Non-Motor Aspects of Parkinson'S Disease: by Leora L. Borek, MD, Melissa M. Amick, PHD, and Joseph H. Friedman, MD

Review Article
Non-Motor Aspects
of Parkinson’s Disease
By Leora L. Borek, MD, Melissa M. Amick, PhD, and Joseph H. Friedman, MD
ABSTRACT
Needs Assessment
Parkinson’s disease is primarily considered Parkinson’s disease has been important in the development of the field of neuropsy-
chiatry. Behavioral symptoms are an important source of distress for many patients
to be a movement disorder and is defined by with the disease. This review will focus on the findings of recent research and treat-
ment of the most common behavioral manifestations of the disease.
its motor signs. Yet, the behavioral manifes-
Learning Objectives
tations of the disease are often more debili-
At the end of this activity, the participant should be able to:
tating than its motor complications. This • List the most common sleep disorders in Parkinson’s disease.
• Give examples of neuropsychological testing that are useful in predicting demen-
review will focus on the non-motor aspects tia in Parkinson’s disease.
• Understand the association between depression, anxiety and motor features of
of Parkinson’s disease, including mood, Parkinson’s disease.
psychosis, cognitive, sleep, fatigue, apathy, • Understand the role of dopaminergic medication in psychosis and appropriate
treatment.
delirium, and repetitive disorders, that may Target Audience: Neurologists and psychiatrists
occur. The phenomenology, pathology, and CME Accreditation Statement: The Mount Sinai School of Medicine is
accredited by the Accreditation Council for Continuing Medical Education to provide
treatment of the behavioral symptoms of Continuing Medical Education for physicians.
The Mount Sinai School of Medicine designates this educational activity for a maxi-
Parkinson’s disease will be discussed. mum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit com-
mensurate with the extent of their participation in the activity.
CNS Spectr. 2006;11(7)541-554
It is the policy of Mount Sinai School of Medicine to ensure objectivity, balance,
independence, transparency, and scientific rigor in all CME-sponsored educational
activities.
INTRODUCTION Faculty Disclosure Policy Statement: All faculty participating in the
Parkinson’s disease is defined by its motor planning or implementation of a sponsored activity are expected to disclose to the
audience any relevant financial relationships and to assist in resolving any conflict of
dysfunction. There are several different sets interest that may arise from the relationship. Presenters must also make a meaning-
of criteria for the diagnosis but all center ful disclosure to the audience of their discussions of unlabeled or unapproved drugs
or devices. This information will be available as part of the course material.
around the presence of the following prob-
This activity has been peer-reviewed and approved by Eric Hollander, MD, chair at
lems: tremor at rest, rigidity, hypokinesia Mount Sinai School of Medicine. Review Date: June 20, 2006.
(bradykinesia or akinesia), the presence of
To Receive Credit for This Activity: Read this article, and the two
gait, posture or balance changes typical of CME-designated accompanying articles, reflect on the information presented,
the disorder, the absence of atypical features, and then complete the CME quiz found on pages 557 and 558. To obtain credits,
you should score 70% or better. Termination date: July 31, 2008. The estimated
and the absence of an alternative explanation, time to complete this activity is 3 hours.
such as medications, strokes, or toxins.1 There
Dr. Borek is geriatric psychiatrist in the department of geriatric psychiatry at Brown University School of Medicine in Providence, Rhode
Island. Dr. Amick is clinical neuropsychologist in the department of psychiatry and human behavior at Brown University Medical School.
Dr. Friedman is clinical professor in the department of clinical neurosciences at Brown University School of Medicine.
Disclosures: Dr. Borek does not have an affiliation with or financial interest in any organization that might pose a conflict of interest. Dr.
Amick receives research support from Janssen. Dr. Friedman is a consultant for ACADIA, AstraZeneca, and Ovation; and he receives
research support from Novartis.
Submitted for publication: December 20, 2005, and accepted on June 15, 2006.
Please direct all correspondence to: Leora L. Borek, MD, 90 Brown Street, Providence, RI 02906; Tel: 781-883-4755; E-mail:
Leolisa@yahoo.com.
CNS Spectr 11:7 (Suppl 7) © MBL Communication Inc. 541 July 2006
Review Article
is no diagnostic test for Parkinson’s disease. It is bance, fatigue, and decreased libido. Depression
only at autopsy that we can definitively confirm in Parkinson’s disease is reported to be qualita-
the diagnosis with the presence of certain spe- tively different from primary major depression in
cific changes. And although James Parkinson 2 that depressed Parkinson’s disease patients have
declared that the senses and intellect were intact, greater rates of anxiety, pessimism, irrational-
the behavioral consequences of the disease are ity, and less guilt and self-reproach compared to
its most devastating problem. depressed non-Parkinson’s disease patients.3,8,9
There are a number of behavioral issues asso- The etiology of depression in Parkinson’s
ciated with Parkinson’s disease and because they disease is unknown but may have a biological
are so prevalent and stereotypic, it is this disor- basis and involve neuronal loss and a reduc-
der that has probably been the most important tion in brain catecholamines. 10 Postmortem
in the development of the field of neuropsychia- findings of Parkinson’s disease patients with a
try. The issue of whether depression is intrinsic history of depression show decreased numbers
or reactive has been a significant focus of atten- of serotonin (5-HT) neurons in the dorsal raphe
tion. However, the most problematic issues have nucleus 11 and reduced dopamine neurons in
been dementia and psychosis. the ventral tegmental area compared to nonde-
There are several behavioral problems in pressed Parkinson’s disease patients.12 There is
Parkinson’s disease (Table), some intrinsic, some a reported lowering of the major 5-HT metabo-
reactive, and others iatrogenic. Complicating our lite 5-hydroxyindoleacetic acid in the cerebro-
understanding, however, has been the increasing spinal fluid in depressed but not nondepressed
knowledge of dementia with Lewy (DLB) bodies, Parkinson’s disease patients, suggesting a role of
which may simply be one end of the Parkinson’s 5-HT deficiency in depression.13 Deep brain stim-
disease spectrum or a different but related dis- ulation in the subthalamic nucleus is reported
ease, but whose overlap with Parkinson’s dis- to have antidepressant, depressant, and mania-
ease confounds clinical studies. inducing effects in Parkinson’s disease patients,14
implicating the subthalamic nucleus in mood
disorders. Depression may also predate motor
DEPRESSION
symptoms,15 suggesting a biochemical alteration
Depression is one of the most common behav-
in Parkinson’s disease depression.
ioral symptoms of Parkinson’s disease, with an
Depression in Parkinson’s disease may also
estimated prevalence of 40% to 50%.3-5 Minor
be “reactive” and result from the psychosocial
depression and dysthymia account for a large
stress of having an incurable, debilitating disease.
proportion of symptoms.3,6,7 Diagnosing depres-
Parkinson’s disease patients are faced with many
sion in Parkinson’s disease is often a challenge,
challenges, including adjustment to the loss of
as the clinical symptoms of depression may be
physical ability and the consequences this may
mistaken for those of Parkinson’s disease, such
bring, such as job loss, marital discord, and social
as flat affect, psychomotor slowing, sleep distur-
isolation. Patients who are diagnosed at an early
age may be particularly susceptible to develop-
TABLE. ing depression since they often have more sig-
Behavioral Problems in Parkinson’s nificant career and financial disruptions. Patients
Disease with early-onset Parkinson’s disease (<55 years of
age) have higher rates of depression compared
Intrinsic Iatrogenic to those diagnosed with Parkinson’s disease at
Depression Hallucinosis a later age. 16,17 In one study, 18 depression was
Anxiety Psychosis more common in Parkinson’s disease patients
Dementia Affective cycling than in matched controls but rates did not differ
Executive dysfunction (on-off motor fluctuations) in patients with rheumatoid arthritis. In addition,
Sleep disorders Sedation
Fatigue Compulsions in the Parkinson’s disease and arthritis groups,
Apathy depression was associated with the severity of
Akathisia illness and functional disability. 18 Studies com-
Weight loss paring depression in Parkinson’s disease to
Pain
control medical populations 19-22 have reported
Borek LL, Amick M, Friedman JH. CNS Spectr. Vol 11, No 7. 2006.
conflicting outcomes, with some studies report-
Review Article
ing Parkinson’s disease patients to be more with medication-refractory depression and usu-
depressed than equally disabled control subjects. ally improves motor function.40,41 Psychotherapy
It is likely that for individual patients there is often can be helpful for patients with mild depression
both an intrinsic and reactive component. who have difficulty coping with their illness. As
An association between depression and particu- depression occurs frequently in Parkinson’s dis-
lar clinical features of Parkinson’s disease has been ease and contributes to disability, it is important
reported. Depression has been found to be higher to screen for this condition as effective manage-
in patients with the akinetic rigid type of Parkinson’s ment of depression is likely to improve the qual-
disease compared to the tremor-predominant ity of life for Parkinson’s disease patients.
type 3,19 and in patients with right sided motor The Geriatric Depression Scale and Hamilton
symptoms.3,16 Cognitive impairment is associated Rating Scale for Depression 42 are useful rating
with depression in Parkinson’s disease patients. scales that can distinguish between depressed
One study 2 0 found that cognitively impaired and nondepressed Parkinson’s disease patients.
patients had an increased risk of developing major Patients are generally started on an SSRI unless
depression. Conversely, depression is related to a particular side effects, as previously discussed, are
more rapid cognitive decline in Parkinson’s disease desired. For example, mirtazepine is highly sedat-
patients.23 An association between depression and ing, increases appetite, and may improve tremor,
greater motor disease severity in Parkinson’s dis- making it the drug of choice for a depressed, trem-
ease has been reported.16,24 ulous Parkinson’s disease patient who has noctur-
Depression is often clinically underrecognized nal sleep problems and is losing weight.
and undertreated and is not as well studied as
the motor aspects of the disease. 25 Depression ANXIETY
contributes significantly to disability in Parkinson’s Anxiety disorders are prevalent in Parkinson’s
disease 7,26 and has been found to be the most disease and are reported to occur in up to 40% of
important impairing factor for the quality of life in patients.43,44 The most common anxiety disorders
Parkinson’s disease patients, even after account- in Parkinson’s disease are panic disorder, gen-
ing for motor disease severity.27,28 eralized anxiety disorder, and social phobia.45,46
There is a lack of systematic clinical trials Anxiety frequently coexists with depression in
evaluating the efficacy of antidepressants in Parkinson’s disease patients.46,47
depressed Parkinson’s disease patients. A recent Anxiety disorder s tend to appear after
meta-analysis29 found a paucity of antidepressant the diagnosis of Parkinson’s disease is estab-
studies and no difference between active treat- lished. 45,47,48 They occur frequently in patients
ment and placebo in Parkinson’s disease depres- who experience “on-off” motor fluctuations,46,47
sion. Treatment is complicated by the potential especially, during the “off” phase. 45,47-49 In one
increased sensitivity to adverse side effects of study, 49 the magnitude of the increase in anx-
antidepressants as well as drug-drug interac- iety level during “off” periods correlated with
tions from the medications the patient is already the change in parkinsonian symptoms. Another
taking. As autonomic dysfunction is integral to study50 found that anxiety improved significantly
Parkinson’s disease, tricyclic antidepressants from the “off” to “on” state but then worsened
(TCAs) can aggravate orthostatic hypotension and when dyskinesias were present. Such studies
its anticholinergic side effects can worsen cogni- suggest that anxiety may be a reaction to motor
tion, dry mouth, and constipation. These same symptoms. Alternatively, changes in neurotrans-
anticholinergic effects, however, may be used to mitters may occur during parkinsonian motor
advantage and reduce drooling and inhibit an fluctuations and contribute to anxiety. Alterations
overactive bladder. Serotonin selective reuptake in 5-HT and norepinephrine are believed to play
inhibitors (SSRIs) are better tolerated, with fewer important roles underlying anxiety in Parkinson’s
side effects and are typically the first choice for an disease. 48,49 While some studies 45,51 have not
antidepressant. There are rare reports that SSRIs found a relationship between anxiety and motor
worsen motor symptoms30-33 but this is generally fluctuations, this clearly occurs in some patients.
not the case.34-38 There is a small but increased Anxiety is an uncommon side effect of
risk for developing 5-HT syndrome when using Parkinson’s disease medications unless motor
selegiline in combination with SSRIs or TCAs.39 fluctuations develop. While some studies 47,48
Electroconvulsive therapy is beneficial in patients report an increase in anxiety and panic attacks
Review Article
in patients on levodopa (L-dopa) therapy, other sus appendicular motor symptoms, and the use
studies45,46,49 failed to find a significant correlation of a greater number of anti-Parkinson’s disease
between anxiety and antiparkinsonian medica- drugs have been suggested. Psychosis, like hal-
tion and some have found that L-dopa52,53 and per- lucinosis, tends to be persistent.59 It is also a bad
golide54 reduce anxiety. prognostic indicator.60-66 Patients who are psy-
The optimal pharmacologic treatment for anx- chotic have an increased rate of nursing home
iety in Parkinson’s disease patients has not been placement and a significantly increased mortality
established. Treatment should take into account rate.62-64,66,67 How much of the symptomatology
comorbid psychiatric and medical conditions, may be due to dementia is uncertain since the
such as depression and dementia, that may influ- Parkinson’s disease drugs can only rarely be dis-
ence the type of medication used to treat anxiety. continued.68 In studies of drug holidays,69 a tech-
There have been no randomized, controlled treat- nique used 3 decades ago in which all Parkinson’s
ment trials of anxiety medication in Parkinson’s disease medications were withdrawn for several
disease. Commonly used medications include days, the psychotic symptoms resolved during
SSRIs, benzodiazepines, TCAs, and buspirone. the time off the drugs, and did not resume when
Citalopram was found to be helpful for anxiety low doses of the drugs were reinstituted, but did
in a small open-label trial treating depression.55 recur when the drug doses started to increase.69
As most patients with Parkinson’s disease are DLB and Parkinson’s disease with dementia and
elderly and susceptible to falls, benzodiazepines psychosis are distinguishable only if the demen-
should be used with caution. Cognitive-behav- tia develops before or within 1 year of the motor
ioral therapy may have a role in alleviating anxi- symptoms, or if hallucinations develop unrelated
ety symptoms in Parkinson’s disease. to medication. 70 Treatment focuses on reduc-
ing the Parkinson’s disease medications to their
PSYCHOSIS lowest level that allows an acceptable degree of
Psychosis is not considered a primary symptom motor function and then adding an antipsychotic
of idiopathic Parkinson’s disease. While there are if psychotic symptoms persist.59
case reports from the pre-L-dopa era of psychosis Based on the experience of polypharmacy
in Parkinson’s disease patients, the inability to reli- in the treatment of epilepsy, most research-
ably discriminate post-encephalitic parkinsonism ers57,59 believe that it is better to reduce and then
from idiopathic Parkinson’s disease and the lack eliminate as many drugs as possible rather than
of recognition of the numerous parkinsonian dis- maintaining low doses of several drugs. Virtually
orders that are not idiopathic Parkinson’s disease all Parkinson’s disease experts71 would recom-
make these reports suspect.56 The occurrence of mend stopping anticholinergic medication first.
psychotic symptoms in an untreated Parkinson’s The other drugs, in the order of stopping prior-
disease patient would constitute an “atypical” ity, are amantadine and monoamine oxidase
feature, casting doubt on the diagnosis. inhibitors, dopamine agonists, and then, L-dopa.
Psychosis in Parkinson’s disease may occur Catechol-O-methyl transferase inhibitors do
as part of a delirium or with a clear sensorium.57 not enter the brain in significant amounts and
In either case, the predominant symptoms are add to the symptoms only by increasing L-dopa
hallucinations and delusions.58,59 These are fairly availability. L-dopa produces the largest motor
stereotypic, with visual hallucinations predomi- effect with the least mental side effects of any of
nating and the delusions are paranoid in nature. the Parkinson’s disease medications.
A particularly unsettling and common hallucina- Although quetiapine has been the first-line
tion is that of spousal infidelity, both for male treatment of choice for psychosis in Parkinson’s
and female patients.58,60,61 The occurrence of psy- disease,59,72,73 this is based entirely on open-label
chotic symptoms has proven to be the single data and anecdotal experience.74 There have been
most important precipitant for nursing home two published placebo-controlled trials of que-
placement in Parkinson’s disease patients and tiapine in Parkinson’s disease and neither found
the most stressful problem for caretakers, out- the drug to be effective.75,76 Both, however, did
weighing the severity of motor dysfunction.62,63 report that quetiapine had no deleterious effect
The only clear risk factor for the development of on motor function. Clozapine has been proven
psychosis has been dementia, although depres- effective in two double-blind, placebo-controlled
sion, sleep disorders of various types, axial ver- multicenter trials. 77,78 In both trials, the mean
Review Article
dose was low (25 mg/day in the United States and are much different than the hallucinations
trial, 37 mg/day in the French study) and the that occur in primary psychiatric disorders,
effect was the same, with significant improve- primarily, because the images usually have
ment in psychosis without worsening of motor no emotional content, but also because most
function. In the US trial, clozapine was shown patients have insight, and recognize the unreal-
to have significant benefit on tremor without ity of the image. The hallucinations are typically
worsening of other symptoms and signs of of people, but may be of animals, such as dogs,
Parkinson’s disease. This supports several other cats and insects. 94,95 Occasionally, objects are
reports on the beneficial effect of clozapine on hallucinated, such as statues or trucks. The hal-
tremor in Parkinson’s disease.77-79 Unfortunately, lucinations tend to be constant from episode
the potential side effect of agranulocytosis is not to episode, so that the same group of people
dose-related so that the same monitoring rules is seen each time, typically wearing the same
need to be used as with higher doses.79 There is clothing. The hallucinated images usually ignore
limited open-label data on ziprasidone.80-82 One the patient, even when the patient tries to attract
trial80 reported benefit using the oral preparation their attention. The images may gesture or
of the drug. Another found mild motor worsen- appear to talk among themselves, but generate
ing in some patients and some psychiatric ben- no sound. Visual hallucinations are more com-
efit.81 The third observed clinical improvement mon in the evening, but are often seen during
in psychosis without harmful motor decline the day. In many cases, the hallucinations are
using the injectable formulation of the drug. 82 better seen or only seen in a lighted portion of a
The other atypicals have had negative effects dark room, than in the twilight.
on motor function. Reports on risperidone The following are illustrative cases we have
have been mixed, with some reports describ- encountered in our clinic. One patient reported
ing motor decline,83,84 and others reporting good seeing three little girls wearing ballet costumes,
tolerance.85,86 Since risperidone clearly produces dancing in her driveway as she washed dishes
parkinsonism in schizophrenia in a dose-related in the evening. Another patient was angry at a
manner, it is likely that some Parkinson’s disease man who stood directly in front of the televi-
patients cannot tolerate it. Olanzapine has been sion, blocking the screen. Auditory hallucina-
the subject of several double-blind, placebo-con- tions occur primarily in patients who also have
trolled trials,87-89 all of which demonstrated sig- visual hallucinations.58,98 They may take the form
nificant motor decline and little antipsychotic of the visual hallucinations talking but more
benefit. Quetiapine has been reported to be free often occur in a separate setting. The patient
of motor effects in Parkinson’s disease, but while hears indistinct voices or music coming from
the open-label studies have shown significant another part of the house or down the street.
antipsychotic benefit, the two double-blind con- All the medications used to treat Parkinson’s
trolled trials have not. 75,76 Finally, aripiprazole disease have the potential to induce hallucina-
has been reported in two open-label prospec- tions and it appears that the hallucinations do
tive trials90,91 to cause motor worsening in some not differ as a function of which drug is taken.101
Parkinson’s disease patients even at doses <5 While studies of hallucinators 66 do not reveal
mg/day, although improving psychosis in some. differences in drug intake, double-blinded stud-
The authors (LLB, JHF) treat psychosis ini- ies comparing dopamine agonist monotherapy
tially with quetiapine, starting with 12.5 or 25 mg to L-dopa monotherapy clearly demonstrate
QPM. We escalate daily, depending on response. that hallucinations are more likely to occur with
If quetiapine is not successful, we stop it and the dopamine agonist.
begin clozapine at 6.25 or 12.5 mg at bedtime. The only confirmed risk factor for the develop-
Hallucinations occur in about one third of ment of hallucinations has been dementia. Age,
drug-treated patients with Parkinson’s disease.92- drug dose, drug type, duration of disease, and
96
This figure is derived from studies performed gender have not been shown to be risk factors.
in both the US and Europe. In almost all cases, Autopsy studies102 have demonstrated that visual
there are visual hallucinations, although audi- hallucinations are clearly related to the presence
tory hallucinations may occur.58,94,97,98 Other types of Lewy bodies and that patients with parkinso-
of hallucinations are considerably less com- nian conditions who do not have Lewy bodies at
mon.99,100 The hallucinations are fairly stereotypic autopsy are unlikely to have had hallucinations.102
Review Article
In DLB patients, visual hallucinations correlate with DEMENTIA AND

the presence of Lewy bodies in the amygdala.102,103 PARKINSON’S DISEASE
Visual hallucinations are predictive of the develop- A significant percentage of Parkinson’s disease
ment of dementia. patients will experience cognitive decline severe
enough to meet criteria for dementia. This section
COGNITIVE DEFICITS IN will briefly review the prevalence, risk factors, and
NON-DEMENTED PARKINSON’S pattern of cognitive dysfunction in patients with
DISEASE PATIENTS Parkinson’s disease.
Parkinson’s disease is a neurodegenerative disor- Prevalence, frequency, and incidence of dementia
der that was once thought to affect only motor func- vary widely across studies,114,115 in part due to differ-
tioning. It is well recognized that this disease process ences in sample size, attrition, differences in patient
disrupts functions across multiple cognitive domains. population, study design, and criteria for diagnosing
While there can be considerable variability among dementia in Parkinson’s disease patients. In a review
individuals, Parkinson’s disease patients in the early of studies published between 1984–2001 on the prev-
stage of the disease do not typically demonstrate alence and frequency of Parkinson’s disease,114 the
impairments in the areas of language, recognition clinic/hospital cohort frequency ranged from 6% to
memory, and praxis. By contrast, mild impairments 29%, whereas the prevalence was relatively higher
in visual spatial abilities, free recall memory, working in community based studies, ranging between
memory, attention, and bradyphrenia are often doc- 12% and 41%. Strikingly, a more recent report of
umented.104-106 Deficient performance on tasks requir- Norwegian Parkinson’s disease patients115 indicated
ing executive functions, such as set shifting, internal that the 8-year prevalence of dementia was 78.2%.
control of attention, sequencing, and temporal order- In a study of New York City patients, individuals with
ing, are also observed in this group.104,105,107,108 Many of Parkinson’s disease were 1.7 times more likely to
the cognitive deficits observed in Parkinson’s disease develop dementia compared to an age- and edu-
patients resemble impairments demonstrated by cation-matched control group.116 By contrast, stud-
patients with damage to the frontal lobes. ies conducted in Norway and England report that
The cognitive impairments characteristic of Parkinson’s disease patients are 5.9 and 5.1 times,
Parkinson’s disease patients are typically attributed respectively, more likely to develop dementia.115,117
to striato-nigral degeneration; that is, the biochemi- The reliable identification of Parkinson’s disease
cal changes related to dopamine loss within the patients at risk of developing dementia is impor-
basal ganglia. Postmortem biochemical analysis tant to patients, caregivers, and physicians for treat-
has shown that depletion of dopamine in the head ment and long-term planning, especially since the
of the caudate was profound, with <4% remaining presence of dementia is a significant predictor of
compared to non-Parkinson’s disease samples. 109 nursing home placement.61 Increasing age117-120 and
The caudate is part of several basal ganglia thala- hallucinations115,117 have been identified as unique
mocortical circuits involving different regions of the predictors of dementia. Findings are mixed for other
prefrontal cortex.110-112 This connectivity pattern sug- variables, such as disease severity117-121 and low lev-
gests that in Parkinson’s disease patients, the pre- els of formal education.117,119 Depression,117,118,120,122
frontal cortex may be functionally deafferented due gender,117-119 and longer duration of illness118,119 appear
to reduced dopamine availability in the striatum. to be unrelated.
Dysregulation of the frontal lobes is frequently cited Neuropsychological measures of frontal system
as the explanation for a range of cognitive impair- functions and memory have also been found to
ments documented in non-demented Parkinson’s predict conversion to dementia. In the domain of
disease patients. Additionally, other neurotransmit- executive function, performance on the Stroop
ter systems necessary for intact cognitive function- interference test, 119,121 verbal fluency, 119,120 digit
ing (ie, aspects of memory and attention) are also span backwards from the Wechsler Memory Scale-
disrupted by the neuropathology of Parkinson’s dis- Revised,122 perseverative errors on the Wisconsin
ease, including the cholinergic networks, noradren- Card Sorting Test, 120 and identities and oddities
ergic system, and reductions in 5-HT.113 In sum, the from the Mattis Dementia Rating Scale 120 were
cognitive deficits observed in Parkinson’s disease the best predictors of dementia. In the domain
are likely due to a disruption of multiple neurotrans- of memory, immediate and delayed recall from a
mitter systems impacting the functions of the frontal selective reminding task,120 encoding and recog-
lobes and their cortical projections. nition from the California Verbal Learning Test,122
Review Article
and the memory subtests of the Cambridge tuations in attention, visual hallucinations, and
Examination for Mental Disorders of the Elderly parkinsonism are consistent with DLB, whereas
section B (CAMCOG)117 were identified as unique patients who develop dementia after 12 months
predictors of conversion to dementia. Hobson of extrapyramidal signs are better characterized
and colleagues117 also report that the language as having Parkinson’s disease dementia. 70,126
subtest of the CAMCOG was predictive of inci- Despite these recently proposed guidelines, it is
dent dementia, while other studies do not con- likely that behavioral studies of Parkinson’s dis-
firm that language skills relate to Parkinson’s ease dementia may have included some patients
disease dementia. 120,122 As larger studies with who met pathological criteria for Alzheimer’s
more precise neuropsychological batteries are disease or DLB, which may explain some of the
conducted, the identification of cognitive mark- inconsistencies noted in previous studies.105
ers for dementia may clarify both the nature and Parkinson’s disease dementia cognitive pro-
causes of Parkinson’s disease dementia. files can be variable, considering that dementia
Neuropathological findings have shown that may indicate a comorbid neurological illness.
the diagnosis of Parkinson’s disease dementia Zakzanis and Freedman127 conducted a meta-anal-
may suggest the presence of an additional neu- ysis reviewing 83 studies on the neuropsycho-
rological disease, such as Alzheimer’s disease, logical performance of non-demented patients
Pick’s disease, progressive supranuclear palsy, with Parkinson’s disease and Parkinson’s disease
corticobasal ganglionic disease, multi-system dementia patients relative to age-equivalent con-
atrophy, DLB, or frontal temporal dementia.123 For trol groups. Of the seven cognitive domains iden-
example, in a sample of 31 patients who devel- tified, the Parkinson’s disease dementia patients
oped dementia after onset of Parkinsonism,123 differed most from the control participants in the
autopsy revealed that 29% had neuropathological domains of manual dexterity, cognitive flexibil-
findings consistent with Alzheimer’s disease, 10% ity, abstraction, and delayed recall (presented in
to 26% had evidence of DLB, 6% had vascular rank order, effect sizes: 2.4–1.8). 127 By contrast,
changes within the basal ganglia, and 55% had relative to the control group, the non-demented
no identifiable cause of dementia. A more recent Parkinson’s disease patients performed more
study using α-synuclein immunohistochemical poorly in the domains of delayed recall and man-
analysis114 reported that 12 out of 13 patients had ual dexterity (effect sizes: 1.3–0.8).127 In general,
findings of DLB as the primary pathological cause this meta-analysis found that Parkinson’s disease
for dementia, one patient was judged to have pro- dementia patients demonstrate more severe
gressive supranuclear palsy and none met crite- impairments in similar cognitive domains relative
ria for Alzheimer’s disease. In a larger study of to non-demented Parkinson’s disease patients,
Parkinson’s disease dementia neuropathology which is dissimilar to other degenerative disorders
(n=88),124 it was also observed that few patients involving cortical functions.
met pathological criteria for Alzheimer’s disease, While prevalence, frequency, and incidence of
whereas cognitive status was linearly related to dementia vary, it is possible to conclude that a
the number of Lewy bodies present. significant portion of Parkinson’s disease patients
D u e t o t h e c o m m o n c o - o c c u rr e n c e o f will develop dementia. Future prospective longi-
Parkinson’s disease dementia, Alzheimer’s dis- tudinal studies linking neuropsychological perfor-
ease, and DLB neuropathology, cognitive pro- mance to neuropathologic confirmation of clinical
files are used to distinguish Parkinson’s disease diagnosis are necessary to determine the rela-
dementia from Alzheimer’s disease and DLB. To tionship between early cognitive changes and
aid in the differentiation of Parkinson’s disease the development of dementia as well as to better
dementia from Alzheimer’s disease, differences define the cognitive phenotypes of Parkinson’s
focus on the amnestic quality of memory loss disease dementia, Alzheimer’s disease, and DLB.
typical of Alzheimer’s disease patients relative to Rivastigmine is the only cognition enhancing
the “dysexecutive syndrome” of Parkinson’s dis- agent tested in Parkinson’s disease dementia on
ease patients, in which acquisition and delayed a large scale. It is equally or more effective in
recall are disrupted, while recognition memory Parkinson’s disease than in Alzheimer’s disease,
remains intact.125 To aid in the differentiation of and does not cause motor worsening. 128 Many
Parkinson’s disease from DLB, the Lewy Body small studies 129-131 of the cholinesterase inhibi-
Consensus Workshop 70 recommends that fluc- tors support these results. Therefore, we advo-
Review Article
cate their use, so long as they are discontinued of consciousness, marked declines in cognitive per-
if they produce no benefit. While published data formance, increased confusion, and disorientation
clearly supports rivastigmine, there is no reason, from baseline are the hallmark signs. In psychotic
a priori, to believe that any one of these drugs is patients, baseline memory, orientation, and cogni-
more helpful than another. tion are unimpaired.138
OTHER BEHAVIORAL SYNDROMES SLEEP

Probably the most important naturally occurring Sleep disorders are common in Parkinson’s
behavioral syndrome is apathy. This is a common disease and are estimated to occur in 60% to
disorder, affecting >10% of Parkinson’s disease 98% of patients. 13 9 - 14 3 Sleep disturbances in
patients.132,133 Apathy is particularly common in Parkinson’s disease include sleep fragmenta-
depressed Parkinson’s disease patients and seems tion, daytime somnolence, sleep apnea, restless
to be increased in demented patients.133 Apathy, of legs syndrome (RLS), nightmares, and rapid eye
course, bothers the caregivers and family and not movement behavior disorder (RBD).144-149
the patient, so it is usually a complaint that is not Frequent nighttime awakenings are the most
spontaneously mentioned by the patient. This type common sleep complaint among Parkinson’s dis-
of information has to be determined by direct ques- ease patients.139,143-145,150 Sleep fragmentation was
tioning of the patient or the family. It is distressing found to occur three times more frequently in
for family members to observe a formerly vibrant Parkinson’s disease patients than in healthy age-
person spend endless hours sitting in front of the matched controls (38.9% versus 12%).139 A study
television, not caring if it is on or off or what pro- using polysomnography151 found that Parkinson’s
gram is playing. Apathy is believed to be a prefron- disease patients not taking antiparkinsonian
tal lobe dysfunction134 and has no known treatment. medication had significantly less total sleep time
It is related to fatigue in that both are amotivational and sleep efficiency, more frequent awakenings,
syndromes and patients may confuse the two. As and greater overall waking time compared to
there is no known effective treatment for apathy controls. A number of factors may contribute
in Parkinson’s disease, we believe in treatment to difficulties maintaining sleep in Parkinson’s
with antidepressants in the hope that the apathy disease patients. These include bladder hyper-
is part of a depressive syndrome. Stimulant medi- activity, sleep apnea, tremors, inability to turn
cation may have a role but has not been tested in over in bed, painful leg cramps, nightmares, and
Parkinson’s disease for this indication. RBD.143-145,152 Several studies139,153-157 found depres-
Although emotional lability has been reported sion to be significantly associated with sleep
to occur in 40% of Parkinson’s disease patients,135 disturbances in the Parkinson’s disease popula-
we believe that is an overestimate. Most cases tion. In a community-based study,139 depression,
of emotional incontinence involve sadness, with rather than stage of Parkinson’s disease, was the
inappropriate tearfulness, such as crying during strongest predictor of disturbed sleep. In a study
a sad movie in a manner that is embarrassing examining mood and sleep in Parkinson’s disease
and different from the premorbid personality. patients attending a movement disorders clinic,157
Inappropriate laughter is much less common136 researchers found depression to be significantly
but both are equally embarrassing. Usually, the associated with poor sleep quality. Anxiety may
emotional state is a gross exaggeration of what interfere with sleep onset and contribute to night-
the patient is feeling but sometimes the affect time arousals. Antiparkinsonian medication may
is completely at odds with the patient’s mood. have an influence on sleep in Parkinson’s disease
Tearfulness is sometimes treated with an SSRI patients. Stimulation of dopaminergic neurons is
but recent data on dextromethorphan, 137 com- associated with arousal and suppression of rapid
bined with quinidine to allow greater drug levels eye movement (REM) sleep. 158,159 One study 160
to reach the brain, has demonstrated that pseudo- found that the daily dose of levodopa or use of a
bulbar affect may be partly controlled. dopamine agonist was the strongest predictor of
Delirium is common in Parkinson’s disease sleep disturbance.
patients due to their comorbid medical problems Excessive daytime sleepiness (EDS) com-
and multiple medications. Distinguishing delirium monly occurs in patients with Parkinson’s dis-
from drug-induced psychosis may be difficult, ease. Studies have found daytime somnolence to
especially in a demented patient. Fluctuating levels be more common in Parkinson’s disease patients
Review Article
compared to controls.161,162 EDS is associated with idiopathic or associated with neurodegenera-

more advanced disease and dopaminergic medi- tive diseases affecting the brainstem. RBD has
cation162,163 as well as longer duration of disease a male predominance157,180-182 and is associated
and male gender.157,163 Potential contributing fac- with longer duration of Parkinson’s disease.157,180
tors to EDS may include intrinsic abnormalities It affects up to one third of Parkinson’s disease
in Parkinson’s disease, concurrent medical illness, patients157,182,183 and can lead to significant inju-
sedating medication, and the effects of nocturnal ries to both the patient and sleeping partner.181
sleep disturbance. Sleep attacks (sudden, irresist- The management of sleep disorder s in
ible onset of sleep without awareness of falling Parkinson’s disease involves identifying and
asleep) have been described in patients taking treating the underlying cause. This includes
dopamine agonists.164-167 The term “sleep attack” assessing for any concurrent medical or psychi-
has been disputed and an alternative view is that atric factors that may contribute to the problem.
Parkinson’s disease patients fall asleep because We recommend the Epworth Sleepiness Scale184
they are continuously sleepy (ie, they have EDS) for measuring daytime somnolence. Actual
and are placed in situations in which resistance diagnoses of sleep disorders require an over-
to sleep is decreased (ie, periods of inactivity).168 night polysomnogram. When evaluating elderly
Sleep attacks are reported to occur with all dopa- patients with Parkinson’s disease, it is important
minergic medication165 and while their frequency to consider that both quantitative and qualitita-
is unknown, they are considered rare. tive changes occur in sleep with normal aging.185
Both central and obstructive sleep apnea Counseling patients in sleep hygiene measures
have been described in Parkinson’s disease may be helpful and if not successful, pharmaco-
patients.169,170 While some studies170,171 report sleep logic approaches should be considered. Sleep
apnea to be more common in Parkinson’s dis- apnea may require a continuous positive air-
ease patients compared to controls, other stud- way pressure mask, although these are often not
ies172,173 found no significant differences. Sleep well tolerated. Occasionally, a jaw prosthesis or
apnea is known to increase with age174 and it is minor surgical procedure can be helpful. RBD
unclear whether sleep apnea in Parkinson’s dis- responds well to low doses of clonazepam given
ease patients is a reflection of the disease process at bedtime. Bladder problems may be insur-
or of age, as most Parkinson’s disease patients are mountable, as sedatives may result in bedwet-
elderly. RLS may occur more often in Parkinson’s ting. Restricting fluid intake prior to bedtime is
disease patients compared to the control popula- recommended. Sedating drugs, such as diphen-
tion.175,176 RLS is characterized by an urge to move hydramine, trazodone, quetiapine, mirtazapine,
the limbs, associated with an unpleasant sensa- and benzodiazepines, may be helpful in treating
tion, that is worsened by rest and relieved with insomnia. Occasionally, anti-soporifics, such as
activity.177 While sleep apnea disrupts sleep con- modafinil 100–400 mg QAM or amphetamines,
tinuity, RLS results in sleep-onset insomnia. can be helpful in improving daytime wakeful-
Other sleep disturbances in the Parkinson’s ness, thus reducing daytime naps, leading to
disease population include nightmares and RBD. better nocturnal sleeping.
Nightmares are associated with nocturnal awak-
ening and contribute to disturbed sleep. The FATIGUE
frequency of nightmares in Parkinson’s disease Fatigue is a common problem in virtually every
patients is estimated to be between 5.7% and medical, neurologic, and psychiatric disorder.186,187
53.3%.152,157,178 An association between nightmares Its importance in neurological diseases, however,
and dopaminergic medication 152,178 has been has been recognized only in the past 2 decades
reported but it is unclear whether this represents or so188 and has largely focused on multiple scle-
a causal association or a parallel progression of rosis.189 It is a frequent symptom in Parkinson’s
the motor and behavioral aspects of the disease. disease and is poorly understood. 190-195 There
RBD is characterized by a loss of muscle ato- are two major categories of fatigue: mental and
nia during REM sleep and prominent motor physical, although others have been described.196
activity associated with dream mentation. 179 Physical fatigue is subdivided into central and
Patients enact their dreams, which are often vio- peripheral components.190 Most studies191-194 of
lent in nature and involve being chased, attacked, fatigue have not distinguished between the two,
or defending oneself from attack. RBD may be which are often present together. In several stud-
Review Article
ies performed in the US and Europe, the follow- some patients develop fatigue later, and some
ing observations were made: ~50% of patients improve, most fatigued Parkinson’s disease
attending a Parkinson’s disease center suffer patients remain fatigued throughout their lifetime.
from fatigue, 191,192,195 considerably higher than There is no data suggesting that these patients
control populations, and about one third of all suffer from severe tremor or medication-induced
Parkinson’s disease patients consider fatigue their dyskinesias, which may cause fatigue.
most severe Parkinson’s disease-related prob- There is no known treatment for fatigue
lem, worse than their motor problems.191 Fatigue unless an etiology, such as anemia, hypothyroid-
is unrelated to motor disability and is encoun- ism, or depression, is identified.
tered early in the disease, usually before the diag-
nosis is made. It has a different character than
REPETITIVE DISORDERS
the fatigue experienced prior to the onset of The recognition that dopamine agonists may
Parkinson’s disease. In a recent study restricted to induce pathological gambling in Parkinson’s dis-
subjects with newly diagnosed, mild Parkinson’s ease patients who were never so inclined, 208-210
disease, who agreed to participate in a large helped place the problem of drug-induced repeti-
multicentered, placebo-controlled drug trial tive behaviors into an interesting perspective.211
(hence, a highly restricted, motivated, and mildly When L-dopa was first introduced, there was an
impaired cohort), one third of patients suffered interest in its potential aphrodisiac properties. This
from fatigue.197 Fatigue was mildly responsive to was difficult to interpret, given the circumstances
L-dopa compared to placebo.197 There is, other- of formerly “frozen” people recovering mobility.
wise, little data on the effects of medications on However, there have been reports on compulsive
fatigue.198 While fatigue is associated with depres- sexual activity linked to L-dopa212,213 and overeat-
sion, it is almost as common in populations that ing,212 but these have been few. A few reports on
exclude patients with depression or sleep disor- “punding” then emerged,214,215 showing a connec-
ders.199 It should be noted that depression, which tion to certain repetitive behaviors seen primarily
is common in Parkinson’s disease, confounds our in amphetamine and cocaine addicts. Compulsive
ability to understand fatigue since fatigue is one behaviors are thought to relieve inner anxiety in
of the core diagnostic symptoms used to diag- that the performance of a stereotypic action as
nose depression in the Diagnostic and Statistical part of a compulsive disorder presumably relieves
Manual, Fourth Edition.200 inner stress. It is unclear if this is the same for
While sleep disorders may overlap with fatigue, punders. They find satisfaction in performing their
it appears that Parkinson’s disease patients are rituals, and become irritable when interrupted,
able to distinguish the tiredness they experience but do not suffer from an underlying anxiety dis-
from sleep impairment, from the experience they order. Punding may arise as the “loss of inhibition
denote by the term “fatigue.”201 of... automatic habits.”211
There is no known gender predilection or The connection between dopaminergic drugs
particular set of motor impairments associ- and repetitive behaviors is unclear. In the case
ated with fatigue. Parkinson’s disease wors- of pathological gambling, there appears to be a
ens motor efficiency so that patients require connection to dopamine agonists, particularly
more energy to breathe and exercise than pramipexole, but this may simply represent a
normal controls. 202-205 However, no difference sampling bias as most cases are reported from
was found in exercise efficiency between the US, where pramipexole is the leading dopa-
fatigued and non-fatigued Parkinson’s disease mine agonist. However, Kurlan 2 16 described
patients.206 Fatigued patients were less active, patients who developed their behavior after
demonstrated reduced endurance, and did not being on stable doses of medication, without res-
require more energy per unit of work.206 olution on reducing the drug dose. Furthermore,
There have been few reports on the long-term the behavior does not respond to antipsychotic
outcome of fatigue in Parkinson’s disease.195,207 medication, as might be expected with a dopa-
Fatigue worsens over time, but the prevalence mine excess disorder.216 Nor does it respond well
of fatigue seems to increase only mildly. The lit- to SSRIs,216 as do typical obsessive-compulsive
tle data that exists suggests that fatigue appears disorders. Our own experience has been that
early in the course, possibly predating onset of reducing or eliminating the dopamine agonist
motor symptoms, and does not resolve. While usually leads to resolution of the behavior.
Review Article
NON-BEHAVIORAL CHANGES REFERENCES

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In DLB patients, visual hallucinations correlate with DEMENTIA AND

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