Background

Parkinson disease is a disorder of the basal ganglia and 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 and the presence of Lewy bodies. Most cases of idiopathic Parkinson disease (IPD) are
believed to be due to a combination of genetic and environmental factors. At both ends of the
spectrum are rare cases that appear to be due solely to one or the other.
Patients with Parkinson disease exhibit 2 onsets of manifestations: onset of initial clinical
manifestations and the onset of motor signs. The initial symptoms typically start insidiously and
emerge slowly over weeks or months, with tremor being the most common initial symptom.
There are 4 cardinal signs of Parkinson disease: resting tremor, rigidity, bradykinesia, and
postural instability. (See Clinical Presentation.)
When a patient presents with tremor, the clinician must compare the patient's signs and
symptoms with the clinical picture of Parkinson disease in order to differentiate parkinsonian
tremor from other types of tremor. In patients with parkinsonism, careful attention to the history
is necessary to exclude etiologic factors such as drugs, toxins, or trauma. (See Diagnosis.)
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. In such cases, the simplest test is a diagnostic trial of
levodopa, as the response to low doses of levodopa is nearly complete. (See Workup.)
Levodopa coupled with a peripheral decarboxylase inhibitor (PDI) (Sinemet) 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, its long-term
use is associated with the development of fluctuations and dyskinesias. (See Treatment Strategies
and Management.)
Levodopa/carbidopa provides the greatest antiparkinsonian efficacy in moderate-to-advanced
disease, with the fewest acute adverse effects. Dopamine agonists (apomorphine [Apokyn],
bromocriptine [Parlodel], ropinirole [Requip and Requip XL]) 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 those who are experiencing fluctuations in their response to
levodopa. MAO-B inhibitors (selegiline [Eldepryl], rasagiline [Azilect]) inhibit the activity of
Monoamine oxidase (MAO)B oxidases that are responsible for inactivating dopamine and
possibly the conversion of compounds into neurotoxic types. (See Medication.)

Anatomy
Parkinson disease is predominantly a disorder of the basal ganglia, which are a group of nuclei
situated at the base of the forebrain, shown below.

Stages in the development of Parkinson disease-related

pathology. Adapted from Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Cell
Tissue Res. 2004 Oct;318(1):121-34.
The corpus 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
globus pallidus (GPe), establishing an indirect pathway to 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). STN is one of the preferred surgical targets for deep brain
stimulation to treat symptoms of advanced Parkinson disease.
The complementary actions of the direct and indirect pathways regulate the neuronal output from
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 the characteristic findings have not been established clearly.
Individuals presenting with primary dementia may exhibit neuropathologic features
indistinguishable from those of Parkinson disease.
There are, however, 2 major neuropathologic findings in Parkinson disease:

Loss of pigmented dopaminergic neurons in the substantia nigra

The presence of Lewy bodies

The loss of dopaminergic neurons occurs most prominently in the ventral lateral substantia nigra.
Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson
disease emerge.
Incidental Lewy bodies have been hypothesized to represent the presymptomatic phase of
Parkinson disease. Alpha-synuclein is a major structural component of Lewy bodies, and 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 IPD. Lewy bodies also are found in the cortex, nucleus basalis, locus
ceruleus, intermediolateral column of the spinal cord, and other areas.
Lewy bodies are not specific to Parkinson disease, as they are found in some cases of atypical
parkinsonism, Hallervorden-Spatz disease, and other disorders. Incidental Lewy bodies are found
at postmortem in patients without clinical signs of parkinsonism. The prevalence of incidental
Lewy bodies increases with age.

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's disease and movement disorders. In: Watts RL, Koller WC, eds.
Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:240.
Used with kind permission. Copyright, McGraw-Hill Companies, Inc.
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 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:

In the direct pathway, outflow from the striatum directly inhibits GPi and SNr. Striatal
neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr.

The indirect pathway comprises inhibitory connections between the striatum and the GPe
and between the GPe and the STN. Striatal neurons containing 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
(SNc) neurons to activate the direct pathway and inhibit the indirect pathway. In Parkinson
disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr (see
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's disease and movement disorders.
In: Watts RL, Koller WC, eds. Movement Disorders: Neurologic Principles and Practice. New
York: McGraw-Hill, 1997:241. Used with kind permission. Copyright, McGraw-Hill Companies,
Inc.
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
Most cases of IPD are believed to be due to a combination of genetic and environmental factors.
At both ends of the spectrum are rare cases that appear to be due solely to one or the other. It has
been estimated that all currently known genetic causes of Parkinson disease account for less than
5% of Parkinson disease cases.

Environmental causes

Environmental risk factors associated with the development of Parkinson disease include use of
pesticides, living in a rural environment, consumption of well water, exposure to herbicides, and
proximity to industrial plants or quarries. Smoking and caffeine consumption are inversely
correlated with Parkinson disease risk.

MPTP
Several individuals have been identified who developed parkinsonism after self-injection of 1methyl-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-4phenylpyridinium (MPP+) by 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. Hydrogen
peroxide normally 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, concordance in genetically identical monozygotic (MZ) twins
will be greater than in dizygotic (DZ) twins, who share only about 50% of genes. Early twin
studies generally found low and similar concordance rates for MZ and DZ pairs.
Genetic factors appear to be very important when the disease begins at or before age 50 years,
according to 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.
The identification of a few families with apparent familial Parkinson disease sparked further
interest in the genetics of the disease. In one large family of 592 members in Salerno, Italy, of
whom 50 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. 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 y), rapid progression
(mean age at death 56.1 y), lack of tremor, and good response to levodopa therapy. Five small
Greek kindreds also were found to have the PD-1 mutation.
In a German family, a different point mutation in the alpha-synuclein gene (a substitution of C
for G at base 88, producing a substitution of proline for alanine at amino acid 30) confirmed that
mutations in the alpha-synuclein gene can cause Parkinson disease. 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.
Several homozygous deletions in a gene dubbed parkin (PARK2), which is located on
chromosome 6, have been found to cause autosomal recessive juvenile parkinsonism. This form
of parkinsonism differs pathologically from Parkinson disease in that no Lewy bodies are found
in the substantia nigra. Several other gene abnormalities have been identified in families with
Parkinson disease and these are designated PARK3 -PARK12.

Alpha-synuclein
Alpha-synuclein is a major component of Lewy bodies in cases of Parkinson disease. All Lewy
bodies stain for alpha-synuclein, and most also stain for ubiquitin, which conjugates with
proteins targeted for proteolysis. Abnormal aggregation of alpha-synuclein into filamentous
structures may precede ubiquitination. One hypothesis states that the PD-1 mutation alters the
configuration of alpha-synuclein into a beta structure that could aggregate into sheets. All
Parkinson disease cases may be associated with abnormal folding of alpha-synuclein, leading to
excessive aggregation and neuronal death.
Although sporadic Parkinson disease is not caused by a mutation in the alpha-synuclein gene,
active investigation is underway into proteins that interact with alpha-synuclein, including those
that guide, promote, or prevent aggregation of the protein. Because Parkinson disease, dementia
with Lewy bodies, and multiple system atrophy all exhibit Lewy bodies that stain for alphasynuclein, they have been designated "alpha-synucleinopathies." One hypothesis suggests that
Parkinson disease is caused by abnormalities of the proteosome system, which is responsible for
clearing abnormal proteins.

Clinical Highlights

Consider MAO-B inhibitors for initial treatment of early disease. These drugs provide
mild symptomatic benefit, have excellent adverse effect profiles, and according to a

Cochrane Review improved long-term outcomes in quality of life indicators by 20-25%.

[1]

Levodopa combined with a peripheral decarboxylase inhibitor (Sinemet) is the accepted

standard of symptomatic treatment of later disease based on 3 well-designed RCTs that
showed a 24% benefit in symptom relief over levodopa alone.[2] It is the most efficacious
medication for motor signs and symptoms, but its use is associated with the development
of response fluctuations (wearing-off) and dyskinesias.

Proactively screen patients receiving oral dopamine agonists (pramipexole, ropinirole) for
adverse events. A review of the Cochrane and PubMed databases from 1990 to 2008
found that although these drugs provide moderate symptomatic benefit and cause less
dyskinesia than levodopa, they caused a 15% increase in adverse events as somnolence,
sudden-onset sleep, hallucinations, edema, and impulse control disorders (eg, pathologic
gambling, shopping, and Internet use; hypersexuality; and hoarding).[3] Note that patients
may be reluctant to mention these events or may not attribute them to their treatment.

Screen Parkinson disease patients for depression, and treat it when present. An evidencebased guideline from the American Academy of Neurology 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.[4, 5]

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 18-328 cases per 100,000 population, with most studies yielding a prevalence of
approximately 120 cases per 100,000 population. 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
Prior to the introduction of levodopa, Parkinson disease caused severe disability or death in 25%
of patients within 5 years of onset, in 65% in the next 5 years, and in 89% of those who survived
for 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 several 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.[7, 8]

Patient Education
For excellent patient education resources, visit eMedicine's Dementia Center. Additionally, see
eMedicine's patient education article Parkinson Disease Dementia.

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, this is often either not noticed by the patient or he or she may not realize that
it is part of the disease. Another common premotor is rapid eye moved (REM) behavior disorder.
In this disorder, 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.
Initial clinical symptoms include the following:

Tremor

A subtle decrease in dexterity, such as 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

REM behavior disorder (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.[4] 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

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

Regional pain, variously described as coldness, tingling, cramping, or aching; some

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

The motor signs of Parkinson disease consist of tremor, bradykinesia, rigidity, and dystonia.

Tremor
Tremor is the most common initial symptom, occurring in approximately 70% of patients. It
usually is described by patients as shakiness or nervousness. Tremor usually begins in one upper
extremity and initially may be intermittent. Upper extremity tremor generally begins in the
fingers or thumb, but also can 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 may vary considerably, emerging only with stress, anxiety, or fatigue. Classically, the
tremor of Parkinson disease 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 or lip are not uncommon. As with most tremors, the amplitude increases with
stress and resolves during sleep.

Bradykinesia
Symptoms of bradykinesia are varied. These may include a subjective sense of weakness,
without true weakness, found on physical examination; loss of dexterity, sometimes described by
patients as the "message not getting to the limb"; fatigability; or aching when performing
repeated actions.
Facial bradykinesia is characterized by decreased blink rate and facial expression. The 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) in patients with mild disease.

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
in 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, as well 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-adult Parkinson disease, which is defined as
symptom onset before age 40 years. Dystonia produces cramping or aching and a tendency of the
extremity (usually the foot) to turn in or the great toe to dorsiflex.
Common dystonic symptoms include curling, inversion, or plantar flexion of the foot, and
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.
One study suggests that this stooped posture may be due to vertebral fractures resulting from
vitamin D deficiency with compensatory hyperparathyroidism.[9] 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, 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 the patient relax his or her arms on the legs while in a
seated position. Having the patient 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 can be observed during the finger-to-nose test.

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 with voluntary movement in the contralateral limb.

Bradykinesia
Bradykinesia refers to slowness of movement but also includes a paucity of spontaneous
movements and decreased amplitude of movement. Bradykinesia is also expressed as
micrographia (small handwriting), hypomimia (decreased facial expression), decreased blink
rate, and hypophonia (soft speech). Thus, the patients 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 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 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 the patient stand with
eyes open and then pulling his or her shoulders back toward the examiner. The patient is told to
be ready for the displacement and to regain balance as quickly as possible. One or 2 steps
backward to regain balance is considered normal. The examiner should be ready to catch the
patient if he or she is unable to regain balance.
Perez et al found that vocal tremor is present in 55% of patients with Parkinson disease.
Interestingly, they found that only 35% of patients with Parkinson disease exhibit a resting vocal
cord tremor, while the remainder exhibited kinetic tremor. The tremor is primarily a vertical

laryngeal movement. Parkinson-plus syndromes (PPS) were 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.[10]

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 to differentiate Parkinson disease
from hyperkinetic disorders such as spasmodic dysphonia.[11]
A soft, monotone voice, vocal tremor, poor articulation, variable speech rate, trouble with the
initiation of speech, and stutteringlike 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 IPD. Common stroboscopy findings in IPD 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 as the
etiology for the parkinsonism if other aspects of the diagnosis are present.

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 incontinence, retention, and bladder
infection can occur, and erectile dysfunction is not uncommon. In addition, many patients note
episodes of sweating.

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.

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 dementia 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. 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% versus 54% correct diagnoses).[12]
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.[13] Many patients with
Parkinson disease have some executive function impairment, even early in the disease.[13]
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 a
year of onset of motor features suggests a diagnosis of Lewy body disease, a disease closely
related to Parkinson disease and marked by the presence of cortical Lewy bodies. 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 dementia, but aphasia is not present.

Parkinson-Plus Syndromes

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 Parkinson-plus syndromes typically have a worse
prognosis than those with Parkinson disease, and Parkinson-plus syndromes respond poorly to
the standard anti-Parkinson treatments.
Go to the Parkinson-Plus Syndromes topic for detailed information regarding clinical clues,
workup, differential diagnosis, and treatment of such disorders as multiple system atrophy,
progressive supranuclear palsy, parkinsonism-dementia-amyotrophic lateral sclerosis complex,
corticobasal ganglionic degeneration, and diffuse Lewy body disease.

Diagnostic Considerations
When a patient presents with tremor, the clinician must compare the patient's signs and
symptoms with the clinical picture of Parkinson disease in order to differentiate parkinsonian
tremor from other types of tremor. For example, an action tremor 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 etiologic
factors such as drugs, toxins, or trauma. Medications that block striatal dopamine receptors, such
as metoclopramide and the neuroleptics, can cause drug-induced parkinsonism.
In patients with neurodegenerative parkinsonism, the differential diagnosis includes Parkinson
disease and the atypical parkinsonisms (also known as Parkinson-plus syndromes): multiple
system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration
(CBD). 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. MSA
is relatively symmetric and characterized by parkinsonism, with additional abnormalities in some
combination of autonomic, corticospinal, and cerebellar systems. 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. CBD is typically very
asymmetric and characterized by both cortical (difficulty identifying objects, apraxias) and basal
ganglionic (usually marked rigidity in an arm) features.
Patients with onset of parkinsonism before age 40 years should be tested for Wilson disease,
starting with serum ceruloplasmin measurement and ophthalmologic evaluation for KayserFleischer rings.

Differentials

Alzheimer Disease

Cardioembolic Stroke

Chorea in Adults

Cortical Basal Ganglionic Degeneration

Dementia With Lewy Bodies

Dopamine-Responsive Dystonia

Essential Tremor

Hallervorden-Spatz Disease

Huntington Disease

Lacunar Syndromes

Multiple System Atrophy

Neuroacanthocytosis

Normal Pressure Hydrocephalus

Olivopontocerebellar Atrophy

Parkinson-Plus Syndromes

Progressive Supranuclear Palsy

Striatonigral Degeneration

Vascular Dementia

Wilson Disease

Approach Considerations

Parkinson disease is a clinical diagnosis. No laboratory biomarkers exist for the condition, and
findings on 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 early
evidence of Parkinson disease but are not routinely needed. 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.
A substantial and sustained response to dopamine medications helps confirm the diagnosis. Over
time, diagnostic accuracy improves as the progression of signs and symptoms and response to
medications unfolds.
When an erroneous diagnosis of Parkinson disease is made, the most likely correct diagnoses are
essential tremor and the atypical parkinsonisms (MSA, PSP, CBD). These disorders also do not
have laboratory biomarkers, and, therefore distinguishing among them is based on clinical
information.
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.
Magnetic Resonance Imaging

MRI is useful to exclude 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.
PET and SPECT

PET and SPECT are useful diagnostic imaging studies, but they are not widely available and
may not be covered by insurance. Moreover, they are not needed for routine clinical diagnosis in
patients with a typical presentation.
At the onset of symptoms, patients with Parkinson disease show approximately 30% decrease in
18F-dopa uptake in the contralateral putamen. 18F-dopa is taken up by the terminals of
dopamine neurons and converted to 18F-dopamine. The rate of striatal 18F accumulation reflects
transport of 18F-dopa into dopamine neurons and its decarboxylation to 18F-dopamine, which is
stored in dopamine nerve terminals in the striatum.
11C-Nomifensine and cocaine analogues such as [123 I]-beta-CIT and [123 I]FP-CIT bind to
dopamine reuptake sites on nigrostriatal terminals and provide an index of the integrity of
nigrostriatal projections.
Deficits on fluorodopa PET or [123 I]-beta-CIT SPECT indicate a dopamine deficiency syndrome
but do not necessarily differentiate Parkinson disease from atypical parkinsonisms, including
multiple system atrophy and progressive supranuclear palsy.

Ioflupane I123 (DaTscan) is a radiopharmaceutical 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, multiple system atrophy, and progressive
supranuclear palsy).
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. 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.
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.
Lewy body pathology is also observed in autonomic nerves of the gut and heart.
Serum Ceruloplasmin

Serum ceruloplasmin concentration is obtained as a screening test for Wilson disease in patients
younger than 40 years who present with parkinsonian symptoms. If the ceruloplasmin level is
low, measurement of 24-hour urinary copper excretion and slit-lamp examination for KayserFleischer rings must be performed.
Sphincter Electromyography

Abnormal results on urinary sphincter electromyography have been noted in patients with
multiple system atrophy, which is a Parkinson-plus syndrome.
Olfactory Testing

Olfactory testing can reveal problems with olfaction, which may precede the motor
complications of Parkinson disease by several years.[14] However, olfactory loss is not specific
and can also occur in Alzheimer disease.
Lumbar Puncture

Lumbar puncture should be performed if signs of normal-pressure hydrocephalus are observed

(eg, incontinence, ataxia, dementia). The clinical picture usually improves 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 cerebrospinal
fluid 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.
Go to the Lumbar Puncture topic 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.

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.[15]
Levodopa coupled with a peripheral decarboxylase inhibitor (PDI) (Sinemet) 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, its long-term
use is associated with the development of fluctuations and dyskinesias. Once fluctuations and
dyskinesias become problematic, they are difficult to resolve.
Medications usually provide good symptomatic control of motor signs for 4-6 years. After this,
disability progresses despite best medical management, and many patients develop long-term
motor complications, including fluctuations and dyskinesias. Additional causes of disability in
late disease include postural instability (balance difficulty) and dementia. Thus, symptomatic
therapy for late disease requires different strategies.
The younger the patient, the more emphasis the authors place on long-term considerations to
guide early treatment. Young patients have a longer life expectancy and are more likely to
develop motor fluctuations and dyskinesias. For older patients and those with cognitive
impairment, less emphasis is placed on long-term considerations; the focus is on providing
adequate symptomatic benefit in the near term with as few adverse effects as possible.
For patients who have motor fluctuations and dyskinesia 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. Experimental
surgical approaches include transplantation and gene therapy.

In addition to treatment for motor signs, patients with Parkinson disease may require therapy for
a host of nonmotor symptoms, including depression, dementia, hallucinations, REM sleep
behavior disorder, orthostatic hypotension, and constipation.
In 2010, the American Academy of Neurology released guidelines on the treatment of nonmotor
symptoms of Parkinson disease. Recommendations included the following[16] :

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.

Levidopa/carbidopa should be considered to treat periodic limb movements of sleep in

Parkinson disease.

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, and anxiety.

Putative Neuroprotective Therapy

Neuroprotective therapies are defined as those that slow underlying loss of dopamine neurons.
Currently, no proven neuroprotective therapies exist for Parkinson disease. If a neuroprotective
therapy were available for Parkinson disease, it would be administered from the time of
diagnosis onward. At the current time, the greatest interest in possible neuroprotection resides
with the MAO-B inhibitors selegiline and rasagiline. Other agents of interest include coenzyme
Q10 and creatine.

Selegiline
Selegiline (Eldepryl) was shown conclusively to delay the need for levodopa therapy in early
Parkinson disease, according to the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy
Of Parkinsonism) study. 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/d) or placebo and tocopherol (2000 IU/d) 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, while those who received selegiline required
levodopa at a projected median of 24 months after enrollment. Tocopherol had no effect on
progression of disability.[17] Because selegiline was observed to provide a small but statistically
significant symptomatic (early) benefit, it is not possible to determine whetheraneuroprotective
effect contributed to the delay in need for levodopa in this study.
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. In the study, patients with early Parkinson disease were randomized to selegiline or
placebo and levodopa was added as needed.[18] After 5 years, subjects treated with placebo had
UPDRS scores that were 35% higher (worse) than those treated with selegiline, even as they
were receiving 19% higher doses of levodopa. This is a striking finding considering that as
monotherapy in early disease, selegiline only provides 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 toxicity, even when the
agent was administered after a delay sufficient to allow the oxidation of MPTP to MPP+,[19] 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 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 delayed-start studies, subjects are randomized to treatment with the
active study medication or placebo (phase I), followed by the active study medication (phase II).
In the second phase of the study, subjects in both arms are receiving active study medication, and
if this period is long enough to allow full wash-in of symptomatic effects, any differences
between the groups should be due to enduring benefits (ie disease modification) that accrue only
to the group receiving the active study medication during the first phase of the study.
Treatment with rasagiline 2 mg/d for 1 year provided significantly greater improvement than
treatment with placebo for 6 months followed by rasagiline 2 mg/d for 6 months, in the TEMPO
(Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients) study, a clinical trial of
patients with early Parkinson disease.[20] When patients were followed long term (5.5-6 y), those
who started rasagiline at the beginning of the study experienced 16% less progression of
disability than those who started it after 6 months.[21]

Similarly, patients who received rasagiline 1 mg/d from the start of the ADAGIO (Attenuation of
Disease progression with Azilect Given Once-daily) trial, a large and rigorous delayed-start study
of rasagiline, had less progression of clinical disability over 18 months than those who received
rasagiline 1 mg/d after a delay of 9 months.[22] These results are potentially consistent with a
disease-modifying effect of rasagiline.
However, 18 months of treatment with rasagiline 2 mg/d did not provide a better outcome than
treatment with placebo for 9 months followed by rasagiline 2 mg/day for 9 months.[22] The reason
for the conflicting results of the 1 mg/d and 2 mg/d delayed-start comparisons in the ADAGIO
study is not known. However, a subanalysis evaluating the most affected quartile at baseline was
positive for both 1 mg/d and 2 mg/d.[23] This suggests the possibility that a symptomatic floor
effect could have interfered with the studies ability to assess disease modification in these very
early patients using the higher dose.

Co-enzyme Q10
In a preliminary study, coenzyme Q10, 1200 mg/d, slowed progression of Parkinson disease
disability. Coenzyme Q10 is a scavenger of free radicals.[24]

Symptomatic Therapy, Early Disease

Medications commonly used for symptomatic benefit in early Parkinson disease include MAO-B
inhibitors, dopamine agonists, and levodopa.

MAO-B inhibitors
MAO-B inhibitors 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.

Levodopa
Levodopa coupled with a PDI (Sinemet) 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, its long-term use is associated with the development of
fluctuations and dyskinesias. Once fluctuations and dyskinesias become problematic, they are
difficult to resolve.
Levodopa/PDI is introduced at a low dose and escalated slowly. Currently available levodopa
preparations in the United States include levodopa/carbidopa, levodopa/carbidopa CR,
levodopa/carbidopa orally disintegrating tablet, and levodopa/carbidopa/entacapone (Stalevo).
The orally disintegrating tablet is bioequivalent to oral levodopa/carbidopa but dissolves on the
tongue without the need to swallow it with water. In the STRIDE-PD study, patients with early

Parkinson disease treated with levodopa/carbidopa/entacapone (Stalevo) developed more

dyskinesia than patients treated with levodopa/ carbidopa; therefore, it is not recommended for
treatment of early disease.[25]
Levodopa is started at a low dose and slowly titrated to control clinical symptoms. Most patients
experience a good response on a daily dosage of 400-600 mg/d (usually divided tid or qid) for 35 years or more. Doses higher than those necessary to control symptoms adequately should be
avoided because higher doses increase the risk for the development of dyskinesia. 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).

Dopamine agonists
Initial treatment with a dopamine agonist, to which levodopa can be added as necessary, has been
shown to cause less development of 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 complications is due to their ability to delay the need for
levodopa/PDI.[26, 27]
Dopamine agonists provide symptomatic benefit reasonably comparable to levodopa/PDI in
early disease but lack sufficient efficacy to control signs and symptoms by themselves in more
advanced disease. They 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 y) who are
cognitively intact. When the dopamine agonist (with or without an MAO-B inhibitor) no longer
provides good control of motor symptoms, the authors then often add levodopa/PDI. However,
dopamine agonists may provide good symptom control for several years.
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 prior to levodopa and add levodopa/PDI when necessary.
For patients who are demented or older than 70 yearswho may be prone to adverse effects,
such as hallucinations, from dopamine agonistsand 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 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 become problematic.
The most common adverse effects of dopamine agonists are nausea, orthostatic hypotension,
hallucinations, somnolence, and impulse control disorders. Nausea usually can be reduced by

having the 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, or sexual
activity. Patients should be warned not to drive if they are experiencing undue sleepiness.
In a small, double-blind crossover study, amantadine was found to ameliorate pathologic
gambling associated with Parkinson disease.[28] However, in a large cross-sectional study,
amantadine was associated with a higher prevalence of impulse control disorders, including
gambling.[29] 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.

Anticholinergic agents
For patients who have disability due to tremor that is not adequately controlled with
dopaminergic medication, an anticholinergic agent can be used. Anticholinergic medications
provide good tremor relief in approximately 50% of patients but do not meaningfully improve
bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication and not
another, a second anticholinergic 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.

Symptomatic Therapy, Advanced Disease

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 immediaterelease levodopa/carbidopa wears off after 4-5 hours. Over time, this shortened duration of
response becomes more fleeting, and clinical status fluctuates more and more closely in concert
with peripheral levodopa concentration. Ultimately, benefit lasts only 1-2 hours. The time when
medication is providing benefit for bradykinesia, rigidity, and tremor is called "on" time, and the
time when medication is not providing benefit is called "off" time.
For patients on CR levodopa/carbidopa, switching to immediate-release levodopa/carbidopa
often provides a more consistent and predictable dosing cycle and allows finer titration. In
general, smaller levodopa doses are administered more frequently. A dose should be sought that
is sufficient to provide benefit without causing troublesome dyskinesia. The time to wearing-off
then determines the appropriate interdose interval. The extreme of this strategy is using liquid
levodopa, a solution with which the dose can be titrated finely and administered every hour.
Amantadine (Symmetrel) may also be of benefit to reduce dyskinesia.
COMT inhibitors inhibit the peripheral metabolism of levodopa to 3-O -methyldopa (3-OMD),
thereby prolonging the levodopa half-life and making more levodopa available for transport
across the blood-brain barrier over a longer time. Because of the potential risk of hepatotoxicity
with tolcapone (Tasmar), liver function test monitoring is required, and it should be used only in

patients who are experiencing motor fluctuations on levodopa that cannot be adequately
controlled with other medications. If dyskinesia emerges, the levodopa dose should be reduced.
In patients who already have dyskinesia, the levodopa dose often is reduced by 30-50% at the
time tolcapone is introduced. Entacapone (Comtan) is a COMT inhibitor that does not cause
hepatotoxicity; liver function tests are not required with this medication. A combination tablet of
levodopa/carbidopa/entacapone is now available.

Dyskinesia
By several months to years after the introduction of levodopa, many patients develop peak-dose
dyskinesia consisting of choreiform, twisting/turning movements that occur when levodopaderived 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 nontroublesome dyskinesia, or on
with troublesome dyskinesia (see image below). The goal of medical management is to minimize
off time and time on with 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.

Motor fluctuations
Treating motor fluctuations in the absence of peak-dose dyskinesia is relatively easy. Several
different strategies, either alone or in combination, can be used to provide more sustained
dopaminergic therapy. Possible strategies include adding a dopamine agonist, catechol-O
-methyltransferase (COMT) inhibitor, or MAO-B inhibitor; dosing levodopa more frequently;
increasing the levodopa dose; or switching from immediate-release to controlled-release (CR)

levodopa/carbidopa or levodopa/carbidopa/entacapone. Unless limited by the emergence of

peak-dose symptoms such as dyskinesia or hallucinations, dopaminergic therapy should be
increased until off time is eliminated.

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 good functional time
through the day as possible. This is accomplished by maximizing on time without troublesome
dyskinesia. An attempt is made to reduce both off time and time with troublesome or disabling
dyskinesia. Unfortunately, a decrease in dopaminergic therapy may increase off time and an
increase in dopaminergic therapy may worsen peak-dose dyskinesia. For patients who have
motor fluctuations and dyskinesia that cannot be adequately managed with medication
manipulation, surgery is considered

Tremor
Levodopa/PDI, dopamine agonists, and anticholinergics each provide good benefit for tremor in
approximately 50% of patients. If a patient is experiencing troublesome tremor and symptoms
are not controlled adequately with one medication, another should be tried. If the tremor is not
controlled adequately with medication, thalamotomy or thalamic stimulation surgery may be
considered at any time during the disease.

Deep Brain Stimulation

Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease
because it does not involve destruction of brain tissue; it is reversible; it can be adjusted as the
disease progresses or adverse events occur; and bilateral procedures can be performed without a
significant increase in adverse events.
Deep brain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of
Parkinson disease largely because of long-term complications of levodopa therapy resulting in
significant disability despite optimal medical management. A better understanding of basal
ganglia physiology and circuitry and improvements in surgical techniques, neuroimaging, and
electrophysiologic recording have allowed surgical procedures to be performed more accurately
and with lower morbidity.
Until recently, surgery for movement disorders 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). (See the image
below.)

Sagittal section, 12 mm lateral of the midline, demonstrating the

subthalamic nucleus (STN; lavender). STN is one of the preferred surgical targets for deep brain
stimulation to treat symptoms of advanced Parkinson disease.
A randomized controlled trial in 255 patients with advanced Parkinson disease found that
bilateral DBS was more effective than best medical therapy in improving on time without
troublesome dyskinesias, motor function, and quality of life at 6 months; however, DBS was
associated with an increased risk of serious adverse events.[30]
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.[31] At a median follow-up period of 12
months and 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's Disease Rating Scale (UPDRS III),
equivalent to a mean improvement of 52%. Significant improvements in dyskinesia duration,
disability, and pain were noted. This confirms that image-guided STN DBS without
microelectrode recording can lead to substantial improvements in motor disability and
improvements of quality of life in well-selected patients with Parkinson disease, with very low
morbidity.
In Australia, guidelines have been developed to help neurologists and general physicians identify
Parkinson disease patients who may benefit from referral to a specialized DBS team; these teams
assess the likely benefits and risks of DBS for each referred patient.[32]
Please go to the topic Deep Brain Stimulation in Parkinson 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 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.
The 2 most commonly performed neuroablative procedures are thalamotomy and pallidotomy, in
which lesions are created in the VL thalamus and the GPi, respectively.

Ventrolateral thalamotomy
The VL thalamus receives afferent innervation from 2 primary sources: the GPi via the ansa
lenticularis and thalamic fasciculus and the contralateral cerebellum via the superior cerebellar
peduncle. These cerebellar fibers synapse primarily in the VIM and ventral oral posterior (VOP),
the most posterior segments of the VL. Oscillating excitatory input from the cerebellum may be
responsible for the tremor observed in Parkinson disease, as cellular activity synchronous with
the frequency of parkinsonian tremor can be recorded in VL. These data support the clinical
observation that lesions placed within VL (and specifically within VIM/VOP) arrest parkinsonian
and essential tremors.
VL thalamotomy was the most frequently performed procedure for movement disorders in the
prelevodopa era because tremor responds best to thalamotomy and can be monitored more easily
in the operating room than gait abnormalities, rigidity, and akinesia.
Thalamotomy involves destruction of a part of the thalamus, generally the VIM, to relieve
tremor. VIM almost unanimously is considered the best target for tremor suppression, with
excellent short- and long-term results 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 GPi and STN, are preferred.
Thalamotomy is indicated in patients with Parkinson disease who are disabled by medically
refractory tremor. The anticipated benefit of tremor reduction or elimination must be considered
carefully. Rest tremor alone is rarely disabling, and bradykinesia and rigidity can reduce
dexterity irrespective of tremor. Most patients with Parkinson disease who undergo thalamotomy
have significant improvement in tremor of the limbs contralateral to the side of the lesion.
Bilateral thalamotomy is generally avoided because complications, especially speech and
cognitive impairment, are common.
The reported morbidity rate for thalamotomy ranges from 9-23%. The predominant complication
is speech impairment with dysarthria and hypophonia. The risk of speech abnormalities is 30%
for unilateral thalamotomy and greater than 60% following bilateral lesions. Other complications
include memory loss, contralateral hemiparesis, and, more rarely, hemineglect, dystonia,
hemiballismus, athetosis, and dyspraxia.
Preoperative memory and language evaluation can help identify patients who are at greatest risk
for postoperative cognitive and language dysfunction. In the largest series, the mortality rate for
thalamotomy ranged from 0.5-1%. Death results almost exclusively from intraparenchymal
hemorrhage.

Pallidotomy
Svenillson and Leksell described ventral posterior pallidotomy in the 1960s;[33] 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.[34]
The negative symptoms of Parkinson disease (ie, rigidity, bradykinesia) are caused, in part, by
excessive inhibitory output from the GPi to the VL thalamus (see Pathophysiology). Lesioning of
the sensorimotor region of the GPi, which lies ventral and posterior in the nucleus, decreases this
hyperinhibition of motor thalamus. 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. Tremor improvement is less consistent than with thalamotomy.
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 out of concern of 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, detailoriented postoperative care. The authors believe that this level of care is best provided by a
multidisciplinary team comprising 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.
At the authors' movement disorder center, patients are evaluated for surgery as follows:
1. Neurologist evaluation
2. Neurosurgeon evaluation to identify potential surgical candidates
3. Psychiatrist evaluation
4. Medical evaluation
First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection
is particularly important for successful STN DBS because a number of factors concur to
determine positive surgical outcome.[35, 36] These can be summarized as follows:

A diagnosis of IPD

Positive response to levodopa

Absence of atypical parkinsonian features

Advanced disease, virtually unmanageable with dopaminergic medications

Relatively young age; however, advanced age (>75 y) 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)

Normal cognition

Absence of active psychiatric disease

Good social support and access to programming

Potential surgical candidates then are 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 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 subtle 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 PET scan may be performed in the unusual circumstance that an alternative
diagnosis of multiple system atrophy cannot be ruled out clinically. A medical evaluation is
performed to determine the patient's general fitness for surgery.
Surgery is reserved for patients with medically refractory Parkinson disease with disabling
problems. Currently, the authors' center adopts the following surgical recommendations for
patients with medically refractory Parkinson disease:

Unilateral pallidotomy is offered to patients with asymmetric Parkinson disease who

develop fluctuations in their response to levodopa, including disabling dyskinesias and
off-state dystonia.

Bilateral pallidotomy is avoided, although investigations are underway to evaluate

contralateral GPi DBS in patients who have undergone a successful pallidotomy and are
experiencing disease progression in the untreated side.

Thalamotomy or 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 tremors).

Thalamic DBS is preferred over thalamotomy, particularly in young patients with

Parkinson disease who are disabled solely by tremor early in the course of their disease,
because it gives the option of removing the stimulator if more effective therapies are
developed or if symptom progression necessitates DBS at another target such as STN.

Bilateral STN DBS is offered to patients with advanced Parkinson disease with bilateral
levodopa-induced dyskinesia, significant gait disturbances and axial symptoms, or
medically refractory rigidity and akinesia.

Prior to surgery, the patient should be informed that these procedures do not cure
Parkinson disease and that progression is expected.

Transplantation
Neural transplantation is a potential treatment for Parkinson disease because the neuronal
degeneration is site and type specific (ie, dopaminergic), the target area is well defined (ie,
striatum), postsynaptic receptors are relatively intact, and the neurons provide tonic stimulation
of the receptors and appear to serve a modulatory function.

Transplantation of autologous adrenal medullary cells and fetal porcine cells have not been found
to be effective in double-blind studies and have been abandoned. Although open-label studies of
fetal dopaminergic cell transplantation yielded promising results, 3 randomized, double-blind,
sham-surgerycontrolled 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.[37]
Lewy bodylike 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.[38]
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-surgerycontrolled study of this technique is under
way.[39] In one case study, however, postmortem examination in a patient who died 6 months after
surgical implantation of 325,000 retinal pigment epithelial cells found only 118 surviving cells.
[40]

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. The goal
of these studies is to modify genes involved in the development of Parkinson disease.
In a phase I trial of gene delivery of the trophic factor neurturin via an adeno-associated type-2
vector (AAV2), the safety and efficacy of intraputaminal AAV2-neurturin was not superior to
sham-surgery, but further study should focus on the possibility of a benefit with additional
targeting of the substantia nigra.[41]
However, a double-blind, phase II, randomized, controlled trial of patients aged 3075 years,
who had progressive levodopa-responsive Parkinson disease and an overnight off-medication
UPDRS motor score of 25, found that the efficacy and safety of bilateral infusion of AAV2-GAD
in the subthalamic nucleus suggested promise for gene therapy for neurological disorders.[42]

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.[43] Based on their review, they suggested that rivastigmine (Exelon) and donepezil
(Aricept) are probably effective in treating the dementia. The risk of potentially exacerbating

motor symptoms may limit their widespread use. Anticholinergic drugs used for the treatment of
motor manifestations of Parkinson disease may exacerbate memory impairment. When possible,
avoid these medications.

Depression
Depression affects as many as 40% of patients with Parkinson disease. This may be due in large
part to neurochemical changes associated with the disease. Limited studies suggest that tricyclic
and selective serotonin reuptake inhibitor (SSRI) antidepressants have efficacy in depression in
this setting.
Case reports exist of worsening of Parkinson disease motor features by SSRIs, but this has not
been demonstrated in population studies. The combination of selegiline and an SSRI potentially
can cause the serotonin syndrome, with symptoms of mental status changes, myoclonus, tremor,
diaphoresis, incoordination, and possibly coma or death. This appears to be very rare and might
be due to individual variations in metabolic pathways. The combination of selegiline at an oral
dose of 10 mg/d or less and an SSRI generally is considered safe, although clinical monitoring is
warranted.
Psychotherapy can play an important role in the treatment of depression,[44] and, in severe
refractory cases, electroconvulsive therapy may be effective.[45] There is limited evidence
showing any benefit with dopamine agonists[46] and monoamine oxidase inhibitors.[47] One study
suggests that dopamine agonist treatment of Parkinson disease carries a substantial risk of
pathological behaviors, which occurred in 16% of patients receiving these agonists.[48] The vast
majority of affected cases (94%) were concurrently taking carbidopa/levodopa, suggesting
concurrent therapy with a dopamine agonist appeared to be an important risk factor.

Anxiety
SSRIs and venlafaxine (Effexor) can be beneficial. Buspirone is well tolerated but has not been
studied in this population. Benzodiazepines may help severe anxiety, but adverse effects such as
cognitive impairment and balance problems may be concerning. Behavior modification
techniques can play an important role in the treatment of anxiety.[49] However, the 2010 American
Academy of Neurology 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.[16]

Sleep disturbances
Benzodiazepines can be helpful in the treatment of rapid eye movement sleep behavior disorder
(RBD), and obstructive sleep apnea 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.[49, 50]

The 2010 American Academy of Neurology 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.[16]

Hallucinations
Hallucinations usually occur in the presence of an underlying dementia. Mild, nonthreatening
hallucinations may be tolerated, but an effort should be made to eliminate more severe or
threatening hallucinations.
In patients who experience hallucinations, minor agents such as amantadine and anticholinergics
should be titrated down and discontinued. If hallucinations are still present, dopamine agonists
should be discontinued slowly, and levodopa/PDI should be titrated to see if hallucinations can
be resolved while still maintaining adequate control of motor symptoms. If hallucinations persist,
an atypical neuroleptic should be added. These agents reduce hallucinations and induce little or
no worsening of parkinsonian motor features.
Quetiapine (Seroquel) is the most widely used medication to treat hallucinations in Parkinson
disease. It is generally effective and does not require blood monitoring. It is introduced at a dose
of 25 mg and increased to 50-300 mg/d as needed.
Clozapine (Clozaril) can be introduced using a chip (approximately one eighth) of a 25-mg
tablet. The dose can be escalated slowly, and most patients experience good benefit at a dose of
12.5-25 mg/d. Weekly blood tests are required because of the risk of agranulocytosis.
Olanzapine (Zyprexa) and risperidone (Risperdal) appear to have slightly more parkinsonian
adverse effects than clozapine or quetiapine.

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 the 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 34% 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 IPD. 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 IPD 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
improve after LSVT without any significant change in supraglottal hyperfunction. Preliminary
PET scans after LSVT training in patients with IPD 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 IPD, but most
data so far support LSVT as the promising therapy for IPD 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.

Dietary Considerations
Proper nutritional support is essential for patients with Parkinson disease, including adequate
dietary fiber to prevent the common problem of constipation.
Protein-restricted diets may be useful in patients who are experiencing motor fluctuations with
long-term levodopa treatment. Levodopa is transported into the brain by a carrier protein that
also transports large neutral amino acids found in dietary protein. Consequently, high-protein
meals can compete for the transport of levodopa and reduce or eliminate its effects. A proteinrestricted diet can therefore improve the response to levodopa and can be useful in patients with
otherwise refractory motor fluctuations.
Two general approaches are used for a protein-restricted diet. In one, the total daily protein
intake is spread more or less equally over the day. The other approach is consuming food very
low in protein or not containing protein during the day and eating a high-protein meal in the
evening.
Generally, these diets are difficult to follow; however, in patients with severe, unpredictable
motor fluctuations, this approach may be worthwhile.

Consultations

Generally, patients with Parkinson disease are best treated and monitored by a neurologist,
except in the early stage of the disease. 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 the 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, and 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.[51] Articulatory problems can persist, and the result of surgery can be
disappointing.

A gastroenterologist and 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
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 medications, provide follow-up
care at least every 3-6 months and periodically adjust medication dosages as necessary.
Medication management provides the most effective treatment of Parkinson disease for the first
4-6 years. Thereafter, this disabling disease advances despite continuing medication
management.