Parkinson Disease

Nutan Sharma, MD, PhD

Synonyms
Shaking palsy
Paralysis agitans
Idiopathic parkinsonism
ICD-9 Codes
332.0 Parkinson disease/parkinsonism
331.1 Essential tremor
333.0 Other degenerative disease of the basal ganglia (This include multiple system
atrophy;progressive supranuclear palsy, and corticobasal degeneration)

DEFINITION
Parkinson disease (PD) is a chronic, progressive neurodegenerative disease. On pathologic
examination, it is characterized by prefential degeneration of dopaminergic neurons in substantia
nigra pars compacta and the presence of cytoplasmic inclutions known as Lewy bodies; clinically, it is
characterized by a resting trmor, bradykinesia, and rigidity. It is important to distinguish PD from the
disorders that are known collectively as Parkinson-plus syndromes. These are relatively rare disorders
that share some of the features of PD, such as rigidity and bradykinesia. However, the Parkinson-plus
syndromes do not respond to medical treatment and have some unique clinical features as well.
The prevalence of PD, in industrialized countries, is estimated at 0,3% of the entire population and
1% of the population older than 60 years. 1 PD is clearly an age-related disease. Studies show that the
prevalance of PD increase up to the ninth decade (ages 80 to 89 years) of life. Reliable information
about prevalence of PD beyond the ninth decade is not available. Some studies have reported a higher
incidence of PD in men than in women, although other studies have refuted this finding. 2-4

SYMPTOMS
The most common initial manifestations of PD are rest tremor and bradykinesia. Less common
presenting complaints include hypophonia, gait difficulty, and fatigue. It is not uncommon for one of
these features to be present for months or even years before others develop.
Pain also a part of PD. An aching pain in the initially affected limb may first be attributed to bursitis
or arthritis. Additional symptoms, seen early in the course of PD, include a resting tremor is
suppressed by either purposeful movement or sleep and exacerbated by anxiety. The sensation of
stiffness occurs in the affected arm or leg and may be accompanied by the perception that one is slow
with movement.
As the disease progress, there is marked difficulty in both initiating and terminating movement. There
is difficulty in rising from a seated position, particularly when one is seated in a sofa or chair without
armrest. Hand-writing becomes smaller and more difficult to read. Friends and family members often
complain that the patients speech is more difficult to understand, particularly on the telephone. The
symptom of a softer voice a decline in enunciation is known as hypophonia.

PHYSICAL EXAMINATION
The most distinctive clinical feature is the rest tremor. It is typically present in a single upper
extremity early in the course of the disease. As the disease progresses, the resting tremor may spread
to both the ipsilateral lower limb and the contralateral limbs. Examination of motor tone reveals
cogwheel rigidity in the affected limb. Motor strength, however, remains unaffected.
Additional features that must be evaluated in an examination include rapid, repetitive limb
movements and gait. Examination of repetitive movements of the fingers or entire hand will reveal
bradykinesia in the affected limb. Examination of gait wiil reveal decreased arm swing on the affected
side, smaller steps, and an inability to pivot turn. Typically, patients make several steps to complete a
turn because of some degree of postural instability. Deep tendon reflexes and sensation are not
affected in PD.
In advanced PD, loss of postural reflexes becomes evident. Individuals are unable to maintain balance
when turning. Other manifestations of advanced PD include freezing episodes and dysphagia.
In examination of someone who is talking medication for PD, it is important to record the time at
which the last dose of medication was taken relative to the time at which the examination occurs.
Medications for PD are particularly in the early stages of the disease. Typically, the rest tremor will

subside for 1 to 3 hours after the last dose of medication. Other features, such as reduced arm swing,
hypophonia and loss of postural reflexes, do not respond to oral medication.

FUNCTIONAL LIMITATIONS
Functional limitations depend on which symptoms are most prominent in a particular patient. Early in
the course of PD, the sole limitation may be in ones ability to write legibly. Affected individuals are
still able to perform activities of daily living, although the rest tremor may result in a feeling of selfconsciousness as it is suppressed with purposeful movement.
As the disease progress, the ability to perform fine motor skills decline, and difficulty with standing
and gait develops. An individual will have difficulty in buttoning a shirt or tying shoelaces. More time
will be required to stand and initiate gail. Postural instability with a tendency to retropulse also
develops. Thus, patients have difficulty in climbing stairs and walking safely and quickly. Slowed
reaction times may also affect ones ability to drive safely. Decisions about whether someone should
drive are often difficult and must be made on an individual basis. Marked hypophonia may make
speaking on the telephone difficult as well. As the voice becomes more affected, dysphagisa is likely
to develop.
One aspect of PD that has historically gotten little attention from medical professionals is the effect it
has on sexual activity. According to the National Parkinson Foundation, almost 81% of men and 43%
of women with PD report experiencing diminished sexual activity. Men may experience a declining
interest in sexual activity, abnormal sexual arousal, or reduced orgasm.
In end-stage PD, limitations include marked dysphagia and severe abnormalities of gait that require
both devices and one or two person for assistance. At this stage, help is necessary for all activities of
daily living as well.

DIAGNOSTIC STUDIES
PD is clinical diagnosis. Conventional laboratory investigations do not contribute to the diagnosis or
management of PD. Computed tomography and magnetic resonance imaging scans of the brain do not
reveal any consistent abnormalities. Positron emission tomography with use of 6-[ 18F] flurolevodopa
reveals reduced accumulations of radioisotope in the striata. There is greater loss contralateral to the
side that is most affected clinically. These findings are consistent with the reduction of dopamine that
occurs in PD. However,

positron emission tomography remains an experimental rather than a

diagnostic tool.
3

Differential Diagnosis
The differential diagnosis includes several diseases known collectively as the Parkinson-Plus
syndromes.
Multiple system atrophy in addition to bradykinesia and rigidity multiple system atrophy is
characterized by ataxia and autonomic dysfunction that typically is manifested as episodes of flushing
or palpitations.
Progressive supranuclear palsy in addition to bradykinesia, rigidity and rest tremor. Progressive
supranuclear palsy is characterized by the inability to voluntarily move the eyes upward and frequent
falls that occur relatively early in the course of the disease.
Corticobasal degeneration in addition to bradykinesia and rigidity corticobasal degeneration is
characterized by a loss of the ability to coordinate specific purposeful movement of the limbs
(apraxia) and a sensation that ones limbs are not ones own (alien-limb syndrome).
Essential tremor: Essential tremor is an involuntary, rhythmic tremor of a body part. Essential tremor
most commonly affects the arms and hands but can also involve the head voice, tongue, trunk, or legs.

TREATMENT
Initial
The decision to initiate medical treatment is based on the degree of disability and discomfort that the
patient is experiencing. Six classes of drugs are used to treat PD (summarized in Table 132-1). The
selection of a particular drug depends on the patients main complaint, which is usually either a rest
tremor or bradykinesia. There is no evidence to suggest that expediting or delaying the onset of
treatment for PD has any effect on the overall course of the disease. However, it is clear that those
who do not receive treatment and are bradykinetic are at greater risk of failing and injuring
themselves.
Anticholinergic agents are oldest class of medications used in PD. They are the oldest class of
medications used in PD. They are most effective in reducing the rest tremor and rigidity associated
with PD. However, the side effects associated with anticholinergic agents typically limit their
usefulness. Amntadine is also used in the treatment of PD. Amantadine produces a limited
improvement in akinesia, rigidity, and tremor.
Dopamine replacement remains the cornerstone of antiparkinson therapy. Levodopa is the natural
precursor to dopamine and is converted to dopamine by the enzyme aromatic amino acid
decarboxylase. To ensure that adequate levels of levodopa reach the central nervous system, levodopa
is administered simultaneously with a peripheal decarboxylase inhibitor is carbidopa. Levodopa is
most effective in reducing tremor, rigidity, and akinesia. The most common side effect, seen with the
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onset of treatment, are nausea, abdominal cramping, and diarrhea. Long-term treatment with levodopa
is associated with three types of complications: hourly fluctuations in motor state, dykinesias, and a
variety of psychiatric complaints including hallucinations and confusion. However, it is not clear
whether the motor fluctuation are due to the levodopa treatment alone, the disease progression alone,
or a complex interplay of imperfect dopamine replacement and the inexorable progression of disease.
In summary, current evidence supports the use of dopamine replacement as soon as the symptoms of
PD become troublesome to the individual patient. There is no evidence that support withholding of
treatment to minimize long-term motor complications. 5

TABLE 132-1 Classes of Antiparkinson Medications, Mechanisms of Action, Beneficial

Effects, and Side Effects
Drug Class

Specific

Mechanusm of

Effective for

Anticholinergic

Agents
Benztropine

Action
Muscarinic

Tremor rigidity Dry mouth, blurred

receptor blocker

Side Effects

vision, urinary
retention, confusion,
hallucinations,

Antiviral

Amantadine

Promotes

impaired concentration
Tremor rigidity Leg edema, livedo

synthesis and

akinesia

release of

reticularis, confusion,
hallucinations

dopamine
Converted to

Tremor rigidity Nausea, diarrhea,

dopamine

akinesia,

confusion,

Dopamine

Bromocriptin Dopamine

freezing
Rigidity,

hallucinations
Leg edema, nausea,

agonists (D1 dan

e, pergolide

akinesia

confusion,

Dopamine

levodopa

replacement

analogues that

D 2)

bind to D1 and D2

hallucinations

Dopamine

Ropinirole,

receptors
Dopamine

Rigidity,

Leg edema, sleep

agonists (D2)

pramipexole

analogues that

akinesia

attacks, nausea,

bind to D2

confusion,
Mild reduction

hallucinations
Nausea, hallucinations,
confusion

Monoamine

Selegiline,

receptors
Inhibit the

oxidase B

rasagoline

metabolism of

in wearing off

dopamine

from levodopa

inhibitors

Catechol O-

Entacapone

Inhibit the

Mild reduction

Dyskinesia, nausea,

methyltransfera

metabolism of

in wearing off

diarrhea

se inhibitor

dopamine

from levodopa

Dopamine agonists, which directly stimulate dopamine receptors, are also used in the treatment of PD.
These agents can be used either as an adjunct to levodopa therapy or as monotherapy. The older
dopamine agonist, which are relatively nonspecific and exert their effects at both D 1 and D2 receptors,
are bromocriptine and pergolide. In comparison to the side effects seen with levodopa, there is a lower
frequency of dyskinesias and a higher frequency of confusion and hallucinations. The newer
dopamine agonists pramipexole and ropinirole are more specific for D 2 receptors. These newer agents
have been reported to cause excessive lethargy and sleep attacks. 6 All dopamine agonist can cause
orthostatic hypotension, particularly when they are first introduced. It is best to start with a small dose
of medication at bed time and then slowly increase the total daily dose
Inhibitors of dopamine metabolism are also used in the medical treatment of PD. Both selegiline and
rasagiline inhibit monoamine oxidase B, which metabolizes dopamine in the central nervous system.
Thus, inhibitors of monoamine oxidase B are thought to improve an individuals response to levodopa
by alleviating the motor fluctuations that are seen with long-term levodopa treatment. Another agent
that inhibits the metabolism of dopamine is entacapone. Entacapone inhibits catechol Omethyltransferase in the periphery. Entacapone is administered in conjunction with levodopa and, by
inhibiting peripheral catechol O-methyltransferase activity, increases the amount of levodopa that
reaches the central nervous system. The benefit of entacapone treatment include a reduction in total
daily levodopa dose and an improvement in the length of time of maximum mobility.7
Constipation is a frequent complaint. Treatment includes increase in physical activity; discontinuation
of anticholinergic drugs; and maintenance of a diet with intake of adequate fluids, fruit, vegetables,
fiber, and lactulose (10 to 20 g daily).

Rehabilitation

The clinical pathologic process seen in PD reveals that patients tend to become more passive,
less active, and less motivated as the disease progresses. The benefits to physical and
occupational therapy are thus more far reaching than a simple improvement in motor
function. The physical benefits include improvement in muscle strength and tone as well as
maintenance of an adequate range of motion in the joints. The psychological benefits include
enlistment of the patient as an active participant in treatment and provision of a sense of
mastery over the effects of PD. Both physical therapy and occupational therapy focus on
mobility, the use of adaptive equipment, and safety in both the home and community.
Because the symptoms of PD gradually worsen over time, individuals can benefits from
periodic physical therapy training throughout the course of their illness. An emphasis on gait
training is particularly helpful to prevent falls and injury. Gait training typically involves
training an individual to be conscious of taking a longer stride and putting the foot down with
each step. Another method is is to use visual cues to maintain a regular size for each step. For
example, one can put strips of masking tape on the floor, at a regular interval that is
comfortable for ones height, weight, and gender. As PD progresses, episodes of frozen gait,
in which the feet seem to be stuck to the floor, occus. Such freezing episodes can be broken
by multiple techniques, such as visualizing that one is stepping over an imaginary line one the
floor, counting in a rhythmic cadence, or marching in place.
Occupational therapy is particularly helpful in recommending adaptive devices or
establishing new routines that allow people with PD to continue to live independently. For
example, the use of a long-handled shoehorn reduces the need to bend over and thus
eliminates the risk that a person with PD will fall while getting dressed. Other examples of
adaptive equipment are a firmly secured grab bar in the bathtub and a relatively high toilet
seat with armrests to minimize the risk of freezing while on the toilet.
Speech therapy plays a critical role for those PD patients who suffer from communication
difficulties. Although dysarthria is difficult to treat, hypophonia can be overcome with
training. Specifically, the Lee Silverman Voice Treatment program has been shown to be
effective in improving both the volume and clarity of speech in those with PD. 8 Swallow
evaluation and therapy are also helpful in the treatment of dysphagia, which occurs as PD
progresses.
Procedures

Feeding tubes are sometimes used in individuals who have severe end-stage PD. Some
patients elect hospice care, without artificial feeding at that point. Individuals who do get
feeding tubes may need to have medication doses adjusted ( e.g., carbidopa-levodopa will
now bypass the esophagus and have a shortened time to onset of action.
Surgery
Although a large number of medications are available for the treatment of early and
moderately advanced PD, they are of limited efficacy in those with advanced PD. Several
surgical procedures are currently available for those with advanced PD. These procedures
consist of either creation of a permanent lesion or insertion of an electrical stimulator in a
specific nucleus of the brain.
Thalamotomy consists of introduction of a lesion in the ventral intermediate nucleus of the
thalamus. Thalamotomy has been reported to produce a reduction in tremor of the
contralatelaral limb in 80% of the patients who were treated.9 There was no improvement in
bradykinesia or in gait or speech abnormalities. Thalamotomy is recommended in PD patients
with an asymmetric, severe, medically intractable tremor.
Unilateral pallidotomy consists of introduction of a lesion in the globus pallidus. The most
striking benefits are a reduction in contralateral drug-induced dyskinesia, contralateral
tremor, bradykinesia, and rigidity.10,11 Unilateral pallidotomy is recommended in PD patients
with bradykinesia, rigidity, and tremor who experience significant drug-induced dyskinesia
despite optimal medical therapy. Few data are available about the cognitive effect of
unilateral pallidotomy. Thus, neurophychological evaluation is recommended in all patients
both before and after surgery.
Deep brain stimulation (DBS) consist of high-frequency electrical stimulation in one of the
following locations : the ventral intermediate nucleus of the thalamus, the globus pallidus, or
the subthalamic nucleus. DBS requires surgery, in which the source of electrical stimulation
is placed subcutaneously in the chest wall and the leads to which it is attached are placed in
one of the locations listed. The advantage of DBS is that the degree of electrical stimulation
can be easily adjusted, externally, once the DBS unit is in place. In contrast, both
thalamotomy and pallidotomy result in permanent, fixed lesions in the brain. DBS of the
ventral intermediate nucleus of the thalamus is effective in the treatment of a severe and
disabling tremor that is unresponsive to medical therapy. DBS of the globus pallidus result in
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a marked reduction in dyskinesia. There are also improvement in bradykinesia, speech, gait,
rigidity, and tremor. DBS of the subthalamic nucleus also results in marked improvement in
tremor, akinesia, gait, and postural stability.12
For the symptoms of PD that no longer fully respond to medication, surgical treatment is an
important therapeutic option. In carefully selected cases, thalamotomy and DBS of the
thalamus can safely and effectively control contralateral tremor. Unilateral pallidotomy has
been demonstrated to be an effective treatment of severe dyskinesias. Most commonly, DBS
of the subthalamic nucleus improves motor function and reduces off time. 13 DBS of the
ventral intermediate nucleus of the thalamus or the globus pallidus remains under
investigstion.

POTENTIAL DISEASE COMPLICATIONS

The true prevalence of depression in those with PD is unknown, but estimates vary from 7%
to 75%.14 It may be difficult to distinguish true depression from the apathy associated with
PD. The crucial factor is to determine whether the patient has a true disturbance of mood,
with loss of interest, sleep disturbance, and sometimes suicidal thoughts. The reason for
depression in PD are a subject of debate. There is a suspicion that the pathologic process of
PD itself may predispose to depression. Regardless of the cause, recognition and treatment of
depression may have a significant impact on the overall disability caused by the illness. Many
PD patients have been treated safely and effectively with selective serotonin reuptake
inhibitors, such as fluoxetine and paroxetine. Tricyclic antidepressants can be used, although
their anticholinergic properties may limit their effectiveness.
Gastrointestinal complications also occur in PD. Dysphagia is typically due to poor control of
the muscles of both mastication and the oropharynx. Soft food is easier to eat, and
antiparkinson medication improves swallowing.

POTENTIAL TREATMENT COMPLICATIONS

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The motor complications seen with pharmacologic treatment are divided in two categories :
fluctuations (off state) and levodopa-induced dyskinesias. The off state consist of a return of
the signs and symptoms of PD : bradykinesia, tremor, and rigidity. Patients may also
experience anxiety, dysphoria, or panic during an off state.
The development of levodopa-induced dyskinesias appers to be related to the degree of
dopamine receptor supersensitivity. As PD progresses, there is an increasing loss dopamine
receptors. This result in an increased sensitivity of the remaining dopamine receptors to
dopamine itself. Thus, there is a greater chance for development of dyskinesias at a given
dose of levodopa. Treatment options are to lower each dose of levodopa but with an increase
in the frequency with which it is taken : to add or to increase the dose of dopamine agonist
while the dose of levodopa is decrease ; and to add amantadine, which has been shown to be
an antidyskinetic agent in some patients.13,15 In addition, those patients who continue to
experience an improvement in their mobility with levodopa but develop dykinesias that
become more pronounced as the day progresses are excellent candidates for DBS.

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