Clinical Insights Parkinsons Disease

Parkinson’s Disease:
Medical and Surgical Treatment

Editor
Joseph Jankovic
Baylor College of Medicine, TX, USA
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Contents
Parkinson’s disease:
medical and s urgical
treatment
Parkinson’s disease: medical and surgical treatment 3

Joseph Jankovic
Prevention of Parkinson’s disease: preparing for the future 7
Connie Marras
Initial and disease-modifying strategies in Parkinson’s 23
disease
Lawrence W Elmer & Robert A Hauser
Prevention and management of levodopa-related motor 43
complications
Cara A Pecina & Alberto J Espay
Management of non- motor symptoms of Parkinson’s 61
disease
Mark Stacy
Management of cognitive and behavioral aspects of 79
Parkinson’s disease
Joseph H Friedman
Surgical therapy for Parkinson’s disease 99
Nawaz Hack & Michael S Okun
Experimental therapeutics for motor symptoms of 115
Susan H Fox & Lorraine V Kalia
Parkinson’s disease treatment pipelines 139
Joseph Jankovic
Multiple choice questions: answers 149
Jankovic
About the Editor
Joseph Jankovic
Joseph Jankovic is Professor of Neurology and Distin-
guished Chair in Movement Disorders, and Found-
ing Director of the Parkinson’s Disease Center and
Movement Disorders Clinic, Department of Neurol-
ogy, Baylor College of Medicine, Houston (TX, USA).
Past President of the international Movement Dis-
order Society, he is the recipient of many honors,
including: the American Academy of Neurology
Movement Disorders Research Award, sponsored by
the Parkinson’s Disease Foundation; the Guthrie Family Humanitarian
Award, presented by the Huntington’s Disease Society of America; the
Tourette Syndrome Association Lifetime Achievement Award; the Dys-
tonia 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 Neuro-
logical 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 sci-
ence 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 dis-
orders. He is current or past member of many scientific and medi-
cal advisory boards of national foundations, including the Dystonia
Medical Research Foundation, International Essential Tremor Foun-
dation, 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 Parkinson’s Research and the National
Parkinson Foundation C linical and Scientific Advisory Board.
2 www.futuremedicine.com
FOREWORD
Parkinson’s disease:
medical and surgical
treatment
Joseph Jankovic
Few neurologic disorders have attracted largely by the need to treat levodopa-
more attention from the scientific com- related motor fluctuations and dyski-
munity than Parkinson’s disease (PD). nesias and by improved understanding
Advances in basic research are now of the functional anatomy underlying
being translated into clinical practice. motor control, as well as refinements
While the progress in the treatment of of neurosurgical techniques and devi-
PD has been remarkable, the cause of ces, coupled with advances in neuro
this neurodegenerative disorder is still imaging and neurophysiology. Howe-
a mystery. In 1817, James Parkinson in ver, despite extraordinary therapeutic
his original ‘Essay on the Shaking Palsy’ advances during the recent past, PD
first described the disorder that now continues to be among the most com-
bears his name and suggested that mon causes of disability, particularly
blood letting and iatrogenic pus forma- among the elderly.
tion were the best treatments. Subse-
quent discovery of dopamine deficiency The various chapters in this book are
in the brains of patients with PD and its organized according to the natural
therapeutic replacement with levodopa course of PD, from pre symptomatic
in the early 1960s heralded a new era to the most advanced stages. In
in the treatment of this devastating dis- Chapter 1, Marras emphasizes that
order. The renewed interest in surgical the pathological changes of PD start
treatment of PD has been stimulated long before any symptomatic, initially
© 2013 Future Medicine Ltd doi:10.2217/EBO.13.214 3

Jankovic
non-motor and later motor, mani- fore initiating levodopa. In Chapter 3,

festations occur. Therefore, the chal- Pecina and Espay review strategies
lenge of implementing any preventive designed to prevent or delay the on-
strategies is to identify individuals set of levodopa-related complica-
who are at risk for developing the dis- tions, particularly motor fluctuations
ease to enrich the target population. and dyskinesias. They also discuss
In addition to carriers of genetic mu- management of these complications,
tations known to cause PD, individuals including adjustment of dosing of
with hyposmia, rapid eye movement levodopa, evaluating patients for evi-
behavioral disorder, constipation and dence of gastroparesis of Helicobacter
other premotor symptoms may have pylori gastritis, the use of amantadine
an increased risk for developing PD. and some investigational drugs for the
Although with the advent of various treatment of dyskinesias and motor
presymptomatic biomarkers, the sen- fluctuations, and subcutaneous injec-
sitivity and specificity of diagnosis of tion of apomorphine as a rescue from
premanifest PD will continue to im- an off state. They also discuss novel
prove, any disease-modifying inter- deliveries of levodopa, including infus-
ventions may be impractical as they ing levodopa/carbidopa intestinal gel
would have to be applied to a very intraduodenally via a percutaneous
large population over long periods of endoscopic gastrostomy tube con-
time to prevent a relatively small num- nected to an infusion pump, and oth-
ber of PD cases. Currently, there are er delivery strategies designed to pro-
no established preventive treatments, vide a more continuous dopaminergic
but there is growing, albeit still rela- stimulation. Deep-brain stimulation
tively weak, evidence that vigorous ex- is an important treatment strategy in
ercise, caffeine, NSAIDs, and elevation suitable patients who are troubled by
of serum urate may possibly have a their motor complications despite op-
favorable disease-modifying effect. In timal medical therapy. In Chapter 4,
Chapter 2, Elmer and Hauser provide Stacy provides a comprehensive re-
general guidelines on the initial treat- view of evidence-based data on the
ment of PD. In addition to encourag- treatment of non-motor symptoms of
ing exercise, they provide evidence PD, including fatigue, anxiety, pain,
that monoamine oxidase inhibitors, insomnia, nocturia, excessive saliva-
such as selegiline and rasagiline, may tion, cognitive difficulties, depression
be considered as the initial treatment and impulse control disorders. The
in patients who have only minimal and management of the latter, cogni-
not troublesome symptoms. These tive and behavioral symptoms, is dis-
drugs are usually followed by the in- cussed in more detail by Friedman in
troduction of dopamine agonists be- Chapter 5. Surgical treatment, with
PD: medical & surgical treatment
emphasis on deep-brain stimulation, Research; Medtronic; Merz Pharma-

is reviewed in some detail by Hack ceuticals; National Institutes of Health;
and Okun in Chapter 6. They empha- National Parkinson Foundation; St Jude
size that proper selection of patients Medical; Teva Pharmaceutical Industries
and setting the appropriate expecta- Ltd; UCB Inc.; University of Rochester;
tions, coupled with a multidiscipli- and Parkinson Study Group.
nary approach, including a team of
experienced surgeons and clinicians, He has received compensation/hono-
are critical in achieving a successful raria for services as a consultant or an
outcome. Finally, in Chapter 7, Fox advisory committee member for Aller-
and Kalia discuss emerging and ex- gan Inc.; Auspex Pharmaceuticals Inc.;
perimental therapies in PD. Although Ipsen Biopharmaceuticals Inc.; Lund-
the therapeutic pipeline in PD is not beck Inc.; Merz Pharmaceuticals; Teva
as robust as we would like, with the Pharmaceutical Industries Ltd; UCB
advances in understanding of cellular Inc.; and US World Meds.
processes underpinning neurodegen-
eration the hope is that future thera- He has also received royalties from
pies will be not only symptomatic but Cambridge; Elsevier; Future Sci-
also target the underlying pathogenic ence Group; Hodder Arnold; Lip-
mechanisms. pincott Williams and Wilkins; and
Wiley-Blackwell.
Financial & competing interests
disclosure The author has no other relevant af-
filiations or financial involvement with
During the past 2 years J Jankovic has any organization or entity with a fi-
received: Research and Center of Ex- nancial interest in or financial conflict
cellence Grants from Allergan Inc.; with the subject matter or materi-
Ceregene Inc.; CHDI Foundation; GE als discussed in the manuscript apart
Healthcare; Huntington’s Disease So- from those disclosed.
ciety of America; Huntington Study
Group; Ipsen Limited; Lundbeck Inc.; No writing assistance was utilized in
Michael J Fox Foundation for Parkinson the production of this manuscript.
www.futuremedicine.com 5
1
CHAPTER
Prevention of Parkinson’s
disease: preparing for
the future
Connie Marras
Contents
Who is at risk & how many will get Parkinson’s 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 Parkinson’s disease? 15
Conclusion 18

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 Parkinson’s
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
Parkinson’s disease, prognosis and environmental etiology of Parkinson’s
disease, and evaluating clinical assessment tools in Parkinson’s disease.
Prevention of Parkinson’s disease: preparing for the future
Learning points
After reading this chapter you will know:
• Numerous genetic and environmental factors that modify the risk

for Parkinson’s disease are known.
• Despite this knowledge, identifying individuals at risk for Parkinson’s
disease remains a challenge.
• Challenges include the fact that Parkinson’s 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. There-
fore, the optimal timing for application of a preventive strategy is
uncertain.
• Once we can identify at-risk individuals, there are a number of prom-
ising strategies for prevention to study in clinical trials based on the
known pathogenesis of the disease, environmental associations or
trophic factors.
Summary
Parkinson’s 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. Parkinson’s disease
affects men more than women, young and old, and no
ethnic group has been reported immune to the disease.
Furthermore, the onset of Parkinson’s 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
Parkinson’s disease is one of the most identifying individuals at risk and sec-
common neurodegenerative diseases, ond, applying preventive measures.
affecting individuals through many years Which screening procedures and pre-
of their lives. The associated financial ventive treatments would be consid-
costs to individuals and society are ered feasible and acceptable in such
substantial and the disease has a major programs depends on a number of
impact on quality of life for patients [1,2]. factors including the size of the popu-
Therefore, prevention of Parkinson’s lation at risk, the size of the popula-
disease would have major benefits. tion ultimately destined to acquire
The focus of current research related the condition, the certainty of disease
to modifying the disease process is on in people positively identified by the
slowing progression of the disease, and screening procedures and the mor-
this is discussed in Chapter 2. However, bidity associated with the disease and
the potential impact of prevention is its treatment. We will first discuss the
far greater. With increasing knowledge problem of identifying individuals who
of the pathogenesis of Parkinson’s will ultimately develop Parkinson’s dis-
disease, causative genes and genetic risk ease. The challenges are summarized in
factors that can be easily tested for and Box 1.1.
known environmental protective factors,
prevention may one day be achievable. Who is at risk & how many
This chapter will review the process of will get Parkinson’s disease?
developing and applying prevention
strategies in the context of Parkinson’s Parkinson’s disease affects a broad spec-
disease. trum of the population. The frequency
of the disease is approximately 1.5-times
Any program of prevention must higher in men than women [3] . Aging
address two separate problems; first, is the strongest known risk factor for
Box 1.1. Challenges identifying individuals at high risk for

Parkinson’s disease.
Who?
• Parkinson’s 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 Parkinson’s disease is highly variable, from mid-life to the
elderly
• Nonspecific symptoms predate the classical motor symptoms by years
Parkinson’s disease; however, onset in feature of the disease and several of

young adulthood is not rare and a sub- these have been demonstrated to
stantial proportion of Parkinson’s dis- predate the motor symptoms by many
ease occurs in individuals under 60 years years [5] . Box 1.2 lists these symptoms.
of age. No ethnicity has been found to It is unknown whether or not these
be immune to the disease. Despite these represent risk factors and thus clues
broad demographics resulting in a large to truly unaffected individuals, or if
worldwide burden of disease, an individ- they represent the earliest features
ual’s lifetime risk of Parkinson’s disease of the disease itself, although the
is still small. Parkinson’s disease affects distribution of neurodegeneration in
approximately 1/100 individuals over the Parkinson’s disease and its sequence
age of 60 years and 1/1000 individuals of pathological evolution in the central
of all ages [4] . Only the most benign nervous system would suggest that
and inexpensive preventive treatments most of them are integral features of
would be feasible to apply to all adults the disease. More problematic still, the
to prevent a disease destined to affect pathological process in the brain may
less than 1 in 100 people and therefore begin well before even non-motor
additional risk factors need to be consid- symptoms become manifest. Thus, it is
ered in order to identify a subpopulation unknown how early a treatment would
to receive a preventive measure. have to be applied to truly prevent
the disease. Longitudinal studies of
When would a preventive presumed at-risk individuals will be
treatment need to be required to sort this out.
applied?
How can we narrow the
Parkinson’s disease presents an target population for a
additional problem beyond frequency preventive strategy?
when it comes to prevention.
Identifying the time of onset of the Environmental risk factors, clinical,
condition with certainty has eluded imaging, biochemical and genetic tests
clinicians and researchers thus far. may all complement demographic
Traditionally, the onset of Parkinson’s characteristics to help to identify those
disease has been designated as the that will ultimately develop Parkinson’s
time at which motor symptoms disease. These tests either identify an
(symptoms related to tremor, rigidity or at-risk state or identify the earliest
bradykinesia) begin. In the last decade, physiological changes associated
non-motor symptoms predating these with Parkinson’s disease. Genetic and
classical motor symptoms have been environmental risk factors have the
increasingly recognized as an integral potential to identify the at-risk state
Marras
Box 1.2. Symptoms and signs predating the motor features of

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, of the condition, but the interpreta-
and therefore present the possibility of tion of these genetic tests is difficult
truly preventing the condition rather because of variable penetrance, lack of
than arresting it at an asymptomatic neuroprotective therapies, and other
or minimally symptomatic state. medical and ethical issues. Genetic risk
Clinical, imaging and biochemical tests factors (in contrast to causative genes)
would identify the early stages of a individually increase the risk for Par-
pathological process, thereby allowing kinson’s disease by small amounts and
it to be arrested by a ‘preventive’ individually are present in only a small
intervention. We will first discuss minority of people with Parkinson’s
genetic and environmental strategies disease. New risk factor genes are be-
then discuss clinical, imaging or ing discovered at rapid rates; however,
biochemical biomarkers of disease. and in combination the genetic risk
conferred may be substantial [7] . It is
Genetic contributors to Parkinson’s dis- conceivable that with the discovery of
ease include both causative mutations, a large number of genetic risk factors
such as mutations in the PINK1, PAR- over the coming years we will be able
KIN or LRRK2 genes and risk-confer- to quantify a person’s genetic risk for
ring mutations or polymorphisms [6] . Parkinson’s disease.
Genetic testing is becoming common
in people with Parkinson’s disease, Environmental risk factors for Parkinson’s
particularly those with a family history disease include pesticide and solvent
Biomarker: an indicator of a biological state; in this context an

indicator of the neurodegenerative condition that is Parkinson’s
disease.
exposure, and specific compounds biochemical markers that identify early

responsible for these associations pathological changes of Parkinson’s
are beginning to be elucidated [8] . disease. Techniques that have shown
Numerous other risk factors, such an ability to distinguish established
as heavy metal exposure and head Parkinson’s disease from unaffected
trauma, have been proposed [9] . Given individuals are clear candidates for bio-
the multiple genetic and environmental markers of the ‘at-risk’ state as well.
associations that are being discovered, Single photon emission computed to-
it is very likely that causative factors mography using ligands specific for the
will vary from individual to individual. dopamine transporter (DAT SPECT) is
Therefore using any specific risk available in Europe and the USA for
factors to identify at-risk populations aiding the diagnosis of Parkinson’s dis-
will identify only a small proportion of ease. Reduced uptake of radiotracer
individuals at risk. Gene–environment in the striatum is the characteristic
interactions are increasingly of interest pattern. This has been shown to be
and may be very relevant in quantifying abnormal prior to the onset of motor
an individual’s risk of Parkinson’s disease. symptoms [11] , suggesting that DAT
For example, pesticide exposure may be SPECT may be a useful screening tool.
of particular relevance in an individual PET using fluorodopa as the tracer spe-
genetically programmed to metabolize cific for dopaminergic terminals shows
these chemicals less efficiently [10] . similar promise [12] . Ultrasound of the
Thus, a risk profile may also need to midbrain can also distinguish individu-
take into account multiple genetic als with Parkinson’s disease from con-
and environmental factors and their trols, showing a larger area of echo-
co-occurrence. genicity in the region of the substantia
nigra in Parkinson’s disease [13] , and
There are many ongoing studies has also been proposed as a useful
attempting to define imaging or test to identify at-risk individuals (see
Dopamine transporter: a transmembrane protein on dopaminer-

gic nerve terminals that carries dopamine from the synapse back
into the cytosol. In Parkinson’s 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.
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 or genetic mutations associated

have been reported for analytes in the with Parkinson’s disease to identify
cerebrospinal fluid (CSF) and blood; differences between these groups
individually, such measurements have and the general population in possible
shown an ability to distinguish es- biomarkers. Olfactory dysfunction and
tablished Parkinson’s disease from reduced color vision are more prevalent
controls [14] . Combinations of these in individuals with RBD, suggesting
markers in CSF are being investigated that individuals with these clinical
to separate Parkinson’s disease from features are at a particularly high risk
controls even more accurately [15] . of developing Parkinson’s disease [16] .
For each of these promising markers, Imaging findings in genetically defined
we need to know the frequency and at-risk populations have suggested
timing of abnormalities in individuals promise for functional and structural
at risk for Parkinson’s disease prior to imaging techniques [17–19] , further
using them to determine the risk of an specifying risk in these enriched
individual. Furthermore, neither imag- populations.
ing modalities nor CSF analysis is prac-
tical to apply to the general population Despite the importance of these cross-
to screen for Parkinson’s disease risk. sectional studies for hypothesis genera-
However, they could represent section, the ability to make inferences from
ond-step screening after an individual their results about predicting risk for
has been identified as at elevated risk developing Parkinson’s disease is limit-
by other simpler tests. ed. Prospective, longitudinal studies are
needed to demonstrate the predictive
More immediately relevant to value of any marker. Longitudinal stud-
prevention, some markers are being ies are currently following cohorts se-
studied either cross-sectionally or lected on the basis of non-motor mani-
prospectively in unaffected populations festations of Parkinson’s disease to test
to assess their potential to identify whether or not a combination of clini-
high-risk groups. Cross-sectional cal tests can identify individuals who
studies take advantage of known will develop Parkinson’s disease [20] .
high-risk populations such as those The Parkinson’s Associated Risk Study
with anosmia, rapid eye movement is evaluating 7500 first-degree relatives
(REM) sleep behavior disorder (RBD) of individuals with Parkinson’s disease
with olfactory testing and a subset with Parkinson’s disease, but none individu-
DAT SPECT scanning to identify those ally could increase the incidence to the
most likely to develop Parkinson’s dis- point of being useful for screening for
ease [101] . The Prospective evaluation premotor Parkinson’s disease due to
of Risk factors for Idiopathic Parkinson’s low specificity. When impaired olfac-
Syndrome study [21] enrolled 1847 in- tion, excessive daytime sleepiness,
dividuals free of Parkinson’s disease low frequency of bowel movements
and followed them longitudinally. After and slow reaction time were assessed
3 years follow-up, 11 subjects had de- in combination, the presence of all
veloped Parkinson’s disease. The best four signs was associated with an inci-
approach for prediction of incident dence of Parkinson’s disease of 215 per
Parkinson’s disease was achieved when 10,000 person years. This represents a
applying inclusion criteria based on age, major improvement over an incidence
positive family history and/or hypos- of 16 per 10,000 person years in those
mia, and substantia nigra hyperecho- with none of the signs. Translated into
genicity. Using this combination, one in the context of a preventive program,
16 individuals meeting all three criteria it would be necessary to apply a pre-
developed Parkinson’s disease. Despite ventive strategy to 100 such high-risk
their success improving prediction rela- individuals for an average of 10 years
tive to incidence of Parkinson’s disease, to prevent 21 new cases of Parkinson’s
the authors concluded that such an disease.
approach would still not be feasible to
apply to the general population given What preventive measures
the long follow-up periods required. A will prevent Parkinson’s
population exhibiting the combination disease?
of hyposmia and RBD is currently be-
ing recruited for a prospective study of Because of the aforementioned
prodromal Parkinson’s disease as part challenges identifying individuals at
of The Parkinson Progression Marker high risk described earlier, the focus
Initiative [22] . The Honolulu Asia Aging of disease modification studies in
Study has provided longitudinal obser- Parkinson’s disease to date have
vations of 8006 Japanese–American been on modifying the course of
men and thus has allowed several po- established disease. This topic is
tential predictive signs and symptoms discussed in Chapter 2. Despite very
to be evaluated retrospectively for active research in disease modification
their predictive power both individually of Parkinson’s disease, currently there
and in combination [23] . They identi- are no established treatments to slow
fied several clinical features that were its progression. There are substantial
associated with increased incidence of obstacles to testing disease-modifying
Marras
treatments for this disease, including environmental associations. Attention

our incomplete understanding of has focused on two main systems:
disease mechanisms, the long duration the ubiquitin proteasome system
and large sample sizes required in (UPS) and mitochondrial function. The
clinical trials and a lack of sensitive role of inflammation in Parkinson’s
or widely available tools to measure disease is also of great interest. The
outcomes [24] . These obstacles are likely UPS is responsible for degrading
to be even more difficult to overcome unwanted or abnormal proteins.
for studying disease prevention Protein misfolding leading to impaired
compared with slowing disease pro clearance by the UPS and aggregation
gression. Any drug that can slow the of proteins and/or defects in the UPS
neurodegenerative process may also system are thought to contribute to
be effective in preventing it, although the neurodegenerative process in
a preventive strategy will have to target Parkinson’s disease. Parkinson’s disease
mechanisms that are active early in the is characterized pathologically by the
disease process. Preventive treatments accumulation of insoluble aggregates
may be developed by applying know of protein called a-synuclein, a major
ledge of pathogenic mechanisms of component of Lewy bodies, the
Parkinson’s disease, by taking direct pathological hallmark of Parkinson’s
advantage of inverse associations disease. Mutations or polymorphisms
observed between modifiable environ in the gene encoding a-synuclein that
mental factors and Parkinson’s disease, promote the accumulation of misfolded
or by using nonspecific neurotrophic a-synuclein increase risk for Parkinson’s
compounds to increase resistance to disease [25,26] . Mutations in the
neurodegneration. This section will gene encoding for Parkin, an integral
briefly summarize the current state of part of the UPS, cause young-onset
knowledge regarding pathogenesis and Parkinson’s disease. Environmental
environmental ‘protective’ factors and toxins that impair the UPS (e.g.,
then discuss how they may be used for maneb, paraquat) increase a-synuclein
preventive strategies. deposition and are also risk factors for
Parkinson’s disease [27] . Mitochondrial
Our understanding of the patho dysfunction has been recognized in
genesis of Parkinson’s disease has patients with Parkinson’s disease for
been shaped by both genetic and 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.
as a key factor in the pathogenesis of it is currently unknown when they

the disease. Once again, genetic and become abnormal and how important
environmental associations support this they are relative to one another. Once
role. Mutations in the Parkin, DJ-1 and high-risk groups can be identified
PINK1 genes that impair mitochondrial with confidence, important next steps
function cause autosomal recessively will be to identify the predominant
inherited Parkinson’s disease [29] . pathological mechanisms active in
The pesticide rotenone is an inhibitor the asymptomatic or premotor phase
of mitochondrial complex 1 and of the disease. In this way the most
exposure to rotenone is a risk factor relevant preventive strategies can
for Parkinson’s disease [30] . These be tested, which might be different
mechanisms are reviewed in detail by from the optimal disease-modifying
Burbulla and Kruger [31] . Inflammation treatments for established Parkinson’s
is a recognized pathological charac disease.
teristic of Parkinson’s disease and in
animal models of Parkinson’s disease, There are a number of known inverse
exacerbates neuronal loss [32] . associations between environmental
The inverse association between factors and incident Parkinson’s dis-
ibuprofen use and incident Parkinson’s ease, such as cigarette smoking, serum
disease [33] (see below) underscores urate, caffeine intake and use of the
the potential relevance of controlling NSAID ibuprofen [37] . Lifestyle factors,
inflammation for prevention. such as physical activity early in life have
also been associated with lower risk of
Based on this information, bolstering developing the disease [38] . The fact
the UPS or mitochondrial function or that these factors are associated with
suppressing inflammation could be reduced occurrence of Parkinson’s dis-
effective preventive strategies. These ease (distinct from slower progression
potential disease-modifying strategies of disease) makes them particularly in-
are currently being evaluated in teresting clues to preventive strategies.
preclinical and clinical studies in an The Safety and Ability to Elevate Urate
attempt to slow the progression of the in Early Parkinson Disease (SURE-PD)
disease [34–36] . Additionally, there are trial is underway to investigate the abil-
active research programs attempting ity of inosine to elevate uric acid levels
to develop agents that will reverse in the blood and CSF of patients with
the pathological effects of known Parkinson’s disease and to establish its
causative genetic mutations, such tolerability [102] . The disease-modifying
as inhibitors of LRRK2. Although we potential of transdermal NICotine in
know that these systems or processes early Parkinson’s Disease (NIC-PD)
are abnormal in Parkinson’s disease, study is being conducted to investigate
Marras
whether or not nicotine slows the pro- Conclusion

gression of Parkinson’s disease [103] .
Caffeine is being studied in established The factors contributing to Parkinson’s
Parkinson’s disease for its effect on disease likely vary from individual to
symptoms and is also of interest as a individual. In one person they may be
possible disease-modifying treatment. predominantly genetic and in another
Exercise is particularly interesting as predominantly environmental, but very
a preventive strategy because of its unlikely are they exclusively one or
potential for widespread application. the other. Even the most common so-
Previous research supports exercise called ‘causative’ gene mutations are
as a beneficial treatment for physical incompletely penetrant (e.g., LRRK2
symptoms in Parkinson’s disease [38,39] gene mutations), implying that other
and it has been shown to have cogni- factors modify the risk. Therefore, ei-
tive benefits in the general population ther personalized or multipronged
as well [40] . strategies may be necessary to achieve
true prevention of the disease. How
Any one of the above strategies ever, before we have the luxury of test-
would be reasonable to investigate as ing these strategies, we must overcome
a preventive strategy, but is unlikely the challenge of identifying those at
to be completely effective on its own highest risk.
as a preventive agent. This is evident
when one considers the fact that some Financial & competing interests
patients with Parkinson’s disease are disclosure
longstanding cigarette smokers and
heavy coffee drinkers, and individuals The author has no relevant affiliations
with gout are not immune. Each of or financial involvement with any or-
these factors is associated with a mild ganization or entity with a financial
to moderate reduction in risk. For interest in or financial conflict with the
example, belonging to the highest subject matter or materials discussed in
quintile of coffee drinking compared the manuscript. This includes employ-
with the lowest is associated with ment, consultancies, honoraria, stock
odds ratios in the range of 0.6–0.75 ownership or options, expert testimo-
for incident Parkinson’s disease [33] . ny, grants or patents received or pend-
Combinations of preventive treatments, ing, or royalties.
or strategies tailored to an individual’s
genetic or environmental exposure No writing assistance was utilized in
profile will likely be necessary. the production of this manuscript.
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Marras
Multiple choice questions
1. Premotor features of Parkinson’s disease include:

a. Olfactory dysfunction
b. Constipation
c. Hearing loss
d. Hallucinations
2. Which is not a risk factor for Parkinson’s disease?
a. Male sex
b. Smoking
c. Pesticides
d. Solvents
3. Which of the following are associated with lower risk of Parkinson’s
disease?
a. Uric acid
b. Caffeine
c. Ibuprofen
d. All of the above
4. Which of the following techniques are being used to distinguish
individuals with Parkinson’s 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
2
CHAPTER
Initial and disease-
modifying strategies in
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

Elmer & Hauser
About the authors
Lawrence W Elmer
Lawrence W Elmer is Professor of Neurology, Medi-
cal Director of the Center for Neurological Health
and Director of the Gardner–McMaster Parkinson’s
Center at the University of Toledo (OH, USA). His
research is primarily focused on emerging medical
treatments for Parkinson’s disease.
Robert A Hauser
Robert A Hauser is Professor of Neurology, Molecu-
lar Pharmacology and Physiology, and Director of the
Parkinson’s 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 Parkinson’s disease
and related disorders.
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 Parkinson’s 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 dopamin-
ergic 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 stabi-
lizing neurons and preventing further neurodegeneratioin. This
requires further investigation.
Summary
Parkinson’s 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.
Elmer & Hauser
The classic motor symptoms of is preceded by pathology involving

Parkinson’s disease (PD) – bradykinesia, olfactory neurons, lower regions of
rigidity and rest tremor – correlate with the brainstem and the enteric nervous
a progressive loss of dopaminergic system [3] . The early motor signs
neurons in the substantia nigra [1,2] characteristic of the disease include
along with their respective projections bradykinesia, rest tremor, postural
to the striatum. Initial symptomatic instability and rigidity (Box 2.1) [2,4,5] .
therapy for these symptoms attempts While postural instability is considered
to restore dopamine levels in key brain one of the ‘classic’ PD symptoms, it is
areas, ameliorating clinical symptoms rarely encountered in early cases and is
while avoiding adverse side effects. not addressed in this chapter.
Optimal therapeutic intervention in PD
would go further, slowing or possibly The major goal of PD therapy is to control
preventing further dopaminergic (and motor symptoms, typically by using
other neuronal) cell loss. therapies that increase dopaminergic
stimulation in the brain, including
Treatment of PD levodopa preparations, dopamine
agonists (DAs) and monoamine
Treatment of the motor oxidase-B (MAO-B) inhibitors [5] .
symptoms of PD Another important consideration is the
avoidance of side effects, including the
Pathologically, PD is characterized risk of developing motor complications
by degeneration of dopaminergic such as ‘wearing off’ and medication-
neurons in the substantia nigra pars induced dyskinesias. Therefore, the
compacta, resulting in a reduction of choice and dosages of medications
striatal dopamine [2] . However, recent must be individualized for each
postmortem findings have suggested patient in order to provide adequate
that damage in the substantia nigra 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 blood–brain 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.
Box 2.1. Motor features of early Parkinson’s 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 4–6 Hz: 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 Parkinson’s disease
fewest side effects and/or long-term a dopa-decarboxylase inhibitor

complications. Patients with early PD (benserazide outside the USA,
are often treated initially with levodopa, carbidopa in the USA) to prevent
a DA, or a MAO-B inhibitor [5,6] . While peripheral metabolism of the drug,
a discussion of the extensive evidence thereby reducing adverse effects (AEs)
demonstrating the efficacy of these associated with peripheral formation
three therapeutic options is beyond of dopamine, specifically nausea and
the scope of this chapter, it is generally vomiting [8,9] . Levodopa is considered
considered that these three types of the most efficacious medication for
medication play important roles in the the treatment of motor features of
treatment of early PD. PD, [5–7] and exhibits a relatively
rapid onset of action and good
Dopaminergic therapies for tolerability [6,10,11] . However, the long-
early PD term use of levodopa is commonly
associated with the development of
Therapy with the dopamine motor fluctuations (e.g., wearing-off,
precursor levodopa is considered on–off fluctuations) and dyskinesias
the gold standard for treatment of [12] , especially in younger patients [11] .
motor features of PD [7] . Levodopa Therefore, the use of levodopa as initial
is generally administered with monotherapy for PD is often reserved
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 Parkinson’s
disease – when their medication is working, they move, look, feel and speak
normally. When their medicine is not working, the symptoms of Parkinson’s
disease predominate, including stiffness, slowness, soft voice, difficulty walking,
among others.
for individuals in whom motor disability confusion and/or hallucinations,

is substantial or a threat to their safety they are not typically recommended
or livelihood and for older patients for use in elderly patients or
(>65 years of age) [6,13] because their those with dementia. Other AEs
risk of neuropsychiatric complications associated with DA therapy include
with other agents (DA) is higher [6] somnolence, sudden onset sleep, and
and their risk of motor complications is impulse control disorders, including
lower [13] . pathological gambling, comp ulsive
shopping, excessive internet use
DAs, such as ropinirole, pramipexole and hypersexuality [17] . Other DAs,
and rotigotine, directly stimulate derived from ergot compounds,
dopamine receptors [11,13] . Because were used in the past for early PD,
levodopa-induced dyskinesias can including bromocriptine, pergolide and
limit the ability to adequately control cabergoline. Due to long-term risk of
parkinsonian motor symptoms, strat cardiac valvulopathies, this subclass of
egies to delay the need for levodopa DAs is rarely, if ever, used.
have been investigated. When used
as initial therapy for PD, DAs delay Selegiline and rasagiline reduce
the onset of motor complications dopamine metabolism centrally
and decrease levodopa use, although through inhibition of MAO-B, thereby
they are generally less effective than increasing brain concentrations of
levodopa for improvement of motor dopamine [18] . The MAO-B inhibitors
symptoms [14–16] . As monotherapy provide a mild symptomatic benefit [6]
in early PD, DAs provide adequate and can also delay the need for
symptomatic benefit in approximately levodopa [7,19] . In addition, there has
50% of patients for up to 3 years and been long-term interest regarding
are a suitable therapy for younger the role of MAO-B inhibitors slowing
patients with mild-to-moderate motor disease progression in PD (see below).
deficits [6] . Because DAs can cause Rasagiline monotherapy can provide
adequate control of motor features in dyskinesias earlier than those patients

approximately 50% of patients for up receiving carbidopa–levodopa [25] .
to 2 years [20] . The coadministration The study was criticized; however, be-
of DAs and MAO-B inhibitors has cause the treatment protocol did not
also been advocated to improve provide continuous levodopa avail-
symptomatic efficacy and further delay ability and the levodopa dose equiva-
the need for levodopa [6,21] . Recent lents were higher in the carbidopa–le-
reports on the efficacy and safety vodopa–entacapone group. The use
of DA/MAO-B inhibitor combination of catechol-O-methyltransferase in-
therapy have been published, including hibitors for early PD has been generally
a longitudinal clinical trial investigating discouraged.
the efficacy and safety of rasagiline in
combination with DAs with or without Alternative therapies for
levodopa [21,22] . If a levodopa delaying early PD
strategy is being employed, a DA can
be added to an MAO-B inhibitor when Amantadine, an antiviral therapy, has
needed to control motor symptoms, also been used for the management
rather than adding levodopa [23] . of early PD symptoms [11,13] . Animal
However, the strategy of delaying studies suggest that amantadine
levodopa until motor symptoms may provide multiple therapeutic
cannot be satisfactorily controlled actions by: enhancing release of
with MAO-B inhibitors and/or DAs has dopamine [26] ; blocking dopamine
been challenged, in part because the reuptake [27] ; increasing D2 dopamine
protection from motor complications is receptor density [28] ; and blocking
relatively short lived [24] . N-methyl-d-aspartate receptors with
concomitant reduction of excitatory
Catechol-O-methyltransferase inhibi- pathways that antagonize the effects
tors (i.e., entacapone and tolcapone) of dopamine [29] . Amantadine may
prolong the peripheral half-life of le- also have anticholinergic activity [9,13] .
vodopa, thereby increasing the central
bioavailability of levodopa. Tolcapone Anticholinergic therapy has been used
may also simultaneously reduce cen- for over a century to treat PD symptoms,
tral dopamine metabolism. In a trial and drugs such as trihexyphenidyl
examining the use of carbidopa– and benztropine have shown efficacy
levodopa–entacapone versus carbido- in improving tremor [11,30] . These
pa–levodopa for early Parkinson’s pa- compounds, when used, are more
tients (STRIDE-PD), the group receiv- commonly administered in younger
ing carbidopa– levodopa– entacapone patients in whom rest tremor is a primary
developed motor fluctuations and symptom and cognitive function is
Elmer & Hauser
preserved [9,11] . The mechanism of widespread use, especially in elderly

action of the anticholinergic drugs in patients [32] .
the context of PD is not completely
known [9] but may involve inhibition of Although all of the therapies described
cholinergic interneurons in the striatum have demonstrated efficacy in the
that are relatively overactive following management of the motor symptoms
loss of dopamine-mediated inhibitory of PD, only levodopa, MAO-B
mechanisms [31] . While anticholinergic inhibitors and DAs are typically
compounds are still used in clinical recommended as first-line therapies for
practice, their AE profile prevents PD (Table 2.1) [6] .
Table 2.1. Levels of recommendation for the treatment of early

Parkinson’s disease†.
Therapeutic Level of recommendation
interventions‡ Symptomatic control Prevention of motor
complications
Levodopa Effective (level A) Not applicable
Levodopa CR Effective (level A) Ineffective (level A)
Apomorphine Not used Not used
Pramipexole Effective (level A) Effective (level A)
Pramipexole CR Effective (level A) Not available
Ropinirole Effective (level A) Effective (level A)
Ropinirole CR Effective (level A) No recommendation
Rotigotine TD Effective (level A) No recommendation
Selegiline Effective (level A) Ineffective (level A)
Rasagiline Effective (level A) No recommendation
Entacapone No recommendation Ineffective (level A)
Tolcapone No recommendation No recommendation
Amantadine Effective (level B) No recommendation
Anticholinergics Effective (level B) 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].
Disease modification in PD: Unified Parkinson’s Disease Rating

MAO-B inhibitors 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 52 patients with early, untreated
MAO-B is an attractive therapeutic tar- PD were randomized in a double-
get 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 12 months thereafter. The patients
crisis with MAO-A inhibition [18] . receiving selegiline required levodopa
much later than those receiving
Selegiline placebo (545 days vs 372 days), but the
symptomatic improvement seen with
Four double-blind, placebo-controlled selegiline was not felt to represent all
trials (Table 2.2) 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 157 patients with early, untreated PD
for levodopa [34–36] . 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 wash-
during 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 8.6 months), again
Table 2.2. Clinical trials assessing monoamine oxidase B inhibitor monotherapy in early
32
Drug Study (year) N Dose Observations Ref.
Selegiline Tetrud and 54 Selegiline Slower clinical disease progression as measured by [34]
Langston (1989) 10 mg/day various scales; delayed need for levodopa
Elmer & Hauser
Selegiline DATATOP (1996) 800 Selegiline Slower rate of decline in UPDRS scores; delayed [37]
10 mg/day need for levodopa
Tocopherol Extension of trial revealed initial advantages of
2000 IU/day selegiline were not sustained
Selegiline Myllylä et al. 52 Selegiline Less disability as measured by various rating scales; [35]
(1992) 10 mg/day delayed need for levodopa
Selegiline Swedish 157 Selegiline Slower rate of progression of clinical disability [36]
Parkinson Study 10 mg/day as measured by UPDRS scores; delayed need for
Group (1998) levodopa
Rasagiline TEMPO (2004, 404 Rasagiline 1 Significantly less functional decline as measured [39,
2009) or 2 mg/day by UPDRS scores and significant improvement in 40]
(early start) quality-of-life scores with rasagiline versus placebo
Rasagiline 2 mg/day Less functional decline as measured by UPDRS
(delayed start) scores with early- versus delayed-start rasagiline
Rasagiline ADAGIO (2009) 1176 Rasagiline 1 All three primary, hierarchical end points met after [42]
or 2 mg/day 72 weeks in 1 mg/day early-start group versus
(delayed start) delayed start, suggesting disease modification,
while 2 mg/day early versus delayed start did not
meet all three hierarchical criteria
Rasagiline 1 At week 36, rasagiline 1 and 2 mg/day significantly
or 2 mg/day improved total UPDRS scores versus placebo
(early start) (secondary end point)
IU: Intrauterine; UPDRS: Unified Parkinson’s Disease Rating Scale.
suggesting a disease-modifying effect entire 6.5 years of observation, the

of selegiline. mean adjusted difference in change
from baseline in total UPDRS scores
Rasagiline was significant in favor of early-start
rasagiline (2.5 units; p = 0.021) [40] .
The efficacy of rasagiline monotherapy
in early PD has been evaluated in two In the ADAGIO trial, 1176 patients with
delayed-start clinical trials (Table 2.2) , early PD were randomized to treatment
TEMPO [39–41] and ADAGIO [42] . In with rasagiline 1 or 2 mg/day for
the TEMPO study, 404 patients were 72 weeks (early start) or placebo for
randomized to three groups – placebo 36 weeks followed by rasagiline 1
for 6 months followed by rasagiline or 2 mg/day for 36 weeks (delayed
2 mg/day for 6 months or rasagiline start). Changes in UPDRS scores over
1 or 2 mg/day for 12 months [39,40] . the course of the study are depicted
At 6 months (26 weeks), rasagiline, 1 in Figure 2.2. Comparison of the
or 2 mg/day, resulted in less disability, 1 mg/day early-start and delayed-
as indicated by lower UPDRS scores, treatment groups found that subjects
and greater improvements in quality- treated with rasagiline 1 mg/day for
of-life scores than placebo [41] . At 72 weeks (early start) met all three
1 year, patients who initially received hierarchical end points comprising
rasagiline (1 or 2 mg/day) from the the primary outcome (i.e., superiority
beginning of the trial (early start group) of slope between weeks 12 and 36;
had less functional decline (smaller superiority in change from baseline to
change from baseline in UPDRS scores) week 72; and noninferiority of slope
than those who received rasagiline during weeks 48–72). Comparison of
for only 6 months. The difference in the 2 mg/day early start and delayed
outcome at 1 year between the early- treatment groups found that subjects
start versus delayed-start groups did treated with rasagiline 2 mg/day for
not appear to be caused by a simple 72 weeks (early start) met only two of
symptomatic benefit alone, suggesting the three hierarchical end points. For
a disease-modifying effect of longer rasagiline 2 mg/day early start versus
treatment with rasagiline [39] . In a delayed start comparison, the end
long-term, open-label, extension points for superiority of slope between
study of these patients, followed weeks 12 and 36 and noninferiority
with total UPDRS scores, early-start of slope during weeks 48–72 were
rasagiline resulted in significantly less met. However, assessment of change
worsening of PD symptoms for up to from baseline to week 72 did not
5.5 years compared with delayed-start reveal significant differences between
rasagiline (Figure 2.1) [40] . Over the these groups.
Elmer & Hauser
90
*
Mean percentage change in total UPDRS
80
*
70 *
60
Improvement
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
Figure 2.1. Mean percentage change from TEMPO baseline in total Unified

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

between the treatment arms involving quartiles. Additionally, data from this
patients in the upper quartile with analysis demonstrated that rasagiline
respect to severity of symptoms at 2 mg/day met all three efficacy end
baseline (i.e., UPDRS score >25.5) was points in the quartile of patients with
performed as part of the ADAGIO the highest (worst) UPDRS scores at
study [42] . In the 2 mg/day group, baseline (>25.5). These results suggest
subjects with baseline UPDRS scores that patients enrolled in the ADAGIO
in the upper quartile had significantly study may have had too little disability
less progression in the early- versus to clearly distinguish between a
delayed-start groups when scores symptomatic and a disease-modifying
from baseline to week 72 were effect, particularly with respect to the
A 5
Delayed start
4 (placebo–rasagiline)
Worsening
UPDRS score (points)

Mean change in 3
2
1
0
Improvement
-1 Early start
-2 (rasagiline–rasagiline)
-3
0 12 24 36 42 48 54 60 66 72
Week
B
5
4
Worsening
Delayed start
UPDRS score (points)
3 (placebo–rasagiline)
Mean change in
2
1
0
Improvement
-1 Early start
(rasagiline–rasagiline)
-2
-3
0 12 24 36 42 48 54 60 66 72
Week
Figure 2.2. Changes in scores on the Unified Parkinson’s 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 Parkinson’s Disease Rating Scale.
Adapted from [42].
2 mg/day rasagiline treatment arms. As a therapeutic group, the delayed

The 2 mg/day dose may have provided functional decline and long-term
sufficient symptomatic improvement benefits observed with early selegiline
to mask a potential disease-modifying and rasagiline treatment may support
effect of this dose. a potential disease-modifying effect
Elmer & Hauser
Clinical diagnosis of early PD
Follow Symptoms Education Symptoms Consider dopaminergic

clinically non-troublesome Exercise moderately replacement
troublesome
Symptoms
mildly
troublesome
Symptoms Symptoms persist

worsen
Consider rasagiline or selegiline and/or worsen
Younger and/or
without cognitive
Initiate or add-on impairment
dopamine agonists Older and/or
with cognitive
impairment
Symptoms Initiate or add-on

worsen
levodopa
Symptoms
worsen
Consider DBS, levodopa Consider MAO-BI

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

COMT: Catechol-O-methyltransferase; DA: Dopamine agonist; DBS: Deep-brain stimulation;
MAO-BI: Monoamine oxidase type B inhibition; PD: Parkinson’s disease.
of these MAO-B inhibitors. Long- status would also be extremely useful,

term results of the ADAGIO trial may particularly if the biomarker is sensitive
provide further evidence of rasagiline’s and specific enough to reliably identify
potential for disease modification. patients with PD in very early stages of
These medications require further the disease, even in the prodromal phase,
study to understand their potential as this population would be ideally
long-term benefits. If they do provide targeted for future neuroprotective or
disease-modifying effects, benefits disease-modifying therapies [43,44] .
would be anticipated in a range of
clinical outcomes, including cognition Disease modification in PD:
and balance, symptoms that are not likely other treatments
to be very amenable to symptomatic
dopaminergic effects. The development Numerous other compounds have
of a validated biomarker of PD disease been tested to date as potential
disease-modifying treatments for an integral part of PD therapy. While

PD other than MAO-B inhibitors, included in the longitudinal treatment
including THC-346, pramipexole, early in this diagram, increasing evidence
ropinirole, levodopa, tocopherol, suggests that exercise may potentially
CoQ10, mitoquinone, creatine, slow progression of PD and/or ameliorate
CEP-1347, immunophilin, GDNF, symptoms such as gait and balance
paliroden, GM1 ganglioside, riluzole disturbances through mechanisms
and minocycline [44,45] . With few distinct and possibly complementary
exceptions, most of these treatments to pharmacological options during all
have not demonstrated clear evidence stages of the disease [46–48] .
of slowing disease progression in PD.
Financial & competing interests
Conclusion disclosure
PD is a neurodegenerative disorder LW Elmer has received honoraria or

manifested by a variety of motor and payments for consulting, advisory
non-motor symptoms. Although the services, speaking services or
motor symptoms initially respond well unrestricted educational grants from
to pharmacologic therapies, primar- Lundbeck, Teva Neuroscience and
ily levodopa, DAs and MAO-B inhibi- UCB Inc. RA Hauser has received
tors, no current PD therapy definitively honoraria or payments for consulting,
slows disease progression. However, advisory services, speaking services
studies involving the MAO-B inhibi- over the past 12 months as listed
tors have provided controversial and below: Abbott Laboratories,
provocative results, suggesting the Allergan Inc., AstraZeneca, Biotie
possibility that these agents may slow Therapies Corporation, Ceregene
PD progression. Further trials, perhaps Inc., Chelsea Therapeutics Inc., GE
including the use of diagnostic and Healthcare, Impax Laboratories
progression biomarkers, novel proto- Inc., Ipsen Biopharmaceuticals Inc.,
col designs and pathogenesis-targeted Lundbeck, Med-IQ, Merck/MSD,
therapies, will hopefully be able to Noven Pharmaceuticals Inc., Straken
demonstrate a favorable effect on the Pharmaceuticals, Ltd, Targacept Inc.,
natural history of PD. Teva Pharmaceuticals Industries, Ltd,
Teva Neuroscience Inc., Upsher-Smith
Early treatment of PD: Laboratories, UCB Inc., UCB Pharma
proposed algorithm SA and Xenoport Inc. RA Hauser’s
institution has received research
As demonstrated in the algorithm shown support over the past 12 months as
in Figure 2.3, exercise has emerged as listed below: Abbot Laboratories,
Elmer & Hauser
Addex Therapeutics, Allergan Inc., and former manufacturers of welding

AstraZeneca, Chelsea Therapeutics consumables.
Inc., GE Healthcare, Impax Laboratories
Inc., Ipsen Biopharmaceuticals Inc., The authors have no other relevant
Merck/MSD, Merz, Michael J Fox affiliations or financial involvement
Foundation for Parkinson’s Research, with any organization or entity with a
Schering-Plough, Teva Neuroscience financial interest in or financial conflict
Inc., UCB Inc. and Vita-Pharm. RA with the subject matter or materials
Hauser has received royalties in the discussed in the manuscript apart from
last 12 months from the University those disclosed.
of South Florida. In addition, RA
Hauser has consulted in litigation with No writing assistance was utilized in
lawyers representing various current the production of this manuscript.
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1. Parkinson’s disease (PD) may be characterized early by the following

clinical features:
a. Rest tremor
b. Bradykinesia
c. Rigidity
d. All of the above
2. 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
3. Levodopa usage in PD has been associated with the development of:
a. Motor fluctuations
b. Dyskinesias
c. a&b
d. None of the above
4. 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
5. Disease modification in PD:
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
3
CHAPTER
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

Pecina & Espay
About the authors
Cara A Pecina
Cara A Pecina is a Fellow in the Department of Neu-
rology, Gardner Family Center for Parkinson’s Dis-
ease and Movement Disorders, at the University of
Cincinnati (OH, USA).
Alberto J Espay
Alberto J Espay is an Associate Professor of Neurol-
ogy in the Department of Neurology, Gardner Fam-
ily Center for Parkinson’s Disease and Movement Dis-
orders, at the University of Cincinnati. He has been
lead investigator in many single- and multi-site clini-
cal trials examining treatments for motor complica-
tions in Parkinson’s disease. He received the Dean’s
Scholar in Clinical Research Award by the University
of Cincinnati (2006–2009), the NIH-funded KL2 Re-
search Scholars Mentored Award (2010–2012) and K23 Career Develop-
ment Award (2011–2016).
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 dur-
ing 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 Parkinson’s 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 Helicobacter pylori gastritis. If medication
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 neurons, which decarboxylate levodopa

motor complications in Parkinson’s into dopamine. The practical implication
disease (PD) is one of the major is that patients may be undertreated in
challenges for both patients and treat efforts to avoid peak-dose complications
ing neurologists. These range from or be overtreated to minimize ‘off’-
peak-dose or ‘on’ complications (e.g., related complications [1,2] . Judicious
peak-dose dyskinesias) to transitional adjustments in levodopa dose and other
and ‘off’ complications (e.g., freezing dopaminergic medications are critical
of gait [FOG]) and limit efforts at to manage the PD symptoms as well
optimizing motor function due to as the common motor complications.
increases in the risk/benefit ratio, which The purpose of this chapter is to aid the
compromises the net therapeutic gain. reader in identifying and treating the
An important reason for these motor various types of levodopa-related motor
complications is the short plasma half- complications and to discuss ongoing
life of levodopa, which is approximately research into treatment strategies that
90 min (less than 3 h). This shortcoming have shown promise in preventing
challenges the physiologic demand for these complications from developing.
tonic rather than phasic stimulation
of striatal dopamine receptors, a pro The frequency of motor complications
cess that becomes accentuated by in PD is estimated to be approximately
the progressive loss of the buffering 40% by 4–6 years of levodopa therapy,
capacity of degenerating nigrostriatal 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).
higher prevalence [3] . Risk factors for or ‘tonic’ fashion. Early on in the dis-
the development of levodopa-related ease course there are a sufficient num-
motor complications include younger ber of nigro striatal neurons capable
age of disease onset (<50 years), longer of continuously generating, storing
duration of disease, longer cumulative and releasing dopamine from endog-
exposure to levodopa and higher enous and exogenous levodopa. As
levodopa dosage (>600 mg/day) [4,5] . the disease progresses and nigrostria-
Levodopa-induced motor complications tal neurons degenerate, this buffer-
can be divided into dyskinesias ing capacity diminishes, resulting in
and motor fluctuations. Peak-dose phasic or pulsatile stimulation of the
levodopa-induced dyskinesia (LID) is putaminal dopamine receptors. This,
the most important ‘on’-related motor in combination with the short half-life
complication. Motor fluctuations in of levodopa, leads to shorter ‘on’ peri-
clude diphasic dyskinesia, dystonia, ods followed by increasingly frequent
predictable ‘wearing-off’, random or ‘wearing-off’ periods, which occur
‘sudden offs’, ‘delayed ons’, dose failures when levodopa levels fall below the
and FOG. However, for management therapeutic threshold, leading to the
purposes, we will separate motor clinical re-emergence of parkinsonian
complications into the clinical states features (e.g., tremor, bradykin esia,
in which they typically occur: primarily rigidity, freezing and akathisia) [6,7] .
‘off’ state, primarily ‘on’ state and The progressive reduction in the ‘on’
intermediary or transitional state. periods can be managed by raising
the individual doses of levodopa or
Primarily ‘off’ state motor increasing its frequency of adminis-
complications tration [8] . Another treatment option
for ‘wearing off’ is adding a medi-
Under normal physiologic circum- cation that reduces the breakdown
stances, the putaminal dopamine of levodopa and/or dopamine, such
receptors are stimulated in a constant 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 Parkinson’s 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.
Pecina & Espay
(COMT) inhibitor (entacapone or tol- administration. Patients using apo

capone) or an monoamine oxidase morphine should be pretreated with
(MAO)-B inhibitor (selegiline or rasa- 300-mg trimethobenzamide three-
giline) [9,10] . If not previously given, times daily for the first 2 months of use
adding a dopamine agonist to a regi- to prevent nausea and vomiting.
men of levodopa may extend the ‘on’
periods and reduce the length or Another common motor complication
depth of ‘wearing-off’ episodes. in the ‘off-state’ is dystonia, manifested
most frequently as flexion of the foot
Despite optimal medication regimens and second through fifth toes with
patients can have unpredictable or extension of the big toe on the most
sudden ‘offs’ that have no relation to affected side [12] . In young-onset PD it
the timing of levodopa administration is commonly seen early in the course of
and can occur at times when the the disease and is thought to be due to
patient expects the medication to be abnormal firing of the globus pallidus
most beneficial [8] . Patients can also with underactivity of the D2-mediated
have ‘delayed-ons’ or dose-failures striatal output to the globus pallidus
in which the medication takes longer externa [4,12,13] . Patients recognize
than usual to kick-in or does not kick-in this complication by complaining of
at all. This can be caused by blocked painful foot cramps at night or in the
absorption of the medication due to early morning when levodopa levels
competition with protein for transport are at a trough [6] . When seen in
into the gut if the patient has consumed the ‘off’ state, dystonia is treated by
a high protein meal [11] . Unpredictable increasing the dose of levodopa or
or delayed gastric emptying is a non- preventing its breakdown with the
motor complication that can cause or aforementioned COMT and MAO-B
compound this phenomenon [7] . A inhibitors. Another consideration,
simple strategy to minimize ‘delayed- particularly for early morning dystonia,
ons’ or dose failures is to instruct is using a controlled release formulation
the patient to take levodopa no later of levodopa or baclofen at bedtime.
than 30 min before and no earlier Botulinum toxin injection may also be
than 90 min after meals. For sudden considered for painful focal dystonias
or unpredictable ‘offs’ patients can remaining refractory to dopaminergic
use subcutaneous apomorphine for dose manipulations [14] . Dystonia can
‘rescue’ therapy. Apomorphine is a also be seen in the dyskinetic ‘on’
rapid-onset (within 5 min) but short- state, in which case it tends to be more
lasting (average: 75 min) dopamine prominent in the most affected hand
agonist equipotent to levodopa, or in the craniocervical region. Since
but only available for parenteral this ‘on’ dystonia would be worsened
by the approach to the more common Pharmacologic interventions to address

‘off’ dystonia, it behooves the clinician FOG are based on increasing levodopa
to attend to the temporal relationship to doses as high as 2000–2500 mg/day,
between this (and, for that matter, any) as tolerated. However, as the disease
motor complication and the dose cycle. progresses this phenomenon becomes
An unusual dyskinetic pattern may be harder to treat and does not respond
seen in patients suspected as having as well to dopaminergic medications or
PD, whereby a levodopa-induced surgical intervention relative to other
dystonia occurs in the oromandibular ‘off’ state features [18] . There are also
region (yielding a ‘risus sardonicus’ patients who have FOG primarily in the
appearance), often in conjunction ‘on’ state, which can be more difficult
with choreiform movements of the to manage as decreasing dopaminergic
feet. In this situation, especially if this medications will generally worsen
pattern emerges as an early motor other parkinsonian symptoms. In
complication, one should consider the rare circumstances, this complication
alternative diagnosis of multiple system may actually be induced or worsened
atrophy [15] . by levodopa in a dose-dependent
manner [19] . It has been speculated
FOG is arguably the most disabling that FOG may be the result of an
potential motor complication of the imbalance between dopaminergic
‘off’-state, becoming an important and noradrenergic pathways due to
source of falls and disability for degeneration of the locus ceruleus.
patients. This episodic complication is Several studies have examined the value
characterized by the patient’s sudden of raising noradrenergic concentrations
inability to lift their feet off the ground with methylphenidate in patients with
to initiate or resume walking, often FOG, with varying results [20–22] .
during gait initiation, turning, stepping
through narrow passages or dual Primarily ‘on’ state motor
tasking. One nonpharmacological complications
approach to the management of FOG
is instructing patients to use sensory The most common ‘on’ state levodopa-
cues, such as placing strips of tape related motor complication is peak-dose
on the floor at home in locations they dyskinesia, consisting of stereotypic,
usually experience freezing. Similarly choreic or ballistic movements most
helpful are canes or walkers that project commonly seen in the upper limbs,
a red laser light onto the floor, which head and trunk [6] . The ascertainment
the patient can then step over [16] . of the topographical distribution
Promising virtual reality devices have of dyskinetic patterns is helpful in
also been under evaluation [17] . distinguishing peak-dose LIDs from
Pecina & Espay
other motor phenomena (Figure 3.1). equivalent in both groups as was quality

While the exact mechanisms underlying of life [26] . It is important to emphasize
the production of dyskinesias have that early initiation of dopamine agonist
yet to be fully elucidated, it results therapy does not protect against the
in part from pulsatile dopaminergic development of dyskinesias once levo
stimulation of putaminal dopamine dopa is started [27,28] . Indeed, next to
receptors from the combination of a young age at onset, disease duration
short-acting levodopa and nigrostriatal has emerged as a major predictor
denervation. Preservation of the of LIDs. Patients often develop this
putaminal neurons is critical for the complication within months, when
generation of dyskinesias, and the levodopa has been delayed for 5 years
reason why the typical upper-body or more, suggesting that the ‘clock’ for
levodopa-induced chorea is not a dyskinesia onset ‘begins to tick’ with
feature of atypical parkinsonisms disease onset, well before initiation of
(with the distinct exception of multiple levodopa treatment (which is ultimately
system atrophy, as noted above). required).
Dyskinesias are ultimately heralded
by an increased striatal output to To minimize the severity and impact
the globus pallidus interna (GPi) and of dyskinesias, clinicians could elect to
substantia nigra reticulata [23] . lower individual dosage of levodopa,
in an effort to prevent high maximum
There is evidence to support starting a concentration in levodopa plasma
dopamine agonist as initial therapy rather concentrations, which may come at the
than levodopa to prevent dyskinesias, cost of worsening other parkinsonian
especially in younger individuals who are symptoms. Alternatively, the NMDA-
more susceptible to the development antagonist amantadine at 100 mg
of this complication [24,25] . However, one- to three-times daily can be added
progressively dwindling efficacy and to decrease LIDs [29–31] . Clinicians
increasing incidence of side effects must be aware of the potential for
(namely, leg edema, hallucinations, amantadine to induce psychosis (mainly,
excessive daytime sleepiness and visual hallucinations and paranoia),
impulse control disorders) render cognitive impairment, myoclonus,
dopamine agonists untenable as mono livedo reticularis and ankle edema, any
therapy in the long term. In a large of which may warrant drug cessation.
study of patients initially receiving Clozapine has also been shown in a
levodopa versus pramipexole it was randomized, double-blind, placebo-
found that while dyskinesias were controlled trial to reduce the duration
more common in the levodopa group and severity of LIDs without worsening
moderate to severe dyskinesias were parkinsonian features [32] . The caveats
A Peak dose B Peak dose C Diphasic D Off dystonia E Advanced PD F Atypical (MSA)
Dystonia† Chorea
Figure 3.1. Typical topographic patterns among various forms of dyskinesia in Parkinson’s disease. Right-sided
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 peak-
dose 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: Parkinson’s disease.
Figure by Martha Headworth, University of Cincinnati Neuroscience Institute. Adapted with permission from [12].
51
Pecina & Espay
are that clozapine is not as effective ‘off’ states. Unlike the aforementioned
for the action-induced component management for peak-dose dyskinesias,
of dyskinesias (which may be most diphasic dyskinesias warrant an increase
disabling) and its use requires frequent in the dose of levodopa or a shortening
blood counts to monitor for the rare risk of the interdose interval in order to
of agranulocytosis. Finally, for patients reduce ‘off’ periods and the transitions
whose dyskinesias remain troublesome between ‘on’ and ‘off’ states. Another
despite exhausting the medication intermediary motor complication is ‘yo-
adjustments suggested above, surgical yoing’, described as rapid fluctuations
intervention with subthalamic nucleus between ‘on’ and ‘off’ states when
(STN) or GPi deep-brain stimulation cerebral dopamine levels hover around
(DBS) is an option. STN DBS allows for the therapeutic threshold. The approach
a decrease in levodopa dose, which to the treat ment is similar to that of
substantially reduces dyskinesias, diphasic dyskinesias, although these
whereas GPi DBS yields a direct patients may also need to be evaluated
antidyskinetic effect, independent of for gastroparesis and Helicobacter
dopaminergic dose reduction (see also pylori gastric infection in order to
Chapter 6 on Surgical Treatment of improve levodopa pharmacokinetics. As
PD). It is important to keep in mind that these complications can be associated
dyskinesias do not always need to be with poor or erratic absorption due
treated, as patients are often unaware to protein–protein interaction, it
of or unimpaired by these movements. is important to educate patients
In fact, LIDs are not major drivers of regarding the need to avoid the intake
quality of life in PD [2,33] . of levodopa during mealtimes as
mentioned earlier [12] .
Intermediary or transitional
state motor complications Surgical intervention &
future strategies
Intermediary state motor complications
generally occur when levodopa is As briefly mentioned, when motor
near the therapeutic threshold and complications cannot be adequately
is either ‘kicking-in’ or ‘wearing-off’. controlled by pharmacological meas
Diphasic dyskinesias are perhaps the ures, DBS of the STN or GPi can provide
most common transitional motor substantial benefits in decreasing
phenomenon. In contrast to peak-dose daily ‘off’ time and dyskinesias [34,35]
dyskinesias, diphasic dyskinesias most (see also Chapter 6 on Surgical
commonly appear as choreiform or Treatment of PD). GPi DBS has a direct
ballistic movements of the lower limbs antidyskinetic effect while the reduction
during the transition between ‘on’ and in dyskinesias in STN DBS is largely
due to the postoperative reduction in double-blind trial of a novel sustained

dopaminergic medications [36–38] . release formulation of levodopa,
While gait can improve after DBS, FOG IXP066, patients with fluctuating PD
has not been shown to improve to the treated with IXP066 had a decrease in
extent of other ‘off’ state features and dose frequency (from five- to 3.5-times
the benefits that may occur tend to be per day), a 1.2 h reduction in the ‘off’
short lived [18] . DBS for ‘on’ state FOG time, and a 1.9 h gain in ‘on’ time without
has not been shown to be effective, troublesome dyskinesias compared
although it may allow the reduction with the standard immediate-release
of dopaminergic medications without carbidopa/levodopa group (Rytary™
worsening other parkinsonian features. [Impax, CA, USA] under FDA review
It is important to note that PD patients at time of press) [40,41] . XP21279 is
are candidates for DBS if their response another investigational sustained-
to levodopa remains excellent (even if release formulation of levodopa
for brief periods within each dose cycle), that appears to be associated with
their cognitive function is preserved, significantly less variability in levodopa
and any psychiatric complication is concentration compared with standard
controlled. levodopa [42] .
Efforts have been made to prevent Continuous levodopa delivery has

the initial development of motor been achieved by infusing levodopa/
complications. As stated, a large body carbidopa intestinal gel intraduodenally
of evidence supports the combined via a percutaneous endoscopic gastro
loss of nigrostriatal neurons in the stomy tube connected to an infusion
setting of pulsatile stimulation of pump. Several studies have shown
dopamine receptors as underlying the marked reductions in daily ‘off’ time as
generation of motor complications. well as reduced severity of pre-existing
Hence, sustained dopaminergic LID (LCIG; Duopa, under FDA review at
stimulation of dopamine receptors time of press) [43–47] .
through long-acting formulations
or continuous levodopa delivery has Clinical trials examining the role
become the focus of recent research. of apomorphine for early morning
Administration of levodopa/carbidopa/ akinesia and, ultimately as a con
entacapone (Stalevo®, Novartis, tinuous subcutaneous delivery pump
Switzerland) four-times daily failed to (already available in Europe), are
prevent the development of motor planned for 2013 in the USA. There
complications [39] , probably because are also ongoing investigations into
of insufficient ‘continuity’ of levodopa new forms of MAO-B and COMT
delivery. In a Phase III randomized, inhibitors that may prove to be useful
Pecina & Espay
adjuncts to levodopa in the future. significant decrease in ‘off’ time versus

Safinamide is a novel reversible MAO-B placebo as well as an increase in ‘on’
inhibitor with additional mechanisms time and an improved score in Unified
of action, including glutamate release Parkinson’s Disease Rating Scale
inhibition and activity dependent (UPDRS) part III and UPDRS parts I–III
sodium channel antagonism that has combined [101] . Full data from the study
been evaluated as a potential adjunct are to be released in the near future.
to dopamine agonists or levodopa Several glutamate receptors have been
in early and advanced PD. Phase III implicated in the development of LIDs;
trials have shown promising results however, only amantadine, a weak
in increasing daily on time (MOTION: NMDA receptor antagonist, is currently
ClinicalTrials NCT01028586 and available on the market. AFQ056,
NCT00605683, SETTLE: ClinicalTrials a mGluR5 receptor antagonist, has
NCT00627640). BIA 9-1067 is a highly shown significant reductions in dyski
potent, peripherally acting COMT nesias as assessed by the modified
inhibitor with a long half-life that is abnormal involuntary movement scale
currently undergoing Phase III studies compared with placebo and significant
to determine efficacy in reducing reductions in the UPDRS IV item 32
daily off time (BIPARKII: ClinicalTrials (dyskinesia severity) in Phase IIb
NCT01227655) [48] . studies [49,50] . Similarly, dipraglurant,
a negative allosteric modulator
Several nondopaminergic neuro of the mGlu5 receptor, showed
transmitter systems have been impli- antidyskinetic effects in animal models
cated in the development of motor of PD and is currently undergoing
complications, including pathways further investigation (ClinicalTrials:
involving glutamate, serotonin, nor- NCT01336088). In addition, stim
adrenaline, adenosine, opioids, canna- ulating nicotinic a7 receptors may
binoids and histamine. yet prove beneficial for the treatment
of motor com plications (‘wearing-
The adenosine A2a receptor subtype off’ and dyskin esias, respectively;
is highly expressed in the basal ClinicalTrials: NCT01474421). Likewise,
ganglia and its activation in PD leads serotonin 5-HT1A receptor agonists
to overactivity of the indirect pathway have recently been evaluated as a
causing parkinsonism. This receptor potential target to reduce dyskinesias
has thus been an attractive target based on histopathological findings of
for emerging therapies in PD. Results increased serotonin innervation density
from a Phase IIb study evaluating the in animal models as well as human PD
adenosine A2a antagonist tozadenant cases [51,52] . Improved understanding
(SYN115) showed a statistically of the mechanisms of motor fluctuations
and dyskinesias, coupled with advances member for Solvay (now Abbott),
in pharmacology, should lead to novel Chelsea Therapeutics, TEVA, Impax,
approaches to these levodopa-related Merz, Solstice Neurosciences and Eli
complications [53,54] . Lilly; and honoraria from Novartis, the
American Academy of Neurology and
Financial & competing interests the Movement Disorders Society. The
disclosure authors have no other relevant affilia-
tions or financial involvement with any
AJ Espay is supported by the K23 organization or entity with a financial
career development award (NIMH, interest in or financial conflict with the
1K23MH092735); has received grant subject matter or materials discussed
support from CleveMed/Great Lakes in the manuscript apart from those
Neurotechnologies, Davis Phin- disclosed.
ney Foundation and Michael J Fox
Foundation; personal compensation as No writing assistance was utilized in
a consultant/scientific advisory board the production of this manuscript.
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1. Risk factors for the development of levodopa-related motor

complications include which of the following?
a. Younger age of disease onset (<50 years)
b. Longer duration of disease
c. Longer cumulative exposure to levodopa
d. Higher levodopa dosage (>600 mg/day)
e. b, c & d
f. All of the above
2. 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
3. Sudden ‘offs’ can be treated acutely by which of the following?
a. Amantadine
b. Selegiline
c. Apomorphine
d. Entacapone
e. None of the above
4. 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 Parkinson’s disease
e. None of the above
Pecina & Espay
5. ‘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
4
CHAPTER
Management of
non-motor symptoms
of P
arkinson’s disease
Mark Stacy
Contents
Cognitive 64
Neuropsychiatric 66
Psychosis 67
Anxiety 68
Impulse control disorders 68
Autonomic 69
Sleep disorders 71
Pain & other sensory symptoms 72
Conclusion 72

Stacy
About the author
Mark Stacy
Mark Stacy is a Professor of Neurology, Chief of the
Movement Disorders Section and Vice Dean for Clin-
ical Research at Duke University (NC, USA). He has
been a member of the American Academy of Neu-
rology 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 commit-
tees including the Benign Essential Blepharospasm Foundation, Inter-
national Essential Tremor Foundation, National Parkinson Foundation
and WE MOVE. He is also a member of the Dystonia Study Group, Par-
kinson 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 inter-
ests include motor and non-motor symptoms in Parkinson’s disease,
and he has served as Steering Committee Chair for two International
Meetings focused on Impulse Control Disorders in Parkinson’s disease.
He has served on numerous multicentered research protocol steering
committees, Drug Safety Monitoring Boards, and Pharmaceutical Com-
pany Advisory Boards. He has participated in more than 100 clinical tri-
al initiatives and published more than 100 peer-reviewed manuscripts,
50 chapters, and is the Editor of the Handbook of Dystonia.
Management of non-motor symptoms of PD
Learning points
After reading this chapter you will know that:
• Parkinson’s 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 de novo PD patient. With advancing disease dopa-
minergic therapy may need to be reduced. Cholinesterase inhibi-
tors have shown benefit in cognitively impaired PD patients in
controlled trials.
Summary
Parkinson’s disease (PD) is classically characterized as a hy-
pokinetic movement disorder, with motor features of bra-
dykinesia, resting tremor and rigidity. The non-motor symp-
toms (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 pa-
thology, and are not confined to traditional dopaminergic
pathways. For instance, cognitive disturbances are often
linked to the cholinergic neuraxis, and depression may re-
sult 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.
Stacy
Depression: a decline in mood that, in Parkinson’s 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.
Parkinson’s disease (PD) is typically a four- to six-fold increase, compared

characterized by motor features: bra- with the general population [4] . Risk
dykinesia, rigidity, tremor and pos- factors linked to the development of
tural instability. However, non-motor PD dementia (PDD) include increasing
symptoms (NMS) often predate motor age (>60 years), longer disease dura-
features and have a profound impact tion and lower striatal binding on β-CIT
on the quality of life in PD patients imaging at baseline [5] . The nontremor
(Box 4.1) [1] . In a review of 1072 pa- dominant phenotype, characterized by
tients with a disease duration aver- pronounced postural instability and gait
aging 5.1 years, 98.6% reported at disorder is also associated with a higher
least one NMS [2] . The most common incidence of cognitive decline [6] . De-
complaints were fatigue (58%), anxi- mentia adds substantially to the bur-
ety (56%), leg pain (38%), insomnia den of disease for both the patient and
(37%), urinary urgency and nocturia the caregiver, while increasing health-
(35%), excessive salivation (31.1%), related costs, risks for nursing home
difficulty in maintaining concentration admission and the duration of hospital
(31%) and depression (22.5%). Anoth- stays [7,8] .
er review reports that de novo patients
(97.8%) report at least one NMS, most Early impairments include deficits in
frequently involving neuro psychiatric executive function, thought to be a
and sleep difficulty [3] . result of dysfunction of the prefrontal
cortex through the cortical–subcorti-
These findings highlight the impor- cal loops with the basal ganglia [9] .
tance of NMS detection in optimizing Measures of phonemic verbal fluency,
treatment of PD patients. This review visual and verbal memory, visuospatial
will address the common cognitive, skills, psychomotor speed, attention
neuropsychiatric, autonomic and sleep and language show deficiencies [4] .
disturbances in PD as well as available As symptoms of dementia become
treatment options. apparent, semantic verbal fluency ap-
pears and recognition memory de-
Cognitive fects arise. Decline in visuospatial and
verbal memory are more prominent in
Epidemiological studies estimate PDD than Alzheimer’s disease, but the
dementia is seen in 30% of PD patients, overall decline is less rapid [10] .
Box 4.1. Non-motor features of Box 4.1. Non-motor features of

Parkinson’s disease. Parkinson’s disease.
Cognitive −− Fecal incontinence
• Mild cognitive impairment • Bladder disturbances
• Dementia −− Urgency
• Isolated deficits in: −− Nocturia
−− Memory −− Frequency
−− Visuospatial processing • Sexual dysfunction 
−− Attention −− Hypersexuality (often drug
−− Concept formation induced)
−− Executive functions −− Erectile dysfunction
• Difficulty in: • Sweating
−− Focusing and sustaining attention • Orthostatic hypotension 
−− Generating hypotheses −− Falls related to orthostatic
−− Planning and reasoning hypotension
−− Problem-solving −− Coat-hanger pain
−− Concept formation • Dry eyes (xerostomia)
−− Temporal ordering of stimuli Sleep disorders
estimation • Restless legs syndrome
−− Maintaining information in • Periodic limb movements 
working memory • Rapid eye movement sleep behavior
−− Associative learning
disorder 
−− Maintaining or shifting sets in re-
• Excessive daytime somnolence 
sponse to changing task demands
• Vivid dreaming 
Neuropsychiatric symptoms
• Insomnia 
• Depression, apathy, anxiety
• Sleep disordered breathing
• Anhedonia 
• Non-rapid eye movement parasom-
• Attention deficits
nias (confusional wandering)
• Hallucinations, illusion, delusions
Sensory symptoms
• Obsessional and repetitive behaviors
• Pain 
• Impulse control disorders
• Paraesthesia
• Dopaminergic dysregulation
• Olfactory disturbance
syndrome
• Visual disturbances
• Confusion
−− Blurred vision
• Delirium −− Diplopia
• Panic attacks −− Impaired contrast-sensitivity
Autonomic symptoms
Other symptoms
• Gastrointestinal symptoms
• Fatigue 
−− Dribbling of saliva
−− Ageusia  • Diplopia 
−− Dysphagia and choking • Blurred vision 
−− Reflux, vomiting • Seborrhea 
−− Nausea • Weight loss 
−− Constipation • Weight gain
−− Unsatisfactory voiding of bowel • Ankle edema
Stacy
Some cognitive difficulties, such as The partial NMDA-receptor antagonist

executive function and memory, may memantine has been evaluated in PDD
respond to dopamine-replacement in four placebo-controlled trials with
therapy (DRT) in early PD, particularly variable success [16] . Only one study
in de novo patients, but usually this met its primary end point, change in
treatment will not affect associative cognition (measured by Clinician Global
learning or spatial recognition memo- Impression of Change) at 24 weeks,
ries [11] . Despite improvement with although improvements in quality of
DRT, patients with PDD still function life have been reported [17] . Given the
at a lower level compared with pre- conflicting data from available studies,
morbid status and the improvement is there is insufficient evidence to recom-
sustained for a shorter time compared mend memantine in the treatment of
with motor benefit [12] . With disease dementia in PD [15] .
progression the cognitive benefit of
DRT wanes and may worsen cognitive Subthalamic deep-brain stimulation
function. (STN-DBS) is frequently considered for
medication-resistant motor complica-
Cholinergic deficits have been consis- tions in PD, although it has been asso-
tently found in association with cognitive ciated with cognitive decline. A meta-
and neuropsychiatric symptoms includ- analysis of 28 cohort studies of cognitive
ing PDD [13] , and medications that in- performance after STN-DBS showed
crease acetylcholine neuro transmission moderate decline in semantic and ver-
are mainstays in the treatment of de- bal fluency and small but significant
mentia. Cholinesterase inhibitors are decreases in executive functions, verbal
generally well tolerated. Rivastigmine learning and memory [18] . A more rapid
is licensed for use in PDD in the USA decline in executive function is also as-
and other countries based on positive sociated with STN-DBS compared with
results in the Exelon in Parkinson’s Dis- best medical treatment [19] .
ease Dementia Study, a 24-week, ran-
domized placebo-controlled trial in over Neuropsychiatric
500 patients with PDD [14] . Donepezil
and galantamine are also reported to Depression
be more effective than placebo in some
cognitive measures. However, based on Depression is reported in 40–50% of
the low numbers of patients evaluated PD patients, but a careful review of
in most studies, study design concerns the population, the PRIAMO study,
and variability in results, evidence sup- reported symptoms of depression in
porting their use is less robust than with 22.5% of 1072 PD patients. Disruption
rivastigmine [15] . 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 or- desipramine are reported as effective in
bitofrontal cortices may be the primary the PD population. However, caution
underlying disturbance. Pathologic glio- must be taken in patients with cognitive
sis and loss of noradrenergic neurons impairment as the anticholinergic effect
in the locus coeruleus and declining of TCAs can worsen mental function.
catecholaminergic activity in the limbic Selective serotonin reuptake inhibitors
system on PET imaging has been dem- (SSRIs) and selective norepinephrine
onstrated in depressed PD patients [20] . reuptake inhibitors (SNRIs) are beneficial
and may be better tolerated than TCAs
Depression in PD is usually of mild-to- in some patients [25] . Antidepressants
moderate intensity and characterized may also improve comorbid psychiatric
by an early loss of initiative and self- symptoms, including anxiety and sleep
esteem, sadness, feelings of guilt and symptoms, and so should be continued
remorse. Other features include loss of if tolerated [26] .
appetite, sleep disturbance, declining
libido, weight gain, loss of concentra- Electroconvulsive therapy (ECT) may
tion and fatigue [21] . Unfortunately, PD be attempted for medically refractory
symptoms may mimic the vegetative depression, and often leads to tempo-
symptoms of depression, making diag- rary benefit in motor symptoms [27] .
nosis challenging. Suicide is rare in PD Repetitive transcranial magnetic stimu-
patients, but has been reported in the lation (rTMS) has shown promise in
setting of STN-DBS [22] . the treatment of PD-related depres-
sion [28] , although this requires further
Dopamine agonists (DA) have proven ef- investigation.
ficacious in the treatment of depression,
independently of motor benefit [23], Psychosis
and mechanistically has been postulated
to stimulation of limbic region D3 re- Psychosis may affect up to 60% of ad-
ceptors [24] . Therefore, optimization of vancing PD patients and is predictive of
DRT may be initially considered before poor prognosis [29] . Psychotic symp-
adding a traditional drug for depression. toms typically begin 10 years after PD
diagnosis, and earlier onset suggests an
Tricyclic antidepressants (TCAs), alternative etiology, such as Lewy body
including amitriptyline, nortriptyline and dementia, Alzheimer’s disease or prior
Stacy
psychiatric disease. Up to 40% of PD psychosis. Olanzapine and aripiprazole

patients have visual hallucinations, ini- have demonstrated worsening of motor
tially reported as a sense of ‘presence’ symptoms in controlled trials. Acetylcho-
before evolving to vague images in the linesterase inhibitors may improve mild
peripheral vision. Delusions, paranoid hallucinations, although the effect may
ideation and delirium become increas- be seen best in patients with PDD [29] .
ingly common as the disease progress-
es [30] . Psychosis has been shown to Anxiety
be a greater stressor for caregivers than
motor dysfunction as well as the single Anxiety disorders are reported in
most important precipitant for nursing 25–49% of the PD population [32], and
home placement [29] . Psychosis in PD is may present as panic attacks, phobias,
associated with neuronal degeneration or generalized anxiety disorder [33] . In-
in the pedunculopontine nucleus, locus creased subjective motor symptoms,
coeruleus, dopaminergic raphe nuclei, more severe gait problems and dyskine-
and the ventral temporal regions of the sias, freezing of gait and drug-induced
brain [31] . motor fluctuations have all been associ-
ated with anxiety, particularly during the
Initial treatment of psychosis involves wearing-off periods [33] .
the reduction of as many psychoactive
drugs as possible followed by an adjust- Anxiety linked to off periods may im-
ment of anti-PD medications; typically prove with changes in DRT that reduce
reducing or eliminating anticholiner- motor fluctuations. Benzodiazepines
gic agents, amantadine, monoamine traditionally improve anxiety; however,
oxidase type B (MAO-B) inhibitors, there is a risk of dependence and these
catechol-O-methyl transferase inhibitors medications increase the risk of falls in
and DA while increasing levodopa. Clo- the elderly. Antidepressants are typi-
zapine (<50 mg/day) has demonstrated cally better tolerated, allow long-term
efficacy in blinded, placebo-controlled therapy and are not associated with
trials without worsening extrapyramidal dependence [34] .
features. Agranulocytosis is a rare (<1%
of patients), but potentially life-threat- Impulse control disorders
ening side effect. Therefore, regular
blood count monitoring is required. Impulse control disorders (ICDs) typi-
Quetiapine also improves psychosis; cally involve behaviors that are per-
however, placebo-controlled trials have formed repetitively, excessively and/or
failed to prove efficacy. Despite this, compulsively, and to an extent that in-
quetiapine (12.5–150 mg/day) is the terferes in major areas of life function-
drug of choice for treating PD-related ing [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 >20 mmHg or in dia-
stolic blood pressure >10 mmHg 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 reliance on levodopa. When tapering

behavior and compulsive shopping. DA, caution is advised as up to 19% of
Dopamine dysregulation syndrome patients may experience DA withdraw-
(DDS) refers to the compulsive use of al syndrome characterized by anxiety,
dopaminergic medications and is often panic attacks, dysphoria, diaphoresis,
accompanied by severe dyskinesia, cy- fatigue, pain, orthostatic hypotension
clical mood disorder, and impairment (OH) and drug cravings [39] . SSRIs,
of social and occupational function. zonisamide, quetiapine, valproic acid,
Compulsive motor behaviors, or pund- naltrexone and topiramate have been
ing, often involve repetitive ritualistic reported as anecdotal treatment [35] .
behaviors or hobbyism [35] .
Both ICD and DDS can improve after
In a study of 3090 patients with treated deep-brain stimulation (DBS) provided
idiopathic PD, 13.6% had evidence of there is an associated reduction in do-
at least one ICD and 3.9% had two or paminergic medications [40] . However,
more [36] . ICD were more common in others have reported the exacerbation
patients treated with a DA (17.1%) than and emergence of ICD/DDS and other
in patients not taking a DA (6.9%). This behavioral problems following DBS [35] .
may be related to the high affinity of DA
for D3 receptors, which have a strong Autonomic
representation in the limbic system and
appear to modulate the physiologic Gastrointestinal
and emotional experience of novelty,
reward and risk assessment [37] . Inter- Approximately half of PD patients
estingly, in 103 de novo untreated PD have constipation and up to 70% will
patients, 17.5% had evidence of at least struggle with impaired gastric mo-
one ICD [38] . tility, with increasing severity in the
later stages. Constipation likely results
Treatment of ICD usually requires discon- from prolonged colon transit time and
tinuing DA treatment entirely with more impaired volitional defecation. Though
Stacy
there is severe loss of both central and urge incontinence [44] . Lower urinary
colonic dopaminergic neurons in PD, symptoms likely result from the loss of
constipation does not respond to DRT. the dopaminergic inhibitory effect on
micturition. Increased urinary frequency
Active lifestyle, physical exercise and due to overactive bladder may improve
diet are the first-line nonpharmacologi- with levodopa. Oxybutynin, tolterodine,
cal approaches for constipation in PD. solifenacin or darifenacin are effective,
Effective medical treatments include although central anticholinergic effects
psyllium, polyethylene glycol bisacodyl can cause confusion. Reducing detrusor
and magnesium sulfate. Lubiprostone is wall activity with botulinum toxin injec-
a locally acting chloride channel activa- tions into the bladder wall has proven
tor that enhances chloride-rich intestinal beneficial without the risk of systemic
fluid secretion and has proven effective side effects [45] . STN-DBS may improve
in PD patients [41] . Tegaserod maleate GU symptoms in some [46] .
is a serotonin receptor type-4 (5-HT4)
partial agonist that stimulates gastroin- Erectile dysfunction can predate mo-
testinal motility that appears effective tor symptoms and has been associated
in PD populations as well. Macrogol, with a 2.7–4-times higher risk of devel-
an isosomotic electrolyte, significantly oping PD compared with age-matched
increases bowel movement frequency controls [47] . DRT can affect sexual
and improves stool consistency in PD behavior and many PD patients report
patients. Alternative therapies include improved arousal during the ‘on’ state.
symbiotic yogurt, neostigmine, lina- Phosphodiesterase inhibitors are effec-
clotide, botulinum toxin injections and tive in the treatment of erectile dys-
sacral nerve stimulation [42] . DBS of function but may unmask or worsen
the STN may improve gastric emptying, OH [48] .
possibly related to alterations in antipar-
kinsonian medications, improvement of Orthostatic hypotension
motor symptoms and direct effects on
the STN and neighboring or connecting OH is defined as a fall in systolic blood
areas [43] . pressure of >20 mmHg or in diastolic
blood pressure >10 mmHg on standing
Genitourinary [49] . Cerebral hypoperfusion can result
in dizziness, visual disturbances (e.g.,
More than 50% of PD patients experi- blurring, color change, white-out,
ence genitourinary (GU) dysfunction, gray-out), transient cognitive impair-
including erectile and ejaculatory fail- ment and syncope. Muscle hypoperfu-
ure, incomplete bladder emptying, sion may result in headache, neck pain
urinary urgency and frequency, and and lower back pain. Fatigue, chest
pain, dyspnea and other respiratory the overnight emergence of motor

problems may also occur. symptoms, pain and nocturia, as well
as sleep–disordered breathing, restless
Conservative measures in the treatment legs syndrome and periodic limb move-
of OH include increased water intake ments [53] . Depression and nocturnal
(2–2.5 l/day), increased salt intake (>8 g hallucinations may also contribute to
or 150 mmol/day), sleeping in a head-up sleep disruption [34] .
position, fragmentation of meals, physi-
cal counter maneuvers such as squatting, Nocturnal motor symptoms often im-
bending over forward, or wearing sup- prove with long-acting DA or mela-
port stockings [15] . Fludrocortisone, mi- tonin [54] . However, caution must be
dodrine, indomethacin, and droxidopa taken with any evening dopaminergic
are effective when nonpharmacologic stimulation, as nocturnal confusion
measures fail [49] . and psychosis can be amplified, espe-
cially in the elderly. STN-DBS has been
Sialorrhea shown to improve subjective sleep
quality, total sleep time, sleep efficien-
Sialorrhea may be seen in up to 77% of cy, and reduced wake time after sleep
PD patients [50] . Nonpharmacological onset [55] .
approaches focus on improving swal-
lowing and using tactile cues such as Excessive daytime sleepiness
chewing gums or candies. Glycopyrro-
late (2 mg daily) and atropine solution Excessive daytime sleepiness (EDS) is
(0.5-mg drop sublingually once daily) likely a result of the underlying neuro
have proven beneficial with a low risk of degenerative process, nocturnal sleep
systemic anticholinergic side effects [51] . disruption and antiparkinsonian medi-
Botulinum toxin is the most effective cations [56] . Although pramipexole
treatment for sialorrhea, acting through and ropinirole were originally linked
blockade of acetylcholine release at the to sleep attacks, the abrupt transition
cholinergic neurosecretory junction of from wakefulness to sleep, almost all
the salivary glands [52] . dopaminergic therapies have been
implicated [57] . EDS appears more
Sleep disorders frequently in advanced PD and is as-
sociated with cognitive disorders, de-
Insomnia pression, longer duration of levodopa
therapy and hallucinations [34] .
Insomnia is the most common sleep
disturbance in PD [34] . Sleep disruption Treatment requires improving sleep
is typically multifactorial and involves hygiene: modifying DRT, reducing
Stacy
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 anti- Pain & other sensory

histamines, hypnotic medications, or symptoms
stimulant drugs, and evaluating for
concomitant conditions such as de- Pain and other sensory symptoms are
pression [57] . In addition, modafinil increasingly recognized as a major cause
(200–400 mg/day) has shown ben- of disability associated with PD [60] . The
efit in PD-related EDS. The nocturnal mechanism of pain in PD may include
administration of sodium oxybate has musculoskeletal, dystonic, radicular
been found to improve EDS and fa- neuropathic and central pain. DRT usu-
tigue in PD patients in an open-label ally improves dystonia- or rigidity-relat-
polysomnographic study [58] . ed pain and if this fails, botulinum toxin
injections can be effective, especially for
Rapid eye movement behavior treatment of painful focal dystonia [61] .
disorder Nonsteroidals and other analgesics as
well as DBS have been reported to suc-
Rapid eye movement (REM) behavior cessfully manage PD-related pain and
disorder (RBD) is characterized by an discomfort.
absence of muscle atonia during REM
sleep [56] . In this setting patients act Conclusion
out dream content, which is often ac-
tion filled or violent [59] . Self-injury or There are a wide variety of NMS asso-
harm to bed-partners or caregivers can ciated with PD, many of which predate
occur. the onset of motor symptoms (RBD, an-
osmia) and others that typically worsen
Night-time clonazepam (0.5–2 mg) as the disease progresses (dementia, au-
is the preferred treatment of RBD, tonomic dysfunction). These wide-rang-
with nearly 90% of patients report- ing symptoms suggest that neuropatho-
ing improvement or resolution [59] . logical changes in PD are not confined to
However, over 50% of patients report the nigrostriatal dopaminergic network,
side effects, including EDS, confusion, but affect a number of regions within
and cognitive changes. Melatonin both the central and peripheral nervous
(3–12 mg) and donepezil (up to 15 mg) systems. Early recognition of NMS is es-
at night time have also shown benefit. sential for the care of patients with PD:
DBS-STN does not seem to affect RBD. reducing cost-burden, improving quality
of life, and offering the potential for ear- interest in or financial conflict with the
lier intervention with better treatment subject matter or materials discussed in
strategies in the future. the manuscript. This includes employ-
ment, consultancies, honoraria, stock
Financial & competing interests ownership or options, expert testimony,
disclosure grants or patents received or pending,
or royalties.
The author has no relevant affilia-
tions or financial involvement with any No writing assistance was utilized in the
organization or entity with a financial production of this manuscript.
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1. Cognitive decline in Parkinson’s 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
2. A symptom of psychosis unique to the Parkinson’s 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
3. Suggested treatment of rapid eye movement behavioral disorder
is:
a. Management of sleep hygiene
b. Dopamine-replacement therapy
c. Clonazepam
d. Quetiapine
e. Clozapine
4. Non-motor symptoms requiring reduction in dopaminergic
therapy include:
a. Impulse control disorder
b. Psychosis
c. Depression
d. Nocturia
e. Both a & b
Stacy
5. Treatment for orthostatic hypotension:

a. Increased fluid uptake
b. Increased salt
c. Thigh-high support stockings
d. Fludrocortisone
e. All of the above
5
CHAPTER
Management of cognitive
and behavioral aspects of
Joseph H Friedman
Contents
Cognitive changes & dementia 82
Psychosis 84
Anxiety 86
Depression 87
Apathy 89
Fatigue 90
Impulse control disorders 91
Sleep 92

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 War-
ren Alpert Medical School of Brown University (RI,
USA). He has been the Clinical Director of the Ameri-
can 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 Parkinson’s disease.
Management of cognitive & behavioral aspects of PD
Learning points
• Behavioral changes occur in almost every person with Parkinson’s

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 is-
sues 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 suc-
cessfully, simply acknowledging them as part of the disease process
is often extremely helpful to the patient and caregivers.
Summary
Parkinson’s 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 under-
treated. 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.
Friedman
Although classified as a movement dis- patients have subtle neuropsychological

order, Parkinson’s disease (PD) is really a changes evident on sophisticated
neurobehavioral disorder and the most testing. Dementia, depending on the
devastating long-term problems are definition and the population studied,
usually behavioral rather than motor. has a variable prevalence rate, but by
Psychiatric problems are more stressful the time of death 80% of PD patients
for caregivers than motor dysfunction, suffer from PD dementia (PDD) [1] .
leading to the corollary result that psy-
chiatric problems are the leading causes The clinical syndrome of PDD is often
for nursing home placement. categorized as a ‘subcortical’ dementia
and differs from that of Alzheimer’s
The major behavioral problems in disease (AD), a ‘cortical’ dementia, in
PD can be divided into those that several important ways [2] . The degree
are thought to be intrinsic and of dementia typically fluctuates during
those which are likely iatrogenic or the day in PDD, but not in AD. The
secondary (Table 5.1) , with some memory loss in PDD is largely due to
problems falling into both categories. problems with accessing memory stores
Iatrogenic problems are those induced so that recent memories are variably
by medication, whereas secondary available and are brought up with cues.
problems are those that are reactive In AD, there is no memory trace so
to the disease constraints, such as that cuing is not helpful. PDD patients
reactive depression or insomnia due to have executive dysfunction, problems
overactive bladder. with planning, ‘multitasking’ and
attention, more so than AD patients.
Cognitive changes & PDD patients have more problems with
dementia visuospatial comprehension, and are
more likely to suffer from depression
Cognitive changes are unfortunately and develop visual hallucinations. A
common in PD. Most newly diagnosed variety of tests used in quantitative
Dementia: affects approximately 30% of Parkinson’s 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
Alzheimer’s 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.
Table 5.1. Neurobehavioral problems associated with Parkinson’s

disease.
Intrinsic problems Iatrogenic or secondary problems
Dementia
Subclinical cognitive changes Psychotic symptoms (hallucinations & delusions)
Depression Impulse control disorders
Apathy Delirium
Anxiety Sedation
Fatigue Dopamine dysregulation syndrome
Akathisia Pain
Sleep disorders
assessment of cognitive impairment different ways, producing, not surpris-

and helpful in following progression ingly, different results, and the rate of
of disease and changes in response decline varies considerably with the
to therapeutic interventions have various neuropsychology tests chosen.
been published [3] . PDD is associated The rate of decline in PDD is probably
with increased rates of depression, the same or slower than in AD.
anxiety, apathy, psychotic symptoms
and mortality. Thus, PDD is not only a The pathophysiology of PDD is not
problem in and of itself, but markedly well understood. In addition to the
increases the likelihood of behavioral usual brainstem changes of PD, brains
problems. of patients with PDD contain Lewy
bodies in the cortex, complementing
The phenomenology of PDD is similar an uncertain and variable degree of
to that seen in dementia with Lewy cortical neuronal loss. In approximately
bodies (DLB), except cognitive changes half the PDD cases, neurofibrillary
and hallucinations usually precede the tangles and amyloid plaques are also
onset of motor symptoms in DLB but seen as sufficiently severe to warrant
typically occur in middle or late stages an associated diagnosis of AD [4] .
in PDD. The overlap on phenomenology The most consistent finding in PDD
between the two disorders has helped has been the cholinergic deficit. Even
fuel the debate regarding whether PDD nondemented PD patients have less
and DLB are the same disease, which acetylcholine than AD patients, but the
start at different parts of the neuraxis deficit is worse in demented patients
(brainstem versus cortex). The rate of and correlates with dementia severity,
decline in PDD has been measured in attention deficits and hallucinations.
Friedman
There have been few reports involving cholinesterase inhibitors have also been
substantial numbers of subjects on found to reduce psychotic symptoms,
the use of any cognitive treatments and may be considered for treating PDD
for PDD. The largest included 541 accompanied by mild hallucinations or
subjects treated with either oral delusions. Dosing is the same as for
rivastigmine or placebo and reported AD, and benefits are similar. As with
moderate to marked improvement all symptomatic therapies, efficacy
in only 19.8% of subjects treated should be assessed after full response
with rivastigmine, versus 14.5% with is achieved, usually within 8 weeks. If
placebo [5] . However, moderate to not helpful, the medication should be
marked worsening over the course stopped as no medication has been
of the 24‑week study occurred in found to slow cognitive decline.
13% rivastigmine-treated patients
versus 23.1% treated with placebo. Psychosis
However, there was a large dropout
rate in both arms (27% rivastigmine vs Psychotic symptoms are common
17% placebo). The data on donepezil, in PD, with visual hallucinations
galantamine and memantine involve affecting approximately 30% of
subject numbers too small to rely on. drug-treated patients and delusions
However, most experts believe that affecting approximately 5–10%. While
the cholinesterase inhibitors have fairly medications clearly contribute to
equivalent efficacies. Rivastigmine is these symptoms, some patients may
the only treatment approved by the develop the same syndromes without
US FDA for PDD. Since the time when medication use. Dementia is the most
the rivastigmine study was performed, important risk factor for hallucinations,
a patch delivery system has been and the appearance of psychotic
released that markedly lowers the rate symptoms is often a herald symptom
of gastrointestinal side effects. Virtually of dementia. Although there have been
all reports have shown these drugs no studies comparing the incidence
to be well tolerated in PD, although of psychotic symptoms with different
occasionally worsening tremor. The PD medications, anti
cholinergics
Psychotic symptoms: usually nonemotionally based visual halluci-

nations 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.
are probably the ones most likely to Only quetiapine and clozapine have
contribute to this problem. Amantadine been demonstrated to be free of motor
and dopamine agonists are probably side effects in PD patients, but only
the next major contributors, and l-dopa clozapine has been demonstrated in
is the least likely. The hallucinations placebo-controlled trials to have potent
typically are visual, and auditory antipsychotic efficacy [8] . Although
hallucinations occur at approximately the doses required to treat psychotic
half the frequency of the visual symptoms in PDD are extremely low,
hallucinations [6,7] . The hallucinations generally between 6.25–50 mg qhs,
typically occur in low stimulus settings, the 1–2% risk of agranulocytosis is
such as reading a book or watching TV not dose related so that weekly blood
alone, and, unlike the hallucinations that count monitoring is still required. No
occur in primary psychiatric disorders, deaths have occurred in the USA using
are generally without emotional the required monitoring system since
content. ‘Minor hallucinations’ include the drug was released in 1991.
‘presence hallucinations’, which are
not true hallucinations, but a strong The first step in treating psychotic
feeling that there is someone or some symptoms is to assess for a possible
animal behind the patient, and ‘passage non-neurological explanation, such
hallucinations’, which are transient as occult infection or metabolic
visual hallucinations or illusions in the derangement. Next, a review of all
peripheral field, perceived as light psychoactive medications is made.
reflections in one’s reading glasses, a Quite often, anticholinergics (given
shadow, or an animal running by. The for overactive bladder), anxiolytics
delusions however, are less benign, in or sedatives may be the cause. PD
that they are predominantly paranoid, medications are then reduced and
with jealous delusions being one stopped, as tolerated, starting with
of the most common [7] . Psychotic anticholinergics, amantadine and
symptoms are far more common in dopamine agonists, in that order. It is
PDD patients, and the occurrence of suggested that single drugs be reduced
hallucinations is often a harbinger of and stopped, aiming for reduced
dementia. Psychotic symptoms are polypharmacy, rather than reducing
associated with an increased mortality. all drugs equally. The next step is to
The psychotic symptoms in PDD are decide whether to add a cholinesterase
phenomenologically identical to those inhibitor or an antipsychotic. Choli
seen in DLB. As in DLB, PD patients are nesterase inhibitors may be used with
exquisitely sensitive to the parkinsonian mild to moderate demented patients in
side effects of most antipsychotic drugs, whom a rapid response is not required.
including most of the atypicals. The antipsychotics typically work
Friedman
within days, but often cause sedation such as shortness of breath, dizziness
or orthostatic hypotension. Most (lightheaded or other), chest pain, fear
neurologists will start with quetiapine of dying and derealization. The spells
12.5 mg qhs and increase as needed. last several minutes and are not usually
The average dose required is generally precipitated by obvious stress. Social
50–100 mg, which usually can be phobias are quite understandable in the
given as a single bedtime dose. When setting of PD. Patients become anxious in
quetiapine is not successful, clozapine, settings where they may need to speak
beginning at 6.25 mg qhs is begun. when they feel they are being watched,
All other antipsychotics have been or when they are in crowds. Much of
associated with parkinsonism, and their fear is reality based due to their
should be used only when quetiapine speech, gait or balance impairments,
and clozapine have failed. In severe so that deciding if a problem is a
and refractory cases, electroconvulsive phobia or a realistic concern may not
therapy may be extremely helpful. be clear. Generalized anxiety disorder is
what most people think of when they
Anxiety describe a ‘nervous’ person.
Anxiety affects approximately 25% of The prevalence of anxiety in the PD

adults in the USA, making it the single patient is considerably higher than
most common psychiatric disorder in the general population, with a
in the general population. There are prevalence of approximately 40% [9] .
several different types of anxiety, Its epidemiology is also different,
which include phobias and obsessive– supporting the hypothesis that it is
compulsive disorders. Most pertinent intrinsic to the disease itself and not
for PD are panic disorder, social phobia simply a reactive process. Anxiety in
and generalized anxiety disorder. the general population primarily affects
Panic attacks are spells that occur young women, whereas PD patients
unexpectedly in which patients may feel develop their anxiety much later
a variety of overwhelming experiences 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.
equally affected. In PD, anxiety is more anxiety, with some experts suggesting
commonly associated with depression selective serotonin-reuptake inhibitors
than it is in an age-matched controlled (SSRIs) and others benzodiazepines or
comparator group. The three categories bupropion. SSRIs have the advantage
of anxiety mentioned are the ones that of a low side-effect profile but may
most commonly affect people with take weeks to produce an uncertain
PD and their relative frequencies vary benefit, whereas benzodiazepines
with the publications [10] . Anxiety is work quickly but increase the risk of
greatly underappreciated by treating falls, confusion, sedation and altered
physicians, including PD specialist sleep cycles. Buspirone has been tested
neurologists. for motor benefits and for reducing
dyskinesias, but not for anxiety; it is
It is common to believe that anxiety well tolerated. Unfortunately, there are
correlates with the motor clinical no data to guide therapy for treating
fluctuations, where the anxiety induces anxiety in PD.
an ‘off’ or the ‘off’ induces anxiety,
data suggest that there is actually Depression
little correlation [11] . Mechanisms
underlying the anxiety have been Depression has long been associated
proposed, but there are little data with PD and is the most studied of
to support any of them. Most the behavioral problems. Estimates
importantly, although anxiety is highly for its prevalence in PD are between
prevalent and often debilitating, there 30 and 50%. Many of the early
are no double-blind placebo-controlled reports on PD addressed the issue of
trials (DBPCTs) of any agent to treat whether depression was intrinsic to
anxiety in PD. A DBPCT on depression, the disease, that is the direct result
which was not sufficiently powered to of neuronal dysfunction in particular
examine anxiety and did not stratify by regions of the brain or whether it was
anxiety, found no benefit for anxiety reactive, that is, a natural response to
with venlafaxine or paroxetine. In a having a progressive, incurable and
non-random survey of PD experts, often disabling disorder. Most experts
there was no consensus on treating 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.
Friedman
due to both factors. Depression in which are often seen in PD patients who
PD usually does not worsen with have no feelings of melancholia and do
time, which might be construed as not feel depressed or sad.
an argument against the hypothesis
of an intrinsic pathological etiology. There have been only two DBPC
It also does not correlate closely with multicenter treatment trials in
motor function. The phenomenology PD-related depression. A large trial
of depression in PD is thought to involving 287 subjects reported a
differ from depression in the general statistically significant but small benefit
population, although this observation of pramipexole, a dopamine agonist
is based on few publications and used to treat motor symptoms [13] . A
applies only to large populations, not smaller study compared paroxetine,
individual patients. Depression is more venlafaxine extended release and
commonly coexistent with anxiety placebo in 115 subjects, demonstrating
in PD than in age-matched non-PD a clinically and statistically significant
depressed controls. It is increased benefit for the drugs [14] . Unfortunately,
in patients with dementia. It has the population was too small to
higher rates of pessimism, with fewer determine if these drugs also produced
feelings of guilt and self-reproach. a benefit in anxiety, which they have in
Suicidal ideation is thought to be the general population. Although the
increased as well, although the rate results were not robust, they provided
of suicide in PD patients is very low, the first proof that PD depression could
especially considering the high rate of be treated with medication, and that
depression. The low suicide rate may the medication was well tolerated.
reflect the high rate of apathy or the Older, smaller studies have found that
lack of impulsive behavior [12] . tricyclic antidepressants may be more
effective than the SSRIs, and their side
As with other behavioral disorders effects, largely due to anticholinergic
that occur in the context of a physical effects, may be helpful with drooling,
disorder, it can often be difficult to insomnia and overactive bladder.
create reliable diagnostic categories.
This was addressed in a consensus Once a decision is made to treat
NIH conference that concluded that depression, the choice of drug will
depression should be diagnosed based depend on concomitant problems, and
on mood alone. Standard criteria for the doctor’s comfort using the various
the diagnosis of depression include the options. Mirtazepine is a tetracyclic
presence of supportive features such as antidepressant that has anti-anxiety
psychomotor slowing, fatigue, altered properties, and causes sedation and
sleep cycles, weight loss, loss of interest, increased appetite, in addition to
sometimes reducing PD tremor, but unmotivated, are often willing to

there are no data in PD depression. participate in activities, if pushed. They
The SSRIs have few side effects other are unlikely to be irritable because they
than affecting sexual function, and are difficult to rouse. They simply do
have anxiolytic properties. Bupropion, not care [17] . On the one hand they
although mildly dopaminergic does do not enjoy things, but on the other
not improve motor dysfunction. Only do not feel the absence of pleasure.
venlafaxine and paroxetine have been It is a form of anhedonia, without
found to be effective in a large DBPCT, the negative connotation and affect.
but these results are thought to extend Apathy is a problem for the family and
to other antidepressants as well. The the constellation of friends, due to the
rule in treating depression is to start loss of the patient’s personality, but
with a low dose and increase after this is not painful for the patient, as the
approximately 4 weeks if the response patient is insulated from the problem
is inadequate. by the apathy itself. Some experts, on
the other hand, believe that apathy
Apathy causes severe impairment and distress.
Apathy is thought to represent a
Apathy affects approximately 40% of frontal lobe disorder and is sometimes
people with PD [15] . The term means thought to be mildly responsive to
loss of emotion and motivation, and dopamine agonists or stimulants, but
is a common symptom in people who data to support the hypothesis are
are depressed. In PD it is thought weak [15] . The relationship between
to be distinct from depression [16] , apathy and dopamine is partly related
primarily because it has a very different to the observation that Parkinson’s
emotional valence. Depressed people syndromes are generally associated with
feel sad, and although not motivated, apathy, both primary and neuroleptic
are reluctant to engage in activities. syndromes, a mild improvement in
They are frequently irritable. Apathetic apathy seen with dopamine stimulation
patients deny depression, and while and the occurrence of significant
Apathy: is a common problem in PD, often confused with depres-

sion, 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.
Friedman
apathy when dopaminergic therapy patients suffer from both. In all parts
is discontinued abruptly. Apathy is of the world, fatigue is found to affect
generally associated with some degree approximately half of PD patients and
of dementia, and is probably most appears early in the course of the
commonly evident in the patient who disease. It is not medication induced.
offers little or no spontaneous speech, Counter-intuitively, it is unrelated
but lets the caregiver answer all the to motor disease severity although
questions, rarely asks questions, and it tends to worsen with duration of
generally talks only when directly disease. A third of PD patients rate
asked a question. The patient then fatigue as their single worst symptom
answers succinctly and does not of PD, and half rate it as one of their
use the opportunity to develop a three most bothersome symptoms.
conversation. Apathy is also part of the Fatigue usually predates onset of
depression syndrome. Apathy due to the motor symptoms, and often
depression is probably treatable with remains regardless of the response to
treatment of the depression. Apathy symptomatic treatment of the motor
outside of depression may show minor aspects of PD. The etiology of fatigue
improvement with cholinesterase in PD remains a mystery, as fatigue is
inhibitors. The degree of potential ubiquitous and present in virtually all
benefit with dopaminergic medications medical and psychiatric disorders. It
is not worth the risk of their side is associated with depression in most
effects. PD studies, but not motor dysfunction
[19] . One physiological study found no
Fatigue correlation between energy efficiency
and fatigue, the hypothesis being that
Fatigue, a feeling of lack of energy, fatigued patients required more energy
and not a syndrome of sleepiness, to perform the same tasks than their
has been found to be a common nonfatigued comparators.
problem in PD, independent of the
culture studied [18] . PD patients are There is a single positive treatment trial,
usually able to distinguish fatigue demonstrating that methylphenidate,
from sleepiness, although many at 15 mg 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 patho-
physiology 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.
and effective [20] . Modafinil has not their jewelry over and over, polish
been found to be helpful for fatigue, pennies, clean an oven, or rearrange
although there are mixed results the contents of a drawer [21] . The more
for daytime somnolence with both common ICDs are gambling (affecting
modafinil and armodafinil. So far, no men and women), hypersexuality (more
data indicate that amantadine, which is commonly affecting men), overeating,
commonly used for fatigue in multiple overspending, collecting, hobbyism and
sclerosis, is useful for fatigue in PD. internet addiction. Unusual forms of ICD
have been well described, each of which
Impulse control disorders may be unique [22,23] . They occur in
approximately 10–15% of PD patients on
Impulse control disorders (ICDs) were dopamine agonists. Patients with these
first brought to attention in 2000 with problems often behave like addicts and
a report on pathological gambling; will lie about them, or minimize them,
however, the first form of ICD, punding, so that reliable information must come
was reported in 1994. The connection from a caregiver. The ICDs have clearly
between the two was made several been linked to the dopamine agonists
years later. Punding refers to a senseless and although they may occur on l-dopa,
repetitive activity, usually taking things alone, are much less likely to do so. The
apart and putting them together, first problem, like psychotic symptoms, may
described in amphetamine addicts in develop after the patient has been on
Sweden. It is an obsessive preoccupation a stable dose of medication for months
with a motor task, producing a calming or years. Risk factors include premorbid
effect. It was described in a small number history of impulsive behavior such as
of PD patients who exhibited similar gambling or drug addiction, younger
behavior, such as tallying the same age and male gender. Although many
figures repetitively, trimming a bush, case reports have described good
reading food cans in a supermarket, responses to antipsychotics, which
pulling weeds and refusing to be are theoretically useful as dopamine
interrupted, even to the point of wetting receptor blockers, and SSRIs, which are
oneself. Patients who pund will catalog often used for obsessive–compulsive
Impulse control disorders: It was over 20 years after the introduc-

tion 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.
Friedman
disorders, the only approach that reliably difficulties of both men and women
reduces or stops the ICD is a reduction with urinary urgency and frequency,
or stoppage of the dopamine agonist. compounded by the slowness of
There is insufficient data to indicate that movement and hurdles in getting in
switching from one agonist to another and out of bed. Although it used to
may be helpful. be taught that tremors resolve during
sleep, the use of polysomnography has
Sleep demonstrated that tremors may appear
during stage 1 sleep, so that tremors
Sleep disorders affect approximately commonly awaken patients. As a result
90% of people with PD [24] . These of awakenings at night, patients are
include problems falling asleep, often sleepy the next day, leading to
difficulties with sleep maintenance, daytime naps, which further erode
inverted sleep cycles, excess daytime the ability to sleep through the night.
sedation, vivid dreams and rapid eye PD patients sometimes have ‘rapid
movement sleep behavior disorder eye movement intrusions’, which are
(RBD). Obstructive sleep apnea dreams that persist for several seconds
and restless legs may occur more after awakening, causing confusion
frequently in PD patients than in age- between sleep and reality. Vivid
matched controls but this is uncertain. dreams may be so realistic that patients
The typical habitus of an obstructive will occasionally believe their dream
sleep apnea PD patient is not obese, was real, causing concern in the family,
as is usually the case in the general who think the patient has become
population, and generally the PD confused. Perhaps most important,
patients are not smokers or recently at least from a diagnostic point, is
ex-smokers. People with PD may have the presence of RBD, which has been
difficulty falling asleep due to problems closely linked to ‘a-synucleinopathies,’
moving and getting comfortable. They namely PD, DLB and multisystem
may have a tremor that interferes atrophy. RBD is extremely rare outside
with relaxation required to fall asleep. of the a-synucleinopathies in middle-
They often have overactive bladder, aged or older people (it occurs
complicating the already common 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.
and spinocerebellar ataxia type 3), and presumably, this narcolepsy-like

and its development often heralds disorder as well.
the development of one of these
disorders, often 5 or more years later. The secondary effects of sleep
In RBD, people act out their dreams, disturbances is difficult to evaluate but
particularly if they involve vigorous it undoubtedly affects cognition [26] ,
physical activity, usually violent actions mood, motivation, likelihood of
such as kicking, punching or jumping. hall
ucinations and probably motor
During normal dream sleep, people are performance as well.
paralyzed except for their breathing
and eye movements. RBD affects Financial & competing interests
approximately 30% of men with PD, disclosure
and approximately 6% of women. The
behavior is extremely irregular so that it JH Friedman has performed lectures
may occur every few months or more. for Teva, General Electric and UCB.
The relationship between sleep talking He has received consulting fees from
and RBD is not clear and sleep talking Teva, Addex Pharm, UCB and Lund-
is more common than RBD in PD. A beck, research funding from Michael
common sleep problem, particularly J Fox Foundation; NIH, EMD Serono,
in advanced patients is an increased Teva, Acadia and Schering Plough;
need for sleep, often up to 16 h per and royalties from Demos Press. The
day. This may occur for several reasons, author has no other relevant affilia-
including sleep apnea, medication side tions or financial involvement with any
effects, and interrupted sleeping at organization or entity with a financial
night. An additional reason is a loss interest in or financial conflict with the
of hypocretin-secreting cells in the subject matter or materials discussed
hypothalamus [25] , thus mimicking in the manuscript apart from those
narcolepsy. Usually PD patients with disclosed.
severe excess sleeping, both day
and night, either have sleep apnea No writing assistance was utilized in
or have some degree of dementia, the production of this manuscript.
References
1. Hely MA, Reid WG, Adena MA et al. heterogeneity of cognitive impairment
The Sydney multicenter study of and dementia in patients with Parkinson’s
Parkinson’s disease: the inevitability disease. Lancet Neurol. 9(12), 1200–1213
of dementia at 20 years. Mov. Disord. (2010).
23(6), 837–844 (2008). 3. Lee W, Williams DR, Storey E. Cognitive
2. Kehagia AA, Barker RA, Robbins testing in the diagnosis of parkinsonian
TW. Neuropsychological and clinical disorders: a critical appraisal of
Friedman
the literature. Mov. Disord. 27(10), 13. Barone P, Poewe W, Albrecht S et al.
1243–1254 (2012). Pramipexole for the treatment of
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changes in cognition in Parkinson disease Parkinson’s disease: a randomized,
with and without dementia. Dementia placebo-controlled trial. Lancet Neurol.
Geriatr. Cogn. Disord. 31(2), 98–108 9(6), 573–580 (2010).
(2011). 14. Richard IH, McDermott MP, Kurlan R et al.
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Rivastigmine for dementia associated controlled trial of antidepressants in
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351(24), 2509–2518 (2004). 1229–1236 (2012).
6. Chou KL, Messing S, Oakes D et al. 15. Starkstein SE. Apathy in Parkinson’s
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among psychosis rating scales. Clin. (2012).
Neuropharmacol. 28(5), 215–219 (2005). 16. Kirsch-Darrow L, Marsiske M, Okun MS
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Disord. 25(7), 838–845 (2010). Fatigue in Parkinson’s disease. Minor
10. Leentjens AFG, Dujardin K, Marsh L inconvenience or major distress? Eur.
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Friedman
1. Which of the following antipsychotic drugs do not cause worsening

of motor problems in Parkinson’s disease (PD)?
a. Risperidone
b. Quetiapine
c. Aripiprazole
d. Clozapine
2. Which one of the following is not considered part of PD?
a. Mania
b. Depression
c. Apathy
d. Fatigue
e. Excessive sleep
3. 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
4. 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 Alzheimer’s brain changes
e. It is associated with an increased risk of depression
5. 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
d. It often predates the onset of PD motor changes

e. It is commonly present in other disorders of a-synuclein
6. 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
7. 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
8. 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
9. 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
Friedman
10. 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
6
CHAPTER
Surgical therapy for
Nawaz Hack & Michael S Okun
Contents
Brief historical perspective 102
Patient selection: knowing when to proceed to DBS therapy 102
Fluctuating motor symptoms (on–off 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-up care 108
Potential DBS-related complications 110
Future directions 111

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 Gaines-
ville (FL, USA). After completion of a neurology resi-
dency at the University of Kentucky (KY, USA), he
pursued his interest for further training in Parkin-
son’s disease at the University of Florida (FL, USA).
His professional interests include spreading cross-
cultural awareness about Parkinson’s disease.
Michael S Okun
Michael S Okun received his MD degree from the Uni-
versity of Florida and completed a movement disor-
ders 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.
Surgical therapy for PD
Learning points
• Parkinson’s 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 5 years
of symptomatic Parkinson’s 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 Parkinson’s 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 [1–3] .
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.
Hack & Okun
Brief historical perspective 1987, the DBS field has expanded and
grown to include multiple diseases
Surgical therapies aimed primarily and multiple potentially disabling, but
at alleviating movement anomalies modifiable symptoms.
inclusive of Parkinson’s disease
(PD) trace their origins to Bucy and Patient selection: knowing
even before, when lesioning of the when to proceed to DBS
corticospinal tract was attempted in therapy
an effort to alleviate hyperkinesia and
chorea [4] . Though early attempts were PD DBS surgery is usually not pursued
unsuccessful, the field evolved over the until the diagnosis has been confirmed,
ensuing decades and gradually specific and in most cases a minimum of
regions of the basal ganglia and the 5 years has elapsed. A 5-year period
thalamocortical circuitry were identified is an arbitrary time interval that
and selectively targeted. helps DBS teams to be reasonably
sure that multiple system atrophy or
The advent of the stereotactic head another parkinsonian disorder will not
frame allowed millimeter-level accuracy develop [1] . The 5-year waiting period
in targeting of deep-brain structures. has not been examined in an evidence-
The first stereotactic frame system was based fashion. Although there are
developed by Sir Victor Alexander Haden no firmly established guidelines, the
Horsley and Robert Henry Clarke [5] . American Academy of Neurology
Hassler, Cooper and many other offered a Level C recommendation that
notable neurosurgeons pressed on with a levodopa challenge test be pursued
the use of lesion therapy, and this was prior to consideration of PD DBS [7–11] .
important to the eventual approaches In addition, most experts recommend
used in deep-brain stimulation (DBS) that multiple classes of medication and
[6] . Early DBS was used mainly to multiple dosage intervals should be
address medication-refractory epilepsy, employed prior to consideration of DBS
pain and spasticity, and also some therapy [1,12] .
movement disorders. Modern DBS
surgery for addressing tremor and PD Many experts have focused on four main
was introduced 1987 by Benabid. Since 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 Parkinson’s disease.
respond well to DBS in general [1,13] . bradykinesia, improved akinesia and

These symptoms include: improvement improved rigidity are all possible
in motor fluctuations and consequent improvements that may be seen
increases in ‘on’ dopaminergic time; following DBS. In a minority of select
suppression of dyskinesia; meaningful cases improvements in freezing, gait
improvements in quality of life; and and balance issues may be realized.
tremor suppression (Figure 6.1). DBS It is important, however, for potential
surgery in advanced PD has been US DBS candidates to be informed that in
FDA-approved since 2002, although most cases improvements in walking,
the procedure does not improve freezing and balance occurs when
all aspects of the syndrome, and symptoms are responsive to levodopa
manifestations are widely variable on a preoperative on–off dopaminergic
across patients. There are many challenge test. In addition, even if
potential benefits to DBS therapy; these symptoms respond, they are
however, these benefits will vary likely to re-emerge, progress and in the
widely among individual patients and future become unresponsive to both
will be widely variable depending on levodopa and to DBS. Speech in many
individual symptomatology. Reduction cases may worsen following DBS,
of dystonia, suppression of tremor, manifested as word-finding difficulty,
improved sleep architecture, decreased hypophonia and dysarthria.
Dyskinesias Motor fluctuations
Major DBS
indications
Quality-of-life improvement Refractory tremors
Figure 6.1. Four of the major symptoms that, in general, have an excellent

response to Parkinson’s disease deep-brain stimulation.
DBS: Deep-brain stimulation.
Hack & Okun
Important risk factors to consider prior evaluate the patients in their off state
to DBS surgery include the presence and after administration of a levodopa
of dementia, significant cognitive dys- challenge prior to consideration of
function, severe untreated depression, DBS. The patients are asked to stop
unstable psychiatric disease, atypical medications for 12 h (the night prior),
parkinsonian signs and unrealistic ex- and a Unified Parkinson’s Disease Rating
pectations. Comorbid medical condi- Scale (UPDRS) III motor scale score is
tions may also increase the risk of DBS, recorded and scored by the doctor.
and therefore comorbidities should be The practitioner then administers a
addressed by the neurologist, neuro supra-threshold dose of levodopa and/
surgeon and the anesthesiologist prior or other parkinsonian medications
to an operation. In select cases an eval- (~1.5–2-times the typical dose) and
uation by an internist or family prac- repeats the UPDRS III motor scale. The
titioner may be required, especially if change from ‘off’ to ‘on’ levodopa as
severe comorbid conditions or bleed- represented by a percentage should
ing disorders are present. A complete exceed 30% to be considered an ideal
interdisciplinary DBS evaluation by a DBS candidate. There are, however,
neurologist, neurosurgeon, psychia- exceptional cases with refractory
trist, physical therapist, occupational tremor or dyskinesia that may also be
therapist and speech therapist can be candidates following an interdisciplinary
critical for adequately assessing patient evaluation and a careful discussion.
safety issues, and also in facilitating These candidates may in some
evaluations that will provide impor- cases miss the 30% threshold [7,14] .
tant data for team discussions on DBS Randomized studies have revealed
candidacy [8] . that the greatest benefit from a DBS
operation is improvement in quality
Fluctuating motor ‘on’ time of approximately 4–6 h [7,14] .
symptoms (on–off In addition, dyskinesia can be a severe
fluctuations & loss of quality and bothersome phenomenon and
‘on’ time) & dyskinesia dyskinesia can impact the quality of life
for the PD sufferer [7,14] . Both globus
If medication therapy has been pallidus interna (GPi) and subthalamic
optimized inclusive of altering in doses, nucleus (STN) can directly suppress
intervals and employing multiple dyskinesia [15] . Bilateral STN DBS has
PD medications, then DBS may be been documented to result in medication
considered. DBS can be effective in reduction [15] , and this reduction may
the improvement of quality ‘on’ time, be an important part of the mechanism
and in suppressing dyskinesia [8] . of dyskinesia suppression. GPi is
In general, most practitioners will thought by many experts to exert a
more direct suppression type of effect DBS surgery [15] . The improvements
on dyskinesia. GPi may also allow more that have been evidenced across studies
flexibility in long-term medication support the notion that well-selected
management, although more studies candidates improve in quality-of-life
are required [15] . It is important when measures following surgery. The exact
considering the use of DBS specifically reasons underpinning quality of life
to suppress dyskinesia to be sure that improvement are unknown. Activities
the dyskinesia is actually bothersome to of daily living scores are improved post-
the sufferer. DBS in almost all studies, and these
improvements, along with motoric
Medication refractory improvements probably contribute to
tremor enhancement of quality of life [15] . In
addition, 10-year data on DBS suggests
It has been estimated that up to that axial and cognitive symptoms will
20–40% of tremors may prove continue to progress and will have the
refractory to medications [16] . In some potential to erode the quality of life
cases tremor may be partially suppressed for a PD sufferer [17] . Communication,
by medications but still remain gait and other domains of quality of life
bothersome. The pharmacological may be less amenable to DBS therapy
management of PD tremor includes and further study will be required
the use of high-dose levodopa in to sort out the individual nuisances
combination with dopamine agonists, in quality of life domains. In one
and in some cases, the addition of study the authors suggested that if
anticholinergics. Anticholinergics are a single DBS lead was employed, use
not frequently utilized in clinical practice of the GPi target resulted in a more
due to the potential for associated robust improvement in quality-of-life
cognitive risks. Tremors may be measures [18] .
embarrassing and in some cases impair
activities of daily living and leisure The role of an
activities. Medication refractory tremor interdisciplinary team
in some cases can be an indication
for DBS therapy, even if a below 30% It has been suggested that the most
levodopa response is documented by a critical component to a successful DBS
dopamine challenge test. intervention is patient selection [1,14] .
The initial process of triaging a potential
Quality of life DBS candidate can be performed
by a single practitioner (neurologist,
Multiple studies have documented an internist, family practitioner, a
enhanced quality of life resulting from registered nurse practioner, physician
Hack & Okun
assistant) through the administration may be candidates with tremor or

of the Florida Surgical Questionnaire bothersome dyskinesia, that although
for Parkinson Disease, or the short not an ideal candidate (e.g., cognition
DBS screener introduced by Moro and or another impaired domain), a DBS
colleagues. The most important aspect operation may still be considered.
of DBS triage is to refer potential Similarly, there may be candidates for a
candidates to experienced centers who palliative DBS operation to relieve one
employ a rigorous interdisciplinary symptom that is impeding quality of
screening process [14] . life. In exceptional cases, and in cases of
palliation, a thorough discussion of the
Each member of the team evaluates risks and benefits should be pursued
the potential candidate and discusses with the DBS board, the patient and
the results in a DBS board type setting the family.
(i.e., an interdisciplinary conference).
For patients deemed potential DBS Targeting symptoms rather
candidates, more discussion of the DBS than disease
target, staging (unilateral vs bilateral or
bilateral staged procedure), anesthesia Since the FDA approval of DBS the
and perioperative management focus has shifted from targeting
can also be deliberated. Successful specific diseases (e.g., advanced PD) to
interdisciplinary teams usually employ a targeting bothersome and modifiable
neurologist, neurosurgeon, psychiatrist, symptoms. This shift in practice has
physical therapist, occupational been evident not only in PD, but also
therapist, speech therapist and a in dystonia, obsessive compulsive
neuropsychologist. Some centers will disorder and essential tremor [1] . There
use a neurologist, neurosurgeon and are three common targets utilized to
neuropsychologist as a core team, treat the symptoms of PD: GPi, STN,
and involve other specialists on an and the ventralis intermedius nucleus
as needed basis. In select cases, a of the thalamus (VIM). All three
financial counselor or a social worker targets have proved successful for the
may also be appropriately utilized. treatment of specific manifestations of
Figure 6.2 summarizes the details of a PD. The VIM thalamic target is rarely
DBS interdisciplinary work-up. used, but is still an option, especially
for upper extremity tremor. VIM is
It is important to keep in mind that employed by some DBS teams when
there are ideal ‘textbook’ candidates cognition or other issues increase the
for DBS, but that there may also risk of surgery [1] . The main issue with
be other sufferers who merit full the VIM target is that although very
consideration. For example, there effective for tremor (upper more than
Physical therapy Psychiatrist

Neurologist
Occupational therapy Psychologist
Neurosurgeon
Speech therapy Social worker
Final decision on
candidate selection
for DBS
Figure 6.2. The interdisciplinary assessment of deep-brain stimulation

candidacy.
lower extremity), it may not alleviate has been preferred by other groups
bradykinesia, rigidity and dyskinesia. when cognitive issues or dyskinesia
are the main problems facing patients
Several randomized and placebo- and families. Recently, the long-term
controlled studies comparing GPi outcome of DBS has revealed more
versus STN implantation have revealed cognitive issues associated with the
similar improvements in UPDRS motor STN target, but this remains to be
scores, and also in dyskinesia, as well validated by larger studies [19] . Verbal
as on–off fluctuation diaries [15] . fluency (i.e., getting words out of the
Since motor symptom improvement mouth) issues may be worsened with
is similar between targets, it is critical either target. It has recently been
to establish the symptoms that demonstrated that verbal fluency issues
an individual patient desires to be are more of a surgical effect rather
improved following an invasive DBS than directly related to the stimulation
surgery. Although there are, as of yet, parameters [15] . It is also important to
no specific rules about which target for be aware that changes in the location
which symptom, there are emerging of stimulation on the DBS lead can
studies that may offer a glimpse of result in worsening mood and cognition
the future. A recent review article on [1] . Suicide risk, impulse control and
tailoring DBS therapy summarizes dopamine dysregulation syndrome
the potential pluses and minuses of will need to be more carefully studied,
each target [15] . Some groups, for although recent emerging evidence has
example, have advocated that STN DBS suggested that in some cases impulse
is preferred in cases where medication control and behavioral symptoms could
reduction is the desired outcome. GPi occur de novo from DBS therapy [20] .
Hack & Okun
The issue of suicide in DBS remains stimulation responses intraoperatively

unresolved, and it is unknown if one and also postoperatively can aid
target imparts a lower risk. in establishing the implantation
effect versus the effect from adding
The choice of unilateral versus bilateral stimulation. An evaluation performed
DBS for PD has recently been gaining pre- and post-operatively, as well
more attention, with a growing as on and off stimulation, can help
body of evidence revealing ipsilateral in sorting out these issues [15] .
benefits in some patients [21] . In The recent randomized study of a
one recent study over a third of DBS constant-current DBS device included
patients in long-term follow-up did not an implantation only arm. In this study
require a second, contralateral, lead at 3 months the dyskinesia diaries
placement [21,22] . The patients in this improved by almost 2 h (enhanced on
cohort were treated for an average time), and verbal fluency was shown
of 3.5 years, and the majority that to be an effect of implantation of the
remained unilateral had a GPi target. DBS lead and not of stimulation [15] .
The most common reason cited for the
addition of a DBS lead was “inadequacy Following implantation of the pulse
in addressing motor symptoms”. A generator, programming typically
second DBS was more likely for those commences a few weeks later. This
with higher baseline UPDRS-III motor delay is to allow the edema effect to
scores, and higher ipsilateral scores. resolve. The programmer will establish
The odds of proceeding to bilateral DBS thresholds for benefit and side effect
were 5.2-times higher for STN than for at each DBS contact on the lead. In
GPi. This information may translate into many cases intensive programming
a clinical decision for GPi in patients occurs over the first 6 months post-
who may possibly benefit from only DBS. Once programming has been
one lead. More studies will be required optimized during those first 6 critical
to sort out the relevant differences in months there are few changes to the
one lead versus two. DBS device. Ironically, the maintenance
of the DBS patient shifts to medication
DBS programming, management [15] . In addition, while
troubleshooting & programming during the first 6 months,
follow-up care medications will need to be optimized.
It is now appreciated by most experts
There are many important tips for that medications are not reduced in
practitioners in optimizing DBS all cases, and that over-aggressive
and in sorting out lesional versus reduction can result in adverse
stimulation-induced effects. Verifying outcomes [15] . Each DBS patient must
therefore be individually tailored and Programming parameters are typically

optimized in both programming and different on the two sides of the brain
medications. In the USA, Medtronic if bilateral implants are present [15] .
(MN, USA) is currently the primary
supplier of neurostimulators (e.g., During DBS programming there should
battery and software sources) for be vigilant monitoring and follow-
movement disorders patients. There are up. Figure 6.3 summarizes important
three model series available: Soletra®, points to address in each follow-up
Kinetra® and Activa®. The Soletra is visit, namely.
the oldest neurostimulator, and can • Optimization of medical therapy,
be connected to a single DBS lead. and monitoring of very slow
The Kinetra model can be connected tapering of medications, if
to two DBS leads (usually one in each appropriate;
brain hemisphere). The newer Activa • Monitoring for hardware-related
SC (single channel, single lead) and issues, and also for programming or
PC (dual channel, multiple leads) medication-related side effects;
devices provide basic menu-driven • Monitoring for mood or behavior
algorithms for programming, and the changes post-DBS surgery, especially
capacity to store clinical responses suicidal tendencies, depression,
observed during programming sess mania and anxiety;
ions. These newer battery sources • Identifying stimulation locations and
also have several options for multiple parameters that consistently alleviate
programs or settings that a patient the motor symptoms of PD;
can adjust at home without returning
• Educating patients on realistic
to the physician’s office. Multiple DBS expectations and also reinforcing
programs for each neurostimulator that once optimized, continued
can be useful, particularly for patients programming adjustments may not
who travel long distances for access be indicated.
to programming sessions. Finally, the
Activa series of neurostimulators can be A common pitfall in DBS programming
set to provide stimulation as a constant- is to reduce medication dosages
current as well as a voltage-driven too rapidly, and also for patients
power source; however, there have and clinicians to believe that there is
been no efficacy studies comparing always a programming setting that
them in movement disorders. There is will alleviate all symptoms. Another
an Activa RC, or rechargeable option, pitfall is the failure to address realistic
for patients using high battery drain expectations pre- and post-operatively.
DBS settings, and who may require Families should be educated that
frequent battery changes. not all symptoms can be alleviated
Hack & Okun
Optimize medications
and set realistic patient
expectations
Monitor hardware and

programming effects Optimal DBS Monitor for mood
but keep in mind programming and behavior changes
implantation effects
Choose parameters that

consistently alleviate the
motor symptoms, but do
not give side effects
Figure 6.3. Principles of deep-brain stimulation programming.

by DBS programming, and that it has emerged in clinical practice, and

will probably take months to achieve has been referred to as DBS failures [2] .
the optimal balance between pro Most of these DBS failures can be
gramming and medications. Patients prevented by a rigorous preoperative
are typically instructed to attend assessment (i.e., an interdisciplinary
programming sessions ‘off’ of their team), adequate medication treatment,
PD medications, so that the effects optimization of DBS programming,
of DBS programming can be assessed and by rechecking the lead position
without the confounding variables by imaging, thresholds and clinical
added by pharmacotherapy. Finally, response [2] . Half of DBS failures can
it is important to order an image of be improved by troubleshooting, and
the DBS lead postsurgery in order to troubleshooting has become a critical
assess the position of the DBS device. part of modern DBS practice [1] .
It is important to keep in mind that
an image alone should not be used Potential DBS-related
to assess lead placement. Clinical complications
response (i.e., scales), threshold testing
at each contact and the image should Compared with medical therapy,
all be assessed together before deciding DBS has been cited to have an
whether a lead has been suboptimally approximately 3.8-times higher
placed [15] . A group of DBS patients risk of serious adverse events
[23] . These adverse events include the occurrence of complications. It is

intracranial hemorrhage, suicide, important for DBS patients to be aware
stroke, pneumonia, im plantation of the risks and the potential bumps in
site infections, sepsis and other the road [15,23] . Burdick and colleagues
permanent neurological deficits [3] . recently published a paper revealing
In one study, involving a total of that the occurrence of adverse events
512 patients who underwent 856 in DBS, although high overall, did not
electrode implantations during a 14- correlate with quality-of-life outcomes
year study period, 58% of whom in DBS patients [27] .
had PD, there were a total of 44
patients (9%) who experienced some Future directions
hardware complication or required
system revision [2] . There were 21 This brief chapter addressed
electrode migrations in 19 patients, caveats in patient selection, patient
and 15 broken wires in 13 patients. expectations, tailoring therapy, and
A device infection was observed in the risks and benefits associated
ten (2%) of the 512 patients, and two with PD DBS. The DBS field has
patients had other complications. been slowly shifting from disease-
Median time from implant to revision specific targeting, to symptom-
was 1.5 years for migrations, 1.6 years specific targeting. The differences
for infections and 3 years for fractured between targets and approaches
wires [2] . As a result of this large and should be vetted carefully. All targets
long-term experience, a systematic and approaches should be chosen
approach to assess hardware thoughtfully for individual patients
complications in DBS patients was in a personalized manner, and an
proposed. experienced interdisciplinary team
should interface with patients during
It should be noted that the incidence this process. Finally, troubleshooting
of permanent neurological deficits DBS failures has the potential to
resulting from DBS remains below enhance outcomes, and this practice
1.5% [24] . Stimulation-induced should become part of routine care
side effects include mania, suicide, in DBS.
depression, pseudobulbar affect,
dyskinesia, motor pulling and sensory Financial & competing interests
paresthesias, among many other disclosure
possible side effects [25,26] . Effective
candidacy screening and optimal The authors have no relevant affilia-
programming as well as vigilant tions or financial involvement with any
medication management can reduce organization or entity with a financial
Hack & Okun
interest in or financial conflict with the testimony, grants or patents received

subject matter or materials discussed or pending, or royalties.
in the manuscript. This includes
employment, consultancies, honorar- No writing assistance was utilized in
ia, stock ownership or options, expert the production of this manuscript.
References
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7. Morishita T, Rahman M, Foote KD Management of referred deep brain
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Subthalamic deep brain stimulation with Unilateral deep brain stimulation surgery
a constant-current device in Parkinson’s in Parkinson’s disease improves ipsilateral
disease: an open-label randomised symptoms regardless of laterality.
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140–149 (2012). 745–748 (2011).
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Hack & Okun
1. Deep-brain stimulation (DBS) surgery should be considered in pa-

tients who have symptoms of Parkinson’s disease for 1 year and
have not tried adequate medication therapy.
a. True
b. False
2. Most Parkinson’s disease motor symptoms that are responsive to
levodopa will be responsive to DBS, with the exception of tremor
and dyskinesia.
a. True
b. False
3. Patient selection is not important in the decision-making process
for DBS.
a. True
b. False
4. When deciding on DBS therapy, one of the most important
considerations should be:
a. The symptoms targeted
b. The patient’s attire
c. The availability of a home nurse
d. The patient’s history of tobacco use
5. 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
7
CHAPTER
Experimental therapeutics
for motor symptoms of
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

Fox & Kalia
About the authors
Susan H Fox
Susan H Fox is Associate Professor of Neurology at
the University of Toronto, Movement Disorders Clin-
ic at Toronto Western Hospital (ON, Canada). She is
the Director of the University of Toronto’s Neurology
Fellowship program. She is an international execu-
tive committee member of the Movement Disorder
Society, on the editorial board of the Movement Dis-
order journal, and a member of the Parkinson Study
Group. Her current research includes preclinical stud-
ies investigating disease mechanisms of Parkinson’s disease and other
movement disorders, as well as Phase II and Phase III clinical trials of
new treatments for Parkinson’s disease and dystonia.
Lorraine V Kalia
Lorraine V Kalia is a movement disorders fellow in
the Division of Neurology at the University of To-
ronto (ON, Canada). She is currently pursuing a com-
bined clinical and research fellowship in the Morton
and Gloria Shulman Movement Disorders Clinic and
Edmond J Safra Program in Parkinson’s Disease at
the Toronto Western Hospital. Her research inter-
ests focus on the molecular mechanisms underlying
the pathogenesis of Parkinson’s Disease with the
goals of rational drug design and the development of novel therapies.
She holds a Canadian Institutes of Health Research Clinician–Scientist
Phase I Award.
Experimental therapeutics for motor symptoms of PD
Learning points
• To date, no therapy has slowed down, or reversed the disease

process, in Parkinson’s 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 Parkinson’s 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 Parkinson’s disease, including so-called ‘disease-
modifying therapies’ (neuroprotective) as well as therapies
for motor symptoms and complications of long-term
levodopa therapy.
Fox & Kalia
Parkinson’s disease (PD) is primarily including oxidative stress, mitochondrial

caused by degeneration of dopaminergic function, apoptosis, excitotoxity, calcium
cells within the substantia nigra pars turnover, protein folding and recycling,
compacta of the brainstem. The cause and inflammation (reviewed in [1]).
of this cell loss is generally unknown,
although probably involves interplay Oxidative stress (damage due to
between genetic susceptibility, environ reactive oxygen species) is a key
mental factors and aging. The disease is factor in dopamine cell loss. Oxidative
slowly progressive over many years but damage and the associated mito
with initial good improvement in motor chondrial dysfunction may result in
symptoms due to the use of the energy depletion, accumulation of
dopamine precursor, levodopa. Long- cytotoxic mediators and cell death.
term use, however, results in the The selective vulnerability of dopamine
development of motor complications cells in the substantia nigra may be
that affect quality of life. In addition, due to an age-related reliance on a
many non-motor symptoms of the certain type of calcium channel, the
disease develop such as psychiatric L-type Ca(v)1.3 Ca2+ channels. With age
issues, cognitive impairment, psychosis, there is a switch in channel type that
mood disorders, pain and autonomic predominates and can make the cells
problems. Thus, there are many aspects vulnerable to oxidative stress. Blocking
to PD that require therapeutic inter this action has thus been proposed
vention. This chapter will focus on as a means of neuroprotection and
experimental therapies for the motor a clinical study using the calcium
symptoms of PD. channel blocker, isradipine is ongoing.
A depletion of antioxidants has been
Disease-modifying agents suggested to be part of the disease
in PD process and thus use of the antioxidant,
glutathione in PD is being evaluated.
Many novel approaches have been Microglial cells play a key role in the
investigated as potentially able to slow oxidative stress process [2] . Myeloper
down disease progression (also called oxidase is a neutrophil and macrophage
neuroprotective) at the preclinical level. product that drives inflammatory
These include agents that target many reactions and tissue oxidation and the
aspects of dopamine cell survival, myeloperoxidase inhibitor, AZD3241, is
Neuroprotection: the process of preventing ongoing neuronal

cell loss.
in development for PD. Mitochondrial nonapoptotic and anti-inflammatory

dysfunction is also a key part of PD mechanisms. Neuronal growth factors
pathophysiology [3] . Supplementation can improve dopamine cell survival
with the mitochondrial respiratory and include glial-derived neurotrophic
chain enhancer, coenzyme Q10, was factor (GDNF) and brain-derived
previously tried but with variable neurotrophic factor (BDNF). Infusion
results. Other targets include peroxi studies with GDNF were not successful
some proliferator-activated receptor g owing to several possible reasons [4] .
coactivator-1a (PGC‑1a), which is under Enhanced delivery of GDNF using viral
expressed in PD subjects and activation vectors is in development (adeno-
of PGC-1a is thought to increase associated virus-2 [AAV2]-GDNF).
mitochondrial respiratory function. PYM50025 is an orally active agent
Thus the PGC‑1a activator, pioglitazone that may enhance growth factors and
is being evaluated. Creatine is also is also being evaluated in early PD.
being evaluated in early PD. Creatine
kinase may increase phosphocreatine Clinical studies have investigated these
or cyclophospho creatine and buffer agents in both advanced PD as well as
against ATP depletion and thus improve early de novo PD. The ability exhibited
mitochondrial function. by an agent to slow down disease at
any stage is termed ‘disease-modifying’.
Epidemiology studies have shown To date, clinical studies have been
that people who smoke and drink disappointing in translating potentially
coffee are less likely to develop PD; promising preclinical work in terms of
the mechanisms are not entirely clear demonstrating any effect on slowing
but nicotine and adenosine have both down disease progression. This has been
neuroprotective properties in vitro due to a number of factors including:
and agents targeting these receptors • Some potential drugs having an
are in clinical development. Likewise, effect on both motor symptoms
patients with gout and high plasma per se as well as neuroprotective
uric acid levels have been shown to action (e.g., monoamine oxidase
have a lower risk of developing PD due type B [MAO-B] inhibitors, selegiline
to antioxidant properties of uric acid. and rasagiline; dopamine agonists,
Inosine can elevate uric acid and is being ropinirole and pramipexole) thus
evaluated in PD. Neuroinflammation making interpretation of outcomes
is also probably a key factor in unclear;
dopamine cell loss. Agents that reduce • Difficulty in measuring
inflammation include filgrastim, which neuroprotection (i.e., remaining
is a granulocyte colony-stimulating dopamine cells) separate from an
factor that improves cell survival via overall assessment of motor disability;
Fox & Kalia
• Giving the interventions too late, as

that inhibit monoamine oxidase
it is now known that PD starts many
enzyme system (MAO-B inhibitors)
years prior to the motor onset with
to prevent breakdown of dopamine
several preclinical symptoms now
recognized. and, as such, have mild symptomatic
effects. Safinamide is one such
Thus, these caveats are important new agent with mild effects in
in future studies for neuroprotective monotherapy and results from a large
drugs in PD (Table 7.1) [5,6] . randomized control trial as add-on
to dopamine agonists are pending.
Targets for motor symptoms Nondopaminergic agents have also
of PD been investigated. For monotherapy
or adjunct therapy for motor
PD motor symptoms include slowness symptoms, these have focused on
(bradykinesia), rigidity, tremor symptoms that are often levodopa-
and gait problems. Levodopa is a resistant. Thus cholinergic dysfunction
dopamine precursor that remains via brainstem circuits involving the
the gold-standard therapy for all PD pedunculopontine nucleus has been
symptoms, at all stages of the disease. proposed to mediate gait and balance
Long-term use, however, results in dysfunction in PD (Table 7.2) .
motor fluctuations and has led to
alternatives to dopamine that may be Targets for motor
used before starting levodopa, termed complications
‘levodopa-sparing’ agents. Other
means of administering dopamine Long-term use of levodopa, although
include the synthetic dopamine effective, can lead to fluctuations
agonists that have a longer half-life in benefit called ‘wearing off’, and
than levodopa and bypass gastric delayed onset of action. This can be
absorption issues. One new dopamine due to erratic absorption of levodopa
D2 receptor agonist, pardoprunox, due to competition with dietary protein
has been investigated as early amino acids for transport across the
monotherapy with a demonstrated gut wall and reduced absorption
mild benefit but titration dose-related due to slow gastric emptying and
side effects. Other strategies are constipation. GSK962040 is a motilin
mild dopamine-enhancing agents agonist that is being investigated in
Motor fluctuations: variations in improvement and loss of benefit

of motor symptoms following dose of levodopa.
Table 7.1. Experimental therapies for disease modification.
Name Proposed mechanism Drug action Clinical study Ref.
of neuroprotection
Isradipine Prevents oxidative stress Calcium channel Phase I/II tolerability study in moderate PD [10]
blocker patients (n = 31). Tolerable in 81%. Side effects
were dizziness and ankle edema
N-acetylcysteine Prevents oxidative stress Increases Phase I/II safety and tolerability study over [101]
glutathione 4 weeks
Intranasal Prevents oxidative stress Increases Phase I/II single ascending dose escalation [102]
tripeptide glutathione study over 12 weeks
glutathione
GM1 ganglioside Enhances dopamine Endogenous Open-label extension of early RCT over 5 years [11]
survival; mechanism sphingolipid in early treated PD (n = 26). Outcome: lower
unclear UPDRS II and III
Transdermal Possibly anti- Nicotine Phase II safety study in early untreated PD [103]
nicotine inflammatory (n =160). Outcome: UPDRS part I, II, III after
52 weeks
Preladenant Prevents glutamate Adenosine A2A Phase III DBRCT in early PD (n = 1000). [104]
excitotoxicty and antagonist Preladenant monotherapy vs rasagiline over
reduces inflammation 26 weeks. Outcome: UPDRS II and III
Inosine Antioxidant Elevates uric Phase II DBRCT dose-finding and tolerability [105]
acid study in early PD (n = 90) and with low serum
urate (5.54 mg/dl) over 12 weeks
AAV2: Adeno-associated virus-2; b.i.d.: Twice daily; DBRCT: Double-blind, randomized controlled trial; GDNF: Glial-derived neuro-
trophic factor; MPO: Myeloperoxidase; PD: Parkinson’s disease; PPARg: Proliferator-activated receptor-g; RCT: Randomized controlled
trial; UPDRS: Unified Parkinson’s Disease Rating Scale.
121
122
of neuroprotection
Fox & Kalia
Filgrastim Nonapoptotic and G-CSF Phase II DBRCT in early treated PD (n = 36) [106]
anti-inflammatory of high- vs low-dose G-CSF and placebo
mechanisms for consecutive 5 days of each 60-day cycle
(6 cycles). Outcome: UPDRS III
AZD3241 Antioxidant via MPO inhibitor Phase IIa DBRCT in early untreated PD (n = 50). [107]
microglial activation Safety and tolerability of AZD3241 over
12 weeks
Pioglitazone Increases mitochondrial PPARg agonist Phase II DBRCT early PD subjects on stable [108]
respiratory function? monoamine oxidase B inhibitor allowed
(n = 216). Safety, tolerability, and futility, of
pioglitazone (15 and 45 mg) over 44 weeks
Creatine Improves mitochondrial Enhances Phase II DBRCT in early PD (n = 200). Creatine [109]
function creatine kinase (10 g/day) and minocycline (200 mg/day)
activity over 12 months. Outcome: neither could be
rejected as futile based on the DATATOP futility
threshold, using change in total UPDRS. Long-
term (5–7 years) RCT using creatine 5 g b.i.d is
ongoing in treated PD patients (n = 1741)
of neuroprotection
PYM50028 Enhances growth Orally active Phase I studies (n = 9), safety in healthy and PD [110]
factors and dopamine synthetic subjects; Phase II RCT in early PD (n = 408) for
cell survival chemical that 28 weeks. Outcome: UPDRS II and III
enhances
growth factors
AAV2-GDNF GDNF may prevent Convection Phase I in advanced PD (n = 28), open-label, [111]
dopamine cell loss enhanced dose-escalation, safety of four different dose
delivery/AAV2- levels of AAV2-GDNF into putamen over
GDNF 5 years
PD01A Vaccine against a- Unknown Phase I tolerability and safety of four injections [112]
and b-synuclein (no of two doses of PD01A formulated with
references to preclinical aluminium oxide in early PD (n = 32)
data provided) over 1 year. One study site (Austria) vs
eight untreated controls
123
Table 7.2. Experimental treatments for symptomatic monotherapy or adjunct therapy.
124
Name Proposed mech Drug action Clinical study Ref.
anism of action
Fox & Kalia
Pardoprunox Dopaminergic 5-HT1A agonist Two Phase III DBRCTs in early PD (n = 687 total). [12]
(SLV208) and dopamine D2 Outcome: small improvement in motor scores versus
agonist placebo; n.s. versus pramipexole. High dropout rate
due to nausea, sleepiness and dizziness
Safinamide Mild dopaminergic Mixed MAO-B Phase IIb DBRCT in early PD on dopamine agonist [13]
effect inhibitor and (n = 270). Outcome: improved UPDRS III (-6.0
glutamate points for safinamide 100 mg vs -3.6 points for
antagonist placebo, p < 0.05)
Phase III study in early PD on dopamine agonist [113]
(n = 679). Outcome: UPDRS II and III
Deferiprone Removal of excess Iron chelator Phase II DBRCT safety and efficacy in early, [114]
iron from substantia untreated PD (20 or 30 mg/kg/day deferiprone vs
nigra placebo) (n = 36). Outcome: MRI and clinical scores
at 6 months
Varenicline Improve gait and Nicotinic partial a4b2 Phase II DBRCT in PD subjects (n = 40) with falls. [115]
balance targeting agonist and full a7 Outcome: Berg Balance Scale and UPDRS at
PPN via cholinergic agonist 9 weeks
system?
Amantadine Improve gait; Glutamate Phase IV RCT in PD with freezing of gait (n = 15). [116]
mechanism antagonist Outcome: freezing of gait using UPDRS part I score
unknown >2 at week 11
DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B; n.s.: Nonsignificant; PD: Parkinson’s disease;
PPN: Pedunculopontine nucleus; RCT: Randomized controlled trial; UPDRS: Unified Parkinson’s Disease Rating Scale.
Table 7.2. Experimental treatments for symptomatic monotherapy or adjunct therapy.
Name Proposed mech Drug action Clinical study Ref.
anism of action
Donepezil To improve gait and Cholinesterase Phase IV DBRCT crossover study in PD with gait [117]
balance via action inhibitor problems (n = 12). Outcome: objective gait analysis
on PPN cholinergic at 21 days
system?
Dalfampridine Mechanism 4-aminopyridine Phase II DBRCT crossover in PD with gait issues [118]
unknown potassium channel (n = 25). Outcome: objective gait velocity and
blocker; mechanism stride length and UPDRS
unclear
DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B; n.s.: Nonsignificant; PD: Parkinson’s disease;
PPN: Pedunculopontine nucleus; RCT: Randomized controlled trial; UPDRS: Unified Parkinson’s Disease Rating Scale.
125
Fox & Kalia
Dyskinesia: involuntary movements that develop as a consequence

of long-term levodopa therapy.
early Phase IIa studies. This agent Treatments for

may increase gastric emptying and levodopa-induced dyskinesia
thus increase levodopa absorption.
Alternative methods of administration Involuntary movements termed dyski-
of levodopa are also being evaluated nesia are a common long-term problem
that bypass these issues. This includes in advanced PD due to chronic levodopa
nasal administration of levodopa use. The pathophysiology of dyskinesia
(CVT-310). An approach to treatment involves overactive glutamatergic path-
of motor fluctuations, in particular ways from cortex to caudate-putamen
wearing off, is the addition of drugs (striatum) that alters output from the
that prevent dopamine breakdown basal ganglia circuitry and abnormal
via enzyme inhibition; for example activation of motor cortex, resulting in
catechol-O-methyl transferase hyperkinetic movement. Agents that
(COMT) or MAO-B inhibition. Several target this abnormal glutamatergic ac-
new agents are in development, tivity have been investigated for reduc-
including a long-acting COMT ing levodopa-induced dyskinesia. The
inhibitor, opicapone, and a novel NMDA receptor antagonist, amanta-
MAO-B inhibitor, safinamide. Another dine, is currently the most commonly
target is the nondopaminergic used agent in clinical practice. An ex-
neuromodulator, adenosine. tended release version (ADS-5102) with
Adenosine A2A antagonists can potentially fewer side effects is being
increase motor function via an action evaluated. Other glutamate receptors
on striatopallidal pathways, thus have also been implicated and several
potentially having an antiparkinsonian agents that target one subtype, so-
action without driving dyskinesia, as called metabotropic mGluR5 receptors,
would occur with direct dopamine are in development; the rationale being
agents. Several such adenosine A2A a wider therapeutic window to reduce
antagonists are in development and side effects. mGluR5 antagonists in clin-
include istradefylline (not approved ical development include mavoglurant
by the US FDA but in development in (AFQ056) and diplagurant (ADX48621).
Japan), tozadenant and preladenant Other potential antiglutamate tar-
with a general trend to improving gets include naftazone that reduces
‘off’ time by an average 1.5 hours glutamate release, although to date
(Table 7.3) . only one small study was conducted.
Table 7.3. Experimental therapies for motor fluctuations.
of action
GSK962040 Increases absorption Motilin Phase II DBRCT in PD subjects with delayed gastric [119]
of levodopa across agonist to emptying (breath test) and motor fluctuations (n = 70)
gastrointestinal mucosa increase of repeat doses of GSK962040 on the pharmacokinetics
gastric of levodopa after 8 days
emptying
CVT-310 More rapid absorption Nasal Phase II RCT in PD subjects with 2 h ‘off’ time/day [120]
(levodopa of levodopa administration (n = 24); safety, efficacy and pharmacokinetics versus
inhalation of levodopa oral levodopa. Outcome: ‘off’ time over 13 weeks
powder)
Opicapone Enhances half life of Long acting Phase III DBRCT in PD subjects with 1.5 h ‘off’ time/ [121]
dopamine COMT day (n = 550); opicapone vs entacapone or placebo.
inhibitor Outcome: UPDRS I–III at 14–15 weeks
Istradefylline Improves motor activity Adenosine Five RCTs studies (total population >1500 patients with [14]
by reducing inhibition A2A motor fluctuations); reduced ‘off’ time by 1–1.3 h, but
of indirect dopamine antagonist two of five studies were n.s. versus placebo
D2 striatopallidal
pathway
COMT: Catechol-O-methyl transferase inhibitor; DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B;
n.s.: Nonsignificant; PD: Parkinson’s disease; RCT: Randomized controlled trial; UPDRS: Unified Parkinson’s Disease Rating Scale.
127
Table 7.3. Experimental therapies for motor fluctuations.
128
of action
Fox & Kalia
Tozadenant Improves motor activity Adenosine Phase II DBRCT in PD with wearing off (n = 400). [122]
(SYN115) by reducing inhibition A2A Outcome: mean total hours of awake time per day
of indirect dopamine antagonist spent in the ‘off’ state
D2 striatopallidal
pathway
Preladenant Improves motor activity Adenosine Phase IIb DBRCT in PD with wearing off (n = 253). [15,
by reducing inhibition A2A Outcome: improved mean daily ‘off’ time (-1.0 h for 123]
of indirect dopamine antagonist preladenant 10 mg/day, -1.2 h for preladenant 20 mg/
D2 striatopallidal day vs -0.5 h for placebo, p < 0.05). 12-week DBRCT in
pathway PD with motor fluctuations (n = 450). Outcome: change
from baseline to week 12 in mean ‘off’ time in hours
per day
Pardoprunox Dopaminergic and Partial Phase III DBRCT PD (n = 295) with motor fluctuations [16]
(SLV208) serotonergic dopamine (>2.5 h/day in ‘off’ state). Outcome: reduction in ‘off’
D2 agonist time (-1.62 h/day for pardoprunox vs -0.92 h/day for
and 5-HT1A placebo, p < 0.05) at 23 weeks
agonist
Safinamide Extends duration of Mixed MAO-B Phase III DBRCT in PD subjects with >1.5 h ‘off’ time [124]
levodopa action by inhibitor and (n = 549). Outcome: change from baseline in daily ‘on’
MAO-B glutamate time at 24 weeks
antagonist
COMT: Catechol-O-methyl transferase inhibitor; DBRCT: Double-blind, randomized controlled trial; MAO-B: Monoamine oxidase B;
n.s.: Nonsignificant; PD: Parkinson’s disease; RCT: Randomized controlled trial; UPDRS: Unified Parkinson’s Disease Rating Scale.
Table 7.4. Experimental agents for dyskinesia.
Name Proposed mechanism Drug Clinical study Ref.
of action action
ADS-5102 Higher daytime drug NMDA Phase III DBRCT in PD with troublesome dyskinesia [125]
(extended levels and lower night antagonist (n = 80). Outcome: UDysRS total score at 8 weeks
release time to avoid nocturnal
amantadine side effects
HCl)
Mavoglurant Antagonism mGluR5 Two Phase IIa studies in PD with troublesome [17,
18,
(AFQ056) of overactive antagonist dyskinesia (total n = 59). Outcome: reduction in
corticostriatal dyskinesia vs placebo over 20 days. Side effect: 126]
glutamate activity dizziness. No worsening of PD motor scores. Phase IIb
DBRCT in PD with troublesome dyskinesia (n = 140).
Outcome: reduction in AIMS after 12 weeks
Dipraglurant Antagonism mGluR5 Phase IIa DBRCT in PD with troublesome dyskinesia [19,
(ADX48621) of overactive antagonist (n = 76). Outcome: safety and dyskinesia severity over 127]
corticostriatal 4 weeks. Side effect: dizziness
glutamate activity
Naftazone Reduction in overactive Reduces Phase II DBRCT (four consecutive 28-day crossovers) [20]
corticostriatal glutamate in PD with troublesome dyskinesia (n = 7). Outcome:
glutamatergic activity release diaries, five/seven patients responded to naftazone for
‘on’-time with troublesome
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: Parkinson’s disease; UDysRS: Unified Dyskinesia Rating Scale.
129
130
of action action
Fox & Kalia
Safinamide Reduction in overactive Glutamate Phase IIb DBRCT in PD with troublesome dyskinesia [128]
corticostriatal antagonism (n = 24). Outcome: UDysRS at 42 days
glutamatergic activity
AQW051 Nicotinic/cholinergic; Positive Phase II DBRCT in PD with troublesome dyskinesia [129]
reduces dopamine allosteric (n = 72). Outcome: safety and tolerability, AIMS at
release following modulation 28 days
desensitization of of a7nAChR
nicotinic receptors in
the striatum
NP002 Nicotinic/cholinergic; Nicotinic Phase II DBRCT in PD with moderate to severe [21,
reduces dopamine agonist dyskinesia (n = 65). Outcome: safety and tolerability, 130]
release following trends favoring NP002 on UDysRS over 12 weeks
desensitization of
nicotinic receptors in
the striatum
Fipamezole Enhances activity a2 Phase IIb DBRCT in PD with dyskinesia (n = 180). [22]
of indirect D2, antagonism Outcome: LIDS after 4 weeks non-significant.
corticostriatal pathway? Subgroup: improvement for US patients (-3.7 points for
Reduces levodopa fipamezole 90 mg vs -1.1 points for placebo, p < 0.05)
conversion to
noradrenaline?
of action action
Levetiracetam Reduces Binds Three Phase II DBRCTs (total n = 86). Outcome: [23
neurotransmitter synaptic reduced ‘on’ time with dyskinesia according to patient –25]
release? vesicle diaries (one positive: -3.8% for levetiracetam 500 mg,
protein 2A -7.8% for levetiracetam 1000 mg, values for placebo
not reported)
DHA Omega-3 fatty acid Omega-3 DBRCT in de novo PD subjects (n = 40). Outcome: [131]
has been suggested to fatty acid safety and efficacy (dyskinesia rating scale not
delay development of specificied) at 1.5 years
dyskinesia in preclinical
models
131
Fox & Kalia
Safinamide, as well as having MAO-B progression as well as improving

inhibitory properties also reduces gluta- levodopa duration of action and
mate release and is being evaluated for lessening impact of dyskinesia [9] .
dyskinesia. To date, any superior effi-
cacy or tolerability of these agents com- Financial & competing interests
pared with amantadine is unknown. disclosure
Other nondopaminergic systems that
have been targeted include nicotinic S Fox has received research funding
cholinergic receptors, a2 adrenoceptors from NIH, Canadian Institute of Health
and SV2 using the antiepileptic leveti- Research and Michael J Fox Founda-
racetam. Another novel approach is via tion for Parkinson’s Research. She has
docosahexaenoic acid, which enhances also received consultancy fees and
omega‑3 fatty acids that may play a funding from Acadia, Asubio, Merck
role in propensity to develop dyskinesia Serono, Merz, Ipsen, Kyowa, Novartis,
(Table 7.4). Teva, Phytopharm and UCB. The au-
thors have no other relevant affilia-
Conclusion tions or financial involvement with any
organization or entity with a financial
Novel therapeutics for PD target interest in or financial conflict with the
a range of neurotransmitters and subject matter or materials discussed
neuromodulators. To date, no single in the manuscript apart from those
agent is better than levodopa as disclosed.
monotherapy or add-on therapy for
symptom relief [7,8] . Several agents are No writing assistance was utilized in
in development for reducing disease the production of this manuscript.
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NCT01563913
Fox & Kalia
1. 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
2. Neurotoxicity in Parkinson’s 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
3. Amantadine is currently recommended for use in PD to treat:
a. Tremor
b. Slowness
c. Dyskinesia
d. Wearing off
e. Stiffness
4. 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
8
CHAPTER
ASK THE EXPERTS
treatment pipelines
Joseph Jankovic
Although levodopa continues to be the most effective symptomatic
therapy in Parkinson’s 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 half-
life 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 Parkinson’s disease, which may precede the onset of motor
symptoms and may be the most disabling aspects of the disease, particu-
larly in the advanced stages. Therefore, current research in experimental
therapeutics has focused on novel approaches to dopaminergic drug de-
livery, new dopaminergic and nondopaminergic agents, gene and cell-
based therapies and neuroprotective or disease-modifying strategies
(Box 8.1) [2] .

Jankovic
About the author
Joseph Jankovic
Joseph Jankovic is Professor of Neurology and Distin-
guished Chair in Movement Disorders, and Found-
ing Director of the Parkinson’s Disease Center and
Movement Disorders Clinic, Department of Neurol-
ogy, Baylor College of Medicine, Houston (TX, USA).
Past President of the international Movement Dis-
order Society, he is the recipient of many honors,
including: the American Academy of Neurology
Movement Disorders Research Award, sponsored by
the Parkinson’s Disease Foundation; the Guthrie Family Humanitarian
Award, presented by the Huntington’s Disease Society of America; the
Tourette Syndrome Association Lifetime Achievement Award; the Dys-
tonia 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 Neuro-
logical 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 sci-
ence 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 dis-
orders. He is current or past member of many scientific and medi-
cal advisory boards of national foundations, including the Dystonia
Medical Research Foundation, International Essential Tremor Foun-
dation, 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 Parkinson’s Research and the National
Parkinson Foundation C linical and Scientific Advisory Board.
Parkinson’s disease treatment pipelines
Box 8.1. Experimental therapeutics of Parkinson’s 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 antago-
nists), 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 chan-
nel 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 2/0.5 g in only 100 ml (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 2000 mg 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
Jankovic
standard levodopa/carbidopa and as such promises to smooth out motor fluctua-

tions and prolong ‘on’ time [5] . Another formulation of levodopa currently undergo-
ing 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 lung’s large alveolar surface has been
undergoing evaluation. In a double-blind, placebo-controlled, randomized trial in-
volving 24 patients randomized to three escalating single doses of inhaled apomor-
phine (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 (10 min for 0.5 mg, 40 min for
0.8 mg, vs 20 min 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 0.8 mg 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 be-
ing 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 recep-
tor and has been tested in 253 advanced PD patients with motor fluctuations. At
5–10 mg 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 dou-
ble-blind, placebo-controlled Phase IIb study of 420 PD patients with end of dose
wearing off to significantly decrease ‘off’ time, increase ‘on’ time, improve Unified
Parkinson’s Disease Rating Scale (UPDRS) parts I–III scores, and show improvements
on clinician- and patient-assessed global impression scores [10] .
Safinamide is a novel reversible monoamine oxidase B inhibitor with additional mech-

anisms of action, including glutamate-release inhibition and sodium channel block-
ing properties. In the MOTION study, designed to evaluate the efficacy and safety
of two fixed doses of safinamide (50 and 100 mg/day), compared with placebo, as
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 pe-
riod [11] . In this study, safinamide 100 mg/day significantly improved motor symp-
toms UPDRS III (mean change), and PDQ-39 compared with placebo. In the SETTLE
study 484 of 549 randomized patients with PD and motor fluctuations completed
24 weeks of treatment with safinamide versus placebo. Safinamide 50–100 mg/
day significantly improved ‘on’ time (without worsening troublesome dyskinesia),
‘off’ time, UPDRS III, 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 76 PD patients with moderate or severe
levodopa-induced dyskinesia (LID) [13] . Using modified Abnormal Involuntary Move-
ment Scale (mAIMS), performed every 30 min for 3 h following a single usual levo-
dopa 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 dyskine-
sias as assessed by mAIMS and by UPDRS IV at 100 mg 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 dyskine-
sia 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 Phase II pilot study involving only 25 PD patients [17] .
3 What are the prospects for gene & cell-based therapies?

In the STEPS trial, a Phase II 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
Jankovic
injections compared with those undergoing sham surgery [18] . Another approach
for therapeutic gene delivery in PD has focused on the targeted delivery of neu-
rotrophic factor neurturin, which has been shown to restore and protect dysfunc-
tional dopaminergic neurons in animal models of PD [19] . A Phase II randomized
sham-surgery controlled trial in 58 patients with advanced PD failed to detect
significant differences in ‘off’ state motor UPDRS scores after 1 year [20] . How-
ever, a subgroup analysis of 30 patients followed up for longer than 12 months
showed significant improvements in the ‘off’ state motor UPDRS of 8 points and a
significant gain in ‘on’ time without troublesome dyskinesia of 2.5 h in the AAV2-
neurturin injected group compared with the control group after 18 months. Seri-
ous 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 improve-
ment based on UPDRS scores. The study did show some statistical benefit accord-
ing 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 Yamanaka’s 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 dis-
orders, 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 Parkinson’s disease & what is
in the pipeline to help tackle this?
Slowing the clinical progression of PD continues to be the central unmet thera-

peutic 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.
There is emerging evidence implicating certain conformations of a-synuclein can be-

come toxic to cells and spread in prion-like fashion causing neurodegeneration [24] .
This new finding may lead to identification of novel targets for candidate neuropro-
tective therapies [25] . Other strategies are currently being investigated in an attempt
to prevent accumulation, enhance clearance or break up formed a-synuclein. For ex-
ample, 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. Neu-
roPhage (MA, USA) recently announced positive preclinical results from its NPT001
compound that apparently reduced synuclein deposits in the brain. PRX002, anti-
body 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 peptide 1 (GLP-1) receptor, have been recently sug-
gested as potential therapeutic agents in neurodegenerative diseases. For example,
Exendin-4 (exenatide), used in the treatment of Type 2 diabetes mellitus, crosses
the blood–brain 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 thera-

pies 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 mo-
tor 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 includ-
ed 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 wors-
ened 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
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] .
Financial & competing interests Inc.; Auspex Pharmaceuticals Inc.; Ipsen

disclosure Biopharmaceuticals Inc.; Lundbeck Inc.;
Merz Pharmaceuticals; Teva Pharma-
During the past 2 years J Jankovic has ceutical Industries Ltd; UCB Inc.; and US
received: Research and Center of Excel- World Meds.
lence Grants from Allergan Inc.; Cere-
gene Inc.; CHDI Foundation; GE Health- He has also received royalties from Cam-
care; Huntington’s Disease Society of bridge; Elsevier; Future Science Group;
America; Huntington Study Group; Hodder Arnold; Lippincott Williams and
Ipsen Limited; Lundbeck Inc.; Michael J Wilkins; and Wiley-Blackwell.
Fox Foundation for Parkinson Research;
Medtronic; Merz Pharmaceuticals; Na- The author has no other relevant affili-
tional Institutes of Health; National Par- ations or financial involvement with any
kinson Foundation; St Jude Medical; organization or entity with a financial
Teva Pharmaceutical Industries Ltd; UCB interest in or financial conflict with the
Inc.; University of Rochester; and Parkin- subject matter or materials discussed
son Study Group. in the manuscript apart from those dis-
closed.
He has received compensation/honorar-
ia for services as a consultant or an ad- No writing assistance was utilized in the
visory committee member for Allergan production of this manuscript.
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3. Klostermann F, Jugel C, Bömelburg M, (2012).
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apomorphine as acute challenge for in Parkinson’s disease. Mov. Disord. 27(2),
rescuing ‘off’ periods in patients with 284–288 (2012).
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J. Neurol. doi:10.1111/ene.12091 (2013) Actively transported levodopa prodrug
(Epub ahead of print). XP21279: a study in patients with
8. Blandini F, Armentero MT. New Parkinson disease who experience motor
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treatment of l-DOPA-induced dyskinesias 35(3), 103–110 (2012).
in Parkinson’s disease: targeting 17. Tani Y, Ogata A, Koyama M, Inoue T.
glutamate and adenosine receptors. Effects of piclozotan (SUN N4057),
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153–168 (2012). on motor complications induced by
9. Hauser RA, Cantillon M, Pourcher E et al. repeated administration of levodopa
Preladenant in patients with Parkinson’s in Parkinsonian rats. Eur. J. Pharmacol.
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a Phase 2, double-blind, randomised 18. Gross RE, Watts RL, Hauser RA
trial. Lancet Neurol. 10(3), 221–229 et al. Spheramine Investigational
(2011). Group. Intrastriatal transplantation
10. Olanow C et al. Tozadenant in the of microcarrier-bound human retinal
treatment of Parkinson’s disease. pigment epithelial cells versus sham
Neurology (AAN 2013), (2013). surgery in patients with advanced
11. Barone P, Fernandez H, Ferreira J et al. Parkinson’s disease: a double-blind,
Safinamide as an add-on therapy to randomised, controlled trial. Lancet
a stable dose of a single dopamine Neurol. 10(6), 509–519 (2011).
agonist: results from a randomized, 19. Bartus RT, Baumann TL, Brown L, Kruegel
placebo-controlled, 24-week multicenter BR, Ostrove JM, Herzog CD. Advancing
trial in early idiopathic Parkinson disease neurotrophic factors as treatments for
(PD) patients (MOTION Study). Neurology age-related neurodegenerative diseases:
(AAN 2013), (2013). developing and demonstrating ‘clinical
12. Schapira AH, Fox S, Hauser R et al. proof-of-concept’ for AAV-neurturin
on behalf of the SETTLE Investigators. (CERE-120) in Parkinson’s disease.
Neurology (AAN 2013). Neurobiol. Aging 34(1), 35–61 (2013).
13. Tison F, Durif F, Corvol JC. Safety, 20. Marks WJ Jr, Bartus RT, Siffert J et al.
tolerability and anti-dyskinetic efficacy of Gene delivery of AAV2-neurturin for
dipraglurant, a novel mGluR5 negative Parkinson’s disease: a double-blind,
allosteric modulator (NAM) in Parkinson’s randomised, controlled trial. Lancet
disease (PD) patients with levodopa- Neurol. 9(12), 1164–1172 (2010).
induced dyskinesia (LID). Neurology 80, 21. Ito D, Okano H, Suzuki N. Accelerating
S23.004 (2013). progress in induced pluripotent stem cell
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23. Kang S, Cooper G, Dunne SF et al. 28. Kalia LV, Brotchie JM, Fox SH. Novel
Ca(V)1.3-selective L-type calcium nondopaminergic targets for motor
channel antagonists as potential new features of Parkinson’s disease: review
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Commun. 3, 1146 (2012). 131–144 (2013).
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AM, Lang AE. a-Synuclein oligomers and S, Vitek JL. History, applications, and
clinical implications for Parkinson disease. mechanisms of deep brain stimulation.
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25. Olanow CW, Brundin P. Parkinson’s 30. Schuepbach WM, Rau J, Knudsen K,
disease and a synuclein: is Parkinson’s et al. Neurostimulation for Parkinson’s
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Disord. 28(1), 31–40 (2013). N. Engl. J. Med. 368(7), 610–622 (2013).
26. Aviles-Olmos I, Limousin P, Lees 31. Tan EK, Jankovic J. Patient selection
A, Foltynie T. Parkinson’s disease, for surgery for Parkinson’s disease. In:
insulin resistance and novel agents Textbook of Stereotactic and Functional
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Brooks DW. Overcoming obstacles in (In press).
Multiple choice
questions: answers
Chapter 1. Prevention of Parkinson’s disease: preparing for the
future
1. Premotor features of Parkinson’s disease include:
a. Olfactory dysfunction
b. Constipation
2. Which is not a risk factor for Parkinson’s disease?
b. Smoking
3. Which of the following are associated with lower risk of Parkinson’s
disease?
d. All of the above
4. Which of the following techniques are being used to distinguish
individuals with Parkinson’s 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 Parkinson’s
disease
1. Parkinson’s disease (PD) may be characterized early by the following
clinical features:
d. All of the above
2. Selegiline and rasagiline are members of which class of compounds:
b. Monoamine oxidase type B inhibitors
© 2013 Future Medicine Ltd 149

3. Levodopa usage in PD has been associated with the development of:
c. A and B
4. DAs may have the following complicating side effects:
d. All of the above
5. Disease modification in PD:
b. Remains a challenging and critically important unmet need
Chapter 3. Prevention and management of levodopa-related motor
complications
1. Risk factors for the development of levodopa-related motor
complications include which of the following?
f. All of the above
2. When occurring in the ‘off’ state, dystonia can be treated by
which of the following?
e. a, b & c
3. Sudden ‘offs’ can be treated acutely by which of the following?
c. Apomorphine
4. Diphasic dyskinesias in general:
c. Can be treated by decreasing the interdose interval of
levodopa administration
5. ‘Off’ state freezing of gait can be treated by which of the following:
d. a&c
Chapter 4. Management of non-motor symptoms of Parkinson’s
disease
1. Cognitive decline in Parkinson’s disease (PD) is associated all of the
following except:
d. Increasing risk of rapid eye movement behavior disorder
2. A symptom of psychosis unique to the PD patient is:
b. A sense that someone or something is ‘present’ in the
room
3. Suggested treatment of rapid eye movement behavioral disorder is:
c. Clonazepam
Multiple choice questions: answers
4. Non-motor symptoms requiring reduction in dopaminergic therapy

include:
e. Both a & b
5. Treatment for orthostatic hypotension:
e. All of the above
Chapter 5. Management of cognitive and behavioral aspects of
1. Which of the following antipsychotic drugs do not cause worsening
of motor problems in Parkinson’s disease (PD)?
b. Quetiapine
d. Clozapine
2. Which one of the following is not considered part of PD?
a. Mania
3. Depression in PD is thought to be:
a. Due to intrinsic brain pathology
c. Reactive to the progressive impairments
4. Which of the following statements concerning dementia in PD is
not correct?
c. It is relatively uncommon
5. 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
6. Which of the following statements concerning apathy in PD is
true?
a. It is defined as a decrease in emotions and motivation
7. Which of the following treatments are effective for controlling
impulse control disorders due to dopamine agonist medications?
a. Reducing or stopping the dopamine agonist
8. Which of the following statements concerning fatigue in PD is
true?
e. It often predates the onset of motor symptoms
9. Which of the following statements regarding behavioral problems
in PD is not true?
c. They usually respond to dopamine-replacement therapy
correct
10. 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 Parkinson’s disease
1. Deep-brain stimulation (DBS) surgery should be considered in pa-
tients who have symptoms of Parkinson’s disease (PD) for 1 year
and have not tried adequate medication therapy.
b. False: DBS surgery should in most cases be considered af-
ter 5 years of symptomatic PD treatment and optimized
medical therapy.
2. 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.
3. Patient selection is not important in the decision-making process
for DBS.
b. False: Patient selection is the most important step in suc-
cessful DBS therapy.
4. 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.
Multiple choice questions: answers
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 Ques-
tionnaire for PD or the short DBS screener. Potential can-
didates identified in triage should have multidisciplinary
screening.
Chapter 7. Experimental therapeutics for motor symptoms of
1. The following neurotransmitter is involved in the pathophysiology
of levodopa-induced dyskinesia:
e. All of the above
2. Neurotoxicity in Parkinson’s disease (PD) predominantly targets
the following cell type and leads to motor dysfunction:
a. Dopamine cells in the substantia nigra
3. Amantadine is currently recommended for use in PD to treat:
c. Dyskinesia
4. Absorption of levodopa in PD can be increased by:
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:
c. PYM50028

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Parkinson’s Disease:

Medical and Surgical Treatment

Future Medicine Ltd,

British Library Cataloguing-in-Publication Data.

Content Development Editor: Lauren Constable

Senior Manager, Production & Design: Karen Rowland

Parkinson’s disease: medical and surgical treatment 3

About the Editor

© 2013 Future Medicine Ltd doi:10.2217/EBO.13.214 3

non-motor and later motor, mani- fore initiating levodopa. In Chapter 3,

emphasis on deep-brain stimulation, Research; Medtronic; Merz Pharma-

© 2013 Future Medicine Ltd doi:10.2217/EBO.13.83 7

About the author

• Numerous genetic and environmental factors that modify the risk

Box 1.1. Challenges identifying individuals at high risk for

Parkinson’s disease; however, onset in feature of the disease and several of

Box 1.2. Symptoms and signs predating the motor features of

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

exposure, and specific compounds biochemical markers that identify early

Dopamine transporter: a transmembrane protein on dopaminer-

Rapid eye movement sleep behavior disorder: a sleep disorder

below). Promising preliminary studies or genetic mutations associated

treatments for this disease, including environmental associations. Attention

Ubiquitin proteasome system: a cellular system responsible for

as a key factor in the pathogenesis of it is currently unknown when they

whether or not nicotine slows the pro- Conclusion

102. Safety of Urate Elevation in Parkinson’s 103. Disease-Modifying Potential of

Multiple choice questions

1. Premotor features of Parkinson’s disease include:

© 2013 Future Medicine Ltd doi:10.2217/EBO.13.119 23

About the authors

• Dopaminergic therapies, including levodopa, dopamine agonists

The classic motor symptoms of is preceded by pathology involving

Dopaminergic: pertaining to the use of medications working

Box 2.1. Motor features of early Parkinson’s disease.

fewest side effects and/or long-term a dopa-decarboxylase inhibitor

Dyskinesias: largely involuntary movements that are typically

for individuals in whom motor disability confusion and/or hallucinations,

adequate control of motor features in dyskinesias earlier than those patients

preserved [9,11] . The mechanism of widespread use, especially in elderly

Table 2.1. Levels of recommendation for the treatment of early

Disease modification in PD: Unified Parkinson’s Disease Rating

suggesting a disease-modifying effect entire 6.5 years of observation, the

* p < 0.05 Rasagiline delayed-start group

Figure 2.1. Mean percentage change from TEMPO baseline in total Unified

Post hoc analysis of differences compared with the three lower

UPDRS score (points)

Figure 2.2. Changes in scores on the Unified Parkinson’s Disease Rating

2 mg/day rasagiline treatment arms. As a therapeutic group, the delayed

Clinical diagnosis of early PD

Follow Symptoms Education Symptoms Consider dopaminergic

Symptoms Symptoms persist

Symptoms Initiate or add-on

Consider DBS, levodopa Consider MAO-BI

Figure 2.3. Proposed algorithm for early treatment of Parkinson’s disease.

of these MAO-B inhibitors. Long- status would also be extremely useful,

disease-modifying treatments for an integral part of PD therapy. While

PD is a neurodegenerative disorder LW Elmer has received honoraria or

Addex Therapeutics, Allergan Inc., and former manufacturers of welding

a randomized controlled trial. JAMA early Parkinson disease. Neurologist

Multiple choice questions

1. Parkinson’s disease (PD) may be characterized early by the following

© 2013 Future Medicine Ltd doi:10.2217/EBO.13.84 43

About the authors

The management of levodopa-related neurons, which decarboxylate levodopa

(COMT) inhibitor (entacapone or tol- administration. Patients using apo

• Parkinson’s disease is the second most common neuro