Parkinson's Disease

Introduction

Parkinson's disease (PD) was first described in 1817 by James Parkinson, in "An Essay on the
Shaking Palsy." It is a neurodegenerative disease, meaning it is caused by degeneration
(dysfunction and death) of neurons within the brain. PD causes motor (movement) and nonmotor
symptoms.

PD is believed to affect approximately one million people in the United States. Misdiagnosis of
PD is common, however, so this figure is not precise. The likelihood of developing PD increases
with age. PD typically begins in a person's 50s or 60s, and slowly progresses with increasing age.
The average age of onset is 62.4 years. Onset before age 30 is rare, but up to 10% of cases begin
by age 40.

While no treatments have yet been shown conclusively to slow the disease, a large number of
drugs are available to treat symptoms, as well as several forms of surgery and numerous
nonpharmacological (non-drug) approaches.

Symptoms

The cardinal motor symptoms are slowed movements (called bradykinesia), resting tremor
(shaking in an arm or leg when it is not being moved), muscle rigidity (stiffness), and postural
instability. Other symptoms are listed in the Box below. Symptoms typically begin on one side
of the body (unilateral) and progress to include both sides.

Symptoms of Parkinson's Disease

(Not all people with PD develop all these symptoms.)

• Motor Symptoms
o Tremor
o Bradykinesia
o Rigidity and freezing in place
o Stooped, shuffling gait
o Decreased arm swing when walking
o Difficulty arising from a chair
o Micrographia (small handwriting)
o Lack of facial expression
o Slowed activities of daily living
o Postural instability
o Difficulty turning in bed
 • Nonmotor Symptoms
o Diminished sense of smell
o Low voice volume
o Painful foot cramps
o Sleep disturbance
o Depression
o Constipation
o Drooling
o Increased sweating
o Urinary frequency/urgency
o Male erectile dysfunction

The Substantia Nigra in PD

The substantia nigra (literally meaning "black substance") is a small region in the brain stem, just
above the spinal cord. It is one of the centers that help control movements. Cells within the
substantia nigra (SN) produce and release a chemical called dopamine. Dopamine is a
neurotransmitter that controls movement and balance and is essential to the proper functioning of
the central nervous system (CNS). Dopamine assists in the effective communication
(transmission) of electrochemical signals from one nerve cell (neuron) to another. Dopamine
released by SN neurons lands on the surface of neurons in other brain centers, controlling their
activities or "firing" and thus regulating movement. The main target regions of dopamine release
from the substantia nigra are called the caudate and the putamen.

In PD, cells of the SN degenerate, and therefore can no longer produce adequate dopamine.
When this occurs, neurons elsewhere in the brain are no longer well regulated and do not behave
in a normal manner. This results in a loss of control of movements, leading to slowed
movements, tremor, and rigidity.

A principal aim of PD therapy is to replace the brain's supply of dopamine with the drug
levodopa, which the brain uses to make more dopamine. Alternatively, drugs called dopamine
agonists can mimic dopamine's effects on its target cells (in the caudate and the putamen).

Risk Factors and Protective Factors

The single biggest risk factor for PD is advancing age. Men have a slightly higher risk compared
to women. Family history is also an important risk factor. Individuals with an affected first-
degree relative (parent or sibling) are estimated to have an approximately doubled risk for
developing PD. This increased risk is likely to be a combination of environmental and genetic
factors that close relations have on common.
The single factor that has been most consistently associated with a reduced risk of PD is cigarette
smoking, which has been demonstrated in numerous studies. It is not known whether smoking
confers a genuine protective effect, or whether individuals who are prone to develop PD for other
reasons are also prone to avoid smoking. Nonetheless, the negative impact on general health
from smoking is enormous, far in excess of any slight reduction in risk for PD. Smoking cannot
be recommended as a strategy for avoiding PD.

Caffeine consumption is also associated with a reduced incidence of PD. In women, hormone
replacement therapy appears to be associated with a reduced incidence in women who consume
only small quantities of caffeine, but may be a risk factor in those who consume more than five
cups per day.

Environmental Causes of PD

The vast majority of cases of PD are thought to be due to the potential interactions of genes and
the environment. Environmental causes are presumed to be one or more widely present but weak
toxins. The effects of these toxins may build up over time and eventually lead to disease in
genetically predisposed individuals. The identity of these toxins is unknown, although several
environmental risk factors have been identified through epidemiological studies.

A strong and consistent finding is that the risk of PD is increased by rural living, exposure to
well water, and agricultural work, suggesting that pesticides or herbicides may cause or
contribute to PD. It should be pointed out, however, that these individual factors do not by any
means guarantee the development of PD, nor does their absence protect against it; there are many
cases of individuals with none of these risk factors who develop PD, and many with them who
do not.

Genetics

There are several genes that are known to cause PD, but they account for a very small minority
of cases. The most important is a gene called parkin. The parkin gene creates a protein, also
called parkin that helps to break down defective proteins inside brain cells (neurons). When the
parkin gene is altered, or mutated, this function is impaired. It is hypothesized that the
accumulation of defective proteins contributes to death of neurons. Two mutated copies of parkin
are needed to develop PD. This type of inheritance pattern is called "autosomal recessive." One
copy of the defective gene is inherited from each parent. Parkin mutations cause young-onset
PD, with symptoms beginning usually in the 40s. Parkin mutations are the most common genetic
cause of PD, but still account for less than one percent of all cases.
Other known genes for PD include alpha-synuclein, DJ-1, PINK-1, and UCHL-1, but altogether
these represent only a small number of PD cases.

Diagnosis

Since there is no specific test or marker for PD, diagnosis is by a physician and depends on the
presence of at least two of the three major signs: tremor at rest, rigidity, and bradykinesia, as well
as the absence of a secondary cause, such as antipsychotic medications or multiple small strokes
in the regions of the brain controlling movement. Patients tend to be most aware of tremor and
bradykinesia, and less so of rigidity.

To diagnose PD, the physician will perform a standard neurological examination, involving
various simple tests of reactions, reflexes, and movements.

• Bradykinesia is tested by determining how quickly the person can tap the finger and thumb
together, or tap the foot up and down.
• Tremor is determined by simple inspection.
• The physician assesses rigidity by moving the neck, upper limbs, and lower limbs while the
patient relaxes, feeling for resistance to movement.
• Postural instability is tested with the "pull test," in which the examiner stands behind the
patient and asks the patient to maintain their balance when pulled backwards. The examiner
pulls back briskly to assess the patient's ability to recover, being careful to prevent the patient
from falling.

The examination also involves recording a careful medical history, especially for exposure to
medications that can block dopamine function in the brain. Several drugs with similar properties
are also used for other purposes, and the physician inquires about these other drugs. A list of
such medications is shown in the table below.

Generic (Trade Name)

Acetophenazine (Tindal®)

Amoxapine (Asendin®)

Chlorpromazine (Thorazine®)

Fluphenazine (Permitil®, Prolixin®)

Haloperidol (Haldol®)
Loxapine (Loxitane®, Daxolin®)

Mesoridazine (Serentil®)

Metaclopramide (Reglan®)

Molindone (Lindone®, Moban®)

Perphenazine (Trilafon® or Triavil®)

Piperacetazine (Quide®)

Prochlorperazine (Compazine®, Combid®)

Promazine (Sparine®)

Promethazine (Phenergan®)

Thiethylperazine (Torecan®)

Thioridazine (Mellaril®)

Thiothixene (Navane®)

Trifluoperazine (Stelazine®)

Triflupromazine (Vesprin®)

Trimeprazine (Temaril®)

Several other disorders have certain features that are similar to those of PD, and are sometimes
mistaken for PD. These include:

• Essential tremor, in which tremor is the only symptom

• Progressive supranuclear palsy, characterized by inability to look downward
• Multiple system atrophy, characterized by early and prominent autonomic symptoms
• Vascular (related to blood vessels) parkinsonism, caused by multiple small strokes
• Poisoning by carbon monoxide, manganese, or certain pesticides
Treatments

Unlike for many other neurodegenerative diseases, there is effective treatment for the symptoms
of Parkinson's disease. For most patients, these treatments can provide several years of
satisfactory treatment. Unfortunately, no therapy has yet been conclusively shown to slow or
reverse the disease. Several candidates have been tested in this regard, and have shown intriguing
results. However, these studies will need to be repeated and expanded before these agents can be
widely recommended.

Several important factors influence decision-making in treatment of PD. These include:

• Levodopa continues to be the most effective treatment for motor symptoms, and all patients
eventually require it.
• Long-term complications of levodopa therapy are a concern, and may influence whether
therapy begins with levodopa or a dopamine agonist.
• Non-motor symptoms, especially depression, are increasingly being seen as important targets of
therapy.
• Surgical treatment has become a mainstay of late-stage management, although not all patients
can afford it or are appropriate candidates.
• Cell transplant therapies are still experimental, and their usefulness is currently lessened by the
possibility of unacceptable complications. Additional studies are needed to understand and
avoid these complications.
• Non-pharmacological treatments remain an important part of the whole treatment program.

Long-term Complications of Treatment

As PD progresses, it becomes increasingly difficult to adequately control symptoms with

medications. The most common problems that arise are motor complications, which include
motor fluctuations and dyskinesias.

Motor fluctuations refer to unanticipated loss of effect of a given dose of levodopa—instead of a

smooth, predictable symptomatic benefit, the patient may lose benefit earlier than usual (termed
"wearing off") or may suddenly switch from "on" (symptoms controlled) to "off" (symptoms
return). Dyskinesias are involuntary movements that occur when dopamine levels are too high.
Motor complications are discussed in more detail in the section "Complications of Treatment."

Drugs Used to Treat PD

Five classes of drugs are used to treat the motor symptoms of PD:

Dopaminergic Agents
Levodopa (precursor to dopamine)
Dopamine agonists
Apomorphine (Apokyn®)
Bromocriptine (Parlodel®)
Cabergoline (Not approved in the US)
Lisuride (Not approved in the US)
Pergolide (Permax® withdrawn from US market March 2007)
Pramipexole (Mirapex®)
Ropinirole (Requip®)

COMT Inhibitors
Entacapone (Comtan®)
Tolcapone (Tasmar®)

MAO-B Inhibitors
Rasagiline as Azilect®
Selegiline as Eldepryl® and Zelapar™ (an orally disintegrating selegiline tablet)

Anticholinergics
Trihexyphenidyl (Artane®)
Benztropine
Ethopropazine

Amantadine (Symmetrel®)

Dopaminergic Agents
Levodopa

Levodopa is converted in the brain into dopamine, the same chemical created by substantia nigra
cells and used to control movement. Levodopa was introduced as a PD therapy in the 1960s, and
remains the most effective therapy for motor symptoms. It lessens and helps to control all the
major motor symptoms of PD, including bradykinesia, which is generally the most disabling
feature of the disease.

Carbidopa is included in the standard oral formulation to increase the effectiveness of a dose of
levodopa and minimize side effects such as nausea and vomiting.

Levodopa is a type of amino acid. Amino acids, which are contained in certain foods, are the
building blocks of proteins. These building blocks are transported into the blood stream through
the wall of the intestines. In similar fashion, levodopa must be absorbed into the blood stream
through the wall of the intestines. This requires the action of a specific "transporter" or amino
acid vehicle in the intestinal lining. Because this transporter can only work so fast, an excessive
amount of dietary protein can slow the transport of levodopa into the blood stream. If sufficient
amounts of levodopa do not get into the blood stream and ultimately to the brain, then the dose
prescribed may not be effective in treating the symptoms of PD. Once levodopa is in the blood
stream, it must then cross into the brain, where it becomes active in controlling the symptoms of
PD. However, the same "transport phenomenon" occurs when levodopa crosses from the
bloodstream into the brain. To avoid the competition of levodopa with other dietary amino acids,
patients with more advanced PD may need to time their doses to avoid meals, or reduce the
protein content of certain meals.

Adverse effects
Nausea and vomiting are the most common side effects, and are due to accumulation of
dopamine in the bloodstream. Orthostatic hypotension (low blood pressure upon standing) also
occurs. The risk of hallucinations and paranoia increases over time. Compulsive behavior,
including gambling and hypersexuality, is another risk.

Drowsiness is a common adverse effect of levodopa and other dopaminergic therapies, and
sudden sleep onset is possible. Patients may not experience any warning signs of sudden sleep
onset. It is important to understand this possibility, especially when levodopa therapy begins,
when increasing doses, or switching agents.

The most troubling adverse effect from long-term levodopa use is dyskinesias. Dyskinesias are
uncontrolled movements, including writhing, twitching, and shaking. Dyskinesias result from the
combination of long-term levodopa use and continued neurodegeneration. They typically begin
to develop in milder forms after 3 to 5 years of treatment, but are more severe after 5 to 10 years
of treatment.

As the disease progresses, the increasing dose of levodopa required for symptom control
approaches the dose at which intolerable dyskinesias occur. This limits the continuing usefulness
of levodopa. At this point, surgery may be the only effective option. Because of this potential,
many physicians recommend starting a younger patient on a dopamine agonist instead of
levodopa, which delays the onset of dyskinesias.

Immediate-release levodopa/carbidopa is formulated in doses of 10/100, 25/100, and 25/250

milligram pills. Onset of effect is usually 20 to 40 minutes, and duration of benefit is 2 to 4 hours
in more advanced stages of PD.

Dissolving the tablets in orange juice is a possible strategy for speeding the onset of effect.
Patients must be sure to consult with their physician before trying this, as the duration of benefit
is usually shorter as well.

Continuous infusion of levodopa into the intestine, through a feeding tube, is being studied as of
mid-2004. The hope is that continuous infusion may lessen the risk for developing dyskinesias.
However, this treatment approach is logistically challenging, and is reserved for only a small
subset of patients with severe motor fluctuations or dyskinesias.
Dopamine Agonists

Dopamine agonists are drugs that imitate or mimic the action of levodopa in the brain by directly
stimulating dopamine receptors, the same receptors that dopamine itself stimulates. While they
are not quite as effective as levodopa, they provide excellent relief of symptoms and delay the
onset of motor complications.

A variety of dopamine agonists are available that differ in their duration of action, chemical
makeup, method of delivery, and adverse effect profile. The currently available agonists are:

Dopamine Agonists (generic name followed by trade name):

• Apomorphine (Apokyn®)
• Bromocriptine (Parlodel®)
• Pergolide (Permax®)
• Pramipexole (Mirapex®)
• Ropinirole (Requip®)

Clinical trials of several of both pramipexole and ropinirole have shown their ability to delay
motor complications when used as monotherapy (the only drug given) early in the disease.
Agonists tend to produce more edema and psychosis than levodopa, effects which may be more
significant than mild dyskinesias, especially in older patients. Hence, in patients who are younger
(less than age 70) and otherwise healthy, initiation of dopaminergic therapy with a dopamine
agonist may be indicated. Older PD patients (especially those with cognitive problems) are
usually treated with levodopa alone.

Adverse Effects
Drowsiness is a common adverse effect of dopamine agonists and levodopa, and sudden sleep
onset is possible. Patients may not experience any warning signs of sudden sleep onset. It is
important to understand this possibility, which is especially likely at the commencement of
therapy, when increasing doses, or switching to a different dopamine agonist.

Other significant adverse effects of dopamine agonists include nausea and vomiting, orthostatic
hypotension, edema, and psychosis.

Fibrosis is a risk from the ergot-derived dopamine agonists, which are pergolide, bromocriptine,
cabergoline, and lisuride. Pulmonary and retroperitoneal fibrosis are rare, while recent studies
suggest fibrosis of the heart valves may be common enough to warrant monitoring of all patients
on ergot-derived agonists, and switching to a non-ergot agonist when possible. Pergolide was
withdrawn from the US market in March 2007 over concern for this effect.
Apomorphine

Apomorphine (Apokyn®) is the dopamine agonist whose symptomatic effect is most like that of
dopamine. However, it cannot be taken in pill form, and must be delivered by injection beneath
the skin (subcutaneously). Its duration of effect is also shorter than levodopa's.

Subcutaneously injected apomorphine is used as a "rescue" therapy for patients with "off"
episodes. Its onset of effect is approximately 10 minutes, and lasts approximately 90 minutes. It
can be used whenever a patient feels an off episode approaching before the next dose of
levodopa takes effect, such as early in the morning, or during that day when wearing off occurs.
It can be used up to 10 times per day. If a patient needs more treatment than that, alternative
therapies should be considered. Injection-site reactions may occur, but are generally not a
problem.

Nausea and vomiting are the principal adverse effects. An antiemetic is required at the beginning
of apomorphine therapy. Trimethobenzamide is the agent usually prescribed. Many patients are
able to stop taking it after several weeks of therapy.

COMT Inhibitors

COMT inhibitors prolong the effectiveness of a dose of levodopa by preventing its breakdown.
Two agents are approved in the United States, entacapone (Comtan®) and tolcapone (Tasmar®).
Both have been shown to decrease the duration of "off" time (the period of time when PD
symptoms are present) in patients with significant off time. Tolcapone is more effective than
entacapone, reducing off time in clinical trials by 2-3 hours, versus 1 to 2 hours for entacapone.
Both treatments usually allow reduction of levodopa dose, in the range of 20% to 25%.

Entacapone is dosed at 200 mg with each levodopa dose. Diarrhea is the most common side
effect, which may require stopping treatment, but it occurs in severe form in only about 5% of
patients.

Tolcapone is dosed at 100 or 200 mg, three times per day. Side effects include diarrhea, which
may eliminate this as a treatment option in up to 15% of patients. Four cases of severe liver
disease (acute fulminant hepatic necrosis), with three deaths, were reported in 1998, and led the
FDA to issue a "black box" warning on tolcapone. This warning recommends that physicians
only prescribe tolcapone for patients whose symptoms cannot be adequately controlled without
it. Frequent liver function monitoring is required for patients commencing therapy. This requires
a blood test every 2-4 weeks for the first 6 months, to be sure that certain critical liver function
values are not rising. After that, blood tests are recommended at intervals deemed clinically
relevant. Treatment should be discontinued if the ALT/AST levels rise above twice the upper
limit of normal.
A combination of levodopa, carbidopa, and entacapone in a single tablet (Stalevo®) is also
available, with a similar side effect profile to the agents used alone.

MAO-B Inhibitors

MAO-B inhibitors slow the breakdown of dopamine in the brain. There are two MAO-B
inhibitors, in three formulations, approved for use in PD in the United States.

Rasagiline (Azilect®)

Rasagiline in an oral tablet is approved for the treatment of signs and symptoms of Parkinson's
disease as initial monotherapy and as adjunct therapy to levodopa.

Selegiline swallowed tablets (Eldepryl®, generics)

Selegiline in tablet form is approved as an adjunct in the management of parkinsonian patients

being treated with levodopa/carbidopa who exhibit deterioration in the quality of their response
to this therapy.

Selegiline orally dissolving tablet (Zelapar®)

An orally dissolving form of selegiline is available for patients who have difficulty swallowing,
or prefer not to take pills. It is approved as an adjunct in the management of patients with
Parkinson's disease being treated with levodopa/carbidopa who exhibit deterioration in the
quality of their response to this therapy.

Side effects of MAO-B inhibitor therapy include insomnia, hallucinations, and orthostatic
hypotension. Patients who are also taking certain types of antidepressants may not be eligible to
take MAO-B inhibitors, since these drugs may interact to dangerously raise blood pressure
(called the serotonin syndrome). Patients are also cautioned to avoid certain types of foods that
are high in tyramine, a dietary amino acid. These foods include certain kinds of aged cheeses,
fermented meats, and fermented soy products.

Selegiline

Selegiline offers mild symptomatic benefit, primarily for patients with early disease. The dose is
5 mg twice each day. Side effects include insomnia, hallucinations, and orthostatic hypotension.
Patients who are also taking certain types of antidepressants may not be eligible to take
selegiline, since these drugs may interact to dangerously raise blood pressure (called the
serotonin syndrome).

MAO-B inhibitors and neuroprotection

Neuroprotection refers to the ability to prevent or slow the death of neurons. Selegiline was the
subject of a major neuroprotective trial in PD, the DATATOP trial. While the initial analysis of
the results appeared to indicate that selegiline slowed disease, more detailed study indicated that
the benefit seen could also be explained by its symptomatic effects. Thus, the results of this trial
were inconclusive.

In 2004, a preliminary trial of rasagiline with a different trial design suggested that rasagiline
may have disease-modifying properties. This study will need to be repeated and expanded before
firm conclusions can be drawn.

Anticholinergics

Anticholinergics have a limited role in PD. They are primarily effective against tremor and
rigidity, and their side effects may be significant, especially in elderly patients. Typical doses for
common anticholinergics are:

• Trihexyphenidyl (Artane®): 2 to 15 mg/day

• Benztropine: 1.0 to 4.5 mg/day
• Ethopropazine: 10 to 200 mg/day

Common side effects are memory loss, dry mouth, urinary retention, constipation, sedation,
delirium, and hallucinations.

Amantadine

Amantadine (Symmetrel®) has a mild symptomatic effect on the motor symptoms of PD, but a
more significant effect on the reduction of dyskinesias. The usual dose is 100 mg 2 to 4 times
each day. Side effects include hallucinations, difficulty falling asleep or staying asleep
(insomnia), agitation, and difficulty concentrating; dry mouth, ankle swelling, and skin mottling
(uneven color tones) may also be present. Amantadine may be ineffective for dyskinesias in up
to one-third of patients.

Treatment Decision-Making
Early Disease

The central questions in commencing treatment of PD are when to begin, and with what agent(s).
Potential Neuroprotection
If and when clearly neuroprotective agents are identified, they will obviously become the first
treatments offered, and will be started as early as possible. As of mid-2007, no agent has been
definitively shown to offer neuroprotection. The MAO-B inhibitors selegiline and rasagiline
offer a mild symptomatic benefit, and are often used early for this in combination with their
proposed (and much debated) effects on slowing disease progression. Coenzyme Q10, available
over the counter, is also used early. Its use is based on a single trial whose results suggested a
possibly mild neuroprotective effect. Most PD experts believe the results of this trial are too
preliminary and not compelling enough to change early treatment practices without repeating the
study and duplicating the results.

Commencing Symptomatic Therapy

The decision of when to begin symptomatic therapy is an individual one made between patient
and physician. Factors include:

• Degree of functional impairment

• Effect of symptoms on employment
• Patient attitudes towards medications

A patient who is fully educated regarding the benefits and limitations of therapy can be a full
partner in the decision-making process. This obvious benefit is especially important in PD
treatment, since treatment must be reevaluated and adjusted so often during the course of the
disease, based on the changing condition of the patient and the response to previous therapy. It is
in the interest of both patient and physician to develop such a partnership from the very
beginning.

Initial Treatment Options

The choice of initial treatment is strongly influenced by patient age and condition. Levodopa is
the usual treatment of choice in the elderly patient, because of its lower risk for psychiatric
complications compared to dopamine agonists. A dopamine agonist may be preferable in the
younger patient, who is likely to be more tolerant of its side effects, and for whom delaying
motor complications is an important goal, given the longer treatment horizon. Selegiline,
rasagiline, amantadine, or an anticholinergic drug may also be appropriate initial treatment for
mild symptoms, provided the side effects can be tolerated.

Depression and anxiety may also be early debilitating symptoms, and therefore may become the
object of initial therapy.

Complications of Treatment

Many PD patients have several years of trouble-free treatment following diagnosis. The
remaining neurons of the substantia nigra are believed to be sufficiently active to smooth out
changes in the levels of levodopa, thus providing a relatively constant amount of dopamine. As
the disease progresses, this "honeymoon" gradually diminishes, and a majority of patients begin
to develop motor complications after five or more years. At this stage, adjustment of medications
becomes a frequent and increasingly complex task for physician and patient. Nonmotor
complications of disease can also be debilitating, and are important objects of treatment.

Motor complications
Motor complications include motor fluctuations ("wearing off"), dyskinesias, off-period
dystonia, freezing, and falls.

Motor fluctuations refer to:

• Wearing off, or premature loss of benefit from a given dose of levodopa

• On-off, or sudden and unpredictable switch to off (usually seen in very advanced PD)
• Dose failure (failure to turn on from a dose)

Dyskinesias are unwanted involuntary movements that typically occur during the peak effect of a
dose of levodopa.

Off-period dystonia may also occur as a motor complication, especially in the morning before
the first dose of medication. Medication adjustments may be used to try to minimize each of
these complications.

Freezing is a type of motor block or hesitation that may appear at the beginning of a movement,
when passing through doorways, or while turning. This type of motor block does not always
respond to medication. Sensory cues, such as auditory, visual, or proprioceptive (touch) triggers,
are employed to overcome the block.

Frequent falling, usually seen in advanced PD only, may require an evaluation for physical
therapy as well as use of a cane, scooter, or wheelchair.

Nonmotor complications
While PD is classified as a movement disorder, there are many nonmotor aspects of the disease.
These may be as disabling as or more disabling than the motor symptoms, and treating them can
improve the quality of life for both patient and family/caregiver. Recognizing that a symptom is
part of the disease is an important step toward effective treatment.

• Depression is reported to affect up to 50% or even more of PD patients. Treatments are usually
very effective, although complete resolution is rare. Treatments include certain antidepressant
medications, usually a class of drugs known as selective serotonin reuptake inhibitors (SSRIs)
including Prozac®, Paxil®, Luvox®, Zoloft®, or others. Another class of drugs, known as tricyclic
antidepressants, may be used including Elavil®, Endep®, and others. With modern techniques
and anesthesia, electroconvulsive therapy (also called electroshock therapy or ECT) may be
effective for relieving depression in PD. It may also improve motor symptoms of the disease,
although it is not prescribed for this reason alone.
 • Anxiety and restlessness are common. When severe, these symptoms may be treated with
benzodiazepines; however, the potential for addiction should be factored into the decision to
use them. Since symptoms are often worse during periods of low levodopa levels, some
adjustment in dosing frequency may be effective as well.

• Sleep disorders are very common in PD, ranging from insomnia to excessive sleepiness to vivid
dreaming. A careful history and reduction of unnecessary or offending medications may be
helpful. Treatment of depression may improve sleep.

• Mild orthostatic hypotension is frequently seen in patients with PD. Strategies for treatment
includes reducing antihypertension medications, increasing salt intake, and use of compressive
stockings. Fludrocortisone or midodrine may be indicated as well.

• Psychosis may be a side effect of antiparkinsonian medications, as well as a feature of disease

progression. Initial features may include vivid dreaming and nightmares, which may progress to
delusions, paranoia, disorientation, and hallucinations. Reducing unnecessary medications is the
first line of treatment, with anticholinergics the first to go. Atypical neuroleptics are valuable for
patients with continued symptoms. Clozapine (Clozaril®) is the most effective, but requires
frequent blood monitoring for the rare occurrence of serious blood disorder (agranulocytosis).
Quetiapine (Seroquel®) and olanzapine (Zyprexa®) may also be useful.

Surgery

Brain surgery is an option for advanced PD patients whose symptoms can no longer be
adequately managed with medications. The best surgical candidate is someone who:

• Responds well to dopaminergic therapy

• Has motor complications (off periods and dyskinesias) that are limiting factors
• Is otherwise healthy and a good surgical risk.

Advanced age is not necessarily a barrier to surgery, but impaired cognition, including
forgetfulness, diminished decision-making ability, and language difficulties, along with gradual
loss of brain matter (brain atrophy or shrinkage), make the surgery more risky and decreases the
likelihood of an optimal outcome.
Depending on the patient, procedure, and skill of the operating team, cognition may be mildly
impaired or largely unaffected by the surgery itself. The most commonly reported adverse
cognitive effects are reduced decision-making abilities and language impairments.

It is impossible to predict the benefit any individual patient can expect from surgery. The general
rule of thumb is that the maximum benefit is equal to the best response from a dose of levodopa
(minus the effect on dyskinesias). Therefore, if a patient's symptoms are 50% better at the peak
of a levodopa dose, the surgery is not likely to improve the patient's symptoms more than that
amount. Importantly though, improvements from surgery are most dramatic during the times the
patient is not experiencing the effects of medications ("off" time). Therefore, surgery may greatly
improve the amount of the day during which symptoms are reduced.

Types of Surgery

There are two surgical procedures—lesioning and deep brain stimulation—and three target
locations in PD surgery: thalamus, globus pallidum internus (GPi), and subthalamic nucleus
(STN). Other surgery-based procedures—cell transplants, gene therapy, and neurotrophic factor
delivery—remain experimental procedures for the treatment of PD.

Lesion procedures (i.e., pallidotomy, thalamotomy) deliver radio-frequency energy to heat and
ablate (destroy) a pea-sized region within the target, where there is abnormal activity related to
the movement problems.

Deep brain stimulation (DBS) uses implanted electrodes to stimulate one or another of these
same regions. The electrical stimulation interferes with the abnormal activity, creating the same
effect as a lesion. The effect lasts as long as the stimulation continues, but ceases when it is shut
off.

During needle-guided (stereotaxic) brain surgery, the patient remains awake. This is for two
reasons. The first is that the brain itself has no pain sensors, and once the initial incision is made
(using a local anesthetic like Novocain), there is no pain. The second is that patients must be able
to respond to the surgical team's questions about what they are experiencing during the surgical
procedure. The pathway to the target lies close to several other important structures in the brain
that may be inadvertently stimulated during the procedure. This may cause unusual sensations
such as flashing lights, tingling, or experience of emotions. Patients then report these sensations
to the surgeon during the procedure. Avoiding these areas is crucial for successful surgery.

Because surgery requires very precise placement of surgical instruments, a three-dimensional

frame is attached to the patient's head to guide the surgeon. The frame may be uncomfortable and
local anesthetic is used to ease the discomfort. Before surgery, patients will also undergo several
imaging procedures, in order to identify the target and other landmarks within the brain.
Depending on the center, the procedures may include magnetic resonance imaging (MRI) scans,
computerized tomography (CT), or ventriculography.
Pallidotomy

Until the late 1990s, pallidotomy was the most common type of PD surgery; deep brain
stimulation or DBS is now being performed more often. A pallidotomy involves destruction of
part of the globus pallidus (GPi), a region of the brain involved with the control of movement.
Destroying part of the GPi may help to restore the balance in that area of brain, which normal
movement requires. Pallidotomy is performed by insertion of a wire probe into the GPi. Once its
placement has been confirmed by electrical tests, the probe heats surrounding tissue by emission
of radio waves. The heat destroys nearby tissue. Effects of the surgery are apparent almost
immediately. Improvements from pallidotomy range from 70% to 90% reduction of dyskinesias
and dystonia, and 25% to 50% for tremor, rigidity, bradykinesia, and gait disturbance. Levodopa
dose may be reduced after the surgery, and dyskinesia improvement is based partly on this
reduction.

Pallidotomy may be unilateral (one-sided) or bilateral (two-sided). Following a unilateral

pallidotomy, improvements are primarily to the side of the body opposite to the lesioned side of
the brain. Bilateral surgery is possible and improves dyskinesias further, but greatly increases the
risk for worsening effects on cognition, swallowing, and speech; hence, it is done very rarely if
at all.

Adverse effects of pallidotomy may include hemorrhage, weakness, visual deficits, speech
deficits, and confusion, but the risk of these is relatively low in centers with an experienced
surgical team. Weight gain is very common following surgery.

Thalamotomy

Thalamotomy is primarily effective for tremor, and is therefore used mainly in patients for whom
tremor is the only disabling symptom. During a thalamotomy, a selected portion of the thalamus
is surgically destroyed (ablated). The thalamus is a paired structure deep within the brain that is
involved in the control of movement. In this procedure, neurosurgeons use specialized
equipment, enabling them to use three-dimensional coordinates to precisely locate an area of the
thalamus. Bilateral (both sides of the brain) procedures are poorly tolerated because of increased
complication risks, including vision and speech problems. The procedure is gradually being
replaced by subthalamic deep brain stimulation (DBS), since this procedure can improve tremor
and other symptoms of PD.
Deep Brain Stimulation

Unlike lesion procedures, DBS leaves electrodes in place in the brain to deliver continuous
stimulation. The electrodes are powered by a programmable stimulator (like a pacemaker), which
is implanted in the chest wall. The stimulator is connected to the electrodes by thin wires (leads)
that are tunneled under the skin in the neck and scalp. The stimulator can be turned on and off by
a magnet waved over the surface. Many patients turn the stimulator off at night or during periods
of prolonged activity, to prolong battery life. Batteries can be replaced as needed, generally after
5 years. Since the battery is in the chest wall, brain surgery is not required to replace them.

Adjusting the stimulator and medications after electrode implantation is a major time
commitment on the part of the neurological team and patient. The maximum effect of the
procedure is achieved once that adjustment occurs, which may be weeks or even months after the
procedure itself.

Risks for DBS procedures include surgical risks (hemorrhage, infection) as well as hardware
complications. These include leads breaking, electrode malfunction, stimulator failure and
battery failure.

Thalamic DBS
Like thalamotomy, thalamic DBS is primarily effective against tremor. Bilateral procedures are
possible, but with a higher risk of adverse effects. Compared to thalamotomy, thalamic DBS has
a lower risk of severe side effects.

GPi DBS
Effects of GPi DBS tend to mimic those of pallidotomy. Dyskinesia improvement is a major
effect, along with some improvement in tremor, rigidity, and bradykinesia, primarily in the off-
medication state. Bilateral DBS is better tolerated than bilateral pallidotomy.

Subthalamic Deep Brain Stimulation (DBS)

The subthalamic nucleus has become a major target for deep brain stimulation (DBS), with many
teams considering it the target of choice for control of PD. It leads to improvement of all major
motor features of PD, with improvement of motor scores of 40% to 60% in the off condition, and
10% in the on condition. Levodopa dosage reduction is typically around 30%, with resulting
improvement in dyskinesias. Bilateral procedures appear to be superior to unilateral, with only a
slightly increased risk of complications.

As DBS has become more common, rare but serious neuropsychiatric adverse events have been
increasingly reported. Onset or worsening of depression occurs post-operatively in a small
percentage of patients, often in those who were at increased risk before the procedure. Suicide, a
well-known risk in depressed patients, has been reported in a small handful of patients. Pre-
operative neuropsychiatric evaluation and post-operative follow-up is a critical part of patient
care.
Experimental Therapies

Cell Transplant Therapy

Transplant of fetal substantia nigra cells has been performed in several hundred patients to date
in multiple centers throughout the world. While results have been encouraging in some
individual patients, two recent double-blind placebo-controlled studies showed that consistent
benefit was only seen in young PD patients (age 60 or below), and side effects in some patients
were significant. In particular, some patients developed off-medication dyskinesias (uncontrolled
movements) even without any levodopa or other dopaminergic medication. The lack of
consistently good results and the significant side effects encountered have been interpreted by
the scientific and medical community to indicate that further research in animal models of PD is
needed to improve upon what has been observed to date before more studies in PD patients are
undertaken.

Another cell transplant technique that shows some promise is the use of retinal pigment epithelial
cells. These cells are derived from tissue at the back of the eye, and they produce and release
dopamine. An open-label trial in six advanced PD patients has shown promise, and as of mid-
2004, a double-blind trial is underway.

Gene Therapy
As of 2004, gene therapy has been tried in only a few PD patients, and is still highly
experimental. While experiments in animal models of PD have shown promise, further research
is needed. The only publicized trial is of delivery of the gene for glutamic acid decarboxylase
(GAD) to the subthalamic nucleus or STN. GAD is a key enzyme in the production of the
inhibitory neurotransmitter GABA. Gene therapy with GAD is meant to increase GABA
production, reducing STN activity in the manner of STN DBS. Monitoring is still in progress.

Growth Factor Delivery

Glial cell-derived neurotrophic factor (GDNF) stimulates sprouting of dopamine neurons in
animal models. Direct delivery of GDNF to the brain has produced promising results in an open-
label trial in a small number of patients, but by mid-2004 a larger, double-blind trial failed to
show efficacy. Further research is needed, especially regarding how to improve delivery of
growth factors to the correct targets in the brain.

Nonpharmacologic Treatments

A wide variety of problems in PD may respond to nonpharmacological treatments. These

include:

• Motor, balance, posture, gait, and mobility

• Difficulties with activities of daily living
• Speech and swallowing
• Inadequate nutrition
 • Sleep disturbance
• Pain
• Constipation
• Sexual dysfunction
• Depression

In all cases, an individualized approach is needed to identify the problems and determine a
treatment plan. Multiple members of the treatment team—physical therapists, occupational
therapists, speech-language pathologists, gerontologists, neurologists, psychologists, and
others—may be involved. Effective treatment may reduce the need for medications and improve
quality of life.

Physical therapy
Goals of physical therapy include maintaining or increasing activity levels, decreasing rigidity
and bradykinesia, optimizing gait, and improving balance and motor coordination. Features of
the PT program may include:

• Regular exercise, such as walking (1+ miles/day), swimming, golf, or dancing, depending on the
patient's preferences and abilities
• Stretching and strengthening
• Exaggerated or patterned movements, such as high stepping and weight shifting
• Mobility aids, orthotics (such as braces or splints)
• Training in transfer techniques
• Training in techniques to improve posture and walking

Occupational therapy
Goals of occupational therapy include maximizing fine motor coordination, especially of the
upper extremities, reducing energy expenditure, increasing safety and independence, and
improved efficiency of activities of daily living. Features of the OT program may include:

• Use of orthoses and adaptive equipment

• Home and workplace modification, improving accessibility, and removing obstructions
• Adaptation and simplification of utensils, toileting articles, beds, etc

Speech and swallowing

Low voice volume (hypophonia) often occurs in PD. Several PD-specific voice training
programs have been developed, which share an emphasis on consciously increasing voice
volume as a key strategy. Other features may include modification of speech patterns such as use
of shorter sentences, breathing exercises, and range-of-motion exercises for the muscles of
speech.

Drooling (sialorrhea) can be a common feature of advanced PD. The origin of the problem is not
in increased saliva production, but reduced spontaneity of swallowing. Awareness of the
problem, and consciously swallowing more often, may be effective. If not, treatments may
include a small dose of an anticholinergic medication under the tongue, or injection of botulinum
toxin into the salivary glands to temporarily paralyze them. Both of these reduce saliva
production.
Management of swallowing difficulties may include instruction to take smaller bites, to
completely empty the mouth before taking the next bite, and eating softer foods.

Sexuality
Sexual dysfunction affects a large proportion of patients with PD and their spouses. Difficulties
include erectile dysfunction in males, vaginal dryness, and loss of libido. Hypersexuality from
levodopa and dopamine agonists also occurs. Many PD patients are reluctant to talk about these
issues with their doctor, and may not connect the symptom to the disease at all. There are useful
treatments, both medical and nonmedical, for many of these problems. Patients should always
have a thorough urological or gynecological evaluation to rule out non-PD related problems.
Sildenafil (Viagra®) has been shown to be safe and effective in men in PD to treat erectile
dysfunction.

Driving
PD patients tend to do worse than controls on tests of driving safety, because of increased
reaction times and movement times caused by PD. Vehicular control skills are generally well
preserved, but attention to safety landmarks declines. Decline in performance seems to be related
to a worsening of motor abilities. Patients tend not to be good judges of their loss of driving
safety, and family members may need to intervene. A good way to determine driving capability
is to have the patient undergo a driving examination at a rehabilitation facility.

Constipation
A good bowel regimen can greatly reduce constipation. Increased fluid intake, a diet rich in
vegetables and fruits, use of stool softeners, and increased dietary and/or supplemental fiber are
just some interventions that can help. Working with one's physician and/or a gastroenterologist is
the approach to take.