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EMEDICINE

Background: Parkinson disease (PD) is a progressive neurodegenerative disorder associated


with a loss of dopaminergic nigrostriatal neurons. It is named after James Parkinson, the
English physician who described the shaking palsy in 1817.
PD is recognized as one of the most common neurological disorders, affecting approximately
1% of individuals older than 60 years. Cardinal features include resting tremor, rigidity,
bradykinesia, and postural instability.
Pathophysiology: The major neuropathologic findings in PD are a loss of pigmented
dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. The loss of
dopaminergic neurons occurs most prominently in the ventral lateral substantia nigra.
Approximately 60-80% of dopaminergic neurons are lost before the motor signs of PD
emerge.
Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and
dense cores. The presence of Lewy bodies within pigmented neurons of the substantia nigra is
characteristic, but not pathognomonic, of idiopathic PD. Lewy bodies also are found in the
cortex, nucleus basalis, locus ceruleus, intermediolateral column of the spinal cord, and other
areas. Lewy bodies are not specific to PD, as they are found in some cases of atypical
parkinsonism, Hallervorden-Spatz disease, and other disorders. Incidental Lewy bodies are
found at postmortem in patients without clinical signs of parkinsonism. The prevalence of
incidental Lewy bodies increases with age. Incidental Lewy bodies have been hypothesized
to represent the presymptomatic phase of PD.
No standard criteria exist for the neuropathologic diagnosis of PD, as the specificity and
sensitivity of the characteristic findings have not been established clearly. Individuals
presenting with primary dementia may exhibit neuropathologic features indistinguishable
from those of PD.
Alpha-synuclein recently was discovered to be a major structural component of Lewy bodies.
All Lewy bodies stain for alpha-synuclein and most also stain for ubiquitin.
Motor circuit in Parkinson disease
The basal ganglia motor circuit modulates cortical output necessary for normal movement
(see Image 1). Signals from the cerebral cortex are processed through the basal gangliathalamocortical motor circuit and return to the same area via a feedback pathway. Output
from the motor circuit is directed through the internal segment of the globus pallidus (GPi)
and the substantia nigra pars reticulata (SNr). This inhibitory output is directed to the
thalamocortical pathway and suppresses movement.
Two pathways exist within the basal ganglia circuit; they are referred to as the direct and
indirect pathways. In the direct pathway, outflow from the striatum directly inhibits GPi and
SNr. The indirect pathway comprises inhibitory connections between the striatum and the
external segment of the globus pallidus (GPe) and the GPe and the subthalamic nucleus
(STN). The subthalamic nucleus exerts an excitatory influence on the GPi and SNr. The
GPi/SNr sends inhibitory output to the ventral lateral (VL) nucleus of the thalamus. Striatal

neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr.
Striatal neurons containing D2 receptors are part of the indirect pathway and project to the
GPe.
Dopamine is released from nigrostriatal (SNc) neurons to activate the direct pathway and
inhibit the indirect pathway. In PD, decreased striatal dopamine causes increased inhibitory
output from the GPi/SNr (see Image 2). This increased inhibition of the thalamocortical
pathway suppresses movement. Via the direct pathway, decreased striatal dopamine
stimulation causes decreased inhibition of the GPi/SNr. Via the indirect pathway, decreased
dopamine inhibition causes increased inhibition of the GPe, resulting in disinhibition of the
STN. Increased STN output increases GPi/SNr inhibitory output to the thalamus.
Frequency:

Internationally: The incidence has been estimated to be 4.5-21 cases per 100,000
population per year. Estimates of PD prevalence range from 18-328 per 100,000
population, with most studies yielding a prevalence of approximately 120 per
100,000.

Sex: PD is about 1.5 times more common in men than in women.


Age: The incidence and prevalence of PD increase with age. The average age of onset is
approximately 60 years. Onset in persons younger than 40 years is relatively uncommon.

CLINICAL

Section 3 of 11

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History: Onset of PD is typically asymmetric, with the most common initial finding being an
asymmetric resting tremor in an upper extremity. About 20% of patients first experience
clumsiness in one hand. Over time, patients notice symptoms related to progressive
bradykinesia, rigidity, and gait difficulty.

Tremor usually begins in one upper extremity and initially may be intermittent. As
with most tremors, the amplitude increases with stress and resolves during sleep. After
several months or as much as a few years, the tremor may affect the extremities on the
other side, but asymmetry usually is maintained. PD tremor may also involve the
tongue, lips, or chin.

The initial symptoms of PD may be nonspecific and include fatigue, depression,


constipation, and sleep problems.

Some patients experience a subtle decrease in dexterity and may notice a lack of
coordination with activities such as playing golf or dressing.

Some patients complain of aching or tightness in the calf or shoulder region.

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.

Decreased swallowing may lead to excess saliva in the mouth and ultimately drooling.

Symptoms of autonomic dysfunction are common and include constipation, sweating


abnormalities, sexual dysfunction, and seborrheic dermatitis.

Sleep disturbances are common.

The best clinical predictors of a pathologic diagnosis of PD are the following:


o Asymmetry
o Presence of resting tremor
o Good response to dopamine replacement therapy

Physical: The 3 cardinal signs of PD are resting tremor, rigidity, and bradykinesia. Of these
cardinal features, 2 of 3 are required to make the clinical diagnosis. Postural instability is the
fourth cardinal sign, but it emerges late in the disease, usually after 8 years or more.

The characteristic PD tremor is present and most prominent with the limb at rest.
o The usual frequency is 3-5 Hz.
o The tremor may appear as a pill-rolling motion of the hand or a simple
oscillation of the hand or arm.
o The same tremor may be observed with the arms outstretched (position of
postural maintenance) and a less prominent, higher frequency kinetic tremor is
also common.

Rigidity refers to an increase in resistance to passive movement about a joint.


o The resistance can be either smooth (lead pipe) or oscillating (cogwheeling).
o Cogwheeling is thought to reflect tremor rather than rigidity and may be
appreciated in tremors not associated with an increase in tone (ie, essential
tremor).
o Rigidity usually is tested by flexing and extending the patient's relaxed wrist.
o Rigidity can be made more obvious with voluntary movement in the
contralateral limb.

Bradykinesia refers to slowness of movement but also includes a paucity of


spontaneous movements and decreased amplitude of movement. Bradykinesia also is
expressed as micrographia (small handwriting), hypomimia (decreased facial
expression), decreased blink rate, and hypophonia (soft speech).

Postural instability refers to imbalance and loss of righting reflexes. Its emergence is
an important milestone, because it is poorly amenable to treatment and a common
source of disability in late disease.

Patients may experience freezing when starting to walk (start-hesitation), during


turning, or while crossing a threshold, such as going through a doorway.

Dementia generally occurs late in PD and affects 15-30% of patients. Short-term


memory and visuospatial function may be impaired, but aphasia is not present.
Cognitive dysfunction within a year of onset of motor features suggests a diagnosis of
Lewy body disease, a disease closely related to PD and marked by the presence of
cortical Lewy bodies.

Causes: Most cases of idiopathic PD are believed to be due to a combination of genetic and
environmental factors. At both ends of the spectrum are rare cases that appear to be due
solely to one or the other.

Environmental risk factors associated with the development of PD include use of


pesticides, living in a rural environment, consumption of well water, exposure to
herbicides, and proximity to industrial plants or quarries.

Several individuals have been identified who developed parkinsonism after selfinjection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
o These patients developed bradykinesia, rigidity, and tremor, which progressed
over several weeks and improved with dopamine replacement therapy.
o MPTP crosses the blood-brain barrier and is oxidized to MPP+ by the enzyme
monoamine oxidase (MAO) type B.
o MPP+ accumulates in mitochondria and interferes with the function of
complex I of the respiratory chain.
o A chemical resemblance between MPTP and some herbicides and pesticides
suggested that an MPTP-like environmental toxin might be a cause of PD, but
no specific agent has been identified. Nonetheless, mitochondrial complex I
activity is reduced in PD, suggesting a common pathway with MPTP-induced
parkinsonism.

The oxidation hypothesis suggests that free radical damage, resulting from dopamine's
oxidative metabolism, plays a role in the development or progression of PD.

o The oxidative metabolism of dopamine by MAO leads to the formation of


hydrogen peroxide. Hydrogen peroxide normally is cleared rapidly by
glutathione.
o If hydrogen peroxide is not cleared adequately, it may lead to the formation of
highly reactive hydroxyl radicals that can react with cell membrane lipids to
cause lipid peroxidation and cell damage. In PD, levels of reduced glutathione
are decreased, suggesting a loss of protection against formation of free
radicals. Iron is increased in the substantia nigra and may serve as a source of
donor electrons, thereby promoting the formation of free radicals.
o Indices of lipid peroxidation are increased in PD.
o Thus, PD is associated with increased dopamine turnover, decreased protective
mechanisms (glutathione), increased iron (a pro-oxidation molecule), and
evidence of increased lipid peroxidation. This hypothesis raised concern that
increased dopamine turnover due to levodopa administration could increase
oxidative damage and accelerate loss of dopamine neurons. However,
currently no evidence suggests that levodopa accelerates disease progression
in patients with PD.

The role of genetic factors has been studied in twins.


o If genetic factors are important, concordance in genetically identical
monozygotic (MZ) twins will be greater than in dizygotic (DZ) twins, who
share only about 50% of genes. Early twin studies generally found low and
similar concordance rates for MZ and DZ pairs.
o In a recent study of 193 twins, overall concordance for MZ and DZ pairs was
similar. However, in 16 pairs of twins in whom PD was diagnosed at or before
age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant. This
suggests that while genetic factors may not be very important when the disease
begins after age 50 years, genetic factors appear to be very important when the
disease begins at or before age 50 years.

The identification of a few large families with apparent familial PD sparked further
interest in the genetics of the disease.
o One large family with highly penetrant, autosomal-dominant, autopsy-proven
PD originated in the town of Contursi in the Salerno province of southern
Italy. Of 592 family members, 50 were affected by PD. These individuals were
characterized by early age of disease onset (mean age 47.5 y), rapid
progression (mean age at death 56.1 y), lack of tremor, and good response to
levodopa therapy.
o Linkage analysis incriminated a region in chromosome bands 4q21-23, and
sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein
gene. Termed PD-1, this mutation codes for a substitution of threonine for
alanine at amino acid 53.

o Five small Greek kindreds also were found to have the PD-1 mutation. In a
German family, a different point mutation in the alpha-synuclein gene (a
substitution of C for G at base 88, producing a substitution of proline for
alanine at amino acid 30) confirmed that mutations in the alpha-synuclein
gene can cause PD. A few additional familial mutations in the alpha-synuclein
gene have been identified and are now collectively called PARK1. It is now
clear that these mutations are an exceedingly rare cause of PD.

Alpha-synuclein is a major component of Lewy bodies in all PD.


o All Lewy bodies stain for alpha-synuclein, and most also stain for ubiquitin,
which conjugates with proteins targeted for proteolysis. Abnormal aggregation
of alpha-synuclein into filamentous structures may precede ubiquitization.
o One hypothesis states that the PD-1 mutation alters the configuration of alphasynuclein into a structure that could aggregate into sheets.
o All PD may be associated with abnormal folding of alpha-synuclein, leading
to excessive aggregation and neuronal death.
o Although sporadic PD is not caused by a mutation in the alpha-synuclein gene,
active investigation is underway into proteins that interact with alphasynuclein, including those that guide, promote, or prevent aggregation of the
protein.
o As PD, dementia with Lewy bodies, and multiple system atrophy (MSA) all
exhibit Lewy bodies that stain for alpha-synuclein, they have been designated
alpha-synucleinopathies.

A recent hypothesis suggests that PD is caused by abnormalities of the proteosome


system, which is responsible for clearing abnormal proteins.

Several homozygous deletions in a gene dubbed Parkin (Park2), which is located on


chromosome 6, have been found to cause autosomal-recessive juvenile parkinsonism
(AR-JP). This form of parkinsonism differs pathologically from PD in that no Lewy
bodies are found in the substantia nigra.

Several other gene abnormalities have been identified in families with PD and these
are designated Park3-Park12.

It has been estimated that all currently known genetic causes of PD account for less
than 5% of PD cases.

DIFFERENTIALS

Section 4 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Alzheimer Disease
Cardioembolic Stroke

Cortical Basal Ganglionic Degeneration


Essential Tremor
Hallervorden-Spatz Disease
Lacunar Syndromes
Multiple System Atrophy
Normal Pressure Hydrocephalus
Parkinson-Plus Syndromes
Progressive Supranuclear Palsy
Striatonigral Degeneration
Other Problems to be Considered:
Jakob-Creutzfeldt and other prion diseases
Parkinsonism can be caused by a variety of degenerative disorders, as well as toxins,
infections, and vascular or structural lesions.
Parkinsonism also can be induced by medications that block dopamine receptors (eg,
neuroleptics, antiemetics) or deplete intraneuronal dopamine stores (eg, reserpine,
tetrabenazine).
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WORKUP

Section 5 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Lab Studies:

No laboratory biomarkers exist for PD.

Serum ceruloplasmin concentration is obtained as a screening test for Wilson disease.


It should be obtained in patients who present with parkinsonian symptoms when
younger than 40 years. In cases in which Wilson disease is suspected, 24-hour urinary
copper and slit lamp examination of the eyes also should be obtained.

Imaging Studies:

Magnetic resonance imaging (MRI) and computed tomography (CT) scan are
unremarkable in PD.
o No imaging study is required in patients with a typical presentation. Such
patients are aged 55 years or older; have a slowly progressive, asymmetric
parkinsonism with resting tremor and bradykinesia or rigidity; and
demonstrate a good response to dopamine replacement therapy.
o MRI is useful to exclude multi-infarct state, hydrocephalus, and the lesions of
Wilson disease.
o 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.

Positron emission tomography (PET) and single photon emission CT (SPECT) are
useful diagnostic imaging studies. They are not widely available and may not be
covered by insurance. Moreover, they are not needed for routine clinical diagnosis in
patients with a typical presentation.
o At the onset of symptoms, PD patients show an approximately 30% decrease
in 18F-dopa uptake in the contralateral putamen.

o 18F-dopa is taken up by the terminals of dopamine neurons and converted to


18F-dopamine. The rate of striatal 18F accumulation reflects transport of 18Fdopa into dopamine neurons and its decarboxylation to 18F-dopamine.
o 11C-Nomifensine and cocaine analogues such as 123I-Beta-CIT bind to
dopamine reuptake sites on nigrostriatal terminals and provide an index of the
integrity of nigrostriatal projections.
TREATMENT

Section 6 of 11

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Medical Care: The goal of medical management of PD is to provide control of signs and
symptoms for as long as possible while minimizing adverse effects. Medications usually
provide good symptomatic control for 4-6 years. After this, disability progresses despite best
medical management, and many patients develop long-term motor complications including
fluctuations and dyskinesia. Additional causes of disability in late disease include postural
instability (balance difficulty) and dementia.

Putative neuroprotective therapy: Neuroprotective therapies are defined as those that


slow the underlying loss of dopamine neurons. Currently, no proven neuroprotective
therapies exist for PD.
o If a neuroprotective therapy were available for PD, it would be administered
from the time of diagnosis onward.
o Selegiline is the medication that first has garnered interest as a possible
neuroprotective agent.
o Laboratory investigations continue to provide evidence that selegiline affords
a neuroprotective effect for dopamine neurons independent of MAO-B
inhibition.
o Selegiline has been demonstrated to protect cultured dopamine neurons from
MPP+ toxicity, an effect that cannot be attributed to MAO-B inhibition. Tatton
and Greenwood demonstrated that selegiline protects dopamine cells in mice
from MPTP toxicity even when administered after a delay sufficient to allow
the oxidation of MPTP to MPP+.
o In cell-culture systems, selegiline's neuroprotective effect is mediated by new
protein synthesis. Selegiline induces transcriptional events that result in
increased synthesis of antioxidant and anti-apoptotic proteins. Recent evidence
indicates that one of selegiline's metabolites, desmethylselegiline, is the active
agent for neuroprotection.
o Selegiline's amphetamine metabolites may interfere with its neuroprotective
actions.

o In the clinical study called deprenyl (selegiline) and tocopherol (vitamin E)


antioxidative therapy of parkinsonism (DATATOP), the Parkinson Study
Group evaluated the ability of these 2 medications to delay progression of
clinical disability in early PD. Eight hundred patients were randomized to
receive selegiline (10 mg/d) or placebo and tocopherol (2000 IU/d) or placebo.
Patients assigned to receive selegiline, with placebo or with tocopherol,
experienced a significant delay in the need for levodopa therapy (hazard ratio
= 0.50, P <0.001). Patients assigned to receive placebo required levodopa at a
projected median of 15 months from enrollment, while those who received
selegiline required levodopa at a projected median of 24 months after
enrollment. Tocopherol had no effect on progression of disability.
o The study conclusively demonstrated that selegiline delays the need for
levodopa therapy in early PD; this result is consistent with the hypothesis that
selegiline may slow disease progression. However, the study also found that
selegiline provided a small symptom-relieving effect, and whether the delay in
the need for levodopa was due entirely or in part to this modest effect is not
clear.
o In one study, selegiline was associated with increased mortality rate in patients
with PD. The Parkinson's Disease Research Group of the United Kingdom
reported a 57% higher mortality rate in patients assigned to receive selegiline
plus levodopa than in those who received levodopa alone (mortality ratio =
1.57, 95% confidence interval 1.09-2.30, P = 0.015). The difference in
mortality rate emerged between the third and fifth years of treatment, and no
obvious explanation regarding its cause was identified.
o Many questions have been raised regarding the results and methodology of
this study. Mortality rates were not significantly different between groups
when the analysis was based on what patients actually were taking and not on
intention to treat. In addition, the mortality rate was unusually high in both
groups (28% in patients receiving selegiline, 18% in those not receiving
selegiline).
o Rasagiline is a new MAO-B inhibitor that exhibits neuroprotective effects in
cell culture and animal models. In a clinical trial (TEMPO), treatment with
rasagiline for 1 year provided significantly greater improvement than
treatment with placebo for 6 months followed by rasagiline for 6 months.
o Co-enzyme Q10 is another drug of interest. It is a scavenger of free radicals.
In a preliminary study, co-enzyme Q10 1200 mg/d slowed progression of PD
disability.
o Further studies of rasagiline and co-enzyme Q10 are required.

Symptomatic therapy

o Levodopa, coupled with a peripheral decarboxylase inhibitor (PDI), remains


the standard of symptomatic treatment for PD. It provides the greatest
antiparkinsonian benefit with the fewest adverse effects in the short term.
o Dopamine agonists provide symptomatic benefit comparable to levodopa/PDI
in early disease but lack sufficient efficacy to control signs and symptoms by
themselves in later disease.
o Dopamine agonists cause more sleepiness, hallucinations, and edema than
levodopa.
o Prospective, double-blind studies have demonstrated that initial treatment with
a dopamine agonist, to which levodopa can be added as necessary, causes less
motor fluctuations and dyskinesias than levodopa alone.
o Dopamine agonists can be used as initial symptomatic therapy in early disease,
rather than levodopa/PDI, to delay the onset of motor fluctuations and
dyskinesia. This strategy is usually reserved for younger individuals (<65-70
y) who are cognitively intact.

Levodopa and motor complications


o As PD progresses, fewer dopamine neurons are available to store and release
levodopa-derived dopamine. The patient's clinical status begins to fluctuate
more and more closely in concert with plasma levodopa levels. Exposing
striatal dopamine receptors to fluctuating dopamine concentrations may cause
a hypersensitivity that is expressed clinically as peak-dose dyskinesia
(twisting, turning movements). Fluctuating levodopa-derived dopamine
concentrations in association with advancing disease therefore may be
responsible for development of motor fluctuations and dyskinesia.
o The Continuous Dopaminergic Stimulation (CDS) hypothesis posits that
pulsatile dopamine receptor stimulation induces dyskinesia, whereas smoother
more continuous dopamine receptor stimulation causes less dyskinesia.
o In contrast to levodopa, the long-acting dopamine agonists (ie, bromocriptine,
pergolide, pramipexole, ropinirole, cabergoline) provide relatively smooth and
sustained receptor stimulation. In marmosets with MPTP-induced
parkinsonism, levodopa administration causes significantly more dyskinesia
than bromocriptine or ropinirole.
o Prospective clinical trials have demonstrated that initial treatment with a
dopamine agonist to which levodopa can be added causes less motor
fluctuations and dyskinesia than levodopa alone.
o A recent MPTP marmoset study found that the addition of entacapone (which
increases the half-life of levodopa) was associated with less motor fluctuations
and less dyskinesia than treatment with the same regimen of levodopa alone.
This finding is consistent with the CDS hypothesis. A clinical trial (STRIDE-

PD) is now underway to determine if levodopa plus entacapone


(levodopa/carbidopa/entacapone) delays the occurrence of dyskinesia
compared with levodopa/carbidopa when levodopa is first required.

Early disease treatment strategies


o The younger the patient, the more emphasis the authors place on long-term
considerations to guide early treatment. Young patients have a longer life
expectancy and are more likely to develop motor fluctuations and dyskinesias.
o For older patients and those with cognitive impairment, less emphasis is
placed on long-term considerations; the focus is on providing adequate
symptomatic benefit in the near term with as few adverse effects as possible.
o At the time of diagnosis, a discussion is initiated to review current information
regarding possible neuroprotective agents currently under study.
o The younger the patient, the more critical the need for neuroprotection, and the
more likely the authors are to recommend a possible neuroprotective agent.
o Symptomatic therapy is introduced when the patient experiences functional
disability. The selection of medication depends in part on the nature and cause
of the disability.
o If disability is due solely to tremor, a tremor-specific medication, such as an
anticholinergic agent, can be used. Anticholinergic medications provide good
tremor relief in approximately 50% of patients but do not improve
bradykinesia or rigidity. Because tremor may respond to one anticholinergic
medication and not another, a second anticholinergic usually is tried if the first
is not successful. These medications should be introduced at a low dose and
escalated slowly to minimize adverse effects, which include memory
difficulty, confusion, and hallucinations. Adverse cognitive effects are
relatively common, especially in the elderly.
o If disability is due to a dopamine-responsive symptom such as bradykinesia,
rigidity, decreased dexterity, slow speech, or shuffling gait, a dopaminergic
medication, such as an MAO-B inhibitor, amantadine, dopamine agonist, or
levodopa, should be introduced. MAO-B inhibitors provide mild symptomatic
improvement but have few side effects. Amantadine also provides mild
symptomatic improvement but may cause cognitive side effects or
hallucinations, especially in older individuals and those with cognitive
dysfunction. Dopamine agonists provide moderate benefit and cause less
fluctuations and dyskinesias, but they have more side effects including
sleepiness, hallucinations, and edema. Levodopa is the strongest symptomatic
agent but its long-term use is associated with the development of fluctuations
and dyskinesias.
o Symptomatic medications are started at a low dose, escalated slowly, and
titrated to control symptoms. Most patients require symptomatic dopaminergic

therapy to ameliorate bradykinesia and rigidity within 1-2 years after


diagnosis.
o For patients younger than 65 years, the authors often utilize a dopamine
agonist and then add levodopa/PDI when the dopamine agonist alone no
longer controls symptoms adequately. Dopamine agonists provide
antiparkinsonian efficacy comparable to levodopa/PDI for 6-18 months or
longer and may control symptoms adequately for several years.
o When the dopamine agonist no longer provides adequate symptomatic control
despite titration to the usual maximum or highest tolerated dose, levodopa/PDI
is added. The relatively sustained dopamine receptor stimulation provided by
the dopamine agonist may buffer receptors from fluctuating levodopa-derived
dopamine concentrations and afford a lower incidence of motor fluctuations
and dyskinesia.
o For patients who are demented or those older than 70 years, who may be prone
to adverse effects from dopamine agonists, and for those likely to require
treatment for only a few years, the authors may elect not to use a dopamine
agonist and depend on levodopa/PDI as primary symptomatic therapy.
o For patients aged 65-70 years, the authors make a judgment based on general
health and cognitive status. The more robust and cognitively intact the patient,
the more likely the authors are to start symptomatic treatment with a dopamine
agonist and add levodopa/PDI when necessary.
o When introducing a dopamine agonist, starting at a low dose and escalating
slowly is important. The dose should be titrated upward until symptoms are
controlled, the maximum dose is reached, or adverse effects become
intolerable. The most common adverse effects of dopamine agonists are
nausea, orthostatic hypotension, hallucinations, and somnolence. Nausea
usually can be reduced by having the patient take the medication after meals.
Domperidone, a peripheral dopamine agonist available outside the US, is very
helpful in relieving refractory nausea.
o Levodopa/PDI is introduced at a low dose and escalated slowly. Currently
available levodopa preparations in the United States include
levodopa/carbidopa, levodopa/carbidopa CR, levodopa/carbidopa orally
disintegrating tablet, and levodopa/carbidopa/entacapone. The orally
disintegrating tablet is bioequivalent to oral levodopa/carbidopa but dissolves
on the tongue without the need to swallow it with water.
o The levodopa dose is titrated to control clinical symptoms; most patients
experience a good response on a daily dosage of 400-600 mg/d for 3-5 years
or more. Doses higher than those necessary to control symptoms adequately
should be avoided.

o If nausea occurs, the dose may be taken following a meal. Additional measures
to alleviate nausea include adding extra carbidopa or introducing
domperidone.

Advanced disease treatment strategies


o Patients initially experience stable, sustained benefit through the day in
response to levodopa medications. However, after several months to years,
many patients notice that the benefit from immediate release
levodopa/carbidopa wears off after 4-5 hours. Over time, this shortened
duration of response becomes more fleeting, and clinical status fluctuates
more and more closely in concert with peripheral levodopa concentration.
Ultimately, benefit lasts only 1-2 hours. The time when medication is
providing benefit for bradykinesia, rigidity, and tremor is called on time, and
the time when medication is not providing benefit is called off time.
o By several months to years after the introduction of levodopa, many patients
develop peak-dose dyskinesia consisting of choreiform, twisting/turning
movements that occur when levodopa-derived dopamine levels are peaking. At
this point, increasing dopamine stimulation is likely to worsen peak-dose
dyskinesias. Over time, the therapeutic window narrows because of a
progressive decrease in the threshold for peak-dose dyskinesia. The
therapeutic window lies above the threshold required to improve symptoms
(on threshold) and below the threshold for peak-dose dyskinesia (dyskinesia
threshold).
o Although many patients prefer dyskinesia to off time, the clinician should
recognize that dyskinesias can be sufficiently severe to be troublesome to the
patient, either by interfering with activities or because of discomfort. Asking
patients how they feel during both off time and time with dyskinesia is
important in titrating medication optimally. Having patients fill out a diary
may be helpful; the diary should be divided into half-hour time periods on
which patients denote whether they are off, on without dyskinesia, on with
nontroublesome dyskinesia, or on with troublesome dyskinesia (see Image 3).
The goal of medical management is to minimize off time and time on with
troublesome dyskinesia.
o Treating motor fluctuations in the absence of peak-dose dyskinesia is
relatively easy. Several different strategies, either alone or in combination, can
be used to provide more sustained dopaminergic therapy. Possible strategies
include adding a dopamine agonist, catechol-O-methyltransferase (COMT)
inhibitor, or MAO-B inhibitor; dosing levodopa more frequently; increasing
the levodopa dose; or switching from immediate release to CR levodopa or
levodopa/carbidopa/entacapone. Unless limited by the emergence of peakdose symptoms such as dyskinesia or hallucinations, dopaminergic therapy
should be increased until off time is eliminated.
o The treatment of patients with both motor fluctuations and troublesome peakdose dyskinesia can be difficult. The goal of treatment in this situation is to

provide as much good functional time through the day as possible. This is
accomplished by maximizing on time without troublesome dyskinesia. An
attempt is made to reduce both off time and time with troublesome or
disabling dyskinesia. Unfortunately, a decrease in dopaminergic therapy may
increase off time and an increase in dopaminergic therapy may worsen peakdose dyskinesia.
o For patients with severe fluctuations and dyskinesia, the best balance between
off time and troublesome dyskinesia is sought. The patient's relative
preference for off time versus dyskinesia needs to be taken into account.
o For patients with motor fluctuations and dyskinesia on levodopa/PDI, the
addition of a dopamine agonist, COMT inhibitor, or MAO-B inhibitor may be
helpful. Dyskinesia may increase when these medications are added,
necessitating the downward titration of levodopa.
o For patients on CR levodopa, switching to immediate release
levodopa/carbidopa often provides a more consistent and predictable dosing
cycle and allows finer titration. In general, smaller levodopa doses are
administered more frequently. A dose should be sought that is sufficient to
provide benefit without causing troublesome dyskinesia. The time to wearingoff then determines the appropriate interdose interval. The extreme of this
strategy is using liquid levodopa, a solution with which the dose can be titrated
finely and administered every hour. Amantadine may be of benefit to reduce
dyskinesia.
o COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-Omethyldopa (3-OMD), thereby prolonging the levodopa half-life and making
more levodopa available for transport across the blood-brain barrier over a
longer time.
o Tolcapone was the first COMT inhibitor available for clinical use. Because of
the potential risk of hepatotoxicity, liver function test monitoring is required,
and it should be used only in patients who are experiencing motor fluctuations
on levodopa that cannot be adequately controlled with other medications.
o If dyskinesia emerges, the levodopa dose should be reduced. In patients who
already have dyskinesia, the levodopa dose often is reduced by 30-50% at the
time tolcapone is introduced.
o Entacapone is a COMT inhibitor that does not cause hepatotoxicity; liver
function tests are not required with this medication. A combination tablet of
levodopa/carbidopa/entacapone is now available.
o Levodopa/PDI, dopamine agonists, and anticholinergics each provide good
benefit for tremor in approximately 50% of patients. If a patient is
experiencing troublesome tremor and symptoms are not controlled adequately
with one medication, another should be tried. If the tremor is not controlled

adequately with medication, thalamotomy or thalamic stimulation surgery may


be considered at any time during the disease.
Surgical Care: Stereotactic surgery has made a resurgence in the treatment of PD, largely
due to long-term complications of levodopa therapy resulting in significant disability despite
optimal medical management.
A better understanding of basal ganglia physiology and circuitry and improvements in
surgical techniques, neuroimaging, and electrophysiologic recording have allowed surgical
procedures to be performed more accurately and with lower morbidity.

Lesion surgeries involve the destruction of targeted areas of the brain to control the
symptoms of PD.
o Thalamotomy involves destruction of a part of the thalamus, generally the
ventral intermediate (VIM) nucleus, to relieve tremor. Thalamotomy has little
effect on bradykinesia, rigidity, motor fluctuations, or dyskinesia.
o The mechanisms of action of thalamotomy are not known; its effects may be
due to destruction of autonomous neural activity (synchronous bursts) at the
same frequency as limb tremor.
o More than 90% of patients with PD who undergo thalamotomy have
significant improvement in tremor of the limbs contralateral to the side of the
lesion.
o Complications from bilateral thalamotomy are common; more than 25% of
patients experience speech impairment. Mental changes also can persist after
bilateral surgery. Therefore, bilateral thalamotomies are generally avoided.
o Pallidotomy involves destruction of a part of the globus pallidus interna (GPi),
which is overactive in PD.
o Results from pallidotomy studies have demonstrated significant improvements
in each of the cardinal symptoms of PD (tremor, rigidity, bradykinesia) as well
as a significant reduction in dyskinesia.
o Bilateral pallidotomy is not recommended. Although bilateral pallidotomy has
been shown to significantly reduce levodopa-induced dyskinesia,
complications are relatively common and include speech difficulties,
dysphagia, and cognitive impairment.
o Subthalamotomy involves destruction of a part of the subthalamic nucleus
(STN), which is also hyperactive in PD.
o Initial results of subthalamotomy have shown significant improvements in the
cardinal features of PD as well as the reduction of motor fluctuations and
dyskinesia.

o Lesion surgeries for PD have largely been replaced by deep brain stimulation
(DBS) that does not involve a permanent lesion in the brain making the
procedure reversible and the device can be adjusted to accommodate for
disease progression and side effects. In addition, bilateral procedures can be
performed without the morbidity seen with bilateral lesion surgeries.

Deep brain stimulation


o DBS is an FDA-approved treatment for PD.
o The DBS system consists of a lead that is implanted into the targeted brain
structure (thalamus, GPi, STN). The lead is connected to an implantable pulse
generator (IPG), which is the power source of the system that is generally
implanted in the subclavicular region of the chest cavity. The lead and the IPG
are connected by an extension wire that is tunneled down the neck under the
skin.
o DBS provides monopolar or bipolar electrical stimulation to the targeted brain
area. Stimulation amplitude, frequency, and pulse width can be adjusted to
control symptoms and eliminate adverse events. The patient can turn the
stimulator on or off using a handheld magnet or Access Review Therapy
Controller. The usual stimulation parameters are frequency of 135-185 Hz,
pulse width of 60-120 microseconds, and amplitude of 1-3 V.
o DBS has been proposed to work by resetting abnormal firing patterns in the
brain leading to a reduction in parkinsonian symptoms.
o The response from DBS is only as good as the patient's best on-time with the
exception of tremor, which may have greater improvement than with
medication; however, after DBS, the amount of daily on-time is significantly
extended.
o DBS requires regular follow-up to adjust stimulation parameters to account for
symptom changes due to disease progression and adverse effects.

Thalamic stimulation
o Thalamic stimulation involves implantation of a DBS lead in the VIM nucleus
of the thalamus.
o Thalamic stimulation provides significant control of PD tremor in
approximately 90% of patients but does not affect the other symptoms of PD
such as rigidity, bradykinesia, dyskinesia, or motor fluctuations.
o Studies of thalamic DBS have demonstrated good initial and long-term tremor
control up to 7 years after implantation; however, long-term studies have
shown a significant worsening in other parkinsonian symptoms such as
bradykinesia, rigidity, and worsening of gait leading to major disability.

o Candidates for thalamic DBS are patients with disabling medication-resistant


tremor who have minimal rigidity or bradykinesia. They should not have
significant cognitive impairment, mood or behavioral disturbances, or other
factors that may increase the risk of surgery.
o The role of thalamic DBS is limited in PD.

Pallidal stimulation
o Pallidal stimulation involves implantation of a DBS lead in the globus pallidus
interna (GPi).
o Pallidal stimulation controls all the cardinal symptoms of PD (tremor, rigidity,
bradykinesia) as well as dyskinesia.
o Several studies have reported significant improvements in tremor,
bradykinesia, rigidity, and dyskinesia after pallidal stimulation.
o Long-term studies up to 4 years after pallidal DBS have continued to show
significant improvements in the cardinal features of PD and dyskinesia
compared to presurgery.
o Candidates for pallidal DBS include levodopa-responsive patients with
medication-resistant disabling motor fluctuations and/or levodopa-induced
dyskinesia. Surgical candidates should not have significant cognitive
impairment or behavioral or mood problems.

Subthalamic stimulation
o Subthalamic stimulation is currently the most common surgical procedure for
PD and involves implantation of a DBS lead in the subthalamic nucleus
(STN).
o STN DBS controls all of the cardinal symptoms of PD as well as motor
fluctuations and dyskinesia. STN DBS also often results in significant
reductions in antiparkinsonian medications.
o On average, dyskinesia and antiparkinsonian medications are reduced by 5080%.
o Multiple studies have examined the effects of STN DBS and have shown
significant improvements in the motor symptoms of tremor, rigidity, and
bradykinesia as well as activities of daily living.
o Long-term follow-up reports have demonstrated that significant improvements
in motor function and activities of daily living are maintained for up to 5 years
after surgery.

o Candidates for STN DBS include levodopa-responsive patients with


medication-resistant disabling motor fluctuations and/or levodopa-induced
dyskinesia. Surgical candidates should not have significant cognitive
impairment or behavioral or mood problems.

Pallidal stimulation versus subthalamic stimulation


o No large controlled trials have been completed comparing STN and GPi
stimulation; however, a large well-designed study is currently underway.
o Several small uncontrolled studies have compared STN and GPi stimulation.
Most studies have shown greater improvement after STN DBS compared with
GPi DBS, and antiparkinsonian medications were reduced only after STN
DBS. Therefore, STN DBS is currently the surgical procedure of choice for
PD.

Complications of DBS
o Complications can be separated into surgical complications occurring within
30 days of the procedure; complications related to the components of the DBS
system; and complications from the stimulation, which generally can be
resolved by adjustments of the stimulation parameters.
o Surgical complications are comparable to those seen with other neurosurgical
procedures. Serious adverse events such hemorrhage, ischemic lesions,
seizures, or death occur in 1-2% of patients. Infection occurs in approximately
3-5% of patients and may require explantation of the device until the infection
is resolved.
o Misplacement of the lead may also occur in approximately 10% of patients
requiring additional surgery to correct lead placement.
o Device-related complications include malfunction of the IPG, displacement of
the lead, skin erosion, and device fractures. These complications can occur in
up to 25% of patients and generally require additional surgery.
o Stimulation side effects include paresthesia, muscle spasms, visual
disturbances, mood changes, and pain. These side effects are generally easily
resolved with adjustments to the stimulation parameters.
o Although not considered a complication, the IPG (battery) is generally
replaced every 3-5 years and requires additional outpatient surgery.

Transplantation
o Neural transplantation is a potential treatment for PD because the neuronal
degeneration is site and type specific (ie, dopaminergic), the target area is well
defined (ie, striatum), postsynaptic receptors are relatively intact, and the

neurons provide tonic stimulation of the receptors and appear to serve a


modulatory function.
o Multiple sources of dopamine-producing cells, including fetal nigral cells,
sympathetic ganglia, carotid body glomus cells, PC-12 cells, and
neuroblastoma cells, have been studied.
o Transplantation of autologous adrenal medullary cells and fetal porcine cells
were not found to be effective in double-blind studies and have been
abandoned.
o A double-blind study of GDNF demonstrated that it was not superior to
placebo in controlling the symptoms of PD and, therefore, due to the lack of
benefit and concerns regarding adverse events, clinical trials have been
discontinued.
o Double-blind studies demonstrated that transplanted fetal mesencephalic cells
can survive transplantation. However, these studies showed only minimal
benefit in measures of PD symptoms and often resulted in the development of
dyskinesia even in the absence of antiparkinsonian medications.
o Transplanted cultured human retinal pigment epithelial cells (RPE) are
currently being evaluated in double-blind studies as a treatment for PD.
o Several studies have recently been initiated to evaluate gene therapy as a
treatment for PD. The goal of these studies is to modify genes involved in the
development of PD.
o In the laboratory, the use of stem cells is being investigated.
Consultations:

Consider physical therapy, occupational therapy, and speech therapy consultations.

Consider neurosurgical consultation for patients with medically refractory tremor or


troublesome dyskinesia and/or motor fluctuations that cannot be controlled with
medication adjustments. Patients with dementia or significant psychiatric or
behavioral problems are not candidates for the current neurosurgical treatments for
PD.

MEDICATION

Section 7 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

The cornerstone of symptomatic treatment for PD is dopamine replacement therapy.

The criterion standard of symptomatic therapy is levodopa (L-dopa), the metabolic precursor
of dopamine, in combination with a peripheral decarboxylase inhibitor (PDI). This
combination provides the greatest symptomatic benefit with the fewest short-term adverse
effects.
Anticholinergic drugs can be used as an alternative to L-dopa for treating resting tremor.
However, they are not highly effective against bradykinesia, gait disturbance, or other
features of advanced parkinsonism.
Dopamine agonists (bromocriptine, pergolide, pramipexole, ropinirole) can be used as
monotherapy to improve symptoms in early disease or as adjuncts to levodopa in patients
whose response to L-dopa is deteriorating and those who are experiencing fluctuations in
their response to L-dopa.
MAO-B inhibitors provide symptomatic benefit as monotherapy in early disease and as
adjuncts to levodopa in patients experiencing motor fluctuations.
Rasagiline is a second-generation MAO-B inhibitor. Unlike selegiline, rasagiline does not
have amphetamine metabolites. It is effective as monotherapy in early PD and as an adjunct
to levodopa in patients with motor fluctuations. It is not yet approved by the FDA but is
available in some countries. Rasagiline has been studied at 0.5-2 mg/d. Recommended dose is
1 mg/d. Pending final review from the FDA.
COMT inhibitors increase the peripheral half-life of levodopa, thereby delivering more
levodopa to the brain over a longer time.

Drug Category: Dopamine prodrugs -- Dopamine does not cross the blood-brain barrier,
but levodopa does. L-dopa is decarboxylated to dopamine in the brain and in the periphery.
The formation of dopamine in the blood causes many of L-dopa's adverse effects.
When administered alone, levodopa induces a high incidence of nausea and vomiting. A PDI
such as carbidopa is combined with levodopa to reduce the incidence of nausea and vomiting
by inhibiting the peripheral conversion of levodopa to dopamine.
Levodopa/PDI is the criterion standard of symptomatic treatment for PD; it provides the
greatest antiparkinsonian efficacy in moderate to advanced disease with the fewest acute
adverse effects.
Drug Name

Levodopa/Carbidopa (Sinemet, Sinemet CR,


Parcopa) -- Large, neutral amino acid that is
absorbed in proximal small intestine by
saturable carrier-mediated transport system.
Absorption decreased by meals, which include
other large neutral amino acids. Only patients
with meaningful motor fluctuations must
consider a low-protein or protein-redistributed
diet. Greater consistency of absorption achieved
when levodopa taken 30 min or more before or
1 h or more after meals. Nausea often reduced if

L-dopa taken immediately following meals.


Some patients with nausea benefit from
additional carbidopa in doses up to 200 mg/d.
No maximal dose per se. Patients should receive
lowest dose that provides good control of
parkinsonian symptoms. If parkinsonian
disability present, dose should be escalated until
adequate control achieved or adverse effects
become intolerable. Some patients require 2000
mg or more per d.
Half-life of levodopa/carbidopa approximately
2.5 h.
CR formulation more slowly absorbed and
provides more sustained levodopa levels than
immediate release form. CR form as effective as
immediate release form when levodopa first
required and may be more convenient when
fewer intakes are required. Patients with
wearing-off motor fluctuations (and no
dyskinesia) often benefit from prolongation of
short duration response when switched from
immediate release to CR form. However,
patients with meaningful fluctuations and
dyskinesia often experience increase in
dyskinesia when switched to CR form. To
convert patient from immediate release to CR
form, increase daily dosage by approximately
20% while number of intakes reduced by 3050%.
Most patients controlled on levodopa dose of
300-600 mg for several years.

Adult Dose

Pediatric Dose

Immediate-release form: 25 mg carbidopa/100


mg levodopa one half tab PO qd; increase daily
dose by one half tab per wk to initial
maintenance dose of 25/100 mg tid; may
increase by 1 tab qd each wk until optimal
clinical response achieved
Parcopa form: 25 mg carbidopa/100 mg
levodopa or 25 mg carbidopa/250 mg levodopa;
dissolves in mouth, may take prn or scheduled if
swallowing tab is difficult or water not available
CR form: 1 tab PO qd; increase daily dose by 1
tab each wk to achieve initial maintenance dose
of 25/100 mg tid or 50/200 mg bid
Not established

Contraindications Documented hypersensitivity, narrow-angle


glaucoma
Malignant melanoma relative contraindication;
if meaningful parkinsonian disability present,

consider benefit/risk ratio


Interactions

Hydantoins, pyridoxine, phenothiazine, and


hypotensive agents may decrease effects of
levodopa; concurrent antacids or nonspecific
MAOIs increase levodopa toxicity

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Most common acute adverse effects are nausea,


hypotension, or hallucinations; long-term
adverse effects include motor fluctuations and
dyskinesia (chorea); for patients experiencing
motor fluctuations, dietary protein can be
distributed evenly throughout day or
redistributed to evening to minimize
fluctuations in levodopa absorption
Abrupt withdrawal of treatment may result in
neuroleptic malignant syndrome (NMS); use
cautiously in patients with history of MI,
arrhythmias, asthma, or peptic ulcer disease

Drug Category: Dopamine agonists -- Dopamine agonists directly stimulate postsynaptic


dopamine receptors to provide antiparkinsonian benefit. All available dopamine agonists
stimulate D2 receptors--an action that is thought to be clinically beneficial. The role of other
dopamine receptors is currently unclear.
Dopamine agonists are effective as monotherapy in early PD and as adjuncts to levodopa/PDI
in moderate to advanced disease. They provide antiparkinsonian efficacy approximately equal
to levodopa/PDI when symptomatic therapy is first required.
After 6 months to a few years, they are not as effective as levodopa/PDI. For patients with
motor fluctuations on levodopa/PDI, the addition of a dopamine agonist reduces off time,
improves motor function, and allows lower levodopa doses.
Dopamine agonists have been proven to reduce the development of motor fluctuations and
dyskinesias when used as an initial therapy and continued once levodopa is added.
Dopamine agonists may slow disease progression based on changes in PET scans, but the
evidence is not yet conclusive.

Drug Name

Apomorphine (Apokyn) -- Short-acting


dopamine agonist approved in the United States
for SC injection as a rescue agent to treat acute
immobility episodes (hypomobility or "offperiods") in PD. These episodes consist of
inability to rise from a chair, speak, or walk and
may occur toward the end of the dose interval or
may be spontaneous and unpredictable in onset.

Adult Dose

Pediatric Dose

Dosage is individualized
Test dose: 2 mg (0.2 mL) SC for 1 dose initially
during hypomobility, if tolerated (ie, blood
pressure remains stable), may use for
subsequent hypomobility episodes
Establishing dose: If patient tolerates test dose
and hypomobility responds, 2 mg is the dose to
use for subsequent hypomobility episodes
If patient tolerates test dose, but hypomobility
does not respond to test dose, may increase dose
by 1 mg (0.1 mL) q2-3 d until response is
observed; not to exceed 6 mg (0.6 mL)/dose
Note: Administer only 1 dose per hypomobility
episode, do not repeat dose; administer with
antiemetic drug
Not established

Contraindications

Documented hypersensitivity to apomorphine or


metabisulfite

Interactions

Coadministration with 5HT3 antagonists used


for emesis or irritable bowel syndrome (eg,
ondansetron, dolasetron, granisetron,
palonosetron, alosetron) may cause hypotension
and loss of consciousness; coadministration
with drugs that increase QTC interval (eg,
thioridazine, quinidine, sotalol, erythromycin,
dofetilide) may increase arrhythmia potential;
metabolized by catechol-o-methyltransferase
(COMT), coadministration with COMT
inhibitors (eg, entacapone, tolcapone) may
decrease elimination

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Causes severe nausea and vomiting and must be


administered with an antiemetic drug (but not
with antiemetic agents that are 5HT3
antagonists); may cause orthostatic hypotension,
faintness, hallucinations, fluid retention, chest
pain, increased sweating, flushing, pallor,
dyskinesia, rhinorrhea, and extreme drowsiness
(may fall asleep during waking hours without
warning)

Drug Name

Bromocriptine (Parlodel) -- Semisynthetic ergot


alkaloid derivative that is strong D2 receptor
agonist and weak D1 receptor antagonist. FDA
approved as adjunct to levodopa/carbidopa; less
effective than other dopamine agonists. May
relieve akinesia, rigidity, and tremor in PD.

Mechanism of therapeutic effect is direct


stimulation of dopamine receptors in corpus
striatum.
Approximately 28% absorbed from GI tract and
metabolized in liver. Elimination half-life
approximately 50 h with 85% excreted in feces
and 3-6% eliminated in urine.
Initiate at low dosage and individualize.
Increase daily dosage slowly until maximum
therapeutic response achieved. If possible,
maintain the dosage of levodopa during this
introductory period. Assess dosage titrations
q2wk to ensure that lowest dosage producing
optimal therapeutic response is not exceeded. If
adverse reactions mandate, reduce dose
gradually in 2.5-mg increments.

Adult Dose

Pediatric Dose
Contraindications

Interactions

1.25 mg (one half of a 2.5 mg tab) PO qd;


increase by 1.25 mg/d per wk to 1.25 mg tid
with meals; increase q2-4wk by 2.5 mg/d with
meals; usual range 10-40 mg/d divided tid/qid;
safety has not been demonstrated in dosages
that exceed 100 mg/d
Not established
Documented hypersensitivity, ischemic heart
disease, peripheral vascular disorders
Ergot alkaloids increase toxicity; amitriptyline,
butyrophenone, imipramine, methyldopa,
phenothiazine, and reserpine may decrease
effects

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Adverse effects include nausea, hypotension,


hallucinations, and somnolence; use cautiously
in patients with renal or hepatic disease

Drug Name

Pergolide (Permax) -- Potent dopamine receptor


agonist at both D1 and D2 receptor sites,
approximately 10 times more potent than
bromocriptine on a mg per mg basis. In PD,
pergolide believed to exert its therapeutic effect
by directly stimulating postsynaptic dopamine
receptors in striatum.
Usually administered in divided doses tid.

Adult Dose

0.05 mg PO qd days 1 and 2; gradually increase


by 0.1 or 0.15 mg/d q3d over next 12 d,
followed by incremental increases of 0.25 mg/d
q3d until optimal therapeutic dose achieved;
usual maximum dose 3-6 mg/d; usually

administered in divided doses tid


Pediatric Dose

Not established

Contraindications Documented hypersensitivity

Interactions

Concurrent use of pergolide and levodopa may


cause or exacerbate preexisting states of
confusion and hallucinations or dyskinesia
Dopamine antagonists such as neuroleptics (eg,
phenothiazine, butyrophenone, thioxanthenes,
metoclopramide) may diminish effectiveness of
pergolide; because pergolide mesylate is >90%
bound to plasma proteins, exercise caution in
coadministering with other drugs known to
affect protein binding

Pregnancy

B - Usually safe but benefits must outweigh the


risks.

Precautions

May cause valvular heart disease (yearly


echocardiograms recommended for patients on
chronic therapy); Inhibits secretion of prolactin;
causes transient rise in serum concentrations of
growth hormone and decrease in serum
concentrations of luteinizing hormone; adverse
effects include nausea, hypotension,
hallucinations, and somnolence; use caution in
patients who have been treated for cardiac
dysrhythmias.

Drug Name

Pramipexole (Mirapex) -- Nonergot dopamine


agonist with specificity for D2 dopamine
receptor. Also binds to D3 and D4 receptors.
Readily absorbed from GI tract with >90%
bioavailability, minimally metabolized in liver
with half-life of approximately 8-12 h.
Primarily excreted in urine; for patients with
CrCl 35-60 mL/min, administer bid (max 1.5
mg bid); for CrCl 15-35 mL/min, administer qd
(not to exceed 1.5 mg/d).
FDA approved as monotherapy in early disease
and as adjunct to levodopa/PDI in more
advanced stages.

Adult Dose

Week 1: 0.125 mg PO tid; week 2: 0.25 mg tid;


week 3: 0.5 mg tid; continue escalating by 0.25
mg tid each week as clinically appropriate;
usual range 1.54.5 mg/d

Pediatric Dose

Not established

Contraindications Documented hypersensitivity


Interactions

Cimetidine may increase toxicity; increases


levels of levodopa if given concurrently

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Adverse effects include nausea, hallucinations,


and somnolence; somnolence may emerge even
after administration at stable dose for many
months; some patients experience relatively
sudden waves of irresistible sleepiness; patients
should be warned not to drive if experiencing
drowsiness; somnolence usually resolves with
dose reduction or discontinuation; use caution
in patients with renal insufficiency and
preexisting dyskinesias

Drug Name

Ropinirole (Requip) -- Nonergot dopamine


agonist that has high relative in vitro specificity
and full intrinsic activity at D2 subfamily of
dopamine receptors; binds with higher affinity
to D3 than to D2 or D4 receptor subtypes. Has
moderate affinity for opioid receptors, and its
metabolites have negligible affinity for
dopamine D1, 5HT 1, 5HT 2, benzodiazepine,
GABA, muscarinic, alpha 1-, alpha 2- and betaadrenoreceptors. Mechanism of action is
stimulation of dopamine receptors in striatum.
Discontinue gradually over 7-d period.
Decrease frequency of administration from tid
to bid for 4 d. For remaining 3 d, decrease
frequency to qd prior to complete withdrawal.
When administered as adjunct to levodopa,
concurrent dose of levodopa may be decreased
gradually as tolerated. FDA approved as
monotherapy in early disease and as adjunct to
levodopa/PDI in more advanced disease.
Readily absorbed from GI tract with 55%
bioavailability and metabolized to inactive
metabolites in liver by CYP1A2. Half-life
approximately 6 h with inactive metabolites
primarily excreted in urine.

Adult Dose

Week 1: 0.25 mg PO tid; week 2: 0.5 mg tid;


week 3: 0.75 mg tid; after week 4, if necessary,
increase by 1.5 mg/d on a weekly basis up to 9
mg/d, and then by 3 mg/d weekly to total dose
as high as 24 mg/d

Contraindications Documented hypersensitivity


Interactions

Estrogens may reduce clearance by 36% (adjust


ropinirole dose if estrogen therapy stopped or
started during treatment); substrates or
inhibitors of CYP1A2 (eg, quinolone
antibiotics, erythromycin, cimetidine, diltiazem,

fluvoxamine, mexiletine, tacrine) may alter


clearance (adjust ropinirole dose if therapy with
potent CYP1A2 inhibitor stopped or started
during treatment); dopamine antagonists (eg,
phenothiazines, butyrophenones, thioxanthenes,
metoclopramide, neuroleptics) may diminish
effectiveness; CNS depressants may have
additive sedative effects
Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Adverse effects include nausea, hypotension,


hallucinations, and somnolence; patients should
be warned not to drive if experiencing
drowsiness; somnolence usually resolves with
dose reduction or discontinuation
Dopamine receptor agonists may potentiate
dopaminergic effects of levodopa and may
cause or exacerbate preexisting dyskinesia;
decreasing dose of levodopa may ameliorate
this effect
Cases of retroperitoneal fibrosis, pulmonary
infiltrates, pleural effusion, and pleural
thickening have been reported; these
complications do not always resolve completely
upon drug cessation
Use caution in patients taking CNS depressants;
monitor for signs and symptoms of orthostatic
hypotension
Cases of rhabdomyolysis have been reported

Drug Category: Catechol-O-methyltransferase (COMT) inhibitors -- These agents


inhibit the peripheral metabolism of levodopa, making more levodopa available for transport
across the blood-brain barrier over a longer time. For patients with motor fluctuations on
levodopa/carbidopa, the addition of a COMT inhibitor decreases off time, improves motor
function, and allows lower levodopa doses. Patients who already have dyskinesia on
levodopa/PDI are likely to experience a worsening of dyskinesia, thereby necessitating a
levodopa dose reduction. In such patients, consider reducing levodopa dose at the time of
introduction, especially with tolcapone.
Drug Name

Tolcapone (Tasmar) -- Adjunct to


levodopa/carbidopa therapy in PD. Mechanism
related to its ability to inhibit COMT and alter
plasma pharmacokinetics of levodopa. When
tolcapone given in conjunction with levodopa
and an aromatic amino acid decarboxylase
inhibitor (eg, carbidopa), plasma levels of
levodopa are more sustained than after
administration of levodopa and an aromatic

amino acid decarboxylase inhibitor alone. These


sustained plasma levels of levodopa may result
in more constant dopaminergic stimulation in
brain, possibly leading to greater effects on
signs and symptoms of PD as well as increased
adverse effects of levodopa (which sometimes
require levodopa dose decrease). Enters CNS to
a minimal extent but has been shown to inhibit
central COMT activity in animals. FDA
approved as adjunct to levodopa/carbidopa for
patients who are experiencing motor
fluctuations.
Because of risk of hepatotoxicity, it is reserved
for patients who have not responded adequately
to or are not appropriate candidates for other
adjunctive medications. Patients should sign
informed consent; strict liver function test
monitoring required. If improvement not
apparent within 3 wk, medication should be
withdrawn. Bioavailability following PO
administration about 65%; extensively
metabolized before excretion. Main metabolic
pathway is glucuronidation. Half-life is
approximately 2-3 h with 60% of metabolites
excreted in urine and 40% in feces.
Patients with levodopa-induced dyskinesia often
experience increase in dyskinesia, necessitating
25-50% reduction in levodopa dose.
Alternatively, levodopa dose can be reduced by
25-50% when tolcapone introduced, then
titrated as clinically indicated.
Adult Dose

100 mg PO tid; may increase to 200 mg tid only


if anticipated incremental clinical benefit
justifies possible risk of hepatotoxicity

Documented hypersensitivity, liver disease,


ALT/AST levels 2 times >reference range or
Contraindications
higher, patients withdrawn from tolcapone
because of induced hepatotoxicity
Interactions

Because of its affinity to cytochrome P450 2C9


in vitro, may interfere with drugs such as
tolbutamide and warfarin; may influence
pharmacokinetics of drugs metabolized by
COMT; when administered with
levodopa/carbidopa, increases relative
bioavailability (AUC) of levodopa by
approximately 2-fold; patients should not be
treated ordinarily with combination of tolcapone
and MAO-A or nonspecific MAO inhibitor; can
be taken concomitantly with selective MAO-B

inhibitor
Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Liver function tests required at baseline, q2wk


for first 6 mo and then prn; discontinue
tolcapone if ALT/AST levels are > 2X ULN; in
controlled trials, elevations usually occurred
within 6 wk to 6 mo of starting treatment;
periodic monitoring of liver enzymes may not
prevent fulminant liver failure
Diarrhea occurs in 16-18% of patients and is
severe enough to necessitate medication
withdrawal in 3-4%; typically begins 6-12 wk
after therapy, but may occur as early as 2 wk or
as late as many mo
Use caution in patients with troublesome
dyskinesia and in those with dementia or
hallucinations

Drug Name

Entacapone (Comtan) -- Adjunct to


levodopa/carbidopa therapy to treat the signs
and symptoms of wearing off.
Mechanism related to its ability to inhibit
COMT and alter plasma pharmacokinetics of
levodopa. When given in conjunction with
levodopa and an aromatic amino acid
decarboxylase inhibitor (eg, carbidopa), plasma
levels of levodopa are more sustained than after
administration of levodopa and an aromatic
amino acid decarboxylase inhibitor alone. These
sustained plasma levels of levodopa may result
in more constant dopaminergic stimulation in
brain. This may lead to greater effects on signs
and symptoms of PD, as well as increased
levodopa adverse effects (which sometimes
require levodopa dose decrease). FDA approved
as adjunct to levodopa/carbidopa for patients
who are experiencing motor fluctuations.
Bioavailability following PO administration
about 35%; extensively metabolized before
excretion. Main metabolic pathway is
glucuronidation and half-life approximately 0.40.7 h with 10% of metabolites excreted in urine
and 90% in feces.

Adult Dose

200 mg PO with each levodopa/carbidopa


intake; not to exceed 8 times daily (1600 mg/d)

Contraindications Documented hypersensitivity


Interactions

When administered with levodopa/carbidopa,

increases relative bioavailability (AUC) of


levodopa by approximately 35%; patients
should not be treated ordinarily with
combination of entacapone and MAO-A or
nonspecific MAO inhibitor; can be taken
concomitantly with selective MAO-B
inhibitors; drugs known to be metabolized by
COMT (eg, isoproterenol, epinephrine,
norepinephrine, dopamine, dobutamine, alphamethyldopa, apomorphine, isoetharine,
bitolterol) should be administered with caution
regardless of route of administration
Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Diarrhea occurs in approximately 10% of


patients, typically within 4-12 wk after starting
treatment; usually mild to moderate in severity,
and generally resolves with discontinuation of
entacapone; advise patients that entacapone may
cause a brownish-orange discoloration of urine
in approximately 10% of patients that is not
clinically relevant

Drug Name

Levodopa, carbidopa, and entacapone (Stalevo)


-- Levodopa, carbidopa, and entacapone
combination for treating PD. Carbidopa inhibits
dopa decarboxylation; thus, allows more
complete levodopa distribution to the CNS.
Levodopa is a dopamine precursor capable of
crossing the blood-brain barrier (BBB), thereby
increases CNS dopamine following conversion.
Entacapone inhibits catechol-Omethyltransferase (COMT), another enzyme
that metabolizes levodopa. COMT inhibition
increases and sustains levodopa plasma levels
enabling more BBB penetration.
Used as a substitute for patients stabilized on
equivalent doses of carbidopa/levodopa
(Sinemet) and entacapone (Comtan), or those
stabilized on carbidopa/levodopa and initiating
entacapone.
Available as tab, each contains entacapone 200
mg with immediate-release carbidopa-levodopa
1:4 ratio (ie, 12.5 mg/50 mg, 25 mg/100 mg,
37.5 mg/150 mg).

Adult Dose

Optimum dose must be carefully titrated; not to


exceed 8 tab/24 h (ie, entacapone 1600 mg/24
h)

Contraindications Documented hypersensitivity; narrow-angle

glaucoma; malignant melanoma; undiagnosed


skin lesions

Interactions

Levodopa/carbidopa: Hydantoins, pyridoxine,


phenothiazine, and hypotensive agents may
decrease effects of levodopa; levodopa toxicity
increases with antacids and MAO inhibitors
Entacapone: When administered with
levodopa/carbidopa, increases relative levodopa
bioavailability (AUC) by approximately 35%;
do not administer with MAO-A or nonspecific
MAO inhibitor (may cause hypertensive crisis);
can be taken concomitantly with selective
MAO-B inhibitor (eg, selegiline); other drugs
metabolized by COMT (eg, isoproterenol,
epinephrine, norepinephrine, dopamine,
dobutamine, methyldopa, apomorphine,
isoetharine, bitolterol) should be administered
with caution regardless of administration route

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Levodopa/carbidopa: Certain adverse CNS


effects (eg, dyskinesias) may occur at lower
dosages and earlier in therapy with SR form;
caution in patients with history of myocardial
infarction, arrhythmias, asthma, and peptic ulcer
disease; sudden discontinuation of levodopa
may cause worsening of PD; high protein diets
should be distributed throughout the day to
avoid fluctuations in levodopa absorption
Entacapone: May cause diarrhea within 4-12 wk
after starting treatment in 10% of patients
(severity typically mild to moderate and
generally resolves when drug discontinued);
may cause urine discoloration (brownish
orange) in approximately 10% of patients that is
not clinically relevant; abrupt withdrawal may
aggravate PD symptoms; hepatic impairment
may require dose reduction; monitor for
enhanced dopaminergic effect (eg, hypotension,
syncope, hallucinations, dyskinesia)

Drug Category: Anticholinergics -- These agents provide benefit for tremor in


approximately 50% of patients but do not improve bradykinesia or rigidity. If one
anticholinergic does not work, try another.
Drug Name

Trihexyphenidyl (Artane, Trihexy) -- Synthetic


tertiary amine anticholinergic agent, reduces
incidence and severity (by 20%) of akinesia,

rigidity, and tremor and secondary symptoms


such as drooling. In addition to suppressing
central cholinergic activity, also may inhibit
reuptake and storage of dopamine at central
dopamine receptors, thereby prolonging action
of dopamine.

Adult Dose

1-2 mg/d PO; increase by 2 mg/d at intervals of


3-5 d; usual range 4-15 mg/d divided tid/qid;
young adults may tolerate 15-20 mg/d divided
tid/qid; older individuals may tolerate no more
than 4-8 mg/d

Documented hypersensitivity; glaucoma,


particularly angle-closure glaucoma; pyloric or
duodenal obstruction, stenosing peptic ulcers;
Contraindications
prostatic hypertrophy or bladder neck
obstructions; achalasia (megaesophagus);
myasthenia gravis; megacolon
Interactions

Decreases effects of levodopa; increases effects


of narcotic analgesics, phenothiazines, tricyclic
antidepressants, quinidine, and anticholinergics

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Adverse effects include dry mouth and dry eyes,


memory difficulty, confusion, and rarely urinary
retention; use caution in patients with
tachycardia, cardiac arrhythmias, hypertension,
hypotension, prostatic hypertrophy (particularly
in elderly), or any tendency toward urinary
retention, liver or kidney disorders, or
obstructive disease of GI or GU tract; when
used to treat extrapyramidal reactions that result
from phenothiazines in psychiatric patients,
antiparkinson agents may exacerbate mental
symptoms and precipitate toxic psychosis

Drug Name

Benztropine mesylate (Cogentin) -- Partially


blocks striatal cholinergic receptors to help
balance cholinergic and dopaminergic activity.

Adult Dose

0.5-6 mg/d PO qd or divided bid; start elderly


patients at lower dose; titrate in 0.5-mg
increments at 5- to 6-d intervals; not to exceed 6
mg/d

Documented hypersensitivity; glaucoma,


particularly angle-closure glaucoma; pyloric or
duodenal obstruction, stenosing peptic ulcers;
Contraindications
prostatic hypertrophy or bladder neck
obstructions; achalasia (megaesophagus);
myasthenia gravis; megacolon

Interactions

Decreases effects of levodopa; increases effects


of narcotic analgesics, phenothiazines, tricyclic
antidepressants, quinidine, and anticholinergics

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Adverse effects include dry mouth and dry eyes,


memory difficulty, confusion, and rarely urinary
retention; use cautiously in patients with
tachycardia, cardiac arrhythmias, hypertension,
hypotension, prostatic hypertrophy (particularly
in elderly); or any tendency toward urinary
retention, liver or kidney disorders, or
obstructive disease of GI or GU tract; when
used to treat extrapyramidal reactions that result
from phenothiazines in psychiatric patients,
antiparkinson agents may exacerbate mental
symptoms and precipitate toxic psychosis

Drug Category: MAO-B inhibitors -- These agents inhibit the activity of MAO-B
oxidases that are responsible for inactivating dopamine and possibly the conversion of
compounds into neurotoxic types.
Drug Name

Selegiline (Eldepryl) -- An irreversible inhibitor


of MAO, it acts as a "suicide" substrate for
enzyme; MAO converts it to an active moiety
which combines irreversibly with active site or
enzyme's essential FAD cofactor. Blocks
breakdown of dopamine and extends duration of
action of each dose of L-dopa. Often allows Ldopa dose reduction that is needed for optimal
effect. Because selegiline has greater affinity for
type B than for type A active sites, it can serve
as selective inhibitor of MAO type B at
recommended dose. However, doses higher than
10 mg/d may inhibit MAO-A sites significantly.
Its metabolites, amphetamine and
methamphetamine, may inhibit dopamine
reuptake and enhance dopamine release.
FDA approved as adjunct to levodopa/carbidopa
in patients who exhibit deterioration in response
to that therapy. For patients who are
experiencing motor fluctuations on
levodopa/carbidopa, addition of selegiline
reduces off time, improves motor function, and
allows levodopa dose reductions. If patient
experiences increase in troublesome dyskinesia,
reduce levodopa dose.
Rapidly absorbed and has 73% bioavailability.

Metabolized in liver to N-desmethylselegiline,


L-amphetamine, and L-methamphetamine.
Half-life approximately 10 h; metabolites
excreted in urine.
Because inhibition of MAO-B is irreversible,
loss of activity is function of new protein
synthesis and may last several months. No
evidence of additional benefit from doses >10
mg/d.
After 2-3 days of treatment, attempt to reduce
dose of levodopa/carbidopa. Reduction of 1030% appears typical. Further reductions of
levodopa/carbidopa may be possible during
continued selegiline therapy.
Adult Dose

5 mg PO bid with breakfast and lunch; not to


exceed 10 mg/d

Documented hypersensitivity; concomitant


meperidine or other opioids; concomitant
Contraindications
tricyclic or serotonin reuptake inhibitor
antidepressants (relative contraindication)

Interactions

Concurrent meperidine may cause stupor,


muscular rigidity, severe agitation, and elevated
temperature; concurrent tricyclic or serotonin
reuptake inhibitor antidepressant may cause
severe toxicity; one case of hypertensive crisis
in a patient taking selegiline and ephedrine has
been reported

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Risks associated with dose >10 mg/d are


associated with nonselective inhibition of
MAO; concurrent tyramine-containing foods
and other indirect-acting sympathomimetics
may cause hypertensive crisis

Drug Name

Rasagiline (Azilect) -- Irreversible MAO-B


inhibitor that blocks dopamine degradation. Not
metabolized to amphetamine derivatives. Main
metabolite, aminoindan, has some activity and
has been shown to improve motor and cognitive
functions in experimental models. Indicated for
Parkinson disease as initial monotherapy or as
adjunctive therapy with levodopa.

Adult Dose

Monotherapy: 1 mg PO qd
Adjunctive therapy with levodopa: 0.5 mg PO
qd; may increase to 1 mg PO qd
Mild hepatic impairment or coadministration
with CYP1A2 inhibitors: 0.5 mg PO qd

Documented hypersensitivity; moderate-tosevere hepatic impairment (Child-Pugh score


>6); concurrent use with meperidine, tramadol,
methadone, propoxyphene; dextromethorphan,
Contraindications St. John's wort, mirtazapine, cyclobenzaprine,
sympathomimetic amines (eg, pseudoephedrine,
cocaine, ephedrine), other MAOIs, or local
anesthetics containing epinephrine;
pheochromocytoma

Interactions

P450 CYP1A2 substrate; coadministration with


drugs that inhibit CYP1A2 (eg, cimetidine,
clarithromycin, erythromycin) may decrease
elimination and increase toxicity;
coadministration with TCAs, SSRIs, serotoninnorepinephrine reuptake inhibitors (SNRIs),
nonselective MAOIs, or selective MAO-B
inhibitors has caused severe CNS toxicity
associated with hyperpyrexia and death;
consuming tyramine-rich foods (eg, cheese, red
wine, beer, sausage, avocado) may cause
hypertensive crisis; also see Contraindications

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

May cause dyskinesias, hallucinations, or


hypotension; if emergent surgery is necessary,
benzodiazepines, mivacurium, rapacuronium,
fentanyl, morphine, or codeine may be used
cautiously; melanoma may develop more
frequently in those taking rasagiline than in
matched controls

Drug Category: N-methyl-D-aspartic acid (NMDA) receptor inhibitors -- Increases


dopaminergic activity in peripheral and central nervous system by augmenting dopamine
release and inhibiting cellular reuptake.
Drug Name

Amantadine (Symmetrel) -- Inhibits the Nmethyl-D-aspartic acid (NMDA) receptormediated stimulation of acetylcholine release in
rat striatum. May also enhance dopamine
release, inhibit dopamine reuptake, stimulate
postsynaptic dopamine receptors, or enhance
dopamine receptor sensitivity. Efficacy as
monotherapy and as adjunct to levodopa/PDI in
treating PD. Provides some benefit for tremor,
rigidity, and bradykinesia.
Readily and almost completely absorbed from
GI tract; is not metabolized. Half-life
approximately 9-37 h and prolonged in renal

insufficiency. Excreted 90% unchanged in


urine.
Adult Dose

100 mg PO in am; increase by 100 mg/d each


wk prn; not to exceed 100 mg qid

Contraindications Documented hypersensitivity

Interactions

Drugs with anticholinergic or CNS stimulant


activity increase toxicity; concurrent
hydrochlorothiazide plus triamterene may
decrease urinary excretion of amantadine with
subsequent increased plasma concentrations

Pregnancy

C - Safety for use during pregnancy has not


been established.

Precautions

Common adverse effects are confusion and


hallucinations; use caution in patients with liver
disease, history of recurrent and eczematoid
dermatitis, uncontrolled psychosis, seizures, and
in those receiving CNS stimulant drugs; reduce
dose in renal disease when treating PD; do not
discontinue medication abruptly

FOLLOW-UP

Section 8 of 11

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Patient Education:

For excellent patient education resources, visit eMedicine's Dementia Center. Also,
see eMedicine's patient education articles Parkinson Disease and Parkinson Disease
Dementia.