Emedicine Parkinsons Diseasae

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Parkinson DiseaseRobert A Hauser, MD, MBA, Professor of Neurology, Molecular Pharmacology and Physiology, Director, Parkinson's Disease andMovement Disorders Center, University of South Florida; Clinical Chair, Signature Interdisciplinary Program in Neuroscience

Rajesh Pahwa, MD, Professor of Neurology, Director, Parkinson Disease and Movement Disorder Center, Department of Neurology,University of Kansas Medical Center; Kelly E Lyons, PhD, Research Associate Professor of Neurology, Director of Research andEducation, Parkinson's Disease and Movement Disorder Center, University of Kansas Medical Center; Theresa McClain, MSN,ARNP, Parkinson's Disease and Movement Disorders Center, University of South Florida

Updated: Apr 27, 2010

Introduction

Background

Parkinson disease (Parkinson's 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.

Parkinson disease is recognized as one of the most common neurological disorders, affecting approximately 1% o

individuals older than 60 years. Cardinal features include resting tremor, rigidity, bradykinesia, and postural instability.

Pathophysiology

The major neuropathologic findings in Parkinson disease 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 lateralsubstantia nigra. Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease

emerge.

Lewy bodies are concentric, eosinophilic, cytoplasmic inclusions with peripheral halos and dense cores. The presence o

Lewy bodies within pigmented neurons of the substantia nigra is characteristic, but not pathognomonic, of idiopathic

Parkinson disease. 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 Parkinson disease, 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. Incidenta

Lewy bodies have been hypothesized to represent the presymptomatic phase of Parkinson disease.

No standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as the specificity and sensitivity of thecharacteristic findings have not been established clearly. Individuals presenting with primary dementia may exhibi

neuropathologic features indistinguishable from those of 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.

Stages in the development of Parkinson disease-related pathology. Adapted from Braak H, Ghebremedhin E, Rub

U, Bratzke H, Del Tredici K. Cell Tissue Res. 2004 Oct;318(1):121-34.


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Recent studies demonstrate that Lewy-body pathology in Parkinson disease actually begins in the olfactory bulb and

lower brainstem (see image above or Media file 4). [1 ]These early stages are associated with premotor symptoms such as

loss of sense of smell and rapid eye movement (REM) sleep behavior disorder (RBD). [2 ]The pathology ascends up the

brainstem to later involve the midbrain and nigrostriatal dopaminergic neurons. This stage correlates with onset of the

motor phase of the disease and patients may exhibit bradykinesia, rigidity, and tremor. The pathology continues to

ascend late in the disease to affect the cortex and patients may then exhibit cognitive dysfunction and dementia.

Motor circuit in Parkinson disease

The basal ganglia motor circuit modulates cortical output necessary for normal movement (see following image or Mediafile 1).

Schematic representation of the basal ganglia - thalamocortical motor circuit and its neurotransmitters in the

normal state. From Vitek J. Stereotaxic surgery and deep brain stimulation for Parkinson's disease and

movement disorders. In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New

York: McGraw-Hill, 1997:240. Used with kind permission. Copyright, McGraw-Hill Companies, Inc.


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Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical 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 theGPe.

Dopamine is released from nigrostriatal (SNc) neurons to activate the direct pathway and inhibit the indirect pathway. In

Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr (see following

image or Media file 2).

Schematic representation of the basal ganglia - thalamocortical motor circuit and the relative

change in neuronal activity in Parkinson disease. From Vitek J. Stereotaxic surgery and deep brain

stimulation for Parkinson's disease and movement disorders. In: Watts RL, Koller WC, eds

Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:241. Used

with kind permission. Copyright, McGraw-Hill Companies, Inc.


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This increased inhibition of the thalamocortical pathway suppresses movement. Via the direct pathway, decreased striata

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

International

The incidence has been estimated to be 4.5-21 cases per 100,000 population per year. Estimates of Parkinson disease

prevalence range from 18-328 per 100,000 population, with most studies yielding a prevalence of approximately 120 per

100,000.

Sex

Parkinson disease is about 1.5 times more common in men than in women.

Age

The incidence and prevalence of Parkinson disease increase with age. The average age of onset is approximately 60

years. Onset in persons younger than 40 years is relatively uncommon.

Clinical

History

Parkinson disease may have a long premotor phase. Mid-life risk factors for the later development of Parkinson

disease include constipation and daytime sleepiness. These may well be the first clinical manifestations of the

disease but are nonspecific. Additional features that commonly precede onset of motor signs include decreased

sense of smell and REM behavior disorder (RBD).

o REM behavior disorder is a sleep disorder in which there is a loss of normal atonia during REM sleep.

o Patients are observed by their bed partners to act out their dreams and the partners may note kicking

hitting, talking, or crying out.

o In one study, 38% of 50-year-old men with REM behavior disorder and no neurologic signs went on to

develop Parkinsonism.[3 ]

o REM behavior disorder is common throughout the course of Parkinson disease.

o Postuma et al found that the subsequent development of Parkinson disease in patients with idiopathic

REM sleep behavior disorder (RBD) could be predicted on the basis of polysomnography results. In a

longitudinally studied cohort of patients with idiopathic RBD who were initially free of neurodegenerative

disease, those who developed Parkinson disease had increased tonic chin electromyographic activity

during REM sleep at baseline compared with those who remained disease-free (62.7 +/- 6% vs 41 +/

6%, p =0.02). The interval between polysomnography and disease onset was 6.7 years.[4 ]

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. 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 years, the tremor may affect

the extremities on the other side, but asymmetry is usually maintained. Parkinson disease tremor may alsoinvolve the lower extremities, tongue, lips, or chin.

The initial symptoms of Parkinson disease 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, sexua

dysfunction, and seborrheic dermatitis.


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Sleep disturbances are common.

The best clinical predictors of a pathology diagnosis of Parkinson disease are the following:

o Asymmetry

o Presence of resting tremor

o Good response to dopamine replacement therapy

Long-term disability in Parkinson disease is usually related to dementia and balance dysfunction.

Physical

The 3 cardinal signs of Parkinson disease are resting tremor, rigidity, and bradykinesia. Of these cardinal features, 2 of 3

are required to make the clinical diagnosis. Postural instability (balance dysfunction) is the fourth cardinal sign, but i

emerges late in the disease, usually after 8 years or more.

The characteristic Parkinson disease 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 present with tremors no

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 is also 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 Parkinson disease 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 Parkinson disease and

marked by the presence of cortical Lewy bodies. See Parkinson Disease Dementia for more information.

Causes

Most cases of idiopathic Parkinson disease 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 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.

Several individuals have been identified who developed parkinsonism after self-injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).[5 ]

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 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.


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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.

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 hydroxy

radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage. In

Parkinson disease, 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 dono

electrons, thereby promoting the formation of free radicals.

o Indices of lipid peroxidation are increased in Parkinson disease.

o Thus, Parkinson disease 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

there is no clear evidence that levodopa accelerates disease progression.

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 Parkinson disease 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 Parkinson disease sparked further interest in the

genetics of the disease.

o One large family with highly penetrant, autosomal-dominant, autopsy-proven Parkinson disease

originated in the town of Contursi in the Salerno province of southern Italy. Of 592 family members, 50

were affected by Parkinson disease. 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 asubstitution 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 differen

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

Parkinson disease. 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 Parkinson disease.

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

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 alpha-synuclein into a

structure that could aggregate into sheets.

o All Parkinson disease may be associated with abnormal folding of alpha-synuclein, leading to excessive

aggregation and neuronal death.

o Although sporadic Parkinson disease is not caused by a mutation in the alpha-synuclein gene, active

investigation is underway into proteins that interact with alpha-synuclein, including those that guide

promote, or prevent aggregation of the protein.

o As Parkinson disease, 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 Parkinson disease is caused by abnormalities of the proteosome system

which is responsible for clearing abnormal proteins.


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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 Parkinson disease in that no Lewy bodies are found in the substantia nigra.

Several other gene abnormalities have been identified in families with Parkinson disease and these are

designated PARK3 -PARK12.

It has been estimated that all currently known genetic causes of Parkinson disease account for less than 5% of

Parkinson disease cases.

Differential Diagnoses

Alzheimer Disease Normal Pressure Hydrocephalus

Cardioembolic Stroke Parkinson-Plus Syndromes

Cortical Basal Ganglionic Degeneration Progressive Supranuclear Palsy

Essential Tremor Striatonigral Degeneration

Hallervorden-Spatz Disease

Lacunar Syndromes

Multiple System Atrophy

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) o

deplete intraneuronal dopamine stores (eg, reserpine, tetrabenazine).

Workup

Laboratory Studies

No laboratory biomarkers exist for Parkinson disease.

Serum ceruloplasmin concentration is obtained as a screening test for Wilson disease. It should be obtained inpatients 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 Parkinson

disease.

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 o

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 o

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, patients with Parkinson disease show 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 18F-dopa into dopamine neurons and its

decarboxylation to 18F-dopamine.


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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.

o Deficits on fluorodopa PET or -CIT SPECT indicate a dopamine deficiency syndrome but do no

necessarily differentiate Parkinson disease from atypical parkinsonisms including multiple system

atrophy and progressive supranuclear palsy.

Treatment

Medical Care

The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long aspossible while minimizing adverse effects. Medications usually provide good symptomatic control of motor signs 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 postura

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 Parkinson disease.

If a neuroprotective therapy were available for Parkinson disease, it would be administered from the time of diagnosis

onward.

Selegiline

o Selegiline is the medication that first has garnered wide interest as a possible neuroprotective agent.

o Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect fo

dopamine neurons independent of MAO-B inhibition.

o Selegiline has been demonstrated to protect cultured dopamine neurons from MPP+ toxicity, an effec

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 DATATOP (deprenyl [selegiline] and tocopherol [vitamin E] antioxidative

therapy of parkinsonism), the Parkinson Study Group evaluated the ability of these 2 medications to

delay progression of clinical disability in early Parkinson disease. 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


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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 In a more recent study, patients with early Parkinson disease were randomized to selegiline or placebo

and levodopa was added as needed. Over 7 years, patients receiving selegiline experienced less clinica

progression and required less levodopa than patients receiving placebo.[7 ]

Rasagilineo Rasagiline is a MAO-B inhibitor that exhibits neuroprotective effects in cell culture and animal models. In

a clinical trial of patients with early Parkinson disease (TEMPO), treatment with rasagiline for 1 year

provided significantly greater improvement than treatment with placebo for 6 months followed by

rasagiline for 6 months. [8 ]When patients were followed long term (5.5-6 y), those who started rasagiline

at the beginning of the study experienced 16% less progression of disability than those who started i

after 6 months.[9 ]

o ADAGIO was a large and rigorous delayed-start study of rasagiline. Patients with early disease were

randomized to active drug (1 or 2 mg) or placebo for 9 months and then all patients went on active drug

for 9 months. Results showed that patients who received rasagiline 1 mg/d from the start of the trial had

less progression of clinical disability than subjects who received rasagiline 1 mg/d after a delay of 9

months.[10 ]

o A study by Olanow et al of 1176 patients with untreated Parkinson disease showed early treatment with

rasagiline provided benefits potentially consistent with disease-modifying effects. The outcome was

positive for rasagiline 1 mg/d but not 2 mg/d, although a subanalysis evaluating the most affected

quartile at baseline was positive for both 1 mg/d and 2 mg/d. The reason behind the discrepancy in

outcome between the 2 doses is not known.[11 ]

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 Parkinson disease disability.[12 ]

Further studies of rasagiline and co-enzyme Q10 are required.

Symptomatic therapy

Levodopa, coupled with a peripheral decarboxylase inhibitor (PDI), remains the standard of symptomatictreatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects

in the short term. However, its chronic use is associated with the development of fluctuations and dyskinesias.

Dopamine agonists provide symptomatic benefit comparable to levodopa/PDI in early disease but lack sufficient

efficacy to control signs and symptoms by themselves in more advanced disease.

Dopamine agonists cause more sleepiness, hallucinations, edema, and impulse control disorders than levodopa.

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.

Subsequent analyses of these studies indicate that the benefit of dopamine agonists in delaying moto

complications is due to their ability to delay the need for levodopa/PDI.[13,14 ]

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(


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The Continuous Dopaminergic Stimulation (CDS) hypothesis posits that pulsatile dopamine receptor stimulation

induces dyskinesia, whereas smoother more continuous dopamine receptor stimulation causes less dyskinesia.

In contrast to levodopa, the long-acting dopamine agonists (ie, bromocriptine, 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.

Dopamine agonists alone (without concurrent treatment with levodopa/PDI) rarely cause fluctuations o

dyskinesia.

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.

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 o

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

Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is not instituted at or shortly

after diagnosis.[15 ]

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.

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.

MAO-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-

term outcomes. These characteristics make MAO-B inhibitors a good choice as initial treatment for many

patients. When the MAO-B inhibitor alone is not sufficient to provide good control of motor symptoms, another

medication (eg, dopamine agonist or levodopa) is added.

Levodopa is the most efficacious symptomatic medication with few short-term side effects, but its chronic use is

associated with the development of fluctuations and dyskinesias. Once fluctuations and dyskinesias become

problematic, they are difficult to resolve.

Dopamine agonists provide moderate symptomatic benefit and rarely cause fluctuations and dyskinesias by

themselves, but they have more side effects than levodopa, including sleepiness and impulse control disordersHowever, these side effects resolve upon lowering the dose or discontinuing the medication.

Dopamine agonists and levodopa are started at a low dose, escalated slowly, and titrated to control symptoms.

For patients younger than 65 years, the authors often use a dopamine agonist and then add levodopa/PDI when

the dopamine agonist (with or without an MAO-B inhibitor) no longer provides good control of motor symptoms.

Dopamine agonists may provide good symptom control for several years.

For patients who are demented or older than 70 years (those who may be prone to adverse effects, such as

hallucinations, 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.

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 treat with a dopamine agonis

prior to levodopa and add levodopa/PDI when necessary. 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, somnolence, and impulse control disorders. Nausea usually can be reduced by having the patien

take the medication after meals. Domperidone, a peripheral dopamine agonist available outside the US, is very

helpful in relieving refractory nausea. Patients on dopamine agonists should be routinely asked about sleepiness

sudden onset of sleep, and impulse control disorders such as pathologic gambling, shopping, internet use, o

sexual activity.

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


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tablet, and levodopa/carbidopa/entacapone. The orally disintegrating tablet is bioequivalent to ora

levodopa/carbidopa but dissolves on the tongue without the need to swallow it with water.

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.

If nausea occurs, the levodopa dose may be taken following a meal. Additional measures to alleviate nausea

include adding extra carbidopa or introducing domperidone.

A recently completed study (FIRST STEP) demonstrated that treatment with levodopa/carbidopa/entacapone

(Stalevo) provided greater symptomatic benefit than levodopa/carbidopa at the same levodopa dose, without an

increase in motor complications.

[16 ]

Another study (STRIDE-PD) is ongoing and will evaluate whethelevodopa/carbidopa/entacapone causes less dyskinesia than levodopa/carbidopa.

For patients who have disability due to tremor that is not adequately controlled with dopaminergic medication, 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.

Advanced disease treatment strategies

Patients initially experience stable, sustained benefit through the day in response to levodopa. 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.

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 and decreasing

dopamine stimulation may worsen Parkinson disease motor signs and increase off time. The therapeutic

window lies above the threshold required to improve symptoms (on threshold) and below the threshold for peak-

dose dyskinesia (dyskinesia threshold). The therapeutic window narrows over time because of a progressivedecrease in the threshold for peak-dose dyskinesia.

Although many patients prefer mild 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 the patient denotes whether they are off, on without dyskinesia, on with nontroublesome dyskinesia, or

on with troublesome dyskinesia (see image below or Media file 3). The goal of medical management is to

minimize off time and time on with troublesome dyskinesia.


12/31

Parkinson disease diary. The patient or caregiver should place 1 check mark in each half-hour

time slot to indicate the patient's predominant response during most of that period. The goa

of therapeutic management is to minimize off time and on time with troublesome dyskinesia

Copyright Robert Hauser, 1996. Used with permission.

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 peak-dose symptoms such as dyskinesia

or hallucinations, dopaminergic therapy should be increased until off time is eliminated.

The treatment of patients with both motor fluctuations and troublesome peak-dose 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 peak-dose dyskinesia.

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.

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.

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 wearing-off then determines the appropriate interdose interval. The extreme


13/31

of this strategy is using liquid levodopa, a solution with which the dose can be titrated finely and administered

every hour. Amantadine may also be of benefit to reduce dyskinesia.

COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-O -methyldopa (3-OMD), thereby prolonging

the levodopa half-life and making more levodopa available for transport across the blood-brain barrier over a

longer time.

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.

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. 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.

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.

For patients who have motor fluctuations and dyskinesia that cannot be adequately managed with medication

manipulation, surgery is considered.

Surgical Care

Stereotactic surgery has made a resurgence in the treatment of Parkinson disease, largely due to long-termcomplications 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 lowe

morbidity. Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease because it

does not involve destruction of brain tissue, it is reversible, it can be adjusted as the disease progresses or adverse

events occur, and bilateral procedures can be performed without a significant increase in adverse events.

Deep brain stimulation

o DBS is an FDA-approved treatment for Parkinson disease.

o The DBS system consists of a lead that is implanted into the targeted brain structure (thalamus, globus

pallidus interna, subthalamic nucleus). 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 an Access Review Therapy Controller or a

handheld magnet. The usual stimulation parameters are amplitude of 1-3 V, frequency of 135-185 Hz,

and pulse width of 60-120 microseconds.

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 tremorwhich 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 ventral intermediate (VIM) nucleus of the

thalamus.

o Thalamic stimulation provides significant control of Parkinson disease tremor but does not affect the

other symptoms of Parkinson disease such as rigidity, bradykinesia, dyskinesia, or motor fluctuations.


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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 and rigidity and worsening of gait leading to major disability.

o Candidates for thalamic DBS are patients with disabling medication-resistant tremor who have minima

rigidity or bradykinesia. They should not have significant cognitive impairment, mood or behaviora

disturbances, or other factors that may increase the risk of surgery.

o The role of thalamic DBS is limited in Parkinson disease.

Pallidal stimulation

o Pallidal stimulation involves implantation of a DBS lead in the globus pallidus interna (GPi).

o Pallidal stimulation significantly controls all the cardinal symptoms of Parkinson disease (tremor, rigidity

bradykinesia) as well as dyskinesia.

o Long-term studies up to 4 years after pallidal DBS have continued to show significant improvements in

the cardinal features of Parkinson disease and dyskinesia compared with presurgery.

o Candidates for pallidal DBS include levodopa-responsive patients with medication-resistant disabling

motor fluctuations and/or levodopa-induced dyskinesia without significant cognitive impairment

behavioral issues, or mood problems.

Subthalamic stimulation

o Subthalamic stimulation is currently the most common surgical procedure for Parkinson disease and

involves implantation of a DBS lead in the subthalamic nucleus (STN).

o STN DBS controls all of the cardinal symptoms of Parkinson disease 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 50-80%.

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 moto

fluctuations and/or levodopa-induced dyskinesia without significant cognitive impairment, behaviora

issues, 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 showngreater 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

Parkinson disease.

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 and require additiona

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.

Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson

disease.

o Lesion surgeries for Parkinson disease have largely been replaced by DBS.


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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, o

dyskinesia.

o Most patients with Parkinson disease who undergo thalamotomy have significant improvement in tremo

of the limbs contralateral to the side of the lesion.

o Bilateral thalamotomy is generally avoided because complications, especially speech and cognitive

impairment, are common.

o Pallidotomy involves destruction of a part of the GPi, which is overactive in Parkinson disease.

o Pallidotomy studies have demonstrated significant improvements in each of the cardinal symptoms of

Parkinson disease (tremor, rigidity, bradykinesia) as well as a significant reduction in dyskinesia.o Bilateral pallidotomy is not recommended because complications are relatively common and include

speech difficulties, dysphagia, and cognitive impairment.

o Subthalamotomy involves destruction of a part of the STN, which is also hyperactive in Parkinson

disease.

o Subthalamotomy studies have shown significant improvements in the cardinal features of Parkinson

disease as well as the reduction of motor fluctuations and dyskinesia.

Transplantation

o Neural transplantation is a potential treatment for Parkinson disease 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 Parkinson disease 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 Parkinson disease

symptoms and often resulted in the development of dyskinesia even in the absence of antiparkinsonian

medications.

o In double-blink studies, transplanted cultured human retinal pigment epithelial cells (RPE) were found tobe no different than sham surgery after 12 months of follow-up.

o Several studies have recently demonstrated the safety of gene therapy as a treatment for Parkinson

disease and larger studies have been initiated to examine the efficacy of this procedure. The goal of

these studies is to modify genes involved in the development of Parkinson disease.

o In the laboratory, the use of stem cells is being investigated.

For more information, see eMedicine article Surgical Treatment of Parkinson Disease.

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 o

significant psychiatric or behavioral problems are not candidates for the current neurosurgical treatments fo

Parkinson disease.

Medication

The cornerstone of symptomatic treatment for Parkinson disease 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.


16/31

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 Parkinson disease and as an adjunct to levodopa in patients with moto

fluctuations. Recommended dose is 1 mg/d.

COMT inhibitors increase the peripheral half-life of levodopa, thereby delivering more levodopa to the brain over a longer

time.

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 iscombined with levodopa to reduce the incidence of nausea and vomiting by inhibiting the peripheral conversion o

levodopa to dopamine.

Levodopa/PDI is the criterion standard of symptomatic treatment for Parkinson disease; it provides the greates

antiparkinsonian efficacy in moderate to advanced disease with the fewest acute adverse effects.

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 moto

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 immediatelyfollowing 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 meaningfu

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 30-50%

Most patients controlled on levodopa dose of 300-600 mg for several years.

Dosing

Adult

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


17/31

Pediatric

Not established

Interactions

Hydantoins, pyridoxine, phenothiazine, and hypotensive agents may decrease effects of levodopa; concurrent antacids or

nonspecific MAOIs increase levodopa toxicity

Contraindications

Documented hypersensitivity, narrow-angle glaucoma' malignant melanoma relative contraindication; if meaningfu

parkinsonian disability present, consider benefit/risk ratio

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh

risk to fetus

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 absorptionAbrupt withdrawal of treatment may result in neuroleptic malignant syndrome (NMS); use cautiously in patients with

history of MI, arrhythmias, asthma, or peptic ulcer disease

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 Parkinson disease 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 ye

conclusive.

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 "off-periods") 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.

Dosing

Adult

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


18/31

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

Pediatric

Not established

Interactions

Coadministration with 5HT3 antagonists used for emesis or irritable bowel syndrome (eg, ondansetron, dolasetrongranisetron, palonosetron, alosetron) may cause hypotension and loss of consciousness; coadministration with drugs tha

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

Contraindications

Documented hypersensitivity to apomorphine or metabisulfite

Precautions

Pregnancy


risk to fetus

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)

Bromocriptine (Parlodel)

Semisynthetic ergot alkaloid derivative that is strong D2 receptor agonist and weak D1 receptor antagonist. FDAapproved 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 tha

lowest dosage producing optimal therapeutic response is not exceeded. If adverse reactions mandate, reduce dose

gradually in 2.5-mg increments.

Dosing

Adult

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

Pediatric

Not established

Interactions

Ergot alkaloids increase toxicity; amitriptyline, butyrophenone, imipramine, methyldopa, phenothiazine, and reserpine

may decrease effects


19/31

Contraindications

Documented hypersensitivity, ischemic heart disease, peripheral vascular disorders

Precautions

Pregnancy


risk to fetus

Precautions

Adverse effects include nausea, hypotension, hallucinations, and somnolence; use cautiously in patients with renal o

hepatic disease

Pergolide (Permax)

Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac

valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need

for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed

another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and

Medscape Alerts: Pergolide Withdrawn From US Market

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 stimulatingpostsynaptic dopamine receptors in striatum

Usually administered in divided doses tid.

Dosing

Adult

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 incrementa

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

Not established

Interactions

Concurrent use of pergolide and levodopa may cause or exacerbate preexisting states of confusion and hallucinations o

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

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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; may cause or exacerbate preexisting states of

confusion and hallucinations or dyskinesia


20/31

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.

Dosing

Adult

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

Not established

Interactions

Cimetidine may increase toxicity; increases levels of levodopa if given concurrently

Contraindications


Precautions

Pregnancy


risk to fetus

Precautions

Adverse effects include nausea, hallucinations, and somnolence; somnolence may emerge even after administration a

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 o

discontinuation; use caution in patients with renal insufficiency and preexisting dyskinesias

Ropinirole (Requip and Requip XL)

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 beta-adrenoreceptors. Mechanism of action is stimulation of dopamine receptors in striatum

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 diseaseReadily 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.

Dosing

Adult

Ropinirole 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; 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 withdrawa

Ropinirole XL: Start at 2 mg/d for 2 wk and then increase by 2 mg q2wk until desired response achieved or dose reaches

24 mg/d; discontinue gradually over 7-d period


21/31

Pediatric

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

Contraindications


Precautions

Pregnancy


risk to fetus

Precautions

Adverse effects include nausea, hypotension, hallucinations, and somnolence; patients should be warned not to drive i

experiencing drowsiness; somnolence usually resolves with dose reduction or discontinuation

Dopamine receptor agonists may potentiate dopaminergic effects of levodopa and may cause or exacerbate preexistingdyskinesia; decreasing dose of levodopa may ameliorate this effec

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

Rotigotine (Neupro)

April 2008: A recall was issued for Neupro patch in the United States because of crystal formation in the patch

resulting in decreased dopamine absorption transdermally. As of August 1, 2008, the patch is still unavailable, although

the manufacturer is working to correct the defect and hopefully return it to the market. For more information, see

Medscape News

Dopamine agonist stimulating D3, D2, and D1 receptors. Improvement in Parkinson-related symptoms thought to be its

ability to stimulate D2 receptors within the caudate putamen in the brain. Available as a transdermal patch that provides

continuous delivery for 24 h (2 mg/24 h [10 cm 2], 4 mg/24 h [20 cm2], or 6 mg/24 h [30 cm2]). Indicated for symptoms o

early Parkinson disease.

Dosing

Adult

2 mg/24 h (10 cm2) transdermal qd initially; may increase qwk by 2 mg/24 h, not to exceed 6 mg/24 h

Remove previous day's patch before applying new patch; rotate application site each day between left and right sides of

body and upper and lower parts of body

Pediatric

Indication not applicable to children

Interactions

Dopamine antagonists (eg, antipsychotics, metoclopramide) may decrease effect

Contraindications


Precautions


22/31

Pregnancy


risk to fetus

Precautions

Common adverse effects include dermal reactions at patch site, dizziness, nausea, vomiting, drowsiness, and insomnia;

less common adverse effects that may be hazardous to patient include sudden sleep onset, hallucinations, and postura

hypotension; weight gain secondary to fluid retention has been observed; rapid dose reduction or abrupt withdrawal may

cause hyperpyrexia and confusion; apply to clean, dry, and intact skin on abdomen, thigh, hip, flank, shoulder, or upper

arm

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.

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 inhibi

reuptake and storage of dopamine at central dopamine receptors, thereby prolonging action of dopamine.

Dosing

Adult

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

Pediatric

Interactions

Decreases effects of levodopa; increases effects of narcotic analgesics, phenothiazines, tricyclic antidepressants

quinidine, and anticholinergics

Contraindications

Documented hypersensitivity; glaucoma, particularly angle-closure glaucoma; pyloric or duodenal obstruction, stenosing

peptic ulcers; prostatic hypertrophy or bladder neck obstructions; achalasia (megaesophagus); myasthenia gravis

megacolon

Precautions

Pregnancy


risk to fetus

PrecautionsAdverse 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

Benztropine mesylate (Cogentin)

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

Dosing


23/31

Adult

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

Pediatric

Interactions

Decreases effects of levodopa; increases effects of narcotic analgesics, phenothiazines, tricyclic antidepressants

quinidine, and anticholinergics

Contraindications

Documented hypersensitivity; glaucoma, particularly angle-closure glaucoma; pyloric or duodenal obstruction, stenosing

peptic ulcers; prostatic hypertrophy or bladder neck obstructions; achalasia (megaesophagus); myasthenia gravis

megacolon

Precautions

Pregnancy


risk to fetus

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

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.

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 L-dopa 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 a

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. Fo

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 severa

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 10-30% appears typical. Further

reductions of levodopa/carbidopa may be possible during continued selegiline therapy.

Dosing

Adult

5 mg PO bid with breakfast and lunch; not to exceed 10 mg/d

Pediatric


24/31

Interactions

Concurrent meperidine may cause stupor, muscular rigidity, severe agitation, and elevated temperature; concurren

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

Contraindications

Documented hypersensitivity; concomitant meperidine or other opioids; concomitant tricyclic or serotonin reuptake

inhibitor antidepressants (relative contraindication)

Precautions

Pregnancy


risk to fetus

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

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 experimenta

models. Indicated for Parkinson disease as initial monotherapy or as adjunctive therapy with levodopa.

Dosing

Adult

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

Pediatric

Interactions

P450 CYP1A2 substrate; coadministration with drugs that inhibit CYP1A2 (eg, cimetidine, clarithromycin, erythromycin)

may decrease elimination and increase toxicity; coadministration with TCAs, SSRIs, serotonin-norepinephrine 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

Contraindications

Documented hypersensitivity; moderate-to-severe hepatic impairment (Child-Pugh score >6); concurrent use with

meperidine, tramadol, methadone, propoxyphene; dextromethorphan, St. John's wort, mirtazapine, cyclobenzaprine

sympathomimetic amines (eg, pseudoephedrine, cocaine, ephedrine), other MAOIs, or local anesthetics containingepinephrine; pheochromocytoma

Precautions

Pregnancy


risk to fetus

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


25/31

N-methyl-D-aspartic acid inhibitors

Increases dopaminergic activity in peripheral and central nervous system by augmenting dopamine release and inhibiting

cellular reuptake.

Amantadine (Symmetrel)

Inhibits the N -methyl-D-aspartic acid (NMDA) receptor-mediated 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.

Dosing

Adult

100 mg PO in am; increase by 100 mg/d each wk prn; not to exceed 100 mg qid

Pediatric

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

Contraindications


Precautions

Pregnancy


risk to fetus

PrecautionsCommon adverse effects are confusion and hallucinations; use caution in patients with liver disease, history of recurren

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

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.

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 o

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


26/31

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