SECTION I

INTRODUCTION

Parkinsons disease (PD) is the second most common neurodegenerative

disease and manifests as bradykinesia, resting tremor, cogwheel rigidity and
posture instability. The slowly progressive character of the disease means that
development may last for 20 years. Although the motor symptoms of PD can be
well controlled by levodopa and other adjunctive medications in the early stages
of the disease, treatment-related complications will inevitably occur after 57
years. As the disease progresses, the cardinal motor symptoms of PD as well as
cognitive decline, neuropsychological problems, autonomic failure and treatment-
related complications associated with levodopa will enormously reduce the
patients activities of daily living (ADL) and health-related quality of life (HR-
QoL).1

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 SECTION II
PARKINSONS REVIEW

2.1 Definition
Parkinsons disease is a chronic progressive neurogenerative disorder of
insidious onset, characterized by the presence of predominantly motoric
symtomatology (bradykinesia, rest tremor, rigidity, and postural disturbance).2
Parkinson has some terminology in Konsensus Tatalaksana Penyakit
Parkinson:
1. Parkinson Disease: Parkinsonism with the loss of pigmented dopaminergic
neurons of the substantia nigra pars compacta and the presence of Lewy
bodies and Lewy neurites.
2. Parkinsonism: a clinical syndrome with the cardinal motor features of rest
tremor, rigidity, bradykinesia, and postural instability.3
Parkinsonism occurs due to disruption of the structure, physiology, or
neurochemical function of the dopaminergic pathway traveling from the
substantia nigra to the subcortical nuclei, including the putamen and caudate
nucleus (striatum), thalami, and cortical circuits. This primary cell system can be
influenced by involvement of the brainstem or other basal ganglia nuclei.4

2.2 Epidemiology
Parkinsons disease is a universal disorder, with a crude incidence rate of
4.519 per 100 000 population per year. The wide variation in incidence estimates
probably reflects differences in methodology and case ascertainment as well as
age distribution of the sample population.2
The crude prevalence rate of PD in European countries has been found to
range from 65.6 per 100,000 to 12,500 per 100,000, and the incidence from 5 per
100,000 to 346 per 100,000. In Asian countries, the crude prevalence rates seem
to be lower and range from 15 per 100,000 to 328 per 100,000.1

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 Although the disease usually begins in the fifth or sixth decade of life,
recent evidence shows increased incidence with advancing age. It has long been
recognized that a small proportion of patients develop the disease at an early age.
Patients presenting with the disease before 40 years of age are generally
designated as having early-onset PD. Among them, those beginning between 21
and 40 years are called young-onset PD while those beginning before the age of
20 years are called juvenile Parkinsonism. Contributions from the field of
genetics have demonstrated that a large proportion of young-onset, and
juvenile cases are of genetic origin, while the majority of the remaining cases
are presently considered to be sporadic. Some of the late-onset PD cases are also
found to have a genetic component.2

2.3 Etiology
Although the etiology of Parkinson disease is still unclear, most cases are
hypothesized to be due to a combination of genetic and environmental factors.
Currently known genetic causes of Parkinson disease account for approximately
10% of cases.5
1. Enviroment Causes
Environmental risk factors commonly associated with the development of
Parkinson disease include use of pesticides, living in a rural environment,
consumption of well water, exposure to herbicides, and proximity to industrial
plants or quarries.5

2. MPTP interference with mitochondrial function

Several individuals were identified who developed parkinsonism after self

injection of 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These patients
developed bradykinesia, rigidity, and tremor, which progressed over several weeks
and improved with dopamine replacement therapy. MPTP crosses the blood-brain
barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) by monoamine
oxidase (MAO)-B.5

3
 MPP+ accumulates in mitochondria and interferes with the function of
complex I of the respiratory chain. A chemical resemblance between MPTP and
some herbicides and pesticides suggested that an MPTP-like environmental toxin
might be a cause of Parkinson disease, but no specific agent has been identified.
Nonetheless, mitochondrial complex I activity is reduced in Parkinson disease,
suggesting a common pathway with MPTP-induced parkinsonism.5

3. Oxydation hypothesis
The oxidation hypothesis suggests that free radical damage, resulting from
dopamine's oxidative metabolism, plays a role in the development or progression
of Parkinson disease.5
4. Genetic Factors
If genetic factors are important in a particular disease, concordance in
genetically identical monozygotic (MZ) twins will be greater than in dizygotic
(DZ) twins, who share only about 50% of genes.5
The identification of a few families with familial Parkinson disease
sparked further interest in the genetics of the disease. In one large family in
Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis
incriminated a region in bands 4q21-23, and sequencing revealed an A-for-G
substitution at base 209 of the alpha-synuclein gene.5
5. Alpha-sysnuclein comformational changes and aggregation
Abnormally aggregated alpha-synuclein is the major component of Lewy
bodies and Lewy neurites, which are characteristic pathologic findings in
Parkinson disease.5

2.4 Pathophysiology
The term Parkinsons disease refers to a group of neurodegenerative
conditions that affect several regions of the brain, including the pigmented nuclei
in midbrain and brainstem, the olfactory tubercle, the cerebral cortex, and
elements of the peripheral nervous. The earliest and most striking physical
disabilities resulting from these changes are motor impairments that, together, are
called parkinsonism. These include paucity and slowness of movement

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(akinesia, bradykinesia), muscle stiffness (rigidity), and tremor at rest. In large
part, these problems result from the prominent degeneration of dopaminergic
neurons in the midbrain, and the consequent deficiency of dopamine in brain areas
that receive dopaminergic inputs from those neurons, specifically the post-
commissural putamen and other basal ganglia regions.6

2.4.1 Circuit anatomy of the basal ganglia

Parkinsonism is considered to result primarily from abnormalities of basal

ganglia function. The basal ganglia include the neostriatum (caudate nucleus and
putamen), the external and internal pallidal segments (GPe, GPi), the subthalamic
nucleus (STN), and the substantia nigra with its pars reticulata (SNr) and pars
compacta (SNc). They participate in anatomically and functionally segregated
loops that involve specific thalamic and cortical areas. These parallel circuits are
divided into motor, associative and limbic loops, depending on the function
of the cortical area involved. The thalamic components of these circuits are
largely separate from those engaged by cerebellar outflow. Striatum and STN
receive glutamatergic afferents from specific areas of the cerebral cortex or
thalamus, and transfer the information to the basal ganglia output nuclei, GPi and
SNr. The projections between the striatum and GPi/SNr are divided into two
separate pathways, a direct (monosynaptic) connection, and an indirect
projection, via the intercalated GPe and STN. Output from GPi/SNr goes largely
to the ventral anterior and ventrolateral nuclei of the thalamus (VA/VL), which, in
turn, project back to the cerebral cortex. Lesser basal ganglia projections reach the
intralaminar centromedian and parafascicular thalamic nuclei (CM/Pf) and
brainstem structures such as the superior colliculus, pedunculopontine nucleus
(PPN), and the reticular formation. Abnormal activity in the motor loop of the
basal ganglia is strongly implicated in the development of parkinsonism. This
looporiginates in precentral motor areas, and involves the post-commissural
putamen and motor regions of GPe, GPi, SNr and STN, as well as VA/VL. CM/Pf
receive collaterals of the GPi/SNr projection to VA/VL, and send efferents back to
the putamen, specifically targeting the direct pathway, and cholinergic striatal

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interneurons. The striatum also receives prominent dopaminergic input, from the
SNc. The nigrostriatal projection terminates predominately at the necks of
dendritic spines of the striatal medium spiny output neurons (MSNs). MSN spines
also receive corticostriatal terminations. This anatomic arrangement places the
dopaminergic inputs in a position to regulate or gate the corticostriatal
transmission. MSNs in the direct pathway carry dopamine D1-receptors, while
those in the indirect pathway carry D2-receptors. The direct and indirect pathways
are thought to have opposing actions: Direct pathway activation may inhibit
GPi/SNr activity, thereby disinhibiting thalamocortical interactions, while indirect
pathway activation does the opposite. Put very simply, dopamine release from the
nigrostriatal projection appears to facilitate transmission at corticostriatal synapses
onto direct pathway-MSNs, and to reduce transmission along indirect pathway-
MSNs. Dopamines net action may thus be to reduce GPi/SNr activity, thereby
facilitating activity in thalamocortical projection neurons, and, through greater
activation of the cerebral cortex, facilitating movement.6

The notion that D1 and D2 receptors co-segregate with direct and indirect
pathways, respectively, has also been challenged, by studies that demonstrate a
high incidence of D1 and D2 receptor co-localization in striatal cells.6

2.4.2 Dopamine loss in the striatum

In Parkinsons disease, the degeneration of dopaminergic SNc neurons and

their projections to the striatum is a slowly evolving process that may take
decades to develop. SNc projections to the putamen degenerate earlier than
projections to associative or limbic portions of the striatum. Corresponding to this
time course of degeneration, the motor symptoms and signs of Parkinsons disease
develop before the non-motor signs. Recognizable motor or non-motor signs
appear only after substantial degeneration of the nigrostriatal neurons, testament
to the remarkable compensatory capacity within the dopaminergic system, or in
the circuits it modulates. Dopamine loss in the basal ganglia triggers prominent
secondary morphological changes. One change that may have pathophysiologic

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significance is the reduction of the density of dendritic spines on MSNs,
particularly in the putamen, which may greatly alter corticostriatal transmission.
Dopamine depletion also triggers changes in the density and sensitivity of
dopamine receptors. The mRNA expression for dopamine D2-receptors and
binding sites in the striatum is increased in patients with Parkinsons disease and
parkinsonian animals. The subcellular locations of dopamine receptors in the
striatum may also change. Thus, the proportion of D1-receptors that are bound to
the plasma membrane is greater, while the proportion in the cytoplasm is smaller,
in parkinsonism than under normal condition.6

Changes in neuronal activity in the basal ganglia In the following sections,

we will describe abnormalities in basal ganglia firing in parkinsonism, focusing
on changes in firing rates, and on the development of abnormal burst patterns,
oscillatory activity and synchrony between neurons.6

In parkinsonian patients, the performance of motor and other tasks often

recruits brain areas that are not activated in non-parkinsonian individuals, such as
areas in the lateral premotor cortex, cerebellum and posterior parietal and
occipital. Similarly, cognitive tasks may affect activation in areas that are not
normally activated. EEG studies in patients have shown that parkinsonism may be
associated with abnormal beta-band synchronization of cortical networks, and a
failure to modulate frontal and central betaband activity with movement.6

There is little doubt that moderate or severe forms of parkinsonism are

associated with increased bursting, oscillatory activity, changes in interneuronal
synchrony, changes in the processing of sensory information, and perhaps changes
in firing rates. The immediate beneficial effects of focal lesions or DBS in the
basal ganglia suggests that such changes may contribute to the development of the
behavioral manifestations of the disease. However, the importance of specific
electrophysiologic features in basal ganglia, thalamic or cortical activity for the
development of the behavioral signs of parkinsonism has not been fully worked
out yet. As it seems increasingly doubtful that changes in firing rates or increased

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bursting are (strongly) pro-parkinsonian, synchronous oscillations within the basal
ganglia-thalamocortical circuits are the current lead suspect for a pro-parkinsonian
circuit dysfunction However, direct links between these oscillations and specific
parkinsonian deficits are still missing. It may seem logical that the oscillations
may result in tremor, but a specific relationship between tremor movements and
oscillatory basal ganglia or cortical firing is often difficult to detect, perhaps due
to the fact that multiple independent oscillators may be at work at any given time.
It is also obvious from primate and human recordings that strongly oscillatory
neuronal activity can, in fact, occur without overt tremor.6

There is evidence that abnormalities in brainstem regions, specifically the

PPN, may be involved in the development of some of the core signs of
parkinsonism. The PPN is tightly connected to the basal ganglia.6

2.5 History
Onset of motor signs in Parkinson disease is typically asymmetric, with
the most common initial finding being an asymmetric resting tremor in an upper
extremity. Over time, patients notice symptoms related to progressive
bradykinesia, rigidity, and gait difficulty. The first affected arm may not swing
fully when walking, and the foot on the same side may scrape the floor. Over
time, axial posture becomes progressively flexed and strides become shorter.7

Some nonmotor symptoms commonly precede motor signs in Parkinson disease.

Most Parkinson disease patients have a substantial reduction in olfactory function
(smell) by the time motor signs emerge. However, either this is not noticed by the
patients or patients may not realize that it is part of the disease. Another common
premotor symptom is rapid eye movement (REM) behavior disorder (RBD). In
this condition, individuals exhibit movements during REM sleep that are often
described as hitting or kicking motions. There are also a number of midlife risk
factors for the later development of Parkinson disease. These include constipation
and excessive daytime sleepiness, although they are far from specific for
Parkinson disease.The most commonly experienced nonmotor symptoms in
patients with early Parkinson disease are excessive saliva, forgetfulness, urinary

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urgency, hyposmia, constipation.7 Initial clinical symptoms in Parkinson disease
include the following:

Tremor
A subtle decrease in dexterity; for example, a lack of coordination with
activities such as playing golf or dressing (about 20% of patients first
experience clumsiness in one hand)
Decreased arm swing on the first-involved side
Soft voice
Decreased facial expression
Sleep disturbances
RBD, in which there is a loss of normal atonia during REM sleep: In one
study, 38% of 50-year-old men with RBD and no neurologic signs went on
to develop parkinsonism; patients act out their dreams and may kick, hit,
talk, or cry out in their sleep
Decreased sense of smell
Symptoms of autonomic dysfunction, including constipation, sweating
abnormalities, sexual dysfunction, and seborrheic dermatitis
A general feeling of weakness, malaise, or lassitude
Depression or anhedonia
Slowness in thinking8
Common early motor signs of Parkinson disease include tremor,
bradykinesia, rigidity, and dystonia.8

1. Tremor

Tremor is most often described by patients as shakiness or nervousness

and usually begins in one upper extremity and initially may be intermittent.
Although tremor is the most common initial symptom in Parkinson disease,
occurring in approximately 70% of patients, it does not have to be present to make
the diagnosis. Upper extremity tremor generally begins in the fingers or thumb,

9
but it can also start in the forearm or wrist. After several months or years, the
tremor may spread to the ipsilateral lower extremity or the contralateral upper
extremity before becoming more generalized; however, asymmetry is usually
maintained.Tremor can vary considerably, emerging only with stress, anxiety, or
fatigue. Classically, the tremor of Parkinson disease is a resting tremor (occurring
with the limb in a resting position) and disappears with action or use of the limb,
but this is not seen in all patients. Initially, the tremor may be noticed during
activities such as eating or reading a newspaper. Although Parkinson disease is a
rare cause of tremor affecting the head or neck, tremors of the chin, lip, or tongue
are not uncommon. As with other tremors, the amplitude increases with stress and
resolves during sleep.8

Table 1. Features differentiating Parkinsons disease from essential tremor 9

Feature Parkinsons disease Essential tremor

Age at onset (y) 5575 1080
Family history +/ ++
Tremor frequency
(Hz) 46 510
Tremor
characteristics Supinationpronation Flexionextension
Influencing factors
Rest Increases Decreases
Action Decreases Increases
Mental
concentration Decreases Increases
Writing Decreases (micrographia) Increases (tremulous)
Walking Increases Decreases
Alcohol Decreases
Postural tremor Re-emergent Without latency
Kinetic tremor +/ Yes
Limb tremor Asymmetric Symmetric
Distribution other
than limbs Face, jaw, lips, chin Head, voice
Neuroimaging Marked dopaminergic Mild dopaminergic deficit

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 Feature Parkinsons disease Essential tremor
dopaminergic
system deficit
Mid-brain
sonography Marked hyper-echogenicity Mild hyper-echogenicity
Mild cerebellar degeneration,
Lewy bodies in the
Nigrostriatal degeneration, substantianigra, brainstem and
Neuropathology Lewy bodies cerebellum some cases
Anticholinergics, Alcohol, beta-blockers,
amantadine, dopaminergic primidone, topiramate,
drugs, deep brain gabapentin, botulinum toxin,
Treatment stimulation deep brain stimulation

2. Bradykinesia

Bradykinesia refers to slowness of movement. Symptoms of bradykinesia

are varied and can be described by patients in different ways. These may include a
subjective sense of weakness, without true weakness on physical examination;
loss of dexterity, sometimes described by patients as the "message not getting to
the limb"; fatigability; or achiness when performing repeated actions.8

Facial bradykinesia is characterized by decreased blink rate and facial

expression. Speech may become softer, less distinct, or more monotonal. In more
advanced cases, speech is slurred, poorly articulated, and difficult to understand.
Drooling is an uncommon initial symptom in isolation but is reported commonly
(especially nighttime drooling) later in the disease course.8

Truncal bradykinesia results in slowness or difficulty in rising from a

chair, turning in bed, or walking. If walking is affected, patients may take smaller
steps and gait cadence is reduced. Some patients experience a transient inability to
walk, as though their feet are frozen to the floor. This "freezing" is seen
commonly in patients with more advanced disease; it is more prominent as
patients attempt to navigate doorways or narrow areas and can result in patients
getting trapped behind furniture or being unable to cross a door threshold easily.9

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 In the upper extremities, bradykinesia can cause small, effortful
handwriting (ie, micrographia) and difficulty using the hand for fine dexterous
activities such as using a key or kitchen utensils. In the lower extremities,
unilateral bradykinesia commonly causes scuffing of that foot on the ground, as it
is not picked up during leg swing. This may also be described as dragging of one
leg.8

3. Rigidity

Some patients may describe stiffness in the limbs, but this may reflect
bradykinesia more than rigidity. Occasionally, individuals may describe a feeling
of ratchety stiffness when moving a limb, which may be a manifestation of
cogwheel rigidity.8

4. Dystonia

Dystonia is a common initial symptom in young-onset Parkinson disease,

which is defined as symptom onset before age 40 years. Dystonia in Parkinson
disease commonly consists of a foot involuntary turning in (inversion) or down
(plantar flexion), often associated with cramping or aching in the leg. Dorsiflexion
of the big toe may also occur. Another common dystonia in Parkinson disease is
adduction of the arm and elbow, causing the hand to rest in front of the abdomen
or chest. Dystonic postures can wax and wane, occurring with fatigue or
exertion.Whether stooped posture is due to truncal dystonia is a matter of debate.
One study suggests that the stooped posture may be due to vertebral fractures
resulting from vitamin D deficiency with compensatory
hyperparathyroidism.Vitamin D supplementation may reduces the risk for stooped
posture.10

2.6 Approach Considerations

Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist

for the condition, and findings on routine magnetic resonance imaging (MRI) and
computed tomography (CT) scan are unremarkable. Positron emission
tomography (PET) and single-photon emission CT (SPECT) may show findings

12
consistent with Parkinson disease, and olfactory testing may provide evidence
pointing toward Parkinson disease, but these studies are not routinely needed.5

No laboratory or imaging study is required in patients with a typical

presentation. Such patients are aged 55 years or older and have a slowly
progressive and asymmetric parkinsonism with resting tremor and bradykinesia or
rigidity. Patients who do not have tremor should generally be considered for MRI
evaluation to exclude brain lesions such as stroke, tumor, or demyelination.5

In patients with an unusual presentation, diagnostic testing may be

indicated to exclude other disorders in the differential diagnosis. Such tests may
include serum ceruloplasmin, sphincter electromyography, or lumbar puncture.5

Serum ceruloplasmin concentration is obtained as a screening test for

Wilson disease in patients younger than 40 years who present with parkinsonian
signs. If the ceruloplasmin level is low, measurement of 24-hour urinary copper
excretion and slit-lamp examination for Kayser-Fleischer rings must be
performed. Abnormal results on urinary sphincter electromyography have been
noted in patients with multiple system atrophy (MSA).5

A substantial and sustained response to dopamine medications (dopamine

agonists or levodopa) helps confirm a diagnosis of Parkinson disease. It is unclear
whether acute levodopa or apomorphine challenge has any advantage over clinical
diagnostic criteria. Over time, diagnostic accuracy improves as the progression of
signs and symptoms and response to medications unfolds.5

In the general community, there is a high diagnosis error rate between

Parkinson disease and essential tremor. For movement disorder neurologists,
when an erroneous diagnosis of Parkinson disease is made, the most likely correct
diagnoses are the atypical parkinsonisms (MSA, progressive supranuclear palsy
[PSP], corticobasal ganglionic degeneration [CBD]). Early in the disease course, it
may be very difficult to distinguish between Parkinson disease and the atypical
parkinsonisms. These disorders also do not have laboratory biomarkers, and,

13
therefore, distinguishing among them is based on clinical criteria. Olfactory
testing may help differentiate Parkinson disease from PSP and CBD, but olfaction
is also reduced in MSA.5

2.6.1 Magnetic resonance imaging

Magnetic resonance imaging (MRI) is useful to exclude strokes, tumors,

multi-infarct state, hydrocephalus, and the lesions of Wilson disease. MRI should
be obtained in patients whose clinical presentation does not allow a high degree of
diagnostic certainty, including those who lack tremor, have an acute or stepwise
progression, or are younger than 55 years.5

The following MRI indicates where a thalamic stimulator is typically

placed.

Picture 1. Axial, fast spin-echo inversion recovery magnetic resonance image at

the level of the posterior commissure. The typical target for placing a thalamic
stimulator is demonstrated (cross-hairs).5

Below is a coronal MRI following bilateral subthalamic nuclei deep brain

stimulation.5

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Picture 2. Postoperative coronal magnetic resonance image (MRI) demonstrating
desired placement of bilateral subthalamic nuclei-deep brain stimulation (STN-
DBS) leads.5

2.6.2 PET and SPECT scanning

Positron emission tomography (PET) and single-photon emission

computed tomography (SPECT) scanning are useful diagnostic imaging studies,
but these are not routinely required. Different radioligands permit imaging of
different components or abnormalities within the brain.5

At the onset of motor signs, patients with Parkinson disease show an

approximately 30% decrease in F-dopa (fluorodopa) uptake on PET imaging in
the contralateral putamen.F-Dopa is taken up by the terminals of dopamine
neurons and converted to18 F-dopamine. The rate of striatal18 F accumulation
reflects transport of F-dopa into dopamine neurons and its decarboxylation to F-
dopamine, which is stored in dopamine nerve terminals in the striatum. Thus, F-
dopa PET imaging provides an index of remaining dopamine neurons. However,
this study is not widely available, is usually not covered by insurance, and is
currently generally considered a research tool.5

15
Carbon-11 C)-nomifensine and cocaine analogues such as I-beta-CIT (iodine-
123-labeled carboxymethoxy-3beta-4-iodophenyl-nortropane) andI-FP-CIT
(fluoropropyl-CIT) bind to dopamine reuptake sites on nigrostriatal terminals and
provide an index of the remaining dopamine neurons. Ioflupane( I) (DaTscan) is a
radiopharmaceutical agent that is indicated for striatal dopamine transporter
visualization using SPECT brain imaging to assist in the evaluation of adults with
suspected Parkinsonian syndromes (PSs). This agent may be used to help
differentiate essential tremor from tremor due to PSs (idiopathic Parkinson disease
[IPD] and Parkinson-plus syndromes [PPS]). Analysis of data from 2 clinical trials
demonstrated that the use of ioflupane with iodine-123 and single-photon
emission computed tomography (SPECT) scanning to diagnose early-stage
Parkinson's disease performed as well as clinical assessment at 1-year follow-up.5

Deficits on I SPECT scans indicate a dopamine deficiency syndrome but

do not differentiate Parkinson disease from atypical parkinsonisms,
including multiple system atrophy (MSA) and progressive supranuclear
palsy (PSP). Ioflupane SPECT imaging reveals a dopamine deficiency in
Parkinson disease, MSA, PSP, corticobasal ganglionic degeneration, and Lewy
body disease. This study is normal in essential tremor, dystonic tremor,
medication-induced parkinsonism or tremor, psychogenic disorders, and in normal
individuals.5

Classic pathologic findings in Parkinson disease include degeneration of

the neurons containing neuromelanin, especially in the substantianigra and the
locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic
inclusions called Lewy bodies (see the following image). The primary
biochemical defects are loss of striatal dopamine, which results from degeneration
of dopamine-producing cells in the substantianigra, as well as hyperactivity of the
cholinergic neurons in the caudate nucleus.5

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Picture 3. Lewy bodies are intracytoplasmiceosinophilic inclusions, often with
halos, that are easily seen in pigmented neurons, as shown in this histologic slide.
They contain polymerized alpha-synuclein; therefore, Parkinson disease is a
synucleinopathy.5

Picture 4. Lewy bodies in the locus coeruleus from a patient with Parkinson
disease. Alpha-synuclein is a major structural component of Lewy bodies; all
Lewy bodies stain for alpha-synuclein, and most also stain for ubiquitin. Lewy

17
bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos
and dense cores.5

The presence of Lewy bodies within pigmented neurons of the

substantianigra is characteristic, but not pathognomonic, of Parkinson disease.
Lewy bodies are also found in the cortex, nucleus basalis, locus ceruleus,
intermediolateral column of the spinal cord, and other areas.5
According to the Braak hypothesis, Lewy body pathology in the brain
begins in the olfactory bulb and lower brainstem and slowly ascends to affect
dopamine neurons in the substantianigra and, ultimately, the cerebral cortex.Lewy
body pathology is also observed in autonomic nerves of the gut and heart.5

2.6.3 Lumbal Puncture

Lumbar puncture should be considered if signs of normal-pressure
hydrocephalus (NPH) are observed (eg, incontinence, ataxia, dementia). In NPH,
clinical signs characteristically improve after removal of about 20 mL of
cerebrospinal fluid.5
Dopa-responsive dystonia should be considered in patients with juvenile-
onset dystonia and parkinsonism, particularly with diurnal fluctuations in
symptoms. In such patients, a trial of levodopa is critical. Additional tests for this
condition include measurement of CSF concentrations of biopterin, neopterin, and
the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic
acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). In both forms of
dopa-responsive dystonia, an altered pattern of decreases in these compounds is
observed.5
In the "Parkinson's Progression Markers Initiative" cross-sectional study of
63 drug-naive patients with early-stage PD and 39 healthy controls, CSF levels of
the Alzheimer's biomarkers -amyloid 1-42 (A1-42), total tau (T-tau), tau
phosphorylated at threonine 181 (P-tau181), and -synuclein were lower in the
PD patients than in the controls. A1-42 and P-tau181 were significant predictors
of Parkinson's disease, and T-tau and -synuclein were associated with the

18
severity of motor dysfunction. In particular, lower A1-42 and P-tau181
concentrations were associated with the postural instabilitygait disturbance
dominant PD phenotype, but were not associated with the tremor-dominant or
intermediate phenotypes.5

2.7 Diagnosis
The characteristic features of PD are bradykinesia, rigidity and rest tremor.
These may not all be present. Postural instability may be a feature, though early
postural instability backwards particularly with a history of falls is more
suggestive of progressive supranuclear palsy (PSP). The clinical findings are
usually asymmetrical in PD. The clinical diagnosis may often appear
straightforward, though it is worth noting that post-mortem studies have shown an
alternative diagnosis in up to a quarter of patients with PD diagnosed by general
neurologists. Of note, there is substantially less diagnostic error in patients
diagnosed in expert movement disorder clinics12 which strengthens the argument
for early referral of patients to specialists expert in movement disorders.11
A number of clinical criteria have been established. Table 2 outlines an
abbreviated form of the UK Parkinsons Disease Society Brain Bank clinical
diagnostic criteria.11
There are a number of other clinical signs that are worth highlighting. A
change of handwriting with micrographia is often an early feature as is reduced
facial expression. A loss of arm swing on one side is also an early and useful
diagnostic feature. A glabellar tap does not seem to be particularly sensitive or
specific.11
A reduced sense of smell is, however, worth asking about since this may
be one of the first symptoms in early PD.13 As the disease becomes more
advanced, hypophonia, drooling of saliva (from reduced swallowing) and
impairment of postural reflexes may develop.11

Table 2. Diagnosis Parkinsons Disease11

19
 Non-motor complications of the disease often become more troublesome
as the disease progresses. It is helpful to enquire about symptoms of depression
which occurs in 40% of PD patients. The commoner conditions that may present
with parkinsonian features and are often confused with PD are listed in Table 3. 11

Table 3. Differential Diagnosis of Parkinsons Disease11

20
 The diagnosis of essential tremor should be considered when a patient
presents with a symmetrical limb tremor, worse with posture and is suppressed by
alcohol. Head or voice tremor may also be present. In this condition, there may be
an autosomal dominant inheritance, suppression of the tremor with alcohol and
there should be no evidence of rigidity or bradykinesia on examination. Adult
onset dystonia may also present with asymmetrical rest tremor and may explain
some patients previously labelled as benign tremulous PD who have scans with
no evidence of dopaminergic defecit.11
Although the diagnosis of PD is a clinical one, there are certain situations
where investigations can prove useful. Conventional brain imaging with MRI or
CT is usually not required unless an alternative diagnosis is suspected such as
normal pressure hydrocephalus or vascular parkinsonism.11
Single photon emission computerized tomography (SPECT) imaging using
a dopamine transporter (DAT) can be helpful in differentiating PD from a number
of conditions, including essential tremor and dystonic tremor, neuroleptic-induced

21
parkinsonism and psychogenic parkinsonism all of which demonstrate normal
DAT scans. Uptake within the basal ganglia is reduced in PD, the parkinsonian
syndromes and DLB.11

2.8 Medications
There is as yet no cure for Parkinson Disease and no medication that slows
or stops the progression. Treatment is, therefore, aimed at suppressing or
reducing the symptoms of disease with the least amount of adverse effects from
the drugs. Most Parkinson Disease experts agree that treatment should not be
started until a patient is experiencing some functional disability from the
disease.11

2.8.1 Early stage treatment:

Early-stage Parkinsons disease includes patients who have had the disease
for less than five years or those who have not developed motor complications
from levodopa use. Treatment with monoamine oxidase-B (MAO-B) inhibitors,
amantadine (Symmetrel), or anticholinergics may modestly improve mild
symptoms; however, most patients need levodopa or a dopamine agonist. The
American Academy of Neurology (AAN) recommends levodopa or a dopamine
agonist, when dopaminergic treatment is required, depending on the need to
improve motor disability (levodopa is better) or decrease motor complications
(dopamine agonists cause fewer motor complications). Table 4 summarizes
medications approved for Parkinsons disease. In general, a dopamine agonist is
initiated in patients with mild disease with onset at a younger age, whereas
levodopa is initiated for older patients with severe motor symptoms.12

Table 4. FDA-Approved Medications for Parkinsons Disease12

22
 1. Levodopa
Levodopa is the most effective pharmacologic agent for Parkinsons disease
and remains the primary treatment for symptomatic patients. Because of its
consistent and dramatic beneficial effects, levodopa has not been tested against
placebo in therapeutic randomized controlled trials. Levodopa is particularly
effective at controlling bradykinesia and rigidity; however, speech, postural reflex,
and gait disturbance are less likely to respond.12
Levodopa is always combined with carbidopa, because carbidopa prevents
peripheral conversion of levodopa to dopamine by blocking dopa decarboxylase.
When combined with levodopa, carbidopa increases cerebral levodopa
bioavailability and reduces the peripheral adverse effects of dopamine (e.g.,
nausea, hypotension). Because dopa decarboxylase is saturated by carbidopa at

23
approximately 70 to 100 mg a day, patients receiving less than this amount of
carbidopa are more likely to experience nausea and vomiting. Dosing should start
with one 25/100-mg carbidopa/levodopa (Sinemet) tablet three times a day.
Sustained-release preparations add no benefit for motor complications compared
with immediaterelease preparations.12
2. Dopamine agonist
Dopamine agonists directly stimulate dopamine receptors and include
bromocriptine (Parlodel), pergolide (Permax), pramipexole (Mirapex), and
ropinirole (Requip). Studies have demonstrated that dopamine agonists, alone or
combined with levodopa, are effective against early Parkinsons disease. Double-
blind controlled trials comparing ropinirole or pramipexole with levodopa showed
that levodopa was more effective at reducing UPDRS scores than dopamine
agonists; however, these studies also noted a lower incidence of motor
complications with dopamine agonists.12
3. Mao-b inhibitors
An evidence-based review showed that the MAO-B inhibitor selegiline
(Eldepryl) had a mild symptomatic benefit in patients with early Parkinsons
disease. A meta-analysis of 17 trials comparing MAO-B inhibitors with placebo or
levodopa in patients with early Parkinsons disease showed that MAO-B
inhibitors reduced disability, the incidence of motor fluctuations, and the need for
levodopa without substantial adverse effects or increased mortality.12
4. Other agents
Anticholinergic agents are commonly used to treat Parkinsons disease.
However, low effectiveness and a high incidence of gastrointestinal and
neuropsychiatric adverse effects limit their use in older patients. Anticholinergics
typically are used in patients younger than 70 years with disabling resting tremors
and preserved cognitive function.12
The N-methyl-d-aspartate receptor inhibitor amantadine was originally used
as an antiviral agent and has been shown to improve akinesia, rigidity, and tremor
in patients with Parkinsons disease. The drug may be clinically useful, although
rigorous studies are lacking.12

2.8.2 Late stage treatment:

24
 Late-stage Parkinsons disease includes patients already receiving
carbidopa/levodopa treatment who have developed motor complications. After
five years of treatment with levodopa, about 40 percent of patients develop motor
fluctuations and dyskinesia (i.e., involuntary choreiform or stereotypic
movements involving the head, trunk, limbs, and, occasionally, the respiratory
muscles). Patients may experience a wearing-off effect characterized by a
shorter duration of benefit from each levodopa dose, causing parkinsonian
symptoms to reemerge. Patients can also experience an on-off effect
characterized by unpredictable, abrupt fluctuations in motor state from when the
medication is effective and symptoms are controlled (on) to when parkinsonian
symptoms worsen (off). These motor complications can be treated by adding a
dopamine agonist, MAO-B inhibitor, or catechol O-methyltransferase (COMT)
inhibitor.12

1. Dopamine agonists
Systematic reviews have demonstrated that dopamine agonists may
significantly reduce off time, improving motor impairment and disability and
reducing the need for levodopa. However, the reviews have also shown a trend
toward increased adverse events (e.g., dizziness, hallucinations, dyskinesia) with
dopamine agonists. Parenteral apomorphine (Apokyn), a powerful dopamine
agonist, is useful for patients experiencing a sudden, unexpected, and resistant
off period. This drug can cause severe adverse effects and should only be
prescribed by those experienced in its complex administration.12
2. comt inhibitors
COMT inhibitors (e.g., entacapone [Comtan], tolcapone [Tasmar]) decrease
the degradation of levodopa and extend its half-life, thus relieving the end-of-dose
wearing-off effect and reducing off time. A Cochrane review showed that,
compared with placebo, adjuvant COMT inhibitors reduced off time and
levodopa dose and modestly improved motor symptoms and disability in patients
with advanced Parkinsons disease and motor complications. The use of tolcapone
requires close monitoring with liver function tests because the drug is rarely

25
associated with potentially fatal hepatotoxicity. Family physicians should consider
consultation if a patient is a candidate for tolcapone therapy. Carbidopa/
levodopa/entacapone (Stalevo) tablets are available for patients currently
receiving levodopa who are experiencing the wearing-off effect.12
3. Mao-b inhibitors
An 18-week, randomized double-blind trial evaluated the MAO-B
inhibitor rasagiline (Azilect), entacapone, and placebo as adjuncts to levodopa in
687 patients with Parkinsons disease and motor fluctuations. Rasagiline and
entacapone reduced off time by about 1.2 hours a day compared with 0.4 hours
with placebo. Both drugs significantly improved Clinical Global Impression
scores and reduced the mean daily dose of levodopa. The frequency of adverse
effects was similar among all groups, and neither active treatment increased
dyskinesia.12
4. Amantadine
A randomized, double-blind trial of amantadine in patients with
Parkinsons disease and dyskinesia showed a 45 percent reduction in dyskinesia
with amantadine compared with placebo. However, the benefit lasted for less than
eight months, and withdrawal of amantadine caused a 10 to 20 percent rebound
increase in dyskinesia.12

2.8.3 Treatment of Nonmotor Symptoms

Depression, dementia, and psychosis are common psychiatric problems
associated with Parkinsons disease. Treatment of these symptoms is described in
Table 5.12
Table 5. Treatment of Nonmotor Symptoms of Parkinsons Disease12

26
2.9 Emergencies in Parkinsons Disease

1. Severe Motor Fluctuations

Motor fluctuations in Parkinson's disease typically are not severe enough

to need urgent interventions; however, some patients may present extremely
disturbing and dramatic 'off' periods, especially when they occur suddenly,
associated with prominent akinesia, dysautonomia, and psychiatric features, such
as anxiety and panic. In these instances, history should look for potential triggers
or aggravating factors, including infections, dopaminergic medication changes,
and inclusion of antidopaminergic drugs. Management involves combined
approaches: fragmentation of daily doses of levodopa, crushed tablets, controlled-
release or dispersible levodopa, subcutaneous dopamine agonists, monoamine
oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) inhibitors, and
elective stereotactic surgery.13

27
2. ParkinsonismHyperpyrexia and DyskinesiaHyperpyrexia Syndromes

Parkinsonismhyperpyrexia syndrome (PHS) mimics neuroleptic

malignant syndrome (NMS) in patients with Parkinson's disease. It is
characterized by hyperthermia, dysautonomia, altered consciousness, severe
rigidity, and elevated serum creatine kinase levels. PHS may be triggered by
infections, hot weather, dehydration, and, particularly, reduction or withdrawal of
antiparkinsonian agents (levodopa, dopamine agonists, and amantadine).
Commonest situations in which PHS occurs in the context of dopaminergic
treatment discontinuation include noncompliance, hospital admission due to
comorbidities, or as part of the preoperative procedure for stereotactic surgery.
Interestingly, recurrent PHS was described after discontinuation of subthalamic
nucleus deep brain stimulation. Potentially fatal complications include venous
thrombosis, pulmonary embolism, aspiration pneumonia, and renal failure.
Treatment is based on supportive measures and reinstitution of adequate
dopaminergic therapy. Occasionally, dantrolene is necessary.13

Dyskinesiahyperpyrexia syndrome (DHS) consists of severe dyskinesias

leading to muscle exhaustion, rhabdomyolysis, hyperthermia, and confusion. It
shares some of the features of PHS; however, dyskinesias not rigidity
predominate. In addition, DHS, contrarily to PHS, should be treated by cautiously
reducing the dosage of dopaminergic drugs.13

3. Acute Parkinsonism/Acute Worsening of Parkinsonism

Acute severe de-novo parkinsonism is uncommon, most frequently caused

by exposure to potent dopamine receptor blockers (DRBs), such as neuroleptics
and antiemetics. Other rare causes include hypoxicischemic encephalopathy,
intoxications, acute hydrocephalus, and infections.13

Acute worsening of motor symptoms in Parkinson's disease, unrelated to

disease progression, typically occurs because of concurrent medical conditions,
such as urinary or respiratory tract infections, metabolic disturbances, or

28
neurological disorders (subdural hematoma, spinal cord lesion, brain tumor,
etc.).13

For both acute situations, treatment should be focused on resolution of

underlying etiologic processes. Occasionally, symptomatic treatment with
dopaminergic agents is required.13

4. Acute Psychosis in Parkinson's Disease

Psychosis occurs in up to half of cases with Parkinson's disease throughout

the disease course, frequently associated and triggered by the same agents used to
treat the motor symptoms; however, acute clinical conditions (infectious,
metabolic, or neurological disorders) may play a role.Manifestations include
visual hallucinations, delusions, confusion, and agitation. After treatment of
potential comorbidities, a stepwise withdrawal of potentially contributing agents
is recommended, starting with anticholinergics, followed by MAO-B inhibitors,
dopamine agonists, amantadine, and COMT inhibitors. Introduction of an
antipsychotic (clozapine or quetiapine) may be necessary.13

5. Neuroleptic Malignant Syndrome

NMS is an idiosyncratic abrupt reaction to DRB.Often, agents include

'classic' neuroleptics; however, newer 'atypical' agents have all also been
implicated, the safest being clozapine and quetiapine. In addition, NMS can occur
with other dopamine-blocking drugs or as PHS, after abrupt withdrawal of
dopaminergic agents.13

Usually, symptoms start during the first 2 weeks of treatment initiation or

dosage change.[14] Risk factors include abrupt dose escalation, depot formulations,
male sex, young age, use of lithium and selective serotonin reuptake inhibitors
(SSRIs), high temperatures, dehydration, exhaustion, extrapyramidal syndromes,
and previous NMS episode. All age groups can be affected, most cases are in their
fourth and fifth decades. Mortality remains high between 20 and 30% of

29
cases.Most survivors recover without sequelae; however, some present cognitive
and motor abnormalities, including rigidity, tremor, and dystonia.13

Diagnostic criteria combine the tetrad of hyperthermia, rigidity, altered

mental status, and dysautonomia. Associated signs include tremor, dystonia,
chorea, myoclonus, seizures, ataxia, hyporeflexia, and extensor plantars. In
addition, laboratory changes include raised serum creatine kinase (>1000 IU/l),
impaired liver, renal, and coagulation status tests, leukocytosis, electrolyte
disturbances, proteinuria, rhabdomyolysis, and myoglobinuria.The most important
differential diagnoses are serotonergic syndrome, malignant hyperthermia, and
catatonia.13

Treatment depends on recognition, exclusion of differential diagnoses,

medication withdrawal, supportive care, and pharmacological interventions
depending on severity and presence of complications.Severe symptoms require
intensive care management and pharmacological reduction of rigidity
(benzodiazepines or dantrolene) and dopaminergic blockage (bromocriptine or
levodopa), as well as control of agitation. Electroconvulsive therapy has been used
anecdotally.[17] Neuroleptics should be stopped for at least 2 weeks after the acute
phase. Management of the underlying psychiatric condition can be then restarted
with low doses, slow titration, avoiding lithium, and with close observation to
prevent recurrence.13

6. Serotonergic Syndrome

Serotonergic syndrome results most often from the combination of two or

more agents that enhance serotonergic activity or concentration in the central
nervous system.This underrecognized syndrome presents with agitation, mental
status changes, myoclonus, ataxia, postural instability, hyperreflexia, rigidity, and
dysautonomia after changes in serotonergic drug regimen.Onset is typically abrupt
but some patients report insidious or recurrent subtle cognitive decline, behavioral

30
abnormalities, and tremor with postural changes days to weeks before the full-
blown syndrome develops.13

Serotonergic syndrome is a predictable reaction. The offending drugs are

those that cause excessive brainstem and spinal cord serotonin or 5-
hydroxytryptamine (5-HT) type 1A receptor stimulation.13

Serum or cerebrospinal fluid serotonin levels are useless for diagnosis,

which is established on clinical grounds.The starting point is obviously the history
of medication exposure, added by clinical manifestations. The most widely used
diagnostic criteria require the positive medication history along with any of the
following: myoclonus, agitation or diaphoresis; unexplained hyperthermia;
hypertonia; and tremor and hyperreflexia, after other causes have been ruled out.
Seizures, renal failure, and coagulopathy may occur. Laboratory abnormalities
include metabolic acidosis, rhabdomyolysis, elevated white cell count, and serum
aminotransferase and creatinine levels. Differential diagnoses include cocaine or
lithium overdose, anticholinergic poisoning, malignant hyperthermia, and NMS,
each readily distinguished from serotonergic syndrome based on medication
exposure history.13

Treatment requires medication withdrawal, enough to improve half of all

cases. Persistent/severe symptoms require pharmacologic treatment. Nonspecific
5-HT receptor blockers (cyproheptadine and methysergide) have been credited
with shortening the syndrome's duration.Other agents include benzodiazepines,
chlorpromazine, and propranolol. Treatment of seizures, arrhythmias,
coagulopathy, rigidity, and hyperthermia may be necessary.Serotonergic syndrome
is potentially fatal, mortality rates range from 2.4 to 12%. As in NMS,
reintroduction of treatment of the underlying psychiatric disorder requires close
monitoring, low dose, and slow titration.13

2.10 Complications

31
 With the progression of the disease, there are a number of non-motor
complications in Parkinson Disease that are often seen. In many cases, these are
not directly related to involvement of dopaminergic pathways and may therefore
develop even in patients where motor symptoms are well controlled.14
a) Sleep
Sleep disorders are frequent in Parkinson Disease. This includes both
disturbed nocturnal sleep and excessive daytime somnolence.Nocturnal
sleep disturbance occurs in 6098% of patients and correlates with disease
severity and levodopa intake. Although the underlying pathology of
Parkinson Disease may be in part responsible, it is important to also
exclude associated disorders such as medication-related sleep disturbance
including off-dystonia, depression, obstructive sleep apnoea, REM sleep
behavioural disturbance (RBD), periodic limb movements of sleep and
restless leg syndrome (RLS). RBD is a parasomnia characterized by the
loss of normal skeletal muscle atonia during REM sleep with prominent
motor activity accompanying dreaming and is increasingly recognized in
patients with neurodegenerative disease, particularly the
synucleinopathies. There is evidence that its development can predict
cognitive impairment in Parkinson Disease patients without dementia. If
troublesome, it may respond to a small amount of clonazepam at night.14

b) Cognition
Cognitive involvement in Parkinson Disease seems to be common. Many
patients with Parkinson Disease develop dementia, typically 10 years or
more after the onset of motor symptoms. The frequency of overt dementia
varies from study to study depending on definition, methods of cognitive
assessment and population differences, but is of the order of 40% for all
Parkinson Disease patients. More subtle cognitive disturbance particularly
of executive function is extremely common even in early Parkinson
Disease. Dementia in Parkinson Disease may be related to a number of
pathologies. However, it seems to be the development of cortical lewy
bodies and/ or Alzheimer pathology which are most relevant. The

32
 cholinesterase inhibitors rivastigmine, donepezil and galantamine have
been shown in open studies to have a modest benefit in cognitive function
and in the amelioration of hallucinations and psychosis in patients with
Parkinson Disease-related dementia, although robust evidence-based data
are strongest at this time for rivastigmine and to a lesser extent donepezil.14

c) Mood disturbance
Depression is the most common mood disturbance in Parkinson Disease
occurring with a prevalence of up to 50% and occurring at any stage of the
illness. Patients should be screened for underlying metabolic disturbances
such as hypothyroidism which can be easily confused with a depressive
illness. Mood fluctuations are commoner in more advanced disease and
have a stronger correlation with motor fluctuations. Depression, when
diagnosed, can be treated with cognitive behavioural therapy and
antidepressants including tricyclics and short acting serotonin uptake
inhibitors (SSRIs). There is evidence that pramipexole has a significant
antidepressant action.14

d) Psychosis and confusion

Psychosis can occur in up to 30% of Parkinson Disease patients. It often

presents with hallucinations which are usually visual together with delusions and
agitation or sometimes aggression. Patients may become paranoid particularly
towards partners or other family members. Psychosis is possibly mediated by loss
of dopaminergic neurones particularly in the nigro-mesolimbic projections. It is
often a feature in the development of PDD or DLB. Most of the older
antipsychotic agents tend to substantially worsen motor symptoms and should be
avoided. The newer atypical antipsychotic agents such as quetiapine and
clozapine are better tolerated and often effective. Clozapine requires close
monitoring of the white cell count because of a 1% incidence of agranulocytosis.
Acetylcholinesterase inhibitors may also be beneficial in reducing hallucinations
and delusions in Parkinson Disease patients.14

33
2.11 Prognosis

Before the introduction of levodopa, Parkinson disease caused severe

disability or death in 25% of patients within 5 years of onset, 65% within 10
years, and 89% within 15 years. The mortality rate from Parkinson disease was 3
times that of the general population matched for age, sex, and racial origin. With
the introduction of levodopa, the mortality rate dropped approximately 50%, and
longevity was extended by many years. This is thought to be due to the
symptomatic effects of levodopa, as no clear evidence suggests that levodopa
stems the progressive nature of the disease.15
The American Academy of Neurology notes that the following clinical
features may help predict the rate of progression of Parkinson disease:
1. Older age at onset and initial rigidity/hypokinesia can be used to predict a
more rapid rate of motor progression in those with newly diagnosed
Parkinson disease and earlier development of cognitive decline and
dementia; however, initially presenting with tremor may predict a more
benign disease course and longer therapeutic benefit from levodopa
2. A faster rate of motor progression may also be predicted if the patient is
male, has associated comorbidities, and has postural instability/gait
difficulty (PIGD)

Older age at onset, dementia, and decreased responsiveness to

dopaminergic therapy may predict earlier nursing home placement and decreased
survival.16

34
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