Parkinson

Parkinsons Disease:
Medical and Surgical Treatment

Editor
Joseph Jankovic
Baylor College of Medicine, TX, USA
Published by Future Medicine Ltd

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Contents
Parkinsons disease:
medical and s urgical
treatment
Parkinsons disease: medical and surgical treatment
Joseph Jankovic
Prevention of Parkinsons disease: preparing for thefuture
Connie Marras
Initial and disease-modifying strategies in Parkinsons
disease
Lawrence W Elmer & Robert A Hauser
Prevention and management of levodopa-related motor
complications
Cara A Pecina & Alberto J Espay
Management of non-
motor symptoms of Parkinsons
disease
Mark Stacy
Management of cognitive and behavioral aspects of
Parkinsons disease
Joseph H Friedman
Surgical therapy for Parkinsons disease
Nawaz Hack & Michael S Okun
Experimental therapeutics for motor symptoms of
Parkinsons disease
Susan H Fox & Lorraine V Kalia
Parkinsons disease treatment pipelines
Joseph Jankovic
Multiple choice questions: answers
3
7
23
43
61
79
99
115
139
149
Jankovic
About the Editor

Joseph Jankovic
Joseph Jankovic is Professor of Neurology and Distinguished Chair in Movement Disorders, and Founding Director of the Parkinsons Disease Center and
Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston (TX, USA).
Past President of the international Movement Disorder Society, he is the recipient of many honors,
including: the American Academy of Neurology
Movement Disorders Research Award, sponsored by
the Parkinsons Disease Foundation; the Guthrie Family Humanitarian
Award, presented by the Huntingtons Disease Society of America; the
Tourette Syndrome Association Lifetime Achievement Award; the Dystonia Medical Research Foundation Distinguished Service Award, the
Baylor College of Medicine Alumni Association Distinguished Faculty
Award; and the Fulbright and Jaworski Faculty Excellence Award. He
has been elected as an Honorary Member of the American Neurological Association, Australian Association of Neurologists, European
Federation of Neurological Societies, French Neurological Society, and
the Movement Disorders Society. In 2004, he was selected by fellow
scientists as a Highly Cited Researcher (www.ISIHighlyCited.com). He
has conducted numerous clinical trials and directs an active basic science research program. He has published over 800 original articles and
chapters and has edited or co-edited over 50 books and volumes. He
has mentored numerous fellows and other trainees, many of whom
have become leaders in the field of neurology and movement disorders. He is current or past member of many scientific and medical advisory boards of national foundations, including the Dystonia
Medical Research Foundation, International Essential Tremor Foundation, Tourette Syndrome Association, and the World Federation of
Neurology Association of Parkinsonism and Related Disorders. He has
also served on the executive scientific advisory boards, including the
Michael J Fox Foundation for Parkinsons Research and the National
Parkinson Foundation C
linical and Scientific Advisory Board.
FOREWORD
Parkinsons disease:
medical and surgical
treatment
Joseph Jankovic
Few neurologic disorders have attracted
more attention from the scientific community than Parkinsons disease (PD).
Advances in basic research are now
being translated into clinical practice.
While the progress in the treatment of
PD has been remarkable, the cause of
this neurodegenerative disorder is still
a mystery. In 1817, James Parkinson in
his original Essay on the Shaking Palsy
first described the disorder that now
bears his name and suggested that
blood letting and iatrogenic pus formation were the best treatments. Subsequent discovery of dopamine deficiency
in the brains of patients with PD and its
therapeutic replacement with levodopa
in the early 1960s heralded a new era
in the treatment of this devastating disorder. The renewed interest in surgical
treatment of PD has been stimulated
largely by the need to treat levodoparelated motor fluctuations and dyskinesias and by improved understanding
of the functional anatomy underlying
motor control, as well as refinements
of neurosurgical techniques and devices, coupled with advances in neuro
imaging and neurophysiology. However, despite extra
ordinary therapeutic
advances during the recent past, PD
continues to be among the most common causes of disability, particularly
among the elderly.
The various chapters in this book are
organized according to the natural
course of PD, from pre
symptomatic
to the most advanced stages. In
Chapter1, Marras emphasizes that
the pathological changes of PD start
long before any symptomatic, initially
doi:10.2217/EBO.13.214
Jankovic
non-motor and later motor, manifestations occur. Therefore, the challenge of implementing any preventive
strategies is to identify individuals
who are at risk for developing the disease to enrich the target population.
In addition to carriers of genetic mutations known to cause PD, individuals
with hyposmia, rapid eye movement
behavioral disorder, constipation and
other premotor symptoms may have
an increased risk for developing PD.
Although with the advent of various
presymptomatic biomarkers, the sensitivity and specificity of diagnosis of
premanifest PD will continue to improve, any disease-modifying interventions may be impractical as they
would have to be applied to a very
large population over long periods of
time to prevent a relatively small number of PD cases. Currently, there are
no established preventive treatments,
but there is growing, albeit still relatively weak, evidence that vigorous exercise, caffeine, NSAIDs, and elevation
of serum urate may possibly have a
favorable disease-modifying effect. In
Chapter2, Elmer and Hauser provide
general guidelines on the initial treatment of PD. In addition to encouraging exercise, they provide evidence
that monoamine oxidase inhibitors,
such as selegiline and rasagiline, may
be considered as the initial treatment
in patients who have only minimal and
not troublesome symptoms. These
drugs are usually followed by the introduction of dopamine agonists be-
fore initiating levodopa. In Chapter3,

Pecina and Espay review strategies
designed to prevent or delay the onset of levodopa-related complications, particularly motor fluctuations
and dyskinesias. They also discuss
management of these complications,
including adjustment of dosing of
levodopa, evaluating patients for evidence of gastroparesis of Helicobacter
pylori gastritis, the use of amantadine
and some investigational drugs for the
treatment of dyskinesias and motor
fluctuations, and subcutaneous injection of apomorphine as a rescue from
an off state. They also discuss novel
deliveries of levodopa, including infusing levodopa/carbidopa intestinal gel
intraduodenally via a percutaneous
endoscopic gastrostomy tube connected to an infusion pump, and other delivery strategies designed to provide a more continuous dopaminergic
stimulation. Deep-brain stimulation
is an important treatment strategy in
suitable patients who are troubled by
their motor complications despite optimal medical therapy. In Chapter4,
Stacy provides a comprehensive review of evidence-based data on the
treatment of non-motor symptoms of
PD, including fatigue, anxiety, pain,
insomnia, nocturia, excessive salivation, cognitive difficulties, depression
and impulse control disorders. The
management of the latter, cognitive and behavioral symptoms, is discussed in more detail by Friedman in
Chapter5. Surgical treatment, with
PD: medical & surgical treatment

emphasis on deep-brain stimulation,
is reviewed in some detail by Hack
and Okun in Chapter6. They emphasize that proper selection of patients
and setting the appropriate expectations, coupled with a multidisciplinary approach, including a team of
experienced surgeons and clinicians,
are critical in achieving a successful
outcome. Finally, in Chapter7, Fox
and Kalia discuss emerging and experimental therapies in PD. Although
the therapeutic pipeline in PD is not
as robust as we would like, with the
advances in understanding of cellular
processes underpinning neurodegeneration the hope is that future therapies will be not only symptomatic but
also target the underlying pathogenic
mechanisms.
Financial & competing interests

disclosure
During the past 2years J Jankovic has
received: Research and Center of Excellence Grants from Allergan Inc.;
Ceregene Inc.; CHDI Foundation; GE
Healthcare; Huntingtons Disease Society of America; Huntington Study
Group; Ipsen Limited; Lundbeck Inc.;
Michael J Fox Foundation for Parkinson
Research; Medtronic; Merz Pharmaceuticals; National Institutes of Health;

National Parkinson Foundation; St Jude
Medical; Teva Pharmaceutical Industries
Ltd; UCB Inc.; University of Rochester;
and Parkinson Study Group.
He has received compensation/honoraria for services as a consultant or an
advisory committee member for Allergan Inc.; Auspex Pharmaceuticals Inc.;
Ipsen Biopharmaceuticals Inc.; Lundbeck Inc.; Merz Pharmaceuticals; Teva
Pharmaceutical Industries Ltd; UCB
Inc.; and US World Meds.
He has also received royalties
Cambridge; Elsevier; Future
ence Group; Hodder Arnold;
pincott Williams and Wilkins;
Wiley-Blackwell.
from
SciLipand
The author has no other 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 apart
from those disclosed.
No writing assistance was utilized in
the production of this manuscript.
CHAPTER
Prevention of Parkinsons
disease: preparing for
thefuture
Connie Marras
Contents
Who is at risk & how many will get Parkinsons disease?
10
When would a preventive treatment need to be applied?
11
How can we narrow the target population for a preventive

strategy?
11
What preventive measures will prevent Parkinsons disease?
15
Conclusion
18
doi:10.2217/EBO.13.83
Marras
About the author

Connie Marras
Connie Marras trained in neurology and movement
disorders at the University of Toronto (ON, Canada).
Research training includes a PhD in epidemiology
at the University of Toronto and further training in
epidemiologic research methods at the Parkinsons
Institute in California (CA, USA). She is currently an
Assistant Professor of Neurology at the University of
Toronto and a neurologist at the Toronto Western
Hospital Movement Disorders Centre (ON, Canada).
Areas of research focus include the epidemiology of genetic forms of
Parkinsons disease, prognosis and environmental etiology of Parkinsons
disease, and evaluating clinical assessment tools in Parkinsons disease.
Learning points
After reading this chapter you will know:
Numerous genetic and environmental factors that modify the risk

for Parkinsons disease are known.
Despite this knowledge, identifying individuals at risk for Parkinsons
disease remains a challenge.
Challenges include the fact that Parkinsons disease affected a
broad range of the population and risk factors likely vary from
individual to individual.
The onset of neurodegeneration is also likely many years prior to the
onset of symptoms, but this interval is currently unknown. Therefore, the optimal timing for application of a preventive strategy is
uncertain.
Once we can identify at-risk individuals, there are a number of promising strategies for prevention to study in clinical trials based on the
known pathogenesis of the disease, environmental associations or
trophic factors.
Summary
Parkinsons disease is common and associated with major
costs to individuals and society. Prevention of the disease
would have enormous public health benefits. There are no
preventive strategies available now or in clinical trials. This
is not because of a lack of candidate treatments, rather it
is due to the challenges in identifying a high-risk group to
which these treatments could apply. Parkinsons disease
affects men more than women, young and old, and no
ethnic group has been reported immune to the disease.
Furthermore, the onset of Parkinsons disease is likely to
occur years before the classical symptoms become manifest
and permit a definitive diagnosis. This chapter will discuss
these challenges and how we might overcome them, and
will outline interesting candidates for preventive strategies.
Marras
Parkinsons disease is one of the most
common neurodegenerative diseases,
affecting individuals through many years
of their lives. The associated financial
costs to individuals and society are
substantial and the disease has a major
impact on quality of life for patients [1,2].
Therefore, prevention of Parkinsons
disease would have major benefits.
The focus of current research related
to modifying the disease process is on
slowing progression of the disease, and
this is discussed in Chapter2. However,
the potential impact of prevention is
far greater. With increasing knowledge
of the pathogenesis of Parkinsons
disease, causative genes and genetic risk
factors that can be easily tested for and
known environmental protective factors,
prevention may one day be achievable.
This chapter will review the process of
developing and applying prevention
strategies in the context of Parkinsons
disease.
Any program of prevention must
address two separate problems; first,
identifying individuals at risk and second, applying preventive measures.

Which screening procedures and preventive treatments would be considered feasible and acceptable in such
programs depends on a number of
factors including the size of the population at risk, the size of the population ultimately destined to acquire
the condition, the certainty of disease
in people positively identified by the
screening procedures and the morbidity associated with the disease and
its treatment. We will first discuss the
problem of identifying individuals who
will ultimately develop Parkinsons disease. The challenges are summarized in
Box1.1.
Who is at risk & how many

will get Parkinsons disease?
Parkinsons disease affects a broad spectrum of the population. The frequency
of the disease is approximately 1.5-times
higher in men than women[3] . Aging
is the strongest known risk factor for
Box 1.1. Challenges identifying individuals at high risk for

Parkinsons disease.
Who?
Parkinsons disease affects a broad spectrum of the population; noone can be
considered immune
Identifiable risk and protective factors are numerous but vary from person to
person
When?
The age at onset of Parkinsons disease is highly variable, from mid-life to the
elderly
Nonspecific symptoms predate the classical motor symptoms by years
10

Parkinsons disease; however, onset in
young adulthood is not rare and a substantial proportion of Parkinsons disease occurs in individuals under 60years
of age. No ethnicity has been found to
be immune to the disease. Despite these
broad demographics resulting in a large
worldwide burden of disease, an individuals lifetime risk of Parkinsons disease
is still small. Parkinsons disease affects
approximately 1/100individuals over the
age of 60years and 1/1000individuals
of all ages [4] . Only the most benign
and inexpensive preventive treatments
would be feasible to apply to all adults
to prevent a disease destined to affect
less than 1 in 100people and therefore
additional risk factors need to be considered in order to identify a subpopulation
to receive a preventive measure.
When would a preventive

treatment need to be
applied?
Parkinsons disease presents an
additional problem beyond frequency
when it comes to prevention.
Identifying the time of onset of the
condition with certainty has eluded
clinicians and researchers thus far.
Traditionally, the onset of Parkinsons
disease has been designated as the
time at which motor symptoms
(symptoms related to tremor, rigidity or
bradykinesia) begin. In the last decade,
non-motor symptoms predating these
classical motor symptoms have been
increasingly recognized as an integral
feature of the disease and several of

these have been demonstrated to
predate the motor symptoms by many
years [5] . Box1.2 lists these symptoms.
It is unknown whether or not these
represent risk factors and thus clues
to truly unaffected individuals, or if
they represent the earliest features
of the disease itself, although the
distribution of neurodegeneration in
Parkinsons disease and its sequence
of pathological evolution in the central
nervous system would suggest that
most of them are integral features of
the disease. More problematic still, the
pathological process in the brain may
begin well before even non-motor
symptoms become manifest. Thus, it is
unknown how early a treatment would
have to be applied to truly prevent
the disease. Longitudinal studies of
presumed at-risk individuals will be
required to sort this out.
How can we narrow the

target population for a
preventive strategy?
Environmental risk factors, clinical,
imaging, biochemical and genetic tests
may all complement demographic
characteristics to help to identify those
that will ultimately develop Parkinsons
disease. These tests either identify an
at-risk state or identify the earliest
physiological
changes
associated
with Parkinsons disease. Genetic and
environmental risk factors have the
potential to identify the at-risk state
11
Marras
Box 1.2. Symptoms and signs predating the motor features of
Parkinsons disease.
Well-established associations
Olfactory deficit
Constipation
Depression
Rapid eye movement behavior disorder
Possible associations
Reduced color vision
Reduced heart rate variability
Anxiety
before the pathological process begins,

and therefore present the possibility of
truly preventing the condition rather
than arresting it at an asymptomatic
or minimally symptomatic state.
Clinical, imaging and biochemical tests
would identify the early stages of a
pathological process, thereby allowing
it to be arrested by a preventive
intervention. We will first discuss
genetic and environmental strategies
then discuss clinical, imaging or
biochemical biomarkers of disease.
Genetic contributors to Parkinsons disease include both causative mutations,
such as mutations in the PINK1, PARKIN or LRRK2 genes and risk-conferring mutations or polymorphisms [6] .
Genetic testing is becoming common
in people with Parkinsons disease,
particularly those with a family history
of the condition, but the interpretation of these genetic tests is difficult

because of variable penetrance, lack of
neuroprotective therapies, and other
medical and ethical issues. Genetic risk
factors (in contrast to causative genes)
individually increase the risk for Parkinsons disease by small amounts and
individually are present in only a small
minority of people with Parkinsons
disease. New risk factor genes are being discovered at rapid rates; however,
and in combination the genetic risk
conferred may be substantial[7] . It is
conceivable that with the discovery of
a large number of genetic risk factors
over the coming years we will be able
to quantify a persons genetic risk for
Parkinsons disease.
Environmental risk factors for Parkinsons
disease include pesticide and solvent
Biomarker: an indicator of a biological state; in this context an

indicator of the neurodegenerative condition that is Parkinsons
disease.
12

exposure, and specific compounds
responsible for these associations
are beginning to be elucidated [8] .
Numerous other risk factors, such
as heavy metal exposure and head
trauma, have been proposed [9] . Given
the multiple genetic and environmental
associations that are being discovered,
it is very likely that causative factors
will vary from individual to individual.
Therefore using any specific risk
factors to identify at-risk populations
will identify only a small proportion of
individuals at risk. Geneenvironment
interactions are increasingly of interest
and may be very relevant in quantifying
an individuals risk of Parkinsons disease.
For example, pesticide exposure may be
of particular relevance in an individual
genetically programmed to metabolize
these chemicals less efficiently [10] .
Thus, a risk profile may also need to
take into account multiple genetic
and environmental factors and their
co-occurrence.
There are many ongoing studies
attempting to define imaging or
biochemical markers that identify early

pathological changes of Parkinsons
disease. Techniques that have shown
an ability to distinguish established
Parkinsons disease from unaffected
individuals are clear candidates for biomarkers of the at-risk state as well.
Single photon emission computed tomography using ligands specific for the
dopamine transporter (DAT SPECT) is
available in Europe and the USA for
aiding the diagnosis of Parkinsons disease. Reduced uptake of radiotracer
in the striatum is the characteristic
pattern. This has been shown to be
abnormal prior to the onset of motor
symptoms [11] , suggesting that DAT
SPECT may be a useful screening tool.
PET using fluorodopa as the tracer specific for dopaminergic terminals shows
similar promise [12] . Ultrasound of the
midbrain can also distinguish individuals with Parkinsons disease from controls, showing a larger area of echogenicity in the region of the substantia
nigra in Parkinsons disease [13] , and
has also been proposed as a useful
test to identify at-risk individuals (see
Dopamine transporter: a transmembrane protein on dopaminergic nerve terminals that carries dopamine from the synapse back
into the cytosol. In Parkinsons disease a reduction in these proteins
in the striatum results from degeneration of dopaminergic neurons
that project from the substantia nigra to the striatum.
Striatum: a nucleus of the basal ganglia, comprised of the caudate nucleus and
putamen. The striatum receives projections from the substantia nigra, therefore
loss of dopamine-containing axon terminals in the striatum originating from the
substantia nigra can be detected using imaging techniques such as PET or single
photon emission computed tomography.
13
Marras
Rapid eye movement sleep behavior disorder: a sleep disorder
characterized by a loss of normal atonia accompanying rapid eye
movement sleep resulting in enactment of dream behavior.
below). Promising preliminary studies

have been reported for analytes in the
cerebrospinal fluid (CSF) and blood;
individually, such measurements have
shown an ability to distinguish established Parkinsons disease from
controls [14] . Combinations of these
markers in CSF are being investigated
to separate Parkinsons disease from
controls even more accurately [15] .
For each of these promising markers,
we need to know the frequency and
timing of abnormalities in individuals
at risk for Parkinsons disease prior to
using them to determine the risk of an
individual. Furthermore, neither imaging modalities nor CSF analysis is practical to apply to the general population
to screen for Parkinsons disease risk.
However, they could represent second-step screening after an individual
has been identified as at elevated risk
by other simpler tests.
More
immediately
relevant
to
prevention, some markers are being
studied either cross-sectionally or
prospectively in unaffected populations
to assess their potential to identify
high-risk
groups.
Cross-sectional
studies take advantage of known
high-risk populations such as those
with anosmia, rapid eye movement
(REM) sleep behavior disorder (RBD)
14
or genetic mutations associated

with Parkinsons disease to identify
differences between these groups
and the general population in possible
biomarkers. Olfactory dysfunction and
reduced color vision are more prevalent
in individuals with RBD, suggesting
that individuals with these clinical
features are at a particularly high risk
of developing Parkinsons disease [16] .
Imaging findings in genetically defined
at-risk populations have suggested
promise for functional and structural
imaging techniques [1719] , further
specifying risk in these enriched
populations.
Despite the importance of these crosssectional studies for hypothesis generation, the ability to make inferences from
their results about predicting risk for
developing Parkinsons disease is limited. Prospective, longitudinal studies are
needed to demonstrate the predictive
value of any marker. Longitudinal studies are currently following cohorts selected on the basis of non-motor manifestations of Parkinsons disease to test
whether or not a combination of clinical tests can identify individuals who
will develop Parkinsons disease [20] .
The Parkinsons Associated Risk Study
is evaluating 7500first-degree relatives
of individuals with Parkinsons disease

with olfactory testing and a subset with
DAT SPECT scanning to identify those
most likely to develop Parkinsons disease [101] . The Prospective evaluation
of Risk factors for Idiopathic Parkinsons
Syndrome study[21] enrolled 1847individuals free of Parkinsons disease
and followed them longitudinally. After
3years follow-up, 11subjects had developed Parkinsons disease. The best
approach for prediction of incident
Parkinsons disease was achieved when
applying inclusion criteria based on age,
positive family history and/or hyposmia, and substantia nigra hyperechogenicity. Using this combination, one in
16individuals meeting all three criteria
developed Parkinsons disease. Despite
their success improving prediction relative to incidence of Parkinsons disease,
the authors concluded that such an
approach would still not be feasible to
apply to the general population given
the long follow-up periods required. A
population exhibiting the combination
of hyposmia and RBD is currently being recruited for a prospective study of
prodromal Parkinsons disease as part
of The Parkinson Progression Marker
Initiative [22] . The Honolulu Asia Aging
Study has provided longitudinal observations of 8006JapaneseAmerican
men and thus has allowed several potential predictive signs and symptoms
to be evaluated retrospectively for
their predictive power both individually
and in combination [23] . They identified several clinical features that were
associated with increased incidence of
Parkinsons disease, but none individually could increase the incidence to the
point of being useful for screening for
premotor Parkinsons disease due to
low specificity. When impaired olfaction, excessive daytime sleepiness,
low frequency of bowel movements
and slow reaction time were assessed
in combination, the presence of all
four signs was associated with an incidence of Parkinsons disease of 215 per
10,000person years. This represents a
major improvement over an incidence
of 16 per 10,000person years in those
with none of the signs. Translated into
the context of a preventive program,
it would be necessary to apply a preventive strategy to 100such high-risk
individuals for an average of 10years
to prevent 21new cases of Parkinsons
disease.
What preventive measures

will prevent Parkinsons
disease?
Because of the aforementioned
challenges identifying individuals at
high risk described earlier, the focus
of disease modification studies in
Parkinsons disease to date have
been on modifying the course of
established disease. This topic is
discussed in Chapter 2. Despite very
active research in disease modification
of Parkinsons disease, currently there
are no established treatments to slow
its progression. There are substantial
obstacles to testing disease-modifying
15
Marras
treatments for this disease, including
our incomplete understanding of
disease mechanisms, the long duration
and large sample sizes required in
clinical trials and a lack of sensitive
or widely available tools to measure
outcomes[24] . These obstacles are likely
to be even more difficult to overcome
for studying disease prevention
compared with slowing disease pro
gression. Any drug that can slow the
neurodegenerative process may also
be effective in preventing it, although
a preventive strategy will have to target
mechanisms that are active early in the
disease process. Preventive treatments
may be developed by applying know
ledge of pathogenic mechanisms of
Parkinsons disease, by taking direct
advantage of inverse associations
observed between modifiable environ
mental factors and Parkinsons disease,
or by using nonspecific neurotrophic
compounds to increase resistance to
neurodegneration. This section will
briefly summarize the current state of
knowledge regarding pathogenesis and
environmental protective factors and
then discuss how they may be used for
preventive strategies.
Our understanding of the patho
genesis of Parkinsons disease has
been shaped by both genetic and
environmental associations. Attention

has focused on two main systems:
the ubiquitin proteasome system
(UPS) and mitochondrial function. The
role of inflammation in Parkinsons
disease is also of great interest. The
UPS is responsible for degrading
unwanted or abnormal proteins.
Protein misfolding leading to impaired
clearance by the UPS and aggregation
of proteins and/or defects in the UPS
system are thought to contribute to
the neurodegenerative process in
Parkinsons disease. Parkinsons disease
is characterized pathologically by the
accumulation of insoluble aggregates
of protein called a-synuclein, a major
component of Lewy bodies, the
pathological hallmark of Parkinsons
disease. Mutations or polymorphisms
in the gene encoding a-synuclein that
promote the accumulation of misfolded
a-synuclein increase risk for Parkinsons
disease [25,26] . Mutations in the
gene encoding for Parkin, an integral
part of the UPS, cause young-onset
Parkinsons disease. Environmental
toxins that impair the UPS (e.g.,
maneb, paraquat) increase a-synuclein
deposition and are also risk factors for
Parkinsons disease [27] . Mitochondrial
dysfunction has been recognized in
patients with Parkinsons disease for
decades [28] and has been proposed
Ubiquitin proteasome system: a cellular system responsible for

the degradation of damaged, oxidized, or misfolded proteins as well
as regulatory proteins.
16

as a key factor in the pathogenesis of
the disease. Once again, genetic and
environmental associations support this
role. Mutations in the Parkin, DJ-1 and
PINK1genes that impair mitochondrial
function cause autosomal recessively
inherited Parkinsons disease [29] .
The pesticide rotenone is an inhibitor
of mitochondrial complex1 and
exposure to rotenone is a risk factor
for Parkinsons disease [30] . These
mechanisms are reviewed in detail by
Burbulla and Kruger [31] . Inflammation
is a recognized pathological charac
teristic of Parkinsons disease and in
animal models of Parkinsons disease,
exacerbates neuronal loss[32] .
The inverse association between
ibuprofen use and incident Parkinsons
disease [33] (see below) underscores
the potential relevance of controlling
inflammation for prevention.
Based on this information, bolstering
the UPS or mitochondrial function or
suppressing inflammation could be
effective preventive strategies. These
potential disease-modifying strategies
are currently being evaluated in
preclinical and clinical studies in an
attempt to slow the progression of the
disease [3436] . Additionally, there are
active research programs attempting
to develop agents that will reverse
the pathological effects of known
causative genetic mutations, such
as inhibitors of LRRK2. Although we
know that these systems or processes
are abnormal in Parkinsons disease,
it is currently unknown when they

become abnormal and how important
they are relative to one another. Once
high-risk groups can be identified
with confidence, important next steps
will be to identify the predominant
pathological mechanisms active in
the asymptomatic or premotor phase
of the disease. In this way the most
relevant preventive strategies can
be tested, which might be different
from the optimal disease-modifying
treatments for established Parkinsons
disease.
There are a number of known inverse
associations between environmental
factors and incident Parkinsons disease, such as cigarette smoking, serum
urate, caffeine intake and use of the
NSAID ibuprofen [37] . Lifestyle factors,
such as physical activity early in life have
also been associated with lower risk of
developing the disease [38] . The fact
that these factors are associated with
reduced occurrence of Parkinsons disease (distinct from slower progression
of disease) makes them particularly interesting clues to preventive strategies.
The Safety and Ability to Elevate Urate
in Early Parkinson Disease (SURE-PD)
trial is underway to investigate the ability of inosine to elevate uric acid levels
in the blood and CSF of patients with
Parkinsons disease and to establish its
tolerability [102] . The disease-modifying
potential of transdermal NICotine in
early Parkinsons Disease (NIC-PD)
study is being conducted to investigate
17
Marras
whether or not nicotine slows the progression of Parkinsons disease [103] .
Caffeine is being studied in established
Parkinsons disease for its effect on
symptoms and is also of interest as a
possible disease-modifying treatment.
Exercise is particularly interesting as
a preventive strategy because of its
potential for widespread application.
Previous research supports exercise
as a beneficial treatment for physical
symptoms in Parkinsons disease [38,39]
and it has been shown to have cognitive benefits in the general population
as well [40] .
Any one of the above strategies
would be reasonable to investigate as
a preventive strategy, but is unlikely
to be completely effective on its own
as a preventive agent. This is evident
when one considers the fact that some
patients with Parkinsons disease are
longstanding cigarette smokers and
heavy coffee drinkers, and individuals
with gout are not immune. Each of
these factors is associated with a mild
to moderate reduction in risk. For
example, belonging to the highest
quintile of coffee drinking compared
with the lowest is associated with
odds ratios in the range of 0.60.75
for incident Parkinsons disease [33] .
Combinations of preventive treatments,
or strategies tailored to an individuals
genetic or environmental exposure
profile will likely be necessary.
18
Conclusion
The factors contributing to Parkinsons
disease likely vary from individual to
individual. In one person they may be
predominantly genetic and in another
predominantly environmental, but very
unlikely are they exclusively one or
the other. Even the most common socalled causative gene mutations are
incompletely penetrant (e.g., LRRK2
gene mutations), implying that other
factors modify the risk. Therefore, either personalized or multipronged
strategies may be necessary to achieve
true prevention of the disease. How
ever, before we have the luxury of testing these strategies, we must overcome
the challenge of identifying those at
highest risk.

disclosure
The author has 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 or patents received or pending, or royalties.
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101. Parkinson Associated Risk Study.
www.parsinfosource.com

102. Safety of Urate Elevation in Parkinsons
Disease.
http://clinicaltrials.gov/ct2/show/
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21
Marras
Multiple choice questions

1.
2.
3.
4.
22
Premotor features of Parkinsons disease include:

a.
Olfactory dysfunction
b.
Constipation
c.
Hearing loss
d.
Hallucinations
Which is not a risk factor for Parkinsons disease?
a.
Male sex
b.
Smoking
c.
Pesticides
d.
Solvents
Which of the following are associated with lower risk of Parkinsons
disease?
a.
Uric acid
b.
Caffeine
c.
Ibuprofen
d.
All of the above
Which of the following techniques are being used to distinguish
individuals with Parkinsons disease from people without:
a.
Ultrasound of the brainstem
b.
Fluorodopa PET scanning
c.
T1- and T2-weighted structural MRI scans of the brain
d.
Dopamine transporter single photon emission computed
tomography scanning
CHAPTER
2
Initial and diseasemodifying strategies in
Parkinsons disease
Lawrence W Elmer & Robert A Hauser
Contents
Treatment of PD
26
Disease modification in PD: MAO-B inhibitors
31
Disease modification in PD: other treatments
36
Conclusion
37
Early treatment of PD: proposed algorithm
37
doi:10.2217/EBO.13.119
23
Elmer & Hauser
About the authors

Lawrence W Elmer
Lawrence W Elmer is Professor of Neurology, Medical Director of the Center for Neurological Health
and Director of the GardnerMcMaster Parkinsons
Center at the University of Toledo (OH, USA). His
research is primarily focused on emerging medical
treatments for Parkinsons disease.
Robert A Hauser
Robert A Hauser is Professor of Neurology, Molecular Pharmacology and Physiology, and Director of the
Parkinsons Disease and Movement Disorders Center
at the University of South Florida in Tampa (FL, USA).
His main research interest is the development and
evaluation of new therapies for Parkinsons disease
and related disorders.
24
Initial & disease-modifying strategies in PD
Learning points
Dopaminergic therapies, including levodopa, dopamine agonists

and monoamine oxidase B inhibitors, form the basis of modern
pharmacological management of Parkinsons disease (PD).
Slowing of PD progression remains a challenging and, as yet, unmet
need in the management of this neurodegenerative disorder.
New forms of exercise, specific to PD, complement the dopaminergic therapies and may improve functional outcomes in PD at
many stages of the illness.
Levodopa remains the most efficacious and widely used agent
for improving PD symptoms. Long-term motor complications of
chronic levodopa therapy may be less prominent as we move to
formulations that last much longer than original oral systems.
The monoamine oxidase-B inhibitors selegiline and, especially,
rasagiline demonstrate provocative and potentially promising
results in numerous studies, suggesting the possibility of stabilizing neurons and preventing further neurodegeneratioin. This
requires further investigation.
Summary
Parkinsons disease is one of the most treatable neuro
degenerative disorders affecting our society. Recent and
anticipated breakthroughs in treatment promise to offer
increased quality of life and, potentially, significantly delay
the progression of the illness.
25
Elmer & Hauser

The classic motor symptoms of
Parkinsons disease (PD) bradykinesia,
rigidity and rest tremor correlate with
a progressive loss of dopaminergic
neurons in the substantia nigra [1,2]
along with their respective projections
to the striatum. Initial symptomatic
therapy for these symptoms attempts
to restore dopamine levels in key brain
areas, ameliorating clinical symptoms
while avoiding adverse side effects.
Optimal therapeutic intervention in PD
would go further, slowing or possibly
preventing further dopaminergic (and
other neuronal) cell loss.
Treatment of PD
Treatment of the motor
symptoms of PD
Pathologically, PD is characterized
by degeneration of dopaminergic
neurons in the substantia nigra pars
compacta, resulting in a reduction of
striatal dopamine [2] . However, recent
postmortem findings have suggested
that damage in the substantia nigra
is preceded by pathology involving

olfactory neurons, lower regions of
the brainstem and the enteric nervous
system [3] . The early motor signs
characteristic of the disease include
bradykinesia, rest tremor, postural
instability and rigidity (Box2.1) [2,4,5] .
While postural instability is considered
one of the classic PD symptoms, it is
rarely encountered in early cases and is
not addressed in this chapter.
The major goal of PD therapy is to control
motor symptoms, typically by using
therapies that increase dopaminergic
stimulation in the brain, including
levodopa preparations, dopamine
agonists (DAs) and monoamine
oxidase-B (MAO-B) inhibitors [5] .
Another important consideration is the
avoidance of side effects, including the
risk of developing motor complications
such as wearing off and medicationinduced dyskinesias. Therefore, the
choice and dosages of medications
must be individualized for each
patient in order to provide adequate
symptomatic
benefit
with
the
Dopaminergic: pertaining to the use of medications working

through a dopamine receptor on nerve cells.
Levodopa: a synthetic precursor to dopamine that can be given
orally, crosses the bloodbrain barrier, and can be taken up, stored
and released by healthy and damaged dopamine neurons.
Dopamine agonist: synthetic substitute for dopamine with variable efficacy and
tolerability.
Monoamine oxidase inhibitor type B: chemical that stops the degradation of
dopamine by blocking the conversion of dopamine to DOPAC.
26

Box2.1. Motor features of early Parkinsons disease.
Bradykinesia
Difficulty in initiating and maintaining movement, examples include masked
faces, decreased blink rate, hypophonia, slowed hand and finger movements,
micrographia, difficulty turning in bed and arising from a chair, decreased arm
swing and shortened stride length while walking and reduced spontaneous
gestures, among others
Rigidity
Increased resistance to passive manipulation, examples include cogwheel or
lead pipe rigidity at elbows, wrists, knees and ankles, restricted mobility and
muscle pain in the shoulder, back and upper leg, occasionally accompanied by
cramping/dystonia
Tremor
Rest tremor of 46Hz: commonly seen in lips and/or lower jaw, hands, fingers,
feet and/or toes. Usually diminishes with movement, but may re-emerge when
holding a fixed posture
Postural instability
Abnormal gait or balance not caused by primary visual, vestibular, cerebellar or
proprioceptive dysfunction: rarely seen in early Parkinsons disease
fewest side effects and/or long-term

complications. Patients with early PD
are often treated initially with levodopa,
a DA, or a MAO-B inhibitor [5,6] . While
a discussion of the extensive evidence
demonstrating the efficacy of these
three therapeutic options is beyond
the scope of this chapter, it is generally
considered that these three types of
medication play important roles in the
treatment of early PD.
Dopaminergic therapies for

early PD
Therapy
with
the
dopamine
precursor levodopa is considered
the gold standard for treatment of
motor features of PD[7] . Levodopa
is
generally
administered
with
a
dopa-decarboxylase
inhibitor
(benserazide
outside
the
USA,
carbidopa in the USA) to prevent
peripheral metabolism of the drug,
thereby reducing adverse effects (AEs)
associated with peripheral formation
of dopamine, specifically nausea and
vomiting [8,9] . Levodopa is considered
the most efficacious medication for
the treatment of motor features of
PD, [57] and exhibits a relatively
rapid onset of action and good
tolerability[6,10,11] . However, the longterm use of levodopa is commonly
associated with the development of
motor fluctuations (e.g., wearing-off,
onoff fluctuations) and dyskinesias
[12] , especially in younger patients [11] .
Therefore, the use of levodopa as initial
monotherapy for PD is often reserved
27
Elmer & Hauser

Dyskinesias: largely involuntary movements that are typically
exaggerated and flailing the direct result of too much dopamine in
the system.
Fluctuations: variable clinical response of people with Parkinsons
disease when their medication is working, they move, look, feel and speak
normally. When their medicine is not working, the symptoms of Parkinsons
disease predominate, including stiffness, slowness, soft voice, difficulty walking,
among others.
for individuals in whom motor disability

is substantial or a threat to their safety
or livelihood and for older patients
(>65years of age) [6,13] because their
risk of neuropsychiatric complications
with other agents (DA) is higher [6]
and their risk of motor complications is
lower [13] .
DAs, such as ropinirole, pramipexole
and rotigotine, directly stimulate
dopamine receptors [11,13] . Because
levodopa-induced dyskinesias can
limit the ability to adequately control
parkinsonian motor symptoms, strat
egies to delay the need for levodopa
have been investigated. When used
as initial therapy for PD, DAs delay
the onset of motor complications
and decrease levodopa use, although
they are generally less effective than
levodopa for improvement of motor
symptoms [1416] . As monotherapy
in early PD, DAs provide adequate
symptomatic benefit in approximately
50% of patients for up to 3years and
are a suitable therapy for younger
patients with mild-to-moderate motor
deficits [6] . Because DAs can cause
28
confusion
and/or
hallucinations,
they are not typically recommended
for use in elderly patients or
those with dementia. Other AEs
associated with DA therapy include
somnolence, sudden onset sleep, and
impulse control disorders, including
pathological gambling, comp
ulsive
shopping, excessive internet use
and hypersexuality [17] . Other DAs,
derived from ergot compounds,
were used in the past for early PD,
including bromocriptine, pergolide and
cabergoline. Due to long-term risk of
cardiac valvulopathies, this subclass of
DAs is rarely, if ever, used.
Selegiline and rasagiline reduce
dopamine
metabolism
centrally
through inhibition of MAO-B, thereby
increasing brain concentrations of
dopamine [18] . The MAO-B inhibitors
provide a mild symptomatic benefit[6]
and can also delay the need for
levodopa [7,19] . In addition, there has
been long-term interest regarding
the role of MAO-B inhibitors slowing
disease progression in PD (see below).
Rasagiline monotherapy can provide

adequate control of motor features in
approximately 50% of patients for up
to 2years [20] . The coadministration
of DAs and MAO-B inhibitors has
also been advocated to improve
symptomatic efficacy and further delay
the need for levodopa [6,21] . Recent
reports on the efficacy and safety
of DA/MAO-B inhibitor combination
therapy have been published, including
a longitudinal clinical trial investigating
the efficacy and safety of rasagiline in
combination with DAs with or without
levodopa [21,22] . If a levodopa delaying
strategy is being employed, a DA can
be added to an MAO-B inhibitor when
needed to control motor symptoms,
rather than adding levodopa [23] .
However, the strategy of delaying
levodopa until motor symptoms
cannot be satisfactorily controlled
with MAO-B inhibitors and/or DAs has
been challenged, in part because the
protection from motor complications is
relatively short lived [24] .
Catechol-O-methyltransferase inhibitors (i.e., entacapone and tolcapone)
prolong the peripheral half-life of levodopa, thereby increasing the central
bioavailability of levodopa. Tolcapone
may also simultaneously reduce central dopamine metabolism. In a trial
examining the use of carbidopa
levodopaentacapone versus carbidopalevodopa for early Parkinsons patients (STRIDE-PD), the group receiving carbidopa levodopa entacapone
developed motor fluctuations and
dyskinesias earlier than those patients

receiving carbidopalevodopa [25] .
The study was criticized; however, because the treatment protocol did not
provide continuous levodopa availability and the levodopa dose equivalents were higher in the carbidopalevodopaentacapone group. The use
of catechol-O-methyltransferase inhibitors for early PD has been generally
discouraged.
Alternative therapies for

early PD
Amantadine, an antiviral therapy, has
also been used for the management
of early PD symptoms [11,13] . Animal
studies suggest that amantadine
may provide multiple therapeutic
actions by: enhancing release of
dopamine [26] ; blocking dopamine
reuptake [27] ; increasing D2 dopamine
receptor density [28] ; and blocking
N-methyl-d-aspartate receptors with
concomitant reduction of excitatory
pathways that antagonize the effects
of dopamine[29] . Amantadine may
also have anticholinergic activity [9,13] .
Anticholinergic therapy has been used
for over a century to treat PD symptoms,
and drugs such as trihexyphenidyl
and benztropine have shown efficacy
in improving tremor[11,30] . These
compounds, when used, are more
commonly administered in younger
patients in whom rest tremor is a primary
symptom and cognitive function is
29
Elmer & Hauser

preserved [9,11] . The mechanism of
action of the anticholinergic drugs in
the context of PD is not completely
known [9] but may involve inhibition of
cholinergic interneurons in the striatum
that are relatively overactive following
loss of dopamine-mediated inhibitory
mechanisms [31] . While anticholinergic
compounds are still used in clinical
practice, their AE profile prevents
widespread use, especially in elderly

patients [32] .
Although all of the therapies described
have demonstrated efficacy in the
management of the motor symptoms
of PD, only levodopa, MAO-B
inhibitors and DAs are typically
recommended as first-line therapies for
PD (Table2.1)[6] .
Table2.1. Levels of recommendation for the treatment of early

Parkinsons disease.
Therapeutic
interventions
Level of recommendation
Symptomatic control
Prevention of motor
complications
Levodopa
Effective (levelA)
Not applicable
Levodopa CR
Effective (levelA)
Ineffective (level A)
Apomorphine
Not used
Not used
Pramipexole
Effective (levelA)
Effective (levelA)
Pramipexole CR
Effective (levelA)
Not available
Ropinirole
Effective (levelA)
Effective (levelA)
Ropinirole CR
Effective (levelA)
No recommendation
Rotigotine TD
Effective (levelA)
No recommendation
Selegiline
Effective (levelA)
Ineffective (levelA)
Rasagiline
Effective (levelA)
No recommendation
Entacapone
No recommendation
Ineffective (levelA)
Tolcapone
No recommendation
No recommendation
Amantadine
Effective (levelB)
No recommendation
Anticholinergics
Effective (levelB)
No recommendation
Classification of evidence and recommendations were made according to European

Federation of Neurological Societies guidance, focusing on the highest levels of evidence
available.
Ergot derivatives are not included due to risk of valvular heart disease.
CR: Controlled release; TD: Transdermal patch.
Adapted with permission from [49].
30
Disease modification in PD:

MAO-B inhibitors
Unified Parkinsons Disease Rating

Scale (UPDRS) scores compared with
those who had originally not received
Monoamine oxidase is a flavin- selegiline (i.e.,were initially treated
containing enzyme [33] located in the with placebo), indicating that the initial
outer mitochondrial membrane[7,33] advantages of selegiline were not
that deaminates monoamine neuro sustained [37] .
transmitters, including dopamine and
biogenic amines, such as tyramine[18] . Several studies have demonstrated
Given the high levels of MAO-B activity the long-term efficacy and safety
in the brain and the ability of MAO-B of selegiline. In one Finnish study,
to deaminate dopamine, inhibition of 52patients with early, untreated
MAO-B is an attractive therapeutic tar- PD were randomized in a doubleget for PD; indeed, selective inhibition blind, placebo-controlled study to
of MAO-B increases dopamine in the receive either selegiline or matching
brain [7,18] . Selective MAO-B inhibitors placebo [35] . They were followed
are favored for the treatment of PD until they needed levodopa rescue
over nonselective MAO inhibitors be- therapy and were followed for up to
cause of the potential for hypertensive 12months thereafter. The patients
crisis with MAO-A inhibition [18] .
receiving selegiline required levodopa
much later than those receiving
placebo (545days vs 372days), but the
Selegiline
symptomatic improvement seen with
Four double-blind, placebo-controlled selegiline was not felt to represent all
trials (Table2.2) in patients with of the difference between the groups,
early PD suggested that selegiline suggesting a disease-modifying effect
monotherapy slowed the progression of of selegiline treatment. In Sweden,
clinical disability and delayed the need 157patients with early, untreated PD
for levodopa [3436] . The largest of were randomized in a double-blind,
these trials was the DATATOP study. An placebo-controlled study to receive
interim analysis of the DATATOP study selegiline or placebo [38] . Patients
revealed that selegiline significantly were followed until they needed
delayed the need for levodopa. A levodopa rescue and were followed
2-year analysis supported the initial thereafter with UPDRS scores. Despite
findings of the study. However, accounting for wash-in and washduring an open-label extension of the out effects of selegiline, the patients
DATATOP study, patients who originally receiving selegiline required levodopa
received
selegiline
demonstrated rescue later than those receiving
no significant difference in their placebo (12.7 vs 8.6months), again
31
32
Swedish
Parkinson Study
Group (1998)
TEMPO (2004,
2009)
Selegiline
Rasagiline
1176
404
157
Rasagiline 1
or 2mg/day
(earlystart)
Rasagiline 1
or 2mg/day
(delayedstart)
Rasagiline 1
or 2mg/day
(earlystart)
Rasagiline 2mg/day
(delayed start)
Selegiline
10mg/day
Selegiline
10mg/day
Selegiline
10mg/day
Tocopherol
2000IU/day
Selegiline
10mg/day
Dose
IU: Intrauterine; UPDRS: Unified Parkinsons Disease Rating Scale.
ADAGIO (2009)
52
Myllyl etal.
(1992)
Selegiline
Rasagiline
800
DATATOP (1996)
Selegiline
54
Tetrud and
Langston (1989)
Selegiline
Study (year)
Drug
All three primary, hierarchical end points met after

72weeks in 1mg/day early-start group versus
delayed start, suggesting disease modification,
while 2mg/day early versus delayed start did not
meet all three hierarchical criteria
At week36, rasagiline 1 and 2mg/day significantly
improved total UPDRS scores versus placebo
(secondary end point)
Significantly less functional decline as measured

by UPDRS scores and significant improvement in
quality-of-life scores with rasagiline versus placebo
Less functional decline as measured by UPDRS
scores with early- versus delayed-start rasagiline
Slower rate of progression of clinical disability

as measured by UPDRS scores; delayed need for
levodopa
Less disability as measured by various rating scales;

delayed need for levodopa
Slower rate of decline in UPDRS scores; delayed

need for levodopa
Extension of trial revealed initial advantages of
selegiline were not sustained
Slower clinical disease progression as measured by

various scales; delayed need for levodopa
Observations
Table2.2. Clinical trials assessing monoamine oxidase B inhibitor monotherapy in early

Parkinsonsdisease.
[42]
[39,
40]
[36]
[35]
[37]
[34]
Ref.
Elmer & Hauser

suggesting a disease-modifying effect
of selegiline.
Rasagiline
The efficacy of rasagiline monotherapy
in early PD has been evaluated in two
delayed-start clinical trials (Table2.2) ,
TEMPO [3941] and ADAGIO [42] . In
the TEMPO study, 404patients were
randomized to three groups placebo
for 6months followed by rasagiline
2mg/day for 6months or rasagiline
1 or 2mg/day for 12months [39,40] .
At 6months (26weeks), rasagiline, 1
or 2mg/day, resulted in less disability,
as indicated by lower UPDRS scores,
and greater improvements in qualityof-life scores than placebo [41] . At
1year, patients who initially received
rasagiline (1 or 2mg/day) from the
beginning of the trial (early start group)
had less functional decline (smaller
change from baseline in UPDRS scores)
than those who received rasagiline
for only 6months. The difference in
outcome at 1year between the earlystart versus delayed-start groups did
not appear to be caused by a simple
symptomatic benefit alone, suggesting
a disease-modifying effect of longer
treatment with rasagiline [39] . In a
long-term,
open-label,
extension
study of these patients, followed
with total UPDRS scores, early-start
rasagiline resulted in significantly less
worsening of PD symptoms for up to
5.5years compared with delayed-start
rasagiline (Figure2.1) [40] . Over the
entire 6.5years of observation, the

mean adjusted difference in change
from baseline in total UPDRS scores
was significant in favor of early-start
rasagiline (2.5units; p=0.021) [40] .
In the ADAGIO trial, 1176patients with
early PD were randomized to treatment
with rasagiline 1 or 2mg/day for
72weeks (early start) or placebo for
36weeks followed by rasagiline 1
or 2mg/day for 36weeks (delayed
start). Changes in UPDRS scores over
the course of the study are depicted
in Figure 2.2. Comparison of the
1mg/day early-start and delayedtreatment groups found that subjects
treated with rasagiline 1mg/day for
72weeks (early start) met all three
hierarchical end points comprising
the primary outcome (i.e., superiority
of slope between weeks12 and 36;
superiority in change from baseline to
week72; and noninferiority of slope
during weeks4872). Comparison of
the 2mg/day early start and delayed
treatment groups found that subjects
treated with rasagiline 2mg/day for
72weeks (early start) met only two of
the three hierarchical end points. For
rasagiline 2mg/day early start versus
delayed start comparison, the end
points for superiority of slope between
weeks12 and 36 and noninferiority
of slope during weeks4872 were
met. However, assessment of change
from baseline to week72 did not
reveal significant differences between
these groups.
33
Elmer & Hauser
Mean percentage change in total UPDRS
Improvement
90
*
80
*
70
60
50
40
30
**
20
10
0
0.0
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0
(404) (378) (324) (285) (272) (254) (237) (222) (206) (197) (164) (106)
Time (years)
* p < 0.05
Rasagiline delayed-start group
** p < 0.0001
Rasagiline early-start group
Figure2.1. Mean percentage change from TEMPO baseline in total Unified

Parkinsons Disease Rating Scale scores; early-start versus delayed-start
with rasagiline. Numbers in brackets indicate subjects.
UPDRS: Unified Parkinsons Disease Rating Scale.
Adapted with permission from [50].
Post hoc analysis of differences

between the treatment arms involving
patients in the upper quartile with
respect to severity of symptoms at
baseline (i.e.,UPDRS score >25.5) was
performed as part of the ADAGIO
study [42] . In the 2mg/day group,
subjects with baseline UPDRS scores
in the upper quartile had significantly
less progression in the early- versus
delayed-start groups when scores
from baseline to week72 were
34
compared with the three lower

quartiles. Additionally, data from this
analysis demonstrated that rasagiline
2mg/day met all three efficacy end
points in the quartile of patients with
the highest (worst) UPDRS scores at
baseline (>25.5). These results suggest
that patients enrolled in the ADAGIO
study may have had too little disability
to clearly distinguish between a
symptomatic and a disease-modifying
effect, particularly with respect to the

A
Delayed start
(placeborasagiline)
4
Mean change in
UPDRS score (points)
Improvement
Worsening
3
2
1
0
-1
Early start
(rasagilinerasagiline)
-2
-3
12
24
36
42
48
54
60
66
72
Week
B
4
Mean change in
UPDRS score (points)
Improvement
Worsening
5
Delayed start
(placeborasagiline)
3
2
1
0
Early start
(rasagilinerasagiline)
-1
-2
-3
12
24
36
42
48
54
60
66
72
Week
Figure2.2. Changes in scores on the Unified Parkinsons Disease Rating

Scale in the four study groups.The mean ( standard error) change from baseline
in the UPDRS score in the efficacy cohort for the second and third primary end points for
patients receiving rasagiline at a dose of 1 mg/day (A) and those receiving 2 mg/day (B) are
shown. The dashed lines indicate placebo, and the solid lines indicate rasagiline.
UPDRS: Unified Parkinsons Disease Rating Scale.
Adapted from [42].
2mg/day rasagiline treatment arms.

The 2mg/day dose may have provided
sufficient symptomatic improvement
to mask a potential disease-modifying
effect of this dose.
As a therapeutic group, the delayed

functional decline and long-term
benefits observed with early selegiline
and rasagiline treatment may support
a potential disease-modifying effect
35
Elmer & Hauser

Clinical diagnosis of early PD
Follow
clinically
Education
Exercise
Symptoms
non-troublesome
Symptoms
mildly
troublesome
Symptoms
worsen
Consider dopaminergic
replacement
Symptoms
moderately
troublesome
Consider rasagiline or selegiline
Symptoms persist
and/or worsen
Younger and/or
without cognitive
impairment
Initiate or add-on
dopamine agonists
Older and/or
with cognitive
impairment
Symptoms
worsen
Initiate or add-on
levodopa
Symptoms
worsen
Consider DBS, levodopa

gel infusion or
apopmorphine infusion
Symptoms
worsen
Consider adjunctive
COMT inhibitor
Symptoms
worsen
Consider MAO-BI
and/or DA therapy if
not previously initiated
Figure 2.3. Proposed algorithm for early treatment of Parkinsons disease.

COMT: Catechol-O-methyltransferase; DA: Dopamine agonist; DBS: Deep-brain stimulation;
MAO-BI: Monoamine oxidase type B inhibition; PD: Parkinsons disease.
of these MAO-B inhibitors. Longterm results of the ADAGIO trial may

provide further evidence of rasagilines
potential for disease modification.
These medications require further
study to understand their potential
long-term benefits. If they do provide
disease-modifying effects, benefits
would be anticipated in a range of
clinical outcomes, including cognition
and balance, symptoms that are not likely
to be very amenable to symptomatic
dopaminergic effects. The development
of a validated biomarker of PD disease
36
status would also be extremely useful,

particularly if the biomarker is sensitive
and specific enough to reliably identify
patients with PD in very early stages of
the disease, even in the prodromal phase,
as this population would be ideally
targeted for future neuroprotective or
disease-modifying therapies [43,44] .

other treatments
Numerous other compounds have
been tested to date as potential

disease-modifying
treatments
for
PD other than MAO-B inhibitors,
including
THC-346,
pramipexole,
ropinirole,
levodopa,
tocopherol,
CoQ10,
mitoquinone,
creatine,
CEP-1347,
immunophilin,
GDNF,
paliroden, GM1 ganglioside, riluzole
and minocycline [44,45] . With few
exceptions, most of these treatments
have not demonstrated clear evidence
of slowing disease progression in PD.
Conclusion
PD is a neurodegenerative disorder
manifested by a variety of motor and
non-motor symptoms. Although the
motor symptoms initially respond well
to pharmacologic therapies, primarily levodopa, DAs and MAO-B inhibitors, no current PD therapy definitively
slows disease progression. However,
studies involving the MAO-B inhibitors have provided controversial and
provocative results, suggesting the
possibility that these agents may slow
PD progression. Further trials, perhaps
including the use of diagnostic and
progression biomarkers, novel protocol designs and pathogenesis-targeted
therapies, will hopefully be able to
demonstrate a favorable effect on the
natural history of PD.
Early treatment of PD:

proposed algorithm
As demonstrated in the algorithm shown
in Figure2.3, exercise has emerged as
an integral part of PD therapy. While

included in the longitudinal treatment
early in this diagram, increasing evidence
suggests that exercise may potentially
slow progression of PD and/or ameliorate
symptoms such as gait and balance
disturbances through mechanisms
distinct and possibly complementary
to pharmacological options during all
stages of the disease [4648] .

disclosure
LW Elmer has received honoraria or
payments for consulting, advisory
services,
speaking
services
or
unrestricted educational grants from
Lundbeck, Teva Neuroscience and
UCB Inc. RA Hauser has received
honoraria or payments for consulting,
advisory services, speaking services
over the past 12months as listed
below:
Abbott
Laboratories,
Allergan Inc., AstraZeneca, Biotie
Therapies Corporation, Ceregene
Inc., Chelsea Therapeutics Inc., GE
Healthcare,
Impax
Laboratories
Inc., Ipsen Biopharmaceuticals Inc.,
Lundbeck,
Med-IQ,
Merck/MSD,
Noven Pharmaceuticals Inc., Straken
Pharmaceuticals, Ltd, Targacept Inc.,
Teva Pharmaceuticals Industries, Ltd,
Teva Neuroscience Inc., Upsher-Smith
Laboratories, UCB Inc., UCB Pharma
SA and Xenoport Inc. RA Hausers
institution has received research
support over the past 12months as
listed below: Abbot Laboratories,
37
Elmer & Hauser

Addex Therapeutics, Allergan Inc.,
AstraZeneca, Chelsea Therapeutics
Inc., GE Healthcare, Impax Laboratories
Inc., Ipsen Biopharmaceuticals Inc.,
Merck/MSD, Merz, Michael J Fox
Foundation for Parkinsons Research,
Schering-Plough, Teva Neuroscience
Inc., UCB Inc. and Vita-Pharm. RA
Hauser has received royalties in the
last 12months from the University
of South Florida. In addition, RA
Hauser has consulted in litigation with
lawyers representing various current
and former manufacturers of welding

consumables.
The authors have no other 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 apart from
those disclosed.
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1.
2.
3.
4.
5.
Parkinsons disease (PD) may be characterized early by the following

clinical features:
a.
Rest tremor
b.
Bradykinesia
c.
Rigidity
d.
All of the above
Selegiline and rasagiline are members of which class of compounds:
a.
Dopamine agonists
b.
Monoamine oxidase type B inhibitors
c.
Dopamine precursors
d.
Anticholinergic agents
Levodopa usage in PD has been associated with the development of:
a.
Motor fluctuations
b.
Dyskinesias
c.
a&b
d.
None of the above
Dopamine agonists may have the following complicating side
effects:
a.
Impulse control disorders
b.
Excessive daytime somnolence
c.
Confusion and/or hallucinations
d.
All of the above
a.
Has been demonstrated with anticholinergic therapies
b.
Remains a challenging and critically important unmet need
c.
May be followed by well-established biomarkers
d.
Can be regarded as insignificant and/or irrelevant in PD
41
CHAPTER
3
Prevention and
management of
levodopa-related motor
complications
Cara A Pecina & Alberto J Espay
Contents
Primarily off state motor complications
47
Primarily on state motor complications
49
Intermediary or transitional state motor complications
52
Surgical intervention & future strategies
52
doi:10.2217/EBO.13.84
43
Pecina & Espay
About the authors

Cara A Pecina
Cara A Pecina is a Fellow in the Department of Neurology, Gardner Family Center for Parkinsons Disease and Movement Disorders, at the University of
Cincinnati (OH, USA).
Alberto J Espay
Alberto J Espay is an Associate Professor of Neurology in the Department of Neurology, Gardner Family Center for Parkinsons Disease and Movement Disorders, at the University of Cincinnati. He has been
lead investigator in many single- and multi-site clinical trials examining treatments for motor complications in Parkinsons disease. He received the Deans
Scholar in Clinical Research Award by the University
of Cincinnati (20062009), the NIH-funded KL2 Research Scholars Mentored Award (20102012) and K23Career Development Award (20112016).
44
Prevention & management of levodopa-related motor complications
Learning points
Off state motor complications can generally be alleviated

by raising the dose or increasing the frequency of levodopa
administration.
Transitional diphasic dyskinesias most commonly appear as
choreiform or ballistic movements of the lower limbs and arise during the transition between on and off states. They can generally
be improved by raising the dose of dopaminergic medications or
increasing their frequency of administration.
Peak-dose dyskinesias can be managed by decreasing the overall
dosage of dopaminergic medications or by adding amantadine.
Off state focal dystonia that is painful and does not respond
to increases in dopaminergic medications can be treated with
botulinum toxin injections.
Summary
Levodopa-related motor complications are common sources
of disability in Parkinsons disease patients. By identifying
whether these complications are occurring in the off,
intermediary, or on state, clinicians can best determine
which treatment strategy to employ. Off state motor
fluctuations as well as diphasic dyskinesias can generally be
alleviated by raising the dose of levodopa or by increasing its
frequency of administration. Peak-dose dyskinesias, the most
common on state motor complication, can be managed by
decreasing the overall dosage of dopaminergic medications.
However, if parkinsonian symptoms preclude a dosing
decrease, amantadine should be considered, with clozapine
as a potential second-line approach. When delayed-ons or
dose-failures are present, particularly when present early
in the course of the disease, the clinician should counsel
on the avoidance of concurrent intake of levodopa with
dietary proteins and consider evaluating these patients for
gastroparesis or Helicobacterpylori gastritis. If medication
45
Pecina & Espay

adjustments fail to control motor complications or come
at the cost of worsening parkinsonian symptoms, surgical
intervention with globus pallidus interna or subthalamic
nucleus deep-brain stimulation should be considered.
The management of levodopa-related
motor complications in Parkinsons
disease (PD) is one of the major
challenges for both patients and treat
ing neurologists. These range from
peak-dose or on complications (e.g.,
peak-dose dyskinesias) to transitional
and off complications (e.g., freezing
of gait [FOG]) and limit efforts at
optimizing motor function due to
increases in the risk/benefit ratio, which
compromises the net therapeutic gain.
An important reason for these motor
complications is the short plasma halflife of levodopa, which is approximately
90min (less than 3h). This shortcoming
challenges the physiologic demand for
tonic rather than phasic stimulation
of striatal dopamine receptors, a pro
cess that becomes accentuated by
the progressive loss of the buffering
capacity of degenerating nigrostriatal
neurons, which decarboxylate levodopa

into dopamine. The practical implication
is that patients may be undertreated in
efforts to avoid peak-dose complications
or be overtreated to minimize offrelated complications[1,2] . Judicious
adjustments in levodopa dose and other
dopaminergic medications are critical
to manage the PD symptoms as well
as the common motor complications.
The purpose of this chapter is to aid the
reader in identifying and treating the
various types of levodopa-related motor
complications and to discuss ongoing
research into treatment strategies that
have shown promise in preventing
these complications from developing.
The frequency of motor complications
in PD is estimated to be approximately
40% by 46years of levodopa therapy,
although some studies report an even
Peak-dose dyskinesia: stereotypic, choreic or ballistic movements

most commonly seen in the upper limbs, head and trunk occurring
when plasma concentrations of levodopa are at supratherapeutic
levels.
Freezing of gait: brief episodes characterized by the inability to take a step as
if the feet were glued to the floor, typically occurring on gait initiation, when
turning, navigating crowded spaces, or when dual tasking (e.g., talking while
walking). Freezing of gait may be immediately preceded by a hastening or
festinating gait, recognized when an increase in cadence (number of steps per
min) occur at the expense of progressively shortening stride length (distance
between steps).
46

higher prevalence [3] . Risk factors for
the development of levodopa-related
motor complications include younger
age of disease onset (<50years), longer
duration of disease, longer cumulative
exposure to levodopa and higher
levodopa dosage (>600mg/day) [4,5] .
Levodopa-induced motor complications
can be divided into dyskinesias
and motor fluctuations. Peak-dose
levodopa-induced dyskinesia (LID) is
the most important on-related motor
complication. Motor fluctuations in
clude diphasic dyskinesia, dystonia,
predictable wearing-off, random or
sudden offs, delayed ons, dose failures
and FOG. However, for management
purposes, we will separate motor
complications into the clinical states
in which they typically occur: primarily
off state, primarily on state and
intermediary or transitional state.
Primarily off state motor

complications
Under normal physiologic circumstances, the putaminal dopamine
receptors are stimulated in a constant
or tonic fashion. Early on in the disease course there are a sufficient number of nigro
striatal neurons capable
of continuously generating, storing
and releasing dopamine from endogenous and exogenous levodopa. As
the disease progresses and nigrostriatal neurons degenerate, this buffering capacity diminishes, resulting in
phasic or pulsatile stimulation of the
putaminal dopamine receptors. This,
in combination with the short half-life
of levodopa, leads to shorter on periods followed by increasingly frequent
wearing-off periods, which occur
when levodopa levels fall below the
therapeutic threshold, leading to the
clinical re-emergence of parkinsonian
features (e.g., tremor, bradykin
esia,
rigidity, freezing and akathisia)[6,7] .
The progressive reduction in the on
periods can be managed by raising
the individual doses of levodopa or
increasing its frequency of administration [8] . Another treatment option
for wearing off is adding a medication that reduces the breakdown
of levodopa and/or dopamine, such
as a catechol-O-methyltransferase
Diphasic dyskinesia: choreiform or ballistic movements most

commonly of the lower limbs that arise during the transition
between on and off states.
Dystonia: abnormal posturing or jerky, irregular tremor, or both,
due to sustained muscle contractions of antagonistic muscle groups. Dystonia
associated with Parkinsons disease is focal or segmental and often occurs in the
most affected foot during the off state, but might also be a manifestation, often
in the hand or cervical region, in transitional or on states.
47
Pecina & Espay

(COMT) inhibitor (entacapone or tolcapone) or an monoamine oxidase
(MAO)-B inhibitor (selegiline or rasagiline) [9,10] . If not previously given,
adding a dopamine agonist to a regimen of levodopa may extend the on
periods and reduce the length or
depth of wearing-off episodes.
Despite optimal medication regimens
patients can have unpredictable or
sudden offs that have no relation to
the timing of levodopa administration
and can occur at times when the
patient expects the medication to be
most beneficial [8] . Patients can also
have delayed-ons or dose-failures
in which the medication takes longer
than usual to kick-in or does not kick-in
at all. This can be caused by blocked
absorption of the medication due to
competition with protein for transport
into the gut if the patient has consumed
a high protein meal [11] . Unpredictable
or delayed gastric emptying is a nonmotor complication that can cause or
compound this phenomenon [7] . A
simple strategy to minimize delayedons or dose failures is to instruct
the patient to take levodopa no later
than 30min before and no earlier
than 90min after meals. For sudden
or unpredictable offs patients can
use subcutaneous apomorphine for
rescue therapy. Apomorphine is a
rapid-onset (within 5min) but shortlasting (average: 75min) dopamine
agonist equipotent to levodopa,
but only available for parenteral
48
administration. Patients using apo

morphine should be pretreated with
300-mg trimethobenzamide threetimes daily for the first 2months of use
to prevent nausea and vomiting.
Another common motor complication
in the off-state is dystonia, manifested
most frequently as flexion of the foot
and second through fifth toes with
extension of the big toe on the most
affected side [12] . In young-onset PD it
is commonly seen early in the course of
the disease and is thought to be due to
abnormal firing of the globus pallidus
with underactivity of the D2-mediated
striatal output to the globus pallidus
externa [4,12,13] . Patients recognize
this complication by complaining of
painful foot cramps at night or in the
early morning when levodopa levels
are at a trough [6] . When seen in
the off state, dystonia is treated by
increasing the dose of levodopa or
preventing its breakdown with the
aforementioned COMT and MAO-B
inhibitors. Another consideration,
particularly for early morning dystonia,
is using a controlled release formulation
of levodopa or baclofen at bedtime.
Botulinum toxin injection may also be
considered for painful focal dystonias
remaining refractory to dopaminergic
dose manipulations [14] . Dystonia can
also be seen in the dyskinetic on
state, in which case it tends to be more
prominent in the most affected hand
or in the craniocervical region. Since
this on dystonia would be worsened

by the approach to the more common
off dystonia, it behooves the clinician
to attend to the temporal relationship
between this (and, for that matter, any)
motor complication and the dose cycle.
An unusual dyskinetic pattern may be
seen in patients suspected as having
PD, whereby a levodopa-induced
dystonia occurs in the oromandibular
region (yielding a risus sardonicus
appearance), often in conjunction
with choreiform movements of the
feet. In this situation, especially if this
pattern emerges as an early motor
complication, one should consider the
alternative diagnosis of multiple system
atrophy [15] .
FOG is arguably the most disabling
potential motor complication of the
off-state, becoming an important
source of falls and disability for
patients. This episodic complication is
characterized by the patients sudden
inability to lift their feet off the ground
to initiate or resume walking, often
during gait initiation, turning, stepping
through narrow passages or dual
tasking. One nonpharmacological
approach to the management of FOG
is instructing patients to use sensory
cues, such as placing strips of tape
on the floor at home in locations they
usually experience freezing. Similarly
helpful are canes or walkers that project
a red laser light onto the floor, which
the patient can then step over[16] .
Promising virtual reality devices have
also been under evaluation [17] .
Pharmacologic interventions to address

FOG are based on increasing levodopa
to doses as high as 20002500mg/day,
as tolerated. However, as the disease
progresses this phenomenon becomes
harder to treat and does not respond
as well to dopaminergic medications or
surgical intervention relative to other
off state features [18] . There are also
patients who have FOG primarily in the
on state, which can be more difficult
to manage as decreasing dopaminergic
medications will generally worsen
other parkinsonian symptoms. In
rare circumstances, this complication
may actually be induced or worsened
by levodopa in a dose-dependent
manner [19] . It has been speculated
that FOG may be the result of an
imbalance between dopaminergic
and noradrenergic pathways due to
degeneration of the locus ceruleus.
Several studies have examined the value
of raising noradrenergic concentrations
with methylphenidate in patients with
FOG, with varying results [2022] .
Primarily on state motor

complications
The most common on state levodoparelated motor complication is peak-dose
dyskinesia, consisting of stereotypic,
choreic or ballistic movements most
commonly seen in the upper limbs,
head and trunk [6] . The ascertainment
of the topographical distribution
of dyskinetic patterns is helpful in
distinguishing peak-dose LIDs from
49
Pecina & Espay

other motor phenomena (Figure3.1).
While the exact mechanisms underlying
the production of dyskinesias have
yet to be fully elucidated, it results
in part from pulsatile dopaminergic
stimulation of putaminal dopamine
receptors from the combination of a
short-acting levodopa and nigrostriatal
denervation. Preservation of the
putaminal neurons is critical for the
generation of dyskinesias, and the
reason why the typical upper-body
levodopa-induced chorea is not a
feature of atypical parkinsonisms
(with the distinct exception of multiple
system atrophy, as noted above).
Dyskinesias are ultimately heralded
by an increased striatal output to
the globus pallidus interna (GPi) and
substantia nigra reticulata [23] .
There is evidence to support starting a
dopamine agonist as initial therapy rather
than levodopa to prevent dyskinesias,
especially in younger individuals who are
more susceptible to the development
of this complication[24,25] . However,
progressively dwindling efficacy and
increasing incidence of side effects
(namely, leg edema, hallucinations,
excessive daytime sleepiness and
im
pulse control disorders) render
dopamine agonists untenable as mono
therapy in the long term. In a large
study of patients initially receiving
levodopa versus pramipexole it was
found that while dyskinesias were
more common in the levodopa group
moderate to severe dyskinesias were
50
equivalent in both groups as was quality

of life [26] . It is important to emphasize
that early initiation of dopamine agonist
therapy does not protect against the
development of dyskinesias once levo
dopa is started [27,28] . Indeed, next to
young age at onset, disease duration
has emerged as a major predictor
of LIDs. Patients often develop this
complication within months, when
levodopa has been delayed for 5years
or more, suggesting that the clock for
dyskinesia onset begins to tick with
disease onset, well before initiation of
levodopa treatment (which is ultimately
required).
To minimize the severity and impact
of dyskinesias, clinicians could elect to
lower individual dosage of levodopa,
in an effort to prevent high maximum
concentration in levodopa plasma
concentrations, which may come at the
cost of worsening other parkinsonian
symptoms. Alternatively, the NMDAantagonist amantadine at 100mg
one- to three-times daily can be added
to decrease LIDs [2931] . Clinicians
must be aware of the potential for
amantadine to induce psychosis (mainly,
visual hallucinations and paranoia),
cognitive impairment, myoclonus,
livedo reticularis and ankle edema, any
of which may warrant drug cessation.
Clozapine has also been shown in a
randomized, double-blind, placebocontrolled trial to reduce the duration
and severity of LIDs without worsening
parkinsonian features [32] . The caveats
Chorea
B Peak dose
C Diphasic
D Off dystonia
E Advanced PD
F Atypical (MSA)
onset of disease is assumed for all cases. (A) Peak-dose levodopa-induced dyskinesias tend to involve the upper trunk, neck and arms,
particularly on the more affected side. (B) Hemidyskinesia with arm-greater-than-leg involvement can also be a manifestation of peakdose dyskinesias, especially among young-onset PD patients. (C) Diphasic dyskinesias predominantly affect the legs, while relatively
sparing the trunk, neck and arms. (D) Unilateral foot dystonia on the more affected side is the typical manifestation of off dystonia.
(E)Facial choreathetotic movements and hand posturing may occur in advanced PD patients. (F) Facial dystonia with feet dyskinesias are
a topographical distribution atypical for PD and suggestive of MSA.
Darker gray emphasizes greater severity.

MSA: Multiple system atrophy; PD: Parkinsons disease.
Figure by Martha Headworth, University of Cincinnati Neuroscience Institute. Adapted with permission from [12].
Figure 3.1. Typical topographic patterns among various forms of dyskinesia in Parkinsons disease. Right-sided
Dystonia
A Peak dose
51
Pecina & Espay

are that clozapine is not as effective
for the action-induced component
of dyskinesias (which may be most
disabling) and its use requires frequent
blood counts to monitor for the rare risk
of agranulocytosis. Finally, for patients
whose dyskinesias remain troublesome
despite exhausting the medication
adjustments suggested above, surgical
intervention with subthalamic nucleus
(STN) or GPi deep-brain stimulation
(DBS) is an option. STN DBS allows for
a decrease in levodopa dose, which
substantially
reduces
dyskinesias,
whereas GPi DBS yields a direct
antidyskinetic effect, independent of
dopaminergic dose reduction (see also
Chapter6 on Surgical Treatment of
PD). It is important to keep in mind that
dyskinesias do not always need to be
treated, as patients are often unaware
of or unimpaired by these movements.
In fact, LIDs are not major drivers of
quality of life in PD [2,33] .
Intermediary or transitional
state motor complications
Intermediary state motor complications
generally occur when levodopa is
near the therapeutic threshold and
is either kicking-in or wearing-off.
Diphasic dyskinesias are perhaps the
most common transitional motor
phenomenon. In contrast to peak-dose
dyskinesias, diphasic dyskinesias most
commonly appear as choreiform or
ballistic movements of the lower limbs
during the transition between on and
52
off states. Unlike the aforementioned

management for peak-dose dyskinesias,
diphasic dyskinesias warrant an increase
in the dose of levodopa or a shortening
of the interdose interval in order to
reduce off periods and the transitions
between on and off states. Another
intermediary motor complication is yoyoing, described as rapid fluctuations
between on and off states when
cerebral dopamine levels hover around
the therapeutic threshold. The approach
to the treat
ment is similar to that of
diphasic dyskinesias, although these
patients may also need to be evaluated
for gastroparesis and Helicobacter
pylori gastric infection in order to
improve levodopa pharmacokinetics. As
these complications can be associated
with poor or erratic absorption due
to proteinprotein interaction, it
is important to educate patients
regarding the need to avoid the intake
of levodopa during mealtimes as
mentioned earlier [12] .
Surgical intervention &

future strategies
As briefly mentioned, when motor
complications cannot be adequately
controlled by pharmacological meas
ures, DBS of the STN or GPi can provide
substantial benefits in decreasing
daily off time and dyskinesias [34,35]
(see also Chapter6 on Surgical
Treatment of PD). GPi DBS has a direct
antidyskinetic effect while the reduction
in dyskinesias in STN DBS is largely

due to the postoperative reduction in
dopaminergic medications [3638] .
While gait can improve after DBS, FOG
has not been shown to improve to the
extent of other off state features and
the benefits that may occur tend to be
short lived [18] . DBS for on state FOG
has not been shown to be effective,
although it may allow the reduction
of dopaminergic medications without
worsening other parkinsonian features.
It is important to note that PD patients
are candidates for DBS if their response
to levodopa remains excellent (even if
for brief periods within each dose cycle),
their cognitive function is preserved,
and any psychiatric complication is
controlled.
double-blind trial of a novel sustained

release formulation of levodopa,
IXP066, patients with fluctuating PD
treated with IXP066had a decrease in
dose frequency (from five- to 3.5-times
per day), a 1.2h reduction in the off
time, and a 1.9h gain in on time without
troublesome dyskinesias compared
with the standard immediate-release
carbidopa/levodopa group (Rytary
[Impax, CA, USA] under FDA review
at time of press) [40,41] . XP21279 is
another investigational sustainedrelease formulation of levodopa
that appears to be associated with
significantly less variability in levodopa
concentration compared with standard
levodopa [42] .
Efforts have been made to prevent

the initial development of motor
complications. As stated, a large body
of evidence supports the combined
loss of nigrostriatal neurons in the
setting of pulsatile stimulation of
dopamine receptors as underlying the
generation of motor complications.
Hence,
sustained
dopaminergic
stim
ulation of dopamine receptors
through
long-acting
formulations
or continuous levodopa delivery has
become the focus of recent research.
Administration of levodopa/carbidopa/
entacapone
(Stalevo,
Novartis,
Switzerland) four-times daily failed to
prevent the development of motor
complications [39] , probably because
of insufficient continuity of levodopa
delivery. In a PhaseIII randomized,
Continuous levodopa delivery has

been achieved by infusing levodopa/
carbidopa intestinal gel intraduodenally
via a percutaneous endoscopic gastro
stomy tube connected to an infusion
pump. Several studies have shown
marked reductions in daily off time as
well as reduced severity of pre-existing
LID (LCIG; Duopa, under FDA review at
time of press) [4347] .
Clinical trials examining the role

of apomorphine for early morning
akinesia and, ultimately as a con
tinuous subcutaneous delivery pump
(already available in Europe), are
planned for 2013 in the USA. There
are also ongoing investigations into
new forms of MAO-B and COMT
inhibitors that may prove to be useful
53
Pecina & Espay

adjuncts to levodopa in the future.
Safinamide is a novel reversible MAO-B
inhibitor with additional mechanisms
of action, including glutamate release
inhibition and activity dependent
sodium channel antagonism that has
been evaluated as a potential adjunct
to dopamine agonists or levodopa
in early and advanced PD. PhaseIII
trials have shown promising results
in increasing daily on time (MOTION:
ClinicalTrials
NCT01028586
and
NCT00605683, SETTLE: ClinicalTrials
NCT00627640). BIA 9-1067 is a highly
potent, peripherally acting COMT
inhibitor with a long half-life that is
currently undergoing PhaseIII studies
to determine efficacy in reducing
daily off time (BIPARKII: ClinicalTrials
NCT01227655) [48] .
Several
nondopaminergic
neuro
transmitter systems have been implicated in the development of motor
complications, including pathways
involving glutamate, serotonin, noradrenaline, adenosine, opioids, cannabinoids and histamine.
The adenosine A2a receptor subtype
is highly expressed in the basal
ganglia and its activation in PD leads
to overactivity of the indirect pathway
causing parkinsonism. This receptor
has thus been an attractive target
for emerging therapies in PD. Results
from a PhaseIIb study evaluating the
adenosine A2a antagonist tozadenant
(SYN115) showed a statistically
54
significant decrease in off time versus

placebo as well as an increase in on
time and an improved score in Unified
Parkinsons Disease Rating Scale
(UPDRS) partIII and UPDRS parts IIII
combined [101] . Full data from the study
are to be released in the near future.
Several glutamate receptors have been
implicated in the development of LIDs;
however, only amantadine, a weak
NMDA receptor antagonist, is currently
available on the market. AFQ056,
a mGluR5 receptor antagonist, has
shown significant reductions in dyski
nesias as assessed by the modified
abnormal involuntary movement scale
compared with placebo and significant
reductions in the UPDRS IV item32
(dyskinesia severity) in PhaseIIb
studies [49,50] . Similarly, dipraglurant,
a negative allosteric modulator
of the mGlu5 receptor, showed
antidyskinetic effects in animal models
of PD and is currently undergoing
further investigation (ClinicalTrials:
NCT01336088). In addition, stim
ulating nicotinic a7 receptors may
yet prove beneficial for the treatment
of motor com
plications (wearingoff and dyskin
esias, respectively;
ClinicalTrials: NCT01474421). Likewise,
serotonin 5-HT1A receptor agonists
have recently been evaluated as a
potential target to reduce dyskinesias
based on histopathological findings of
increased serotonin innervation density
in animal models as well as human PD
cases [51,52] . Improved understanding
of the mechanisms of motor fluctuations

and dyskinesias, coupled with advances
in pharmacology, should lead to novel
approaches to these levodopa-related
complications[53,54] .

disclosure
AJ Espay is supported by the K23
career development award (NIMH,
1K23MH092735); has received grant
support from CleveMed/Great Lakes
Neurotechnologies,
Davis
Phinney Foundation and Michael J Fox
Foundation; personal compensation as
a consultant/scientific advisory board
member for Solvay (now Abbott),

Chelsea Therapeutics, TEVA, Impax,
Merz, Solstice Neurosciences and Eli
Lilly; and honoraria from Novartis, the
American Academy of Neurology and
the Movement Disorders Society. The
authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial
subject matter or materials discussed
in the manuscript apart from those
disclosed.
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Actively transported levodopa prodrug
XP21279: a study in patients with
Parkinson disease who experience motor
fluctuations. Clin. Neuropharmacol.
35(3), 103110 (2012).
34. Kleiner-Fisman G, Herzog J, Fisman DN

etal. Subthalamic nucleus deep brain
stimulation: summary and meta-analysis
of outcomes. Mov. Disord. 21(14),
S290S304 (2006).
43. Fernandez HH, Vanagunas A, Odin P

etal. Levodopa-carbidopa intestinal gel
in advanced Parkinsons disease openlabel study: interim results. Park. Relat.
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35. Weaver FM, Follett KA, Stern M et

al. Randomized trial of deep brain
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5565 (2012).
44. Fernandez HH, Odin P. Levodopacarbidopa intestinal gel for treatment of

advanced Parkinsons disease. Curr. Med.
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36. Kumar R, Lang AE, Rodriguez-Oroz

MC etal. Deep brain stimulation of
the globus pallidus pars interna in
advanced Parkinsons disease. Neurology
55(Suppl.6), S34S39 (2000).
45. Nyholm D, Nilsson Remahl AI, Dizdar

N etal. Duodenal levodopa infusion
monotherapyvs oral polypharmacy in
advanced Parkinson disease. Neurology
64(2), 216223 (2005).
37. Lyons KE, Wilkinson S, Trster AI,

Pahwa R. Long-term efficacy of globus
pallidus stimulation for the treatment
of Parkinsons disease. Sterotact. Funct.
Neurosurg. 79(34), 214220 (2002).
46. Stocchi F, Vacca L, Ruggieri S, Olanow

CW. Intermittent vs continuous levodopa
administration in patients with advanced
Parkinson disease: a clinical and
pharmacokinetic study. Arch. Neurol.
62(6), 905910 (2005).
38. Rodriguez-Oroz MC, Obeso JA, Lang AE

etal. Bilateral deep brain stimulation in
47. OlanowCW, AntoniniA, KieburtzK

etal. Randomized, double-blind, double-
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Pecina & Espay

dummy study of continuous infusion
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Discovery of a long-acting, peripherally
selective inhibitor of catechol-Omethyltransferase. J.Med. Chem. 53(8),
33963411 (2010).
49. Berg D, Godau J, Trenkwalder C etal.
AFQ056 treatment of levodopa induced
dyskinesias: results of 2 randomized
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12431250 (2011).
50. Stocchi F, Destee A, Hattori N etal.
A 13week, double-blind, placebo
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antagonist in Parkinsons disease patients
with moderate-to-severe L-dopa induced
dyskinesias. Mov. Disord. 24(Suppl. 1),
S6S7 (2011).
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etal. Maladaptive plasticity of serotonin
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underlying the onset and expression
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Website
101. Biotie Therapies.
www.biotie.com/en/investors/releases/
release?NewsItemID=

1.
2.
3.
4.
Risk factors for the development of levodopa-related motor

complications include which of the following?
a.
Younger age of disease onset (<50years)
b.
Longer duration of disease
c.
Longer cumulative exposure to levodopa
d.
Higher levodopa dosage (>600mg/day)
e.
b, c & d
f.
All of the above
When occurring in the off state, dystonia can be treated by
which of the following?
a.
Increasing levodopa dose
b.
Adding a COMT inhibitor
c.
Botulinum toxin injections
d.
Adding amantadine
e.
a, b & c
f.
All of the above
Sudden offs can be treated acutely by which of the following?
a.
Amantadine
b.
Selegiline
c.
Apomorphine
d.
Entacapone
e.
None of the above
Diphasic dyskinesias in general:
a.
Involve the trunk and upper extremities
b.
Can be treated by lowering the dose of levodopa
c.
Can be treated by decreasing the interdose interval of
levodopa administration
d.
Are only seen in young-onset Parkinsons disease
e.
None of the above
59
Pecina & Espay
5.
60
Off state freezing of gait can be treated by which of the following:

a.
Increasing the dosage of levodopa
b.
Walking in narrow spaces
c.
Using sensory cues such as tape on the floor or canes with
laser lights
d.
a&c
e.
All of the above
f.
None of the above
CHAPTER
4
Management of
non-motor symptoms
of P
arkinsons disease
Mark Stacy
Contents
Cognitive
64
Neuropsychiatric
66
Psychosis
67
Anxiety
68
68
Autonomic
69
Sleep disorders
71
Pain & other sensory symptoms
72
Conclusion
72
doi:10.2217/EBO.13.122
61
Stacy
About the author

Mark Stacy
Mark Stacy is a Professor of Neurology, Chief of the
Movement Disorders Section and Vice Dean for Clinical Research at Duke University (NC, USA). He has
been a member of the American Academy of Neurology since 1988, and was named a Fellow in 2006.
He has been a member of the Movement Disorders
Society since 1990. He is also the Co-Editor of the
MDS Newsletter, Moving Along. He received medical
training at the University of Missouri and completed
a Movement Disorders fellowship at Baylor College of Medicine (TX,
USA). He remains an active member of a number of advisory committees including the Benign Essential Blepharospasm Foundation, International Essential Tremor Foundation, National Parkinson Foundation
and WE MOVE. He is also a member of the Dystonia Study Group, Parkinson Study Group and Tremor Study Group. Prior to moving to Duke
University, he served as the Director of the Muhammad Ali Parkinson
Research Center in Phoenix (AZ, USA). His clinical and research interests include motor and non-motor symptoms in Parkinsons disease,
and he has served as Steering Committee Chair for two International
Meetings focused on Impulse Control Disorders in Parkinsons disease.
He has served on numerous multicentered research protocol steering
committees, Drug Safety Monitoring Boards, and Pharmaceutical Company Advisory Boards. He has participated in more than 100 clinical trial initiatives and published more than 100peer-reviewed manuscripts,
50 chapters, and is the Editor of the Handbook of Dystonia.
62
Management of non-motor symptoms of PD
Learning points
After reading this chapter you will know that:
Parkinsons disease (PD) patients who develop hallucinations have

a much higher potential for development of dementia or being
placed in a nursing home setting.
Treatment of impulse control disorders almost always requires
reduction of dopaminergic therapy.
Sialorrhea, or excessive salivation, often responds to botulinum
toxin injections to the salivary glands.
Cognitive difficulties may improve with dopaminergic therapy in
the early or denovo PD patient. With advancing disease dopaminergic therapy may need to be reduced. Cholinesterase inhibitors have shown benefit in cognitively impaired PD patients in
controlled trials.
Summary
Parkinsons disease (PD) is classically characterized as a hypokinetic movement disorder, with motor features of bradykinesia, resting tremor and rigidity. The non-motor symptoms (NMS) of PD often precede better-recognized motor
features in PD but are increasingly recognized, and include
cognitive, neuropsychiatric, sleep, autonomic and sensory
disturbances. These NMS may be intrinsic to the disease pathology, and are not confined to traditional dopaminergic
pathways. For instance, cognitive disturbances are often
linked to the cholinergic neuraxis, and depression may result from alterations in the serotonergic system. In addition,
some NMS, particularly impulse control disorders or sleep
disorders, may be triggered as a result of treatment with
dopaminergic agents. Treatment may include interventions
independent of traditional, dopaminergic antiparkinson
therapy or may be tailored to increase or reduce dopamine
responsiveness of the symptom. This chapter will highlight
the importance of NMS detection in optimizing treatment
of PD patients.
63
Stacy
Depression: a decline in mood that, in Parkinsons disease, is usually
of mild-to-moderate intensity and characterized by an early loss of
initiative and self-esteem, sadness, feelings of guilt and remorse.
Parkinsons disease (PD) is typically

characterized by motor features: bradykinesia, rigidity, tremor and postural instability. However, non-motor
symptoms (NMS) often predate motor
features and have a profound impact
on the quality of life in PD patients
(Box 4.1) [1] . In a review of 1072 patients with a disease duration averaging 5.1 years, 98.6% reported at
least one NMS [2] . The most common
complaints were fatigue (58%), anxiety (56%), leg pain (38%), insomnia
(37%), urinary urgency and nocturia
(35%), excessive salivation (31.1%),
difficulty in maintaining concentration
(31%) and depression (22.5%). Another review reports that denovo patients
(97.8%) report at least one NMS, most
frequently involving neuro
psychiatric
and sleep difficulty [3] .
These findings highlight the importance of NMS detection in optimizing
treatment of PD patients. This review
will address the common cognitive,
neuropsychiatric, autonomic and sleep
disturbances in PD as well as available
treatment options.
Cognitive
Epidemiological
studies
estimate
dementia is seen in 30% of PD patients,
64
a four- to six-fold increase, compared

with the general population [4] . Risk
factors linked to the development of
PD dementia (PDD) include increasing
age (>60 years), longer disease duration and lower striatal binding on -CIT
imaging at baseline [5] . The nontremor
dominant phenotype, characterized by
pronounced postural instability and gait
disorder is also associated with a higher
incidence of cognitive decline[6] . Dementia adds substantially to the burden of disease for both the patient and
the caregiver, while increasing healthrelated costs, risks for nursing home
admission and the duration of hospital
stays[7,8] .
Early impairments include deficits in
executive function, thought to be a
result of dysfunction of the prefrontal
cortex through the corticalsubcortical loops with the basal ganglia [9] .
Measures of phonemic verbal fluency,
visual and verbal memory, visuospatial
skills, psychomotor speed, attention
and language show deficiencies [4] .
As symptoms of dementia become
apparent, semantic verbal fluency appears and recognition memory defects arise. Decline in visuospatial and
verbal memory are more prominent in
PDD than Alzheimers disease, but the
overall decline is less rapid [10] .

Box 4.1. Non-motor features of
Parkinsons disease.
Box 4.1. Non-motor features of

Parkinsons disease.
Cognitive
Mild cognitive impairment
Dementia
Isolated deficits in:
Memory
Visuospatial processing
Attention
Concept formation
Executive functions
Difficulty in:
Focusing and sustaining attention
Generating hypotheses
Planning and reasoning
Problem-solving
Concept formation
Temporal ordering of stimuli
estimation
Maintaining information in
working memory
Associative learning
Maintaining or shifting sets in response to changing task demands
Neuropsychiatric symptoms
Depression, apathy, anxiety
Anhedonia
Attention deficits
Hallucinations, illusion, delusions
Obsessional and repetitive behaviors
Dopaminergic dysregulation
syndrome
Confusion
Delirium
Panic attacks
Autonomic symptoms
Gastrointestinal symptoms
Dribbling of saliva
Ageusia
Dysphagia and choking
Reflux, vomiting
Nausea
Constipation
Unsatisfactory voiding of bowel
Fecal incontinence
Bladder disturbances
Urgency
Nocturia
Frequency
Sexual dysfunction
Hypersexuality (often drug
induced)
Erectile dysfunction
Sweating
Orthostatic hypotension
Falls related to orthostatic
hypotension
Coat-hanger pain
Dry eyes (xerostomia)
Sleep disorders
Restless legs syndrome
Periodic limb movements
Rapid eye movement sleep behavior
disorder
Excessive daytime somnolence
Vivid dreaming
Insomnia
Sleep disordered breathing
Non-rapid eye movement parasomnias (confusional wandering)
Sensory symptoms
Pain
Paraesthesia
Olfactory disturbance
Visual disturbances
Blurred vision
Diplopia
Impaired contrast-sensitivity
Other symptoms
Fatigue
Diplopia
Blurred vision
Seborrhea
Weight loss
Weight gain
Ankle edema
65
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Some cognitive difficulties, such as
executive function and memory, may
respond to dopamine-replacement
therapy (DRT) in early PD, particularly
in de novo patients, but usually this
treatment will not affect associative
learning or spatial recognition memories [11] . Despite improvement with
DRT, patients with PDD still function
at a lower level compared with premorbid status and the improvement is
sustained for a shorter time compared
with motor benefit [12] . With disease
progression the cognitive benefit of
DRT wanes and may worsen cognitive
function.
Cholinergic deficits have been consistently found in association with cognitive
and neuropsychiatric symptoms including PDD [13] , and medications that increase acetylcholine neuro
transmission
are mainstays in the treatment of dementia. Cholinesterase inhibitors are
generally well tolerated. Rivastigmine
is licensed for use in PDD in the USA
and other countries based on positive
results in the Exelon in Parkinsons Disease Dementia Study, a 24-week, randomized placebo-controlled trial in over
500 patients with PDD [14] . Donepezil
and galantamine are also reported to
be more effective than placebo in some
cognitive measures. However, based on
the low numbers of patients evaluated
in most studies, study design concerns
and variability in results, evidence supporting their use is less robust than with
rivastigmine [15] .
66
The partial NMDA-receptor antagonist

memantine has been evaluated in PDD
in four placebo-controlled trials with
variable success [16] . Only one study
met its primary end point, change in
cognition (measured by Clinician Global
Impression of Change) at 24 weeks,
although improvements in quality of
life have been reported [17] . Given the
conflicting data from available studies,
there is insufficient evidence to recommend memantine in the treatment of
dementia in PD[15] .
Subthalamic deep-brain stimulation
(STN-DBS) is frequently considered for
medication-resistant motor complications in PD, although it has been associated with cognitive decline. A metaanalysis of 28cohort studies of cognitive
performance after STN-DBS showed
moderate decline in semantic and verbal fluency and small but significant
decreases in executive functions, verbal
learning and memory[18] . A more rapid
decline in executive function is also associated with STN-DBS compared with
best medical treatment[19] .
Neuropsychiatric
Depression
Depression is reported in 4050% of
PD patients, but a careful review of
the population, the PRIAMO study,
reported symptoms of depression in
22.5% of 1072PD patients. Disruption
of monoaminergic pathways between

Psychosis: loss of contact with reality that usually includes visual
hallucinations, reported as vague images in the peripheral vision,
delusions, paranoid ideation and delirium.
brainstem nuclei and prefrontal and orbitofrontal cortices may be the primary
underlying disturbance. Pathologic gliosis and loss of noradrenergic neurons
in the locus coeruleus and declining
catecholaminergic activity in the limbic
system on PET imaging has been demonstrated in depressed PD patients[20] .
Depression in PD is usually of mild-tomoderate intensity and characterized
by an early loss of initiative and selfesteem, sadness, feelings of guilt and
remorse. Other features include loss of
appetite, sleep disturbance, declining
libido, weight gain, loss of concentration and fatigue [21] . Unfortunately, PD
symptoms may mimic the vegetative
symptoms of depression, making diagnosis challenging. Suicide is rare in PD
patients, but has been reported in the
setting of STN-DBS [22] .
Dopamine agonists (DA) have proven efficacious in the treatment of depression,
independently of motor benefit [23],
and mechanistically has been postulated
to stimulation of limbic region D3 receptors [24] . Therefore, optimization of
DRT may be initially considered before
adding a traditional drug for depression.
Tricyclic
antidepressants
(TCAs),
including amitriptyline, nortriptyline and
desipramine are reported as effective in

the PD population. However, caution
must be taken in patients with cognitive
impairment as the anticholinergic effect
of TCAs can worsen mental function.
Selective serotonin reuptake inhibitors
(SSRIs) and selective norepinephrine
reuptake inhibitors (SNRIs) are beneficial
and may be better tolerated than TCAs
in some patients[25] . Antidepressants
may also improve comorbid psychiatric
symptoms, including anxiety and sleep
symptoms, and so should be continued
if tolerated[26] .
Electroconvulsive therapy (ECT) may
be attempted for medically refractory
depression, and often leads to temporary benefit in motor symptoms[27] .
Repetitive transcranial magnetic stimulation (rTMS) has shown promise in
the treatment of PD-related depression [28] , although this requires further
investigation.
Psychosis
Psychosis may affect up to 60% of advancing PD patients and is predictive of
poor prognosis [29] . Psychotic symptoms typically begin 10 years after PD
diagnosis, and earlier onset suggests an
alternative etiology, such as Lewy body
dementia, Alzheimers disease or prior
67
Stacy
psychiatric disease. Up to 40% of PD
patients have visual hallucinations, initially reported as a sense of presence
before evolving to vague images in the
peripheral vision. Delusions, paranoid
ideation and delirium become increasingly common as the disease progresses [30] . Psychosis has been shown to
be a greater stressor for caregivers than
motor dysfunction as well as the single
most important precipitant for nursing
home placement [29] . Psychosis in PD is
associated with neuronal degeneration
in the pedunculopontine nucleus, locus
coeruleus, dopaminergic raphe nuclei,
and the ventral temporal regions of the
brain [31] .
Initial treatment of psychosis involves
the reduction of as many psychoactive
drugs as possible followed by an adjustment of anti-PD medications; typically
reducing or eliminating anticholinergic agents, amantadine, monoamine
oxidase type B (MAO-B) inhibitors,
catechol-O-methyl transferase inhibitors
and DA while increasing levodopa. Clozapine (<50mg/day) has demonstrated
efficacy in blinded, placebo-controlled
trials without worsening extrapyramidal
features. Agranulocytosis is a rare (<1%
of patients), but potentially life-threatening side effect. Therefore, regular
blood count monitoring is required.
Quetiapine also improves psychosis;
however, placebo-controlled trials have
failed to prove efficacy. Despite this,
quetiapine (12.5150 mg/day) is the
drug of choice for treating PD-related
68
psychosis. Olanzapine and aripiprazole

have demonstrated worsening of motor
symptoms in controlled trials. Acetylcholinesterase inhibitors may improve mild
hallucinations, although the effect may
be seen best in patients with PDD[29] .
Anxiety
Anxiety disorders are reported in
2549% of the PD population [32], and
may present as panic attacks, phobias,
or generalized anxiety disorder [33] . Increased subjective motor symptoms,
more severe gait problems and dyskinesias, freezing of gait and drug-induced
motor fluctuations have all been associated with anxiety, particularly during the
wearing-off periods[33] .
Anxiety linked to off periods may improve with changes in DRT that reduce
motor fluctuations. Benzodiazepines
traditionally improve anxiety; however,
there is a risk of dependence and these
medications increase the risk of falls in
the elderly. Antidepressants are typically better tolerated, allow long-term
therapy and are not associated with
dependence [34] .

Impulse control disorders (ICDs) typically involve behaviors that are performed repetitively, excessively and/or
compulsively, and to an extent that interferes in major areas of life functioning [35] . These include pathological

Impulse control disorders: psychological disorders characterized by
the repeated inability to refrain from performing a particular action
that is harmful to a patient or others. Examples include pathological
gambling, binge eating and hyperlibidinous behaviors.
Orthostatic hypotension: a fall in systolic blood pressure of >20mmHg or in diastolic blood pressure >10mmHg on standing. A blood pressure drop may lead to
cerebral hypoperfusion and dizziness, visual disturbances, fatigue and sometimes
loss of consciousness.
gambling, binge eating, hyperlibidinous

behavior and compulsive shopping.
Dopamine dysregulation syndrome
(DDS) refers to the compulsive use of
dopaminergic medications and is often
accompanied by severe dyskinesia, cyclical mood disorder, and impairment
of social and occupational function.
Compulsive motor behaviors, or punding, often involve repetitive ritualistic
behaviors or hobbyism [35] .
In a study of 3090patients with treated
idiopathic PD, 13.6% had evidence of
at least one ICD and 3.9% had two or
more [36] . ICD were more common in
patients treated with a DA (17.1%) than
in patients not taking a DA (6.9%). This
may be related to the high affinity of DA
for D3 receptors, which have a strong
representation in the limbic system and
appear to modulate the physiologic
and emotional experience of novelty,
reward and risk assessment [37] . Interestingly, in 103 de novo untreated PD
patients, 17.5% had evidence of at least
one ICD [38] .
Treatment of ICD usually requires discontinuing DA treatment entirely with more
reliance on levodopa. When tapering

DA, caution is advised as up to 19% of
patients may experience DA withdrawal syndrome characterized by anxiety,
panic attacks, dysphoria, diaphoresis,
fatigue, pain, orthostatic hypotension
(OH) and drug cravings[39] . SSRIs,
zonisamide, quetiapine, valproic acid,
naltrexone and topiramate have been
reported as anecdotal treatment[35] .
Both ICD and DDS can improve after
deep-brain stimulation (DBS) provided
there is an associated reduction in dopaminergic medications [40] . However,
others have reported the exacerbation
and emergence of ICD/DDS and other
behavioral problems following DBS [35] .
Autonomic
Gastrointestinal
Approximately half of PD patients
have constipation and up to 70% will
struggle with impaired gastric motility, with increasing severity in the
later stages. Constipation likely results
from prolonged colon transit time and
impaired volitional defecation. Though
69
Stacy
there is severe loss of both central and
colonic dopaminergic neurons in PD,
constipation does not respond to DRT.
Active lifestyle, physical exercise and
diet are the first-line nonpharmacological approaches for constipation in PD.
Effective medical treatments include
psyllium, polyethylene glycol bisacodyl
and magnesium sulfate. Lubiprostone is
a locally acting chloride channel activator that enhances chloride-rich intestinal
fluid secretion and has proven effective
in PD patients [41] . Tegaserod maleate
is a serotonin receptor type-4 (5-HT4)
partial agonist that stimulates gastrointestinal motility that appears effective
in PD populations as well. Macrogol,
an isosomotic electrolyte, significantly
increases bowel movement frequency
and improves stool consistency in PD
patients. Alternative therapies include
symbiotic yogurt, neostigmine, linaclotide, botulinum toxin injections and
sacral nerve stimulation[42] . DBS of
the STN may improve gastric emptying,
possibly related to alterations in antiparkinsonian medications, improvement of
motor symptoms and direct effects on
the STN and neighboring or connecting
areas [43] .
Genitourinary
More than 50% of PD patients experience genitourinary (GU) dysfunction,
including erectile and ejaculatory failure, incomplete bladder emptying,
urinary urgency and frequency, and
70
urge incontinence [44] . Lower urinary

symptoms likely result from the loss of
the dopaminergic inhibitory effect on
micturition. Increased urinary frequency
due to overactive bladder may improve
with levodopa. Oxybutynin, tolterodine,
solifenacin or darifenacin are effective,
although central anticholinergic effects
can cause confusion. Reducing detrusor
wall activity with botulinum toxin injections into the bladder wall has proven
beneficial without the risk of systemic
side effects[45] . STN-DBS may improve
GU symptoms in some [46] .
Erectile dysfunction can predate motor symptoms and has been associated
with a 2.74-times higher risk of developing PD compared with age-matched
controls [47] . DRT can affect sexual
behavior and many PD patients report
improved arousal during the on state.
Phosphodiesterase inhibitors are effective in the treatment of erectile dysfunction but may unmask or worsen
OH [48] .
Orthostatic hypotension
OH is defined as a fall in systolic blood
pressure of >20 mmHg or in diastolic
blood pressure >10mmHg on standing
[49] . Cerebral hypoperfusion can result
in dizziness, visual disturbances (e.g.,
blurring, color change, white-out,
gray-out), transient cognitive impairment and syncope. Muscle hypoperfusion may result in headache, neck pain
and lower back pain. Fatigue, chest

pain, dyspnea and other respiratory
problems may also occur.
Conservative measures in the treatment
of OH include increased water intake
(22.5l/day), increased salt intake (>8g
or 150mmol/day), sleeping in a head-up
position, fragmentation of meals, physical counter maneuvers such as squatting,
bending over forward, or wearing support stockings [15] . Fludrocortisone, midodrine, indomethacin, and droxidopa
are effective when nonpharmacologic
measures fail [49] .
Sialorrhea
Sialorrhea may be seen in up to 77% of
PD patients [50] . Nonpharmacological
approaches focus on improving swallowing and using tactile cues such as
chewing gums or candies. Glycopyrrolate (2 mg daily) and atropine solution
(0.5-mg drop sublingually once daily)
have proven beneficial with a low risk of
systemic anticholinergic side effects[51] .
Botulinum toxin is the most effective
treatment for sialorrhea, acting through
blockade of acetylcholine release at the
cholinergic neurosecretory junction of
the salivary glands [52] .
Sleep disorders
Insomnia
Insomnia is the most common sleep
disturbance in PD [34] . Sleep disruption
is typically multifactorial and involves
the overnight emergence of motor

symptoms, pain and nocturia, as well
as sleepdisordered breathing, restless
legs syndrome and periodic limb movements [53] . Depression and nocturnal
hallucinations may also contribute to
sleep disruption [34] .
Nocturnal motor symptoms often improve with long-acting DA or melatonin [54] . However, caution must be
taken with any evening dopaminergic
stimulation, as nocturnal confusion
and psychosis can be amplified, especially in the elderly. STN-DBS has been
shown to improve subjective sleep
quality, total sleep time, sleep efficiency, and reduced wake time after sleep
onset [55] .
Excessive daytime sleepiness

Excessive daytime sleepiness (EDS) is
likely a result of the underlying neuro
degenerative process, nocturnal sleep
disruption and antiparkinsonian medications [56] . Although pramipexole
and ropinirole were originally linked
to sleep attacks, the abrupt transition
from wakefulness to sleep, almost all
dopaminergic therapies have been
implicated [57] . EDS appears more
frequently in advanced PD and is associated with cognitive disorders, depression, longer duration of levodopa
therapy and hallucinations [34] .
Treatment requires improving sleep
hygiene: modifying DRT, reducing
71
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Rapid eye movement behavior disorder: absence of muscle
atonia during rapid eye movement sleep, leading to an increased risk
for a patient to act out dream content, potentially causing harm to a
patient, bed-partner or caregiver.
or discontinuing concomitant antihistamines, hypnotic medications, or

stimulant drugs, and evaluating for
concomitant conditions such as depression [57] . In addition, modafinil
(200400 mg/day) has shown benefit in PD-related EDS. The nocturnal
administration of sodium oxybate has
been found to improve EDS and fatigue in PD patients in an open-label
polysomnographic study [58] .
Rapid eye movement behavior

disorder
Rapid eye movement (REM) behavior
disorder (RBD) is characterized by an
absence of muscle atonia during REM

sleep [56] . In this setting patients act
out dream content, which is often action filled or violent [59] . Self-injury or
harm to bed-partners or caregivers can
occur.
Night-time clonazepam (0.52 mg)
is the preferred treatment of RBD,
with nearly 90% of patients reporting improvement or resolution [59] .
However, over 50% of patients report
side effects, including EDS, confusion,
and cognitive changes. Melatonin
(312mg) and donepezil (up to 15mg)
at night time have also shown benefit.
DBS-STN does not seem to affect RBD.
72
Pain & other sensory

symptoms
Pain and other sensory symptoms are
increasingly recognized as a major cause
of disability associated with PD[60] . The
mechanism of pain in PD may include
musculoskeletal, dystonic, radicular
neuropathic and central pain. DRT usually improves dystonia- or rigidity-related pain and if this fails, botulinum toxin
injections can be effective, especially for
treatment of painful focal dystonia [61] .
Nonsteroidals and other analgesics as
well as DBS have been reported to successfully manage PD-related pain and
discomfort.
Conclusion
There are a wide variety of NMS associated with PD, many of which predate
the onset of motor symptoms (RBD, anosmia) and others that typically worsen
as the disease progresses (dementia, autonomic dysfunction). These wide-ranging symptoms suggest that neuropathological changes in PD are not confined to
the nigrostriatal dopaminergic network,
but affect a number of regions within
both the central and peripheral nervous
systems. Early recognition of NMS is essential for the care of patients with PD:
reducing cost-burden, improving quality

of life, and offering the potential for earlier intervention with better treatment
strategies in the future.

disclosure
The author has no relevant affiliations or financial involvement with any

subject matter or materials discussed in
the manuscript. This includes employment, consultancies, honoraria, stock
ownership or options, expert testimony,
grants or patents received or pending,
or royalties.
No writing assistance was utilized in the
production of this manuscript.
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1.
2.
3.
4.
Cognitive decline in Parkinsons disease is associated all of the

following except:
a.
Increasing need for dopamine-replacement therapy
b.
Increasing risk of hallucinations
c.
Increasing risk of nursing home placement
d.
Increasing risk of rapid eye movement behavior disorder
A symptom of psychosis unique to the Parkinsons disease patient
is:
a.
Auditory symptoms
b.
A sense that someone or something is present in the
room
c.
Delusion of grandeur
d.
Early or rapid onset of symptoms
Suggested treatment of rapid eye movement behavioral disorder
is:
a.
Management of sleep hygiene
b.
Dopamine-replacement therapy
c.
Clonazepam
d.
Quetiapine
e.
Clozapine
Non-motor symptoms requiring reduction in dopaminergic
therapy include:
a.
Impulse control disorder
b.
Psychosis
c.
Depression
d.
Nocturia
e.
Both a & b
77
Stacy
5.
78
Treatment for orthostatic hypotension:

a.
Increased fluid uptake
b.
Increased salt
c.
Thigh-high support stockings
d.
Fludrocortisone
e.
All of the above
CHAPTER
Management of cognitive
and behavioral aspects of
Parkinsons disease
Joseph H Friedman
Contents
Cognitive changes & dementia
82
Psychosis
84
Anxiety
86
Depression
87
Apathy
89
Fatigue
90
91
Sleep
92
doi:10.2217/EBO.13.112
79
Friedman
About the author

Joseph H Friedman
Joseph H Friedman is the Director of the Movement
Disorders Program at Butler Hospital, Professor and
Chief, Division of Movement Disorders at the Warren Alpert Medical School of Brown University (RI,
USA). He has been the Clinical Director of the American Parkinson Disease Aassociation Information and
Referral Center in Rhode Island for over 25 years. He
has had a longstanding clinical research interest in
the behavioral aspects of Parkinsons disease.
80
Management of cognitive & behavioral aspects of PD
Learning points
Behavioral changes occur in almost every person with Parkinsons

disease (PD) and may be the most important symptoms of the
disease.
Dementia ultimately affects the vast majority of PD patients and
has some response to cholinesterase inhibitors.
Depression and psychotic symptoms (hallucinations and delusions)
can be treated successfully, and should always be included in the
history.
PD patients and their families should learn that the behavioral issues are as much a part of the disease as their motor symptoms,
and should be addressed in the same way.
Even when PD-related behavioral problems cannot be treated successfully, simply acknowledging them as part of the disease process
is often extremely helpful to the patient and caregivers.
Summary
Parkinsons disease (PD) is a neurobehavioral disorder
involving disturbances of motor control, mood, motivation,
sleep and cognition. With long-term disease the behavioral
problems become more pronounced and form the major
determinants of quality of life. Dementia ultimately affects
80% of PD patients and is usually the most devastating
problem, partly because of the direct consequences, but
also because it increases the likelihood of depression,
anxiety, psychotic symptoms and sleep disturbances. While
the behavioral problems have been well documented, they
are often under-recognized and have certainly been undertreated. This chapter provides a brief review of the major
behavior problems in PD, including those that are intrinsic
to the disorder as well as those thought to occur as a result
of the treatment of the motor problems.
81
Friedman
Although classified as a movement disorder, Parkinsons disease (PD) is really a
neurobehavioral disorder and the most
devastating long-term problems are
usually behavioral rather than motor.
Psychiatric problems are more stressful
for caregivers than motor dysfunction,
leading to the corollary result that psychiatric problems are the leading causes
for nursing home placement.
The major behavioral problems in
PD can be divided into those that
are thought to be intrinsic and
those which are likely iatrogenic or
secondary (Table5.1) , with some
problems falling into both categories.
Iatrogenic problems are those induced
by medication, whereas secondary
problems are those that are reactive
to the disease constraints, such as
reactive depression or insomnia due to
overactive bladder.
Cognitive changes &

dementia
Cognitive changes are unfortunately
common in PD. Most newly diagnosed
patients have subtle neuropsychological

changes evident on sophisticated
testing. Dementia, depending on the
definition and the population studied,
has a variable prevalence rate, but by
the time of death 80% of PD patients
suffer from PD dementia (PDD) [1] .
The clinical syndrome of PDD is often
categorized as a subcortical dementia
and differs from that of Alzheimers
disease (AD), a cortical dementia, in
several important ways [2] . The degree
of dementia typically fluctuates during
the day in PDD, but not in AD. The
memory loss in PDD is largely due to
problems with accessing memory stores
so that recent memories are variably
available and are brought up with cues.
In AD, there is no memory trace so
that cuing is not helpful. PDD patients
have executive dysfunction, problems
with planning, multitasking and
attention, more so than AD patients.
PDD patients have more problems with
visuospatial comprehension, and are
more likely to suffer from depression
and develop visual hallucinations. A
variety of tests used in quantitative
Dementia: affects approximately 30% of Parkinsons disease (PD)

patients, but by the time of death, 80% have become demented.
The cognitive deficit in PD dementia is similar to that seen in
dementia with Lewy body (DLB), but the latter is more likely to be
associated with fluctuating cognition and orientation and visual
hallucinations in early stages, even before parkinsonian motor signs. As in
Alzheimers disease and DLB, there is a direct relationship between the degree of
dementia and the cholinergic deficit. Rivastigmine is the only approved treatment
for PD dementia.
82

Table 5.1. Neurobehavioral problems associated with Parkinsons
disease.
Intrinsic problems
Iatrogenic or secondary problems
Dementia
Subclinical cognitive changes Psychotic symptoms (hallucinations & delusions)
Depression
Apathy
Delirium
Anxiety
Sedation
Fatigue
Dopamine dysregulation syndrome
Akathisia
Pain
Sleep disorders
assessment of cognitive impairment

and helpful in following progression
of disease and changes in response
to therapeutic interventions have
been published[3] . PDD is associated
with increased rates of depression,
anxiety, apathy, psychotic symptoms
and mortality. Thus, PDD is not only a
problem in and of itself, but markedly
increases the likelihood of behavioral
problems.
The phenomenology of PDD is similar
to that seen in dementia with Lewy
bodies (DLB), except cognitive changes
and hallucinations usually precede the
onset of motor symptoms in DLB but
typically occur in middle or late stages
in PDD. The overlap on phenomenology
between the two disorders has helped
fuel the debate regarding whether PDD
and DLB are the same disease, which
start at different parts of the neuraxis
(brainstem versus cortex). The rate of
decline in PDD has been measured in
different ways, producing, not surprisingly, different results, and the rate of
decline varies considerably with the
various neuropsychology tests chosen.
The rate of decline in PDD is probably
the same or slower than in AD.
The pathophysiology of PDD is not
well understood. In addition to the
usual brainstem changes of PD, brains
of patients with PDD contain Lewy
bodies in the cortex, complementing
an uncertain and variable degree of
cortical neuronal loss. In approximately
half the PDD cases, neurofibrillary
tangles and amyloid plaques are also
seen as sufficiently severe to warrant
an associated diagnosis of AD [4] .
The most consistent finding in PDD
has been the cholinergic deficit. Even
nondemented PD patients have less
acetylcholine than AD patients, but the
deficit is worse in demented patients
and correlates with dementia severity,
attention deficits and hallucinations.
83
Friedman
There have been few reports involving
substantial numbers of subjects on
the use of any cognitive treatments
for PDD. The largest included 541
subjects treated with either oral
rivastigmine or placebo and reported
moderate to marked improvement
in only 19.8% of subjects treated
with rivastigmine, versus 14.5% with
placebo [5] . However, moderate to
marked worsening over the course
of the 24week study occurred in
13% rivastigmine-treated patients
versus 23.1% treated with placebo.
However, there was a large dropout
rate in both arms (27% rivastigmine vs
17% placebo). The data on donepezil,
galantamine and memantine involve
subject numbers too small to rely on.
However, most experts believe that
the cholinesterase inhibitors have fairly
equivalent efficacies. Rivastigmine is
the only treatment approved by the
US FDA for PDD. Since the time when
the rivastigmine study was performed,
a patch delivery system has been
released that markedly lowers the rate
of gastrointestinal side effects. Virtually
all reports have shown these drugs
to be well tolerated in PD, although
occasionally worsening tremor. The
cholinesterase inhibitors have also been

found to reduce psychotic symptoms,
and may be considered for treating PDD
accompanied by mild hallucinations or
delusions. Dosing is the same as for
AD, and benefits are similar. As with
all symptomatic therapies, efficacy
should be assessed after full response
is achieved, usually within 8weeks. If
not helpful, the medication should be
stopped as no medication has been
found to slow cognitive decline.
Psychosis
Psychotic symptoms are common
in PD, with visual hallucinations
affecting approximately 30% of
drug-treated patients and delusions
affecting approximately 510%. While
medications clearly contribute to
these symptoms, some patients may
develop the same syndromes without
medication use. Dementia is the most
important risk factor for hallucinations,
and the appearance of psychotic
symptoms is often a herald symptom
of dementia. Although there have been
no studies comparing the incidence
of psychotic symptoms with different
PD
medications,
anti
cholinergics
Psychotic symptoms: usually nonemotionally based visual hallucinations and, to a lesser extent, auditory hallucinations, affect
approximately 30% of drug-treated PD patients. Approximately a
quarter of these also have delusions, typically paranoid in nature,
often of spousal infidelity. The incidence of psychotic symptoms is
much higher in the demented, but also occurs in the cognitively intact. Treatment
requires either lowering of PD medications or introducing quetiapine or clozapine.
84

are probably the ones most likely to
contribute to this problem. Amantadine
and dopamine agonists are probably
the next major contributors, and l-dopa
is the least likely. The hallucinations
typically are visual, and auditory
hallucinations occur at approximately
half the frequency of the visual
hallucinations [6,7] . The hallucinations
typically occur in low stimulus settings,
such as reading a book or watching TV
alone, and, unlike the hallucinations that
occur in primary psychiatric disorders,
are generally without emotional
content. Minor hallucinations include
presence hallucinations, which are
not true hallucinations, but a strong
feeling that there is someone or some
animal behind the patient, and passage
hallucinations, which are transient
visual hallucinations or illusions in the
peripheral field, perceived as light
reflections in ones reading glasses, a
shadow, or an animal running by. The
delusions however, are less benign, in
that they are predominantly paranoid,
with jealous delusions being one
of the most common [7] . Psychotic
symptoms are far more common in
PDD patients, and the occurrence of
hallucinations is often a harbinger of
dementia. Psychotic symptoms are
associated with an increased mortality.
The psychotic symptoms in PDD are
phenomenologically identical to those
seen in DLB. As in DLB, PD patients are
exquisitely sensitive to the parkinsonian
side effects of most antipsychotic drugs,
including most of the atypicals.
Only quetiapine and clozapine have

been demonstrated to be free of motor
side effects in PD patients, but only
clozapine has been demonstrated in
placebo-controlled trials to have potent
antipsychotic efficacy [8] . Although
the doses required to treat psychotic
symptoms in PDD are extremely low,
generally between 6.2550mg qhs,
the 12% risk of agranulocytosis is
not dose related so that weekly blood
count monitoring is still required. No
deaths have occurred in the USA using
the required monitoring system since
the drug was released in 1991.
The first step in treating psychotic
symptoms is to assess for a possible
non-neurological explanation, such
as occult infection or metabolic
derangement. Next, a review of all
psychoactive medications is made.
Quite often, anticholinergics (given
for overactive bladder), anxiolytics
or sedatives may be the cause. PD
medications are then reduced and
stopped, as tolerated, starting with
anticholinergics,
amantadine
and
dopamine agonists, in that order. It is
suggested that single drugs be reduced
and stopped, aiming for reduced
polypharmacy, rather than reducing
all drugs equally. The next step is to
decide whether to add a cholinesterase
inhibitor or an antipsychotic. Choli
nesterase inhibitors may be used with
mild to moderate demented patients in
whom a rapid response is not required.
The antipsychotics typically work
85
Friedman
within days, but often cause sedation
or orthostatic hypotension. Most
neurologists will start with quetiapine
12.5mg qhs and increase as needed.
The average dose required is generally
50100mg, which usually can be
given as a single bedtime dose. When
quetiapine is not successful, clozapine,
beginning at 6.25mg qhs is begun.
All other antipsychotics have been
associated with parkinsonism, and
should be used only when quetiapine
and clozapine have failed. In severe
and refractory cases, electroconvulsive
therapy may be extremely helpful.
Anxiety
Anxiety affects approximately 25% of
adults in the USA, making it the single

most common psychiatric disorder
in the general population. There are
several different types of anxiety,
which include phobias and obsessive
compulsive disorders. Most pertinent
for PD are panic disorder, social phobia
and generalized anxiety disorder.
Panic attacks are spells that occur
unexpectedly in which patients may feel
a variety of overwhelming experiences
such as shortness of breath, dizziness

(lightheaded or other), chest pain, fear
of dying and derealization. The spells
last several minutes and are not usually
precipitated by obvious stress. Social
phobias are quite understandable in the
setting of PD. Patients become anxious in
settings where they may need to speak
when they feel they are being watched,
or when they are in crowds. Much of
their fear is reality based due to their
speech, gait or balance impairments,
so that deciding if a problem is a
phobia or a realistic concern may not
be clear. Generalized anxiety disorder is
what most people think of when they
describe a nervous person.
The prevalence of anxiety in the PD
patient is considerably higher than
in the general population, with a
prevalence of approximately 40%[9] .
Its epidemiology is also different,
supporting the hypothesis that it is
intrinsic to the disease itself and not
simply a reactive process. Anxiety in
the general population primarily affects
young women, whereas PD patients
develop their anxiety much later
and the genders are approximately
Anxiety: is far more common in PD than in the general population

and is a major factor reducing quality of life, yet it is often not
recognized as part of the disease. There have been no published
treatment trials for anxiety in PD and recommendations are based
on individual experience, generally including the benzodiazepines
despite their increasing the risk of falls, daytime somnolence and delirium, and
the selective serotonin-reuptake inhibitors, although they take time to work and
have no evidence-based medical support.
86

equally affected. In PD, anxiety is more
commonly associated with depression
than it is in an age-matched controlled
comparator group. The three categories
of anxiety mentioned are the ones that
most commonly affect people with
PD and their relative frequencies vary
with the publications [10] . Anxiety is
greatly underappreciated by treating
physicians, including PD specialist
neurologists.
It is common to believe that anxiety
correlates with the motor clinical
fluctuations, where the anxiety induces
an off or the off induces anxiety,
data suggest that there is actually
little correlation [11] . Mechanisms
underlying the anxiety have been
proposed, but there are little data
to support any of them. Most
importantly, although anxiety is highly
prevalent and often debilitating, there
are no double-blind placebo-controlled
trials (DBPCTs) of any agent to treat
anxiety in PD. A DBPCT on depression,
which was not sufficiently powered to
examine anxiety and did not stratify by
anxiety, found no benefit for anxiety
with venlafaxine or paroxetine. In a
non-random survey of PD experts,
there was no consensus on treating
anxiety, with some experts suggesting

selective serotonin-reuptake inhibitors
(SSRIs) and others benzodiazepines or
bupropion. SSRIs have the advantage
of a low side-effect profile but may
take weeks to produce an uncertain
benefit, whereas benzodiazepines
work quickly but increase the risk of
falls, confusion, sedation and altered
sleep cycles. Buspirone has been tested
for motor benefits and for reducing
dyskinesias, but not for anxiety; it is
well tolerated. Unfortunately, there are
no data to guide therapy for treating
anxiety in PD.
Depression
Depression has long been associated
with PD and is the most studied of
the behavioral problems. Estimates
for its prevalence in PD are between
30 and 50%. Many of the early
reports on PD addressed the issue of
whether depression was intrinsic to
the disease, that is the direct result
of neuronal dysfunction in particular
regions of the brain or whether it was
reactive, that is, a natural response to
having a progressive, incurable and
often disabling disorder. Most experts
currently believe that depression is
Depression: affects somewhere between 30 and 50% of people

with PD. It is often not appreciated by physicians and is often
diagnosed when not present, due to the psychomotor slowing
intrinsic to the disease itself, as well as the often present symptom of
apathy. Depression is responsive to antidepressant medications, which
appear to work as well in this population as they do in the general population.
87
Friedman
due to both factors. Depression in
PD usually does not worsen with
time, which might be construed as
an argument against the hypothesis
of an intrinsic pathological etiology.
It also does not correlate closely with
motor function. The phenomenology
of depression in PD is thought to
differ from depression in the general
population, although this observation
is based on few publications and
applies only to large populations, not
individual patients. Depression is more
commonly coexistent with anxiety
in PD than in age-matched non-PD
depressed controls. It is increased
in patients with dementia. It has
higher rates of pessimism, with fewer
feelings of guilt and self-reproach.
Suicidal ideation is thought to be
increased as well, although the rate
of suicide in PD patients is very low,
especially considering the high rate of
depression. The low suicide rate may
reflect the high rate of apathy or the
lack of impulsive behavior [12] .
As with other behavioral disorders
that occur in the context of a physical
disorder, it can often be difficult to
create reliable diagnostic categories.
This was addressed in a consensus
NIH conference that concluded that
depression should be diagnosed based
on mood alone. Standard criteria for
the diagnosis of depression include the
presence of supportive features such as
psychomotor slowing, fatigue, altered
sleep cycles, weight loss, loss of interest,
88
which are often seen in PD patients who

have no feelings of melancholia and do
not feel depressed or sad.
There have been only two DBPC
multicenter
treatment
trials
in
PD-related depression. A large trial
involving 287subjects reported a
statistically significant but small benefit
of pramipexole, a dopamine agonist
used to treat motor symptoms [13] . A
smaller study compared paroxetine,
venlafaxine extended release and
placebo in 115subjects, demonstrating
a clinically and statistically significant
benefit for the drugs [14] . Unfortunately,
the population was too small to
determine if these drugs also produced
a benefit in anxiety, which they have in
the general population. Although the
results were not robust, they provided
the first proof that PD depression could
be treated with medication, and that
the medication was well tolerated.
Older, smaller studies have found that
tricyclic antidepressants may be more
effective than the SSRIs, and their side
effects, largely due to anticholinergic
effects, may be helpful with drooling,
insomnia and overactive bladder.
Once a decision is made to treat
depression, the choice of drug will
depend on concomitant problems, and
the doctors comfort using the various
options. Mirtazepine is a tetracyclic
antidepressant that has anti-anxiety
properties, and causes sedation and
increased appetite, in addition to

sometimes reducing PD tremor, but
there are no data in PD depression.
The SSRIs have few side effects other
than affecting sexual function, and
have anxiolytic properties. Bupropion,
although mildly dopaminergic does
not improve motor dysfunction. Only
venlafaxine and paroxetine have been
found to be effective in a large DBPCT,
but these results are thought to extend
to other antidepressants as well. The
rule in treating depression is to start
with a low dose and increase after
approximately 4weeks if the response
is inadequate.
Apathy
Apathy affects approximately 40% of
people with PD [15] . The term means

loss of emotion and motivation, and
is a common symptom in people who
are depressed. In PD it is thought
to be distinct from depression [16] ,
primarily because it has a very different
emotional valence. Depressed people
feel sad, and although not motivated,
are reluctant to engage in activities.
They are frequently irritable. Apathetic
patients deny depression, and while
unmotivated, are often willing to

participate in activities, if pushed. They
are unlikely to be irritable because they
are difficult to rouse. They simply do
not care [17] . On the one hand they
do not enjoy things, but on the other
do not feel the absence of pleasure.
It is a form of anhedonia, without
the negative connotation and affect.
Apathy is a problem for the family and
the constellation of friends, due to the
loss of the patients personality, but
this is not painful for the patient, as the
patient is insulated from the problem
by the apathy itself. Some experts, on
the other hand, believe that apathy
causes severe impairment and distress.
Apathy is thought to represent a
frontal lobe disorder and is sometimes
thought to be mildly responsive to
dopamine agonists or stimulants, but
data to support the hypothesis are
weak [15] . The relationship between
apathy and dopamine is partly related
to the observation that Parkinsons
syndromes are generally associated with
apathy, both primary and neuroleptic
syndromes, a mild improvement in
apathy seen with dopamine stimulation
and the occurrence of significant
Apathy: is a common problem in PD, often confused with depression, partly because apathy is a common concomitant symptom in
the depressed. Apathy refers to a loss of emotional feeling and
expression as well as a loss of motivation. It differs from depression
in that patients are not melancholic or irritable. They simply do not
care very much and do not miss their previous pleasures. It is more of a problem
for those around them than for the patients themselves. Its treatment remains
speculative.
89
Friedman
apathy when dopaminergic therapy
is discontinued abruptly. Apathy is
generally associated with some degree
of dementia, and is probably most
commonly evident in the patient who
offers little or no spontaneous speech,
but lets the caregiver answer all the
questions, rarely asks questions, and
generally talks only when directly
asked a question. The patient then
answers succinctly and does not
use the opportunity to develop a
conversation. Apathy is also part of the
depression syndrome. Apathy due to
depression is probably treatable with
treatment of the depression. Apathy
outside of depression may show minor
improvement
with
cholinesterase
inhibitors. The degree of potential
benefit with dopaminergic medications
is not worth the risk of their side
effects.
Fatigue
Fatigue, a feeling of lack of energy,
and not a syndrome of sleepiness,

has been found to be a common
problem in PD, independent of the
culture studied [18] . PD patients are
usually able to distinguish fatigue
from sleepiness, although many
patients suffer from both. In all parts

of the world, fatigue is found to affect
approximately half of PD patients and
appears early in the course of the
disease. It is not medication induced.
Counter-intuitively, it is unrelated
to motor disease severity although
it tends to worsen with duration of
disease. A third of PD patients rate
fatigue as their single worst symptom
of PD, and half rate it as one of their
three most bothersome symptoms.
Fatigue usually predates onset of
the motor symptoms, and often
remains regardless of the response to
symptomatic treatment of the motor
aspects of PD. The etiology of fatigue
in PD remains a mystery, as fatigue is
ubiquitous and present in virtually all
medical and psychiatric disorders. It
is associated with depression in most
PD studies, but not motor dysfunction
[19] . One physiological study found no
correlation between energy efficiency
and fatigue, the hypothesis being that
fatigued patients required more energy
to perform the same tasks than their
nonfatigued comparators.
There is a single positive treatment trial,
demonstrating that methylphenidate,
at 15mg three-times daily, was safe
Fatigue: occurs early in PD, often predating motor symptoms, and

is often among the most bothersome of all PD symptoms, including
the motor, and may be severe enough to be disabling. Its pathophysiology remains a mystery, and only a single treatment trial,
using low-dose methylphenidate, has reported success. It does not
generally respond to the treatment of motor symptoms.
90

and effective [20] . Modafinil has not
been found to be helpful for fatigue,
although there are mixed results
for daytime somnolence with both
modafinil and armodafinil. So far, no
data indicate that amantadine, which is
commonly used for fatigue in multiple
sclerosis, is useful for fatigue in PD.

Impulse control disorders (ICDs) were
first brought to attention in 2000 with
a report on pathological gambling;
however, the first form of ICD, punding,
was reported in 1994. The connection
between the two was made several
years later. Punding refers to a senseless
repetitive activity, usually taking things
apart and putting them together, first
described in amphetamine addicts in
Sweden. It is an obsessive preoccupation
with a motor task, producing a calming
effect. It was described in a small number
of PD patients who exhibited similar
behavior, such as tallying the same
figures repetitively, trimming a bush,
reading food cans in a supermarket,
pulling weeds and refusing to be
interrupted, even to the point of wetting
oneself. Patients who pund will catalog
their jewelry over and over, polish

pennies, clean an oven, or rearrange
the contents of a drawer [21] . The more
common ICDs are gambling (affecting
men and women), hypersexuality (more
commonly affecting men), overeating,
overspending, collecting, hobbyism and
internet addiction. Unusual forms of ICD
have been well described, each of which
may be unique [22,23] . They occur in
approximately 1015% of PD patients on
dopamine agonists. Patients with these
problems often behave like addicts and
will lie about them, or minimize them,
so that reliable information must come
from a caregiver. The ICDs have clearly
been linked to the dopamine agonists
and although they may occur on l-dopa,
alone, are much less likely to do so. The
problem, like psychotic symptoms, may
develop after the patient has been on
a stable dose of medication for months
or years. Risk factors include premorbid
history of impulsive behavior such as
gambling or drug addiction, younger
age and male gender. Although many
case reports have described good
responses to antipsychotics, which
are theoretically useful as dopamine
receptor blockers, and SSRIs, which are
often used for obsessivecompulsive
Impulse control disorders: It was over 20years after the introduction of dopamine agonists to treat PD that impulse control disorders
were recognized as potential side effects. While the most common
are pathological gambling, hypersexuality, binge eating, excessive
spending and hobbyism, the range of uncontrolled compulsive
behaviors is enormous. These are rarely recognized as medication-related
problems by the patient or family and must be asked about by the physician.
91
Friedman
disorders, the only approach that reliably
reduces or stops the ICD is a reduction
or stoppage of the dopamine agonist.
There is insufficient data to indicate that
switching from one agonist to another
may be helpful.
Sleep
Sleep disorders affect approximately
90% of people with PD [24] . These
include problems falling asleep,
difficulties with sleep maintenance,
inverted sleep cycles, excess daytime
sedation, vivid dreams and rapid eye
movement sleep behavior disorder
(RBD). Obstructive sleep apnea
and restless legs may occur more
frequently in PD patients than in agematched controls but this is uncertain.
The typical habitus of an obstructive
sleep apnea PD patient is not obese,
as is usually the case in the general
population, and generally the PD
patients are not smokers or recently
ex-smokers. People with PD may have
difficulty falling asleep due to problems
moving and getting comfortable. They
may have a tremor that interferes
with relaxation required to fall asleep.
They often have overactive bladder,
complicating the already common
difficulties of both men and women

with urinary urgency and frequency,
compounded by the slowness of
movement and hurdles in getting in
and out of bed. Although it used to
be taught that tremors resolve during
sleep, the use of polysomnography has
demonstrated that tremors may appear
during stage1 sleep, so that tremors
commonly awaken patients. As a result
of awakenings at night, patients are
often sleepy the next day, leading to
daytime naps, which further erode
the ability to sleep through the night.
PD patients sometimes have rapid
eye movement intrusions, which are
dreams that persist for several seconds
after awakening, causing confusion
between sleep and reality. Vivid
dreams may be so realistic that patients
will occasionally believe their dream
was real, causing concern in the family,
who think the patient has become
confused. Perhaps most important,
at least from a diagnostic point, is
the presence of RBD, which has been
closely linked to a-synucleinopathies,
namely PD, DLB and multisystem
atrophy. RBD is extremely rare outside
of the a-synucleinopathies in middleaged or older people (it occurs
in young people with narcolepsy
Sleep disorder: some type of sleep disorder affects approximately

90% of PD patients. These range from the obvious difficulties falling
asleep, overactive bladder, pain, tremor to vivid dreams, nightmares,
rapid eye movement sleep behavior disorder and narcoleptic-like
need for increased sleep and sleep attacks. Treatment approaches
must be highly individualized and can be challenging.
92

and spinocerebellar ataxia type3),
and its development often heralds
the development of one of these
disorders, often 5 or more years later.
In RBD, people act out their dreams,
particularly if they involve vigorous
physical activity, usually violent actions
such as kicking, punching or jumping.
During normal dream sleep, people are
paralyzed except for their breathing
and eye movements. RBD affects
approximately 30% of men with PD,
and approximately 6% of women. The
behavior is extremely irregular so that it
may occur every few months or more.
The relationship between sleep talking
and RBD is not clear and sleep talking
is more common than RBD in PD. A
common sleep problem, particularly
in advanced patients is an increased
need for sleep, often up to 16h per
day. This may occur for several reasons,
including sleep apnea, medication side
effects, and interrupted sleeping at
night. An additional reason is a loss
of hypocretin-secreting cells in the
hypothalamus [25] , thus mimicking
narcolepsy. Usually PD patients with
severe excess sleeping, both day
and night, either have sleep apnea
or have some degree of dementia,
and presumably, this narcolepsy-like

disorder as well.
The secondary effects of sleep
disturbances is difficult to evaluate but
it undoubtedly affects cognition[26] ,
mood, motivation, likelihood of
hall
ucinations and probably motor
performance as well.

disclosure
JH Friedman has performed lectures
for Teva, General Electric and UCB.
He has received consulting fees from
Teva, Addex Pharm, UCB and Lundbeck, research funding from Michael
J Fox Foundation; NIH, EMD Serono,
Teva, Acadia and Schering Plough;
and royalties from Demos Press. The
author has no other relevant affiliations or financial involvement with any
disclosed.
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The Sydney multicenter study of
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Kehagia AA, Barker RA, Robbins

TW. Neuropsychological and clinical
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and dementia in patients with Parkinsons
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(2010).
3.
Lee W, Williams DR, Storey E. Cognitive

testing in the diagnosis of parkinsonian
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Johnson DK, Galvin JE. Longitudinal

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Emre M, Aarsland D, Albanese A etal.

Rivastigmine for dementia associated
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Chou KL, Messing S, Oakes D etal.

Drug induced psychosis in Parkinsons
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7.
Ravina B, Marder K, Fernandez HH

etal. Diagnostic criteria for psychosis in
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Parkinson Study Group. Low dose

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etal. Symptomatology and markers of
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Martinez-Martin P, Richard IH, Starkstein
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13. Barone P, Poewe W, Albrecht S etal.

Pramipexole for the treatment of
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95
Friedman

1.
2.
3.
4.
5.
96
Which of the following antipsychotic drugs do not cause worsening

of motor problems in Parkinsons disease (PD)?
a.
Risperidone
b.
Quetiapine
c.
Aripiprazole
d.
Clozapine
Which one of the following is not considered part of PD?
a.
Mania
b.
Depression
c.
Apathy
d.
Fatigue
e.
Excessive sleep
Depression in PD is thought to be:
a.
Due to intrinsic brain pathology
b.
Due to dopamine deficits
c.
Reactive to the progressive impairments
d.
Responsive to dopamine replacement
Which of the following statements concerning dementia in PD is
not correct?
a.
It is related to a deficit of acetylcholine
b.
It increases the risk of psychotic symptoms
c.
It is relatively uncommon
d.
It often involves Alzheimers brain changes
e.
It is associated with an increased risk of depression
Which one of the following statements about rapid eye movement
sleep behavior disorder is not correct?
a.
It affects men more than women
b.
It affects approximately 30% of men
c.
It is usually a side effect of medications used to treat PD
motor symptoms
6.
7.
8.
9.
d.
e.
It often predates the onset of PD motor changes

It is commonly present in other disorders of a-synuclein
Which of the following statements concerning apathy in PD is
true?
a.
It is defined as a decrease in emotions and motivation
b.
It reduces the risk of hallucinations or paranoia
c.
It is associated with a reduced risk of falling
d.
It is a desirable outcome as it relieves patient distress
e.
It is very responsive to antidepressant medications
Which of the following treatments are effective for controlling
impulse control disorders due to dopamine agonist medications?
a.
Reducing or stopping the dopamine agonist
b.
Adding quetiapine or clozapine
c.
Adding a serotonin reuptake inhibitor
d.
Adding anafranil
Which of the following statements concerning fatigue in PD is
true?
a.
It is directly related to the degree of motor impairment
b.
It is due to depression
c.
It is due to apathy and loss of motivation
d.
It is a direct result of motor inefficiency
e.
It often predates the onset of motor symptoms
Which of the following statements regarding behavioral problems
in PD is not true?
a.
They often are major determinants of quality of life
b.
They often predate the onset of motor symptoms
c.
They usually respond to dopamine-replacement therapy
correct
d.
One or more affect the vast majority of PD patients
e.
They are closely linked to olfactory dysfunction
97
Friedman
10.
98
Which of the following statements concerning psychotic symptoms

in PD is true?
a.
They primarily consist of visual hallucinations and delusions
b.
They often include auditory hallucinations
c.
When delusions are present they are usually paranoid in
nature
d.
They often include grandiosity and hypomania
CHAPTER
6
Surgical therapy for
Parkinsons disease
Nawaz Hack & Michael S Okun
Contents
Brief historical perspective
102
Patient selection: knowing when to proceed to DBS therapy 102

Fluctuating motor symptoms (onoff fluctuations & loss of
quality on time) & dyskinesia
104
Medication refractory tremor
105
Quality of life
105
The role of an interdisciplinary team
105
Targeting symptoms rather than disease
106
DBS programming, troubleshooting & follow-upcare
108
Potential DBS-related complications
110
Future directions
111
doi:10.2217/EBO.13.121
99
Hack & Okun
About the authors

Nawaz Hack
Nawaz Hack is an Adjunct Clinical Fellow at the
Center for Movement Disorders & Neurorestoration,
University of Florida College of Medicine in Gainesville (FL, USA). After completion of a neurology residency at the University of Kentucky (KY, USA), he
pursued his interest for further training in Parkinsons disease at the University of Florida (FL, USA).
His professional interests include spreading crosscultural awareness about Parkinsons disease.
Michael S Okun
Michael S Okun received his MD degree from the University of Florida and completed a movement disorders fellowship at Emory University (GA, USA). He is
the Adelaide Lackner Professor of Neurology and the
Administrative Director and Co-Director of the Center
for Movement Disorders and Neurorestoration (FL,
USA). He has published over 300 peer-reviewed articles
and chapters and his research has focused on motor
and non-motor effects of deep-brain stimulation.
100
Surgical therapy for PD
Learning points
Parkinsons disease is the second most common neuro

degenerative movement disorder and should be optimally treated
medically before consideration of surgical therapy.
Deep-brain stimulation (DBS) surgery should be considered after 5years
of symptomatic Parkinsons disease treatment and when medication
therapy is optimized but there are still disabling symptoms.
Levodopa responsive symptoms will respond best to DBS therapy
with the exception of medication-refractory tremors and dyskinesia,
which may still be responsive to surgical therapy.
Patient selection is the most critical step in successful DBS therapy.
Setting realistic expectations is a very important part of DBS
management and should occur preoperatively.
Summary
Deep-brain stimulation (DBS) has largely replaced surgical
ablative techniques for the treatment of Parkinsons disease.
Comparisons of DBS to lesion therapy have, in general,
revealed a few important advantages of DBS therapy. These
advantages include reversibility, adjustability and a lower
risk of pseudobulbar and cognitive issues, particularly when
employing bilateral DBS therapy [1] . There are, however,
reasons to lesion, including cost, access to programming,
age (e.g., thinning skin) and immunosuppression [13] .
This chapter will focus exclusively on DBS, and will cover
the areas of patient selection, patient expectations and
surgical risk. In addition, we will provide a brief overview
of the actual surgery, important caveats to target selection,
and the basics involved in DBS programming. We will also
discuss how the field has shifted from disease-specific to
symptom-specific targeting. We will provide a discussion of
adverse events, troubleshooting and of the management
of DBS failures. Finally, we will summarize the important
points relevant to employing an interdisciplinary team.
101
Hack & Okun
Brief historical perspective

Surgical therapies aimed primarily
at alleviating movement anomalies
inclusive of Parkinsons disease
(PD) trace their origins to Bucy and
even before, when lesioning of the
corticospinal tract was attempted in
an effort to alleviate hyperkinesia and
chorea [4] . Though early attempts were
unsuccessful, the field evolved over the
ensuing decades and gradually specific
regions of the basal ganglia and the
thalamocortical circuitry were identified
and selectively targeted.
The advent of the stereotactic head
frame allowed millimeter-level accuracy
in targeting of deep-brain structures.
The first stereotactic frame system was
developed by Sir Victor Alexander Haden
Horsley and Robert Henry Clarke[5] .
Hassler, Cooper and many other
notable neurosurgeons pressed on with
the use of lesion therapy, and this was
important to the eventual approaches
used in deep-brain stimulation (DBS)
[6] . Early DBS was used mainly to
address medication-refractory epilepsy,
pain and spasticity, and also some
movement disorders. Modern DBS
surgery for addressing tremor and PD
was introduced 1987 by Benabid. Since
1987, the DBS field has expanded and

grown to include multiple diseases
and multiple potentially disabling, but
modifiable symptoms.
Patient selection: knowing

when to proceed to DBS
therapy
PD DBS surgery is usually not pursued
until the diagnosis has been confirmed,
and in most cases a minimum of
5years has elapsed. A 5-year period
is an arbitrary time interval that
helps DBS teams to be reasonably
sure that multiple system atrophy or
another parkinsonian disorder will not
develop [1] . The 5-year waiting period
has not been examined in an evidencebased fashion. Although there are
no firmly established guidelines, the
American Academy of Neurology
offered a LevelC recommendation that
a levodopa challenge test be pursued
prior to consideration of PD DBS [711] .
In addition, most experts recommend
that multiple classes of medication and
multiple dosage intervals should be
employed prior to consideration of DBS
therapy [1,12] .
Many experts have focused on four main
symptom complexes that are known to
Deep-brain stimulation surgery: a surgical intervention that

involves the placement of electrodes in the brain in order to
electrically modulate key nuclei and to attempt to alleviate select
symptoms of Parkinsons disease.
102

respond well to DBS in general [1,13] .
These symptoms include: improvement
in motor fluctuations and consequent
increases in on dopaminergic time;
suppression of dyskinesia; meaningful
improvements in quality of life; and
tremor suppression (Figure6.1). DBS
surgery in advanced PD has been US
FDA-approved since 2002, although
the procedure does not improve
all aspects of the syndrome, and
manifestations are widely variable
across patients. There are many
potential benefits to DBS therapy;
however, these benefits will vary
widely among individual patients and
will be widely variable depending on
individual symptomatology. Reduction
of dystonia, suppression of tremor,
improved sleep architecture, decreased
bradykinesia, improved akinesia and

improved rigidity are all possible
improvements that may be seen
following DBS. In a minority of select
cases improvements in freezing, gait
and balance issues may be realized.
It is important, however, for potential
DBS candidates to be informed that in
most cases improvements in walking,
freezing and balance occurs when
symptoms are responsive to levodopa
on a preoperative onoff dopaminergic
challenge test. In addition, even if
these symptoms respond, they are
likely to re-emerge, progress and in the
future become unresponsive to both
levodopa and to DBS. Speech in many
cases may worsen following DBS,
manifested as word-finding difficulty,
hypophonia and dysarthria.
Dyskinesias
Motor fluctuations
Major DBS
indications
Quality-of-life improvement
Refractory tremors
Figure6.1. Four of the major symptoms that, in general, have an excellent

response to Parkinsons disease deep-brain stimulation.
DBS: Deep-brain stimulation.
103
Hack & Okun

Important risk factors to consider prior
to DBS surgery include the presence
of dementia, significant cognitive dysfunction, severe untreated depression,
unstable psychiatric disease, atypical
parkinsonian signs and unrealistic expectations. Comorbid medical conditions may also increase the risk of DBS,
and therefore comorbidities should be
addressed by the neurologist, neuro
surgeon and the anesthesiologist prior
to an operation. In select cases an evaluation by an internist or family practitioner may be required, especially if
severe comorbid conditions or bleeding disorders are present. A complete
interdisciplinary DBS evaluation by a
neurologist, neurosurgeon, psychiatrist, physical therapist, occupational
therapist and speech therapist can be
critical for adequately assessing patient
safety issues, and also in facilitating
evaluations that will provide important data for team discussions on DBS
candidacy [8] .
Fluctuating motor
symptoms (onoff
fluctuations & loss of quality
on time) & dyskinesia
If medication therapy has been
optimized inclusive of altering in doses,
intervals and employing multiple
PD medications, then DBS may be
considered. DBS can be effective in
the improvement of quality on time,
and in suppressing dyskinesia [8] .
In general, most practitioners will
104
evaluate the patients in their off state

and after administration of a levodopa
challenge prior to consideration of
DBS. The patients are asked to stop
medications for 12h (the night prior),
and a Unified Parkinsons Disease Rating
Scale (UPDRS) III motor scale score is
recorded and scored by the doctor.
The practitioner then administers a
supra-threshold dose of levodopa and/
or other parkinsonian medications
(~1.52-times the typical dose) and
repeats the UPDRS III motor scale. The
change from off to on levodopa as
represented by a percentage should
exceed 30% to be considered an ideal
DBS candidate. There are, however,
exceptional cases with refractory
tremor or dyskinesia that may also be
candidates following an interdisciplinary
evaluation and a careful discussion.
These candidates may in some
cases miss the 30% threshold[7,14] .
Randomized studies have revealed
that the greatest benefit from a DBS
operation is improvement in quality
on time of approximately 46h[7,14] .
In addition, dyskinesia can be a severe
and bothersome phenomenon and
dyskinesia can impact the quality of life
for the PD sufferer[7,14] . Both globus
pallidus interna (GPi) and subthalamic
nucleus (STN) can directly suppress
dyskinesia [15] . Bilateral STN DBS has
been documented to result in medication
reduction [15] , and this reduction may
be an important part of the mechanism
of dyskinesia suppression. GPi is
thought by many experts to exert a

more direct suppression type of effect
on dyskinesia. GPi may also allow more
flexibility in long-term medication
management, although more studies
are required [15] . It is important when
considering the use of DBS specifically
to suppress dyskinesia to be sure that
the dyskinesia is actually bothersome to
the sufferer.
Medication refractory
tremor
It has been estimated that up to
2040% of tremors may prove
refractory to medications [16] . In some
cases tremor may be partially suppressed
by medications but still remain
bothersome. The pharmacological
management of PD tremor includes
the use of high-dose levodopa in
combination with dopamine agonists,
and in some cases, the addition of
anticholinergics. Anticholinergics are
not frequently utilized in clinical practice
due to the potential for associated
cognitive risks. Tremors may be
embarrassing and in some cases impair
activities of daily living and leisure
activities. Medication refractory tremor
in some cases can be an indication
for DBS therapy, even if a below 30%
levodopa response is documented by a
dopamine challengetest.
Quality of life
Multiple studies have documented an
enhanced quality of life resulting from
DBS surgery [15] . The improvements

that have been evidenced across studies
support the notion that well-selected
candidates improve in quality-of-life
measures following surgery. The exact
reasons underpinning quality of life
improvement are unknown. Activities
of daily living scores are improved postDBS in almost all studies, and these
improvements, along with motoric
improvements probably contribute to
enhancement of quality of life [15] . In
addition, 10-year data on DBS suggests
that axial and cognitive symptoms will
continue to progress and will have the
potential to erode the quality of life
for a PD sufferer [17] . Communication,
gait and other domains of quality of life
may be less amenable to DBS therapy
and further study will be required
to sort out the individual nuisances
in quality of life domains. In one
study the authors suggested that if
a single DBS lead was employed, use
of the GPi target resulted in a more
robust improvement in quality-of-life
measures [18] .
The role of an
interdisciplinary team
It has been suggested that the most
critical component to a successful DBS
intervention is patient selection [1,14] .
The initial process of triaging a potential
DBS candidate can be performed
by a single practitioner (neurologist,
internist,
family
practitioner,
a
registered nurse practioner, physician
105
Hack & Okun

assistant) through the administration
of the Florida Surgical Questionnaire
for Parkinson Disease, or the short
DBS screener introduced by Moro and
colleagues. The most important aspect
of DBS triage is to refer potential
candidates to experienced centers who
employ a rigorous interdisciplinary
screening process [14] .
Each member of the team evaluates
the potential candidate and discusses
the results in a DBS board type setting
(i.e., an interdisciplinary conference).
For patients deemed potential DBS
candidates, more discussion of the DBS
target, staging (unilateral vs bilateral or
bilateral staged procedure), anesthesia
and
perioperative
management
can also be deliberated. Successful
interdisciplinary teams usually employ a
neurologist, neurosurgeon, psychiatrist,
physical
therapist,
occupational
therapist, speech therapist and a
neuropsychologist. Some centers will
use a neurologist, neurosurgeon and
neuropsychologist as a core team,
and involve other specialists on an
as needed basis. In select cases, a
financial counselor or a social worker
may also be appropriately utilized.
Figure6.2 summarizes the details of a
DBS interdisciplinary work-up.
It is important to keep in mind that
there are ideal textbook candidates
for DBS, but that there may also
be other sufferers who merit full
consideration. For example, there
106
may be candidates with tremor or

bothersome dyskinesia, that although
not an ideal candidate (e.g., cognition
or another impaired domain), a DBS
operation may still be considered.
Similarly, there may be candidates for a
palliative DBS operation to relieve one
symptom that is impeding quality of
life. In exceptional cases, and in cases of
palliation, a thorough discussion of the
risks and benefits should be pursued
with the DBS board, the patient and
the family.
Targeting symptoms rather

than disease
Since the FDA approval of DBS the
focus has shifted from targeting
specific diseases (e.g., advanced PD) to
targeting bothersome and modifiable
symptoms. This shift in practice has
been evident not only in PD, but also
in dystonia, obsessive compulsive
disorder and essential tremor [1] . There
are three common targets utilized to
treat the symptoms of PD: GPi, STN,
and the ventralis intermedius nucleus
of the thalamus (VIM). All three
targets have proved successful for the
treatment of specific manifestations of
PD. The VIM thalamic target is rarely
used, but is still an option, especially
for upper extremity tremor. VIM is
employed by some DBS teams when
cognition or other issues increase the
risk of surgery [1] . The main issue with
the VIM target is that although very
effective for tremor (upper more than

Physical therapy
Occupational therapy
Speech therapy
Neurologist
Neurosurgeon
Psychiatrist
Psychologist
Social worker
Final decision on
candidate selection
for DBS
Figure6.2. The interdisciplinary assessment of deep-brain stimulation

candidacy.
lower extremity), it may not alleviate

bradykinesia, rigidity and dyskinesia.
Several randomized and placebocontrolled studies comparing GPi
versus STN implantation have revealed
similar improvements in UPDRS motor
scores, and also in dyskinesia, as well
as onoff fluctuation diaries [15] .
Since motor symptom improvement
is similar between targets, it is critical
to establish the symptoms that
an individual patient desires to be
improved following an invasive DBS
surgery. Although there are, as of yet,
no specific rules about which target for
which symptom, there are emerging
studies that may offer a glimpse of
the future. A recent review article on
tailoring DBS therapy summarizes
the potential pluses and minuses of
each target [15] . Some groups, for
example, have advocated that STN DBS
is preferred in cases where medication
reduction is the desired outcome. GPi
has been preferred by other groups

when cognitive issues or dyskinesia
are the main problems facing patients
and families. Recently, the long-term
outcome of DBS has revealed more
cognitive issues associated with the
STN target, but this remains to be
validated by larger studies [19] . Verbal
fluency (i.e., getting words out of the
mouth) issues may be worsened with
either target. It has recently been
demonstrated that verbal fluency issues
are more of a surgical effect rather
than directly related to the stimulation
parameters [15] . It is also important to
be aware that changes in the location
of stimulation on the DBS lead can
result in worsening mood and cognition
[1] . Suicide risk, impulse control and
dopamine dysregulation syndrome
will need to be more carefully studied,
although recent emerging evidence has
suggested that in some cases impulse
control and behavioral symptoms could
occur denovo from DBS therapy [20] .
107
Hack & Okun

The issue of suicide in DBS remains
unresolved, and it is unknown if one
target imparts a lower risk.
The choice of unilateral versus bilateral
DBS for PD has recently been gaining
more attention, with a growing
body of evidence revealing ipsilateral
benefits in some patients [21] . In
one recent study over a third of DBS
patients in long-term follow-up did not
require a second, contralateral, lead
placement [21,22] . The patients in this
cohort were treated for an average
of 3.5years, and the majority that
remained unilateral had a GPi target.
The most common reason cited for the
addition of a DBS lead was inadequacy
in addressing motor symptoms. A
second DBS was more likely for those
with higher baseline UPDRS-III motor
scores, and higher ipsilateral scores.
The odds of proceeding to bilateral DBS
were 5.2-times higher for STN than for
GPi. This information may translate into
a clinical decision for GPi in patients
who may possibly benefit from only
one lead. More studies will be required
to sort out the relevant differences in
one lead versus two.
DBS programming,
troubleshooting &
follow-upcare
There are many important tips for
practitioners in optimizing DBS
and in sorting out lesional versus
stimulation-induced effects. Verifying
108
stimulation responses intraoperatively

and also postoperatively can aid
in establishing the implantation
effect versus the effect from adding
stimulation. An evaluation performed
pre- and post-operatively, as well
as on and off stimulation, can help
in sorting out these issues [15] .
The recent randomized study of a
constant-current DBS device included
an implantation only arm. In this study
at 3months the dyskinesia diaries
improved by almost 2h (enhanced on
time), and verbal fluency was shown
to be an effect of implantation of the
DBS lead and not of stimulation [15] .
Following implantation of the pulse
generator, programming typically
commences a few weeks later. This
delay is to allow the edema effect to
resolve. The programmer will establish
thresholds for benefit and side effect
at each DBS contact on the lead. In
many cases intensive programming
occurs over the first 6months postDBS. Once programming has been
optimized during those first 6 critical
months there are few changes to the
DBS device. Ironically, the maintenance
of the DBS patient shifts to medication
management [15] . In addition, while
programming during the first 6months,
medications will need to be optimized.
It is now appreciated by most experts
that medications are not reduced in
all cases, and that over-aggressive
reduction can result in adverse
outcomes [15] . Each DBS patient must

therefore be individually tailored and
optimized in both programming and
medications. In the USA, Medtronic
(MN, USA) is currently the primary
supplier of neurostimulators (e.g.,
battery and software sources) for
movement disorders patients. There are
three model series available: Soletra,
Kinetra and Activa. The Soletra is
the oldest neurostimulator, and can
be connected to a single DBS lead.
The Kinetra model can be connected
to two DBS leads (usually one in each
brain hemisphere). The newer Activa
SC (single channel, single lead) and
PC (dual channel, multiple leads)
devices provide basic menu-driven
algorithms for programming, and the
capacity to store clinical responses
observed during programming sess
ions. These newer battery sources
also have several options for multiple
programs or settings that a patient
can adjust at home without returning
to the physicians office. Multiple DBS
programs for each neurostimulator
can be useful, particularly for patients
who travel long distances for access
to programming sessions. Finally, the
Activa series of neurostimulators can be
set to provide stimulation as a constantcurrent as well as a voltage-driven
power source; however, there have
been no efficacy studies comparing
them in movement disorders. There is
an Activa RC, or rechargeable option,
for patients using high battery drain
DBS settings, and who may require
frequent battery changes.
Programming parameters are typically

different on the two sides of the brain
if bilateral implants are present [15] .
During DBS programming there should
be vigilant monitoring and followup. Figure6.3 summarizes important
points to address in each follow-up
visit, namely.
Optimization of medical therapy,
and monitoring of very slow
tapering of medications, if
appropriate;
Monitoring for hardware-related
issues, and also for programming or
medication-related side effects;
Monitoring for mood or behavior
changes post-DBS surgery, especially
suicidal tendencies, depression,
mania and anxiety;
Identifying stimulation locations and
parameters that consistently alleviate
the motor symptoms of PD;
Educating patients on realistic
expectations and also reinforcing
that once optimized, continued
programming adjustments may not
be indicated.
A common pitfall in DBS programming
is to reduce medication dosages
too rapidly, and also for patients
and clinicians to believe that there is
always a programming setting that
will alleviate all symptoms. Another
pitfall is the failure to address realistic
expectations pre- and post-operatively.
Families should be educated that
not all symptoms can be alleviated
109
Hack & Okun
Optimize medications
and set realistic patient
expectations
Monitor hardware and

programming effects
but keep in mind
implantation effects
Optimal DBS
programming
Monitor for mood

and behavior changes
Choose parameters that

consistently alleviate the
motor symptoms, but do
not give side effects
Figure6.3. Principles of deep-brain stimulation programming.

by DBS programming, and that it

will probably take months to achieve
the optimal balance between pro
gramming and medications. Patients
are typically instructed to attend
programming sessions off of their
PD medications, so that the effects
of DBS programming can be assessed
without the confounding variables
added by pharmacotherapy. Finally,
it is important to order an image of
the DBS lead postsurgery in order to
assess the position of the DBS device.
It is important to keep in mind that
an image alone should not be used
to assess lead placement. Clinical
response (i.e., scales), threshold testing
at each contact and the image should
all be assessed together before deciding
whether a lead has been suboptimally
placed [15] . A group of DBS patients
110
has emerged in clinical practice, and

has been referred to as DBS failures[2] .
Most of these DBS failures can be
prevented by a rigorous preoperative
assessment (i.e., an interdisciplinary
team), adequate medication treatment,
optimization of DBS programming,
and by rechecking the lead position
by imaging, thresholds and clinical
response [2] . Half of DBS failures can
be improved by troubleshooting, and
troubleshooting has become a critical
part of modern DBS practice [1] .
Potential DBS-related
complications
Compared with medical therapy,
DBS has been cited to have an
approximately
3.8-times
higher
risk of serious adverse events

[23] . These adverse events include
intracranial hemorrhage, suicide,

stroke, pneumonia, im
plantation
site infections, sepsis and other
permanent neurological deficits[3] .
In one study, involving a total of
512patients who underwent 856
electrode implantations during a 14year study period, 58% of whom
had PD, there were a total of 44
patients (9%) who experienced some
hardware complication or required
system revision [2] . There were 21
electrode migrations in 19patients,
and 15broken wires in 13patients.
A device infection was observed in
ten (2%) of the 512patients, and two
patients had other complications.
Median time from implant to revision
was 1.5years for migrations, 1.6years
for infections and 3years for fractured
wires [2] . As a result of this large and
long-term experience, a systematic
approach
to
assess
hardware
complications in DBS patients was
proposed.
It should be noted that the incidence
of permanent neurological deficits
resulting from DBS remains below
1.5%
[24] .
Stimulation-induced
side effects include mania, suicide,
depression,
pseudobulbar
affect,
dyskinesia, motor pulling and sensory
paresthesias, among many other
possible side effects [25,26] . Effective
candidacy screening and optimal
programming as well as vigilant
medication management can reduce
the occurrence of complications. It is

important for DBS patients to be aware
of the risks and the potential bumps in
the road [15,23] . Burdick and colleagues
recently published a paper revealing
that the occurrence of adverse events
in DBS, although high overall, did not
correlate with quality-of-life outcomes
in DBS patients [27] .
Future directions
This
brief
chapter
addressed
caveats in patient selection, patient
expectations, tailoring therapy, and
the risks and benefits associated
with PD DBS. The DBS field has
been slowly shifting from diseasespecific targeting, to symptomspecific targeting. The differences
between targets and approaches
should be vetted carefully. All targets
and approaches should be chosen
thoughtfully for individual patients
in a personalized manner, and an
experienced interdisciplinary team
should interface with patients during
this process. Finally, troubleshooting
DBS failures has the potential to
enhance outcomes, and this practice
should become part of routine care
inDBS.

disclosure
The authors have no relevant affiliations or financial involvement with any
111
Hack & Okun

in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received

or pending, or royalties.
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Unilateral deep brain stimulation surgery
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(2010).
27. Burdick AP, Fernandez HH, OkunMS,
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113
Hack & Okun

1.
2.
3.
4.
5.
114
Deep-brain stimulation (DBS) surgery should be considered in patients who have symptoms of Parkinsons disease for 1year and
have not tried adequate medication therapy.
a.
True
b.
False
Most Parkinsons disease motor symptoms that are responsive to
levodopa will be responsive to DBS, with the exception of tremor
and dyskinesia.
a.
True
b.
False
Patient selection is not important in the decision-making process
for DBS.
a.
True
b.
False
When deciding on DBS therapy, one of the most important
considerations should be:
a.
The symptoms targeted
b.
The patients attire
c.
The availability of a home nurse
d.
The patients history of tobacco use
The initial process of triaging a potential DBS candidate can be
performed by:
a.
A nurse practitioner
b.
A general practitioner
c.
An internist
d.
A physician assistant
e.
All of the above
CHAPTER
Experimental therapeutics
for motor symptoms of
Parkinsons disease
Susan H Fox & Lorraine V Kalia
Contents
Disease-modifying agents in PD
118
Targets for motor symptoms of PD
120
Targets for motor complications
120
Treatments for levodopa-induced dyskinesia
126
Conclusion
132
doi:10.2217/EBO.13.113
115
Fox & Kalia
About the authors

Susan H Fox
Susan H Fox is Associate Professor of Neurology at
the University of Toronto, Movement Disorders Clinic at Toronto Western Hospital (ON, Canada). She is
the Director of the University of Torontos Neurology
Fellowship program. She is an international executive committee member of the Movement Disorder
Society, on the editorial board of the Movement Disorder journal, and a member of the Parkinson Study
Group. Her current research includes preclinical studies investigating disease mechanisms of Parkinsons disease and other
movement disorders, as well as PhaseII and Phase III clinical trials of
new treatments for Parkinsons disease and dystonia.
Lorraine V Kalia
Lorraine V Kalia is a movement disorders fellow in
the Division of Neurology at the University of Toronto (ON, Canada). She is currently pursuing a combined clinical and research fellowship in the Morton
and Gloria Shulman Movement Disorders Clinic and
Edmond J Safra Program in Parkinsons Disease at
the Toronto Western Hospital. Her research interests focus on the molecular mechanisms underlying
the pathogenesis of Parkinsons Disease with the
goals of rational drug design and the development of novel therapies.
She holds a Canadian Institutes of Health Research ClinicianScientist
PhaseI Award.
116
Experimental therapeutics for motor symptoms of PD
Learning points
To date, no therapy has slowed down, or reversed the disease

process, in Parkinsons disease.
Novel targets for motor symptoms include better delivery
of levodopa, as well as nondopaminergic targets to prevent
levodopa-induced side effects.
Treating levodopa-induced motor complications is the largest area
of research.
Summary
Study into the causes and treatments for Parkinsons disease
remains an active area of research, both in academia as
well as the pharmaceutical industry. This chapter will
outline concepts behind novel therapeutics for a number of
aspects of Parkinsons disease, including so-called diseasemodifying therapies (neuroprotective) as well as therapies
for motor symptoms and complications of long-term
levodopa therapy.
117
Fox & Kalia

Parkinsons disease (PD) is primarily
caused by degeneration of dopaminergic
cells within the substantia nigra pars
compacta of the brainstem. The cause
of this cell loss is generally unknown,
although probably involves interplay
between genetic susceptibility, environ
mental factors and aging. The disease is
slowly progressive over many years but
with initial good improvement in motor
symptoms due to the use of the
dopamine precursor, levodopa. Longterm use, however, results in the
development of motor complications
that affect quality of life. In addition,
many non-motor symptoms of the
disease develop such as psychiatric
issues, cognitive impairment, psychosis,
mood disorders, pain and autonomic
problems. Thus, there are many aspects
to PD that require therapeutic inter
vention. This chapter will focus on
experimental therapies for the motor
symptoms of PD.
Disease-modifying agents
in PD
Many novel approaches have been
investigated as potentially able to slow
down disease progression (also called
neuroprotective) at the preclinical level.
These include agents that target many
aspects of dopamine cell survival,
including oxidative stress, mitochondrial

function, apoptosis, excitotoxity, calcium
turnover, protein folding and recycling,
and inflammation (reviewed in [1]).
Oxidative stress (damage due to
reactive oxygen species) is a key
factor in dopamine cell loss. Oxidative
damage and the associated mito
chondrial dysfunction may result in
energy depletion, accumulation of
cytotoxic mediators and cell death.
The selective vulnerability of dopamine
cells in the substantia nigra may be
due to an age-related reliance on a
certain type of calcium channel, the
L-type Ca(v)1.3Ca2+ channels. With age
there is a switch in channel type that
predominates and can make the cells
vulnerable to oxidative stress. Blocking
this action has thus been proposed
as a means of neuroprotection and
a clinical study using the calcium
channel blocker, isradipine is ongoing.
A depletion of antioxidants has been
suggested to be part of the disease
process and thus use of the antioxidant,
glutathione in PD is being evaluated.
Microglial cells play a key role in the
oxidative stress process [2] . Myeloper
oxidase is a neutrophil and macrophage
product that drives inflammatory
reactions and tissue oxidation and the
myeloperoxidase inhibitor, AZD3241, is
Neuroprotection: the process of preventing ongoing neuronal

cell loss.
118

in development for PD. Mitochondrial
dysfunction is also a key part of PD
pathophysiology [3] . Supplementation
with the mitochondrial respiratory
chain enhancer, coenzyme Q10, was
previously tried but with variable
results. Other targets include peroxi
some proliferator-
activated receptorg
coactivator-1a (PGC1a), which is under
expressed in PD subjects and activation
of PGC-1a is thought to increase
mitochondrial respiratory function.
Thus the PGC1a activator, pioglitazone
is being evaluated. Creatine is also
being evaluated in early PD. Creatine
kinase may increase phosphocreatine
or cyclophospho
creatine and buffer
against ATP depletion and thus improve
mitochondrial function.
Epidemiology studies have shown
that people who smoke and drink
coffee are less likely to develop PD;
the mechanisms are not entirely clear
but nicotine and adenosine have both
neuroprotective properties invitro
and agents targeting these receptors
are in clinical development. Likewise,
patients with gout and high plasma
uric acid levels have been shown to
have a lower risk of developing PD due
to antioxidant properties of uric acid.
Inosine can elevate uric acid and is being
evaluated in PD. Neuroinflammation
is also probably a key factor in
dopamine cell loss. Agents that reduce
inflammation include filgrastim, which
is a granulocyte colony-stimulating
factor that improves cell survival via
nonapoptotic and anti-inflammatory

mechanisms. Neuronal growth factors
can improve dopamine cell survival
and include glial-derived neurotrophic
factor (GDNF) and brain-derived
neurotrophic factor (BDNF). Infusion
studies with GDNF were not successful
owing to several possible reasons [4] .
Enhanced delivery of GDNF using viral
vectors is in development (adenoassociated virus-2 [AAV2]-GDNF).
PYM50025 is an orally active agent
that may enhance growth factors and
is also being evaluated in early PD.
Clinical studies have investigated these
agents in both advanced PD as well as
early denovo PD. The ability exhibited
by an agent to slow down disease at
any stage is termed disease-modifying.
To date, clinical studies have been
disappointing in translating potentially
promising preclinical work in terms of
demonstrating any effect on slowing
down disease progression. This has been
due to a number of factors including:
Some potential drugs having an
effect on both motor symptoms
perse as well as neuroprotective
action (e.g., monoamine oxidase
type B [MAO-B] inhibitors, selegiline
and rasagiline; dopamine agonists,
ropinirole and pramipexole) thus
making interpretation of outcomes
unclear;
Difficulty in measuring
neuroprotection (i.e., remaining
dopamine cells) separate from an
overall assessment of motor disability;
119
Fox & Kalia

Giving the interventions too late, as
it is now known that PD starts many
years prior to the motor onset with
several preclinical symptoms now
recognized.
Thus, these caveats are important
in future studies for neuroprotective
drugs in PD (Table7.1) [5,6] .
Targets for motor symptoms

of PD
PD motor symptoms include slowness
(bradykinesia),
rigidity,
tremor
and gait problems. Levodopa is a
dopamine precursor that remains
the gold-standard therapy for all PD
symptoms, at all stages of the disease.
Long-term use, however, results in
motor fluctuations and has led to
alternatives to dopamine that may be
used before starting levodopa, termed
levodopa-sparing agents. Other
means of administering dopamine
include the synthetic dopamine
agonists that have a longer half-life
than levodopa and bypass gastric
absorption issues. One new dopamine
D2 receptor agonist, pardoprunox,
has been investigated as early
monotherapy with a demonstrated
mild benefit but titration dose-related
side effects. Other strategies are
mild dopamine-enhancing agents
that inhibit monoamine oxidase

enzyme system (MAO-B inhibitors)
to prevent breakdown of dopamine
and, as such, have mild symptomatic
effects. Safinamide is one such
new agent with mild effects in
monotherapy and results from a large
randomized control trial as add-on
to dopamine agonists are pending.
Nondopaminergic agents have also
been investigated. For monotherapy
or adjunct therapy for motor
symptoms, these have focused on
symptoms that are often levodoparesistant. Thus cholinergic dysfunction
via brainstem circuits involving the
pedunculopontine nucleus has been
proposed to mediate gait and balance
dysfunction in PD (Table7.2) .
Targets for motor

complications
Long-term use of levodopa, although
effective, can lead to fluctuations
in benefit called wearing off, and
delayed onset of action. This can be
due to erratic absorption of levodopa
due to competition with dietary protein
amino acids for transport across the
gut wall and reduced absorption
due to slow gastric emptying and
constipation. GSK962040 is a motilin
agonist that is being investigated in
Motor fluctuations: variations in improvement and loss of benefit

of motor symptoms following dose of levodopa.
120
Prevents oxidative stress
Enhances dopamine
survival; mechanism
unclear
Possibly antiinflammatory
Prevents glutamate
excitotoxicty and
reduces inflammation
Antioxidant
Isradipine
N-acetylcysteine
Intranasal
tripeptide
glutathione
GM1 ganglioside
Transdermal
nicotine
Preladenant
Inosine
Elevates uric
acid
Adenosine A2A
antagonist
Nicotine
Endogenous
sphingolipid
Increases
glutathione
Increases
glutathione
Calcium channel
blocker
Drug action
PhaseII DBRCT dose-finding and tolerability

study in early PD (n=90) and with low serum
urate (5.54mg/dl) over 12weeks
PhaseIII DBRCT in early PD (n=1000).

Preladenant monotherapy vs rasagiline over
26weeks. Outcome: UPDRS II and III
PhaseII safety study in early untreated PD

(n =160). Outcome: UPDRS part I, II, III after
52weeks
Open-label extension of early RCT over 5years

in early treated PD (n=26). Outcome: lower
UPDRS II and III
PhaseI/II single ascending dose escalation

study over 12weeks
PhaseI/II safety and tolerability study over

4weeks
PhaseI/II tolerability study in moderate PD

patients (n=31). Tolerable in 81%. Side effects
were dizziness and ankle edema
Clinical study
[105]
[104]
[103]
[11]
[102]
[101]
[10]
Ref.
AAV2: Adeno-associated virus-2; b.i.d.: Twice daily; DBRCT: Double-blind, randomized controlled trial; GDNF: Glial-derived neurotrophic factor; MPO: Myeloperoxidase; PD:Parkinsons disease; PPARg:Proliferator-activated receptor-g; RCT: Randomized controlled
trial; UPDRS: Unified Parkinsons Disease Rating Scale.
Proposed mechanism
of neuroprotection
Name
Table 7.1. Experimental therapies for disease modification.
121
122
Nonapoptotic and
anti-inflammatory
mechanisms
Antioxidant via
microglial activation
Increases mitochondrial
respiratory function?
Improves mitochondrial
function
Filgrastim
AZD3241
Pioglitazone
Creatine
Enhances
creatine kinase
activity
PPARg agonist
MPO inhibitor
G-CSF
Drug action
PhaseII DBRCT in early PD (n=200). Creatine

(10g/day) and minocycline (200mg/day)
over 12months. Outcome: neither could be
rejected as futile based on the DATATOP futility
threshold, using change in total UPDRS. Longterm (57years) RCT using creatine 5g b.i.d is
ongoing in treated PD patients (n=1741)
PhaseII DBRCT early PD subjects on stable

monoamine oxidase B inhibitor allowed
(n=216). Safety, tolerability, and futility, of
pioglitazone (15 and 45mg) over 44weeks
PhaseIIa DBRCT in early untreated PD (n=50).

Safety and tolerability of AZD3241 over
12weeks
PhaseII DBRCT in early treated PD (n=36)

of high- vs low-dose G-CSF and placebo
for consecutive 5days of each 60-day cycle
(6cycles). Outcome: UPDRS III
Clinical study
[109]
[108]
[107]
[106]
Ref.
Proposed mechanism
of neuroprotection
Name
Fox & Kalia
Convection
enhanced
delivery/AAV2GDNF
Unknown
GDNF may prevent

dopamine cell loss
Vaccine against aand b-synuclein (no

references to preclinical
data provided)
AAV2-GDNF
PD01A
PhaseI tolerability and safety of fourinjections
of two doses of PD01A formulated with
aluminium oxide in early PD (n=32)
over 1year. One study site (Austria) vs
eightuntreated controls
PhaseI in advanced PD (n=28), open-label,

dose-escalation, safety of fourdifferent dose
levels of AAV2-GDNF into putamen over
5years
PhaseI studies (n=9), safety in healthy and PD

subjects; PhaseII RCT in early PD (n=408) for
28weeks. Outcome: UPDRSII and III
Clinical study
[112]
[111]
[110]
Ref.
Orally active
synthetic
chemical that
enhances
growth factors
Enhances growth
factors and dopamine
cell survival
PYM50028
Drug action
Proposed mechanism
of neuroprotection
Name
123
124
Glutamate
antagonist
[113]
[13]
[12]
Ref.
PhaseIV RCT in PD with freezing of gait (n=15).

Outcome: freezing of gait using UPDRS part I score
>2 at week11
[116]
[115]
[114]
PhaseII DBRCT safety and efficacy in early,
untreated PD (20 or 30mg/kg/day deferiprone vs
placebo) (n=36). Outcome: MRI and clinical scores
at 6months
Nicotinic partial a4b2 PhaseII DBRCT in PD subjects (n=40) with falls.

agonist and full a7
Outcome: Berg Balance Scale and UPDRS at
agonist
9weeks
Iron chelator
PhaseIIb DBRCT in early PD on dopamine agonist

(n=270). Outcome: improved UPDRSIII (-6.0
points for safinamide 100mg vs -3.6 points for
placebo, p<0.05)
PhaseIII study in early PD on dopamine agonist
(n=679). Outcome: UPDRS II and III
Two PhaseIII DBRCTs in early PD (n=687 total).

Outcome: small improvement in motor scores versus
placebo; n.s. versus pramipexole. High dropout rate
due to nausea, sleepiness and dizziness
5-HT1A agonist
and dopamine D2
agonist
Mixed MAO-B
inhibitor and
glutamate
antagonist
Clinical study
Drug action
DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B; n.s.: Nonsignificant; PD: Parkinsons disease;
PPN:Pedunculopontine nucleus; RCT: Randomized controlled trial; UPDRS: Unified Parkinsons Disease Rating Scale.
Improve gait;
mechanism
unknown
Removal of excess
iron from substantia
nigra
Deferiprone
Amantadine
Mild dopaminergic
effect
Safinamide
Improve gait and

balance targeting
PPN via cholinergic
system?
Dopaminergic
Pardoprunox
(SLV208)
Varenicline
Proposed mech
anism of action
Name
Table 7.2. Experimental treatments for symptomatic monotherapy or adjunct therapy.
Fox & Kalia
To improve gait and

balance via action
on PPN cholinergic
system?
Mechanism
unknown
Donepezil
Dalfampridine
4-aminopyridine
potassium channel
blocker; mechanism
unclear
Cholinesterase
inhibitor
Drug action
PhaseII DBRCT crossover in PD with gait issues

(n=25). Outcome: objective gait velocity and
stride length and UPDRS
PhaseIV DBRCT crossover study in PD with gait

problems (n=12). Outcome: objective gait analysis
at 21days
Clinical study
DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B; n.s.: Nonsignificant; PD: Parkinsons disease;
PPN:Pedunculopontine nucleus; RCT: Randomized controlled trial; UPDRS: Unified Parkinsons Disease Rating Scale.
Proposed mech
anism of action
Name
Table 7.2. Experimental treatments for symptomatic monotherapy or adjunct therapy.
[118]
[117]
Ref.
125
Fox & Kalia

Dyskinesia: involuntary movements that develop as a consequence
of long-term levodopa therapy.
early PhaseIIa studies. This agent

may increase gastric emptying and
thus increase levodopa absorption.
Alternative methods of administration
of levodopa are also being evaluated
that bypass these issues. This includes
nasal administration of levodopa
(CVT-310). An approach to treatment
of motor fluctuations, in particular
wearing off, is the addition of drugs
that prevent dopamine breakdown
via enzyme inhibition; for example
catechol-O-methyl
transferase
(COMT) or MAO-B inhibition. Several
new agents are in development,
including a long-acting COMT
inhibitor, opicapone, and a novel
MAO-B inhibitor, safinamide. Another
target is the nondopaminergic
neuromodulator,
adenosine.
Adenosine A2A antagonists can
increase motor function via an action
on striatopallidal pathways, thus
potentially having an antiparkinsonian
action without driving dyskinesia, as
would occur with direct dopamine
agents. Several such adenosine A2A
antagonists are in development and
include istradefylline (not approved
by the US FDA but in development in
Japan), tozadenant and preladenant
with a general trend to improving
off time by an average 1.5hours
(Table7.3) .
126
Treatments for
levodopa-induced dyskinesia
Involuntary movements termed dyskinesia are a common long-term problem
in advanced PD due to chronic levodopa
use. The pathophysiology of dyskinesia
involves overactive glutamatergic pathways from cortex to caudate-putamen
(striatum) that alters output from the
basal ganglia circuitry and abnormal
activation of motor cortex, resulting in
hyperkinetic movement. Agents that
target this abnormal glutamatergic activity have been investigated for reducing levodopa-induced dyskinesia. The
NMDA receptor antagonist, amantadine, is currently the most commonly
used agent in clinical practice. An extended release version (ADS-5102) with
potentially fewer side effects is being
evaluated. Other glutamate receptors
have also been implicated and several
agents that target one subtype, socalled metabotropic mGluR5 receptors,
are in development; the rationale being
a wider therapeutic window to reduce
side effects. mGluR5 antagonists in clinical development include mavoglurant
(AFQ056) and diplagurant (ADX48621).
Other potential antiglutamate targets include naftazone that reduces
glutamate release, although to date
only one small study was conducted.
Increases absorption
Motilin
of levodopa across
agonist to
gastrointestinal mucosa increase
gastric
emptying
More rapid absorption

of levodopa
Enhances half life of

dopamine
GSK962040
CVT-310
(levodopa
inhalation
powder)
Opicapone
PhaseII DBRCT in PD subjects with delayed gastric

emptying (breath test) and motor fluctuations (n=70)
of repeat doses of GSK962040 on the pharmacokinetics
of levodopa after 8days
Clinical study
FiveRCTs studies (total population >1500patients with
motor fluctuations); reduced off time by 11.3h, but
two of fivestudies were n.s. versus placebo
PhaseIII DBRCT in PD subjects with 1.5h off time/

day (n=550); opicapone vs entacapone or placebo.
Outcome: UPDRSIIII at 1415weeks
[14]
[121]
[120]
[119]
Ref.
COMT: Catechol-O-methyl transferase inhibitor; DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B;
n.s.: Nonsignificant; PD: Parkinsons disease; RCT: Randomized controlled trial; UPDRS: Unified Parkinsons Disease Rating Scale.
Istradefylline Improves motor activity Adenosine

by reducing inhibition
A2A
of indirect dopamine
antagonist
D2 striatopallidal
pathway
Long acting
COMT
inhibitor
Nasal
PhaseII RCT in PD subjects with 2h off time/day
administration (n=24); safety, efficacy and pharmacokinetics versus
of levodopa
oral levodopa. Outcome: off time over 13weeks
Proposed mechanism Drug action

of action
Name
Table 7.3. Experimental therapies for motor fluctuations.
127
128
Mixed MAO-B PhaseIII DBRCT in PD subjects with >1.5h off time
inhibitor and
(n=549). Outcome: change from baseline in daily on
time at 24weeks
glutamate
antagonist
[124]
[16]
[15,
123]
[122]
Ref.
COMT: Catechol-O-methyl transferase inhibitor; DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B;
n.s.: Nonsignificant; PD: Parkinsons disease; RCT: Randomized controlled trial; UPDRS: Unified Parkinsons Disease Rating Scale.
Extends duration of
levodopa action by
MAO-B
PhaseIII DBRCT PD (n=295) with motor fluctuations

(>2.5h/day in off state). Outcome: reduction in off
time (-1.62h/day for pardoprunox vs -0.92h/day for
placebo, p<0.05) at 23weeks
PhaseIIb DBRCT in PD with wearing off (n=253).

Outcome: improved mean daily off time (-1.0h for
preladenant 10mg/day, -1.2h for preladenant 20mg/
day vs -0.5h for placebo, p<0.05). 12-week DBRCT in
PD with motor fluctuations (n=450). Outcome: change
from baseline to week12 in mean off time in hours
per day
Safinamide
Improves motor activity Adenosine

A2A
antagonist
D2 striatopallidal
pathway
Preladenant
PhaseII DBRCT in PD with wearing off (n=400).

Outcome: mean total hours of awake time per day
spent in the off state
Partial
dopamine
D2 agonist
and 5-HT1A
agonist
Improves motor activity Adenosine

A2A
antagonist
D2 striatopallidal
pathway
Tozadenant
(SYN115)
Clinical study
Pardoprunox Dopaminergic and

(SLV208)
serotonergic
Proposed mechanism Drug action

of action
Name
Table 7.3. Experimental therapies for motor fluctuations.
Fox & Kalia
Higher daytime drug

levels and lower night
time to avoid nocturnal
side effects
Antagonism
of overactive
corticostriatal
glutamate activity
Antagonism
of overactive
corticostriatal
glutamate activity
Reduction in overactive
corticostriatal
glutamatergic activity
ADS-5102
(extended
release
amantadine
HCl)
Mavoglurant
(AFQ056)
Dipraglurant
(ADX48621)
Naftazone
Reduces
glutamate
release
mGluR5
antagonist
mGluR5
antagonist
NMDA
antagonist
Drug
action
PhaseII DBRCT (four consecutive 28-day crossovers)

in PD with troublesome dyskinesia (n=7). Outcome:
diaries, five/seven patients responded to naftazone for
on-time with troublesome
PhaseIIa DBRCT in PD with troublesome dyskinesia

(n=76). Outcome: safety and dyskinesia severity over
4weeks. Side effect: dizziness
Two PhaseIIa studies in PD with troublesome

dyskinesia (total n=59). Outcome: reduction in
dyskinesia vs placebo over 20days. Side effect:
dizziness. No worsening of PD motor scores. PhaseIIb
DBRCT in PD with troublesome dyskinesia (n=140).
Outcome: reduction in AIMS after 12weeks
PhaseIII DBRCT in PD with troublesome dyskinesia

(n=80). Outcome: UDysRS total score at 8weeks
Clinical study
AIMS: Abnormal involuntary movement scale; DBRCT: Double-blind, randomized controlled trial; DHA: Docosahexaenoic acid;
LIDS:Levodopa-induced dyskinesia scale; mGluR5: Metabotropic glutamate receptor; NMDA: N-Methyl- d -aspartate receptor;
PD:Parkinsons disease; UDysRS: Unified Dyskinesia Rating Scale.
Proposed mechanism
of action
Name
Table 7.4. Experimental agents for dyskinesia.
[20]
[19,
127]
[17,
18,
126]
[125]
Ref.
129
130
Nicotinic/cholinergic;
reduces dopamine
release following
desensitization of
nicotinic receptors in
the striatum
Nicotinic/cholinergic;
reduces dopamine
release following
desensitization of
nicotinic receptors in
the striatum
Enhances activity
a2
of indirect D2,
antagonism
corticostriatal pathway?
Reduces levodopa
conversion to
noradrenaline?
AQW051
NP002
Fipamezole
PhaseIIb DBRCT in PD with dyskinesia (n=180).

Outcome: LIDS after 4weeks non-significant.
Subgroup: improvement for US patients (-3.7points for
fipamezole 90mg vs -1.1points for placebo, p<0.05)
PhaseII DBRCT in PD with moderate to severe

dyskinesia (n=65). Outcome: safety and tolerability,
trends favoring NP002 on UDysRS over 12weeks
PhaseII DBRCT in PD with troublesome dyskinesia

(n=72). Outcome: safety and tolerability, AIMS at
28days
PhaseIIb DBRCT in PD with troublesome dyskinesia

(n=24). Outcome: UDysRS at 42days
Clinical study
Nicotinic
agonist
Positive
allosteric
modulation
of a7nAChR
Glutamate
antagonism
Reduction in overactive
corticostriatal
glutamatergic activity
Safinamide
Drug
action
Proposed mechanism
of action
Name
[22]
[21,
130]
[129]
[128]
Ref.
Fox & Kalia
Reduces
neurotransmitter
release?
Omega-3 fatty acid

has been suggested to
delay development of
dyskinesia in preclinical
models
Levetiracetam
DHA
Omega-3
fatty acid
Binds
synaptic
vesicle
protein2A
Drug
action
[23
25]
[131]
DBRCT in denovo PD subjects (n=40). Outcome:

safety and efficacy (dyskinesia rating scale not
specificied) at 1.5years
Ref.
Three PhaseII DBRCTs (total n=86). Outcome:

reduced on time with dyskinesia according to patient
diaries (one positive: -3.8% for levetiracetam 500mg,
-7.8% for levetiracetam 1000mg, values for placebo
not reported)
Clinical study
Proposed mechanism
of action
Name
131
Fox & Kalia

Safinamide, as well as having MAO-B
inhibitory properties also reduces glutamate release and is being evaluated for
dyskinesia. To date, any superior efficacy or tolerability of these agents compared with amantadine is unknown.
Other nondopaminergic systems that
have been targeted include nicotinic
cholinergic receptors, a2 adrenoceptors
and SV2 using the antiepileptic levetiracetam. Another novel approach is via
docosahexaenoic acid, which enhances
omega3 fatty acids that may play a
role in propensity to develop dyskinesia
(Table7.4).
Conclusion
Novel therapeutics for PD target
a range of neurotransmitters and
neuromodulators. To date, no single
agent is better than levodopa as
monotherapy or add-on therapy for
symptom relief [7,8] . Several agents are
in development for reducing disease
progression as well as improving

levodopa duration of action and
lessening impact of dyskinesia [9] .

disclosure
S Fox has received research funding
from NIH, Canadian Institute of Health
Research and Michael J Fox Foundation for Parkinsons Research. She has
also received consultancy fees and
funding from Acadia, Asubio, Merck
Serono, Merz, Ipsen, Kyowa, Novartis,
Teva, Phytopharm and UCB. The authors have no other relevant affiliations or financial involvement with any
disclosed.
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New synaptic and molecular targets for
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Peterson LJ, Flood PM. Oxidative stress

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Meissner WG, Frasier M, Gasser T etal.

Priorities in Parkinsons disease research.
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Henchcliffe C, Beal MF. Mitochondrial

biology and oxidative stress in Parkinson
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Clinical utility of neuroprotective
agents in neurodegenerative diseases:
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for Alzheimers, Parkinsons and
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Randomized controlled trial of
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7.
Ferreira JJ, Katzenschlager R, Bloem BR

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25(4), 433447 (2012).
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448459 (2012).
10. Simuni T, Borushko E, Avram MJ
etal. Tolerability of isradipine in early
Parkinsons disease: a pilot dose
escalation study. Mov. Disord. 25(16),
28632866 (2010).
11. Schneider JS, Sendek S, Daskalakis
C, Cambi F. GM1ganglioside in
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292(12), 4551 (2010).
12. Sampaio C, Bronzova J, Hauser RA
etal. Pardoprunox in early Parkinsons
disease: results from 2 large,
randomized double-blind trials. Mov.
Disord. 26(8), 14641476 (2011).
13. Stocchi F, Borgohain R, Onofrj M etal.
A randomized, double-blind, placebocontrolled trial of safinamide as add-on
therapy in early Parkinsons disease
patients. Mov. Disord. 27(1), 106112
(2012).
14. Chen W, Wang H, Wei H, Gu S, Wei
H. Istradefylline, an adenosine A(2A)
receptor antagonist, for patients with
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15. Hauser RA, Cantillon M, Pourcher
E etal. Preladenant in patients
with Parkinsons disease and motor
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221229 (2011).
16. Rascol O, Bronzova J, Hauser RA etal.

Pardoprunox as adjunct therapy to
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12431250 (2011).
18. Stocchi F, Destee A, Hattori N etal.
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19. Tison F, Durif F, Corvol JC etal. Safety,
tolerability and anti-dyskinetic efficacy
of dipragulant, a novel mGluR5
negative allosteric modulator (NAM),
in Parkinsons disease patients with
levodopa-induced dyskinesia (LID).
Presented at: 16th International
Congress of Parkinsons Disease and
Movement Disorders. Dublin, Ireland,
1721 June 2012.
20. Rascol O, Ferreira J, Ngre-Pages L
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22. LeWitt PA, Hauser RA, Lu M etal.
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(FJORD study). Neurology 79(2), 163
(2012).
23. Stathis P, Konitsiotis S, Tagaris G,
Peterson D. Levetiracetam for the
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Disord. 26(2), 264270 (2011).
24. Wolz M, Lhle M, Strecker K etal.
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117(11), 12791286 (2010).
25. Wong KK, Alty JE, Goy AG etal. A
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NCT00449865
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111. NCT01621581
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NCT01617135
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NCT01280123
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NCT00627640
125. NCT01397422
NCT01397422
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NCT01491529
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NCT01336088
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NCT01113320
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NCT01474421
130. NCT00957918
NCT00957918
131. NCT01563913
NCT01563913
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Fox & Kalia

1.
2.
3.
4.
136
The following neurotransmitter is involved in the pathophysiology

of levodopa-induced dyskinesia:
a.
Dopamine
b.
Glutamate
c.
Adenosine
d.
GABA
e.
All of the above
Neurotoxicity in Parkinsons disease (PD) predominantly targets
the following cell type and leads to motor dysfunction:
a.
Dopamine cells in the substantia nigra
b.
Glutamate neurons in the cortex
c.
Cholinergic neurons in the brainstem
d.
Purkinje cells in the cerebellum
e.
Corticospinal myelinated neurons
Amantadine is currently recommended for use in PD to treat:
a.
Tremor
b.
Slowness
c.
Dyskinesia
d.
Wearing off
e.
Stiffness
Absorption of levodopa in PD can be increased by:
a.
Treating constipation
b.
Taking medication on empty stomach
c.
Improving gastric motility
d.
Stopping anticholinergics
e.
All of the above
5.
Oxidative stress is part of the pathophysiology of PD; which of

the following drugs does NOT work via this mechanism of action:
a.
Isradipine
b.
Inosine
c.
PYM50028
d.
Glutathione
e.
AZD3241
137
CHAPTER
ASK THE EXPERTS

Parkinsons disease
treatment pipelines
Joseph Jankovic
Although levodopa continues to be the most effective symptomatic
therapy in Parkinsons disease, its long-term use is associated with the
development of motor complications, particularly motor fluctuations
and dyskinesias, possibly as a result of short peripheral and central halflife resulting in pulsatile dopamine receptor stimulation [1] . Furthermore,
levodopa does not seem to favorably alter the underlying progression of
the disease and it is not very effective in the treatment of non-motor
symptoms of Parkinsons disease, which may precede the onset of motor
symptoms and may be the most disabling aspects of the disease, particularly in the advanced stages. Therefore, current research in experimental
therapeutics has focused on novel approaches to dopaminergic drug delivery, new dopaminergic and nondopaminergic agents, gene and cellbased therapies and neuroprotective or disease-modifying strategies
(Box8.1) [2] .
doi:10.2217/EBO.13.224
139
Jankovic
About the author

Joseph Jankovic
Joseph Jankovic is Professor of Neurology and Distinguished Chair in Movement Disorders, and Founding Director of the Parkinsons Disease Center and
Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston (TX, USA).
Past President of the international Movement Disorder Society, he is the recipient of many honors,
including: the American Academy of Neurology
Movement Disorders Research Award, sponsored by
the Parkinsons Disease Foundation; the Guthrie Family Humanitarian
Award, presented by the Huntingtons Disease Society of America; the
Tourette Syndrome Association Lifetime Achievement Award; the Dystonia Medical Research Foundation Distinguished Service Award, the
Baylor College of Medicine Alumni Association Distinguished Faculty
Award; and the Fulbright and Jaworski Faculty Excellence Award. He
has been elected as an Honorary Member of the American Neurological Association, Australian Association of Neurologists, European
Federation of Neurological Societies, French Neurological Society, and
the Movement Disorders Society. In 2004, he was selected by fellow
scientists as a Highly Cited Researcher (www.ISIHighlyCited.com). He
has conducted numerous clinical trials and directs an active basic science research program. He has published over 800 original articles and
chapters and has edited or co-edited over 50 books and volumes. He
has mentored numerous fellows and other trainees, many of whom
have become leaders in the field of neurology and movement disorders. He is current or past member of many scientific and medical advisory boards of national foundations, including the Dystonia
Medical Research Foundation, International Essential Tremor Foundation, Tourette Syndrome Association, and the World Federation of
Neurology Association of Parkinsonism and Related Disorders. He has
also served on the executive scientific advisory boards, including the
Michael J Fox Foundation for Parkinsons Research and the National
Parkinson Foundation C
linical and Scientific Advisory Board.
140

Box8.1. Experimental therapeutics of Parkinsons disease.
Novel deliveries
Levodopa methyl ester, IPX066, XP21279, inhalable levodopa (CVT-301) and
apomorphine, DuoDopa (intestinal gel)
Monoamine oxidase inhibitors
Safinamide (MOTION; glutamate release and monoamine oxidase inhibitor)
Dopamine agonists
Pardoprunox (SLV308), aplindore (DAB-452)
Motor fluctuations/dyskinesias
IPX066, sarizotan and piclozotan (5-HT1A antagonists), perampanel (AMPA
antagonist), fipamezole (JP-1730: a2 adrenergic antagonist), AFQ056 and ADX
48621 (mGluR5 antagonists), safinamide (SETTLE), istradefylline (KW-6002),
preladenant, viapadenant, and SYN115 (tozadenant; A2A adenosine antagonists), nebicapone (BIA 3-202) and BIA 9-1067 (COMT inhibitors); SYN118
(an HPPD inhibitor), dipraglurant (ADX48621; mGlu5 receptor modulator),
antibiotics against Helicobactor pylori
Drugs for nondopaminergic symptoms
Droxidopa (noradrenergic precursor), lubiprostone (Amitiza; chloride channel activator), pimavanserin (ACP-13, 5-HT2A inverse agonist/antipsychotic),
paroxetine or venlafaxine (SAD-PD), eszopiclone
Trophic agents
Neurturin (CERE-120), cogane (PYM50028), davunetide
Disease-modifying drugs
Creatine (NET-PD LS1), isradipine (calcium channel inhibitor), inosine (elevates
urate), AZD-3241 (myeloperoxidase inhibitor), pioglitazone, PD01 vaccine
Surgery
Deep-brain stimulation (St Jude), spheramine; autologous mesenchymal stem
cells, gene delivery of GAD, AADC, TH and CH-1
Other
Repetitive transcranial magnetic stimulation, resonator device, expiratory muscle
strength training
1 What novel drug delivery approaches are currently in the pipeline?

A novel formulation of infusible levodopa has been developed where the drug is
embedded in a carboxymethyl cellulose gel providing a concentration of levodopa/
carbidopa of 2/0.5g in only 100ml (DuoDopa, Abbott Laboratories, IL, USA)[3,4] .
This novel intrajejunal delivery system uses a portable pump with programmable
rates of infusion for amounts between 10 and 2000mg of levodopa per hour.
IPX066 is a novel levodopa/carbidopa extended-release oral formulation, which has
a significantly longer duration of action from a single dose of IPX066 compared with
141
Jankovic
standard levodopa/carbidopa and as such promises to smooth out motor fluctuations and prolong on time [5] . Another formulation of levodopa currently undergoing clinical trials is XP21279 (XenoPort Inc., CA, USA), a sustained-release prodrug
of levodopa that is actively absorbed by a high-capacity natural nutrient transport
mechanisms located throughout the length of the gastrointestinal tract before being
is rapidly converted to levodopa [6] .
Apomorphine, a dopamine agonist that can be delivered via oral inhalation with
rapid access to the systemic circulation via the lungs large alveolar surface has been
undergoing evaluation. In a double-blind, placebo-controlled, randomized trial involving 24patients randomized to three escalating single doses of inhaled apomorphine (0.2-, 0.5- and 0.8-mg fine particle dose) versus placebo inhaled apomorphine
did not significantly increase the proportion of patients switching from off to on
or decrease the time from off to on post-treatment (10min for 0.5mg, 40min for
0.8mg, vs 20min for placebo) [7] . However, there was a suggestion of benefit at the
higher doses (five out of 12 switched on at the 0.5 or 0.8mg doses, vs one out of six
for placebo). There were no serious adverse events and treatment was well tolerated.
2 What novel dopaminergic & nondopaminergic drugs are being

developed?
Besides dopaminergic therapies, drugs that target other systems are currently being investigated [8] . Istradefylline was one of the first A2A adenosine antagonists
investigated in the treatment of PD but the effects on motor complications have
been relatively modest. Preladenant is another A2A adenosine antagonist receptor and has been tested in 253 advanced PD patients with motor fluctuations. At
510mg doses it was found to significantly reduce off time and increase daily on
time without prolonging troublesome dyskinesias [9] . Tozadenant (SYN115; UCB
BIOSCIENCES GmbH), a novel highly selective A2A antagonist, was found in a double-blind, placebo-controlled PhaseIIb study of 420PD patients with end of dose
wearing off to significantly decrease off time, increase on time, improve Unified
Parkinsons Disease Rating Scale (UPDRS) partsIIII scores, and show improvements
on clinician- and patient-assessed global impression scores [10] .
Safinamide is a novel reversible monoamine oxidase B inhibitor with additional mechanisms of action, including glutamate-release inhibition and sodium channel blocking properties. In the MOTION study, designed to evaluate the efficacy and safety
of two fixed doses of safinamide (50 and 100mg/day), compared with placebo, as
142

add-on treatment to early PD patients receiving a stable dose of a single dopamine
agonist, 607 out of 679 randomized patients completed the 24-week treatment period [11] . In this study, safinamide 100mg/day significantly improved motor symptoms UPDRSIII (mean change), and PDQ-39 compared with placebo. In the SETTLE
study 484 of 549 randomized patients with PD and motor fluctuations completed
24weeks of treatment with safinamide versus placebo. Safinamide 50100mg/
day significantly improved on time (without worsening troublesome dyskinesia),
off time, UPDRSIII, Clinical Global Impression (CGI)-S, CGI-C, PD Questionnaire
(PDQ)-39 and off time following the first morning levodopa dose (i.e., latency to
on) compared with placebo. The discontinuation rate and serious adverse events
were similar across treatments [12] . The most commonly reported treatment-related
adverse effects were dyskinesia (<2% rated as severe in the safinamide group), fall,
urinary tract infection, nausea, headache and back pain.
Dipraglurant (ADX48621), a novel mGluR5 NAM, was studied in a randomized,
double-blind, placebo-controlled trial of 76PD patients with moderate or severe
levodopa-induced dyskinesia (LID) [13] . Using modified Abnormal Involuntary Movement Scale (mAIMS), performed every 30min for 3h following a single usual levodopa dose as well as diary data, dipraglurant significantly reduced peak dose mAIMS
score without affecting levodopa efficacy. Furthermore, dipraglurant significantly
increased daily on time without dyskinesia and reduced daily off time.AFQ056, a
mGluR5-negative allosteric modulator, has shown significant reductions in dyskinesias as assessed by mAIMS and by UPDRS IV at 100mg twice daily dose compared
with placebo [14] .
Perampanel, a selective and noncompetitive AMPA receptor antagonist, was not
found to be effective in the treatment of motor fluctuations or LIDs [15] . Fipamezole,
an adrenergic a-2 receptor antagonist, was found to significantly decrease dyskinesia and prolong the levodopa response compared with placebo [16] . Piclozotan, a
5-HT1A receptor agonist, has been reported to significantly improve LID and on time
without dyskinesia in a PhaseII pilot study involving only 25PD patients [17] .
3 What are the prospects for gene & cell-based therapies?

In the STEPS trial, a PhaseII randomized controlled trial in patients with advanced
PD, cultured human retinal epithelial cells supported by microcarriers (spheramine)
as a cell-based approach of intrastriatal dopamine delivery failed to establish
significant differences between patients receiving intraputaminal spheramine
143
Jankovic
injections compared with those undergoing sham surgery [18] . Another approach
for therapeutic gene delivery in PD has focused on the targeted delivery of neurotrophic factor neurturin, which has been shown to restore and protect dysfunctional dopaminergic neurons in animal models of PD [19] . A PhaseII randomized
sham-surgery controlled trial in 58patients with advanced PD failed to detect
significant differences in off state motor UPDRS scores after 1year [20] . However, asubgroup analysis of 30patients followed up for longer than 12months
showed significant improvements in the off state motor UPDRS of 8points and a
significant gain in on time without troublesome dyskinesia of 2.5h in the AAV2neurturin injected group compared with the control group after 18months. Serious adverse events occurred in 34% of the patients treated with AAV2-neurturin
and in 20% of the sham-surgery group. Another just completed trial has targeted
not only the putamen but also the substantia nigra (ClinicalTrials.gov indentifier:
NCT00985517). The latter strategy is based on the hypothesis that neurturin will
be transported from degenerating terminals to their cell bodies in the substantia
nigra to the striatum. Unfortunately, this Phase II clinical trial did not demonstrate
statistically significant efficacy for its primary end point, which was an improvement based on UPDRS scores. The study did show some statistical benefit according to a secondary end point self-reported daily diaries from patients that asked
them to assess their own motor function throughout the course of the day. The
trial also continued to show that the drug was safe.
The 2006 discovery by Yamanakas group of a method for reprogramming somatic
cells by introducing transcription factors, which enabled the generation of induced
pluripotent stem cells with pluripotency comparable to that of embryonic stem cells
are attracting considerable attention as potential therapies in neurodegenerative disorders, including PD [21] . These approaches may have some advantages to the use
of autologous cell preparations [22] .
4 What is the major unmet clinical need in Parkinsons disease & what is
in the pipeline to help tackle this?
Slowing the clinical progression of PD continues to be the central unmet therapeutic need in this illness. Past trials testing putative neuroprotective agents using
different end points and clinical designs have, unfortunately, either failed or results
have been inconclusive [1,2] . Targets include cellular calcium homeostasis [23] ,
oxidative stress and mitochondrial energy production, as well as anti-apoptotic
mechanisms.
144

There is emerging evidence implicating certain conformations of a-synuclein can become toxic to cells and spread in prion-like fashion causing neurodegeneration [24] .
This new finding may lead to identification of novel targets for candidate neuroprotective therapies [25] . Other strategies are currently being investigated in an attempt
to prevent accumulation, enhance clearance or break up formed a-synuclein. For example, Austrian-based biotech company AFFiRiS AG (Vienna) is conducting an early
Phase clinical safety study to test AFFITOPE PD01, a first-in-human PD vaccine. NeuroPhage (MA, USA) recently announced positive preclinical results from its NPT001
compound that apparently reduced synuclein deposits in the brain. PRX002, antibody against alpha-synuclein, is also being evaluated in PD (Prothena Biosciences,
CA, USA). QR Pharma (PA, USA) is testing their compound Posiphen for its ability to
target and break up clumps of a-synuclein in both the brain and intestine.
Agonists for the glucagon-like peptide1 (GLP-1) receptor, have been recently suggested as potential therapeutic agents in neurodegenerative diseases. For example,
Exendin-4 (exenatide), used in the treatment of Type 2 diabetes mellitus, crosses
the bloodbrain barrier and it has been suggested to act as an anti-inflammatory
agent, facilitator of neurogenesis and mitochondrial biogenesis. This is based on the
observation that peroxisome proliferator activated receptor g coactivator 1-a, a key
regulator of enzymes involved in mitochondrial respiration and insulin resistance,
may be important in the pathogenesis of neurodegeneration in PD and established
treatments for insulin resistance (pioglitazone and exenatide) may, therefore, exert
disease-modifying effects [26] .
In addition to numerous scientific challenges in finding pathogenesis-targeted therapies there are many economic and regulatory obstacles that must be overcome to
advance the treatment of PD and other neurodegenerative disorders [27] . Future
goals in experimental therapeutics are not only to provide symptomatic relief of motor and non-motor symptoms associated with PD but to discover novel therapeutic
targets [2,28] .
Finally, there is increasing recognition that early surgical intervention may favorably
modify the course of PD [29] . For example, in the the EARLYSTIM trial, which included patients with onset of levodopa-induced motor complications for only 3 years or
less 251 patients were randomized to STN DBS plus medical therapy versus medical
therapy alone [30] . For the primary outcome of quality of life, the mean score for the
DBS group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (p=0.002). Furthermore, DBS was superior to medical therapy
with respect to motor disability, activities of daily living, levodopa-induced motor
145
Jankovic
complications, and time with good mobility and no dyskinesia. Serious adverse
events occurred in 54.8% of the patients in the DBS group and in 44.1% of those in
the medical-therapy group. In view of these new findings, the selection criteria for
DBS candidates will need to be continuously monitored and modified [31] .

disclosure
During the past 2years J Jankovic has
received: Research and Center of Excellence Grants from Allergan Inc.; Ceregene Inc.; CHDI Foundation; GE Healthcare; Huntingtons Disease Society of
America; Huntington Study Group;
Ipsen Limited; Lundbeck Inc.; Michael J
Fox Foundation for Parkinson Research;
Medtronic; Merz Pharmaceuticals; National Institutes of Health; National Parkinson Foundation; St Jude Medical;
Teva Pharmaceutical Industries Ltd; UCB
Inc.; University of Rochester; and Parkinson Study Group.
He has received compensation/honoraria for services as a consultant or an advisory committee member for Allergan
Inc.; Auspex Pharmaceuticals Inc.; Ipsen

Biopharmaceuticals Inc.; Lundbeck Inc.;
Merz Pharmaceuticals; Teva Pharmaceutical Industries Ltd; UCB Inc.; and US
World Meds.
He has also received royalties from Cambridge; Elsevier; Future Science Group;
Hodder Arnold; Lippincott Williams and
Wilkins; and Wiley-Blackwell.
The author has no other relevant affiliations or financial involvement with any
in the manuscript apart from those disclosed.
No writing assistance was utilized in the
production of this manuscript.
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Brooks DW. Overcoming obstacles in
148
Multiple choice
questions: answers
Chapter 1. Prevention of Parkinsons disease: preparing for the
future
1.
2.
3.
4.
Premotor features of Parkinsons disease include:

a.
Olfactory dysfunction
b.
Constipation
Which is not a risk factor for Parkinsons disease?
b.
Smoking
Which of the following are associated with lower risk of Parkinsons
disease?
d.
All of the above
Which of the following techniques are being used to distinguish
individuals with Parkinsons disease from people without:
a.
Ultrasound of the brainstem
b.
Fluorodopa PET scanning
d.
Dopamine transporter single photon emission computed
tomography scanning
Chapter 2. Initial and disease-modifying strategies in Parkinsons

disease
1.
2.
Parkinsons disease (PD) may be characterized early by the following

clinical features:
d.
All of the above
Selegiline and rasagiline are members of which class of compounds:
b.
Monoamine oxidase type B inhibitors
149
3.
4.
5.
Levodopa usage in PD has been associated with the development of:

c.
A and B
DAs may have the following complicating side effects:
d.
All of the above
b.
Remains a challenging and critically important unmet need
Chapter 3. Prevention and management of levodopa-related motor

complications
1.
2.
3.
4.
5.
Risk factors for the development of levodopa-related motor

complications include which of the following?
f.
All of the above
When occurring in the off state, dystonia can be treated by
which of the following?
e.
a, b & c
Sudden offs can be treated acutely by which of the following?
c.
Apomorphine
Diphasic dyskinesias in general:
c.
Can be treated by decreasing the interdose interval of
levodopa administration
Off state freezing of gait can be treated by which of the following:
d.
a&c
Chapter 4. Management of non-motor symptoms of Parkinsons

disease
1.
2.
3.
150
Cognitive decline in Parkinsons disease (PD) is associated all of the

following except:
d.
Increasing risk of rapid eye movement behavior disorder
A symptom of psychosis unique to the PD patient is:
b.
A sense that someone or something is present in the
room
Suggested treatment of rapid eye movement behavioral disorder is:
c.
Clonazepam
4.
5.
Non-motor symptoms requiring reduction in dopaminergic therapy

include:
e.
Both a & b
Treatment for orthostatic hypotension:
e.
All of the above
Chapter 5. Management of cognitive and behavioral aspects of

Parkinsons disease
1.
2.
3.
4.
5.
6.
7.
8.
Which of the following antipsychotic drugs do not cause worsening

of motor problems in Parkinsons disease (PD)?
b.
Quetiapine
d.
Clozapine
Which one of the following is not considered part of PD?
a.
Mania
Depression in PD is thought to be:
a.
Due to intrinsic brain pathology
c.
Reactive to the progressive impairments
Which of the following statements concerning dementia in PD is
not correct?
c.
It is relatively uncommon
Which one of the following statements about rapid eye movement
sleep behavior disorder is not correct?
c.
It is usually a side effect of medications used to treat PD
motor symptoms
Which of the following statements concerning apathy in PD is
true?
a.
It is defined as a decrease in emotions and motivation
Which of the following treatments are effective for controlling
impulse control disorders due to dopamine agonist medications?
a.
Reducing or stopping the dopamine agonist
Which of the following statements concerning fatigue in PD is
true?
e.
It often predates the onset of motor symptoms
151
9.
10.
Which of the following statements regarding behavioral problems

in PD is not true?
c.
They usually respond to dopamine-replacement therapy
correct
Which of the following statements concerning psychotic symptoms
in PD is true?
a.
They primarily consist of visual hallucinations and delusions
b.
They often include auditory hallucinations
c.
When delusions are present they are usually paranoid in
nature
Chapter 6. Surgical therapy for Parkinsons disease
1.
2.
3.
4.
152
Deep-brain stimulation (DBS) surgery should be considered in patients who have symptoms of Parkinsons disease (PD) for 1year
and have not tried adequate medication therapy.
b.
False: DBS surgery should in most cases be considered after 5years of symptomatic PD treatment and optimized
medical therapy.
Most PD motor symptoms that are responsive to levodopa will be
responsive to DBS, with the exception of tremor and dyskinesia.
a.
True: Levodopa responsive symptoms will respond best to
DBS therapy except for medication, refractory tremors and
dyskinesias, which will usually respond to surgical therapy.
Patient selection is not important in the decision-making process
for DBS.
b.
False: Patient selection is the most important step in successful DBS therapy.
When deciding on DBS therapy, one of the most important
considerations should be:
a.
The symptoms targeted: DBS should be targeted to the
specific symptoms that are most bothersome to the patient.
5.
The initial process of triaging a potential DBS candidate can be

performed by:
e.
All of the above: The initial process of triaging can be
done by a single practitioner in the health care field using
simple questionnaires such as the Florida Surgical Questionnaire for PD or the short DBS screener. Potential candidates identified in triage should have multidisciplinary
screening.
Chapter 7. Experimental therapeutics for motor symptoms of

Parkinsons disease
1.
2.
3.
4.
5.
The following neurotransmitter is involved in the pathophysiology

of levodopa-induced dyskinesia:
e.
All of the above
Neurotoxicity in Parkinsons disease (PD) predominantly targets
the following cell type and leads to motor dysfunction:
a.
Dopamine cells in the substantia nigra
Amantadine is currently recommended for use in PD to treat:
c.
Dyskinesia
Absorption of levodopa in PD can be increased by:
e.
All of the above
Oxidative stress is part of the pathophysiology of PD; which of
the following drugs does NOT work via this mechanism of action:
c.
PYM50028
153

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Parkinsons Disease:

Medical and Surgical Treatment

Published by Future Medicine Ltd

About the Editor

2013 Future Medicine Ltd

fore initiating levodopa. In Chapter3,

PD: medical & surgical treatment

Financial & competing interests

Research; Medtronic; Merz Pharmaceuticals; National Institutes of Health;

The author has no other relevant affiliations or financial involvement with

When would a preventive treatment need to be applied?

How can we narrow the target population for a preventive

What preventive measures will prevent Parkinsons disease?

2013 Future Medicine Ltd

About the author

Prevention of Parkinsons disease: preparing for thefuture

Numerous genetic and environmental factors that modify the risk

identifying individuals at risk and second, applying preventive measures.

Who is at risk & how many

Box 1.1. Challenges identifying individuals at high risk for

Prevention of Parkinsons disease: preparing for thefuture

When would a preventive

feature of the disease and several of

How can we narrow the

before the pathological process begins,

of the condition, but the interpretation of these genetic tests is difficult

Biomarker: an indicator of a biological state; in this context an

Prevention of Parkinsons disease: preparing for thefuture

biochemical markers that identify early

below). Promising preliminary studies

or genetic mutations associated

Prevention of Parkinsons disease: preparing for thefuture

What preventive measures

environmental associations. Attention

Ubiquitin proteasome system: a cellular system responsible for

Prevention of Parkinsons disease: preparing for thefuture

it is currently unknown when they

Financial & competing interests

Prevention of Parkinsons disease: preparing for thefuture

Findley LJ, Wood E, Lowin J etal.

Chrischilles EA, Rubenstein LM, Voelker

Van Den Eeden SK, Tanner CM, Bernstein

Marras C, Tanner CM. The epidemiology

Kumar KR, Djarmati-Westenberger A,

Nalls MA, Plagnol V, Hernandez DG

Caudle WM, Guillot TS, Lazo CR etal.

Wirdefeldt K, Adami HO, Cole P etal.

10. Elbaz A, Levecque C, Clavel J etal.

11. Booij J, Knol RJJ. SPECT imaging of the

32. Phani S, Loike JD, Przedborski S.

Prevention of Parkinsons disease: preparing for thefuture

103. Disease-Modifying Potential of

Multiple choice questions

Premotor features of Parkinsons disease include:

Disease modification in PD: MAO-B inhibitors

Disease modification in PD: other treatments

Early treatment of PD: proposed algorithm

2013 Future Medicine Ltd

Elmer & Hauser

About the authors

Initial & disease-modifying strategies in PD

Dopaminergic therapies, including levodopa, dopamine agonists

Elmer & Hauser

is preceded by pathology involving

When would a preventive treatment need to be applied?

What preventive measures will prevent Parkinsons disease?

Disease modification in PD: MAO-B inhibitors

Disease modification in PD: other treatments

Early treatment of PD: proposed algorithm