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Training Manual

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Parkinson's Disease
Chapter 1: Diagnosis, Prevalence and Burden
Motor symptoms: Parkinson's Disease (PD) is a chronic and progressive movement disorder
resulting from loss of dopamine-producing brain cells, and associated with four primary motor
Olanow CW, 2009
tremor or trembling in
hands, arms, legs, jaw,
and face
rigidity, or stiffness of
the limbs and trunk
bradykinesia, or
slowness of movement
postural instability, or
impaired balance and
Figure 1 Medscape
Non-motor symptoms: Besides these
primary motor symptoms, PD is associated
with many non-motor symptoms that may
become of equal or even greater concern.
These include loss of smell (anosmia),
constipation, sleep disorders, mood
disorders, and orthostatic hypotension. The
advanced stages of PD are commonly also
associated with dementia and psychosis.
Figure 2 Medscape
Currently, there are no definitive biochemical tests to predict PD, and diagnosis is based on medical
history and neurological examination. Since PD evolves slowly, over many years, and shares many
symptoms ("Parkinsonism")
National Parkinson Foundation
with other neurological diseases, it is very difficult to
make an accurate, early diagnosis. This is unfortunate, because typically, by the time a definitive
diagnosis is made, significant neuro-anatomical degenerative changes have already occurred.
Early symptoms of PD can include non-motor changes such as autonomic disturbances, hyposmia,
visual changes, gastrointestinal and olfactory dysfunctions, depression and sleep disorders, and
efforts are being made to incorporate these into diagnostic algorithms that will enable detection at a
stage that may be more amenable to intervention.
Figure 3
Descriptive changes through mild, moderate and advanced stages of PD
Parkinson's Disease Foundation
Mild PD:
Movement symptoms may be inconvenient, but to not affect daily activities.
movement symptoms, often tremor, occur on one side of the body.
Friends may notice changes in posture, walking ability, or facial expression.
PD medications suppress movement symptoms effectively.
Regular exercise improves and maintains mobility, flexibility, range of motion and balance, and
also reduces depression and constipation.
Moderate PD:
Movement symptoms occur on both sides of the body.
The body moves more slowly.
Trouble with balance and coordination may develop.
"Freezing" episodes - when the feet feel stuck to the ground - may occur.
PD medications may "wear off" between doses.
PD medications may cause side effects, including dyskinesias (involuntary movements).
Regular exercise, perhaps with physical therapy, continues to be important for good mobility.
and balance.
Occupational therapy may provide strategies for maintaining independence.
Advanced PD:
Great difficulty walking: in wheelchair or bed most of the day.
Not able to live alone.
Assistance needed with all daily activities.
Cognitive problems may be prominent, including hallucinations and delusions.
Balancing the benefits of medications with their side effects becomes more challenging.
Hoehn and Yahr scale
Although the exact nature and rate of progression of PD symptoms vary considerably, a grading
system originally used to classify patients participating in research studies, the Hoehn and Yahr
Scale, is widely utilized internationally to designate the severity of Parkinson's Disease. This scale
defines FIVE stages of severity:
Hoehn MM and Yahr MD, 1967
Stage 1: Unilateral involvement
only, usually with minimal or no
functional impairment
Stage 2: Bilateral or midline
involvement, without impairment of
Stage 3: First signs of impaired
righting reflexes.
Stage 4: Fully-developed, severely
disabling disease.
Stage 5: Confinement to bed or
wheelchair unless aided.
Figure 4
UPDRS scale
The Unified Parkinson's Disease Rating Scale (UPDRS) is the most widely used clinical rating scale
for PD.
Goetz CG, 2008a
It is comprised of the following six sections, which incorporate the Hoehn and Yahr
scale and the Schwab and England Activities of Daily Living (ADL) scale. It is thus more
comprehensive than either of those scales, and takes into account cognitive difficulties, ability to carry
out daily activities, and treatment complications.
Part I: evaluation of mentation, behavior, and mood
Part II: self-evaluation of the activities of daily life, including speech, swallowing,
handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food.
Part III: clinician-scored monitored motor evaluation
Part IV: complications of therapy
Part V: Hoehn and Yahr staging of severity of Parkinson's disease
Part VI: Schwab and England Activities of Daily Living (ADL) scale
MDS-UPDRS scale:
In 2007, the Movement Disorder Society (MDS) published a revision of the UPDRS, the MDS-
UPDRS, to accommodate new advances and to resolve problematic areas. It retains four parts
(besides the H&Y scale and ADL scale), but the parts have been modified to provide a section to
integrate nonmotor elements of PD, and other changes to provide for more uniform rating
Goetz CG 2007
Prevalence and Healthcare Burden
Presently, approximately 0.5% of adults 30 years of age or older, in the major industrialized countries
(G7) have diagnosed PD. This translates to 2.5 million individuals, and is expected to grow to 3.5
million in 20 years due to population aging. Moreover, it has been estimated that for every case of
diagnosed PD there are 3 more individuals with mild Parkinsonian signs.
Lerche S, 2014
According to the Parkinson's Disease Foundation, there are as many as one million Americans living
with Parkinson's Disease, with approximately 60,000 new diagnoses each year.
The direct and indirect costs of diagnosis and treatment of these patients, combined with social
security payments and loss of income, is nearly $25 billion per year. These costs are expected to
grow substantially with projected increases in the elderly proportion of the population.
Kowal SL, 2013
Motor Complications:
Although treatment of motor symptoms of PD is effectively treated with levodopa in the early stages,
over time it loses efficacy and leads to erratic movements (dyskinesias) and periods of akinesia
("OFF" periods) that are difficult to manage (see Chapters 3-4), and require a combination of dosage
adjustment of levodopa with use of adjunctive therapies.
Non-motor complications:
Even when motor symptoms are controlled, patients with PD can experience many non-motor
symptoms, including constipation, sleep and mood disturbances, loss of sense of smell (anosmia),
fatigue, orthostatic hypotension, dementia and psychosis. These symptoms may have an equal or
greater impact on quality of life, and are the focus of many adjunctive PD therapies.
Dementia: is estimated to be three times more prevalent among those with PD than those without
Aarsland D, 2003
, and is associated with increasing age and Hoehn and Yahr stage
Riedel O, 2008
, with a
mean onset of about 10 years following a diagnosis of PD.
Aarsland D, 2010
Psychosis, including hallucinations and delusions, is a common occurrence in PD as the disease
progresses, and a major challenge of treatment.
Michael J. Fox Foundation for Parkinson's Research: MICHAELJFOX.ORG
Figure 5
Chapter 1 Summary:
Parkinson's Disease is a syndrome of motor and non-motor symptoms that develop gradually over a person's
lifetime, and are attributable to degeneration of dopamine-producing neuronal tissue in the central nervous
system - most specifically in the substantia nigra and other regions of the basal ganglia. These symptoms and
the speed of their progression vary considerably among individuals, but typically include the "signature"motor
symptoms of tremor, rigidity of the limbs and trunk, slowness of movement (bradykinesia) and impaired
balance and coordination (postural instability) as well as many non-motor symptoms such as loss of smell,
constipation, sleep and mood disorders, orthostatic hypotension, dementia and psychosis.
Diagnosis is difficult because (A) the disease develops slowly, (B) substantial neuroanatomical damage can
accumulate before any symptoms are manifest, and (C) there are not yet any definitive molecular or
biochemical "markers" that would allow early identification. Several clinical rating scales, such as the Hoehn
and Yahr scale, the UPDRS scale, and the MDS-UPDRS scale are useful to stage the severity of PD for research
and treatment purposes. However, unfortunately even the first stage of these scales is associated with
significant neuropathology. The high prevalence of diagnosed PD in industrialized countries (approximately
0.5% of those over 30 years of age), the probability of many more undiagnosed or "prodromal" cases, and the
sharply higher risk with increasing age, make PD a huge and growing healthcare burden.
There is currently no treatment for PD that alters the course of disease, and therapy, for now, remains focused
on ameliorating symptoms. In most patients, initial treatment of motor symptoms is achieved with levodopa
administration, but this is usually insufficient, because (A) efficacy of levodopa typically "wears off" after many
years of therapy, and (B) many non-motor symptoms of PD and of levodopa treatment itself need to be
addressed with adjunctive therapies. These are discussed in more detail in Chapters 3-4.
Chapter 2: Etiology
The "What" and the "Why"
the "What": The advanced stages of PD are accompanied by clearly identifiable pathological
changes in the basal ganglia, particularly loss of neurons in the substantia nigra, and accumulation of
Lewy bodies throughout these and other brain regions.
Figure 6: Arrows shows strong staining of dopamine-containing neurons in the substantia nigra (SN) in the normal brain
(left), that is much reduced in brain on the right, from patient with PD. (
Figure 7, left panel shows histological samples of normal (left panel) tissue from substantia nigra and locus caeruleus,
compared to that of patient with PD (right panel), with eosinophilic (purple-stained) inclusions (Lewy bodies) with halos
(yellow arrow) containing alpha-synuclein, which is a protein accumulation associated with advanced PD. (
These observations, in turn, are associated with reduced neuronal traffic from the substantia nigra
that normally modulates the output of the basal ganglia to the thalamus. The net effect is excessive
inhibition of thalamocortical nerve traffic to the cortex, and the resulting primary motor symptoms of
this disease.
The figure on the right illustrates
these changes, with the red
arrows signifying excitation, and
the blue arrows signifying
inhibition. In PD, the loss of
dopaminergic stimulation of the
striatum leads, via the indirect
pathway, to excessive inhibition of
the thalamus.
Figure 8: Modified from Kase H, Biosci. Biotechnol. Biochem. 65(7): 1447-1457, 2001
the "Why": The key question as to WHAT TRIGGERS the abovementioned pathophysiological
changes remains unsolved. What is known is that PD is strongly associated in some cases with
inherited genes and environmental pollutants, in the majority of cases there is no identifiable external
trigger. Thus, it is not yet clear whether the syndrome of PD symptoms has one, or multiple etiologies.
Possible Triggers / Causes:
Aging: This is the strongest risk factor for PD, and risk of PD clearly increases with advancing age,
particularly after age 60. That said, even if many of the associated symptoms and pathological
processes are to some extent eventually manifested in the very elderly, the question remains as to
why this progression is greatly accelerated in those diagnosed with PD in middle age.
de Rijk MC, 2000
Gender and Race/Ethnicity: PD is nearly twice as prevalent in men than in women. It also varies by
race/ethnicity, being highest in Hispanics, followed by non-Hispanic whites, Asians, and African
VanDenEeden, SK, 2003
Genetic: A minority of PD cases are linked to genetic mutations, and the proteins encoded by these
mutations strongly suggest that improper protein processing, oxidative stress, and mitochondrial
dysfunction involvement in the pathophysiology.
Toulouse A, 2008; Gao HM, 2011
Environmental: The strongest evidence of an environmental trigger for PD is that of pesticide
exposure, especially to rotenone and paraquat, which disrupt mitochondrial activity and oxidative
stress, respectively.
Tanner CM, 2011
Other environmental factors that have been linked to PD are various
toxins and organic solvents, potable well water, and prior head injury.
Fang F, 2012; Noyce AJ, 2012; Gardner RC,
Diet and Lifestyle: PD patients can have increased iron deposits in the substantia nigra of PD and
increased iron levels in individual dopaminergic neurons. Since free iron can induce oxidative stress
and neuron death, investigators have focused on effects of dietary iron intake, reporting a 30%
increase in dietary non-heme iron associated with PD.
Logroscino G, 2008
Hypertension and high
cholesterol are also associated with increased risk of developing PD.
Hu G, 2008; Elbaz A, 2008
Diabetes and
diets high in saturated fats have also been studied as possible correlates of PD.
D’Amelio M, 2009;
Schernhammer E, 2011
On the other hand, caffeine may be protective, via its weak antagonism of adenosine
A2A receptors and nonspecific additional effects. Smoking has somewhat surprisingly been
associated with reduced risk of PD, possibly through nicotine's inhibition of the monoamine oxidase
(MAO) pathway.
Kalda A, 2006; Rivera-Oliver M, 2014
However, a causal relationship has not yet been
Disease Progression: By the time of diagnosis of PD, an estimated 50% of dopaminergic neurons in
the substantia nigra have been lost,
Hawkes CH, 2008; Toulouse A, 2008; Mullin S, 2015
and neuronal degeneration is
found throughout the brain stem in non-dopaminergic neurons. Other evidence suggests that as early
as two decades before PD diagnosis, threshold motor symptoms and olfactory and sleep
disturbances are manifest.
Hawkes CH, 2008; Postuma RB, 2012
Individual variation in these symptoms makes it
difficult to use these symptoms as predictors, but nevertheless, it is clear that substantial disease
progression has occurred prior to the first therapeutic interventions. To the extent that interventions
help to maintain dopaminergic activity, they provide symptomatic relief, and allow patients to function
initially. However, they do not forestall the underlying, continued disease progression.
As PD progresses, additional non-motor symptoms typically arise, including urinary symptoms,
orthostatic hypotension, dementia and psychosis. Additionally, after long-term treatment with
levodopa, dyskinesias develop which require modified treatment regimens to minimize "OFF" time.
Other motor symptoms that commonly arise in the late phase of treatment are dysphagia, postural
instability, freezing of gait and falls.
Kalia LV, 2015
Proposed Mechanisms:
Oxidative stress and mitochondrial dysfunction: Several lines of evidence suggest that these
factors may be central to the etiology of PD. These include involvement of PD-related genes in
mitochondrial integrity and function,
Wood-Kaczmar A, 2008; Winklhofer KF, 2010
evidence of structural and
functional mitochondrial impairment in the brains of PK patients,
Schapira AH,1989; Schapira AH,1990
and the
ability of certain toxins to cause PD-like syndromes mediated by their effects on the
Navarro A, 2009; Tanner CM, 2011; Langston JW, 1983
Impaired protein processing: Accumulation of α-synuclein protein and Lewy bodies are hallmarks
of PD that may be directly involved in neuronal degeneration, through interference with normal
intracellular protein degradation.
Goedert M, 2013; Xu W, 2015
Alternatively this can be a consequence of
oxidative damage.
Tan EK, 2007
Chapter 2: Summary
Clearly, the loss of functioning dopaminergic neurons of the substantia nigra that is the
hallmark of PD has predictable consequences. That is, these neurons normally exert a
modulatory effect on inhibitory stimulation of the thalamus, and their loss results in excessive
inhibition of voluntary movements. However, this knowledge begs the question as to WHY this
neuronal damage occurs. Histologic correlates such as the accumulation of Lewy bodies and
synuclein protein in the basal ganglia may be involved in the etiology, but it is not yet known
whether they are causative. Even if they are, it remains to be determined what factor or
factors lead to those histological changes.
A number of other correlates of PD, including aging, gender, race, ethnicity, and genetic,
environmental, diet and lifestyle factors are the focus of numerous research studies into
mechanisms of PD. Two general mechanisms that have been proposed are (A) that PD results
from primary defects in the capacity of mitochondria in neurons to handle oxidative stress,
and (B) that genetic or environmentally-induced damage to neuronal tissue leads to the
aforementioned accumulation of Lewy bodies and synuclein protein, which in turn interfere
with normal intracellular protein degradation and precipitate cell death. These two concepts
are not the only ones, and are not necessarily mutually exclusive either. In fact, PD may be a
manifestation of multiple causes that share a common end result.
What is well-characterized is the interplay of neuronal pathways in the basal ganglia that
control the net outflow of inhibitory activity to the thalamus, how this is normally "balanced"
by activity of dopaminergic neurons in the substantia nigra, the consequences of death of
those neurons in PD, and potential for pharmacologic interventions to help restore the normal
Chapter 3: Treatment
Effective treatment of PD requires multiple therapies to treat both the motor symptoms and
the non-motor symptoms of this disease.
The central objective of treatment for the primary motor symptoms of PD is to preserve and/or
enhance dopaminergic activity of the substantia nigra (SN) to counteract disease-related loss of that
activity. This can be achieved by:
1. Administration of dopamine precursors or agonists
2. Administration of inhibitors of dopamine breakdown
3. Administration of agents that increase sensitivity of dopaminergic receptors
4. Deep brain stimulation (electrical)
However, these interventions at best mitigate the motor symptoms, but do not alter the trajectory of
the underlying disease. To do that would require interventions that can protect surviving neurons,
counteract the effects of responsible genes, dissolve Lewy bodies and/or α-synuclein protein
aggregates, or replace lost neurons with cell-based therapies, none of which are yet available.
Non-motor symptoms including autonomic dysfunctioning, dementia and psychoses are also a
major healthcare burden of PD, and their treatment is not only important for quality of life issues, but
also in limiting the necessary dosage of levodopa, and thereby forestalling long-term adverse effects
of that treatment.
Dopamine precursors and agonists:
Levodopa: is a dopamine precursor that can be administered into the peripheral circulation, cross
the blood-brain barrier and thereby be delivered to the CNS where it is converted into dopamine. It is
the mainstay of treatment for PD, but initiation of treatment with it is often delayed because it tends to
lose effectiveness over time, at which point dyskinesia can develop.
Jankovic J, 2005
It is most commonly
used in combination with carbidopa, to limit nausea and other side effects, and to prolong the effect of
each dose.
Pramipexole, ropinirole, rotigotine and
apomorphine: are dopamine agonists
that mimic the effects of dopamine without
requiring conversion. They can be used as
first-line treatment for PD, and also as
adjuncts with levodopa-carbidopa in the
later stages of PD. Apomorphine is an
injectable agent, predominantly used as a
"rescue" agent for patients with advanced
PD and severe "OFF" episodes and severe
Figure 9
Inhibitors of dopamine breakdown:
MAO inhibitors: These agents, which reduce dopamine metabolism, have been prescribed as
monotherapy for early PD and are now also approved in the U.S.A. and Europe as adjuncts to
levodopa. Younger patients may start with the MAO-B inhibitor, rasagiline, combined with the
dopamine agonist, ropinirole, to manage early symptoms and delay initiation of levodopa treatment. A
new MAO-B inhibitor, safinamide is also approved in the EU for adjunctive use for PD patients.
COMT inhibitors: Agents of this class increase the duration of benefit of each dose of levodopa by
reducing its metabolism. These agents, currently entacapone and tolcapone, have been shown to
produce modest symptomatic relief for PD, and are only approved for patients who have failed other
adjunctive therapies.
Other Classes of oral agents:
Antiglutamatergic agents: These compounds block glutamate signaling and are used adjunctively
with levodopa to reduce tremors and dyskinesias. Amantadine, an NMDA receptor antagonist of this
class, is most commonly used in cases of advanced PD when reduction of levodopa dosage is not an
Adenosine A
receptor antagonists: istradefylline and tozadenant are two emerging agents that
have been shown to sensitize dopamine receptors in the basal ganglia by virtue of their
antagonism of adenosine A
receptors. These are mostly used as adjunctive therapy in combination
with levodopa and sometimes with other non-dopaminergic agents in early stages of PD, and in later
stages to minimize "OFF" time due to dyskinesias that develop when levodopa's efficacy wears off.
Anticholinergic Agents: This is the oldest class of medications used to treat PD, but the mechanism
is not well understood.
They are most helpful to younger patients with whom the chief
complaint is a tremor, and their side effects (confusion, hallucinations, decreased short-term
memory, dry mouth, blurry vision and urinary retention limit their usefulness. Two examples of this
class are Artane and Cogentin.
Additionally, the acetylcholinesterase inhibitor, rivastigmine, and the NMDA receptor antagonist,
memantine, are both approved for treatment of PD-related dementia. Typical antipsychotic agents
have limited clinical utility for PD because they commonly worsen motor symptoms, but clozapine,
and quetiapine do not induce this complication, and have been used somewhat effectively to treat PD
Below is a list of pharmacologic agents used in treatment of motor and non-motor symptoms of PD,
and a schematic (Figure 10) illustrating their mechanisms of action.
Table 1
Figure 10 DR/Decision Resources, LLC
Continuous treatment
When patients with dyskinesia and motor fluctuations can no longer be controlled by oral
medications, the following therapeutic options are considered:
Continuous dopaminergic drug delivery (CDD): This is achieved by administration of
apomorphine either by continuous subcutaneous apomorphine infusions (CSAI) or via infusions of
levodopa (duodopa) into the duodenum using portable minipumps. The resulting constant stimulation
of dopamine receptors is associated with increased 'ON' time and a reduction in motor fluctuation and
motor complications, such as dyskinesia.
Wenzel K, 2014;
Abbruzzese G, 2012
Deep Brain Stimulation: This intervention entails stereotactic implantion of stimulating electrodes in
either the subthalamic nuclei or the
internal glob us pallidus (GP
Stimulation sessions and adjustments are
made during regular physician office
visits. It is limited to patients no older than
70 years of age, with no cognitive
impairment or psychiatric medical history,
and usually to control tremor or dyskinesia
that do not respond to oral drug therapy.
This has been widely used, with great
benefit, since it was first established in the
early 1990's.
Benabid AL, 2009
its effectiveness
in this subgroup of patients has led it to
be increasingly considered at earlier
stages of PD. Figure 11 Medscape
Treatment of Psychosis
The only medication approved by the U.S. FDA for the treatment of hallucinations and delusions
associated with PD psychosis Nuplazid (pimavanserin).
Cummings J and Zhong K, 2015
Treatment of Dementia
Rivastigmine (trade name Exelon) is a parasympathomimetic agent for treatment of PD-related
dementia. It is the first agent approved globally for this purpose (2006). It is available in capsule and
liquid formulations and since 2007, also as a transdermal patch. It has been shown to provide
meaningful symptomatic relief. Its side effects include nausea, vomiting, decreased appetite and
weight loss.
Treatment Guidelines
The American Academy of Neurology (AAN) and the Movement Disorders Society (MDS):
Evidence Based Medicine, have established a set of international guidelines for diagnosis and
treatment of PD, and which form the basis for individual country guidelines. These guidelines, which
are currently being updated, are broken down as follows:
Diagnosis and prognosis of PD
Suchowersky O, 2006a
Initiation of treatment for newly diagnosed PD
Miyasaki JM, 2002
Initiation of treatment for PD based on symptom presentation
Miyasaki JM, 2006; Pahwa R, 2006
Current PD therapies for neuroprotective or disease-modifying properties
Suchowersky O, 2006b
American Academy of Neurology (AAN) Guidelines:
International Parkinson and Movement Disorder Society:
Individual country guidelines:
United States:
United Kingdom:
Chapter 3: Summary
The first aim of treatment for PD is to restore balance to the neuronal circuits of the basal
ganglia that determine the level of inhibitory stimulation of the thalamus. The standard
method is administration of levodopa, which crosses the blood-brain barrier, where it is
converted to dopamine and supports dopaminergic activity of surviving neurons in the
substantia nigra. Unfortunately, no treatment for PD has yet been shown to significantly slow
or arrest disease progression.
For most patients levodopa administration controls motor symptoms of PD initially, but tends
to lose efficacy after decades of use, at which point it becomes necessary to moderate dosage
to minimize dyskinesias and akinesias, respectively, at the peaks and troughs of plasma
levodopa concentration. Additionally, many non-motor symptoms of PD are not improved, or
even negatively impacted by levodopa administration. Thus, the treatment regimen becomes
increasingly dependent on adjunctive agents and other interventions to mitigate these motor
dysfunctions as well as serious non-motor symptoms. Common classes of treatment adjuncts
are dopamine agonists, anticholinergic and anti-glutaminergic agents, MAO-B inhibitors and
COMT inhibitors which oppose metabolism of dopamine and extend its half-life in the
circulation, and adenosine A
receptor antagonists, which help to normalize striatopallidal
neuronal activity by a non-dopaminergic mechanism.
In some cases, adverse effects of dopaminergic therapy can be improved by longer-acting oral
formulations, continuous subcutaneous apomorphine infusions (CSAI), or intraduodenal
infusion using portable minipumps, although the latter is an invasive surgical procedure. For
those patients who either do not respond to, or are not suitable candidates for any of these
interventions, deep brain stimulation may be considered when there is no cognitive
impairment or psychiatric medical history. Psychiatric symptoms of PD and/or dopaminergic
treatments are a major concern, and require adjunctive treatment with agents specific for
psychosis (i.e. pimavanserin) and dementia (i.e. rivastigmine).
Two medical societies: the American Academy of Neurology (AAN) and the Movement
Disorders Society (MDS) have established diagnostic and treatment guidelines for PD that are
widely emulated by specific guidelines of developed nations, and regularly updated.
Chapter 4: Treatment Marketplace
Until development of pharmacotherapies that can actually alter the course of the disease process
underlying PD, treatment is all about managing both the motor and non-motor symptoms (including
psychiatric), some of which are caused by the treatments themselves. One of the principal challenges
of therapy for PD is the management of the "wearing off" episodes that gradually emerge with long-
term levodopa administration. These are periods of the day when the medication is not working well,
as its plasma level diminishes, and during which time the patient experiences hyperkinetic "writhing
movements" (dyskinesias) that are incapacitating. These motor fluctuations occur in up to 80% of PD
patients after 5-10 years of L-DOPA treatment.
Ahlskog JE, 2001
Thus, treatment regimens incorporating
adjunctive pharmacotherapies are designed to delay initiation of levodopa therapy as long as
feasible, and once initiated, to use the lowest possible dosage of levodopa, delivered as evenly as
possible, consistent with the patient's needs.
Definitions: motor fluctuations and dyskinesias
"OFF-time" refers to periods of the day when the medication is not working well, causing worsening of
Parkinsonian symptoms. Conversely, the term "ON-time" refers to periods of adequate control of PD
"Wearing-off" episodes can develop predictably and gradually, or they may emerge suddenly and
unexpectedly. PD symptoms arise in the hours just before the next dose as the plasma level of the
drug falls below the critical level. Wearing-off periods may be improved with appropriate changes in
the medication regimen, such as by adding an extra dose of levodopa or dopamine agonist, or using
a long-acting levodopa or a COMT inhibitor. Wearing off may also be better controlled by shortening
the time between medication doses.
Levodopa-induced dyskinesia (LID) refers to hyperkinetic "writhing" movements, often as the result of
long-term dopamine therapy. The percentage of PD patients affected by these motor fluctuations
increases over time.
Obeso JA, 2000
Dyskinesia most commonly occurs at the time of peak L-dopa plasma
concentrations and is thus referred to as peak-dose dyskinesia (PDD). With disease progression,
patients may evidence diphasic dyskinesia (DD), which occurs when the drug concentration rises or
falls. If dyskinesia becomes too severe or impairs the patient's quality of life, a reduction in L-dopa
might be necessary. However, this may be accompanied by a worsening of motor performance. Thus,
patients often choose to tolerate mild dyskinesia, and reducing their dose of L-dopa only when the
dyskinesia becomes severe and "troublesome". Once established, LID is difficult to treat.
How PD motor fluctuation develops with LD over time: Long-term levodopa administration,
particularly when dosage fluctuates, can give rise over time to motor complications as illustrated in
the schematic figures below. These include incapacitating dyskinesias (PDD) at peak plasma dopa
levels, diphasic dyskinesias (DD) in the therapeutic range, and akinesias ("OFF" periods with no
movement) at the lowest plasma dopa concentrations . Non-motor symptoms of "OFF" periods
include an increase in anxiety, visual disturbances, sweating or pain in the limbs.
Guridi J, 2012
Figure 12
Guridi J, 2012
Another manifestation of "OFF" time is seen in the figure
on the right, comparing handwriting of a patient with PD
before and during such an episode. Moreover, non-motor
symptoms of PD such as dementia, psychoses and
autonomic disturbances can become equally concerning.
Consequently, most patients with PD are managed with
multiple agents, and adjunctive treatments are continually
emerging to meet the need to decrease "OFF" time, while
minimizing the occurrence of dyskinesias, by the following
Figure 13
"Needs" for improved PD treatment regimens:
More continuous delivery levodopa and dopamine agonists
Agents for "first line" use to delay initiation of levodopa treatment
Non-dopaminergic agents or interventions to manage levodopa-associated
dyskinesias and other "wearing off" symptoms including tremors, tiredness, pain,
constipation, sweating and shortness of breath.
Agents to mitigate psychological symptoms of PD, especially dementia and
Agents with less frequent and/or more "patient friendly" administration
Better "rescue therapies"
Table 2
Current and emerging pharmacotherapeutic agents
for PD
The PD pharmacotherapy market is projected to rise from $2.5
billion in 2014 to almost $ 3.5 billion in 2024.
Decision Resources, slide 12
Main "drivers"
Since PD is largely a disease of the elderly, the aging of the
population in industrialized countries of the world is the principal
factor in overall healthcare burden of PD. Three other major
factors are the increasing utilization of currently approved
treatments, the emergence of premium-priced therapies, and
trends toward greater use of multiple agents (polypharmacy)
optimize the benefits of treatment regimens for both motor and
non-motor symptoms of PD, while mitigating adverse effects.
Main "constraints" Figure 14 DR/Decision Resources
Levodopa (L-DOPA), a generic, orally administered dopamine precursor, crosses the blood-brain
barrier, and is very effective as a mainstay of PD treatment. There is also a trend toward other PD
treatments and treatment adjuncts becoming available in generic form. Moreover, most of the high-
priced emerging treatments are targeted to relatively smaller "niche" populations.
Current brand leaders
The MAO-B inhibitor rasagiline and the dopamine agonist, rotigotine, are expected to have sales of
about $580 million and $270 million, respectively in 2019.
MAO-B inhibitor: rasagiline (Teva/Lundbeck's Azilect) $486 million (2014)
Dopamine agonist: rotigotine (UCB/Otsuka's Neupro/Neupro Patch) $208 million (2014)
levodopa entacapone-levodopa-carbidopa (Novartis/Orion's Stalevo) $230 million (2014)
Reformulation of levodopa
Sales of a thrice-daily longer-acting oral capsule formulation of levodopa/carbidopa (Impax
Laboratories' Rytary/Numient) are projected to reach $200 million prior to projected generic entry in
2018 in the U.S. This is a modified-release oral capsule formulation of levodopa/carbidopa.
New rescue therapies
Two new rescue therapies - Acorda Therapeutics' CVT-301 (an inhaled reformulation of levodopa-
carbidopa, and Cynapsis Therapeutics' APL-130277 (a sublingual reformulation of apomorphine), will
launch in the U.S. in 2017 and are expected to be well-received due to their more patient-friendly
injection procedure. Combined U.S. sales are projected to reach $500 million by 2024.
New treatment for PD-associated Psychosis
Pimavanserin (Acadia Pharmaceutical's Nuplazid), recently approved in the US (April, 2016), is the
first agent specifically approved for treatment of PD-associated psychosis, is projected to have sales
of more than $ 600 million by 2021.
Emerging levodopa-adjunctive therapies
Three new agents in this category have expected near-term launches in the US, including a new
MAO_B inhibitor, safinamide (Newron/Zambon/Meiji Seika), a COMT inhibitor, opicapone (Bial/Ono),
and two new adenosine A
receptor antagonists, istradefylline (Kyowa Hakko Kirin) and
tozadenant (Biotie). Collectively, these new agents are projected to have sales of up to $ 450 million
by 2024.
Figure 15: Market Share of Parkinson's Disease Drug Classes in 2014 and 2024
Source: DR/Decision Resources, LLC
Chapter 4: Summary
Despite the efficacy of levodopa administration in initially controlling motor symptoms of PD
in most patients, approximately 80% of them develop troublesome motor fluctuations after 5-
10 years of such treatment, and are known, collectively, as levodopa-induced dyskinesias
(LID). These include hyperkinetic "writhing movements" (PDD: peak dose dyskinesias)
coinciding with peak plasma levodopa concentrations, periods of akinesia ("OFF time") when
the dosage is low and ineffective, and diphasic dyskinesias (DD) when dosage is fluctuating
between these extremes. Once established, LID is difficult to treat. Thus, the need to maintain
the essential benefits of dopaminergic therapy for PD patients, while simultaneously
addressing these serious adverse effects, is a major driver of drug development in this
therapeutic area.
Delayed initiation of levodopa therapy and titration of its dosage to the minimum needed to
avoid "troublesome" dyskinesias and serious non-motor symptoms are two basic approaches
to this challenge. Other approaches are: utilization of a longer-acting formulation (Numient,
Stalevo), continuous subcutaneous delivery (Neupro patch), and adjunctive use of a MAO-B
inhibitor (rasagiline, safinamide) or COMT inhibitor (opicapone) to extend dopamine half-life in
the circulation by inhibiting its breakdown. Additionally, use of a dopamine agonist (rotigotine)
or one of the newly developed adenosine A
receptor antagonists (istradefylline, tozadenant)
may provide enough symptomatic relief to enable reduction of levodopa dosage. All of these
adjunctive treatments have additional benefits in mitigating both motor and non-motor
symptoms of PD that are important considerations in development of an individualized
treatment regimen for PD.
Some recent advances include the first agent specifically approved for PD-associated
psychosis, pimavanserin (Nuplazid) and two new rescue therapies (Acorda's CVT-01 and
Chapter 5: Istradefylline
All of the therapeutic agents for PD that directly (dopamine agonists) or indirectly (MAO-B and COMT
inhibitors) increase dopamine concentrations pose a risk of causing worrisome dyskinesias and other
adverse effects of dopamine itself. Istradefylline, however, works by inhibition of the striatopallidal
dopamine D2 pathway through antagonism of adenosine A
receptors. As an adjunctive treatment, it
can allow the dose of levodopa to be lowered, and through this and other effects improve overall
efficacy/safety of the treatment regimen. Istradefylline can also be given as an adjunct to a MAO-B or
COMT inhibitor, in the early stages of PD, to help delay initiation of levodopa treatment. Not all A
receptor antagonists are the same. For example, preladenant failed to show efficacy in Phase 3 trials.
Pharmacology and Mechanism of Action
The advantage the adenosine A
receptor antagonist, istradefylline offers is that it can augment
dopaminergic signaling in the striatum without acting directly on dopamine receptors. Thus, it
provides symptomatic relief for PD patients without inducing dyskinesia, which is an unfortunate
adverse effect of levodopa and dopamine agonists that develops over time in most patients.
Pharmacology: Istradefylline is a xanthine-based antagonist of adenosine A
receptors that are
located along with dopamine receptors on the surfaces of neurons in the basal ganglia. Since
activation of these receptors opposes effects of stimulation of dopamine receptors, the converse is
also true. That is, their antagonism by agents such as istradefylline reduces excitation of the
striatopallidal pathway, thereby normalizing basal ganglia activity in PD.
Cieslak, 2008
Mechanism of action: (A) Figure 16 (B)
from Kase H, Biosci. Biotechnol. Biochem. 65(7): 1447-1457, 2001
(A) The loss of dopaminergic stimulation of the striatum by neurons of the substantia nigra (SN
) in
PD removes inhibition of striatopallidal activity, leading ultimately to excess inhibition of the thalamus.
(B) Administration of istradefylline (IST) antagonizes the stimulatory effect of activation of adenosine
receptors in the striatum, thereby reducing striatopallidal activity and inhibitory stimulation of the
thalamus toward normal.
Timeline of development
NDA approved in Mar 2013 and launched in May 2013
Indication: Improvement of "wearing-off" phenomena in PD patients treated with levodopa
Dose and regimen: Once daily at 20 mg/day, and 40 mg/day if needed
2000/2002: Proof-of-Concept, U.S.A Phase IIA studies
2002.2006: Phase IIB/III in U.S.A. and Europe; Phase II/III in Japan
2007: U.S.A. new drug application filed
2008: U.S.A. non-approval letter
2013: Japan new drug application approval and product launch
2013: RESTART U.S.A / EU development "1-STEP" with n=609 patient study
2016 December study results
2017-18 FDA/EMA submision reviews
Not filed yet
Clinical Studies
The NDA for istradefylline included five studies (of 7 total) which showed statistically significant
decreases in "OFF" time, which was the primary endpoint. This can be seen in the values shown in
the green-shaded cells under the heading of “Off Time (ANCOVA)* in the table below.
Table 3
This table summarizes results from seven clinical studies (4 in U.S.A., 1 in Europe, 2 in Japan) that
investigated the ability of istradefylline to reduce the amount of awake time spent in the OFF state for
PD patients. Five of these studies showed efficacy of istradefylline in terms of this primary endpoints,
whereas two did not. Improvement in the OFF time of the treated groups ranged from 0.73 - 1.08
hours. Three studies also showed improvement in the Unified Parkinson’s Disease Rating Scale
(UPDRS) Part III (motor), a measure of severity of PD and a secondary endpoint of those studies.
Analysis is broken down here in terms of Phase IIB studies and Phase III studies.
Phase IIB studies: Patients enrolled in the two U.S. Phase IIB studies had at least 2 hours of mean
OFF time at Baseline and were on stable doses of levodopa and a peripheral dopa-decarboxylase
inhibitor. In US-005, the 40 mg/day dose of istradefylline was associated with significant reduction in
both the percent off time (-4.33%, p=0.007) and number of hours OFF (1.08 hours, p=0.005)
compared to the placebo group. The US-006 study reported reduction in percent OFF time of 4.35%
(p=0.026) for the 20 mg/day dose, and reduction in percent OFF time (4.49%, p=0.24) and number of
hours OFF (0.77, p=0.23) for the 60 mg/day dose. A Japanese study (0608) also found reductions in
percent OFF time (4.00%, p=0.014) and number of hours OFF (0.92 hours, p=0.013) at a dose of 20
mg/day, and (5.67%, p=0.001) and (0.92 hours, p=0.001), respectively, at a dose of 40 mg/day. This
study (0608) also reported improvement in UPDRS III score of -2.0 at both doses (p=0.001).
Phase III studies: Three multicenter, randomized, double-blind, placebo-controlled, parallel group
studies with a 12 to 16 week duration were conducted in the US and Europe to investigate the safety
and efficacy of istradefylline as an adjunctive treatment for subjects with Parkinson’s disease and end
of levodopa dosing wearing-off phenomenon (US-013, 018, and EU 007). Additionally Study EU-007
used entacapone as an active control to ensure study validity and assay sensitivity. In US-013, a 20
mg/day dose of istradefylline improved percent OFF time compared to placebo by 4.57% (p=0.025)
and OFF time by 0.73 hours (p=0.033). Similar trends in US-018 (10, 20, 40 mg/day) and EU-007 (40
mg/day, with and without entacapone) did not reach statistical significance in terms of percent or
hours of OFF time, and high placebo response and site variability were seen as the main causes.
However, both of these studies reported significant improvement in UPDRS III score (US-018: -2.1,
p=0.028; EU007: -1.8, p=0.043) at the 40 mg/day dose (EU-007: 40 mg/day plus entacapone). Lastly,
a Japanese Phase III study showed significant decreases in both percent and time OFF in patients
treated with either 20 mg/day istradefylline (5.00%, p=0.002; 0.76 hours, p=0.003) or 40 mg/day
(4.62%, p=0.003; 0.74 hours, p=0.003), as well as improvement in UPDRS III score (-2.1, p=0.001).
Istradefylline (20 mg tablets) was approved in Japan on
25MAR2013 under the trade name NOURIAST® tablets,
and was marketed on 30MAY2013. It is estimated that
approximately 6800 patients have been treated with
NOURIAST in Japan since it was first prescribed on
30MAY2013. Figure 18
Twenty-two Phase II and Phase III clinical studies of istradefylline in Parkinson’s disease have been
completed, including 4 long-term follow-on studies. Only non-troublesome dyskinesia and nausea
were reported to occur an incidence more than 5%.
Future Directions: Much of the unmet needs for PD therapy are for safe and efficacious
treatment of non-motor symptoms, including psychiatric symptoms, autonomic dysfunction, sleep
disorders, orthostatic hypotension, and neuroprotection. Istradefylline's high selectivity for adenosine
receptors and relatively good safety data in most clinical studies suggest expanded applications
as a treatment adjunct for PD.
Depression: Emotional fluctuations associated with "OFF" periods are a major contributor to
depression in patients with PD, so reduction of these periods with lowered dopaminergic stimulation
is the primary approach. In terms of adjunctive agents, treatment with tricyclic antidepressants
(nortriptyine, despiramine) may have the best benefit / risk profile. Pramipexole may have
antidepressant effects over and above its anti-parkinsonian effects. Pramipexole and SNRIs appear
to have better acceptability than SSRI's.
Liu J, 2013; Grover S, 2015
There is no data yet on istradefylline's
effects on depression.
Psychotic Symptoms: Approximately 30% of PD patients experience psychotic symptoms,
including hallucinations, illusions, delusions and paranoid beliefs.
Friedman JH, 2013
These adverse effects
are well-known consequences of dopaminergic therapy, particularly of dopamine agonists,
Zahodne LB,
and are associated with increased mortality.
Aarsland D, 2000 slide 69
. Besides reducing dopaminergic
therapy, these symptoms can be treated with clozapine, which does not aggravate motor function, but
with the caveat that it increases the risk of agranulocytosis and thus requires regular blood
monitoring. Quetiapine is also used, but it is less effective than clozapine. A new agent, Nuplazid, is
the first drug approved specifically for for PD-associated psychosis. Istradefylline has not shown any
clinically significant increase in psychosis.
Dementia: This is a frequent comorbidity of PD, affecting approximately 30% of PD patients
Aarsland D,
, and rendering them less able to tolerate normal doses of levodopa. It is also a contraindication to
use of PD medications such as amantadine, anti-cholinergics, and dopamine agonists, which can
aggravate cognitive decline. Consequently, treatment for PD-associated dementia currently entails
discontinuation of these potential aggravators of the condition. Currently, the anti-cholinesterase
inhibitor, rivastigmine, is the first and only therapy specifically approved for PD-associated dementia.
To a lesser degree, the NMDA receptor antagonist, memantine, is also utilized. Istradefylline has not
been shown to worsen cognition in PD. Clinical trial data on use of anti-dementia agents for PD is
limited and inadequate.
Connolly BS, 2014
Impulse control: Patients with PD frequently have difficulty controlling their impulses, such as with
gambling. Current treatment relies primarily on reduction of dopamine agonist dose, with the only
other approaches being cognitive behavioral therapy and possibly repetitive transcranial magnetic
Zurowski M 2015
Thus far there is no evidence that istradefylline contributes to loss of impulse
Autonomic dysfunction: PD symptoms of urinary urgency and incontinence were not increased by
istradefylline in initial reports of positive effects in Japan at MDS 2016. This study awaits replication.
With regard to constipation, current recommendation is to improve gastrointestinal motility by
reducing or discontinuing drugs with anticholinergic activity. Istradefylline has not been associated
with increased burden of these symptoms.
Sleep disorders: Nighttime disturbances and daytime hyper-somnolence are common in patients
receiving PD medications, but have not been associated with istradefylline.
Orthostatic hypotension: Postural hypotension can affect 20% to 50% of PD patients. It can occur
at any stage, but usually is most bothersome in patients with moderate to advanced PD, and
worsened by dopaminergic medications. However, there has been no reported clinical worsening by
Neuroprotection: There are presently no treatments that have demonstrated significant
neuroprotection for PD, but this prospect remains of much interest. Besides the fact that caffeine, a
nonspecific adenosine receptor antagonist, is a protective factor against developed PD, it is known
that blockade of adenosine A
receptors affords neuroprotection in animal models of epilepsy,
depression, Alzheimer's and PD. This initially involves control of synaptotoxicity by neuronal A
receptors, whereas astrocytic and microglia A
receptors might control the spread of damage.
Chapter 5: Summary
Unlike most pharmacotherapies for PD, istradefylline restores inhibition of the indirect
striatopallidal pathway by non-dopaminergic means. This is achieved through its antagonism
of adenosine A
receptors, which normally oppose the effects of dopaminergic neurons of the
substantia nigra, but which are depleted in PD. The net result is attenuation of the excessive
inhibitory stimulation of the thalamus that is characteristic of PD. By avoiding additional
dopaminergic stimulation of the basal ganglia and other CNS tissues, this approach helps
ameliorate motor and non-motor symptoms of PD while sparing the patient typical adverse
effects of such stimulation, and perhaps also enabling a reduction in levodopa dosage.
Currently, istradefylline has been approved for use in PD in Japan (Nouriast
), but not yet in
the US and Europe. The new drug application (NDA) in the US was filed in 2007 but not
approved (2008), and has since been resubmitted. No new drug application has yet been filed
in the EU. In 5 of the 7 studies in the NDA, istradefylline treatment was associated with
statistically significant improvement in both the percent and the total number of hours of
"OFF" time (range: 073 - 1.08 hours versus placebo). In three of these studies, the Unified
Parkinson's Disease Rating Scale (UPDRS Part III, motor) improved with istradefylline
treatment. Two of the US Phase III studies failed to find significant improvement in "OFF" time,
and possible reasons for this are the high placebo responses and site variability in those
Because of its high selectivity for adenosine A
receptors, istradefylline has thus far avoided
association with adverse effects on psychosis, sleep disorders, impulse control, orthostatic
hypotension and gastrointestinal motility that are commonly reported for other PD therapies.
There are no data yet on its effects on depression, and inadequate or limited data on its
effects on dementia. Experimental data suggests the potential of adenosine A
antagonists to confer neuroprotection in models of epilepsy, depression, Alzheimer's and PD,
and this awaits testing in clinical studies.
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