dopaminergic disease, but for certain aspects (e.g., gastrointestinal symptoms and BP control) PD
must be considered a systemic illness.

Sidebar
Executive Summary

Introduction

 Clinical diagnosis of Parkinson's disease (PD) could be performed in the presence of motor
symptoms such as resting tremor, rigidity, akinesia, bradykinesia and postural instability.

 Nonmotor symptoms, such as depression, anxiety, psychosis, dementia, impulse-control

disorders (ICDs), sleep disturbances and autonomic dysfunctions, are often an integral part of the
disease.

 Nonmotor symptoms worsen quality of life for PD patients, being the cause of hospitalization and
institutionalization in some cases.

Depression & anxiety

 Depression and anxiety in PD patients are very common and may represent the first
manifestation of PD, years before the onset of motor symptoms.

 A combination of dysfunction of dopaminergic, norepineprinergic and serotoninergic systems has

been implicated in the pathogenesis of depression in PD.

 They have been associated with a worse motor progression and with akinetic-rigid subtype of PD,
and may fluctuate during the day in some cases in relation to motor fluctuations.

 Dopamine agonists may be useful in depression associated (or not) with PD and pramipexole has
been demonstrated to have the same efficacy of selective serotonin-reuptake inhibitors (SSRIs).

 Tricyclic antidepressants are effective in PD, but not well tolerated. SSRIs are better tolerated
and effective in the treatment of depression in PD. The selective serotonin and norepinephrine
inhibitors have not yet been systematically studied in the treatment of depression associated with
PD. Mirtazapine also has a role in reducing Parkinsonian tremor.

 In refractory cases, noninvasive brain stimulation may represent an effective treatment option.

Psychosis

 Hallucinations, in most cases in visual modality, occur in 15–40% of PD-treated patients.

 Hallucinations tend to persist over time without a therapeutical change.

  The pathogenesis of hallucinations is multifactorial: dopaminergic load, peripheral ocular and
retinal dysfunction, central visual dysfunction of visual processing and dementia are the best
known factors.

 Clinical practice recommends excluding general causes of hallucination/confusion (e.g., fever and
metabolic dysfunction), reducing the dose or the number of drugs (in the following order:
anticholinergics, monoamine oxidase inhibitors, amantadine, dopamine agonist and levodopa),
and adding antipsychotics (clozapine and quetiapine).

 Novel antipsychotics, such as ziprasidone and aripiprazole, in the treatment of psychosis in PD

remain controversial.

 Cholinesterase inhibitors are useful, especially in the presence of cognitive impairment.

Dementia

 Dementia in PD (PD-D) is very frequent with a prevalence of 30–40%.

 Risk factors for PD-D include advanced current age, visual hallucinations, and rigido–akinetic
subtype of PD.

 Neuropsychological features include a 'dysexecutive' syndrome, with a prominent impairment in

attention, executive and visuospatial functions.

 Management of dementia in PD involves: the systematic assessment and resolution of features,

such as systemic illness, intoxication or adverse effect of drugs; withdrawal of anticholinergics,
amantadine and benzodiazepines; reduction of dopaminergic therapy; and the addition of
cholinesterase inhibitors (donepezil and rivastigmine).

Sleep dysfunction

 Disorders of sleep initiation and maintenance, excessive daytime sleepiness (EDS) and sleep
attacks (SA) are often due to motor manifestations of PD and bladder dysfunction.

 Management of insomnia include: counseling on good sleep hygiene; improving control of motor
symptoms; adequate treatment of depression and psychosis; and only using hypnotic agents
when previous measures are not sufficient.

 EDS and dopamine have been related with dopaminergic treatment, especially with dopamine
agonists, although large-scale studies have not shown univocal results.

 Management of EDS and SA include: avoiding concomitant sedative medication; reducing the
dose or substituting with another dopamine agonist; advising patients not to drive until the issue is
resolved; adding modafinil.

 Rapid eye movements-sleep behavior disorder (RBD) is associated with PD and can be a
preclinical marker of an evolving Parkinsonian disorder.

 Rapid eye movements-sleep behavior disorder is often successfully treated with clonazepam.
Impulse-control disorders

 ICDs (pathological gambling, hypersexuality and compulsive buying) have been reported in PD
with a prevalence ranging from 6 to 25%.

 Patients who develop ICDs are usually males, have younger age at PD onset, longer duration,
early disease onset, have a personal or immediate family history of alcohol-use disorders, or a
prior history of ICDs.

 However, the strongest risk factor is the exposure to dopaminergic drugs. The role of dopamine
doses in increasing the risk for developing ICDs is controversial.

 Management of ICDs consists of: patient and caregiver education; modification of dopamine-
replacement therapy (switch, reduce or discontinue dopamine agonist); add psychoactive drugs
(clozapine, risperidone, quetiapine, valproate and lithium).

Autonomic dysfunction

 Dysautonomia is a common occurrence in PD and is probably due to the neurodegenerative

disease process itself taking place inside either the CNS or peripheral postganglionic axons.

 Symptoms such constipation, nocturia or orthostatic hypotension confer significant alterations on

quality-of-life scores of PD patients.

 A dysfunction of the autonomic nervous system can be induced as a side effect of drug treatment
interaction.

 Cardiovascular symptoms include orthostatic hypotension and supine hypertension.

 The management of orthostatic hypotension includes: trying nonpharmacological measures such

as elevation of the head of the bed by 10–30°; increasing salt and fluid intake; the use of waist-
high compression stockings; reducing dopaminergic treatment; and adding domperidone, α-
adrenergic agents and a salt-retaining mineralcorticoids such as fludrocortisone to the therapy
regimen.

 Gastrointestinal symptoms include constipation, delayed gastric emptying, dysphagia, nausea

and hypersalivation.

References

1. Chaudhuri KR, Healy DG, Schapira AH: Nonmotor symptoms of Parkinson's disease: diagnosis
and management. Lancet Neurol. 5(3), 235–245 (2006).

2. Veazey C, Aki SO, Cook KF, Lai EC, Kunik ME: Prevalence and treatment of depression in
Parkinson's disease. J. Neuropsychiatry Clin. Neurosci. 17(3), 310–323 (2006).

3. Reijnders JS, Ehrt U, Weber WE, Aarsland D, Leentjens AF: A systematic review of prevalence
studies of depression in Parkinson's disease. Mov. Disord. 23(2), 183–189 (2008).
4. Shiba M, Bower JH, Maraganore DM et al.: Anxiety disorders and depressive disorders preceding
Parkinson's disease: a case-control study. Mov. Disord. 15(4), 669–677 (2000).

5. Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB: Recognition and treatment of depression
in Parkinson's disease. J. Geriatr. Psychiatry Neurol. 16, 178–183 (2003).

6. Ravina B, Camicioli R, Como PG et al.: The impact of depressive symptoms in early Parkinson
disease. Neurology 69(4), 342–347 (2007).

7. Marsh L, McDonald WM, Cummings J, Ravina B, and the NINDS/NIMH Work Group on
Depression and Parkinson's Disease: Provisional diagnostic criteria for depression in Parkinson's
disease: report of an NINDS/NIMH work group. Mov. Disord. 21(2), 148–158 (2005).

8. Cummings JL: Depression and Parkinson's disease: a review. Am. J. Psychiatry 149(4), 443–454
(1992).

9. Richard IH, Schiffer RB, Kurlan R: Anxiety and Parkinson's disease. J. Neuropsychiatry Clin.
Neurosci. 8(4), 383–392 (1996).

10. Slaughter JR, Slaughter KA, Nichols D, Holmes SE, Martens MP: Prevalence, clinical
manifestations, etiology, and treatment of depression in Parkinson's disease. J. Neuropsychiatry
Clin. Neurosci. 13(2), 187–196 (2001).

11. Remy P, Doder M, Lees A, Turjanski N, Brooks D: Depression in Parkinson's disease: loss of
dopamine and noradrenaline innervation in the limbic system. Brain 128(6), 1314–1322 (2005).

12. Paulus W, Jellinger K: The neuropathologic basis of different clinical subgroups of Parkinson's
disease. J. Neuropathol. Exp. Neurol. 50(6), 743–755 (1991).

13. Boileau I, Warsh JJ, Guttman M et al.: Elevated serotonin transporter binding in depressed
patients with Parkinson's disease: a preliminary PET study with [11C]DASB. Mov. Disord. 23(12),
1776–1780 (2008).

14. Starkstein SE, Mayberg HS, Leiguarda R, Preziosi TJ, Robinson RG: A prospective longitudinal
study of depression, cognitive decline, and physical impairments in patients with Parkinson's
disease. J. Neurol. Neurosurg. Psychiatry 55(5), 377–382 (1992).

15. Papapetropoulos S, Ellul J, Argyriou AA, Chroni E, Lekka NP: The effect of depression on motor
function and disease severity of Parkinson's disease. Clin. Neurol. Neurosurg. 108(5), 465–469
(2006).

16. Starkstein SE, Petracca G, Chemerinski E et al.: Depression in classic versus akinetic-rigid
Parkinson's disease. Mov. Disord. 13(1), 29–33 (1998).

17. Menza MA, Sage J, Marshall E, Cody R, Duvoisin R: Mood changes and 'on-off' phenomena in
Parkinson's disease. Mov. Disord. 5(2), 148–151 (1990).

18. Maricle RA, Nutt JG, Carter JH: Mood and anxiety fluctuation in Parkinson's disease associated
with levodopa infusion: preliminary findings. Mov. Disord. 10(3), 329–332 (1995).
19. Richard IH, Justus AW, Kurlan R: Relationship between mood and motor fluctuations in
Parkinson's disease. J. Neuropsychiatry Clin. Neurosci. 13(1), 35–41 (2001).

20. Hughes TA, Ross HF, Musa S et al.: A 10-year study of the incidence of and factors predicting
dementia in Parkinson's disease. Neurology 54(8), 1596–1602 (2000).

21. Tandberg E, Larsen JP, Aarsland D, Laake K, Cummings JL: Risk factors for depression in
Parkinson disease. Arch. Neurol. 54(5), 625–630 (1997).

22. Nuti A, Ceravolo R, Piccinni A et al.: Psychiatric comorbidity in a population of Parkinson's

disease patients. Eur. J. Neurol. 11(5), 315–320 (2004).

23. Aarsland D, Larsen JP, Lim NG et al.: Range of neuropsychiatric disturbances in patients with
Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 67(4), 492–496 (1999).

24. Bronnick K, Aarsland D, Larsen JP: Neuropsychiatric disturbances in Parkinson's disease

clusters in five groups with different prevalence of dementia. Acta Psychiatr. Scand. 112(3), 201–
207 (2005).

25. Levy ML, Cummings JL, Fairbanks LA et al.: Apathy is not depression. J. Neuropsychiatry Clin.
Neurosci. 10(3), 314–319 (1998).

26. Starkstein SE, Merello M, Jorge R, Brockman S, Bruce D, Power B: The syndromal validity and
nosological position of apathy in Parkinson's disease. Mov. Disord. 24(8), 1211–1216 (2009).

27. Oguru M, Tachibana H, Toda K, Okuda B, Oka N: Apathy and depression in Parkinson
disease. J. Geriatr. Psychiatry Neurol. 23(1), 35–41 (2010).

28. Leentjens AF, Verhey FR, Luijckx GJ, Troost J: The validity of the beck depression inventory as a
screening and diagnostic instrument for depression in patients with Parkinson's disease. Mov.
Disord. 15(6), 1221–1224 (2000).

29. Leentjens AF, Verhey FR, Lousberg R, Spitsbergen H, Wilmink FW: The validity of the Hamilton
and Montgomery-Asberg depression rating scales as screening and diagnostic tools for
depression in Parkinson's disease. Int. J. Geriatr. Psychiatry 15(7), 644–649 (2000).

30. Sethi K: Levodopa unresponsive symptoms in Parkinson disease. Mov. Disord. 23,S521–S533
(2008).

31. Rektorová I, Rektor I, Bares M et al.: Pramipexole and pergolide in the treatment of depression in
Parkinson's disease: a national multicentre prospective randomized study. Eur. J. Neurol. 10(4),
399–406 (2003).

32. Corrigan MH, Denahan AQ, Wright CE, Ragual RJ, Evans DL: Comparison of pramipexole,
fluoxetine, and placebo in patients with major depression. Depress. Anxiety 11(2), 58–65 (2000).

33. Leentjens AF, Koester J, Fruh B, Shephard DT, Barone P, Houben JJ: The effect of pramipexole
on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-
controlled studies. Clin. Ther. 31(1), 89–98 (2009).
34. Barone P, Poewe W, Albrecht S et al.: Pramipexole for the treatment of depressive symptoms in
patients with Parkinon's disease: a randomized, double-blind, placebo controlled trial. Lancet
Neurol. 9, 573–580 (2010).

•• Large multicenter randomized, double-blind, placebo-controlled trial of pramipexole on

depression in patients with mild-to-moderate Parkinson's disease.

35. Pahwa R, Stacy MA, Factor SA et al.: Ropinirole 24-hour prolonged release: randomized,
controlled study in advanced Parkinson disease. Neurology 68(14), 1108–1115 (2007).

36. Menza M, Dobkin RD, Marin H et al.: A controller trial of antidepressants in patients with
Parkinson disease and depression. Neurology 72, 886–892 (2009).

37. Jiménez-Jiménez FJ, Tejeiro J, Martínez-Junquera G, Cabrera-Valdivia F, Alarcón J, García-

Albea E: Parkinsonism exacerbated by paroxetine. Neurology 44(12), 2406 (1994).

38. Meltzer HY, Young M, Metz J, Fang VS, Schyve PM, Arora RC: Extrapyramidal side effects and
increased serum prolactin following fluoxetine, a new antidepressant. J. Neural. Transm. 45(2),
165–175 (1979).

39. Ceravolo R, Nuti A, Piccinni A et al.: Paroxetine in Parkinson's disease: effects on motor and
depressive symptoms. Neurology 55(8), 1216–1218 (2000).

40. Hauser RA, Zesiewicz TA: Sertraline for the treatment of depression in Parkinson's disease. Mov.
Disord. 12(5), 756–759 (1997).

41. Montastruc JL, Fabre N, Blin O, Senard JM, Rascol O, Rascol A: Does fluoxetine aggravate
Parkinson's disease? A pilot prospective study. Mov. Disord. 10(3), 355–357 (1995).

42. Rampello L, Chiechio S, Raffaele R, Vecchio I, Nicoletti F: The SSRI, citalopram, improves
bradykinesia in patients with Parkinson's disease treated with L-dopa. Clin.
Neuropharmacol. 25(1), 21–24 (2002).

43. Barone P, Scarzella L, Marconi R et al.: Pramipexole versus sertraline in the treatment of
depression in Parkinson's disease: a national multicenter parallel-group randomized study. J.
Neurol. 253(5), 601–607 (2006).

44. Birmes P, Coppin D, Schmitt L et al.: Serotonin syndrome: a brief review. CMAJ 168, 1439–1442
(2003).

45. Pact V, Giduz T: Mirtazapine treats resting tremor, essential tremor, and levodopa-induced
dyskinesias. Neurology 53(5), 1154 (1999).

46. Moellentine C, Rummans T, Ahlskog JE et al.: Effectiveness of ECT in patients with

Parkinsonism. J. Neuropsychiatry Clin. Neurosci. 10(2), 187–193 (1998).

47. Aarsland D, Larsen JP, Waage O, Langeveld JH: Maintenance electroconvulsive therapy for
Parkinson's disease. Convuls. Ther. 13(4), 274–277 (1997).
48. Epstein CM, Evatt ML, Funk A et al.: An open study of repetitive transcranial magnetic stimulation
in treatment-resistant depression with Parkinson's disease. Clin. Neurophysiol. 118(10), 2189–
2194 (2007).

49. Kormos TC: Efficacy of rTMS in the treatment of co-morbid anxiety in depressed patients with
Parkinson's disease. Mov. Disord. 22(12), 1836 (2007).

50. Popeo D, Kellner C. ECT for Parkinson's disease. Med. Hypoth. 468–469 (2009).

51. Menza MA, Robertson-Hoffman DE, Bonapace AS: Parkinson's disease and anxiety. Biol.
Psychiatry 34(7), 465–470 (1993).

52. Richard IH: Anxiety disorders in Parkinson's disease. Adv. Neurol. 96, 42–55 (2005).

53. Witjas T, Kaphan E, Azulay JP et al.: Non motor fluctuations in Parkinson's disease: frequent and
disabling. Neurology 59, 408–413 (2002).

54. Mondolo F, Jahanshhi M, Grana A, Biasutti E, Cacciatori E, Di Benedetto P: Evaluation of anxiety

in Parkinson's disease with some commonly used rating scales. Neurol. Sci. 28, 270–275 (2007).

55. Dissanayaka NNW, Sellbach A, Matheson S et al.: Anxiety disorders in Parkinson's disease:
prevalence and risk factors. Mov. Disord. 25(7), 838–845 (2010).

56. Hammerstad JP, Carter J, Nutt JG et al.: Buspirone in Parkinson's disease. Clin.
Neuropharmacol. 9(6), 556–560 (1986).

57. Fénelon G, Mahieux F, Huon R, Ziégler M: Hallucinations in Parkinson's disease: prevalence,

phenomenology and risk factors. Brain 123, 733–745 (2000).

•• Prospective observational study about the phenomenology, prevalence and risk factors of
hallucinations in Parkinson's disease.

58. Giladi N, Treves TA, Paleacu D et al.: Risk factors for dementia, depression and psychosis in
long-standing Parkinson's disease. J. Neural Transm. 107(1), 59–71 (2000).

59. Inzelberg R, Kipervasser S, Korczyn AD: Auditory hallucinations in Parkinson's disease. J.

Neurol. Neurosurg. Psychiatry 64, 533–535 (1998).

60. De Maindreville AD, Fenelon G, Mahieux F: Hallucinations in Parkinson's disease: a follow-up

study. Mov. Disord. 20, 212–217 (2005).

61. Marsh L, Williams JR, Rocco M, Grill S, Munro C, Dawson TM: Psychiatric comorbidities in
patients with Parkinson disease and psychosis. Neurology 63(2), 293–300 (2004).

62. Sanchez-Ramos JR, Ortoll R, Paulson GW: Visual hallucinations associated with Parkinson
disease. Arch. Neurol. 53(12), 1265–1268 (1996).

63. Graham JM, Grünewald RA, Sagar HJ: Hallucinosis in idiopathic Parkinson's disease. J. Neurol.
Neurosurg. Psychiatry 63(4), 434–440 (1997).
64. Factor SA, Molho ES, Podskalny GD, Brown D: Parkinson's disease: drug-induced psychiatric
states. Adv. Neurol. 65, 115–138 (1995).

65. Chou KL, Messing S, Oakes D, Feldman PD, Breier A, Friedman JH: Drug-induced psychosis in
Parkinson disease: phenomenology and correlations among psychosis rating instruments. Clin.
Neuropharmacol. 28(5), 215–219 (2005).

66. Fénelon G, Thobois S, Bonnet AM, Broussolle E, Tison F: Tactile hallucinations in Parkinson's
disease. J. Neurol. 249(12), 1699–1703 (2002).

67. Tousi B, Frankel M: Olfactory and visual hallucinations in Parkinson's disease. Parkinsonism
Relat. Disord. 10(4), 253–254 (2004).

68. Holroyd S, Currie L, Wooten GF: Prospective study of hallucinations and delusions in Parkinson's
disease. J. Neurol. Neurosurg. Psychiatry 70(6), 734–738 (2001).

69. Factor SA, Feustel PJ, Friedman JH et al.: Longitudinal outcome of Parkinson's disease patients
with psychosis. Neurology 60(11), 1756–1761 (2003).

70. Diederich NJ, Fénelon G, Stebbins G, Goetz CG: Hallucinations in Parkinson disease. Nat. Rev.
Neurol. 5(6), 331–342 (2009).

71. Friedman A, Sienkiewicz J: Psychotic complications of long-term levodopa treatment of

Parkinson's disease. Acta. Neurol. Scand. 84(2), 111–113 (1991).

72. Horstink M, Tolosa E, Bonuccelli U et al.: Review of the therapeutic management of Parkinson's
disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS)
and the Movement Disorder Society-European Section (MDS-ES). Part II: late (complicated)
Parkinson's disease. Eur. J. Neurol. 13(11), 1186–1202 (2006).

73. Saint-Cyr JA, Taylor AE, Lang AE: Neuropsychological and psychiatric side effects in the
treatment of Parkinson's disease. Neurology 43(12 Suppl. 6),S47–S52 (1993).

74. Ecker D, Unrath A, Kassubek J, Sabolek M: Dopamine agonists and their risk to induce psychotic
episodes in Parkinson's disease: a case-control study. BMC Neurol. 9, 23 (2009).

75. Etminan M, Gill S, Samii A: Comparison of the risk of adverse events with pramipexole and
ropinirole in patients with Parkinson's disease: a meta-analysis. Drug Saf. 26(6), 439–444 (2003).

76. Thanvi BR, Lo TC, Harsh DP: Psychosis in Parkinson's disease. Postgrad. Med. J. 81(960), 644–
646 (2005).

77. Fénelon G, Goetz CG, Karenberg A: Hallucinations in Parkinson disease in the prelevodopa
era. Neurology 66(1), 93–98 (2006).

78. Dotchin CL, Jusabani A, Walker RW: Non-motor symptoms in a prevalent population with
Parkinson's disease in Tanzania. Parkinsonism Relat. Disord. 15, 457–460 (2009).

79. Teunisse RJ, Cruysberg JR, Hoefnagels WH, Verbeek AL, Zitman FG: Visual hallucinations in
psychologically normal people: Charles Bonnet's syndrome. Lancet 347(9004), 794–797 (1996).
80. Diederich NJ, Goetz CG, Stebbins GT: Repeated visual hallucinations in Parkinson's disease as
disturbed external/internal perceptions: focused review and a new integrative model. Mov.
Disord. 20(2), 130–140 (2005).

81. Pacchetti C, Manni R, Zangaglia R et al.: Relationship between hallucinations, delusions, and
rapid eye movement sleep behavior disorder in Parkinson's disease. Mov. Disord. 20(11), 1439–
1448 (2005).

82. Comella CL, Tanner CM, Ristanovic RK: Polysomnographic sleep measures in Parkinson's
disease patients with treatment-induced hallucinations. Ann. Neurol. 34(5), 710–714 (1993).

83. Papapetropoulos S, Argyriou AA, Ellul J: Factors associated with drug-induced visual
hallucinations in Parkinson's disease. J. Neurol. 252(10), 1223–1228 (2005).

84. Ramirez-Ruiz B, Junque C, Marti MJ, Valldeoriola F, Tolosa E: Cognitive changes in Parkinson's
disease patients with visual hallucinations. Dement. Geriatr. Cogn. Disord. 23(5), 281–288
(2007).

85. Kiferle L, Ceravolo R, Petrozzi L et al.: Visual hallucinations in Parkinson's disease are not
influenced by polymorphisms of serotonin 5-HT2A receptor and transporter genes. Neurosci.
Lett. 422(3), 228–231 (2007).

86. Goetz CG, Burke PF, Leurgans S et al.: Genetic variation analysis in Parkinson disease patients
with and without hallucinations: case-control study. Arch. Neurol. 58(2), 209–213 (2001).

87. Weintraub D, Hurtig HI: Presentation and management of psychosis in Parkinson's disease and
dementia with Lewy bodies. Am. J. Psychiatry 164(10), 1491–1498 (2007).

88. Goetz CG, Fan W, Leurgans S, Bernard B, Stebbins GT: The malignant course of 'benign
hallucinations' in Parkinson disease. Arch. Neurol. 63(5), 713–716 (2006).

89. Goetz CG, Fan W, Leurgans S: Antipsychotic medication treatment for mild hallucinations in
Parkinson's disease: positive impact on long-term worsening. Mov. Disord. 23(11), 1541–1545
(2008).

90. Frieling H, Hillemacher T, Ziegenbein M, Neundörfer B, Bleich S: Treating dopamimetic psychosis

in Parkinson's disease: structured review and meta-analysis. Eur. Neuropsychopharmacol. 17(3),
165–171 (2007).

91. The French Clozapine Parkinson Study Group: Clozapine in drug-induced psychosis in
Parkinson's disease. Lancet 353(9169), 2041–2042 (1999).

92. Klein C, Gordon J, Pollak L, Rabey JM: Clozapine in Parkinson's disease psychosis: 5-year
follow-up review. Clin. Neuropharmacol. 26(1), 8–11 (2003).

93. Pollak P, Tison F, Rascol O et al.: Clozapine in drug induced psychosis in Parkinson's disease: a
randomised, placebo controlled study with open follow up. J. Neurol. Neurosurg. Psychiatry 75(5),
689–695 (2004).
94. Miyasaki J, Shannon K, Voon V et al.: Practice Parameter: evaluation and treatment of
depression, psychosis and dementia in Parkinson disease (an evidenced-based review): report of
the Quality Standards Subcommittee of the American Academy of NeurologyNeurology 66, 996–
1002 (2006).

95. Fernandez HH, Friedman JH, Jacques C, Rosenfeld M: Quetiapine for the treatment of drug-
induced psychosis in Parkinson's disease. Mov. Disord. 14, 484–487 (1999).

96. Morgante L, Epifanio A, Spina E et al.: Quetiapine and clozapine in Parkinsonian patients with
dopaminergic psychosis. Clin. Neuropharmacol. 27, 153–156 (2004).

97. Reddy S, Factor SA, Molho ES, Feustel PJ: The effect of quetiapine on psychosis and motor
function in Parkinsonian patients with and without dementia. Mov. Disord. 17, 676–681 (2002).

98. Fernandez HH, Trieschmann ME, Burke MA, Jacques C, Friedman JH: Long-term outcome of
quetiapine use for psychosis among Parkinsonian patients. Mov. Disord. 18, 510–514 (2003).

99. Juncos JL, Roberts VJ, Evatt ML et al.: Quetiapine improves psychotic symptoms and cognition
in Parkinson's disease. Mov. Disord. 19, 29–35 (2004).

100. Ondo WG, Tintner R, Voung KD, Lai D, Ringholz G: Double-blind, placebo-controlled,
unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in
Parkinson's disease. Mov. Disord. 20(8), 958–963 (2005).

101. Rabey JM, Prokhorov T, Miniovitz A, Dobronevsky E, Klein C: Effect of quetiapine in

psychotic Parkinson's disease patients: a double-blind labeled study of 3 month's duration. Mov.
Disord. 22(3), 313–318 (2007).

102. Shotbolt P, Samuel M, Fox C, David AS: A randomized controlled trial of quetiapine for
psychosis in Parkinson's disease. Neuropsychiatr. Dis. Treatment 5, 327–332 (2009).

103. Ondo WG, Levy JK, Vuong KD, Hunter C, Jankovic J: Olanzapine treatment for
dopaminergic-induced hallucinations. Mov. Disord. 17(5), 1031–1035 (2002).

104. Goetz CG, Blasucci LM, Leurgans S, Pappert EJ: Olanzapine and clozapine:
comparative effects on motor function in hallucinating PD patients. Neurology 55(6), 789–794
(2000).

105. Breier A, Sutton VK, Feldman PD et al.: Olanzapine in the treatment of dopamimetic-
induced psychosis in patients with Parkinson's disease. Biol. Psychiatry 52(5), 438–445 (2002).

106. Mohr E, Mendis T, Hildebrand K, De Deyn PP: Risperidone in the treatment of dopamine-
induced psychosis in Parkinson's disease: an open pilot trial. Mov. Disord. 15(6), 1230–1237
(2000).

107. Ellis T, Cudkowicz ME, Sexton PM, Growdon JH: Clozapine and risperidone treatment of
psychosis in Parkinson's disease. J. Neuropsychiatry Clin. Neurosci. 12(3), 364–369 (2000).

108. Leopold NA: Risperidone treatment of drug-related psychosis in patients with

Parkinsonism. Mov. Disord. 15(2), 301–304 (2000).
109. Meco G, Alessandria A, Bonifati V, Giustini P: Risperidone for hallucinations in levodopa-
treated Parkinson's disease patients. Lancet 343(8909), 1370–1371 (1994).

110. Shiah IS, Lin CL, Mao WC, Luu SU: Ziprasidone in the treatment of Parkinson's disease
psychosis. Eur. Psychiatry 21(8), 578–579 (2006).

111. Gómez-Esteban JC, Zarranz JJ, Velasco F et al.: Use of ziprasidone in Parkinsonian
patients with psychosis. Clin. Neuropharmacol. 28(3), 111–114 (2005).

112. Gao K, Kemp DE, Ganocy SJ et al.: Antipsychotic-induced extrapyramidal side effect in
bipolar disorder and schizophrenia: a systematic review. J. Clin. Psychipharmacol. 28, 203–209
(2008).

113. Friedman JH, Berman RM, Goetz CG et al.: Open-label flexible-dose pilot study to
evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with
Parkinson's disease. Mov. Disord. 21(12), 2078–2081 (2006).

114. Fernandez HH, Trieschmann ME, Friedman JH: Aripiprazole for drug-induced psychosis
in Parkinson disease: preliminary experience. Clin. Neuropharmacol. 27(1), 4–5 (2004).

115. Ballard C, Lane R, Barone P, Ferrara R, Tekin S: Cardiac safety of rivastigmine in Lewy
body and Parkinson's disease dementias. Int. J. Clin. Pract. 60(6), 639–645 (2006).

116. Barbato L, Monge A, Stocchi F et al.: Melperone in the treatment of iatrogenic psychosis
in Parkinson's disease. Funct. Neurol. 11, 201–207 (1996).

117. Friedman JH: Parkinson's disease psychosis 2010: a review article. Parkinsonism Relat.
Disord. DOI 10.1016/j.parkreldis.2010.05.004 (2010) (Epub ahead of print).

118. Fabbrini G, Barbanti P, Aurilia C, Pauletti C, Lenzi GL, Meco G: Donepezil in the
treatment of hallucinations and delusions in Parkinson's disease. Neurol. Sci. 23(1), 41–43
(2002).

119. Ravina B, Putt M, Siderowf A et al.: Donepezil for dementia in Parkinson's disease: a
randomised, double blind, placebo controlled, crossover study. J. Neurol. Neurosurg.
Psychiatry 76(7), 934–939 (2005).

120. Aarsland D, Hutchinson M, Larsen JP: Cognitive, psychiatric and motor response to
galantamine in Parkinson's disease with dementia. Int. J. Geriatr. Psychiatry 18(10), 937–941
(2003).

121. Burn D, Emre M, McKeith I et al.: Effects of rivastigmine in patients with and without
visual hallucinations in dementia associated with Parkinson's disease. Mov. Disord. 21(11),
1899–1907 (2006).

122. Meltzer HY, Mills R, Revell S et al.: Pimavanserin, a serotonin(2A) receptor inverse
agonist, for the treatment of Parkinson's disease psychosis. Neuropsychopharmacology 35(4),
881–892 (2010).
123. Friedman JH, Ravina B, Mills R et al.: A multi center, placebo controlled, double blind trial
to examine the safety and efficacy of pimavanserin in the treatment of psychosis in Parkinson's
disease. Presented at: American Academy of Neurology. Toronto, Canada, 17–20 April 2010.

124. Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P: Risk of

dementia in Parkinson's disease: a community-based, prospective study. Neurology 56, 730–736
(2001).

125. Cooper JA, Sagar HJ, Jordan N, Harvey NS, Sullivan EV: Cognitive impairment in early,
untreated Parkinson's disease and its relationship to motor disability. Brain 114, 2095–2122
(1991).

126. Goldman WP, Baty JD, Buckles VD, Sahrmann S, Morris JC: Cognitive and motor
functioning in Parkinson disease: subjects with and without questionable dementia. Arch.
Neurol. 55, 674–880 (1998).

127. Cummings JL: Intellectual impairment in Parkinson's disease: clinical, pathologic, and
biochemical correlates. J. Geriatr. Psychiatry Neurol. 1, 24–36 (1988).

128. Aarsland D, Zaccai J, Brayne C: A systematic review of prevalence studies of dementia

in Parkinson's disease. Mov. Disord. 20, 1255–1263 (2005).

129. de Lau LM, Schipper CM, Hofman A et al.: Prognosis of Parkinson disease: risk of
dementia and mortality: the Rotterdam Study. Arch. Neurol. 62, 1265–1269 (2005).

130. Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sørensen P: Prevalence and

characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch. Neurol. 60,
387–392 (2003).

131. Mayeux R, Denaro J, Hemenegildo N et al.: A population-based investigation of

Parkinsons-disease with and without dementia – relationship to age and gender. Arch.
Neurol. 49, 492–497 (1992).

132. Aarsland D, Tandberg E, Larsen JP, Cummings JL: Frequency of dementia in Parkinson
disease. Arch. Neurol. 53, 538–542 (1996).

133. Hobson P, Meara J: Risk and incidence of dementia in a cohort of older subjects with
Parkinson's disease in the United Kingdom. Mov. Disord. 19, 1043–1049 (2004).

134. Marttila RJ, Rinne UK: Dementia in Parkinson's disease. Acta. Neurol. Scand. 54, 431–
441 (1976).

135. Mayeux R, Chen J, Mirabello E et al.: An estimate of the incidence of dementia in

idiopathic Parkinson's disease. Neurology 40, 1513–1517 (1990).

136. Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG: The Sydney multicenter study of
Parkinson's disease: the inevitability of dementia at 20 years. Mov. Disord. 23(6), 837–844
(2008).
 •• Large, observational prospective study of 20 years where a large proportion of Parkinson's
disease patients demonstrated dementia development.

137. Lees AJ, Smith E: Cognitive deficits in the early stages of Parkinson's disease. Brain 106,
257–270 (1983).

138. Schrag A, Jahanshahi M, Quinn N: How does Parkinson's disease affect quality of life? A
comparison with quality of life in the general population. Mov. Disord. 15, 1112–1118 (2000).

139. Nussbaum M, Treves TA, Inzelberg R, Rabey JM, Korczyn AD: Survival in Parkinson's
disease: the effect of dementia. Parkinsonism Rel. Disord. 4, 179–181 (1998).

140. Aarsland D, Larsen JP, Karlsen K, Lim NG, Tandberg E: Mental symptoms in Parkinson's
disease are important contributors to caregiver distress. Int. J. Geriatr. Psych. 14, 866–874
(1999).

141. Levy G, Schupf N, Tang MX et al.: Combined effect of age and severity on the risk of
dementia in Parkinson's disease. Ann. Neurol. 51, 722–729 (2002).

142. Aarsland D, Kvaløy JT, Andersen K et al.: The effect of age of onset of PD on risk of
dementia. J. Neurol. 254, 38–45 (2007).

143. Schrag A, Ben-Schlomo Y, Brown R et al.: Young-onset Parkinson's disease revisited-

clinical features, natural history, and mortality. Mov. Disord. 13, 885–894 (1998).

144. Harhangi BS, de Rijk MC, van Duijin CM et al.: APOE and the risk of PD with or without
dementia in a population based study. Neurology 54, 1272–1276 (2000).

145. Kraybill ML, Larson EB, Tsuang DW et al.: Cognitive differences in dementia patients
with autopsy-verified AD, Lewy body pathology, or both. Neurology 64, 2069–2073 (2005).

146. Aarsland D, Perry R, Brown A et al.: Neuropathology of dementia in Parkinson's disease:

a prospective, community-based study. Ann. Neurol. 58, 773–776 (2005).

147. Mikolaenko I, Pletnikova O, Kawas CH et al.: α-synuclein lesions in normal aging,

Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of
Aging (BLSA). J. Neuropathol. Exp. Neurol. 64, 156–162 (2005).

148. Farlow M, Cummings J: A modern hypothesis: the distinct pathologies of dementia

associated with Parkinson's disease versus Alzheimer's disease. Dement. Geriatr. Cogn.
Disord. 25, 301–308 (2008).

149. Bohnen NI, Kaufer DI, Ivanco LS et al.: Cortical cholinergic function is more severely
affected in Parkinsonian dementia than in Alzheimer disease: an in vivo positron emission
tomographic study. Arch. Neurol. 60, 1745–1748 (2003).

150. Tiraboschi P, Hansen LA, Alford M et al.: Cholinergic dysfunction in diseases with Lewy
bodies. Neurology 54, 407–411 (2000).
151. Muslimovic D, Post B, Speelman JD, Schmand B: Cognitive profile of patients with newly
diagnosed Parkinson disease. Neurology 65, 1239–1245 (2005).

152. Janvin C, Aarsland D, Larsen JP, Hugdahl K: Neuropsychological profile of patients with
Parkinson's disease without dementia. Dement. Geriatr. Cogn. Disord. 15, 126–131 (2003).

153. Aarsland D, Litvan I, Salmon D, Galasko D, Wentzel-Larsen T, Larsen JP: Performance

on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy
bodies: comparison with progressive supranuclear pasly and Alzheimer's disease. J. Neurol.
Neurosurg. Psychiatry 74, 1215–1220 (2003).

154. Cahn-Weiner DA, Grace J, Ott BR et al.: Cognitive and behavioural features discriminate
between Alzheimer's and Parkinson's disease. Neuropsychiatry Neuropsychol. Behav.
Neurol. 15, 79–87 (2002).

155. Costa A, Peppe A, Brusa L et al.: Levodopa improves time-based prospective memory in
Parkinson's disease. J. Int. Neuropsychol. Soc. 14, 601–610 (2008).

156. Turle-Lorenzo N, Maurin B, Puma C et al.: The dopamine agonist piribedil with L-DOPA
improves attentional dysfunction: relevance for Parkinson's disease. J. Pharmacol. Exp.
Therap. 319(2), 914–923 (2006).

157. Hoops S, Nazem S, Siderowf AD et al.: Validity of the MoCA and MMSE in the detection
of MCI and dementia in Parkinson disease. Neurology 73, 1738–1745 (2009).

158. Rossi C, Volterrani D, Nicoletti V et al.: 'Parkinson-dementia' diseases: a comparison by

double tracer SPECT studies. Parkinsonism Relat. Disord. 15, 762–766 (2009).

159. Aarsland D, Ballard CG, Halliday G: Are Parkinson's disease with dementia and dementia
with Lewy bodies the same entity? J. Geriatr. Psychiatry Neurol. 17, 137–145 (2004).

160. McKeith IG, Mosimann UP: Dementia with Lewy bodies and Parkinson's
disease. Parkinsonism Relat. Disord. 10,S15–S18 (2004).

161. Gnanalingham KK, Byrne EJ, Thornton A, Sambrook MA, Bannister P: Motor and
cognitive function in Lewy body dementia: comparison with Alzheimer's and Parkinson's
disease. J. Neurol. Neurosurg. Psychiatry 62, 243–252 (1997).

162. Leverenz JB, McKeith IG: Dementia with Lewy bodies. Med. Clin. North Am. 86, 519–535
(2002).

163. McKeith IG, Burn DJ, Ballard CG et al.: Diagnosis and management of dementia with
Lewy bodies: third report of the DLB consortium. Neurology 65, 1863–1872 (2005).

164. Leroi I, Brandt J, Reich SG, Lyketsos CG, Grill S, Thompson R, Marsh L: Randomized
placebo-controlled trial of donepezil in cognitive impairment in Parkinson's disease. Int. J. Geriatr.
Psychiatry 19, 1–8 (2004).
165. Aarsland D, Laake K, Larsen JP, Janvin C: Donepezil for cognitive impairment in
Parkinson's disease: a randomised controlled study. J. Neurol. Neurosurg. Psychiatry 72, 708–
712 (2002).

166. Emre M, Aarsland D, Albanese A et al.: Rivastigmine for dementia associated with
Parkinson's disease. N. Engl. J. Med. 351, 2509–2518 (2004).

167. Poewe W, Wolters E, Emre M et al.: Long-term benefits of rivastigmine in dementia

associated with Parkinson's disease: an active treatment extension study. Mov. Disord. 21, 456–
461 (2006).

168. Wesnes KA, McKeith I, Edgar C, Emre M, Lane R: Benefits of rivastigmine on attention in
dementia associated with Parkinson disease. Neurology 65, 1654–1656 (2005).

169. Seeman P, Caruso C, Lasaga M: Memantine agonist action at dopamine

D2 receptors. Synapse 62, 149–153 (2008).
High

170. Lees AJ, Blackburn NA, Campbell VL: The nighttime problems of Parkinson's
disease. Clin. Neuropharmacol. 11, 512–519 (1988).

171. Olanow CW, Watts RL, Koller WC: An algorithm (decision tree) for the management of
Parkinson's disease: treatment guidelines. Neurology 56,S1–S88 (2001).

172. Boeve BF, Silber MH, Saper CB et al.: Pathophysiology of REM sleep behaviour disorder
and relevance to neurodegenerative disease. Brain 130, 2770–2788 (2007).

173. Adler CH: Nonmotor complications in Parkinson's disease. Mov. Disord. 20(Suppl.
11),S23–S29 (2005).

174. Adler CH, Thorpy MJ: Sleep issues in Parkinson's disease. Neurology 64,S12–S20
(2005).

175. Tandberg E, Larsen JP, Karlsen K: A community-based study of sleep disorders in

patients with Parkinson's disease. Mov. Disord. 13, 895–899 (1998).

176. Larsen JP: Sleep disorders in Parkinson's disease. Adv. Neurol. 91, 329–334 (2003).

177. Ondo WG, Vuong KD, Jankovic J: Exploring the relationship between Parkinson disease
and restless legs syndrome. Arch. Neurol. 59, 421–424 (2002).

178. Nomura T, Inoue Y, Miyake M et al.: Prevalence and clinical characteristics of restless
legs syndrome in Japanese patients with Parkinson's disease. Mov. Disord. 21, 380–384 (2006).

179. Arnulf I, Konofal E, Merino-Andreu M et al.: Parkinson's disease and sleepiness: an

integral part of PD. Neurology 58, 1019–1024 (2002).

180. Hobson DE, Lang AE, Martin WR et al.: Excessive daytime sleepiness and sudden-onset
sleep in Parkinson disease: a survey by the Canadian Movement Disorders Group. JAMA 287,
455–463 (2002).
181. Soldatos CR, Allaert FA, Ohta T, Dikeos DG: How do individuals sleep around the world?
Results from a single-day survey in ten countries. Sleep Med. 6, 5–13 (2005).

182. Simuni T: Somnolence and other sleep disorders in Parkinson's disease: the challenge
for the practicing neurologist. Neurol. Clin. 22,S107–S126 (2004).

183. Rye DB, Bliwise DL, Dihenia B, Gurecki P: FAST TRACK: daytime sleepiness in
Parkinson's disease. J. Sleep Res. 9, 63–69 (2000).

184. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE: A five-year study
of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with
ropinirole or levodopa (056 Study Group). N. Engl. J. Med. 342(20), 1484–1491 (2000).

185. Parkinson Study Group: Pramipexole vs levodopa as initial treatment for Parkinson
disease. A randomized controlled trial. JAMA 284(15), 1931–1938 (2000).

186. Oertel WH, Wolters E, Sampaio C et al.: Pergolide versus levodopa monotherapy in early
Parkinson's disease patients. The PELMOPET study. Mov. Disord. 21(3), 343–353 (2006).

187. Frucht SJ, Rogers JD, Greene PE et al.: Falling asleep at the wheel: motor vehicle
mishaps in persons taking pramipexole and ropinirole. Neurology 52, 908–910 (1999).

188. Ferreira JJ, Galitzky M, Montastruc JL, Rascol O: Sleep attacks and Parkinson's disease
treatment. Lancet 355, 1333–1334 (2000).

189. Schapira AH: Sleep attacks (sleep episodes) with pergolide. Lancet 3551332–1333
(2000).

190. Ferreira JJ, Thalamas C, Montastruc JL, Castro-Caldas A, Rascol O: Levodopa

monotherapy can induce 'sleep attacks' in Parkinson's disease patients. J. Neurol. 248(5), 426–
427 (2001).

191. Olanow CW, Schapira A, Roth T: Waking up to sleep episodes in Parkinson's

disease. Mov. Disord. 15, 212–215 (2000).

192. Fabbrini G, Barbanti P, Aurilia C, Vanacore N, Paoletti C, Meco G: Excessive daytime

sleepiness in de novo and treated Parkinson's disease. Mov. Disord. 17, 1026–1030 (2002).

193. Kaynak D, Kiziltan G, Kaynak H, Benbir G, Uysal O: Sleep and sleepiness in patients
with Parkinson's disease before and after dopaminergic treatment. Eur. J. Neurol. 12, 199–207
(2005).

194. Sanjiv CC, Schulzer M, Mak E et al.: Daytime somnolence in patients with Parkinson's
disease. Parkinsonism Relat. Disord. 7, 283–286 (2001).

195. O'Suilleabhain PE, Dewey RB: Contributions of dopaminergic drugs and disease severity
to daytime sleepiness in Parkinson disease. Arch. Neurol. 59, 986–989 (2002).

196. Tan EK, Lum SY, Fook-Chong SMC et al.: Evaluation of somnolence in Parkinson's
disease: comparison with age and sex-matched controls. Neurology 58, 465–468 (2002).
197. Högl B, Seppi K, Brandauer E et al.: Increased daytime sleepiness in Parkinson's
disease: a questionnaire survey. Mov. Disord. 18, 319–323 (2003).

198. Furumoto H: Excessive daytime somnolence in Japanese patients with Parkinson's

disease. Eur. J. Neurol. 11, 535–540 (2004).

199. Ferreira JJ, Desboeuf K, Galitzky M et al.: Sleep disruption, daytime somnolence
and 'sleep attacks' in Parkinson's disease: a clinical survey in PD patients and age-matched
healthy volunteers. Eur J. Neurol. 13, 209–214 (2006).

200. Happe S, Berger K; On Behalf of the Faqt Study Investigators: The association of
dopamine agonists with daytime sleepiness, sleep problems and quality of life in patients with
Parkinson's disease. A prospective study. J. Neurol. 248, 1062–1067 (2001).

201. Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C, Jankovic J: Daytime sleepiness and
other sleep disorders in Parkinson's disease. Neurology 57, 1392–1396 (2001).

202. Pal S, Bhattacharja KF, Agapito C, Chauduri KR: A study of excessive daytime
sleepiness and its clinical significance in three groups of Parkinson's disease patients taking
pramipexole, cabergoline and levodopa mono and combination therapy. J. Neural Transm.108,
71–77 (2001).

203. Razmy A, Lang AE, Shapiro CM: Predictors of impaired daytime sleep and wakefulness
in patients with Parkinson disease treated with older (ergot) vs newer (non-ergot) dopamine
agonists. Arch. Neurol. 61, 97–102 (2004).

204. Montastruc JL, Brefel-Courbon C, Senard JM et al.: Sleep attacks and antiParkinsonian
drugs: a pilot prospective pharmacoepidemiologic study. Clin. Neuropharmacol. 3, 181–183
(2001).

205. Schlesinger I, Ravin PD: Dopamine agonists induce episodes of irresistible daytime
sleepiness. Eur. Neurol. 49, 30–33 (2003).

206. Paus S, Brecht HM, Köster J, Seeger G, Klockgether T, Wüllner U: Sleep attacks,
daytime sleepiness, and dopamine agonists in Parkinson's disease. Mov. Disord. 6, 659–667
(2003).

207. Brodsky MA, Godbold J, Roth T, Olanow CW: Sleepiness in Parkinson's disease: a
controlled study. Mov. Disord. 18, 668–672 (2003).

208. Körner Y, Meindorfner C, Möller JC et al.: Predictors of sudden onset of sleep in

Parkinson's disease. Mov. Disord. 19, 1298–1305 (2004).

209. Avorn J, Schneewiss S, Sudarsky LR et al.: Sudden uncontrollable somnolence and

medication use in Parkinson disease. Arch. Neurol. 62, 1242–1248 (2005).

210. Paus S, Seeger G, Brecht HM et al.: Association study of dopamine D2, D3, D4 receptor
and serotonin transporter gene polymorphisms with sleep attacks in Parkinson's disease. Mov.
Disord. 19(6), 705–707 (2004).
211. Risling I, Jeller F, Bandmann O et al.: Dopamine receptor gene polymorphisms in
Parkinson's disease patients reporting sleep attacks. Mov. Disord. 19(11), 1279–1284 (2004).

212. Risling I, Korner Y, Geller F, Stiasny-Kolster K, Oertel WH, Moller JC: Preprohypocretin
polymorphisms in Parkinson disease patients reporting sleep attacks. Sleep 28(7), 871–875
(2005).

213. Hogl B, Saletu M, Brandauer E et al.: Modafinil for the treatment of daytime sleepiness in
Parkinson's disease: a double-blind, randomized, crossover, placebo-controlled polygraphic
trial. Sleep 25(8), 905–909 (2002).

214. Adler CH, Caviness JN, Hentz JG, Lind M, Tiede J: Randomized trial of modafinil for
treating subjective daytime sleepiness in patients with Parkinson's disease. Mov. Disord. 18(3),
287–293 (2003).

215. Ondo WG, Fayle R, Atassi F, Jankovic J: Modafinil for daytime somnolence in
Parkinson's disease: double blind, placebo controlled parallel trial. J. Neurol. Neurosurg.
Psychiatry 76, 1636–1639 (2005).

216. Medeiros CA, Carvalhedo de Bruin PF, Lopes LA et al.: Effect of exogenous melatonin
on sleep and motor dysfunction in Parkinson's disease. A randomized, double blind, placebo-
controlled study. J. Neurol. 254, 459–464 (2007).

217. Fantini ML, Gagnon JF, Petit D et al.: Slowing of electroencephalogram in rapid eye
movement sleep behavior disorder. Ann. Neurol. 53, 774–780 (2003).

218. Chaudhuri KR, Schapira AH: Non-motor symptoms of Parkinson's disease: dopaminergic
pathophysiology and treatment. Lancet Neurol. 8, 464–474 (2009).

219. Comella CL, Nardine TM, Diederich NJ, Stebbins GT: Sleep-related violence, injury, and
REM sleep behavior disorder in Parkinson's disease. Neurology 51, 526–529 (1998).

220. Gagnon JF, Postuma RB, Mazza S et al.: Rapid-eye-movement sleep behaviour disorder
and neurodegenerative diseases. Lancet Neurol. 5, 424–432 (2006).

221. Tan A, Salgado M, Fahn S: Rapid eye movement sleep behavior disorder preceding
Parkinson's disease with therapeutic response to levodopa. Mov. Disord. 11, 214–216 (1996).

222. Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J: Potential early markers of
Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 66, 845–851 (2006).

223. Fantini ML, Gagnon JF, Filipini D, Montplaisir J: The effects of pramipexole in REM sleep
behavior disorder. Neurology 61, 1418–1420 (2003).

224. Ringman JM, Simmons JH: Treatment of REM sleep behaviour disorder with donepezil: a
report of three cases. Neurology 55, 870–871 (2000).

225. Boeve BF, Silber MH, Ferman TJ: Melatonin for treatment of REM sleep behavior
disorder in neurologic disorders: results in 14 patients. Sleep Med. 4, 281–284 (2003).
226. Grant JE, Levine L, Kim D, Potenza MN: Impulse control disorders in adult psychiatric
inpatients. Am. J. Psychiatry 162, 2184–2188 (2005).

227. Weintraub D: Dopamine and impulse control disorders in Parkinson's disease. Ann.
Neurol. 64 (Suppl. 2),S93–S100 (2008).

228. Holden C: 'Behavioral' addictions: do they exist? Science 294, 980–982 (2001).

229. Tamminga CA, Nestler EJ: Pathological gambling: focusing on the addiction, not the
activity. Am. J. Psychiatry 163, 303–312 (2006).

230. Brewer JA, Potenza MN: The neurobiology and genetics of impulse control disorders:
relationships to drug addictions. Biochem. Pharmacol. 75, 63–75 (2008).

231. Hollander E, Allen A: Is compulsive buying a real disorder, and is it really

compulsive? Am. J. Psychiatry 163, 1670–1672 (2006).

232. Driver-Dunckley E, Samanta J, Stacy M: Pathological gambling associated with

dopamine agonist therapy in Parkinson's disease. Neurology 61, 422–423 (2003).

233. Lu C, Bharmal A, Suchowersky O: Gambling and Parkinson's disease. Arch. Neurol. 63,
298 (2006).

234. Grosset KA, Macphee G, Pal G et al.: Problematic gambling on dopamine agonists: not
such a rarity. Mov. Disord. 21, 2206–2208 (2006).

235. Voon V, Hassan K, Zurowski M et al.: Prospective prevalence of pathological gambling

and medication association in Parkinson disease. Neurology 66, 1750–1752 (2006).

236. Weintraub D, Siderowf AD, Potenza MN et al.: Association of dopamine agonist use with
impulse control disorders in Parkinson disease. Arch. Neurol. 63, 969–973 (2006).

237. Isaias IU, Siri C, Cilia R, De Gaspari D, Pezzoli G, Antonini A: The relationship between
impulsivity and impulse control disorders in Parkinson's disease. Mov. Disord. 23, 411–415
(2008).

238. Christenson GA, Faber RJ, de Zwaan M: Compulsive buying: descriptive characteristics
and psychiatric comorbidity. J. Clin. Psychiatry 55, 5–11 (1994).

239. Crockford D, Quickfall J, Currie S, Furtado S, Suchowersky O, El-Guebaly N: Prevalence

of problem and pathological gambling in Parkinson's disease. J. Gambl. Stud. 24(4), 411–422
(2008).

240. Avanzi M, Baratti M, Cabrini S, Uber E, Brighetti G, Bonfà F: Prevalence of pathological

gambling in patients with Parkinson's disease. Mov. Disord. 21, 2068–2072 (2006).

241. Ceravolo R, Frosini D, Rossi C et al.: Prevalence of impulse control disorders in

Parkinson's disease. Neurol. Sci. 30(Suppl.), 456 (2009).
242. Klos KJ, Bower JH, Josephs KA, Matsumoto JY, Ahlskog JE: Pathological hypersexuality
predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple
system atrophy. Parkinsonism Relat. Disorders 11, 381–386 (2005).

243. Weintraub D, Koester J, Potenza MN et al.: Impulse control disorders in Parkinson

disease. A cross-sectional study of 3090 patients. Arch. Neurol. 67(5), 589–595 (2010).

•• Largest cross-sectional study to ascertain prevalence of impulse control disorder in Parkinson's

disease.

244. Giladi N, Weitzman N, Schreiber S, Shabtai H, Peretz C: New-onset heightened interest

or drive for gambling, eating, shopping or sexual activity in patients with Parkinson's disease: the
role of dopamine agonist treatment and age at motor symptoms onset. J. Psychopharmacol. 21,
501–506 (2007).

245. Gallagher DA, O'Sullivan SS, Evans AH, Lees AJ, Schrag A: Pathological gambling in
Parkinson's disease: risk factors and differences from dopamine dysregulation. An analysis of
published case series. Mov. Disord. 22, 1757–1763 (2007).

246. Evans AH, Lawrence AD, Potts J, Appel S, Lees AJ: Factors influencing susceptibility to
compulsive dopaminergic drug use in Parkinson disease. Neurology 65, 1570–1574 (2005).

247. Singh A, Kandimala G, Dewey RB Jr, O'Suilleabhain P: Risk factors for pathologic
gambling and other compulsions among Parkinson's disease patients taking dopamine
agonists. J. Clin. Neurosci. 14, 1178–1181 (2007).

248. Voon V, Thomsen T, Miyasaki JM et al.: Factors associated with dopaminergic drug-
related pathological gambling in Parkinson disease. Arch. Neurol. 64, 212–216 (2007).

249. Pontone G, Williams JR, Bassett SS, Marsh L: Clinical features associated with impulse
control disorders in Parkinson disease. Neurology 67, 1258–1261 (2006).

250. Santangelo G, Vitale C, Trojano L, Verde F, Grossi D, Barone P: Cognitive dysfunctions

and pathological gambling in patients with Parkinson's disease. Mov. Disord. 24, 899–905 (2009).

251. Driver-Dunckley ED, Noble BN, Hentz JG et al.: Gambling and increased sexual desire
with dopaminergic medications in restless legs syndrome. Clin. Neuropharmacol. 30, 249–255
(2007).

252. Gerlach M, Double K, Arzberger T, Leblhuber F, Tatschner T, Rieder P: Dopamine

receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined
in the human striatum. J. Neurol. Transm. 75(1), 63–75 (2003).

253. Dodd ML, Klos KJ, Bower JH, Geda YE, Josephs KA, Ahlskog JE: Pathological gambling
caused by drugs used to treat Parkinson disease. Arch. Neurol. 62, 1377–1381 (2005).

254. Mamikonyan E, Siderowf AD, Duda JE et al.: Long-term follow-up of impulse control
disorders in Parkinson's disease. Mov. Disord. 23, 75–80 (2008).
255. Ardouin C, Voon V, Worbe Y et al.: Pathological gambling in Parkinson's disease
improves on chronic subthalamic nucleus stimulation. Mov. Disord. 21, 1941–1946 (2006).

256. Kurlan R: Disabling repetitive behaviors in Parkinson's disease. Mov. Disord. 19, 433–
437 (2004).

257. Courty E, Durif F, Zenut M, Courty P, Lavarenne J: Psychiatric and sexual disorders
induced by apomorphine in Parkinson's disease. Clin. Neuropharmacol. 20, 140–147 (1997).

258. Jiménez-Jiménez FJ, Sayed Y, García-Soldevilla MA, Barcenilla B: Possible zoophilia

associated with dopaminergic therapy in Parkinson disease. Ann. Pharmacother. 36, 1178–1179
(2002).

259. Gschwandtner U, Aston J, Renaud S, Fuhr P: Pathologic gambling in patients with

Parkinson's disease. Clin. Neuropharmacol. 24, 170–172 (2001).

260. Giovannoni G, O'Sullivan JD, Turner K, Manson AJ, Lees AJ: Hedonistic homeostatic
dysregulation in patients with Parkinson's disease on dopamine replacement therapies. J. Neurol.
Neurosurg. Psychiatry 68, 423–428 (2000).

261. Grant JE, Potenza MN: Impulse control disorders: clinical characteristics and
pharmacological management. Ann. Clin. Psychiatry 16, 27–34 (2004).

262. Evans AH, Katzenschlager R, Paviour D et al.: Punding in Parkinson's disease: its
relation to the dopamine dysregulation syndrome. Mov. Disord. 19, 397–405 (2004).

263. Miyasaki JM, Al Hassan K, Lang AE, Voon V: Punding prevalence in Parkinson's
disease. Mov. Disord. 22(8), 1179–1181 (2007).

264. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders.
Fourth edition, text revision. American Psychiatric Association, Washington, DC, USA (2000).

265. Pezzella FR, Colosimo C, Vanacore N et al.: Prevalence and clinical features of
hedonistic homeostatic dysregulation in Parkinson's disease. Mov. Disord. 20(1), 77–81 (2005).

266. Lawrence AD, Evans AH, Lees AJ: Compulsive use of dopamine replacement therapy in
Parkinson's disease: reward systems gone awry? Lancet Neurol. 2(10), 595–604 (2003).

267. Bearn J, Evans A, Kelleher M, Turner K, Lees A: Recognition of a dopamine replacement

therapy dependence syndrome in Parkinson's disease: a pilot study. Drug Alcohol Depend. 76(3),
305–310 (2004).

268. Braak H, Ghebremedhin E, Rub U et al.: Stages in the development of Parkinson's

disease-related pathology. Cell Tissue Res. 318, 121–134 (2004).

•• Review regarding the pathological staging of Parkinson's disease.

269. Simuni T, Sethi K: Nonmotor manifestations of Parkinson's disease. Ann.

Neurol. 64(Suppl.),S65–S80 (2008).
270. Benarroch EE, Schmeichel AM, Parisi JE: Involvement of the ventrolateral medulla in
Parkinsonism with autonomic failure. Neurology 54, 963–968 (2000).

271. Jost WH: Autonomic dysfunctions in idiopathic Parkinson's disease. J. Neurol. 250(Suppl.
1),I28–I30 (2003).

272. Chaudhuri KR: Autonomic dysfunction in movement disorders. Curr. Opin. Neurol. 14,
505–511 (2001).

273. Goldstein DS: Orthostatic hypotension as an early finding in Parkinson's disease. Clin.
Auton. Res. 16, 46–54 (2006).

274. Braune S, Reinhardt M, Schnitzer R et al.: Cardiac uptake of [123I]MIBG separates

Parkinson's disease from multiple system atrophy. Neurology 53, 1020–1025 (1999).

275. Goldstein DS: Imaging of the autonomic nervous system: focus on cardiac sympathetic
innervation. Semin. Neurol. 23, 423–433 (2003).

276. Pathak A, Senard JM: Blood pressure disorders during Parkinson's disease:
epidemiology, pathophysiology and management. Expert Rev. Neurother. 6, 1173–1180 (2006).

277. Schmidt C, Berg D, Herting et al.: Loss of nocturnal blood pressure fall in various
extrapyramidal syndromes. Mov. Disord. 24(14), 2136–2142 (2009).

278. McGrath BP: Ambulatory blood pressure monitoring. Med. J. Aust. 176, 588–592 (2002).

279. Baratti M, Calzetti S: Fluctuation of arterial blood pressure during end-of-dose akinesia in
Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 47, 1241–1243 (1984).

280. Pursiainena V, Korpelainena JT, Haapaniemia TH, Sotaniemia KA, Myllyla VV: Blood
pressure and heart rate in Parkinsonian patients with and without wearing-off. Eur. J. Neurol. 14,
373–378 (2007).

281. Goetz CG, Lutge W, Tanner CM: Autonomic dysfunction in patients with Parkinson's
disease. Neurology 36, 73–75 (1986).

282. Ejaz AA, Kazory A, Heinig ME: 24 hour blood pressure monitoring in the evaluation of
supine hypertension and orthostatic hypotension. J. Clin. Hypertens. 9, 952–955 (2007).

283. Schoffer KL, Henderson RD, O'Maley K, O'Sullivan JD: Nonpharmacological treatment,
fludrocortisone, and domperidone for orthostatic hypotension in Parkinson's disease. Mov.
Disord. 22, 1543–1549 (2007).

284. Singer W, Sandroni P, Opfer-Gehrking TL et al.: Pyridostigmine treatment trial in

neurogenic orthostatic hypotension. Arch. Neurol. 63, 513–518 (2006).

285. Cersosimo MG, Benarroch EE: Neural control of the gastrointestinal tract: implications for
Parkinson disease. Mov. Disord. 23, 1065–1075 (2008).
286. Magerkurth C, Schnitzer R, Braune S: Symptoms of autonomic failure in Parkinson's
disease: prevalence and impact on daily life. Clin. Auton. Res. 15, 76–82 (2005).

287. Abbott RD, Ross GW, Petrovitch H et al.: Bowel movement frequency in late-life and
incidental Lewy bodies. Mov. Disord. 22, 1581–1586 (2007).

288. Eichhorn TE, Oertel WH: Macrogol 3350/electrolyte improves constipation in Parkinson's
disease and multiple system atrophy. Mov. Disord. 16, 1176–1177 (2001).

289. Degen L, Petrig C, Studer D, Schroller S, Beglinger C: Effect of tegaserod on gut transit
in male and female subjects. Neurogastroenterol Motil. 17, 821–826 (2005).

290. Zangaglia R, Martignoni E, Glorioso M et al.: Macrogol for the treatment of constipation in
Parkinson's disease. A randomized placebo-controlled study. Mov. Disord. 22, 1239–1244
(2007).

291. Kapoor S: Management of constipation in the elderly: emerging therapeutic

strategies. World J. Gastroenterol. 14, 5226–5227 (2008).

292. Sampson EL, Candy B, Jones L: Enteral tube feeding for older people with advanced
dementia. Cochrane Database Syst Rev. 15(2),CD007209 (2009).

293. Jost WH: Treatment of drooling in Parkinson's disease with botulinum toxin. Mov.
Disord. 14, 1057 (1999).

294. Chancellor MB, Anderson RU, Boone TB: Pharmacotherapy for neurogenic detrusor
overactivity. Am. J. Phys. Med. Rehabil. 85, 536–545 (2006).

295. Ouslander JG: Management of overactive bladder. N. Engl. J. Med. 350, 786–799
(2004).

296. Sahai A, Khan MS, Arya M, John J, Singh R, Patel HR: The overactive bladder: review of
current pharmacotherapy in adults. Part 2: treatment options in cases refractory to
anticholinergics. Expert Opin. Pharmacother. 7, 529–538 (2006).

297. Verbaan D, van Rooden SM, Visser M, Marinus J, van Hilten JJ: Nighttime sleep
problems and daytime sleepiness in Parkinson's disease. Mov. Disord. 23, 35–41 (2008).

298. Wolters E, Braak H: Parkinson's disease: premotor clinicopathological correlations. J.

Neural Transm. Suppl. 70, 309–319 (2006).

299. Doty RL: The olfactory vector hypothesis of neurodegenerative disease. Is it viable? Ann.
Neurol. 63, 7–15 (2008).

300. Büttner T, Kuhn W, Müller T et al.: Distorted color discrimination in 'de novo' Parkinsonian
patients. Neurology 45, 386–387 (1995).

301. Nguyen-Legros J: Functional neuroarchitecture of the retina: hypothesis on the

dysfunction of retinal dopaminergic circuitry in Parkinson's disease. Surg. Radiol. Anat. 10, 137–
144 (1998).
 302. Rodnitzky RL: Visual dysfunction in Parkinson's disease. Clin. Neurosci. 5, 102–106
(1998).

303. Beiske AG, Loge JH, Ronningen A et al.: Pain in Parkinson's disease: prevalence and
characteristics. Pain 141, 173–177 (2009).

304. Barone P, Antonini A, Colosimo C et al.: The PRIAMO study: a multi center assessment
of non motor symptoms and their impact on quality of life in Parkinson's disease. Mov. Disord. 11,
1641–1649 (2009).

305. Quinn NP, Lang A, Koller WC et al.: Painful Parkinson's disease. Lancet 1, 1366–1369
(1986).

306. Djaldetti R, Shifrin A, Rogowski Z et al.: Quantitative measurement of pain sensation in

patients with Parkinson disease. Neurology 62, 2171–2175 (2004).

307. Brefel-Courbon C, Payoux P, Thalamas C et al.: Effect of levodopa on pain threshold in

Parkinson's disease: a clinical and positron emission tomography study. Mov. Disord. 20(12),
1557–1563 (2005).

308. Basbaum AI, Fields HL: Endogenous pain control systems: brainstem spinal pathways
and endorphin circuitry. Annu. Rev. Neurosci. 7, 309–338 (1984).

309. Braak H, Braak E, Yilmazer D, de Vos RA, Jansen EN, Bohl J: Pattern of brain
destruction in Parkinson's and Alzheimer's diseases. J. Neural Transm. 103(4), 455–490 (1996).

310. Djaldetti R, Yust-Katz S, Kolianov V et al.: The effect of duloxetine on primary pain
symptoms in Parkinson disease. Clin. Neuropharmacol. 30, 201–205 (2007).

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•• of considerable interest

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The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants
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No writing assistance was utilized in the production of this manuscript.

Future Neurology. 2010;5(6):851-871. © 2010 Future Medicine Ltd.