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Parkinson Disease
Updated: Jan 24, 2019
Author: Robert A Hauser, MD, MBA; Chief Editor: Selim R Benbadis, MD
Overview
Practice Essentials
Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than
60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic
findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the
presence of Lewy bodies and Lewy neurites. See the images below.
Lewy bodies are intracytoplasmic eosinophilic inclusions, often with halos, that are easily seen in pigmented neurons, as
shown in this histologic slide. They contain polymerized alpha-synuclein; therefore, Parkinson disease is a synucleinopathy.
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Stages in the development of Parkinson disease (PD)-related pathology (path.). Adapted from Braak H, Ghebremedhin E,
Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004
Oct;318(1):121-34.
Signs and symptoms
Initial clinical symptoms of Parkinson disease include the following:
Tremor
Subtle decrease in dexterity
Decreased arm swing on the first-involved side
Soft voice
Decreased facial expression
Sleep disturbances
Rapid eye movement (REM) behavior disorder (RBD; a loss of normal atonia during REM sleep)
Decreased sense of smell
Symptoms of autonomic dysfunction (eg, constipation, sweating abnormalities, sexual dysfunction, seborrheic dermatitis)
A general feeling of weakness, malaise, or lassitude
Depression or anhedonia
Slowness in thinking
Onset of motor signs include the following:
Typically asymmetric
The most common initial finding is a resting tremor in an upper extremity
Over time, patients experience progressive bradykinesia, rigidity, and gait difficulty
Axial posture becomes progressively flexed and strides become shorter
Postural instability (balance impairment) is a late phenomenon
Nonmotor symptoms
Nonmotor symptoms are common in early Parkinson disease. Recognition of the combination of nonmotor and motor symptoms
can promote early diagnosis and thus early intervention, which often results in a better quality of life.
See Clinical Presentation for more detail.
Diagnosis
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic
resonance imaging and computed tomography scans are unremarkable.
Clinical diagnosis requires the presence of 2 of 3 cardinal signs:
Resting tremor
Rigidity
Bradykinesia
See Workup for more detail.
Management
The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while
minimizing adverse effects.
Symptomatic drug therapy
Usually provides good control of motor signs of Parkinson disease for 4-6 years
Levodopa/carbidopa: The gold standard of symptomatic treatment
Monoamine oxidase (MAO)–B inhibitors: Can be considered for initial treatment of early disease
Other dopamine agonists (eg, ropinirole, pramipexole): Monotherapy in early disease and adjunctive therapy in moderate
to advanced disease
Anticholinergic agents (eg, trihexyphenidyl, benztropine): Second-line drugs for tremor only
Treatment for nonmotor symptoms
Sildenafil citrate (Viagra): For erectile dysfunction
Polyethylene glycol: For constipation
Modafinil: For excessive daytime somnolence
Methylphenidate: For fatigue (potential for abuse and addiction)
Deep brain stimulation
Surgical procedure of choice for Parkinson disease
Does not involve destruction of brain tissue
Reversible
Can be adjusted as the disease progresses or adverse events occur
Bilateral procedures can be performed without a significant increase in adverse events
See Treatment and Medication for more detail.
Background
Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals
older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia
nigra pars compacta (SNpc) and the presence of Lewy bodies (see the following image). Most cases of Parkinson disease
(idiopathic Parkinson disease [IPD]) are hypothesized to be due to a combination of genetic and environmental factors.
However, no environmental cause of Parkinson disease has yet been proven. A known genetic cause can be identified in
approximately 10% of cases, and these are more common in younger-onset patients.
Gross comparison of the appearance of the substantia nigra between a normal brain and a brain affected by Parkinson
disease. Note the well-pigmented substantia nigra in the normal brain specimen on the left. In the brain of a Parkinson
disease patient on the right, loss of pigmented substantia nigra due to depopulation of pigmented neurons is observed.
The classic motor features of Parkinson disease typically start insidiously and emerge slowly over weeks or months, with tremor
being the most common initial symptom. The 3 cardinal signs of Parkinson disease are resting tremor, rigidity, and bradykinesia.
Postural instability (balance impairment) is sometimes listed as the fourth cardinal feature. However, balance impairment in
Parkinson disease is a late phenomenon, and in fact, prominent balance impairment in the first few years suggests that
Parkinson disease is not the correct diagnosis. (See Presentation.)
When a patient presents with tremor, the clinician evaluates the patient's history and physical examination findings to
differentiate Parkinson disease tremor from other types of tremor. In patients with parkinsonism, careful attention to the history is
necessary to exclude causes such as drugs, toxins, or trauma. (See Differential Diagnosis.) Other common causes of tremor
include essential tremor, physiologic tremor, and dystonic tremor.
No laboratory or imaging study is required in patients with a typical presentation of Parkinson disease. Such patients are aged
55 years or older and have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity.
There are no red flags such as prominent autonomic dysfunction, balance impairment, dementia, or eye-movement
abnormalities. In such cases, the diagnosis is ultimately considered confirmed once the patient goes on dopaminergic therapy
(levodopa or a dopamine agonist) as needed for motor symptom control and exhibits a robust and sustained benefit. (See
Workup.)
Imaging studies can be considered, depending on the differential diagnosis. Magnetic resonance imaging (MRI) of the brain can
be considered to evaluate possible cerebrovascular disease (including multi-infarct state), space-occupying lesions, normal-
pressure hydrocephalus, and other disorders.
Iodine-123–labeled fluoropropyl-2beta-carbomethoxy-3beta-4-iodophenyl-nortroptane (FP-CIT I123) (Ioflupane, DaTscan)

single-photon emission computed tomography (SPECT) can be considered in cases of uncertain parkinsonism to help
differentiate disorders associated with a loss of dopamine neurons (Parkinson disease and atypical parkinsonisms, including
multiple system atrophy [MSA] and progressive supranuclear palsy [PSP]) from those disorders not associated with a loss of
dopamine neurons (eg, essential tremor, dystonic tremor, vascular parkinsonism, medication-induced parkinsonism or tremor,
psychogenic conditions).[1]
Levodopa coupled with a peripheral decarboxylase inhibitor (PDI), such as carbidopa, remains the gold standard of symptomatic
treatment of motor features of Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse
effects in the short term. However, its long-term use is associated with the development of fluctuations and dyskinesias.
Moreover, the disease continues to progress, and patients accumulate long-term disability. (See Treatment.)
Dopamine agonists such as pramipexole (Mirapex) and ropinirole (Requip) can be used as monotherapy to improve symptoms
in early Parkinson disease or as adjuncts to levodopa in patients who are experiencing motor fluctuations. Monoamine oxidase
(MAO)-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Azilect) provide mild benefit as monotherapy in early disease
and as adjuncts to levodopa in patients with motor fluctuations. (See Medication.) Entacapone (Comtan), a catechol-o-
methyltransferase (COMT) inhibitor, reduces the peripheral metabolism of levodopa, thereby making more levodopa available to
enter the brain over a longer period; this agent is used as an adjunct to levodopa in patients with motor fluctuations.
Anatomy
Parkinson disease is predominantly a disorder of the basal ganglia, which are a group of nuclei situated at the base of the
forebrain. The striatum, composed of the caudate and putamen, is the largest nuclear complex of the basal ganglia. The
striatum receives excitatory input from several areas of the cerebral cortex, as well as inhibitory and excitatory input from the
dopaminergic cells of the substantia nigra pars compacta (SNc). These cortical and nigral inputs are received by the spiny
projection neurons, which are of 2 types: those that project directly to the internal segment of the globus pallidus (GPi), the
major output site of the basal ganglia; and those that project to the external segment of the globus pallidus (GPe), establishing
an indirect pathway to the GPi via the subthalamic nucleus (STN).
For an illustration of the subthalamic nucleus, see the image below.
Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN) (lavender). The STN is one of the
preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease.
The actions of the direct and indirect pathways regulate the neuronal output from the GPi, which provides tonic inhibitory input to
the thalamic nuclei that project to the primary and supplementary motor areas.
Pathophysiology
No specific, standard criteria exist for the neuropathologic diagnosis of Parkinson disease, as the specificity and sensitivity of its
characteristic findings have not been clearly established. However, the following are the 2 major neuropathologic findings in
Parkinson disease:
Loss of pigmented dopaminergic neurons of the substantia nigra pars compacta
The presence of Lewy bodies and Lewy neurites
The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra. Approximately 60-80% of
dopaminergic neurons are lost before the motor signs of Parkinson disease emerge.
Some individuals who were thought to be normal neurologically at the time of their deaths are found to have Lewy bodies on
autopsy examination. These incidental Lewy bodies have been hypothesized to represent the presymptomatic phase of
Parkinson disease. The prevalence of incidental Lewy bodies increases with age. Note that Lewy bodies are not specific to
Parkinson disease, as they are found in some cases of atypical parkinsonism, Hallervorden-Spatz disease, and other disorders.
Nonetheless, they are a characteristic pathology finding of Parkinson disease.
Motor circuit in Parkinson disease
The basal ganglia motor circuit modulates the cortical output necessary for normal movement (see the following image).
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 disease and movement disorders. In: Watts RL,
Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:240. Copyright,
McGraw-Hill Companies, Inc. Used with permission.
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, the direct and indirect pathways, as follows:
In the direct pathway, outflow from the striatum directly inhibits the GPi and SNr; striatal neurons containing D1 receptors
constitute the direct pathway and project to the GPi/SNr
The indirect pathway contains inhibitory connections between the striatum and the external segment of the globus
pallidus (GPe) and between the GPe and the subthalamic nucleus (STN); striatal neurons with D2 receptors are part of
the indirect pathway and project to the GPe
The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory output to the ventral lateral nucleus
(VL) of the thalamus. Dopamine is released from nigrostriatal (substantia nigra pars compacta [SNpc]) 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 via both the direct and indirect pathways (see the following image).
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 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.
The 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.
Etiology
Although the etiology of Parkinson disease is still unclear, most cases are hypothesized to be due to a combination of genetic
and environmental factors. Currently known genetic causes of Parkinson disease account for approximately 10% of cases.
Environmental causes
Environmental risk factors commonly associated with the development of Parkinson disease include use of pesticides, living in a
rural environment, consumption of well water, exposure to herbicides, and proximity to industrial plants or quarries.[2]
A meta-analysis of 89 studies, including 6 prospective and 83 case-control studies, found that exposure to pesticides may
increase the risk for PD by as much as 80%.[3, 4] Exposure to the weed killer paraquat or to the fungicides maneb or mancozeb
is particularly toxic, increasing the risk for PD about 2-fold. Many of the agents studied are no longer used in the United States
and Europe; however, some are still found in developing parts of the world.[3, 4]
In case-control studies, PD was associated with exposure to any type of pesticide, herbicide, insecticide, and solvent, with risks
ranging from 33% to 80%.[3, 4] Increased PD risk was also associated with proxy conditions of exposure to organic pollutants,
such as farming, well-water drinking, and rural living. In addition, risk seemed to increase with length of exposure.[3, 4]
The National Institutes of Health-AARP Diet and Health Study, as well as a meta-analysis of prospective studies, found that
higher caffeine intake was associated with lower risk of Parkinson disease in both men and women. A similar association was
found for smoking and Parkinson disease risk.[5] The biological mechanisms underlying the inverse relationship between
caffeine or smoking and Parkinson disease risk are not well elucidated.
MPTPinterference with mitochondrial function
Several individuals were identified who developed parkinsonism after self-injection of 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP). These patients developed bradykinesia, rigidity, and tremor, which progressed over several weeks
and improved with dopamine replacement therapy. MPTP crosses the blood-brain barrier and is oxidized to 1-methyl-4-
phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B.[6]
MPP+ accumulates in mitochondria and interferes with the function of complex I of the respiratory chain. A chemical
resemblance between MPTP and some herbicides and pesticides suggested that an MPTP-like environmental toxin might be a
cause of Parkinson disease, but no specific agent has been identified. Nonetheless, mitochondrial complex I activity is reduced
in Parkinson disease, suggesting a common pathway with MPTP-induced parkinsonism.
Oxidation hypothesis
The oxidation hypothesis suggests that free radical damage, resulting from dopamine's oxidative metabolism, plays a role in the
development or progression of Parkinson disease. The oxidative metabolism of dopamine by MAO leads to the formation of
hydrogen peroxide. Normally, hydrogen peroxide is cleared rapidly by glutathione, but 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 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 donor
electrons, thereby promoting the formation of free radicals.
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 has 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.
Genetic factors
If genetic factors are important in a particular disease, concordance in genetically identical monozygotic (MZ) twins will be
greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early Parkinson disease twin studies generally found
low and similar concordance rates for MZ and DZ pairs.
However, genetic factors in Parkinson disease appear to be very important when the disease begins at or before age 50 years.
In a study of 193 twins, overall concordance for MZ and DZ pairs was similar, but 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.[7]
The identification of a few families with familial Parkinson disease sparked further interest in the genetics of the disease. In one
large family in Salerno, Italy, 50 of 592 members had Parkinson disease; linkage analysis incriminated a region in bands 4q21-
23, and sequencing revealed an A-for-G substitution at base 209 of the alpha-synuclein gene.[8] Termed PD-1, this mutation
codes for a substitution of threonine for alanine at amino acid 53. These individuals were characterized by early age of disease
onset (mean age, 47.5 years), rapid progression (mean age at death, 56.1 years), lack of tremor, and good response to
levodopa therapy.[8] Five small Greek kindreds were also 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 Parkinson
disease.[9] A few additional familial mutations in the alpha-synuclein gene have been identified and are collectively called
PARK1. It is now clear that these mutations are an exceedingly rare cause of Parkinson disease.
A total of 18 loci in various genes have now been proposed for Parkinson disease. Mutations within 6 of these loci (SNCA,
LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are well-validated causes of familial parkinsonism.[10] Inheritance is autosomal
dominant for SNCA and LRRK2 (although LRRK2 mutations exhibit variable penetrance). Inheritance is autosomal recessive for
PRKN, DJ1, PINK1, and ATP13A2. In addition, polymorphisms within SNCA and LRRK2, as well as variations in MAPT and
GBA, are risk factors for Parkinson disease.[10]
(For more information on genes/loci underlying monogenic parkinsonism and susceptibility genes/loci for Parkinson disease,
see Tables 1 and 2, respectively, in The Genetics of Parkinson Disease.[10] )
In one study of 953 patients with Parkinson disease with age at onset of 50 years or younger, 64 patients (6.7%) had a PRKN
mutation, 1 patient (0.2%) had a DJ1 mutation, 35 patients (3.6%) had an LRRK2 mutation, and 64 patients (6.7%) had a GBA
mutation.[11] . Mutations were more common in patients with age at onset of 30 years or younger (40.6%) than in those with age
at onset between 31 and 50 years (14.6%); more common in patients of Jewish ancestry (32.4%) than in non-Jewish patients
(13.7%); and more common in patients reporting a first-degree family history of Parkinson disease (23.9%) than in those without
such a family history (15.1%).[11]
Although the mechanisms by which genetic mutations cause Parkinson disease is not known, evidence to date converges on
mechanisms related to abnormal protein aggregation, defective ubiquitin-mediated protein degradation, mitochondrial
dysfunction, and oxidative damage.
Alpha-synuclein conformational changes and aggregation
Abnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are characteristic
pathologic findings in Parkinson disease. Missense mutations and multiplications in the SNCA gene that encodes alpha-
synuclein, although rare, cause autosomal dominant Parkinson disease. However, genome-wide association studies have also
demonstrated a link between SNCA and sporadic Parkinson disease.
Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson disease, and understanding its
relationship to the disease process holds major promise for the development of a cure.
Alpha-synuclein is a 140-amino-acid protein that is unfolded at neutral pH. However, when bound to membranes or vesicles
containing acidic phospholipids, it takes on an alpha-helical structure. Normally, alpha-synuclein is found mainly in neuronal
presynaptic terminals and may play a role in assembly and function of SNARE (soluble N-ethylmaleimide-sensitive factor
activating protein receptor) proteins that are involved in neurotransmitter release.
Under certain conditions, alpha-synuclein aggregates into oligomers that are gradually converted to the beta–sheet-rich fibrillary
structures that form Lewy bodies and neurites in Parkinson disease. Most evidence currently suggests that it is the intermediate
soluble oligomers that are toxic to neurons.
Multiple mechanisms have been suggested as to how abnormally aggregated alpha-synuclein could exert neurotoxicity.[12] One
hypothesis suggests that oligomeric alpha-synuclein can promote formation of ion-permeable pores on neuronal membranes,
leading to increased calcium influx. Aberrant pore formation could also lead to neurotransmitter leaks from synaptic vesicles into
the cytosol. In addition, overexpression of alpha-synuclein has been demonstrated to impair mitochondrial complex I activity,
and oligomeric alpha-synuclein may have a direct effect on mitochondrial membranes. Other lines of evidence suggest that
oligomerization of alpha-synuclein could cause cytoskeletal disruption, possibly by an effect on the microtubule-stabilizing
protein, tau.[13]
Elevated levels of alpha-synuclein promote abnormal aggregation. levels are normally regulated by a balance between
synthesis and degradation. SNCA multiplications lead to increased synthesis of alpha-synuclein and can cause Parkinson
disease. Alpha-synuclein appears to be degraded by the ubiquitin proteasome system and the autophagy-lysosome pathway.
Several genetic mutations associated with Parkinson disease may lead to decreased alpha-synuclein degradation. For example,
increased risk of Parkinson disease in carriers of GBA (beta-glucocerebrosidase gene) mutations, which encode for the
lysosomal enzyme glucocerebrosidase, may be due to lysosomal dysfunction and consequent alpha-synuclein accumulation
and oligomerization.
How the Parkinson disease process begins is not known. Once it is initiated, however, it may propagate by a prionlike process in
which misconformed proteins induce the templated misfolding of other protein molecules. In Parkinson disease, synuclein
pathology begins in the lower brainstem and olfactory bulb, ascends up the midbrain, and eventually affects the neocortex. One
set of observations in support of a prionlike process comes from experience with fetal dopaminergic grafts transplanted into the
striata of patients with Parkinson disease, because these grafts develop Lewy bodies, suggesting host-graft transmission of
disease.[14]
Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowing or stopping Parkinson disease
progression.
Melanoma
For years, there has been speculation about a relationship between PD and melanoma. Initially, it was theorized that the drug
levodopa led to an increased risk of skin cancer, but studies did not confirm this. However, subsequent trials have since found
an increased risk for melanoma in patients with PD. One particular study conducted in 2017 found that Parkinson patients have
about a 4-fold increased risk of having preexisting melanoma.[15, 16] Another study found the risk to be 7-fold.[17]
Diabetes
In a large cohort study, researchers found that individuals with type 2 diabetes had a 32% increased risk of developing later
Parkinson's disease than those without diabetes. The study involved 2 million people with type 2 diabetes and compared them
to a reference cohort of 6,173,208 people without diabetes and results showed significantly elevated rates of Parkinson's
disease in the type 2 diabetes cohort (hazard ratio [HR], 1.32, 95% confidence interval [CI], 1.29 - 1.35; P < .001). The relative
increase was greater in patients with diabetic complications and in younger individuals with type 2 diabetes aged 25 to 44 years.
[18]
Epidemiology
Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals
older than 60 years. The incidence of Parkinson disease has been estimated to be 4.5-21 cases per 100,000 population per
year, and estimates of prevalence range from 18 to 328 cases per 100,000 population, with most studies yielding a prevalence
of approximately 120 cases per 100,000 population. The wide variation in reported global incidence and prevalence estimates
may be the result of a number of factors, including the way data are collected, differences in population structures and patient
survival, case ascertainment, and the methodology used to define cases.[19]
The incidence and prevalence of Parkinson disease increase with age, and the average age of onset is approximately 60 years.
Onset in persons younger than 40 years is relatively uncommon. Parkinson disease is about 1.5 times more common in men
than in women.
Prognosis
Before the introduction of levodopa, Parkinson disease caused severe disability or death in 25% of patients within 5 years of
onset, 65% within 10 years, and 89% within 15 years. The mortality rate from Parkinson disease was 3 times that of the general
population matched for age, sex, and racial origin. With the introduction of levodopa, the mortality rate dropped approximately
50%, and longevity was extended by many years. This is thought to be due to the symptomatic effects of levodopa, as no clear
evidence suggests that levodopa stems the progressive nature of the disease.[20, 21]
The American Academy of Neurology notes that the following clinical features may help predict the rate of progression of
Parkinson disease[22] :
Older age at onset and initial rigidity/hypokinesia can be used to predict (1) a more rapid rate of motor progression in
those with newly diagnosed Parkinson disease and (2) earlier development of cognitive decline and dementia; however,
initially presenting with tremor may predict a more benign disease course and longer therapeutic benefit from levodopa
A faster rate of motor progression may also be predicted if the patient is male, has associated comorbidities, and has
postural instability/gait difficulty (PIGD)
Older age at onset, dementia, and decreased responsiveness to dopaminergic therapy may predict earlier nursing home
placement and decreased survival
Patient Education
Patients with Parkinson disease should be encouraged to participate in decision making regarding their condition.[23] In
addition, individuals and their caregivers should be provided with information that is appropriate for their disease state and
expected or ongoing challenges.[21] Psychosocial support and concerns should be addressed and/or referred to a social worker
or psychologist as needed.
Prevention of falls should be discussed. The UK National Institute for Health and Clinical Excellence has several guidance
documents including those for patients and caregivers.
Other issues that commonly need to be addressed at appropriate times in the disease course include cognitive decline,
personality changes, depression, dysphagia, sleepiness and fatigue, and impulse control disorders. Additional information is
also often needed for financial planning, insurance issues, disability application, and placement (assisted living facility, nursing
home).
For patient education information, see the Brain & Nervous System Center, as well as Parkinson's Disease Dementia.
Presentation
History
Onset of motor signs in Parkinson disease is typically asymmetric, with the most common initial finding being an asymmetric
resting tremor in an upper extremity. Over time, patients notice symptoms related to progressive bradykinesia, rigidity, and gait
difficulty. The first affected arm may not swing fully when walking, and the foot on the same side may scrape the floor. Over time,
axial posture becomes progressively flexed and strides become shorter.
Some nonmotor symptoms commonly precede motor signs in Parkinson disease. Most Parkinson disease patients have a
substantial reduction in olfactory function (smell) by the time motor signs emerge. However, either this is not noticed by the
patients or patients may not realize that it is part of the disease. Another common premotor symptom is rapid eye movement
(REM) behavior disorder (RBD). In this condition, individuals exhibit movements during REM sleep that are often described as
hitting or kicking motions. There are also a number of midlife risk factors for the later development of Parkinson disease. These
include constipation and excessive daytime sleepiness, although they are far from specific for Parkinson disease.
In a British study, the frequency of nonmotor symptoms in 159 patients with newly diagnosed Parkinson’s disease was found to
be significantly greater than that in 99 healthy age-matched control patients (mean, 8.4 vs 2.8).[24] The most commonly
experienced nonmotor symptoms in patients with early Parkinson disease in this study included the following[25] :
Excessive saliva
Forgetfulness
Urinary urgency
Hyposmia
Constipation
Initial clinical symptoms in Parkinson disease include the following:
Tremor
A subtle decrease in dexterity; for example, a lack of coordination with activities such as playing golf or dressing (about
20% of patients first experience clumsiness in one hand)
Decreased arm swing on the first-involved side
Soft voice
Decreased facial expression
Sleep disturbances
RBD, in which there is a loss of normal atonia during REM sleep: In one study, 38% of 50-year-old men with RBD and no
neurologic signs went on to develop parkinsonism[26] ; patients “act out their dreams” and may kick, hit, talk, or cry out in
their sleep
Decreased sense of smell
Symptoms of autonomic dysfunction, including constipation, sweating abnormalities, sexual dysfunction, and seborrheic
dermatitis
A general feeling of weakness, malaise, or lassitude
Depression or anhedonia
Slowness in thinking
Common early motor signs of Parkinson disease include tremor, bradykinesia, rigidity, and dystonia.
Tremor
Although tremor is the most common initial symptom in Parkinson disease, occurring in approximately 70% of patients, it does
not have to be present to make the diagnosis. Tremor is most often described by patients as shakiness or nervousness and
usually begins in one upper extremity and initially may be intermittent. Upper extremity tremor generally begins in the fingers or
thumb, but it can also start in the forearm or wrist. After several months or years, the tremor may spread to the ipsilateral lower
extremity or the contralateral upper extremity before becoming more generalized; however, asymmetry is usually maintained.
Tremor can vary considerably, emerging only with stress, anxiety, or fatigue. Classically, the tremor of Parkinson disease is a
resting tremor (occurring with the limb in a resting position) and disappears with action or use of the limb, but this is not seen in
all patients. Initially, the tremor may be noticed during activities such as eating or reading a newspaper. Although Parkinson
disease is a rare cause of tremor affecting the head or neck, tremors of the chin, lip, or tongue are not uncommon. As with other
tremors, the amplitude increases with stress and resolves during sleep.
Bradykinesia
Bradykinesia refers to slowness of movement. Symptoms of bradykinesia are varied and can be described by patients in
different ways. These may include a subjective sense of weakness, without true weakness on physical examination; loss of
dexterity, sometimes described by patients as the "message not getting to the limb"; fatigability; or achiness when performing
repeated actions.
Facial bradykinesia is characterized by decreased blink rate and facial expression. Speech may become softer, less distinct, or
more monotonal. In more advanced cases, speech is slurred, poorly articulated, and difficult to understand. Drooling is an
uncommon initial symptom in isolation but is reported commonly (especially nighttime drooling) later in the disease course.
Truncal bradykinesia results in slowness or difficulty in rising from a chair, turning in bed, or walking. If walking is affected,
patients may take smaller steps and gait cadence is reduced. Some patients experience a transient inability to walk, as though
their feet are frozen to the floor. This "freezing" is seen commonly in patients with more advanced disease; it is more prominent
as patients attempt to navigate doorways or narrow areas and can result in patients getting trapped behind furniture or being
unable to cross a door threshold easily.
In the upper extremities, bradykinesia can cause small, effortful handwriting (ie, micrographia) and difficulty using the hand for
fine dexterous activities such as using a key or kitchen utensils. In the lower extremities, unilateral bradykinesia commonly
causes scuffing of that foot on the ground, as it is not picked up during leg swing. This may also be described as dragging of one
leg.
Rigidity
Some patients may describe stiffness in the limbs, but this may reflect bradykinesia more than rigidity. Occasionally, individuals
may describe a feeling of ratchety stiffness when moving a limb, which may be a manifestation of cogwheel rigidity.
Dystonia
Dystonia is a common initial symptom in young-onset Parkinson disease, which is defined as symptom onset before age 40
years. Dystonia in Parkinson disease commonly consists of a foot involuntary turning in (inversion) or down (plantar flexion),
often associated with cramping or aching in the leg. Dorsiflexion of the big toe may also occur. Another common dystonia in
Parkinson disease is adduction of the arm and elbow, causing the hand to rest in front of the abdomen or chest. Dystonic
postures can wax and wane, occurring with fatigue or exertion.
Whether stooped posture is due to truncal dystonia is a matter of debate. One study suggests that the stooped posture may be
due to vertebral fractures resulting from vitamin D deficiency with compensatory hyperparathyroidism.[27] Vitamin D
supplementation may reduce the risk for stooped posture.
Physical Examination
There are 4 cardinal signs of Parkinson disease, with 2 of the first 3 listed below required to make the clinical diagnosis. The
fourth cardinal sign, postural instability (balance difficulty), emerges late in the disease, usually after 8 years or more.
Resting tremor
Rigidity
Bradykinesia
Postural instability
Resting tremor
Resting tremor is assessed by having patients relax their arms in their lap while in a seated position. Having patients count
aloud backward from 10 may help bring out the tremor. The arms should also be observed in an outstretched position to assess
postural tremor, and kinetic tremor (tremor with voluntary movement) can be observed during the finger-to-nose test. Although a
resting tremor is the tremor characteristic of Parkinson disease, many Parkinson disease patients also have some postural
and/or kinetic tremor.
Rigidity
Rigidity refers to an increase in resistance to passive movement about a joint. The resistance can be either smooth (lead pipe)
or oscillating (cogwheeling). Cogwheeling is thought to reflect tremor rather than rigidity and may be present with tremors not
associated with an increase in tone (ie, essential tremor). Rigidity is usually tested by flexing and extending the patient's relaxed
wrist and can be made more obvious by having the patient perform voluntary movements, such as tapping, with the contralateral
limb.
Bradykinesia
Bradykinesia refers to slowness of movement but also includes reduced 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). Thus, the patient’s blink rate and facial expression should be observed.
In addition, speed and amplitude of movements are assessed by having the patient open his or her hand (each limb is assessed
individually) and tap his or her thumb and index finger repetitively, trying to perform the movement as big and as fast as
possible. Similarly, the patient should be asked to tap the toes of each foot as big and as fast as possible. Finally, the patient
should be asked to arise from a seated position with the arms crossed to assess the ability to arise from a chair. The patient is
then observed while walking to assess stride length and speed, as well as arm swing.
Postural instability
Postural instability refers to imbalance and loss of righting reflexes. Its emergence in a patient with Parkinson disease is an
important milestone, because it is poorly amenable to treatment and a common source of disability in late disease. Postural
stability is typically assessed by having patients stand with their eyes open and then pulling their shoulders back toward the
examiner. Patients are told to be ready for the displacement and to regain their balance as quickly as possible. Taking 1 or 2
steps backward to regain balance is considered normal. The examiner should be ready to catch patients if they are unable to
regain balance.
Laryngeal dysfunction and dysphagia
As the patient is speaking, the vocal loudness, intonation, and quality, including fluidity of speech and articulation, should be
assessed. Sustaining vowel phonation (eg, "ah") for maximum duration, counting to 50, and reading a passage that tests
articulation (eg, the rainbow passage) provide reasonable speech samples. Closely listening for reduced or diminishing
loudness and intonation and increasing breathiness and hoarseness helps differentiate Parkinson disease from hyperkinetic
disorders such as spasmodic dysphonia.[28]
A soft, monotone voice, vocal tremor, poor articulation, variable speech rate, trouble with the initiation of speech, and stuttering-
like qualities are all characteristics of Parkinson disease. Perhaps the most telling vocal symptom is the marked contrast
between habitual vocal volume (soft and diminishing) and the patient's response to a request to increase loudness. A request to
"say that again, twice as loud" often results in increased loudness, improved voice quality, and a dramatic improvement in
speech intelligibility.
Dysphagia is common, especially in advanced Parkinson disease. Manifestations may range from drooling to aspiration.
An otolaryngologist can perform a more detailed assessment of laryngeal dysfunction in patients with Parkinson disease, using
neurolaryngeal examination and stroboscopy. Because distortion can occur when the tongue is held forward during rigid
stroboscopy, the neurolaryngeal examination is best performed by viewing the larynx with a flexible laryngoscope. The larynx is
evaluated for vocal fold mobility, paresis or paralysis, coordination of movement, agility, fatigability, flexibility, and use of
accessory muscles during phonation while the patient says various phrases and syllables. Hyperfunctional and hypofunctional
disorders can often be differentiated by isolating the abductor and adductor muscle groups. The larynx is also visualized at rest.
Rigid stroboscopy plays a key role in the assessment of the vibratory characteristics of the vocal folds, including the presence of
masses, lesions, or scar and glottic configuration abnormalities, including an elliptical closure pattern, phase asymmetry, and
abnormal phase closure. Stroboscopy and neurolaryngeal examination are complementary in the evaluation of the patient with
Parkinson disease. Common stroboscopy findings in Parkinson disease include true vocal fold atrophy or other evidence of
glottal incompetence, including a chasing wave or a shorter closed phase.
Pooling of secretions, decreased sensation, and aspiration are also characterizations of the Parkinson disease larynx. A
paralyzed vocal fold suggests Parkinson-plus syndrome (PPS) as the etiology for the parkinsonism if other aspects of the
diagnosis are present.
Perez et al found that vocal tremor is present in 55% of patients with Parkinson disease.[29] Interestingly, only 35% of patients
with Parkinson disease exhibited a resting vocal cord tremor, whereas the remainder exhibited kinetic tremor. The tremor is
primarily a vertical laryngeal movement. PPS was found to carry a higher incidence of vocal tremor (64%), with most tremors
located in the arytenoids. The authors found no vertical laryngeal tremor in patients with PPS.[29]
Autonomic dysfunction
Autonomic dysfunction is common in patients with Parkinson disease. Orthostatic hypotension often becomes a concern in late
disease, and impaired intestinal motility can lead to constipation and, sometimes, vomiting or impaired absorption. Urinary
symptoms, retention, and bladder infection can occur, and erectile dysfunction is not uncommon. In addition, many patients note
episodes of sweating.
Prominent autonomic dysfunction, especially frank urinary incontinence or profound orthostatic hypotension, may suggest
multiple system atrophy (MSA) rather than Parkinson disease.
Cardiopulmonary impairment
The flexed posture of patients with Parkinson disease can lead to kyphosis, cause a reduction in pulmonary capacity, and
produce a restrictive lung disease pattern.
Staging
Investigators have proposed a staging system to improve the assessment of overall Parkinson disease severity. In an
observational, cross-sectional study of 933 patients with Parkinson disease, Ray Chaudhuri and colleagues found a wide
discrepancy between the severity of nonmotor symptoms as measured by the NonMotor Symptoms Scale (NMSS) and motor
symptoms as measured by the Hoehn and Yahr scale.[30, 31] The investigators proposed a staging system for nonmotor
symptom burden based on NMSS scores, which was correlated with measures of disability and quality of life. The staging
system rates nonmotor symptom burden (NMSB) on a scale of 0 (no NMSB) to 4 (very severe NMSB).[30, 31]
Depression
Given the high prevalence of mood disorders in Parkinson disease, these patients should be screened regularly for depression.
However, assessment of depression in patients with Parkinson disease is complicated by the fact that some symptoms of
Parkinson disease overlap with those of depression (eg, masklike facies, insomnia, psychomotor slowing, difficulty
concentrating, fatigue). Guilt and self-reproach are less prominent in depression in patients with Parkinson disease, whereas
anxiety and pessimism are more prominent.
Dementia
Hoops et al found that in Parkinson disease, the Montreal Cognitive Assessment (MoCA) is superior to the Mini-Mental State
Examination (MMSE) for screening for mild cognitive impairment or dementia.[32] MoCA and MMSE demonstrated similar
overall discriminant validity for detection of any cognitive disorder, but as a screening instrument, MoCA was better than MMSE
(64% vs 54% correct diagnoses).[32]
The prevalence of dementia in Parkinson disease ranges from 20-40%, with the disease conferring a 2- to 6-fold increased risk
compared with control populations.[33] Many patients with Parkinson disease have some executive function impairment, even
early in the disease.[33] Substantial cognitive impairment and dementia typically occur 8 years or more after the onset of motor
features.
Dementia generally occurs late in Parkinson disease; substantial cognitive dysfunction within 1 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. In the affected age group, comorbidity with other neurodegenerative disorders, particularly Alzheimer
disease and cerebrovascular disease, is common. The relatively high prevalence of depression in patients with Parkinson
disease is another confounder in the diagnosis of Parkinson disease dementia.
Executive function, short-term memory, and visuospatial ability may be impaired in patients with Parkinson disease dementia,
but aphasia is not present. In a long-term Australian study that compared neuropsychologic measures between patients with
Parkinson disease who had early dementia (< 10 years of disease onset) and those with late dementia, investigators reported
that dementia in parkinsonism appears to occur at about age 70 years regardless of the time of onset of Parkinson disease.[34]
However, although early and late dementia had similar effects in cognitive domains, individuals with early onset of parkinsonism
had a preserved linguistic ability before the onset of dementia.[34]
Atypical Parkinsonisms
Atypical parkinsonisms, or Parkinson-plus syndromes, are primary neurodegenerative disorders that have parkinsonian features
and are associated with complex clinical presentations that reflect degeneration in various neuronal systems. Patients with
atypical parkinsonisms typically have a worse prognosis than those with Parkinson disease, and atypical parkinsonisms respond
poorly to standard anti-Parkinson disease treatments.
(For more information, see Parkinson-Plus Syndromes for detailed information regarding clinical clues, workup, differential
diagnosis, and treatment of atypical parkinsonisms, including multiple system atrophy, progressive supranuclear palsy,
parkinsonism-dementia-amyotrophic lateral sclerosis complex, corticobasal ganglionic degeneration, and diffuse Lewy body
disease.)
DDx
Diagnostic Considerations
The most common tremor disorders are Parkinson disease and essential tremor. When a patient presents with tremor, the
clinician should pay particular attention to the body parts involved, positions/conditions in which the tremor occurs (ie, resting,
postural, kinetic, intention), and the frequency of the tremor. It is also critical to look for potential associated signs. The patient
should be examined for evidence of parkinsonism (bradykinesia, rigidity, postural instability), dystonia, and other neurologic
signs.
An 8-12 Hz action (postural/kinetic) tremor of the upper extremities that is temporarily relieved by drinking alcohol is
characteristic of essential tremor, whereas the presence of a pill-rolling rest tremor, bradykinesia, and rigidity is consistent with
Parkinson disease and argues against essential tremor.
In patients with parkinsonism, careful attention to the history is necessary to exclude secondary causes such as medications,
toxins, or trauma. Medications that block striatal dopamine receptors, such as metoclopramide and neuroleptics, can cause
drug-induced parkinsonism. Certain toxins such as MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and manganese (at
high levels of exposure) can also cause parkinsonism.
Consider evaluating patients with parkinsonism for osteoporosis and osteopenia. In a meta-analysis of 23 studies, Tornsey and
colleagues found evidence that individuals with Parkinson disease have an increased risk for osteoporosis and osteopenia.[35,
36] A pooled analysis of 2 of the studies, for example, indicated that in patients with Parkinson disease, the odds ratio for
developing osteoporosis, when compared with healthy controls, was 2.61, although the increase was lower in men than in
women.
Analysis of 14 studies found bone mineral densities in patients with Parkinson disease to be significantly lower at the hip, lumbar
spine, and femoral neck, whereas, after an examination of 9 studies, the investigators estimated that bone fracture risk is
doubled in Parkinson patients.[35, 36]
Early clinical features that suggest an atypical parkinsonism rather than Parkinson disease include the following[22] :
Falls at presentation or early in the disease
Poor response to levodopa
Symmetry at disease onset
Rapid disease progression
No tremor
Dysautonomia (eg, urinary incontinence, fecal incontinence, catheterization for urinary retention, persistent erectile
failure, prominent symptomatic orthostatic hypotension)
The atypical parkinsonisms are usually associated with little or no tremor, relatively early speech and balance difficulty, and little
or no response to dopaminergic medications. Multiple system atrophy (MSA) is relatively symmetric and characterized by
parkinsonism, often with some combination of autonomic, corticospinal, and cerebellar dysfunction. Progressive supranuclear
palsy (PSP) is relatively symmetric and characterized by parkinsonism with early falls (often in the first year) and a supranuclear
gaze palsy in which the patient has difficulty with voluntary down-gaze. Corticobasal ganglionic degeneration (CBD) is typically
very asymmetric and characterized by both cortical (difficulty identifying objects, apraxias) and basal ganglionic (usually marked
rigidity in an arm) features.
Lewy body disease is characterized by substantial cognitive dysfunction within 1 year of onset of parkinsonism. Hallucinations
are common.
Patients with onset of parkinsonism before age 40 years should be tested for Wilson disease, starting with serum ceruloplasmin
measurement and ophthalmologic evaluation for Kayser-Fleischer rings.
Differential Diagnoses
Alzheimer Disease
Cardioembolic Stroke
Chorea in Adults
Cortical Basal Ganglionic Degeneration
Lewy Body Dementia
Dopamine-Responsive Dystonia
Essential Tremor
Pantothenate Kinase-Associated Neurodegeneration (PKAN)
Huntington Disease
Lacunar Syndrome
Multiple System Atrophy
Neuroacanthocytosis
Neurological Manifestations of Vascular Dementia
Normal Pressure Hydrocephalus
Olivopontocerebellar Atrophy
Parkinson-Plus Syndromes
Progressive Supranuclear Palsy
Striatonigral Degeneration
Workup
Workup
Approach Considerations
Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and findings on routine magnetic
resonance imaging (MRI) and computed tomography (CT) scan are unremarkable. Positron emission tomography (PET) and
single-photon emission CT (SPECT) may show findings consistent with Parkinson disease, and olfactory testing may provide
evidence pointing toward Parkinson disease, but these studies are not routinely needed. (Olfactory testing can reveal hyposmia,
which may precede the motor signs of Parkinson disease by several years.[37] However, olfactory loss is not specific and can
also occur in Alzheimer disease.)
No laboratory or imaging study is required in patients with a typical presentation. Such patients are aged 55 years or older and
have a slowly progressive and asymmetric parkinsonism with resting tremor and bradykinesia or rigidity. Patients who do not
have tremor should generally be considered for MRI evaluation to exclude brain lesions such as stroke, tumor, or demyelination.
In patients with an unusual presentation, diagnostic testing may be indicated to exclude other disorders in the differential
diagnosis. Such tests may include serum ceruloplasmin, sphincter electromyography, or lumbar puncture.
Serum ceruloplasmin concentration is obtained as a screening test for Wilson disease in patients younger than 40 years who
present with parkinsonian signs. If the ceruloplasmin level is low, measurement of 24-hour urinary copper excretion and slit-lamp
examination for Kayser-Fleischer rings must be performed. Abnormal results on urinary sphincter electromyography have been
noted in patients with multiple system atrophy (MSA).
A substantial and sustained response to dopamine medications (dopamine agonists or levodopa) helps confirm a diagnosis of
Parkinson disease. It is unclear whether acute levodopa or apomorphine challenge has any advantage over clinical diagnostic
criteria.[22] Over time, diagnostic accuracy improves as the progression of signs and symptoms and response to medications
unfolds.
In the general community, there is a high diagnosis error rate between Parkinson disease and essential tremor. For movement
disorder neurologists, when an erroneous diagnosis of Parkinson disease is made, the most likely correct diagnoses are the
atypical parkinsonisms (MSA, progressive supranuclear palsy [PSP], corticobasal ganglionic degeneration [CBD]). Early in the
disease course, it may be very difficult to distinguish between Parkinson disease and the atypical parkinsonisms. These
disorders also do not have laboratory biomarkers, and, therefore, distinguishing among them is based on clinical criteria.
Olfactory testing may help differentiate Parkinson disease from PSP and CBD, but olfaction is also reduced in MSA.
Radiologic Studies
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is useful to exclude strokes, tumors, multi-infarct state, hydrocephalus, and the lesions of
Wilson disease. MRI should be obtained in patients whose clinical presentation does not allow a high degree of diagnostic
certainty, including those who lack tremor, have an acute or stepwise progression, or are younger than 55 years.
The following MRI indicates where a thalamic stimulator is typically placed.
Axial, fast spin-echo inversion recovery magnetic resonance image at the level of the posterior commissure. The typical target
for placing a thalamic stimulator is demonstrated (cross-hairs).
Below is a coronal MRI following bilateral subthalamic nuclei deep brain stimulation.
Postoperative coronal magnetic resonance image (MRI) demonstrating desired placement of bilateral subthalamic nuclei-
deep brain stimulation (STN-DBS) leads.
PET and SPECT scanning
Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scanning are useful
diagnostic imaging studies, but these are not routinely required. Different radioligands permit imaging of different components or
abnormalities within the brain.
At the onset of motor signs, patients with Parkinson disease show an approximately 30% decrease in18 F-dopa (fluorodopa)
uptake on PET imaging in the contralateral putamen.18 F-Dopa is taken up by the terminals of dopamine neurons and
converted to18 F-dopamine. The rate of striatal18 F accumulation reflects transport of18 F-dopa into dopamine neurons and its
decarboxylation to18 F-dopamine, which is stored in dopamine nerve terminals in the striatum. Thus,18 F-dopa PET imaging
provides an index of remaining dopamine neurons. However, this study is not widely available, is usually not covered by
insurance, and is currently generally considered a research tool.
Carbon-11 (11 C)-nomifensine and cocaine analogues such as123 I-beta-CIT (iodine-123-labeled carboxymethoxy-3beta-4-
iodophenyl-nortropane) and123 I-FP-CIT (fluoropropyl-CIT) bind to dopamine reuptake sites on nigrostriatal terminals and
provide an index of the remaining dopamine neurons. Ioflupane (123 I) (DaTscan) is a radiopharmaceutical agent that is
indicated for striatal dopamine transporter visualization using SPECT brain imaging to assist in the evaluation of adults with
suspected Parkinsonian syndromes (PSs). This agent may be used to help differentiate essential tremor from tremor due to PSs
(idiopathic Parkinson disease [IPD] and Parkinson-plus syndromes [PPS]).[1] Analysis of data from 2 clinical trials demonstrated
that the use of ioflupane with iodine-123 and single-photon emission computed tomography (SPECT) scanning to diagnose
early-stage Parkinson's disease performed as well as clinical assessment at 1-year follow-up.[38, 39]
Deficits on123 I SPECT scans indicate a dopamine deficiency syndrome but do not differentiate Parkinson disease from atypical
parkinsonisms, including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Ioflupane SPECT imaging
reveals a dopamine deficiency in Parkinson disease, MSA, PSP, corticobasal ganglionic degeneration, and Lewy body disease.
This study is normal in essential tremor, dystonic tremor, medication-induced parkinsonism or tremor, psychogenic disorders,
and in normal individuals.
Histologic Findings
Classic pathologic findings in Parkinson disease include degeneration of the neurons containing neuromelanin, especially in the
substantia nigra and the locus ceruleus. Surviving neurons often contain eosinophilic cytoplasmic inclusions called Lewy bodies
(see the following image). The primary biochemical defects are loss of striatal dopamine, which results from degeneration of
dopamine-producing cells in the substantia nigra, as well as hyperactivity of the cholinergic neurons in the caudate nucleus.
Lewy bodies are intracytoplasmic eosinophilic inclusions, often with halos, that are easily seen in pigmented neurons, as
shown in this histologic slide. They contain polymerized alpha-synuclein; therefore, Parkinson disease is a synucleinopathy.
Lewy bodies in the locus coeruleus from a patient with Parkinson disease.
Alpha-synuclein is a major structural component of Lewy bodies; all Lewy bodies stain for alpha-synuclein, and most also stain
for ubiquitin. Lewy 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
Parkinson disease. Lewy bodies are also found in the cortex, nucleus basalis, locus ceruleus, intermediolateral column of the
spinal cord, and other areas.
According to the Braak hypothesis, Lewy body pathology in the brain begins in the olfactory bulb and lower brainstem and
slowly ascends to affect dopamine neurons in the substantia nigra and, ultimately, the cerebral cortex.[40] Lewy body pathology
is also observed in autonomic nerves of the gut and heart.
Lumbar Puncture
Lumbar puncture should be considered if signs of normal-pressure hydrocephalus (NPH) are observed (eg, incontinence,
ataxia, dementia). In NPH, clinical signs characteristically improve after removal of about 20 mL of cerebrospinal fluid.
Dopa-responsive dystonia should be considered in patients with juvenile-onset dystonia and parkinsonism, particularly with
diurnal fluctuations in symptoms. In such patients, a trial of levodopa is critical. Additional tests for this condition include
measurement of CSF concentrations of biopterin, neopterin, and the neurotransmitter metabolites homovanillic acid (HVA), 5-
hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG). In both forms of dopa-responsive dystonia,
an altered pattern of decreases in these compounds is observed.
In the "Parkinson's Progression Markers Initiative" cross-sectional study of 63 drug-naive patients with early-stage PD and 39
healthy controls, CSF levels of the Alzheimer's biomarkers β-amyloid 1-42 (Aβ1-42), total tau (T-tau), tau phosphorylated at
threonine 181 (P-tau181), and α-synuclein were lower in the PD patients than in the controls. Aβ1-42 and P-tau181 were
significant predictors of Parkinson's disease, and T-tau and α-synuclein were associated with the severity of motor dysfunction.
In particular, lower Aβ1-42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant
PD phenotype, but were not associated with the tremor-dominant or intermediate phenotypes.[41, 42]
See Lumbar Puncture for detailed information on indications for the procedure, contraindications, and a step-by-step discussion
containing images and video on how to perform the procedure.
Treatment
Approach Considerations
The goal of medical management of Parkinson disease is to provide control of signs and symptoms for as long as possible while
minimizing adverse effects. Studies demonstrate that a patient's quality of life deteriorates quickly if treatment is not instituted at
or shortly after diagnosis.[43]
Symptomatic and neuroprotective therapy
Pharmacologic treatment of Parkinson disease can be divided into symptomatic and neuroprotective (disease modifying)
therapy. At this time, there is no proven neuroprotective or disease-modifying therapy.
Levodopa, coupled with carbidopa, a peripheral decarboxylase inhibitor (PDI), remains the gold standard of symptomatic
treatment for Parkinson disease. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the systemic circulation,
allowing for greater levodopa distribution into the central nervous system. Levodopa provides the greatest antiparkinsonian
benefit for motor signs and symptoms, with the fewest adverse effects in the short term; however, its long-term use is associated
with the development of motor fluctuations (“wearing-off”) and dyskinesias. Once fluctuations and dyskinesias become
problematic, they are difficult to resolve.
Monoamine oxidase (MAO)-B inhibitors can be considered for initial treatment of early disease. These drugs provide mild
symptomatic benefit, have excellent adverse effect profiles, and, according to a Cochrane review, have improved long-term
outcomes in quality-of-life indicators by 20-25%.[44]
Dopamine agonists (ropinirole, pramipexole) provide moderate symptomatic benefit and delay the development of dyskinesia
compared with levodopa. Proactively screen patients receiving oral dopamine agonists for adverse events. A review of the
Cochrane and PubMed databases from 1990 to 2008 found that these agents caused a 15% increase in adverse events such
as somnolence, sudden-onset sleep, hallucinations, edema, and impulse control disorders (eg, pathologic gambling, shopping,
and Internet use; hypersexuality; and hoarding).[45] Note that patients may be reluctant to mention these events or may not
attribute them to their treatment.
Symptomatic anti-Parkinson disease medications usually provide good control of motor signs of Parkinson disease for 4-6
years. After this, disability often progresses despite best medical management, and many patients develop long-term motor
complications, including fluctuations and dyskinesias. Additional causes of disability in late disease include postural instability
(balance difficulty) and dementia. Thus, symptomatic therapy for late disease requires different strategies.
Neuroprotective therapy aims to slow, block, or reverse disease progression; such therapies are defined as those that slow
underlying loss of dopamine neurons. Although no therapy has been proven to be neuroprotective, there remains interest in the
long-term effects of MAO-B inhibitors. Other agents currently under investigation include creatine and isradipine.
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; instead, the focus is on providing
adequate symptomatic benefit in the near term, with as few adverse effects as possible.
For patients who have motor fluctuations and dyskinesias that cannot be adequately managed with medication manipulation,
surgery is considered. The principal surgical option is deep brain stimulation (DBS), which has largely replaced neuroablative
lesion surgeries. Levodopa/carbidopa intestinal gel infusion is available in some countries and is in clinical trials in others,
including the United States.[12]
Nonmotor symptoms
It is now recognized that in Parkinson disease, nonmotor symptoms may be as troublesome as, or more troublesome than,
motor symptoms. Nonmotor symptoms can be categorized as autonomic, cognitive/psychiatric, and sensory[46] and may
include depression, dementia, hallucinations, rapid eye movement (REM) sleep behavior disorder (RMD), orthostatic
hypotension, and constipation. Nonmotor symptoms can also fluctuate, especially depression, pain, numbness,
paresthesia/dysesthesia, akathisia, and restless-legs syndrome. Recognition of nonmotor symptoms of Parkinson disease is
essential for appropriate management.[46]
Screen Parkinson disease patients for depression, and treat it when present. An evidence-based guideline from the American
Academy of Neurology (AAN) reports that physician recognition of depression is low in Parkinson disease, at less than 30% of
clinically proven cases. There are many factors that confound its diagnosis in these patients; and depression has the single
largest effect on the quality of life of patients with Parkinson disease.[26, 47]
In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations
included the following[48] :
Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction
Polyethylene glycol may be considered to treat constipation
Modafinil should be considered for patients who subjectively experience excessive daytime somnolence
For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that
are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for poor sleep
quality
Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but there are
insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that of restless-legs
syndrome
Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)
Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety,
and RMD
Symptomatic Therapy, Early Disease

Medications commonly used for symptomatic benefit of motor symptoms in early Parkinson disease include levodopa,
monoamine oxidase (MAO)-B inhibitors, and dopamine agonists.
Levodopa
Levodopa, coupled with a peripheral dopa decarboxylase inhibitor such as carbidopa, remains the standard of symptomatic
treatment for Parkinson disease. It provides the greatest antiparkinsonian benefit with the fewest adverse effects in the short
term. However, long-term use of levodopa is associated with the development of fluctuations and dyskinesias. Once fluctuations
and dyskinesias become problematic, they are difficult to resolve. These adverse effects are the reason to consider delaying the
initiation of levodopa if other alternatives are able to control symptoms.
Levodopa/carbidopa is introduced at a low dose and escalated slowly. Carbidopa inhibits the decarboxylation of levodopa to
dopamine in the systemic circulation, allowing for greater levodopa delivery into the central nervous system.
Currently available levodopa preparations in the United States include levodopa/carbidopa immediate-release (IR) tablets
(Sinemet), levodopa/carbidopa controlled-release (CR) tablets (Sinemet CR), and levodopa/carbidopa orally disintegrating
tablets (Parcopa). The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa IR, but it dissolves on the tongue
without the need to swallow it with water. The orally disintegrating tablet is not absorbed in the mouth but travels in the saliva to
absorption sites in the proximal small bowel (where other levodopa preparations are also absorbed).
Levodopa/carbidopa is also available in combination with entacapone, a catechol-O-methyltransferase (COMT) inhibitor. When
entacapone is given in conjunction with levodopa and carbidopa, plasma levels of levodopa are higher and more sustained than
after administration of levodopa and carbidopa alone. Levodopa/carbidopa/entacapone is useful in advanced Parkinson disease
in patients with motor fluctuations. In the STRIDE-PD (STalevo Reduction In Dyskinesia Evaluation) study, patients with early
Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo) developed more dyskinesia than patients treated with
levodopa/carbidopa; therefore, levodopa/carbidopa/entacapone is not recommended for treatment of early disease.[49]
Levodopa in combination with a dopa decarboxylase inhibitor is started at a low dose and slowly titrated to control clinical
symptoms. Most patients experience a good response on a daily levodopa dosage of 300–600 mg/day (usually divided 3 or 4
times daily) for 3–5 years or longer. Doses higher than those necessary to control symptoms adequately should be avoided,
because higher doses increase the risk for the development of dyskinesia.[50] If nausea occurs, the levodopa dose can be
taken immediately following a meal. Additional measures to alleviate nausea include adding extra carbidopa or introducing
domperidone (available outside the United States). Other side effects include dizziness and headache. In elderly patients,
confusion, delusions, agitation, hallucinations, and psychosis may be more commonly seen.
MAO-B inhibitors
MAO-B inhibitors, such as selegiline and rasagiline, may be used for early symptomatic treatment of Parkinson disease. These
medications provide mild symptomatic benefit, have excellent adverse 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, a dopamine agonist or levodopa) can
be added.
Selegiline is indicated as adjunctive therapy (5 mg every morning; maximum, 10 mg/day) in the treatment of Parkinson disease
in patients being treated with levodopa/carbidopa. Rasagiline is indicated for the treatment of the signs and symptoms of
Parkinson disease as initial monotherapy (1 mg/day) and as adjunctive therapy (0.5-1.0 mg/day) to levodopa. Potential side
effects include nausea, headaches, and dizziness.
Dopamine agonists
Initial treatment with a dopamine agonist, to which levodopa can be added as necessary, is associated with fewer motor
fluctuations and dyskinesias than levodopa alone in prospective, double-blind studies. Subsequent analyses of these studies
indicate that the benefit of dopamine agonists in delaying motor symptoms is due to their ability to delay the need for
levodopa/carbidopa.[51, 52] Commonly used dopamine agonists include pramipexole and ropinirole.
Dopamine agonists provide symptomatic benefit that is comparable to that with levodopa/carbidopa in early disease, but these
agents lack sufficient efficacy to control signs and symptoms by themselves in more advanced disease. Dopamine agonists
provide moderate symptomatic benefit and rarely cause fluctuations and dyskinesias by themselves, but they have more
adverse effects than levodopa, including sleepiness, hallucinations, edema, and impulse control disorders. However, these
adverse effects resolve upon lowering the dose or discontinuing the medication.
Dopamine agonists are commonly reserved for younger individuals (< 65-70 years) who are cognitively intact. When the
dopamine agonist (with or without an MAO-B inhibitor) no longer provides good control of motor symptoms, levodopa can be
added. However, dopamine agonists may provide good symptom control for several years before levodopa is required.
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 agonist before levodopa and add
levodopa/carbidopa when necessary. For patients with cognitive impairment and those older than 70 years—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 instead depend on levodopa/PDI (peripheral decarboxylase
inhibitor) as primary symptomatic therapy.
When introducing a dopamine agonist, it is important to start at a low dose and escalate slowly. The dose should be titrated
upward until symptoms are controlled, the maximum dose is reached, or adverse effects emerge.
The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension, hallucinations, somnolence, and
impulse control disorders. Nausea can usually be reduced by having the patient take the medication after meals. Domperidone,
a peripheral dopamine agonist available outside the United States, 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, and sexual activity. These adverse effects typically resolve with
reduction in dose or discontinuation of the medication. Patients should be warned not to drive if they are experiencing undue
sleepiness. They should also be warned about the possibility of impulse control disorders and the need to let their physician
know if such an effect occurs.
Anticholinergic agents
Anticholinergic agents can be used for patients who have disability due to tremor that is not adequately controlled with
dopaminergic medication, but these are not first-line drugs, because of their limited efficacy and the possibility of
neuropsychiatric side effects. Anticholinergic medications provide good tremor relief in approximately 50% of patients but do not
meaningfully improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication but not another, a
second anticholinergic agent usually can be 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 elderly persons.
One of the most commonly used anticholinergic is trihexyphenidyl. The initial dose of trihexyphenidyl should be low and
gradually increased. It is recommended to begin therapy with a single 1-mg dose. Dosage can be titrated by 1 mg each week or
so, until a total of 4-6 mg is given daily or until satisfactory control is achieved. Some patients may require higher doses.
Benztropine (Cogentin) is also commonly used, with an initial dose of 0.5-1 mg daily at bedtime. Dose can be titrated at weekly
intervals in increments of 0.5 mg to a maximum of 6 mg/day.
Amantadine
Amantadine is an antiviral agent that has antiparkinsonian activity. Its mechanism of action is not fully understood, but
amantadine appears to potentiate CNS dopaminergic responses. It may release dopamine and norepinephrine from storage
sites and inhibit the reuptake of dopamine and norepinephrine. Amantadine may offer additional benefit in patients experiencing
maximal or waning effects from levodopa.
Amantadine is commonly introduced at a dose of 100 mg per day and slowly increased to an initial maintenance dose of 100 mg
2 or 3 times daily. The most concerning potential side effects of amantadine are confusion and hallucinations. Common side
effects include nausea, headache, dizziness, and insomnia. Less frequently reported side effects include anxiety and irritability,
ataxia, livedo reticularis, peripheral edema, and orthostatic hypotension.
In a small, double-blind crossover study, amantadine was found to ameliorate pathologic gambling associated with Parkinson
disease.[53] However, in a large cross-sectional study, amantadine was associated with a higher prevalence of impulse control
disorders, including gambling.[54] Thus, further research is needed to understand the role of amantadine as a treatment or
cause of impulse control disorders in patients with Parkinson disease.
Symptomatic Therapy, Advanced Disease

Motor fluctuations
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 (IR) 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 about 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.
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 the following:
Adding a dopamine agonist, catechol-O -methyltransferase (COMT) inhibitor, or monoamine oxidase (MAO)-B inhibitor
Dosing levodopa more frequently
Increasing the levodopa dose
Adding intermittent levodopa inhaled doses
Switching from immediate-release (IR) to sustained-release (CR) levodopa/carbidopa or levodopa/carbidopa/entacapone
Continuous intrajejunal infusion of a carbidopa/levodopa enteral suspension[55]
In January 2015, the FDA approved a carbidopa/levodopa enteral suspension (Duopa) that is infused into the jejunum by a
portable pump. The efficacy of the enteral suspension to decrease off-time and increase on-time was shown in a multicenter,
international study. From baseline to 12 weeks, mean off-time decreased by 4.04 hours for 35 patients allocated to the
levodopa/carbidopa intestinal group compared with a decrease of 2.14 hours for 31 patients allocated to immediate-release oral
levodopa/carbidopa (p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 hours in the intestinal gel
group and 2.24 hours in the immediate-release oral group (p=0.0059).[55]
Safinamide (Xadago), a MAO-B inhibitor, was approved by the FDA in March 2017 as add-on treatment for patients with
Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes. It is the first new chemical
entity approved in the United States in more than 10 years. Approval was based on 2 phase-III trials that included nearly 1200
patients who had PD with motor fluctuations. Results showed that safinamide as add-on treatment to levodopa/carbidopa
provided a significant reduction in off-time and a significant increase in on-time without troublesome dyskinesia in patients
experiencing motor fluctuations.[56, 57]
Levodopa inhaled (Inbrija), a dopamine agonist, was approved in December 2018 for intermittent treatment of "off" episodes in
patients who are already treated with oral carbidopa/levodopa. The inhaled dosage form bypasses the digestive system, thereby
providing a quick onset of action as soon as 10 minutes. Approval was based on the phase 3 SPAN-PD trial (N = 339). The
change at week 12 in UPDRS III score was -9.83 for patients receiving the 84-mg dose compared with -5.91 for the group taking
placebo (P = 0.009).[132]
Unless limited by the emergence of peak-dose symptoms such as dyskinesia or hallucinations, dopaminergic therapy should be
increased until off-time is eliminated. Once-daily formulations of the dopamine agonists ropinirole and pramipexole are now
available. These medications appear to provide efficacy and safety similar to the IR formulations that are administered 3 times
daily.[58]
Dyskinesia
By several months to years after the introduction of levodopa, many patients develop peak-dose dyskinesia consisting of
choreiform, which is 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 progressive decrease 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 non-troublesome dyskinesia; or on with troublesome dyskinesia (see the following image). The goal of
medical management is to minimize off time and time on with troublesome dyskinesia. Stated another way, the goal is to
maximize on time without troublesome dyskinesia.
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 goal of therapeutic management is to minimize off time and on
time with troublesome dyskinesia. Copyright Robert Hauser, 1996. Used with permission.
Treatment of motor fluctuations with dyskinesia
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 functional time throughout 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 on the levodopa/carbidopa CR formulation, switching to levodopa/carbidopa IR 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 of this strategy is using liquid levodopa, a solution with which the
dose can be titrated finely and administered every hour.
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 period. Because of the
potential risk of hepatotoxicity with tolcapone (Tasmar), liver function test monitoring is required, and this medication should be
used only in patients who are experiencing motor fluctuations on levodopa that cannot be adequately controlled with other
medications. If dyskinesia occurs, 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 (Comtan) is a COMT inhibitor that does not cause hepatotoxicity; liver function tests are not required with this
medication. Levodopa/carbidopa/entacapone (Stalevo) is currently available as a drug combination for Parkinson disease.
Similarly, dopamine agonists can be added to levodopa to try to smooth the response. If the patient has both fluctuations and
dyskinesias on levodopa, adding a dopamine agonist is likely to decrease the disease severity and could delay dyskinesias and
motor fluctuations; then, an attempt can be made to lower the levodopa dose.
The FDA approved amantadine (Gocovri) extended-release (ER) capsules for the treatment of dyskinesia in Parkinson disease
patients receiving levodopa-based therapy, with or without concomitant dopaminergic medications. Amantadine ER, previously
known as ADS-5102, is the first drug FDA-approved for this indication.
The safety and efficacy of amantadine ER was seen in two Phase 3 controlled trials in Parkinson disease patients with
dyskinesia. In the Easy LID trial, amantadine ER-treated patients had statistically significant and clinically relevant reductions in
dyskinesia as per the Unified Dyskinesia Rating Scale (UDysRS) total score vs. placebo at Week 12 (37% vs. 12%). In the Easy
LID 2 trial, amantadine ER-treated patients had a 46% reduction in UDysRS compared with 16% in the placebo arm. For both
studies, treatment with amantadine ER increased functional time daily (ON time without troublesome dyskinesia) for patients at
Week 12 (3.6 hours and 4.0 hours, respectively) vs. placebo (0.8 hour and 2.1 hours, respectively).[59, 60]
This should be considered for patients who have clinically relevant dyskinesia and who appear likely to be able to tolerate this
medication. Results from the 3-month, parallel-group, washout AMANDYSK (AMANtadine for DYSKinesia) study showed that
amantadine treatment maintained its antidyskinetic effect over several years in patients with Parkinson disease and levodopa-
induced dyskinesia.[61, 62]
The principal side effects of amantadine are hallucinations and confusion, so the drug is usually not appropriate for patients with
preexisting cognitive dysfunction.
For patients who have motor fluctuations and dyskinesia that cannot be adequately managed with medication manipulation,
surgery is considered.
Tremor
Levodopa/carbidopa, dopamine agonists, and anticholinergics each provide good benefit for tremor in approximately 50-60% of
patients. If a patient is experiencing troublesome tremor and if symptoms are not controlled adequately with one medication,
another should be tried. If the tremor is not controlled adequately with medication, surgical therapy may be considered at any
time during the disease.
Bradykinesia
A study published in Neurology found that laser shoes can improve freezing episodes in patients with PD. The shoes are
specially designed to emit a laser beam on the ground ahead, providing a visual cue to the patient and a target to aim for. In the
study, the shoes cut freezing episodes and their overall duration by 49.5% when patients were off medication and 37.7% when
patients were on medication.[63]
Putative Neuroprotective Therapy

Neuroprotective therapies are defined as those that slow underlying loss of 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. At the current time, the greatest interest in possible neuroprotection resides
with the monoamine oxidase (MAO)-B inhibitors, selegiline, and rasagiline. Other agents of interest include creatine and
isradipine. Clinical trials have not provided support for neuroprotective effects for vitamin E or coenzyme Q10.
Selegiline
Selegiline (Eldepryl, Zelapar) is an irreversible inhibitor of MAO-B. In humans, brain dopamine is metabolized by MAO-B, and
the blockade of this enzyme will reduce the metabolism of dopamine. Selegiline was shown conclusively to delay the need for
levodopa therapy in early Parkinson disease, in the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of
Parkinsonism) study.[64, 65] The Parkinson Study Group evaluated the ability of selegiline and tocopherol to delay progression
of clinical disability in early Parkinson disease by randomizing 800 patients to receive selegiline (10 mg/day) or placebo and
tocopherol (2000 IU/day) or placebo. Patients who received selegiline, with placebo or with tocopherol, experienced a significant
delay in the need for levodopa therapy. Patients who received placebo required levodopa at a projected median of 15 months
from enrollment, whereas those who received selegiline required levodopa
ataprojectedmedianof24monthsafterenrollment.Tocopherolhadnoeffectonprogression of disability.[64, 65]
Because selegiline was observed to provide a small but statistically significant symptomatic (early) benefit, it is not possible to
determine whether a neuroprotective effect contributed to the delay in need for levodopa in the DATATOP study.[64, 65]
In another study, patients with early Parkinson disease who received selegiline over a 7-year period experienced less clinical
progression and required less levodopa than patients receiving placebo.[66] In this study, patients with early Parkinson disease
were randomized to selegiline or placebo, and levodopa was added as needed. After 5 years, patients who were treated with
placebo had Unified Parkinson Disease Rating Scale (UPDRS) scores that were 35% higher (worse) than those treated with
selegiline, even as they were receiving 19% higher doses of levodopa.[66] This is a striking finding, considering that as
monotherapy in early disease, selegiline provides only modest symptomatic improvement.
Selegiline is the medication that first garnered wide interest as a possible neuroprotective agent for Parkinson disease.
Laboratory investigations continue to provide evidence that selegiline affords a neuroprotective effect for dopamine neurons
independent of MAO-B inhibition. Selegiline was reported to protect dopamine cells in mice from MPTP (1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine) toxicity, even when the agent was administered after a delay sufficient to allow the oxidation of MPTP
to MPP+ (1-methyl-4-phenylpyridinium),[67] an effect that cannot be attributed to MAO-B inhibition.
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 antiapoptotic proteins. Evidence indicates that one of
selegiline's metabolites, desmethylselegiline, is the active agent for neuroprotection. It is possible that selegiline's amphetamine
metabolites may interfere with its neuroprotective actions.
Rasagiline
Rasagiline (Azilect) is also an MAO-B inhibitor that exhibits neuroprotective effects in cell culture and animal models. Possible
disease-modifying effects of rasagiline were studied in 2 large, delayed-start studies. In such studies, subjects are randomized
to treatment with active study medication or to placebo followed by active study medication. This creates 2 phases within the
study. In phase I, one group is on placebo, and the other is on active study medication; in phase II, both groups are receiving
active study medication. If phase II is long enough to allow full wash-in of symptomatic effects, any differences between the
groups at the end of the study should be due to enduring benefits (ie, disease modification) that accrue only to the group that
received active study medication during phase I.
Stated another way, in a delayed-start design, half of the subjects in the study take the trial drug from day 1 and the other half
take placebo. However, halfway through the study, the placebo group is switched from placebo to the trial drug. If the drug is
truly beneficial in slowing progression of the disease, those that started the trial on placebo should never catch up, in terms of
disease progression, to those who were given the trial drug from the beginning of the study.
ADAGIO and TEMPO studies
In October 2011, the US Food and Drug Administration’s (FDA’s) Peripheral and Central Nervous System Drugs Advisory
Committee voted against approval of an indication for disease-modifying effects for rasagiline. The advisory committee
determined that the 2 delayed-start rasagiline studies did not provide compelling evidence that rasagiline slows progression of
Parkinson disease. These trials were the ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily)[68, 69]
and TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients)[70, 71] studies, which are discussed below.
In the TEMPO study, patients were randomized to treatment with rasagiline 1 mg/day for 12 months; rasagiline 2 mg/day for 12
months; or placebo for 6 months, followed by rasagiline 2 mg/day for 6 months.[70] Rasagiline administered at a dosage of 1 or
2 mg/day for the first 6 months resulted in improved Unified Parkinson Disease Rating Scale (UPDRS) scores relative to
placebo; there was also a higher proportion of patients with treatment responses in the active treatment groups than in the
placebo group.[70] In addition, both of the rasagiline groups showed significant differences, compared with the placebo group, in
the motor and activities of daily living (ADL) subscales of the UPDRS and in the Parkinson Disease Quality of Life (PDQUALIF)
scale.[70]
Over the 12 months of the TEMPO study, patients who were initially treated with placebo had a greater progression in clinical
symptomatology as assessed by UPDRS scores than did patients who were treated with rasagiline for the full 12 months. This
finding suggested that there was an effect over and above a simple symptomatic effect and potentially consistent with a disease-
modifying effect.[72] When the TEMPO investigators looked at the long-term (6.5-year follow-up period) outcome of early
rasagiline therapy relative to late therapy in early Parkinson disease, patients in the early rasagiline treatment group—who
received the drug from the beginning of the TEMPO study—had significantly less worsening of their total UPDRS scores than
patients in the delayed-start group, even as investigators added other antiparkinson medications as needed.[71]
In the large and rigorous delayed-start study called ADAGIO, patients with early Parkinson disease were randomized to
rasagiline 1 mg/day for 18 months; rasagiline 2 mg/day for 18 months; placebo for 9 months, followed by rasagiline 1 mg/day for
9 months; or placebo for 9 months, followed by rasagiline 2 mg/day for 9 months. Results demonstrated that rasagiline at 1 or 2
mg/day was associated with a slower rate of worsening in the active drug groups, relative to the placebo groups.[69] Over 18
months, rasagiline 1 mg/day started early resulted in less worsening in mean total UPDRS score than when it was started late.
However, for the groups that received rasagiline 2 mg/day, there was no difference at 18 months between the early-start and
delayed-start groups.[69]
Based on their findings, the ADAGIO investigators concluded that early treatment with rasagiline at a dose of 1 mg/day provided
benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg/day
did not.[69] They speculated that the effect of the 2-mg dose on symptoms may have masked any disease-modifying effects in
patients with mild Parkinson disease; they also noted that it was possible that results with 1 mg/day were false positive, rather
than the results with 2 mg/day being false negative.[69]
Thus, there remains interest as to whether selegiline and rasagiline improve long-term outcome for Parkinson disease patients,
but this is not definitively proven, and the mechanism is unclear.
Levodopa
Clinical trial data suggest that levodopa therapy in early Parkinson disease can potentially slow progression or has a prolonged
effect on the symptoms of the disease.[73] However, neuroimaging studies also indicate that loss of nigrostriatal dopamine
nerve terminals may be accelerated or the dopamine terminals may be modified with use of levodopa.[73] In a study by
Parkkinen et al that evaluated whether chronic levodopa use accelerates pathologic cerebral processes in parkinsonism, the
investigators did not find such a progression based on nigral neuronal count and Lewy body pathology.[74] Nonetheless, the
lowest dose that is necessary to maintain good function should be used to avoid motor complications.[23] Additional research is
needed to determine whether levodopa accelerates, slows, or has no effect on disease progression.
Dopamine agonists
Dopamine agonists have been used to provide symptomatic relief in early Parkinson disease. In vivo experiments have
demonstrated that the ergot and nonergot dopamine agonists protect cultured cells from death due to oxidative damage. Clinical
data in patients with early Parkinson disease provide neuroimaging results that suggest a possible neuroprotective effect.[73,
75] Various studies have been conducted with ropinirole and pramipexole; however, definitive neuroprotection cannot be
confirmed on the basis of these studies.[76, 77]
Deep Brain Stimulation

Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease for the following reasons:
It does not involve destruction of brain tissue
It is reversible
It can be adjusted as the disease progresses or adverse events occur
Bilateral procedures can be performed without a significant increase in adverse events
Deep brain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of Parkinson disease largely
because long-term complications of levodopa therapy result in significant disability over time. 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.
Surgery for movement disorders previously involved predominantly destructive lesioning of abnormally hyperactive deep brain
nuclei; however, the observation that high-frequency electrostimulation in the ventral lateral nucleus (VL) of the thalamus
eliminates tremors in patients undergoing thalamotomy led to investigation of long-term DBS as a reversible alternative to
lesioning procedures.
Continued refinement of the knowledge of basal ganglia circuitry and Parkinson disease pathophysiology has narrowed the
focus of movement disorder surgery to 3 key gray-matter structures: the thalamus, the globus pallidus, and the subthalamic
nucleus (STN). Currently, the STN is the most commonly targeted site for Parkinson disease. (See the following image.)
Sagittal section, 12 mm lateral of the midline, demonstrating the subthalamic nucleus (STN) (lavender). The STN is one of the
preferred surgical targets for deep brain stimulation to treat symptoms of advanced Parkinson disease.
DBS surgery includes subthalamic nucleus (STN) stimulation, globus pallidus interna (GPi) stimulation, and thalamic deep brain
stimulation (see the following images). The UK National Collaborating Centre for Chronic Conditions notes the following
indications for STN and GPi in patients with Parkinson disease[23] :
The presence of motor complications refractory to medical therapy
The absence of significant comorbidities in a biologically fit individual
The absence of significant mental health problems (eg, depression, dementia)
Response to levodopa
A key to patient selection is that appropriate patients still experience a good response to levodopa, but that response cannot be
adequately maintained through the day or is complicated by excessive dyskinesia.
The deep brain stimulating lead is equipped with 4 electrode contacts, each of which may be used, alone or in combination,
for therapeutic stimulation.
Implantation of the deep brain stimulation (DBS) lead.
Insertion of an electrode during deep brain stimulation for Parkinson disease.
Thalamic DBS has been used in patients with predominantly severe and disabling tremor.[23] However, this surgery is now
rarely used in patients with Parkinson disease, because it has been shown that other symptoms continue to progress, causing
significant disability that is not controlled by thalamic DBS.
Recent landmark studies have demonstrated the effectiveness of STN and GPi DBS for appropriate Parkinson disease patients.
[78] In a randomized, controlled trial of 255 patients enrolled in the Veterans Affairs (VA) Cooperative Studies Program (CSP)
trial for patients with advanced Parkinson disease, bilateral DBS (STN and GPi) was more effective than best medical therapy in
improving on time without troublesome dyskinesia, motor function, and quality of life at 6 months; however, DBS was associated
with an increased risk of serious adverse events.[79] In the same study, when the 2-year outcomes of 147 patients who received
STN DBS and 152 patients who received GPi DBS were compared, motor function and adverse events were not significantly
different between the 2 sites.[80] However, those who received STN DBS had a greater reduction in dopaminergic medications,
and individuals who received GPi DBS had significantly less depression.[80]
Investigators from the EARLYSTIM Study Group reported that relative to medical therapy alone, STN DBS in conjunction with
medical therapy offers benefits earlier in the course of PD, before the appearance of severe disabling motor complications.[81,
82] Moreover, subthalamic stimulation plus medical therapy was superior to medical therapy alone on several key measures of
quality of life and motor function. However, 54.8% of the patients in the DBS group suffered serious adverse events, compared
to 44.1% of those in the medical-therapy group[81, 82] ; 17.7% of patients suffered serious adverse events related to surgical
implantation or the neurostimulation device.
A study by Foltynie assessed 79 consecutive patients who underwent bilateral subthalamic nucleus DBS at the National
Hospital for Neurology and Neurosurgery using an MRI-guided surgical technique without microelectrode recording.[83] At a
median follow-up period of 12-14 months, a mean improvement of 27.7 points (standard deviation, 13.8) was noted in the off-
medication motor part of the Unified Parkinson Disease Rating Scale (UPDRS III), equivalent to a mean improvement of 52%.
Significant improvements in dyskinesia duration, disability, and pain were noted. This suggests that in well-selected patients with
Parkinson disease, image-guided STN DBS without microelectrode recording can lead to substantial improvements in motor
disability and improvements in quality of life, with very low morbidity.
A randomized trial by Moreau et al assessed the effectiveness of the drug methylphenidate in improving gait disorders and
freezing of gait in patients with advanced Parkinson disease without dementia who also received subthalamic nucleus
stimulation (STN). Eighty-one patients from 13 movement disorders departments in France were randomly assigned to
methylphenidate or placebo for 90 days. Compared with patients in the placebo group, patients in the methylphenidate group
used fewer steps at 90 days. These results suggest methylphenidate may improve gait hypokinesia and freezing although
further study is needed to determine long-term risks.[84]
There is evidence that long-term motor improvement from STN DBS is sustained overall. However, axial signs progressively
decline over time and contribute to a waning of the initial benefit of this procedure.[85]
Although not specifically approved by the Food and Drug Administration (FDA) for pain, STN DBS may be effective in improving
specific types of pain related to Parkinson disease,[86, 87] such as musculoskeletal pain[86, 88] and dystonic pain. However,
there is a risk of postoperative deterioration of somatic pain exacerbated by Parkinson disease and radicular/peripheral
neuropathic pain due to lumbar spine diseases. Patients with central pain have had a poor response to STN DBS.[86]
STN DBS may result in either a favorable or an unfavorable outcome in patients with Parkinson disease and impulse control and
related disorders.[89] Although there may be resolution or improvement of impulse control disorders following STN DBS, the
procedure may also induce, exacerbate, reveal, or have no effect on these conditions.[89]
In 2017, the FDA approved the Vercise DBS system to treat symptoms of Parkinson disease. The device is a rechargeable
implantable pulse generator with a potential battery life of 15 years. It has been available in Europe since 2012.[90]
(See Deep Brain Stimulation forParkinson Disease for a more extensive discussion of deep brain stimulation in this setting,
including mechanisms of action, advantages and disadvantages, and stages of the procedure.)
Neuroablative Lesion Surgeries

Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson disease. Lesion
surgeries for Parkinson disease have largely been replaced by deep brain stimulation (DBS). During neuroablation, a specific
deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to heat the lesioning
electrode tip to the prescribed temperature in a controlled fashion.
Thalamotomy and pallidotomy
Thalamotomy involves destruction of a part of the thalamus, generally the ventralis intermedius (VIM), to relieve tremor. The VIM
nucleus is considered the best target for tremor suppression, with excellent short- and long-term tremor suppression in 80-90%
of patients with Parkinson disease. Thalamotomy has little effect on bradykinesia, rigidity, motor fluctuations, or dyskinesia.
When rigidity and akinesia are prominent, other targets, including the globus pallidus interna (GPi) and subthalamic nucleus
(STN), are preferred.
Svenillson and Leksell described ventral posterior pallidotomy in the 1960s[91] ; however, their report was largely overlooked.
The original pallidotomy target was in the medial and anterodorsal part of the nucleus. This so-called medial pallidotomy
effectively relieved rigidity but inconsistently improved tremor. Leksell subsequently moved the target to the posteroventral and
lateral GPi, resulting in sustained improvement in as many as 96% of patients. In 1992, Laitinen et al reported reduced tremor,
rigidity, akinesia, and levodopa-induced dyskinesia in 38 patients treated with pallidotomy, prompting a reappraisal of the
procedure performed with more modern techniques.[92]
Pallidotomy involves destruction of a part of the GPi. 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.
The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual field.
This complication occurs when the GPi lesion extends into the optic tract, which lies immediately below the GPi. The risk of
visual-field deficit is reduced greatly by accurate delineation of the ventral GPi border by microelectrode recording. Less
frequent complications (< 5%) include injury to the internal capsule, facial paresis, and intracerebral hemorrhage (1-2%).
Abnormalities of speech, swallowing, and cognition may also be observed.
Bilateral pallidotomy is not recommended because complications are relatively common and include speech difficulties,
dysphagia, and cognitive impairment.
Subthalamotomy
Hyperactivity of the excitatory STN projections to the GPi is a crucial physiologic feature of Parkinson disease. Subthalamotomy
involves destruction of a part of the STN. Although lesioning the STN usually has been avoided because of the concern about
producing hemiballismus, results obtained by experimental lesions of the STN in animals and humans suggest that
subthalamotomy may be performed safely and may reverse parkinsonism dramatically. Subthalamotomy studies have shown
significant improvements in the cardinal features of Parkinson disease, as well as the reduction of motor fluctuations and
dyskinesia.
Preoperative Evaluation
Good surgical outcomes begin with careful patient selection and end with attentive, detail-oriented postoperative care. The
authors believe that this level of care is best provided by a multidisciplinary team that includes a movement disorder neurologist,
a neurosurgeon who is well-versed in stereotactic technique, a neurophysiologist, a psychiatrist, and a neuropsychologist.
Additional support from neuroradiology and rehabilitation medicine is essential.
First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection is particularly important for
successful subthalamic nucleus (STN) deep brain stimulation (DBS), because a number of factors determine positive surgical
outcome.[93, 94] These can be summarized as follows:
A diagnosis of Parkinson disease
Positive response to levodopa
Absence of atypical parkinsonian features
Advanced disease, virtually unmanageable with dopaminergic medications
Relatively young age; however, advanced age (>75 years) is not an absolute contraindication to surgery (if a patient
otherwise meets the selection criteria for a procedure and the quality of life is predicted to improve substantially, surgery
should be offered)
No significant cognitive impairment
Absence of active psychiatric disease
Good social support and access to programming
Potential surgical candidates are then evaluated by the neurosurgeon, who determines whether the patient is indeed a surgical
candidate and decides which procedure(s) would benefit the patient most. Close collaboration between the neurologist and the
neurosurgeon aids the decision-making process, minimizing patient confusion and stress. If the neurologist and neurosurgeon
agree that the patient is a good surgical candidate, further workup includes the following:
Brain magnetic resonance imaging (MRI) to rule out comorbid conditions and to assess the degree of brain atrophy;
significant atrophy may increase the risk of perioperative hemorrhage
Detailed neuropsychological testing to rule out cognitive impairment, which can be worsened by the surgical procedure
A psychiatrist with expertise in psychiatric complications of movement disorders may be consulted to rule out active psychiatric
disease and screen for relevant past psychiatric history that may pose a contraindication to surgery (eg, major depression,
suicidality).
A fluorodopa positron emission tomography (PET) scan may be performed in the unusual circumstance of diagnostic
uncertainty. A medical evaluation is performed to determine the patient's general fitness for surgery.
Surgery is reserved for patients with disabling motor fluctuations and dyskinesia or disabling tremor that cannot be adequately
controlled with medications. Key points to consider are as follows:
Ablative surgery such as thalamotomy, pallidotomy, and subthalamotomy have largely been replaced by DBS
Thalamic DBS is offered to the minority of patients with Parkinson disease who have predominant and disabling tremor
(more commonly, this procedure is performed on patients with disabling essential tremor)
Bilateral STN DBS (or globus pallidus interna [GPi] DBS) is offered to patients with advanced Parkinson disease with
disabling motor fluctuations and/or dyskinesia or disabling tremor that cannot be adequately controlled by medications;
outcomes have been shown to be similar after STN and GPi DBS
Before surgery, the patient should be informed that these procedures do not cure Parkinson disease and that progression
is expected
Neural Transplantation
Neural transplantation is a potential treatment for Parkinson disease, because the most significant 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.
Transplantation of autologous adrenal medullary cells and fetal porcine cells has not been found to be effective in double-blind
studies and has been abandoned. Although open-label studies of fetal dopaminergic cell transplantation yielded promising
results, 3 randomized, double-blind, sham-surgery–controlled studies found no net benefit. In addition, some patients receiving
these transplants developed a potentially disabling form of dyskinesia that persisted even after withdrawal of levodopa. Features
such as gait dysfunction, freezing, falling, and dementia are likely due to nondopaminergic pathology and hence are unlikely to
respond to dopaminergic grafts.[95]
Lewy body–like inclusions have been found in grafted nigral neurons in long-term transplant recipients; these inclusions stained
positively for alpha-synuclein and ubiquitin and had reduced immunostaining for dopamine transporter, suggesting that
Parkinson disease may affect grafted cells.[14]
Human retinal pigment epithelial cells produce levodopa, and retinal pigment epithelial cells in gelatin microcarriers have been
implanted into the putamen in preliminary studies. A phase II double-blind, randomized, multicenter, sham-surgery–controlled
study of this technique has been completed.[96, 97] Parkinson disease patients received no benefit from this procedure
compared to sham surgery. In addition, in one case study, postmortem examination in a patient who died 6 months after surgical
implantation of 325,000 retinal pigment epithelial cells found only 118 surviving cells.[98]
Gene Therapy
Several studies have 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. Three investigational strategies that use gene transfer for targeted
protein expression are as follows[99] :
Improving dopamine availability to the striatum using more continuous delivery,
Reducing STN activity with local induction of gamma-aminobutryic acid (GABA) expression
Protection/restoration of nigrostriatal neuronal function with trophic factor expression
A double-blind, phase II, randomized, controlled trial of gene delivery of the trophic factor neurturin via an adeno-associated
type-2 vector (AAV2) in Parkinson patients aged 30-75 years suggested mild efficacy. Further studies are ongoing.[100]
Management of Psychiatric Comorbidities

Dementia
Although no specific therapy exists for dementia, the American Academy of Neurology evaluated the evidence regarding the use
of cholinesterase inhibitors in Parkinson disease dementia.[101] Based on their review, they suggested that rivastigmine
(Exelon) and donepezil (Aricept) are probably effective in treating Parkinson disease dementia. Anticholinergic drugs used for
the treatment of motor symptoms of Parkinson disease may exacerbate memory impairment. When possible, avoid these
medications.
Depression
Depression is one of the most common nonmotor symptoms of Parkinson disease, occurring in approximately 35% of patients.
[102, 103] This condition is more common in patients with Parkinson disease than in the general elderly population and in those
with chronic conditions such as osteoarthritis. Depression in Parkinson disease has a profound impact on quality of life and is
associated with reduced function, cognitive impairment, and increased caregiver stress.
A systematic review of prevalence studies of depression in Parkinson disease found that 17% of patients present with major
depression, 22% with minor depression, and 13% with dysthymia[104] Moreover, multiple studies have found that a history of
depression is a risk factor for the subsequent development of Parkinson disease.[105]
Imaging, cerebrospinal fluid, and autopsy studies indicate that depression in Parkinson disease is associated with dysfunction of
basal ganglia dopaminergic circuits that project to the frontal lobes, as well as noradrenergic limbic and brainstem structures.
[103] Whether serotonin (5-HT) dysfunction plays a role in depression in PD is unclear.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used medications to treat depression in Parkinson
disease in clinical practice. However, several randomized controlled trials, systematic reviews, and meta-analyses have
suggested that SSRIs may be no more effective than placebo in this situation.[47, 103, 106]
Positive results in randomized clinical trials have been demonstrated for nortriptyline (a tricyclic antidepressant [TCA] with
serotoninergic and adrenergic activity), desipramine (a predominantly noradrenergic reuptake inhibitor TCA), venlafaxine (a
serotonin-noradrenaline uptake inhibitor), citalopram (an SSRI), and paroxetine (an SSRI).[103] For example, in Parkinson
disease patients that were diagnosed with depressive disorder or operationally-defined subsyndromal depression, venlafaxine
extended release or paroxetine significantly reduced scores on the Hamilton Rating Scale for Depression compared to placebo.
Both venlafaxine and paroxetine were well tolerated and did not worsen motor function.[107]
There is a suggestion that noradrenergic or dual action (noradrenergic/serotoninergic) antidepressants may be more effective
for treating depression in Parkinson disease than SSRIs. However, whether this is an artifact of clinical-trials methodology is not
yet clear, and more research is necessary.
Antiparkinsonian medications can also exert an antidepressant effect. In a large, randomized trial, pramipexole (mean daily
dose, 2.18 mg) significantly reduced depression scores relative to placebo.[108] The monoamine oxidase (MAO)-B inhibitor
selegiline was also demonstrated to provide an antidepressant effect in patients with early Parkinson disease who were not
clinically depressed.[109]
Preliminary studies suggest that repetitive transcranial magnetic stimulation (rTMS) may be effective for depression in Parkinson
disease, but more research is required. Electroconvulsive therapy (ECT) can be considered for refractory moderate to severe
depression.
Psychotic symptoms (hallucinations or delusions)
Antiparkinsonian drugs can trigger psychosis in patients with Parkinson disease. In Parkinson disease patients with psychosis,
antiparkinsonian medications other than levodopa should be withdrawn in an effort to resolve psychosis while maintaining motor
control with levodopa. In individuals with only mild hallucinations that are well tolerated, active antipsychotic treatment may not
be necessary.
Pimavanserin (Nuplazid) was approved in April 2016 for treatment of hallucinations and delusions associated with Parkinson
disease psychosis. It is the first drug to be approved for this condition. It is a selective serotonin inverse agonists (SSIA). It not
only preferentially targets 5-HT2A receptors, but also avoids activity at dopamine and other receptors commonly targeted by
antipsychotics. Efficacy was shown in a 6-week clinical trial (n=199), where it was shown to be superior to placebo in decreasing
the frequency and/or severity of hallucinations and delusions without worsening the primary motor Parkinson disease symptoms
(p=0.001).[110]
Use of some other typical antipsychotics can exacerbate motor symptoms of Parkinson disease and should be avoided.[23]
Quetiapine is the atypical neuroleptic agent most commonly used by movement-disorder experts, because it rarely exacerbates
motor symptoms and blood monitoring is not required. However, its efficacy has not been confirmed in clinical trials. Quetiapine
is used in Parkinson disease at doses much lower than those used in schizophrenia. It is usually introduced at a dose of 25 mg
at bedtime and can be increased to 50 mg or more at bedtime as necessary.
Clozapine can also be used, but blood monitoring is required due to its potential for agranulocytosis and other severe side
effects.[23, 111] For this reason, clozapine is usually reserved for patients who are not adequately controlled with quetiapine.
Other atypical neuroleptics generally have more potential to worsen Parkinson disease motor symptoms than quetiapine and
clozapine.
Anxiety
The 2010 American Academy of Neurology (AAN) practice parameter on the treatment of nonmotor symptoms in Parkinson
disease found insufficient evidence to support or refute the treatment of anxiety in Parkinson disease with levodopa.[48]
However, SSRIs and venlafaxine (Effexor, Effexor XR) may be beneficial. Buspirone is well tolerated but has not been studied in
this population. Benzodiazepines can be considered, but adverse effects such as cognitive impairment, somnolence, and
balance problems may be concerning. Behavior modification techniques can play an important role in the treatment of anxiety.
[112]
Impulse behaviors
Cognitive-behavioral therapy (CBT) can help control impulse behaviors in PD. In a study of 45 patients with idiopathic PD and
associated impulse control behaviors that had not responded to standard treatment, CBT significantly improved symptom
severity, neuropsychiatric disturbances, and depression and anxiety levels. Of the 45 patients, 17 were randomly assigned to a
6-month wait list for CBT along with standard medical care and 28 were randomized to CBT starting immediately. Among the 28
patients in the treatment group, 58% completed all 12 sessions of CBT and 88% completed at least 6. Three-quarters of those
receiving the treatment had improved symptom severity compared with only about a third of those who did not receive the
therapy.[113, 114]
In a placebo-controlled pilot study of 50 patients with idiopathic PD who developed impulse control disorder (ICD) symptoms
while receiving dopamine agonist treatment, Papay and colleagues found that the opioid antagonist naltrexone improved ICD
symptoms, as measured on a PD-specific rating scale.[115, 116]
Naltrexone was administered at 50 mg daily for 4 weeks and then increased to 100 mg daily for 4 weeks in nonresponders. The
difference in response rate on the Clinical Global Impression-Change (CGI-C) scale between the naltrexone (54.5%) and
placebo (34.8%) groups was not significant (P = 0.23). Estimated changes on the patient-completed Questionnaire for
Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) from baseline to week 8, however, significantly
favored naltrexone: a change of 14.9 points for naltrexone vs 7.5 points for placebo (P = 0.04). Nausea and headache were the
most common side effects of naltrexone treatment.[115, 116]
Sleep disturbances
Benzodiazepines can be helpful in the treatment of rapid eye movement (REM) sleep behavior disorder (RBD), and obstructive
sleep apnea (OSA) can be treated with positive airway pressure with either continuous pressure or bilevel pressure. Sleep
hygiene techniques include avoiding stimulants/fluids near bedtime, avoiding heavy late-night meals, and following a regular
sleep schedule.[112, 117] It is advised that patients with Parkinson disease and sudden-onset sleep avoid driving and take
precautions against potential occupational hazards.[23]
The 2010 AAN practice parameter found insufficient evidence to support or refute beneficial effects from the treatment of RBD in
Parkinson disease. Other sleep disorders may benefit from treatment. Levodopa/carbidopa should be considered to treat
periodic limb movements of sleep. Modafinil may improve patients’ subjective perceptions of excessive daytime somnolence
(EDS), and methylphenidate may be considered in patients with fatigue.[48]
Exercise and Physical Therapy
Exercise therapy in patients with Parkinson disease using a variety of physiotherapy interventions may play a role in improving
gait, balance and flexibility, aerobic capacity, initiation of movement, and functional independence. Studies generally have
suggested improvement in functional outcomes, but the observed benefits were small in magnitude and were not sustained
following discontinuation of the exercise.[77]
A systematic review of 33 randomized trials involving 1518 patients evaluated various physiotherapy interventions, including
general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. There were significant improvements for
walking speed, walking endurance and step length, mobility (the Timed Up & Go test), and balance. Unified Parkinson’s Disease
Rating Scale (UPDRS) scores were also improved with physiotherapy. There was no benefit observed for falls or patient-rated
quality of life, and there was no evidence that one type of physiotherapy was superior to others.[118]
There has been a resurgence of interest in the potential benefit of exercise in Parkinson disease, including a possible
neuroprotective effect.[119] Vigorous exercise in mid-life is associated with a reduced risk of subsequent Parkinson disease. In
animal models, vigorous exercise provides a protective effect against a variety of toxins that cause parkinsonism. In addition, in
healthy people, serum brain-derived neurotrophic factor (BDNF) increases after exercise, in proportion to the intensity of the
activity. In Parkinson disease, BDNF levels in the substantia nigra are reduced, and in animal models of Parkinson disease,
BDNF provides a neuroprotective effect. This is an area of active research.
Speech Therapy
The laryngeal manifestations of Parkinson disease often lead to decreased participation in the activities of daily living because
of an inability to communicate effectively. During the course of the disease, 45-89% of patients report speech problems, and
more than 30% find speech problems to be the most debilitating part of the disease.
Medications and surgery cannot effectively treat the laryngeal manifestations of Parkinson disease. For this reason, speech
therapy plays a key role in the disease's vocal treatment regimen. Speech therapy is effective in treating the laryngeal
manifestations of Parkinson disease, but despite the significant number of patients with vocal symptoms, only an estimated 3-
4% of patients with Parkinson disease undergo speech therapy.
The Lee Silverman Voice Treatment (LSVT) is a program designed to increase vocal intensity in patients with Parkinson
disease. The treatment focuses on a simple set of tasks that are practiced intensively, 4 sessions per week during a 4-week
period, resulting in maximization of phonatory and respiratory functions. The goal of LSVT is to improve vocal performance for
6-24 months without interval intervention. LSVT focuses on maximizing vocal effort ("think loud, think shout") and maximizing
sensory perception of vocal effort and loudness by therapists. Therapists who quantify results give constant feedback to patients
during sessions and encourage patients to self-monitor and internally calibrate their loudness. After LSVT, patients with
Parkinson disease speak at a normal volume and with a healthy voice quality despite the need to "think loud, think shout."
In studies with a 2-year follow-up, patients who received LSVT maintained or improved vocal intensity compared with
pretreatment levels. Glottal incompetence and swallowing ability both improved after LSVT, without any significant change in
supraglottal hyperfunction. Preliminary positron emission tomography (PET) scans after LSVT training in patients with Parkinson
disease show reduced activity in the globus pallidus, an effect similar to pallidotomy. LSVT may also stimulate coordination of
motor output beyond the phonatory system in the form of increased orofacial expression.
Other therapies have been suggested for the treatment of the vocal symptoms in Parkinson disease, but most data so far
support LSVT as the most promising therapy for Parkinson disease laryngeal symptoms. Alternative methods of delivering
therapy that do not involve 16 face-to-face sessions with a therapist are currently being studied. These methods incorporate
webcam delivery of LSVT (eLOUD) and software programs that patients can perform at home. These technologically enhanced
methods, when used to replace half of the face-to-face sessions, have documented outcomes that are equivalent to classic
LSVT. The hope is that such alternatives will be implemented to allow a less transportation-intensive therapy course for the
patient and to allow follow-up review of the LSVT techniques as needed.
A systematic review of clinical trials of speech and language therapy in Parkinson disease identified 3 randomized controlled
trials that included 61 patients. The authors concluded that although improvements were noted, they were not able to
conclusively confirm or refute the benefit of speech and language therapy in Parkinson disease due to the small number of
patients in these trials, methodologic limitations, and possible publication bias.[120]
Dietary Considerations
Proper nutritional support is essential for patients with Parkinson disease, including adequate dietary fiber to prevent the
common problem of constipation. Patients recently diagnosed with Parkinson disease are often confused regarding dietary
protein, because they receive conflicting information.
Levodopa is absorbed via a large neutral amino acid active carrier system and therefore competes with dietary proteins for
absorption; this effect is generally relatively small and is not clinically important for most patients, especially those with early or
moderate disease. However, as the disease progresses and patients become more and more sensitive to maintaining relatively
narrow therapeutic serum concentrations of levodopa, this effect can become clinically relevant. These patients usually have
significant motor fluctuations. Some report that when they are "on" and they eat a meal including protein, they turn "off." Others
find that if they eat a protein meal, their next levodopa dose does not kick in. These patients may benefit from a low protein or a
protein redistributed diet.
In a low-protein diet, the total daily protein intake is spread more or less equally over the day. In a protein-redistributed diet,
individuals only consume food very low in protein during the day and then eat a high-protein meal in the evening. Unfortunately,
these diets are difficult to follow; dietary consultation may be beneficial for patients in whom such diets are considered.
For patients with early and moderate Parkinson disease, the considerations are quite different. As with patients with more
advanced Parkinson disease, patients with early and moderate Parkinson disease will get the most complete and consistent
absorption of levodopa by taking their levodopa doses a half hour or more before meals or 1 hour or more after meals. However,
most patients with early or moderate disease will not notice a difference in clinical benefit, whether they take their levodopa with
meals or apart from meals.
Even if there is some reduction in clinical benefit when levodopa is taken with meals, this can be mitigated by increasing the
levodopa dose, if necessary. In patients with early disease, the primary concern regarding levodopa is typically nausea, which is
less likely to occur if they take their levodopa dose at the completion of meals. Therefore, in early Parkinson disease, it is
common to instruct patients to take their levodopa after meals to reduce the likelihood of nausea as the dose is titrated to clinical
effect.
Some studies have shown mild motor benefit with Mucuna pruriens (cowhage, velvet bean), which contain levodopa, and Vicia
faba (broad or fava bean) may have short-term benefits.[77] However, additional studies are needed.
Vitamin E and coenzyme Q10 have not been shown to have a neuroprotective effect in Parkinson disease,[64, 121] and they
are not currently recommended as dietary supplements for this condition.
Consultations
Generally, patients with Parkinson disease are best treated and monitored by a neurologist or movement disorder specialist.
Depending on the patient, consultations may include the following:
Neurosurgeon
Psychiatrist
Urologist
Physiatrist
Nutritionist
Otolaryngologist
Gastroenterologist
Speech therapist
Neurosurgical consultation may be appropriate in patients with tremor, dyskinesias, motor fluctuations, or dystonia refractory to
medical treatment. However, patients with dementia or significant psychiatric or behavioral problems are not candidates for
current neurosurgical treatments for Parkinson disease.
Psychiatric consultation may be required to control mood disorders and psychiatric symptoms, especially in patients with
refractory depression or psychosis.
A urologist is consulted for evaluation and treatment of urinary frequency, urgency, incontinence, or erectile dysfunction.
A physiatrist, physical therapist, or occupational therapist may be able to improve the patient's ability to perform activities of daily
living, reduce pain, and avoid fractures and compression neuropathies from falls. Botulinum injections for limb dystonia can be
very helpful and are administered by specially trained physiatrists or neurologists.
A nutritionist can help ensure adequate energy intake, particularly when low-protein diets are needed to avoid adverse effects of
levodopa.
An otolaryngologist can offer vocal fold bulking procedures in the form of vocal fold injection or Gore-Tex thyroplasty as a
possibility in treating refractory true vocal fold bowing. Bilateral injections to medialize the vocal fold can offer improvement,
unless the patient is already aphonic due to advanced disease. Bilateral collagen, gel, fat, and hydroxyapatite injections have
been used for this purpose.[122] Articulatory problems can persist, and the result of surgery can be disappointing.
A gastroenterologist and a speech therapist may be needed to evaluate dysphagia, a common complication in patients with
more advanced Parkinson disease. Excessive sialorrhea can be treated with botulinum toxin injections into the salivary glands,
usually administered by neurologists or otolaryngologists. In some patients, a gastrostomy may be needed to maintain adequate
nutrition.
Long-Term Monitoring
Patients with Parkinson disease must have regular follow-up care to ensure adequate treatment of motor and behavioral
abnormalities. Once patients are stable on a medication regimen, provide follow-up care at least every 3-6 months, and
periodically adjust medication dosages as necessary. Patients also need to be monitored for adverse events, including
somnolence, sudden-onset sleep, impulse control disorders, and psychosis. In addition, patients should be evaluated and
treated for emergence of clinically relevant nonmotor symptoms, including dementia, psychosis, sleep disorders, and mood
disorders.
Future Treatments for Parkinson Disease

Future treatments for Parkinson disease are covered in Future Treatments for Parkinson’s Disease: Surfing the PD Pipeline.
This article provides a discussion of new therapies in clinical development that may alleviate motor features or slow disease
progression, including A2a antagonists, levodopa formulations, other antiparkinsonian medications, antidyskinesia medications,
and gene therapy.[123]
Guidelines
Guidelines Summary
American Academy of Neurology (AAN)
In 2010, the AAN released guidelines on the treatment of nonmotor symptoms of Parkinson disease. Recommendations
included the following[48] :
Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction
Polyethylene glycol may be considered to treat constipation
Modafinil should be considered for patients who subjectively experience excessive daytime somnolence
For insomnia, evidence is insufficient to support or refute the use of levodopa to improve objective sleep parameters that
are not affected by motor symptoms; evidence is also insufficient to support or refute the use of melatonin for poor sleep
quality
Levodopa/carbidopa should be considered to treat periodic limb movements of sleep in Parkinson disease, but there are
insufficient data to support or refute the use of nonergot dopamine agonists to treat this condition or that of restless-legs
syndrome
Methylphenidate may be considered for fatigue (note: methylphenidate has the potential for abuse and addiction)
Evidence is insufficient to support or refute specific treatments of orthostatic hypotension, urinary incontinence, anxiety,
and RMD
Medication
Medication Summary
The cornerstone of symptomatic treatment for Parkinson disease (PD) is dopamine replacement therapy. The criterion standard
of symptomatic therapy is levodopa (L-dopa), the metabolic precursor of dopamine, in combination with carbidopa, a peripheral
decarboxylase inhibitor (PDI). This combination provides the greatest symptomatic benefit with the fewest short-term adverse
effects.
Dopamine agonists such as pramipexole and ropinirole can be used as monotherapy to improve symptoms in early disease or
as adjuncts to levodopa in patients whose response to levodopa is deteriorating and in those who are experiencing fluctuations
in their response to levodopa.
Monoamine oxidase (MAO)-B inhibitors (eg, rasagiline, safinamide, selegiline) provide symptomatic benefit as monotherapy in
early disease and as adjuncts to levodopa in patients experiencing motor fluctuations.
Catechol-O -methyl transferase (COMT) inhibitors inhibitors such as entacapone and tolcapone may be used to increase the
peripheral half-life of levodopa, thereby delivering more levodopa to the brain over a longer time.
Anticholinergic medications can be used for the treatment of resting tremor. However, they are not particularly effective for
bradykinesia, rigidity, gait disturbance, or other features of advanced Parkinson disease; and cognitive side effects are common.
Therefore anticholinergics are usually reserved for the treatment of tremor that is not adequately controlled with dopaminergic
medications.
Pimavanserin is the first medication approved by the FDA for hallucinations and delusions associated with PD. It is a selective
serotonin inverse agonists (SSIA) which preferentially targets 5-HT2A receptors and avoids activity at dopamine and other
receptors commonly targeted by antipsychotics.
Dopamine Agonists
Class Summary
Dopamine agonists are effective as monotherapy in early PD and as adjuncts to levodopa/PDI (peripheral decarboxylase
inhibitor) in moderate to advanced disease. 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 to treat motor features of early PD, and they cause less development of motor fluctuations and
dyskinesia than levodopa. 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.
Carbidopa/levodopa (Sinemet, Sinemet CR, Rytary, Duopa)

Carbidopa/levodopa is approved for the treatment of symptoms of idiopathic PD, postencephalitic parkinsonism, and
symptomatic parkinsonism that may follow injury to the nervous system by carbon monoxide and/or manganese intoxication.
Levodopa, combined with a peripheral decarboxylase inhibitor (PDI) such as carbidopa, 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. When administered alone, levodopa causes a high incidence of nausea and vomiting due to the formation of
dopamine in the peripheral circulation. Carbidopa inhibits the decarboxylation of levodopa to dopamine in the peripheral
circulation thereby reducing nausea and allowing for greater levodopa distribution into the CNS. Carbidopa does not cross the
blood-brain barrier.
Sustained-release capsules (Rytary) may improve drug delivery for patients unable to swallow effectively. The capsule may be
either swallowed whole or opened and sprinkled on a small amount of applesauce for immediate consumption.
An enteral suspension (Duopa) is administered by a portable pump into the jejunum over a 16-hr period to improve on-time and
decrease off-time in patients with motor fluctuations with advanced Parkinson disease.
Levodopa inhaled (Inbrija)

Powder for inhalation is systemically absorbed via lungs, and therefore bypasses GI absorption, which may be variable in
patients with PD. Levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and is converted to dopamine
in the brain. It is indicated for intermittent treatment of "off" episodes in patients with Parkinson disease who are taking oral
carbidopa/levodopa.
Apomorphine (Apokyn)
Apomorphine is a nonergoline dopamine agonist indicated for the acute, intermittent treatment of hypomobility "off" episodes
("end-of-dose wearing off" and unpredictable "on/off" episodes) associated with advanced PD. It is administered by a
subcutaneous injection. Although the exact mechanism by which apomorphine exerts its therapeutic effects in PD is unknown, it
is thought to occur via activation of postsynaptic D2 receptors in the striatum.
Pramipexole (Mirapex, Mirapex ER)

Pramipexole is approved as monotherapy in early disease and as adjunctive therapy to levodopa/PDI in more advanced stages.
The mechanism of action of pramipexole as a treatment for PD is unknown, although it is believed to be related to its ability to
stimulate D2 dopamine receptors in the striatum. It is available as an immediate-release and an extended-release tablet.
Ropinirole (Requip and Requip XL)

Ropinirole is approved as monotherapy in early disease and as adjunctive therapy to levodopa/PDI in more advanced disease.
Ropinirole is a nonergot dopamine agonist that has high relative in vitro specificity and full intrinsic activity at the D2 subfamily of
dopamine receptors; it binds with higher affinity to D3 than to D2 or D4 receptor subtypes. The mechanism of action of ropinirole
is stimulation of dopamine D2 receptors in striatum. It is available as an immediate-release and an extended-release tablet.
Amantadine (Gocovri)
Amantadine is approved for the treatment of idiopathic PD, postencephalitic parkinsonism, and symptomatic parkinsonism,
which may follow injury to the nervous system by carbon monoxide intoxication. The extended-release capsule is indicated for
dyskinesia in patients with PD. Amantadine is available as a syrup, tablet, capsule, and an extended-release capsule. The exact
mechanism of amantadine for the treatment of PD and dyskinesia associated with PD is unknown. Amantadine is a weak,
noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist.
Rotigotine (Neupro)
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. Indicated for the treatment of the signs and symptoms of
idiopathic Parkinson disease (PD). Dosage ranges differ for early-stage PD and advanced-stage PD. Available as transdermal
patch that provides continuous delivery for 24 h
Anticholinergic
Class Summary
Anticholinergics are commonly used as symptomatic treatment of PD, both as monotherapy and as part of combination therapy.
Anticholinergic agents provide benefit for tremor in approximately 50% of patients but do not substantially improve bradykinesia
or rigidity. If one anticholinergic does not work, try another.
Trihexyphenidyl
Trihexyphenidyl is indicated as an adjunct for all forms of parkinsonism (postencephalitic, arteriosclerotic, and idiopathic). It is
often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa.
It is a synthetic tertiary amine anticholinergic agent. It has a direct antispasmodic action on smooth muscle and has weak
mydriatic, antisecretory, and positive chronotropic activities. In addition to suppressing central cholinergic activity,
trihexyphenidyl may also inhibit reuptake and storage of dopamine at central dopamine receptors, thereby prolonging the action
of dopamine. It is commonly used in combination with other antiparkinsonian agents. Generally, anticholinergic agents can help
control tremor but are less effective for treating bradykinesia or rigidity.
Benztropine mesylate (Cogentin)

Benztropine mesylate is approved for use as an adjunct in the therapy of all forms of PD. It partially blocks striatal cholinergic
receptors, and by blocking muscarinic cholinergic receptors in the CNS, benztropine reduces the excessive cholinergic activity
present in parkinsonism and related states. It can also block dopamine reuptake and storage in CNS cells. In general,
anticholinergic agents can help control tremor but are less effective for treating bradykinesia or rigidity.
MAO-B inhibitors
Class Summary
MAO-B inhibitors inhibit the activity of MAO-B oxidases that are responsible for inactivating dopamine.
Selegiline (Eldepryl, Zelapar)

Selegiline is approved as adjunctive therapy to levodopa/carbidopa in patients who exhibit deterioration in response to that
therapy. For patients who are experiencing motor fluctuations on levodopa/carbidopa, the addition of selegiline reduces off time,
improves motor function, and allows levodopa dose reductions. If a patient experiences an increase in troublesome dyskinesia,
reduce the levodopa dose. Selegiline blocks the breakdown of dopamine and extends the duration of action of each dose of
levodopa.
Rasagiline (Azilect)
Rasagiline is indicated for the treatment of the signs and symptoms of idiopathic PD as initial monotherapy and as adjunctive
therapy to levodopa. Rasagiline is an irreversible MAO-B inhibitor that blocks dopamine degradation. Rasagiline at a dosage of
1 mg once daily is given as monotherapy. When it is given as adjunctive therapy, an initial dose of 0.5 mg once daily is
administered. Dosage adjustments are required if clinical response is not seen.
Safinamide (Xadago)
Safinamide inhibits MAO-B activity, by blocking the catabolism of dopamine. It is indicated as add-on treatment for patients with
Parkinson disease who are currently taking levodopa/carbidopa and experiencing “off” episodes.
Acetylcholinesterase Inhibitors, Central
Class Summary
Pathologic changes in dementia associated with PD involve cholinergic neuronal pathways that project from the basal forebrain
to the cerebral cortex and hippocampus. These pathways may be involved in memory, attention, learning, and other cognitive
processes. Acetylcholinesterase inhibitors may exert their therapeutic effect by enhancing cholinergic function through inhibition
of acetylcholinesterase.
Donepezil (Aricept)
Donepezil is a reversible inhibitor of ACh and exerts its beneficial effects by enhancing cholinergic function. It is indicated for the
treatment for dementia of the Alzheimer type.
Rivastigmine (Exelon)
Rivastigmine is indicated for the treatment of mild to moderate dementia associated with PD. In addition, it is also approved for
the treatment of mild to moderate dementia of the Alzheimer type.
Rivastigmine is a selective, competitive, and reversible acetylcholinesterase (ACh) inhibitor. It may reversibly inhibit
cholinesterase, which may, in turn, increase concentrations of ACh available for synaptic transmission in CNS and thereby
enhance cholinergic function. The effect may lessen as the disease process advances and fewer cholinergic neurons remain
functionally intact. It is available as a capsule and an extended-release transdermal.
Galantamine (Razadyne, Razadyne ER)

Galantamine is a competitive and reversible inhibitor of ACh. It is approved for the treatment of mild to moderate dementia of the
Alzheimer type.
NMDA Antagonists
Class Summary
Persistent activation of CNS N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been
hypothesized to contribute to the symptomatology of dementia. Agents such as memantine, which is an NMDA receptor
antagonist, can prevent activation of the NMDA receptors.
Memantine (Namenda, Namenda XR)

Memantine is approved for the treatment of moderate to severe dementia in Alzheimer disease. Initial dosage is 5 mg once daily
for immediate-release tablets and 7 mg once daily for extended-release tablets. Dosage titration may be required based on
clinical response.
Memantine is postulated to exert its therapeutic effect through its action as a low- to moderate-affinity, uncompetitive NMDA
receptor antagonist. Blockade of NMDA receptors by memantine slows the intracellular calcium accumulation and helps prevent
further nerve damage.
COMT Inhibitors
Class Summary
Catechol-O -methyl transferase (COMT) inhibitors 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.
Tolcapone (Tasmar)
Tolcapone is an adjunct to levodopa/carbidopa therapy in PD in patients who are experiencing motor fluctuations. Because of
the risk of hepatotoxicity, tolcapone is reserved for patients who have not responded adequately to, or are not appropriate
candidates for, other adjunctive medications. If improvement is not apparent within 3 weeks, this medication should be
withdrawn.
Tolcapone is a selective and reversible inhibitor of COMT. In the presence of a decarboxylase inhibitor such as carbidopa,
COMT is the major degradation pathway for levodopa. By inhibiting COMT, there are more sustained plasma levels of levodopa,
as well as enhanced central dopaminergic activity.
Entacapone (Comtan)
Entacapone is approved as an adjunct to levodopa/carbidopa for patients who are experiencing signs and symptoms of end-of-
dose "wearing-off." The mechanism of action of entacapone is 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 the brain. This may lead to greater effects on signs and symptoms of PD, as well as increased levodopa adverse effects
(which sometimes require a levodopa dose decrease).
Carbidopa, levodopa, and entacapone (Stalevo)

Carbidopa/levodopa/entacapone is indicated for the treatment of PD to substitute (with equivalent strengths of each of the 3
components) for immediate-release carbidopa/levodopa and entacapone previously administered as individual products. It is
also used to replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients experience the signs
and symptoms of end-of-dose "wearing-off" (only for patients taking a total daily dose of levodopa of 600 mg or less and not
experiencing dyskinesias).
Carbidopa inhibits dopa decarboxylation, thereby allowing more complete levodopa distribution to the CNS. Levodopa is a
dopamine precursor capable of crossing the blood-brain barrier, thereby increasing CNS dopamine following conversion.
Entacapone inhibits COMT, another enzyme that metabolizes levodopa. COMT inhibition increases and sustains levodopa
plasma levels, enabling more blood-brain barrier penetration.
Selective Serotonin Inverse Agonists (SSIA)
Class Summary
SSIAs preferentially target 5-HT2A receptors, but does not affect activity of dopamine and other receptors commonly targeted by
antipsychotics.
Pimavanserin (Nuplazid)
Pimavanserin is an SSIA which preferentially targets 5-HT2A receptors and avoids activity at dopamine and other receptors
commonly targeted by antipsychotics. It is indicated for hallucinations and delusions associated with PD.
Questions & Answers

Overview
Which major neurological findings are characteristic of Parkinson disease (PD)?
Why is it important to recognize both motor and nonmotor symptoms in patients with suspected Parkinson disease (PD)?
What are the initial clinical symptoms of Parkinson disease (PD)?
What are the initial motor signs of Parkinson disease (PD)?
What are the diagnostic criteria for Parkinson disease (PD)?
What is the goal of medical management of Parkinson disease (PD)?
Which medications are used to control symptoms of Parkinson disease (PD)?
Which medications are used to control the nonmotor symptoms of Parkinson disease (PD)?
What is deep brain stimulation for Parkinson disease (PD)?
What causes Parkinson disease (PD)?
What are the three motor signs of Parkinson disease (PD)?
What causes of tremor should be considered in the differential diagnoses of Parkinson disease (PD)?
How is a diagnosis confirmed in patients with a typical Parkinson disease (PD) presentation?
When are imaging studies considered in the diagnosis of Parkinson disease (PD)?
Which medications are used to control the motor symptoms of Parkinson disease (PD)?
What part of the brain is affected by Parkinson disease (PD)?
What are the neuropathologic findings of Parkinson disease (PD)?
How does Parkinson disease (PD) affect the basal ganglia motor circuit?
What is the etiology of Parkinson disease (PD)?
Which environmental risk factors may increase the risk of developing Parkinson disease (PD)?
Does exposure to pesticides, herbicides, or other pollutants increase the risk of developing Parkinson disease (PD)?
Does high caffeine intake or smoking increase the risk of developing Parkinson disease (PD)?
Does 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) cause Parkinson disease (PD)?
What is the oxidation hypothesis of the etiology of Parkinson disease (PD)?
What is the role of genetic factors in the development of Parkinson disease (PD)?
Which gene mutations may be related to Parkinson disease (PD)?
Which genetic mechanisms are thought to cause Parkinson disease (PD)?
What is the role of alpha-synuclein in the pathogenesis of Parkinson disease (PD)?
What is the relationship between melanoma and Parkinson disease (PD)?
What is the incidence of Parkinson disease (PD)?
How does the incidence of Parkinson disease (PD) change with age, and are men and women equally affected?
What is the impact of levodopa treatment on the prognosis and mortality rate of Parkinson disease (PD)?
What factors are predictive of the rate of progression of Parkinson disease (PD)?
What educational information should be given to patients with Parkinson disease (PD)?
Presentation
What are the initial physical findings of Parkinson disease (PD)?
Which nonmotor symptoms precede the motor signs of Parkinson disease (PD)?
What are the initial clinical symptoms of Parkinson disease (PD)?
What is the typical presentation of tremors due to Parkinson disease (PD)?
What is bradykinesia in patients with Parkinson disease (PD)?
What are the characteristics of facial bradykinesia in patients with Parkinson disease (PD)?
What are the characteristics of truncal bradykinesia in patients with Parkinson disease (PD)?
How does bradykinesia manifest in activities of daily life in patients with Parkinson disease (PD)?
What is cogwheel rigidity in patients with Parkinson disease (PD)?
How does dystonia present in patients with Parkinson disease (PD)?
What are the cardinal signs of Parkinson disease (PD)?
How is resting tremor assessed in a physical exam in patients with Parkinson Disease (PD)?
How is rigidity assessed in a physical exam in patients with Parkinson disease (PD)?
How is bradykinesia assessed in a physical exam in patients with Parkinson disease (PD)?
How is postural instability assessed in patients with Parkinson disease (PD)?
Which speech tendencies should be assessed in patients with Parkinson disease (PD)?
What are manifestations of dysphagia in patients with Parkinson disease (PD)?
How is laryngeal dysfunction assessed in patients with Parkinson disease (PD)?
What are characterizations of the Parkinson disease (PD) larynx?
What is the prevalence of vocal tremor in patients with Parkinson disease (PD)?
Is autonomic dysfunction common in patients with Parkinson disease (PD)?
Does prominent autonomic dysfunction suggest an alternative diagnosis to Parkinson disease (PD)?
Which cardiopulmonary impairments may be caused by Parkinson disease (PD)?
How is Parkinson disease (PD) severity assessed and staged?
How is depression assessed in patients with Parkinson disease (PD)?
Which assessment is most effective in screening for mild cognitive impairment or dementia in patients with Parkinson disease
(PD)?
What is the prevalence of dementia in patients with Parkinson disease (PD)?
When in the course Parkinson disease (PD) does dementia or other cognitive impairment typically occur?
What are atypical parkinsonisms (Parkinson-plus syndromes)?
What is the prognosis of atypical parkinsonisms (Parkinson-plus syndromes)?
DDX
How is essential tremor differentiated from Parkinson disease (PD)?
Which secondary causes of parkinsonism (Parkinson-plus syndromes) should be considered in the differential diagnoses of
Parkinson disease (PD)?
Does Parkinson disease (PD) increase the risk of osteoporosis and osteopenia?
Does Parkinson disease (PD) increase the risk of bone fracture?
What features differentiate an atypical parkinsonism (Parkinson-plus syndromes) from Parkinson disease (PD)?
How is Lewy body disease characterized in patients with parkinsonism?
When should Wilson disease be considered in patients with parkinsonism?
What are the differential diagnoses for Parkinson Disease?
Workup
Which lab studies are useful in the diagnosis of Parkinson disease (PD)?
Are any lab tests or imaging studies required for the diagnosis of Parkinson disease (PD)?
What tests may be indicated in patients with an unusual presentation of Parkinson disease (PD)?
How is Wilson disease screened for in the evaluation of patients with suspected Parkinson disease (PD)?
How is the clinical diagnosis of Parkinson disease (PD) confirmed?
Why is there a high diagnosis error rate between Parkinson disease (PD) and other movement disorders?
When is MRI indicated in the evaluation of patients with suspected Parkinson disease (PD)?
What is the role of PET scanning and SPECT in the evaluation of patients with Parkinson disease (PD)?
What are the usual histologic findings in Parkinson disease (PD)?
What histologic findings i Lewy bodies in patients with Parkinson disease (PD)?
What were the results of the Parkinson's Progression Markers Initiative (PPMI)?
When is lumbar puncture considered in the evaluation of patients with suspected Parkinson disease (PD)?
When should dopa-responsive dystonia be considered in the evaluation of Parkinson disease (PD)?
Treatment
What is the goal of medical management of Parkinson disease (PD)?
Are there neuroprotective (disease modifying) treatment options for Parkinson disease (PD)?
What is the role of levodopa in the management of Parkinson disease (PD)?
What is the role of monoamine oxidase (MAO)-B inhibitors in the management of Parkinson disease (PD)?
What is the role of dopamine agonists (ropinirole, pramipexole) in the treatment of Parkinson disease (PD)?
How long are medications effective in controlling the motor signs of Parkinson disease (PD)?
What is neuroprotective (disease modifying) therapy in the context of Parkinson disease (PD)?
How does the management of Parkinson disease (PD) differ in younger patients?
What are the indications for surgery in patients with Parkinson disease (PD)?
How are the nonmotor symptoms of Parkinson disease (PD) categorized?
What are the American Academy of Neurology (AAN) guidelines for the treatment of nonmotor symptoms of Parkinson disease
(PD)?
Which medications are commonly used to control motor symptoms in early Parkinson disease (PD)?
What are the long-term risks of levodopa for the management of Parkinson disease (PD)?
What is the benefit of combining carbidopa with levodopa in the management of Parkinson disease (PD)?
What are the available preparations of levodopa/carbidopa?
How is the combination of levodopa, carbidopa, and entacapone used in the management of Parkinson disease (PD)?
What is the recommended dosage for levodopa and a dopa decarboxylase inhibitor in the management of Parkinson disease
(PD)?
What are the benefits of using MAO-B inhibitors (selegiline and rasagiline) in the treatment of Parkinson disease (PD)?
When are selegiline and rasagiline indicated in the treatment of Parkinson disease (PD)?
How effective are dopamine agonists in the treatment of Parkinson disease (PD)?
Should dopamine agonists be used in the treatment of Parkinson disease (PD) in patients older than 65 years?
What dosage is recommended for the introduction of a dopamine agonist in the treatment of Parkinson disease (PD)?
What are the adverse effects of dopamine agonists?
When are anticholinergic medications indicated in the treatment of Parkinson disease (PD)?
How effective are anticholinergic agents in the treatment of Parkinson disease (PD)?
What are the possible adverse effects of anticholinergic agents in patients with Parkinson disease (PD)?
What are the recommended dosages of anticholinergic agents in the treatment of Parkinson disease (PD)?
What is amantadine’s mechanism of action in controlling parkinsonian activity?
What is the recommended dosage for amantadine in the treatment of Parkinson disease (PD)?
What are the potential adverse effects of amantadine?
Does amantadine increase or decrease impulse control disorders in patients with Parkinson disease (PD)?
Which drugs reduce dyskinesis in patients with Parkinson disease (PD)?
Does the benefit of levodopa for the management of Parkinson disease (PD) decrease over time?
What options are available to provide more sustained dopaminergic therapy in patients with Parkinson disease (PD)?
How effective is carbidopa/levodopa enteral suspension (Duopa) in increasing the benefit of levodopa in the treatment of
How effective is safinamide (Xadago) in in increasing the benefit of levodopa in the management of Parkinson disease (PD)?
When should dopaminergic therapy be increased to eliminate off-time in patients with Parkinson disease (PD)?
What is peak-dose dyskinesia in patients with Parkinson disease (PD)?
Is it safe to continue increasing dosage of levodopa if the patient develops dyskinesia?
What is the goal of treating patients with Parkinson disease (PD) who experience both motor fluctuation and peak-dose
dyskinesia?
What is the benefit of switching from levodopa/carbidopa CR to levodopa/carbidopa IR in the treatment of Parkinson disease
(PD)?
What is the role of COMT inhibitors in the treatment of Parkinson disease (PD)?
Are dopamine agonists beneficial in the management of Parkinson disease (PD) patients with both motor fluctuation and peak-
dose dyskinesia?
What are the potential adverse effects of amantadine?
Are there any surgical options for patients with Parkinson disease (PD) who have both motor fluctuations and dyskinesia?
What are the treatment options for tremor in patients with Parkinson disease (PD)?
What is the role of laser shoes in reducing freezing episodes among patients with Parkinson disease (PD)?
Are any neuroprotective therapies available for Parkinson disease (PD)?
Does selegiline (Eldepryl, Zelapar) have neuroprotective effects in patients with Parkinson disease (PD)?
Does rasagiline (Azilect) have neuroprotective effects in patients with Parkinson disease (PD)?
What were the results of the TEMPO (Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients) study?
What were the results of the ADAGIO (Attenuation of Disease progression with Azilect Given Once-daily) study?
What are the potential neuroprotective effects of levodopa therapy in early Parkinson disease (PD)?
What are the potential neuroprotective effects of dopamine agonists in Parkinson disease (PD)?
Why is deep brain stimulation (DBS) the surgical procedure of choice for Parkinson disease (PD)?
Which gray-matter structures are involved in deep brain stimulation (DBS) surgery for Parkinson disease (PD)?
What are the indications for deep brain stimulation (DBS) surgery in patients with Parkinson disease (PD)?
How are patients with Parkinson disease (PD) selected for deep brain stimulation (DBS)?
Is thalamic deep brain stimulation (DBS) indicated for patients with Parkinson disease (PD)?
How effective is subthalamic nucleus (STN) stimulation and globus pallidus interna (GPi) deep brain stimulation (DBS) in the
management of Parkinson disease (PD)?
How effective is bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease (PD)?
Is methylphenidate effective in improving gait disorders in patients with advanced Parkinson disease (PD)?
What is the long-term effectiveness of subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson
disease (PD)?
Is subthalamic nucleus (STN) deep brain stimulation (DBS) effective for treating pain related to Parkinson disease (PD)?
Does subthalamic nucleus (STN) deep brain stimulation (DBS) increase or decrease impulse control disorders in patients with
When are lesion surgeries indicated in the treatment of Parkinson disease (PD)?
Is thalamotomy effective in the treatment of Parkinson disease (PD)?
Is pallidotomy effective in the treatment of Parkinson disease (PD)?
What are the potential adverse effects of pallidotomy?
Is bilateral pallidotomy recommended in patients with Parkinson disease (PD)?
Is subthalamotomy effective in the treatment of Parkinson disease (PD)?
Which specialists should provide care for a patient undergoing surgical procedures for the treatment of Parkinson disease (PD)?
What is the patient evaluation and selection process for individuals with Parkinson disease (PD) considering subthalamic
nucleus (STN) deep brain stimulation (DBS)?
After patient selection, what is the process for determining the correct surgical procedure for management of Parkinson disease
(PD)?
What is the role of a psychiatrist in the preoperative evaluation of a patient with Parkinson disease (PD)?
When is a fluorodopa positron emission tomography (PET) scan indicated in the preoperative evaluation of patients with
When is surgery indicated in the treatment of Parkinson disease (PD)?
How is neural transplantation used in the treatment of Parkinson disease (PD)?
What are the effects of neural transplantation in patients with Parkinson disease (PD)?
Is gene therapy safe and effective in the treatment of Parkinson disease (PD)?
How is dementia managed in patients with Parkinson disease (PD)?
What is the prevalence of depression in patients with Parkinson disease (PD)?
How is depression treated in patients with Parkinson disease (PD)?
Can medications for Parkinson disease (PD) trigger psychosis?
How is psychosis treated in patients with Parkinson disease (PD)?
How is anxiety treated in patients with Parkinson disease (PD)?
How are impulse behaviors treated in patients with Parkinson disease (PD)?
How are sleep disturbances treated in patients with Parkinson disease (PD)?
How effective is exercise and physical therapy in patients with Parkinson disease (PD)?
What is the prevalence of speech problems in patients with Parkinson disease (PD)?
What is the role of speech therapy in the treatment of Parkinson disease (PD)?
What is the Lee Silverman Voice Treatment (LSVT) program for Parkinson disease (PD)?
How effective is the Lee Silverman Voice Treatment (LSVT) program in improving laryngeal symptoms in patients with
Are there effective alternative therapies to the Lee Silverman Voice Treatment (LSVT) program?
Are speech and language therapy effective in the treatment of Parkinson disease (PD)?
Why is dietary fiber recommended for patients with Parkinson disease (PD)?
What is the effect of dietary protein on levodopa in patients with Parkinson disease (PD)?
How is levodopa-induced nausea avoided in patients with Parkinson disease (PD)?
Are there dietary options that are beneficial in the management of Parkinson disease (PD)?
Do vitamin E and coenzyme Q10 have a neuroprotective effect in patients with Parkinson disease (PD)?
What consultations may be indicated for patients with Parkinson disease (PD)?
When is a neurosurgical consultation indicated in patients with Parkinson disease (PD)?
When is a psychiatric consultation indicated in patients with Parkinson disease (PD)?
When is consultation with a urologist indicated in patients with Parkinson disease (PD)?
What is the benefit of consultation with a physiatrist, physical therapist, or occupational therapist in patients with Parkinson
disease (PD)?
What is the benefit of consultation with a nutritionist in patients with Parkinson disease (PD)?
What is the benefit of an otolaryngologist consultation for patients with Parkinson disease (PD)?
How are dysphagia, excessive sialorrhea, or nutrition issues managed in patients with Parkinson disease (PD)?
How often should patients with Parkinson disease (PD) be monitored?
What types of treatments may be available in the future for Parkinson disease (PD)?
Guidelines
What are the AAN treatment guidelines for nonmotor symptoms of Parkinson disease (PD)?
Medications
Which medications are used in the treatment of Parkinson disease (PD)?
Which medications in the drug class Dopamine Agonists are used in the treatment of Parkinson Disease?
Which medications in the drug class Anticholinergic are used in the treatment of Parkinson Disease?
Which medications in the drug class MAO-B inhibitors are used in the treatment of Parkinson Disease?
Which medications in the drug class Acetylcholinesterase Inhibitors, Central are used in the treatment of Parkinson Disease?
Which medications in the drug class NMDA Antagonists are used in the treatment of Parkinson Disease?
Which medications in the drug class COMT Inhibitors are used in the treatment of Parkinson Disease?
Which medications in the drug class Selective Serotonin Inverse Agonists (SSIA) are used in the treatment of Parkinson
Disease?
Contributor Information and Disclosures
Author
Robert A Hauser, MD, MBA Professor of Neurology, Molecular Pharmacology and Physiology, Director, USF Parkinson's
Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, Byrd Institute, Clinical Chair,
Signature Interdisciplinary Program in Neuroscience, University of South Florida College of Medicine
Robert A Hauser, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Medical
Association, American Society of Neuroimaging, International Parkinson and Movement Disorder Society
Disclosure: Received consulting fee from Cerecor for consulting; Received consulting fee from L&M Healthcare for consulting;
Received consulting fee from Cleveland Clinic for consulting; Received consulting fee from Heptares for consulting; Received
consulting fee from Gerrson Lehrman Group for consulting; Received consulting fee from Indus for consulting; Received
consulting fee from University of Houston for consulting; Received consulting fee from AbbVie for consulting; Received
consulting fee from Adama.
Coauthor(s)
Kelly E Lyons, PhD Research Professor of Neurology, Director of Research and Education, Parkinson’s Disease and
Movement Disorder Center, University of Kansas Medical Center
Kelly E Lyons, PhD is a member of the following medical societies: American Academy of Neurology, International Parkinson
and Movement Disorder Society
Disclosure: Received honoraria from Novartis for speaking and teaching; Received honoraria from Teva Neuroscience for
speaking and teaching; Received honoraria from St Jude Medical for board membership.
Theresa A McClain, RN, MSN, ARNP-BC Advanced Registered Nurse Practitioner and Investigator, Parkinson’s Disease and
Movement Disorders Center, University of South Florida College of Medicine
Theresa A McClain, RN, MSN, ARNP-BC is a member of the following medical societies: Sigma Theta Tau International
Disclosure: Received consulting fee from Teva for consulting; Received consulting fee from Schering Plough for consulting;
Received consulting fee from Biotie for consulting; Received consulting fee from Novartis for consulting.
Rajesh Pahwa, MD Professor of Neurology, Director, Parkinson Disease and Movement Disorder Center, Department of
Neurology, University of Kansas Medical Center
Rajesh Pahwa, MD is a member of the following medical societies: American Academy of Neurology, International Parkinson
and Movement Disorder Society
Disclosure: Nothing to disclose.
Chief Editor
Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery,
Tampa General Hospital, University of South Florida Morsani College of Medicine
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of
Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Ceribell, Eisai, Greenwich,
Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a speakers
bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion, LivaNova, Greenwich, Sunovion,
SK biopharmaceuticals, Takeda, UCB.
Acknowledgements
Ron L Alterman, MD Associate Professor of Neurosurgery, Mount Sinai School of Medicine; Consulting Surgeon, Department of
Neurosurgery, Mount Sinai School of Medicine, Elmhurst Hospital, and Walter Reed Army Medical Center
Ron L Alterman, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological
Surgeons, Congress of Neurological Surgeons, Medical Society of the State of New York, and New York County Medical Society
Heather S Anderson, MD Assistant Professor, Staff Neurologist, Department of Neurology, Alzheimer and Memory Center,
University of Kansas Medical Center
Heather S Anderson, MD is a member of the following medical societies: American Academy of Neurology
Jeff Blackmer, MD, FRCP(C) Associate Professor, Medical Director, Neurospinal Service, Division of Physical Medicine and
Rehabilitation, The Rehabilitation Centre, University of Ottawa Faculty of Medicine; Executive Director, Office of Ethics,
Canadian Medical Association
Jeff Blackmer, MD, FRCP(C) is a member of the following medical societies: American Paraplegia Society, Canadian
Association of Physical Medicine and Rehabilitation, Canadian Medical Association, and Royal College of Physicians and
Surgeons of Canada
Thomas L Carroll, MD Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Tufts University School of
Medicine and Director, The Center for Voice and Swallowing, Tufts Medical Center
Thomas L Carroll, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Otolaryngology-Head and Neck Surgery, American Bronchoesophagological Association, American Laryngological Association,
and American Medical Association
Disclosure: Merz aesthetics inc. Consulting fee Speaking and teaching
Richard J Caselli, MD Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of
Neurology, Mayo Clinic of Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of
Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma
Xi
Arif I Dalvi, MD Director, Movement Disorders Center, NorthShore University HealthSystem, Clinical Associate Professor of
Neurology, University of Chicago Pritzker Medical School
Arif I Dalvi, MD is a member of the following medical societies: European Neurological Society and Movement Disorders Society
Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders,
Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology,
American College of Physicians, and Movement Disorders Society
Stephen T Gancher, MD Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University
Stephen T Gancher, MD is a member of the following medical societies: American Academy of Neurology, American
Neurological Association, and Movement Disorders Society
Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA Professor of Neurology, University of Central Florida College of
Medicine; Director of Cognitive Neurology, Director of Stroke Program, James A Haley Veterans Affairs Hospital
Michael Hoffmann, MBBCh, MD, FCP(SA), FAAN, FAHA is a member of the following medical societies: American Academy of
Neurology, American Headache Society, American Heart Association, and American Society of Neuroimaging
Daniel H Jacobs MD, FAAN, Associate Professor of Neurology, University of Florida College of Medicine; Director for Stroke
Services, Orlando Regional Medical Center
Daniel H Jacobs is a member of the following medical societies: American Academy of Neurology, American Society of
Neurorehabilitation, and Society for Neuroscience
Disclosure: Teva Pharmaceutical Grant/research funds Consulting; Biogen Idex Grant/research funds Independent contractor;
Serono EMD Royalty Speaking and teaching; Pfizer Royalty Speaking and teaching; Berlex Royalty Speaking and teaching
Robert M Kellman, MD Professor and Chair, Department of Otolaryngology and Communication Sciences, State University of
New York Upstate Medical University
Robert M Kellman, MD is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive
Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Medical
Association, American Neurotology Society, American Rhinologic Society, American Society for Head and Neck Surgery,
Medical Society of the State of New York, and Triological Society
Disclosure: GE Healthcare Honoraria Review panel membership; Revent Medical Honoraria Review panel membership
Milton J Klein, DO, MBA Consulting Physiatrist, Heritage Valley Health System-Sewickley Hospital and Ohio Valley General
Hospital
Milton J Klein, DO, MBA is a member of the following medical societies: American Academy of Disability Evaluating Physicians,
American Academy of Medical Acupuncture, American Academy of Osteopathy, American Academy of Physical Medicine and
Rehabilitation, American Medical Association, American Osteopathic Association, American Osteopathic College of Physical
Medicine and Rehabilitation, American Pain Society, and Pennsylvania Medical Society
Kat Kolaski, MD Assistant Professor, Departments of Orthopedic Surgery and Pediatrics, Wake Forest University School of
Medicine
Kat Kolaski, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental
Medicine and American Academy of Physical Medicine and Rehabilitation
Jose G Merino, MD Medical Director, Suburban Hospital Stroke Program
Jose G Merino, MD is a member of the following medical societies: American Heart Association and American Stroke
Association
Arlen D Meyers, MD, MBA Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of
Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and
Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and American Head and Neck Society
Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation Unrestricted gift Unknown; Axis Three
Corporation Ownership interest Consulting; Omni Biosciences Ownership interest Consulting; Sentegra Ownership interest
Board membership; Syndicom Ownership interest Consulting; Oxlo Consulting; Medvoy Ownership interest Management
position; Cerescan Imaging Honoraria Consulting; GYRUS ACMI Honoraria Consulting
Lorraine Ramig, PhD Professor, Department of Speech Language Hearing Sciences, University of Colorado at Boulder; Senior
Scientist, National Center for Voice and Speech (NCVS); Adjunct Professor, Department of Biobehavior, Columbia University
Teacher's College
Alan D Schmetzer, MD Professor Emeritus, Interim Chairman, Vice-Chair for Education, Associate Residency Training Director
in General Psychiatry, Fellowship Training Director in Addiction Psychiatry, Department of Psychiatry, Indiana University School
of Medicine; Addiction Psychiatrist, Midtown Mental Health Cener at Wishard Health Services
Alan D Schmetzer, MD is a member of the following medical societies: American Academy of Addiction Psychiatry, American
Academy of Clinical Psychiatrists, American Academy of Psychiatry and the Law, American College of Physician Executives,
American Medical Association, American Neuropsychiatric Association, American Psychiatric Association, and Association for
Convulsive Therapy
Disclosure: Eli Lilly & Co. Grant/research funds Other
Roy Sucholeiki, MD Director, Comprehensive Seizure and Epilepsy Program, The Neurosciences Institute at Central DuPage
Hospital
Roy Sucholeiki, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy
Society, and American Neuropsychiatric Association
Margaret M Swanberg, DO Assistant Professor of Neurology, Uniformed Services University; Chief of Neurobehavior Service,
Walter Reed Army Medical Center; Assistant Chief, Department of Neurology, Walter Reed Army Medical Center
Margaret M Swanberg, DO is a member of the following medical societies: American Academy of Neurology and American
Neuropsychiatric Association
Michele Tagliati, MD Associate Professor, Department of Neurology, Mount Sinai School of Medicine; Division Chief of
Movement Disorders, Mount Sinai Medical Center
Michele Tagliati, MD is a member of the following medical societies: American Academy of Neurology, American Medical
Association, and Movement Disorders Society
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy;
Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment

B Viswanatha, MBBS, MS, DLO Professor of Otolaryngology (ENT), Chief of ENT III Unit, Sri Venkateshwara ENT Institute,
Victoria Hospital, Bangalore Medical College and Research Institute; PG and UG Examiner, Manipal University, India and
Annamalai University, India
B Viswanatha, MBBS, MS, DLO is a member of the following medical societies: Association of Otolaryngologists of India, Indian
Medical Association, and Indian Society of Otology
References
1. Hauser RA, Grosset DG. [(123) I]FP-CIT (DaTscan) SPECT Brain Imaging in Patients with Suspected Parkinsonian Syndromes. J
Neuroimaging. 2011 Mar 16. [Medline].
2. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the
evidence. Eur J Epidemiol. 2011 Jun. 26 Suppl 1:S1-58. [Medline].
3. Anderson P. More Evidence Links Pesticides, Solvents, With Parkinson's. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/804834. Accessed: June 11, 2013.
4. Pezzoli G, Cereda E. Exposure to pesticides or solvents and risk of Parkinson disease. Neurology. 2013 May 28. 80(22):2035-41.
[Medline].
5. Liu R, Guo X, Park Y, Huang X, Sinha R, Freedman ND, et al. Caffeine Intake, Smoking, and Risk of Parkinson Disease in Men and
Women. Am J Epidemiol. 2012 Apr 13. [Medline].
6. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP):
seven cases. Neurology. 1985 Jul. 35(7):949-56. [Medline].
7. Tanner CM, Ottman R, Goldman SM, Ellenberg J, Chan P, Mayeux R, et al. Parkinson disease in twins: an etiologic study. JAMA.
1999 Jan 27. 281(4):341-6. [Medline].
8. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in
families with Parkinson's disease. Science. 1997 Jun 27. 276(5321):2045-7. [Medline].
9. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in
Parkinson's disease. Nat Genet. 1998 Feb. 18(2):106-8. [Medline].
10. Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. J Geriatr Psychiatry Neurol. 2010 Dec. 23(4):228-42. [Medline].
[Full Text].
11. Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Ross BM, et al. Frequency of known mutations in early-onset
Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. Arch Neurol.
2010 Sep. 67(9):1116-22. [Medline].
12. Samanta J, Hauser RA. Duodenal levodopa infusion for the treatment of Parkinson's disease. Expert Opin Pharmacother. 2007 Apr.
8(5):657-64. [Medline].
13. Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L. Pathological roles of a-synuclein in neurological disorders. Lancet
Neurol. 2011 Nov. 10(11):1015-25. [Medline].
14. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic nigral transplants in
Parkinson's disease. Nat Med. 2008 May. 14(5):504-6. [Medline].
15. Dalvin LA, Damento GM, Yawn BP, Abbott BA, Hodge DO, Pulido JS. Parkinson Disease and Melanoma: Confirming and
Reexamining an Association. Mayo Clin Proc. 2017 Jul. 92 (7):1070-1079. [Medline].
16. Mulcahy, N. Melanoma, Parkinson's: See One, Be Aware of the Other. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/883195. July 19, 2017; Accessed: July 26, 2017.
17. Constantinescu R, Elm J, Auinger P, Sharma S, Augustine EF, Khadim L, et al. Malignant melanoma in early-treated Parkinson's
disease: the NET-PD trial. Mov Disord. 2014 Feb. 29 (2):263-5. [Medline].
18. De Pablo-Fernandez E, Goldacre R, Pakpoor J, Noyce AJ, Warner TT. Association between diabetes and subsequent Parkinson
disease: A record-linkage cohort study. Neurology. 2018 Jun 13. [Medline].
19. Muangpaisan W, Mathews A, Hori H, Seidel D. A systematic review of the worldwide prevalence and incidence of Parkinson's
disease. J Med Assoc Thai. 2011 Jun. 94(6):749-55. [Medline].
20. Grimes DA, Lang AE. Treatment of early Parkinsons disease. Can J Neurol Sci. 1999 Aug. 26 Suppl 2:S39-44. [Medline].
21. Thobois S, Delamarre-Damier F, Derkinderen P. Treatment of motor dysfunction in Parkinsons disease: an overview. Clin Neurol
Neurosurg. 2005 Jun. 107(4):269-81. [Medline].
22. Suchowersky O, Reich S, Perlmutter J, Zesiewicz T, Gronseth G, Weiner WJ. Practice Parameter: diagnosis and prognosis of new
onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of
Neurology. Neurology. 2006 Apr 11. 66(7):968-75. [Medline].
23. National Collaborating Centre for Chronic Conditions. Parkinson's disease: National clinical guideline for diagnosis and management
in primary and secondary care. London, UK: Royal College of Physicians; 2006.
24. Hughes S. Consider Nonmotor Symptoms for Diagnosis of Parkinson's? Medscape Medical News. January 18, 2013. Available at
http://www.medscape.com/viewarticle/777874. Accessed: January 22, 2013.
25. Khoo TK, Yarnall AJ, Duncan GW, Coleman S, O'Brien JT, Brooks DJ, et al. The spectrum of nonmotor symptoms in early Parkinson
disease. Neurology. 2013 Jan 15. 80(3):276-81. [Medline].
26. Simuni T, Sethi K. Nonmotor manifestations of Parkinson's disease. Ann Neurol. 2008 Dec. 64 Suppl 2:S65-80. [Medline].
27. Sato Y, Iwamoto J, Honda Y. Vitamin D Deficiency-Induced Vertebral Fractures May Cause Stooped Posture in Parkinson Disease.
Am J Phys Med Rehabil. 2011 Jan 5. [Medline].
28. Brin MF, Velickovic M, Remig LO. Dysphonia due to Parkinson's disease; pharmacological, surgical, and behavioral management
perspectives. Vocal Rehabilitation in Medical Speech-Language Pathology. Austin: Pro-Ed; 2004. 209-69.
29. Perez KS, Ramig LO, Smith ME, Dromey C. The Parkinson larynx: tremor and videostroboscopic findings. J Voice. 1996 Dec.
10(4):354-61. [Medline].
30. Ray Chaudhuri K, Rojo JM, Schapira AH, Brooks DJ, Stocchi F, Odin P, et al. A proposal for a comprehensive grading of Parkinson's
disease severity combining motor and non-motor assessments: meeting an unmet need. PLoS One. 2013. 8(2):e57221. [Medline].
[Full Text].
31. Johnson K. Nonmotor PD Symptoms Bolster Disease Severity Assessment. Medscape [serial online]. Available at
http://www.medscape.com/viewarticle/812182. Accessed: October 13, 2013.
32. Hoops S, Nazem S, Siderowf AD, Duda JE, Xie SX, Stern MB. Validity of the MoCA and MMSE in the detection of MCI and
dementia in Parkinson disease. Neurology. 2009 Nov 24. 73(21):1738-45. [Medline]. [Full Text].
33. Weintraub D, Comella CL, Horn S. Parkinson's disease--Part 3: Neuropsychiatric symptoms. Am J Manag Care. 2008 Mar. 14(2
Suppl):S59-69. [Medline].
34. Reid WG, Hely MA, Morris JG, Loy C, Halliday GM. Dementia in Parkinson's disease: a 20-year neuropsychological study (Sydney
Multicentre Study). J Neurol Neurosurg Psychiatry. 2011 Sep. 82(9):1033-7. [Medline].
35. Parkinson's Tied to Higher Risk of Osteoporosis and Osteopenia. Medscape. Apr 3 2014. [Full Text].
36. Torsney KM, Noyce AJ, Doherty KM, et al. Bone health in Parkinson's disease: a systematic review and meta-analysis. J Neurol
Neurosurg Psychiatry. 2014 Mar 21. [Medline].
37. Tolosa E, Gaig C, Santamaría J, Compta Y. Diagnosis and the premotor phase of Parkinson disease. Neurology. 2009 Feb 17. 72(7
Suppl):S12-20. [Medline].
38. King J. New contrast agent enables earlier diagnosis in Parkinson's. Medscape Medical News. June 18, 2013. [Full Text].
39. Seibyl J, Jennings D, Grachev I, Coffey C, Marek K. Accuracy of DaTscan™ (ioflupane I 123 injection) in diagnosis of early
parkinsonian syndromes (PS) [abstract 191]. Presented at: 2013 Annual Meeting of the Society of Nuclear Medicine and Molecular
Imaging (SNMMI); June 10, 2013; Vancouver, British Columbia, Canada.
40. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology.
Cell Tissue Res. 2004 Oct. 318(1):121-34. [Medline].
41. Kang JH, Irwin DJ, Chen-Plotkin AS, Siderowf A, Caspell C, Coffey CS, et al. Association of Cerebrospinal Fluid ß-Amyloid 1-42, T-
tau, P-tau181, and a-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease. JAMA Neurol.
2013 Aug 26. [Medline].
42. Jeffrey S. Biomarkers for Parkinson's Diagnostic, Prognostic. Medscape [serial online]. Available at
http://www.medscape.com/viewarticle/810262. Accessed: September 9, 2013.
43. Grosset D, Taurah L, Burn DJ, MacMahon D, Forbes A, Turner K, et al. A multicentre longitudinal observational study of changes in
self reported health status in people with Parkinson's disease left untreated at diagnosis. J Neurol Neurosurg Psychiatry. 2007 May.
78(5):465-9. [Medline]. [Full Text].
44. Caslake R, Macleod A, Ives N, Stowe R, Counsell C. Monoamine oxidase B inhibitors versus other dopaminergic agents in early
Parkinson's disease. Cochrane Database Syst Rev. 2009. (4):CD006661. [Medline].
45. Antonini A, Cilia R. Behavioural adverse effects of dopaminergic treatments in Parkinson's disease: incidence, neurobiological basis,
management and prevention. Drug Saf. 2009. 32(6):475-88. [Medline].
46. Bayulkem K, Lopez G. Clinical approach to nonmotor sensory fluctuations in Parkinson's disease. J Neurol Sci. 2011 Nov 15. 310(1-
2):82-5. [Medline].
47. Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, et al. Practice Parameter: evaluation and treatment of
depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology. 2006 Apr 11. 66(7):996-1002. [Medline].
48. [Guideline] Zesiewicz TA, Sullivan KL, Arnulf I, et al. Practice Parameter: treatment of nonmotor symptoms of Parkinson disease:
report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010 Mar 16. 74(11):924-31.
[Medline].
49. Stocchi F, Rascol O, Kieburtz K, et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease:
the STRIDE-PD study. Ann Neurol. 2010 Jul. 68(1):18-27. [Medline].
50. Hauser RA, McDermott MP, Messing S. Factors associated with the development of motor fluctuations and dyskinesias in Parkinson
disease. Arch Neurol. 2006 Dec. 63(12):1756-60. [Medline].
51. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients
with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med. 2000 May 18.
342(20):1484-91. [Medline].
52. Constantinescu R, Romer M, McDermott MP, Kamp C, Kieburtz K. Impact of pramipexole on the onset of levodopa-related
dyskinesias. Mov Disord. 2007 Jul 15. 22(9):1317-9. [Medline].
53. Thomas A, Bonanni L, Gambi F, Di Iorio A, Onofrj M. Pathological gambling in Parkinson disease is reduced by amantadine. Ann
Neurol. Sep 2010. 68(3):400-4.
54. Weintraub D, Sohr M, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Amantadine use associated with impulse control disorders
in Parkinson disease in cross-sectional study. Ann Neurol. 2010 Dec. 68(6):963-8. [Medline].
55. Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. Continuous intrajejunal infusion of levodopa-
carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy
study. Lancet Neurol. 2014 Feb. 13(2):141-9. [Medline].
56. Schapira AH, Fox SH, Hauser RA, Jankovic J, Jost WH, Kenney C, et al. Assessment of Safety and Efficacy of Safinamide as a
Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial. JAMA Neurol. 2017 Feb
1. 74 (2):216-224. [Medline].
57. Borgohain R, Szasz J, Stanzione P, Meshram C, Bhatt M, Chirilineau D, et al. Randomized trial of safinamide add-on to levodopa in
Parkinson's disease with motor fluctuations. Mov Disord. 2014 Feb. 29 (2):229-37. [Medline]. [Full Text].
58. Schapira AH, Barone P, Hauser RA, Mizuno Y, Rascol O, Busse M, et al. Extended-release pramipexole in advanced Parkinson
disease: a randomized controlled trial. Neurology. 2011 Aug 23. 77(8):767-74. [Medline].
59. Pahwa R, Tanner CM, Hauser RA, Isaacson SH, Nausieda PA, Truong DD, et al. ADS-5102 (Amantadine) Extended-Release
Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study): A Randomized Clinical Trial. JAMA Neurol.
2017 Aug 1. 74 (8):941-949. [Medline]. [Full Text].
60. Hauser RA, Pahwa R, Tanner CM, Oertel W, Isaacson SH, Johnson R, et al. ADS-5102 (Amantadine) Extended-Release Capsules
for Levodopa-Induced Dyskinesia in Parkinson's Disease (EASE LID 2 Study): Interim Results of an Open-Label Safety Study. J
Parkinsons Dis. 2017. 7 (3):511-522. [Medline]. [Full Text].
61. Ory-Magne F, Corvol JC, Azulay JP, et al, on behalf of the NS-Park CIC Network. Withdrawing amantadine in dyskinetic patients with
Parkinson disease: The AMANDYSK trial. Neurology. 2013 Dec 26. [Medline].
62. Brooks M. Amantadine has lasting benefit on levodopa-induced dyskinesia. Medscape Medical News. January 8, 2014. [Full Text].
63. Barthel C, Nonnekes J, van Helvert M, Haan R, Janssen A, Delval A, et al. The laser shoes: A new ambulatory device to alleviate
freezing of gait in Parkinson disease. Neurology. 2017 Dec 20. [Medline].
64. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N Engl
J Med. 1993 Jan 21. 328(3):176-83. [Medline].
65. Shults CW. Effect of selegiline (deprenyl) on the progression of disability in early Parkinson's disease. Parkinson Study Group. Acta
Neurol Scand Suppl. 1993. 146:36-42. [Medline].
66. Palhagen S, Heinonen E, Hagglund J, Kaugesaar T, Maki-Ikola O, Palm R. Selegiline slows the progression of the symptoms of
Parkinson disease. Neurology. 2006 Apr 25. 66(8):1200-6. [Medline].
67. Tatton WG, Greenwood CE. Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res. 1991 Dec.
30(4):666-72. [Medline].
68. Olanow C, Rascol O. Early Rasagaline treatment slows UPDRS decline in the ADAGIO delayed start study. Poster work in progress
(WIP-11). 12th Congress of European Federation of Neurological Societies. Sept 23, 2008.
69. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A. A double-blind, delayed-start trial of rasagiline in Parkinson's
disease. N Engl J Med. 2009 Sep 24. 361(13):1268-78. [Medline].
70. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002 Dec. 59(12):1937-43. [Medline].
71. Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ. Long-term outcome of early versus delayed rasagiline
treatment in early Parkinson's disease. Mov Disord. 2009 Mar 15. 24(4):564-73. [Medline].
72. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 2004 Apr. 61(4):561-6.
[Medline].
73. Fahn S, Oakes D, Shoulson I, Kieburtz K, Rudolph A, Lang A, et al. Levodopa and the progression of Parkinson's disease. N Engl J
Med. 2004 Dec 9. 351(24):2498-508. [Medline].
74. Parkkinen L, O'Sullivan SS, Kuoppamäki M, Collins C, Kallis C, Holton JL, et al. Does levodopa accelerate the pathologic process in
Parkinson disease brain?. Neurology. 2011 Oct 11. 77(15):1420-6. [Medline].
75. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA.
2002 Apr 3. 287(13):1653-61. [Medline].
76. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA. 2004 Jan 21.
291(3):358-64. [Medline].
77. Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ. Practice Parameter: neuroprotective strategies and
alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology. 2006 Apr 11. 66(7):976-82. [Medline].
78. Shemisa K, Hass CJ, Foote KD, Okun MS, Wu SS, Jacobson CE 4th, et al. Unilateral deep brain stimulation surgery in Parkinson's
disease improves ipsilateral symptoms regardless of laterality. Parkinsonism Relat Disord. 2011 Dec. 17(10):745-8. [Medline].
79. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr. Bilateral deep brain stimulation vs best medical therapy for patients
with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009 Jan 7. 301(1):63-73. [Medline]. [Full Text].
80. Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson's
disease. N Engl J Med. 2010 Jun 3. 362(22):2077-91. [Medline].
81. Brooks M. Neurostimulation has benefits in early Parkinson's disease. Medscape Medical News. February 15, 2013. [Full Text].
82. Schuepbach WM, Rau J, et al, for the EARLYSTIM Study Group. Neurostimulation for Parkinson's disease with early motor
complications. N Engl J Med. 2013 Feb 14. 368(7):610-22. [Medline].
83. Foltynie T, Zrinzo L, Martinez-Torres I, Tripoliti E, Petersen E, Holl E, et al. MRI-guided STN DBS in Parkinson's disease without
microelectrode recording: efficacy and safety. J Neurol Neurosurg Psychiatry. 2011 Apr. 82(4):358-63. [Medline].
84. Moreau C, Delval A, Defebvre L, Dujardin K, Duhamel A, Petyt G, et al. Methylphenidate for gait hypokinesia and freezing in patients
with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet
Neurol. 2012 Jul. 11(7):589-596. [Medline].
85. Castrioto A, Lozano AM, Poon YY, Lang AE, Fallis M, Moro E. Ten-year outcome of subthalamic stimulation in Parkinson disease: a
blinded evaluation. Arch Neurol. 2011 Dec. 68(12):1550-6. [Medline].
86. Oshima H, Katayama Y, Morishita T, Sumi K, Otaka T, Kobayashi K, et al. Subthalamic nucleus stimulation for attenuation of pain
related to Parkinson disease. J Neurosurg. 2012 Jan. 116(1):99-106. [Medline].
87. Kim HJ, Jeon BS, Paek SH. Effect of deep brain stimulation on pain in Parkinson disease. J Neurol Sci. 2011 Nov 15. 310(1-2):251-
5. [Medline].
88. Kim HJ, Jeon BS, Lee JY, Paek SH, Kim DG. The benefit of subthalamic deep brain stimulation for pain in Parkinson disease: a 2-
year follow-up study. Neurosurgery. 2012 Jan. 70(1):18-23; discussion 23-4. [Medline].
89. Broen M, Duits A, Visser-Vandewalle V, Temel Y, Winogrodzka A. Impulse control and related disorders in Parkinson's disease
patients treated with bilateral subthalamic nucleus stimulation: a review. Parkinsonism Relat Disord. 2011 Jul. 17(6):413-7. [Medline].
90. Timmermann L, Jain R, Chen L, Brucke T, Seijo F, San Martin ES, et al. 134 VANTAGE Trial: Three-Year Outcomes of a
Prospective, Multicenter Trial Evaluating Deep Brain Stimulation With a New Multiple-Source, Constant-Current Rechargeable
System in Parkinson Disease. Neurosurgery. 2016 Aug. 63 Suppl 1:155. [Medline].
91. Svennilson E, Torvik A, Lowe R, Leksell L. Treatment of parkinsonism by stereotatic thermolesions in the pallidal region. A clinical
evaluation of 81 cases. Acta Psychiatr Scand. 1960. 35:358-77. [Medline].
92. Laitinen LV, Bergenheim AT, Hariz MI. Leksell's posteroventral pallidotomy in the treatment of Parkinson's disease. J Neurosurg.
1992 Jan. 76(1):53-61. [Medline].
93. Lang AE, Widner H. Deep brain stimulation for Parkinson's disease: patient selection and evaluation. Mov Disord. 2002. 17 Suppl
3:S94-101. [Medline].
94. Okun MS, Fernandez HH, Pedraza O, Misra M, Lyons KE, Pahwa R. Development and initial validation of a screening tool for
Parkinson disease surgical candidates. Neurology. 2004 Jul 13. 63(1):161-3. [Medline].
95. Olanow CW, Kordower JH, Lang AE, Obeso JA. Dopaminergic transplantation for Parkinson's disease: current status and future
prospects. Ann Neurol. 2009 Nov. 66(5):591-6. [Medline].
96. Silberstein P, Bittar RG, Boyle R, Cook R, Coyne T, O'Sullivan D. Deep brain stimulation for Parkinson's disease: Australian referral
guidelines. J Clin Neurosci. 2009 Aug. 16(8):1001-8. [Medline].
97. Stover NP, Watts RL. Spheramine for treatment of Parkinson's disease. Neurotherapeutics. 2008 Apr. 5(2):252-9. [Medline].
98. Farag ES, Vinters HV, Bronstein J. Pathologic findings in retinal pigment epithelial cell implantation for Parkinson disease.
Neurology. 2009 Oct 6. 73(14):1095-102. [Medline]. [Full Text].
99. Witt J, Marks WJ Jr. An update on gene therapy in Parkinson's disease. Curr Neurol Neurosci Rep. 2011 Aug. 11(4):362-70.
[Medline].
100. Lewitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, et al. AAV2-GAD gene therapy for advanced
Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011 Apr. 10(4):309-19. [Medline].
101. Miyasaki JM, Shannon K, Voon V, Ravina B, Kleiner-Fisman G, Anderson K, et al. Practice Parameter: evaluation and treatment of
depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology. 2006 Apr 11. 66(7):996-1002. [Medline].
102. Frisina PG, Borod JC, Foldi NS, Tenenbaum HR. Depression in Parkinson''s disease: Health risks, etiology, and treatment options.
Neuropsychiatr Dis Treat. 2008 Feb. 4(1):81-91. [Medline]. [Full Text].
103. Barbas NR. Cognitive, affective, and psychiatric features of Parkinson's disease. Clin Geriatr Med. 2006 Nov. 22(4):773-96, v-vi.
[Medline].
104. Truong DD, Bhidayasiri R, Wolters E. Management of non-motor symptoms in advanced Parkinson disease. J Neurol Sci. 2008 Mar
15. 266(1-2):216-28. [Medline].
105. Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord. 2007 Aug. 13(6):323-32.
[Medline].
106. Hassan A, Bower JH, Kumar N, Matsumoto JY, Fealey RD, Josephs KA, et al. Dopamine agonist-triggered pathological behaviors:
Surveillance in the PD clinic reveals high frequencies. Parkinsonism Relat Disord. 2011 May. 17(4):260-4. [Medline].
107. Richard IH, McDermott MP, Kurlan R, Lyness JM, Como PG, Pearson N, et al. A randomized, double-blind, placebo-controlled trial
of antidepressants in Parkinson disease. Neurology. 2012 Apr 17. 78(16):1229-1236. [Medline].
108. Barone P, Poewe W, Albrecht S, Debieuvre C, Massey D, Rascol O, et al. Pramipexole for the treatment of depressive symptoms in
patients with Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010 Jun. 9(6):573-80.
[Medline].
109. Allain H, Pollak P, Neukirch HC. Symptomatic effect of selegiline in de novo Parkinsonian patients. The French Selegiline Multicenter
Trial. Mov Disord. 1993. 8 Suppl 1:S36-40. [Medline].
110. Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, et al. Pimavanserin for patients with Parkinson's disease
psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014 Feb 8. 383 (9916):533-40. [Medline].
111. Treatment of Parkinson's disease. Psychological disorders: striking a balance in order to optimise antiparkinsonian treatment.
Prescrire Int. 2011 Oct. 20(120):242-5. [Medline].
112. Ferreri F, Agbokou C, Gauthier S. Recognition and management of neuropsychiatric complications in Parkinson's disease. CMAJ.
2006 Dec 5. 175(12):1545-52. [Medline].
113. Okai D, Askey-Jones S, Samuel M, O'Sullivan SS, Chaudhuri KR, Martin A, et al. Trial of CBT for impulse control behaviors affecting
Parkinson patients and their caregivers. Neurology. 2013 Feb 26. 80(9):792-799. [Medline]. [Full Text].
114. Anderson P. Cognitive Therapy Controls Impulse Behaviors in Parkinson's. Available at

http://www.medscape.com/viewarticle/779914. Accessed: March 21, 2013.
115. Brooks M. Naltrexone for Impulse Control Disorders in Parkinson's?. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/829633. Accessed: August 9, 2014.
116. Papay K, Xie SX, Stern M, Hurtig H, Siderowf A, Duda JE, et al. Naltrexone for impulse control disorders in Parkinson disease: A
placebo-controlled study. Neurology. 2014 Jul 18. [Medline].
117. Friedman JH, Millman RP. Sleep disturbances and Parkinson's disease. CNS Spectr. 2008 Mar. 13(3 Suppl 4):12-7. [Medline].
118. Tomlinson CL, Patel S, Meek C, Clarke CE, Stowe R, Shah L, et al. Physiotherapy versus placebo or no intervention in Parkinson's
disease. Cochrane Database of Systematic Reviews. Feb 2012.
119. Ahlskog JE. Does vigorous exercise have a neuroprotective effect in Parkinson disease?. Neurology. 2011 Jul 19. 77(3):288-94.
[Medline]. [Full Text].
120. Herd CP, Tomlinson CL, Deane KHO, Brady MC, Smith CH, Sackley C, et al. Speech and language therapy versus placebo or no
intervention for speech problems in Parkinson's disease. Cochrane Database Syst Rev. 2011 Apr 11. CD002812.
121. Fahn S. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease. Ann Neurol. 1992. 32 Suppl:S128-32.
[Medline].
122. Berke GS, Gerratt B, Kreiman J, Jackson K. Treatment of Parkinson hypophonia with percutaneous collagen augmentation.
Laryngoscope. 1999 Aug. 109(8):1295-9. [Medline].
123. Kim HJ, Jeon BS, Paek SH. Effect of deep brain stimulation on pain in Parkinson disease. J Neurol Sci. 2011 Nov 15. 310(1-2):251-
5. [Medline].
124. Hauser RA. Future treatments for Parkinson's disease: surfing the PD pipeline. Int J Neurosci. 2011. 121 Suppl 2:53-62. [Medline].
125. Koller WC. Levodopa in the treatment of Parkinson's disease. Neurology. 2000. 55(11 Suppl 4):S2-7; discussion S8-12. [Medline].
126. Marks WJ Jr, Bartus RT, Siffert J, et al. Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised,
controlled trial. Lancet Neurol. 2010 Dec. 9(12):1164-72. [Medline].
127. PBR Regulatory Affairs. Teva's AZILECT gets FDA approval to treat all stages of Parkinson’s disease. June 10, 2014. Available at
http://regulatoryaffairs.pharmaceutical-business-review.com/news/tevas-azilect-gets-fda-approval-to-treat-all-stages-of-parkinsons-
disease-100614-4289261. Accessed: June 16, 2014.
128. [Guideline] Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and pharmacological management of Parkinson's disease.
A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2010 Jan. 61 p. (SIGN
publication; no. 113). [Full Text].
129. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S. Effects of coenzyme Q10 in early Parkinson disease: evidence of
slowing of the functional decline. Arch Neurol. 2002 Oct. 59(10):1541-50. [Medline].
130. Teva Pharmaceutical Industries Ltd. FDA approves expanded label for AZILECT for treatment across all stages of Parkinson’s
disease [press release]. June 9, 2014. Available at http://ir.tevapharm.com/phoenix.zhtml?c=73925&p=irol-
newsArticle&ID=1938203&highlight=. Accessed: June 16, 2014.
131. Whone AL, Watts RL, Stoessl AJ, Davis M, Reske S, Nahmias C, et al. Slower progression of Parkinson's disease with ropinirole
versus levodopa: The REAL-PET study. Ann Neurol. 2003 Jul. 54(1):93-101. [Medline].
132. LeWitt PA, Hauser RA, Pahwa R, Isaacson SH, Fernandez HH, Lew M, et al. Safety and efficacy of CVT-301 (levodopa inhalation
powder) on motor function during off periods in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled
phase 3 trial. Lancet Neurology. 2019 Feb 01;18(2):145-154.

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Signs and symptoms

Initial clinical symptoms of Parkinson disease include the following:

Subtle decrease in dexterity

Decreased arm swing on the first-involved side

Decreased facial expression

Decreased sense of smell

A general feeling of weakness, malaise, or lassitude

Onset of motor signs include the following:

The most common initial finding is a resting tremor in an upper extremity

Axial posture becomes progressively flexed and strides become shorter

Postural instability (balance impairment) is a late phenomenon

See Clinical Presentation for more detail.

Clinical diagnosis requires the presence of 2 of 3 cardinal signs:

See Workup for more detail.

Symptomatic drug therapy

Levodopa/carbidopa: The gold standard of symptomatic treatment

Treatment for nonmotor symptoms

Sildenafil citrate (Viagra): For erectile dysfunction

Polyethylene glycol: For constipation

Modafinil: For excessive daytime somnolence

Methylphenidate: For fatigue (potential for abuse and addiction)

Deep brain stimulation

Surgical procedure of choice for Parkinson disease

Does not involve destruction of brain tissue

Can be adjusted as the disease progresses or adverse events occur

Bilateral procedures can be performed without a significant increase in adverse events

See Treatment and Medication for more detail.

Iodine-123–labeled fluoropropyl-2beta-carbomethoxy-3beta-4-iodophenyl-nortroptane (FP-CIT I123) (Ioflupane, DaTscan)

For an illustration of the subthalamic nucleus, see the image below.

Loss of pigmented dopaminergic neurons of the substantia nigra pars compacta

The presence of Lewy bodies and Lewy neurites

Motor circuit in Parkinson disease

MPTPinterference with mitochondrial function

Alpha-synuclein conformational changes and aggregation

Initial clinical symptoms in Parkinson disease include the following:

Decreased arm swing on the first-involved side

Decreased facial expression

Decreased sense of smell

A general feeling of weakness, malaise, or lassitude

Laryngeal dysfunction and dysphagia

doubled in Parkinson patients.[35, 36]

Falls at presentation or early in the disease

Poor response to levodopa

Symmetry at disease onset

Rapid disease progression

Cortical Basal Ganglionic Degeneration

Lewy Body Dementia

Pantothenate Kinase-Associated Neurodegeneration (PKAN)

Multiple System Atrophy

Neurological Manifestations of Vascular Dementia

Normal Pressure Hydrocephalus

Progressive Supranuclear Palsy

The following MRI indicates where a thalamic stimulator is typically placed.

PET and SPECT scanning

Symptomatic and neuroprotective therapy

Sildenafil citrate (Viagra) may be considered to treat erectile dysfunction

Polyethylene glycol may be considered to treat constipation

Symptomatic Therapy, Early Disease

Symptomatic Therapy, Advanced Disease

Dosing levodopa more frequently

Increasing the levodopa dose

Adding intermittent levodopa inhaled doses