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Parkinson's Disease

Nonpharmacologic
Treatments
Problems That May Respond to Nonpharmacological Approaches

Motor, balance, posture, gait, mobility

Activities of daily living difficulties
Speech and swallowing: hypophonia (soft voice), sialorrhea
(excessive saliva), dysphagia (difficulty swallowing)
Inadequate nutrition
Sleep disturbance
Autonomic dysfunction: pain and constipation
Skin breakdown
Sexual dysfunction
Depression

Nonpharmacologic Treatments

Physical therapy
Exercise
Occupational therapy
Speech/language therapy
Diet and nutrition
Patient/caregiver education
Psychosocial interventions

Physical Therapy: Goals

Maintain or increase activity level

Decrease rigidity and bradykinesia
Facilitate movement and flexibility; optimize gait
Maximize gross motor coordination and balance
Maximize independence, safety, function

Physical Therapy: Features

Exercise: e.g., walking (1+ mile/day), swimming, golf,

dancing
Stretching and strengthening
Exaggerated or patterned movements, high stepping, weight
shifting, repetition, verbal cues
Mobility aids, orthotics, adaptive footwear
Transfer techniques
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Occupational Therapy: Goals

Maximize independence, safety, function

Facilitate active movement
Increase trunk flexibility and upright posture
Maximize fine motor coordination
Improve endurance, reduce energy expenditure
Improve body image, self-esteem, psychosocial adjustment

Occupational Therapy: Features

Patient and caregiver education

- explain the goals of program
- demonstrate transfers, task simplification, positioning, etc.
Home exercise program
Home and workplace modifications
Upper extremity splinting
Adaptive equipment

Adaptive Equipment and Environmental Modifications

Customize for disability, budget

Seating: wheelchairs, cushions, lateral supports, etc.
Toilet and hygeine: tub/shower seat, grab bars, etc.
Feeding: wide-handled utensils, sip cups, etc.
Clothing: velcro, pullovers, shoehorns, etc.
Bed: rails, hospital bed, trapeze, etc.
Equipment: book holders, large-button phone, key holders,
etc.
Consider door sills, throw rugs, other obstructions

Speech and Communication Problems

May be one of the first symptoms of PD

Characterized by:
- soft voice and imprecise articulation
- bursts of rapid speech alternating with periods of silence
- loss of inflection
Can be significant for employment
Presence of dyskinesias may worsen speech

Speech-Language Pathology Options

Options are often underutilized

Early therapy is especially effective
Emphasis on control of respiration and voice production
At-home exercises; modification of daily activities
Amplification devices rarely useful
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Techniques to Improve Speech

Increase loudness
Face the listener directly
Emphasize key words
Use short sentences
Range-of-motion exercises for muscles of speech
Breathing exercises
Attend speech therapy

Nutritional Risk Factors

Inactivity
Food preparation problems
Dyskinesia and feeding problems
Chewing and swallowing problems
Increased metabolic needs
Depression and dementia
Medication-related dietary restrictions
Drug side effects: anorexia, nausea, vomiting, constipation

Dietary Recommendations

Eat a balance diet, including all food groups

Consume sufficient calories to maintain weight
Consume adequate fiber and fluids to avoid constipation
Take vitamin D and calcium to prevent osteoporosis
Reduce protein to minimum daily allowance
- concentrate in evening meal

Management of Sialorrhea and Swallowing Difficulty

Do not rush
Be aware of saliva accumulation and swallow often
Eat soft foods
Eat small bites of food
Swallow only well-chewed food
Empty mouth before next bite
Family should learn Heimlich maneuver

Sexual Desire and Function

Individual variation in effect of PD

Some patients have short-lived hypersexuality with
dopaminergic drugs
Erectile dysfunction
Side effect of alpha- and beta-adrenergic blockers,
anxiolytics, digoxin, cimetidine
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Other causes of sexual dysfunction

- depression
- SSRIs (Prozac, Paxil, etc.)
- endocrine dysfunction

Miscellaneous Concerns

Seborrheic dermatitis
- treated with shampoos or lotions with ketoconazole,
selenium, pyrithione zinc
Driving
- patient should be assessed regularly for reaction speed,
judgment, mental status
- patient should retake driver's test

Education, Support and Counseling

Patient/caregiver education: newsletters, Web resources

Support groups: patient, caregivers
- may be appropriate to wait for disability progression
- early-onset patients may desire separate group
Counseling
- both patient and caregiver/family; assess needs separately
- anxiety, grief, guilt, anger, isolation, depression

Community Resources

Social worker intervention:

- Social Security office
- Medicare, Medicaid
In-home programs
Meals on Wheels, home visiting, etc.

See E-MOVE articles:

PD: Physical and occupational therapies (AAN report)

Sialorrhea and Hypophonia
Patient Profile
Exercise and Speech Regulation
Alternative Therapy Use in PD
Treadmill Training

Pharmacologic Treatments
The pharmacological management of PD is a complex and dynamic
task; there is no one "right" strategy for what drugs to use at a
particular stage of the disease. There are now many different
drugs, in several different classes, that may be effective, and there
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are still differences of opinion among leading PD researchers about

the best course of treatment.

Levodopa, a chemical very similar to dopamine, remains the "gold

standard" of PD therapy. It is the most potent anti-parkinsonian
drug available. However, long-term use of levodopa therapy often
leads to complications later in the disease, most importantly
dyskinesia, or uncontrolled movements. Thus, alternatives that
reduce the exposure to levodopa have been explored, and the trend
in treatment is toward combination therapy - the substitution or
addition of other drugs at different times in the disease progression
- and delaying the use of levodopa.

Levodopa may be given with a COMT inhibitor. This class of drug

prevents the breakdown of levodopa before it is absorbed by the
brain, thus prolonging the action of a single dose, and reducing the
total amount of levodopa needed.

Dopamine agonists (DAs) may be used to delay the start of

levodopa therapy, and may continue to be used once levodopa is
started. DAs may be added on to levodopa therapy later in the
disease as well, to help limit the amount of levodopa needed to
control motor symptoms. While it is generally true that the
individual doses of drugs will be lower when used in combination
than if used alone, there are times when this will not be true. For
example, when a DA is added on to levodopa later in the disease,
the levodopa dose may remain the same to provide optimal control
of symptoms.

Other drugs used in treatment of Parkinson's disease include

selegiline, anticholinergics, and amantadine.

Levodopa
Levodopa is a chemical cousin of dopamine. After ingestion,
enzymes in the brain convert levodopa into dopamine, which can
then fulfill the role normally played by the brain's own dopamine.
Levodopa is a highly effective drug for treatment of all
parkinsonian symptoms. Side effects include nausea, vomiting, dry
mouth, dizziness, and orthostatic hypotension, or lowering of blood
pressure upon standing.

The effectiveness of a dose of levodopa is reduced by enzymes that

break it down before it can be converted to dopamine. These
enzymes are called AADCs or simply DCs. The DC inhibitors
carbidopa and benserazide block these enzymes, increasing the
length of time the levodopa remains active. Levodopa is most often
prescribed with a DC inhibitor.
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The levodopa drugs used to treat Parkinson's disease are

levodopa/carbidopa (Sinemet) and levodopa/benserazide
(Madopar). Madopar is not available in the United States.

Controlled-release formulations (Sinemet CR, Madopar HBS)

further extend the length of action by increasing the time it takes
for the levodopa to enter the bloodstream. These drugs delay the
onset of action of a levodopa dose. A newer class of drugs, the
COMT inhibitors, can also extend the action of levodopa by
inhibiting its breakdown by another enzyme, COMT. These drugs do
not delay the onset of action of a levodopa dose.

Despite its high effectiveness early on, long-term therapy with

levodopa ultimately leads to poor response, and complications
including dyskinesia (abnormal involuntary movements) and
psychiatric effects.

COMT Inhibitors
COMT inhibitors increase the availability of a dose of levodopa by
inhibiting COMT (catechol O-methyltransferase), an enzyme that
breaks down levodopa before it can be converted to dopamine in
the brain. In this way, COMT inhibitors prolong the availability of a
single dose of levodopa, without delaying the onset of its effects.

COMT inhibitors include tolcapone (Tasmar) and entacapone

(Comtan). Entacapone is available in the United States, Canada,
and many other countries. Tolcapone is available in the United
States, but not in Canada or Europe.

Because of concerns for liver toxicity, tolcapone is only indicated

for patients whose symptoms are not adequately controlled by
other medications. A regular program of liver monitoring is
required for patients taking tolcapone. Entacapone does not
require liver monitoring.

See E-MOVE articles:

New warnings on Tasmar

Entacapone and Tolcapone (PD Congress report)
Tolcapone's effect on mitochondria is reduced by serum
protein (PD Congress report)
Entacapone Approved by FDA
Panel Recommendations Regarding Tolcapone

Dopamine Agonists
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Dopamine agonists (DAs) stimulate the same brain centers as

dopamine does. Because of this, DAs can be used instead of
levodopa, or with levodopa to reduce the levodopa dose. Many
physicians are now prescribing DAs as the first drug for Parkinson's
disease, instead of beginning with levodopa.

There are currently seven DAs available throughout the world:

Apomorphine**
Bromocriptine (Parlodel)
Cabergoline* (Dostinex)
Lisuride** (Dopergine)
Pergolide (Permax)
Pramipexole (Mirapex)
Ropinirole (Requip)

* Not currently approved in the United States for the treatment of

PD
**Not currently available in the United States

The various dopamine agonists differ in several respects, including

the duration of action of a single dose. Each has slightly different
side effects, and both side effects and drug efficacy may vary from
person to person. DAs differ in their degree of stimulation of the
various subtypes of dopamine receptors (for a more complete
discussion of dopamine receptors and the properties of dopamine
agonists, click here). Finally, some DAs are ergot-derived, while
others are not.

Dopamine agonists are used to treat all the motor symptoms of

Parkinson's disease. If a particular DA is not effective at a tolerable
dose, another DA may be tried.

Side effects typical of all DAs include drowsiness, nausea, vomiting,

dry mouth, dizziness, and orthostatic hypotension, or lowering of
blood pressure upon standing. At higher doses, DAs may cause
confusion, hallucinations, or psychosis.

Sleepiness and "Sleep Attacks" with Dopamine Agonists

Sleepiness, drowsiness, or sedation may be a significant side effect
of some dopamine agonists in some people, and may interfere with
driving or other activities. If you are taking a dopamine agonist,
you may wish to consult with your physician about the risks of
driving or other activities requiring high levels of alertness.

"Ergot" Versus "Non-ergot" Dopamine Agonists

Bromocriptine, cabergoline, lisuride, and pergolide have chemical
structures based on ergot, a plant alkaloid produced by the fungus
Claviceps purpurea. They are termed "ergot-derived" or "ergoline"
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DAs. In contrast, pramipexole and ropinirole are not chemically

related to ergot, but have structures similar to dopamine, and are
called "non-ergoline" DAs.

While side effects occur with all DAs (and indeed, with all
medications of any type), ropinirole and pramipexole may lead to
fewer of those side effects that are linked specifically to ergot
compounds, such as decreased circulation to the extremities
(digital vasospasm) and fibrous growth in the thoracic and
abdominal cavities (pleuropulmonary and retroperitoneal fibrosis).

Early Montherapy with Dopamine Agonists

Dopamine agonists are increasingly being prescribed as the first
drug for patients with Parkinson's disease, instead of levodopa. In
many patients, DAs may be effective as monotherapy for several
years, depending on the rate of disease progression. Recent clinical
trials indicate that delaying levodopa therapy may delay the onset
of dyskinesias. These findings suggest that DAs may be the most
appropriate initial therapy for most patients, especially those with
earlier onset who are expected to require drug therapy for many
years.

See E-MOVE articles:

Dopamine agonists: Adverse effects (AAN report)

Cabergoline (PD Congress report)
Early ropinirole reduces dyskinesias (PD Congress report)

Dopamine Receptors and

Dopamine Agonists
There are Two Major Families of Dopamine Receptors
Investigations have revealed that there is not just one type of
dopamine receptor, but at least five. They are classified into two
families, the D1-like or D2-like. While some dopamine agonists
stimulate both D1 and D2 receptor types, other agonists stimulate
only one type or the other. There are even some that stimulate D2
receptors, but antagonize (turn off) D1 receptors.

Why Does This Matter?

Research has shown that D1 and D2 receptors work together to
produce natural movements. Stimulating both types at the same
time provides the most effective treatment. Levodopa stimulates
both, accounting for its superior efficacy on all parkinsonian
symptoms.
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Furthermore, prolonged stimulation is better than short, intense

stimulation. The ideal dopamine agonist, then would be a long-
acting stimulator of both D1 and D2 receptors. And, it would be
easy to administer and without severe side effects. Unfortunately,
each of the available dopamine agonists provides some, but not all,
of these ideal features.

What Are the Features of the Different Dopamine Agonists?

(In the discussion below, half-life refers to the time required for the
blood concentration to fall to half the maximum level seen after a
single dose. A longer half-life means a longer duration of effect, and
less frequent dosing.)

Apomorphine: Apomorphine very effectively stimulates both D1 and

D2 receptors. Unfortunately, it has a very short half-life - 1-2 hours
- and cannot be given by mouth. Apomorphine can be injected, or
absorbed into the bloodstream across the membranes of the nose,
under the tongue, or rectum. It can also be given continuously via a
pump in the abdomen. Because of its high propensity to cause
nausea, it usually must be administered with an antiemetic such as
domperidone or trimethobenzamide. Domperidone is not currently
available in the United States, but trimethobenzamide is.
Apomorphine is not currently approved in the United States for
treatment of Parkinson's disease.

Bromocriptine (Parlodel): Bromocriptine is a D2 agonist, but

antagonizes, or blocks, D1 receptors. It has a relatively long half-
life (6 hours) and can be taken orally.

Cabergoline (Dostinex): Cabergoline is a D2 agonist only. It has a

very long half-life (65 hours), requiring only once-a-day dosing. It
has been show to be especially useful in the control of motor
fluctuations and nighttime symptoms. It is not approved in the
United States for the treatment of Parkinson's disease.

Lisuride (Dopergine): Lisuride is a D2 agonist. It has a relatively

short half-life - 2-4 hours - but can be administered continuously
under the skin via a pump, allowing maintenance of even levels in
the bloodstream. Lisuride is not available in the United States.

Pergolide (Permax): Pergolide is a very potent D2 agonist, and is

the only agonist with some D1 agonist activity. It has a relatively
long half-life (12-27 hrs).

Pramipexole (Mirapex): Pramipexole stimulates D2 receptors,

and has no effect on D1 receptors. It has a relatively long half-life
(8 hr).
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Ropinirole (Requip): Ropinirole is a D2 agonist only, with a

relatively short half-life (6 hr).

Other dopamine agonists are currently being researched and

developed. There are no drugs commercially available yet that
exclusively stimulate D1 receptors, but this is an especially active
area of research. Combining an exclusive D1 agonist with an
exclusive D2 agonist might be an ideal combination therapy,
allowing individual adjustment of the doses to maximize the benefit
in each patient.

See tables: Dopamine Agonists: Incidence of Typical Dopaminergic

Side Effects

Selegiline, Amantadine,
Anticholinergics, and Other
Drugs
Anticholinergics
Anticholinergic drugs inhibit other types of nerve cells whose
actions oppose dopamine. Anticholinergics are used mainly for
tremor or rigidity. Anticholinergics used to treat Parkinson's
disease include benztropine, trihexyphenidyl, and ethopropazine.
These drugs are rarely used in elderly patients or those with
dementia, because increased confusion can be one of the
significant side effects of anticholinergics. Other side effects may
include dry mouth, sedation, delirium, hallucination, constipation,
and urinary retention.

Selegiline (Eldepryl)
Selegiline is an inhibitor of the enzyme MAO-B (monoamine oxidase
B). Since this enzyme breaks down dopamine, inhibiting it with
selegiline prolongs the action of dopamine in the brain, and may
improve the symptoms of Parkinson's disease.

Selegiline's potential as a neuroprotective agent is uncertain.

Selegiline's side effects may include hallucinations, orthostatic

hypotension (a drop in blood pressure upon standing, possibly
leading to lightheadedness), insomnia and, on occasion, nausea.
There is also potential for a serious reaction with certain
antidepressants, known as the serotonin syndrome, in which
patients may develop extremely high blood pressure and other
associated symptoms.
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Amantadine (Symmetrel)
Amantadine may be effective against the major motor symptoms of
Parkinson's disease, and may reduce dyskinesia. Side effects may
include dry mouth, difficulty concentrating, confusion, insomnia,
nightmares, agitation, and hallucinations. Amantadine may cause
orthostatic hypotension, as well as peripheral edema (fluid
accumulation in the extremities) and mottled skin.

Baclofen (Lioresal)
Baclofen is used to treat foot dystonia, a symptom sometimes seen
in early morning in Parkinson's disease patients. Baclofen's side
effects may include sedation, drowsiness, fatigue, confusion,
nausea, and dizziness.

Surgery
Three types of surgery are currently used for the treatment of
Parkinson's disease:

Pallidotomy
Thalamotomy
Deep Brain Stimulation

A fourth procedure, Fetal Nigral Cell Transplantation, is an

experimental procedure still under development.

Pallidotomy
A pallidotomy involves destruction of part of the globus pallidus
(GPi), a region of the brain involved with the control of movement.
Normally, the effects of dopamine help to regulate the GPi. Loss of
dopamine leads to overactivity in the GPi. Destroying part of the
GPi may help to restore the balance that 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.

In a unilateral pallidotomy, only one side of the GPi is destroyed.

Because structures on one side of the brain control movements on
the opposite side of body, destroying the right-hand side of the GPi
leads to motor improvements in the left side of the body, and vice
versa. Dyskinesia may improve slightly on the same side of the
body. Results from bilateral pallidotomy, in which both sides are
destroyed, have not been promising.
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Pallidotomy is most useful for the treatment of peak-dose

dyskinesias and for dystonia that occurs at the end of a dose. It
may also improve bradykinesia and tremor somewhat on the side
opposite the pallidotomy. By eliminating peak-dose dyskinesia,
pallidotomy may allow an increase in levodopa dose, resulting in
more effective symptom management.

Pallidotomy is most effective in patients under age 70. The

procedure does involve risk, and complications occur in about 10-
20% of patients. The surgical probe may strike a blood vessel
during insertion, causing a slight stroke. Damage to other brain
areas is also possible.

Thalamotomy
A thalamotomy destroys part of the thalamus, another brain region
involved in movement control. Thalamotomy can be effective for
the treatment of tremor, rigidity, and peak-dose dyskinesia.
However, the risks of thalamotomy are increased by the nearby
location of other important brain structures and the potential for
worsening some PD symptoms, including gait and speech
difficulties. For these reasons, thalamotomy is not as widely used as
it once was. Nonetheless, it can be an effective treatment,
especially for tremor, in patients without pre-existing gait and
speech problems.

Deep Brain Stimulation

Deep brain stimulation (DBS) uses an implanted electrode to
deliver continuous high-frequency electrical stimulation to either
the thalamus, globus pallidus (GPi), or the subthalamic nucleus
(STN), another part of the brain controlling movement. High
frequency stimulation of cells in these areas actually shuts them
down, helping to rebalance control messages throughout the
movement control centers in the brain.

DBS of the thalamus is primarily used to treat disabling

tremor, especially tremor that affects one side of the body
substantially more than the other. Studies have shown that
DBS may significantly reduce tremor in about two thirds of
patients with Parkinson's disease. Tremor may not be
eliminated, and may continue to cause some impairment.
DBS of the globus pallidus is useful in treatment of
dyskinesias as well as tremor, and may improve other
symptoms, as well.
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DBS of the subthalamic nucleus may have an effect on most

of the main motor features of PD, including bradykinesia,
tremor, and rigidity.

DBS of the GPi or STN may allow a reduction in levodopa dose,

which may improve dyskinesias as well.

Because it relies on continuous stimulation, DBS requires

placement of an electrode in the brain, connected by a wire to a
battery source. Electrode placement is performed under local
anesthesia. The wire is implanted under the scalp and neck, and
the battery is implanted in the chest wall just below the collar
bone. A series of stimulation adjustments are required in the weeks
following implantation. Battery replacement, required every 3-5
years, requires only an incision in the chest, and is performed as an
outpatient procedure.

In the United States, the Food and Drug Administration has

approved bilateral (both-sided) deep brain stimulation of the STN
or GPi (using a system from Medtronic) for treatment of
Parkinson's disease. The side controlling the most severely affected
limbs is usually the one chosen for a unilateral implant. Unilateral
DBS may be performed on a person who has already had
pallidotomy or thalamotomy on the opposite side.

Transplant Surgery
Fetal nigral cell transplantation introduces dopamine-producing
cells to the brain of a Parkinson's patient to replace the patient's
degenerating substantia nigra. These cells may restore dopamine
production which, in the proper areas of the brain, may allow more
normal control of movement. The procedure is experimental and
currently performed at only a few medical centers in the world.

Fetal cells are used rather than those from an adult source (such as
a cadaver) because, unlike mature nerve cells, fetal cells have not
developed long extensions which put the cell at risk of death when
cut. In addition, they are programmed to grow and make
connections within the brain, exactly the behavior needed following
transplantation. Fetal cells are obtained following elective abortion.
To prevent conflicts of interest, the option of donating fetal tissue
for research is offered only after the decision to abort is made by
the mother.

As this procedure is currently performed, fetal nigral cells are

injected into the brain through a series of small holes made in the
skull. In most medical centers, drugs that suppress the immune
system are given for several months following the transplant.
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Over 150 transplants have been performed to date. Results have

been promising but inconsistent so far, with some patients
experiencing significant improvements and others little or none. On
average, small improvements have been seen in several disease
aspects, including motor performance during both "on" and "off"
periods, increased "on" time, and requirement of less L-dopa.
Duration of improvement has been from 6 months to several years
or more.

Results from the first double-blind placebo-controlled trial of fetal

graft transplantation surgery for advanced Parkinson's disease
show the greatest treatment benefit in younger patients, and on the
symptoms of rigidity and bradykinesia. However, the surgery
carries the long-term risk of causing unpredictable and disabling
dyskinesias in some patients. For more about this study, see these
two E-MOVE reports: PD: Fetal transplants (AAN report), and
Long-term Outcomes in PD Fetal Transplants (MovDis Congress
2000)

Continued research to determine the best combination of technique

and patient selection may improve the consistency and
effectiveness of this procedure.