SEBORRHEA

Excessive secretion of oil by sebaceous glands is common in PD.

Management.

Coal tar shampoos can be used not only for dandruff but also for seborrhea
over the eyebrows and forehead. They should not be used more than once or
twice weekly. Selenium-based shampoos also work in some patients when used
in a similar manner. Topical hydrocortisone is most effective on the face
but needs to be applied daily.


FALLS

Falls are a leading cause of morbidity and mortality in the elderly
population and frequently contribute to nursing home placement. The causes
of falls in the elderly are usually multifactorial and can be divided into
intrinsic and extrinsic factors.
Intrinsic factors are age- and disease-related elements in an individual
that predispose him to fails. These factors include gait, balance, and
weakness (10 to 25%), dizziness and vertigo (5 to 20%), orthostatic
hypotension (2 to 15%), syncope (2 to 10%), drop attacks (1 to 10%), and
other causes, such as acute illness, confusion, poor eyesight, and drugs (1
to 10%).

Extrinsic factors are environmental elements that may cause an individual
to fall. Environmental factors account for 30 to 50% of falls in elderly
individuals.

Falling is a significant problem in PD. Older age, longer duration of
disease, advanced stage of disease increased disability, rigidity,
bradykinesia, inability to rise from chair, posture and gait impairment,
and postural instability are factors that predispose patients with PD to
falls. Mental status changes, OH, dyskinesias, and age-related physical
changes are other possible factors.


POSTURAL INSTABILITY

Postural instability often responds poorly to drug therapy especially with
advanced disease. Although postural instability improves with the
administration of levodopa - or other medications in some patients
especially those with more recent onset disease - most patients with more
advanced disease fail to improve with a change in levodopa dosage or the
addition of dopamine agonists, gait training and physical therapy may be
beneficial, In patients with severe postural instability, wheelchairs can
be used to prevent morbidity from falls.


SYMPTOMATIC OH

Symptomatic OH can cause falls in patients with PD, It is critical for the
physician to distinguish this cause from other conditions that also can
cause falling. Treatment of OH is discussed in the "Dysautonomias" section.


MOTOR FLUCTUATIONS

Motor fluctuations, including dyskinesias and episodic freezing, may be
additive to postural instability and contribute to the tendency to fall.
(These problems will also discussed in the "Motor problems" section to
follow.)


FREEZING AND FESTINATIONS

Freezing  refers to a patient's feet getting stuck to the ground while
walking, with an inability to initiate lower limb movement for a few
seconds to minutes.

In PD, the center of gravity is shifted forward and during ambulation the
flexed trunk precedes the lower limbs, leading the patient to take
increasingly frequent, short steps, often ending with a fall, This
phenomenon is known as "festination."
Pharmacologic treatment of freezing and festination is sometimes effective
but can be very disappointing in more advanced patients. Occasionally,
decreasing or. increasing daily levodopa dosage or adding a dopamine
agonist may help.

When drugs are of no benefit in freezing and festinations, physical therapy
may he helpful. Behavioral therapy is often beneficial in freezing.

Gait modification by the use of motor and sensory tricks, such as
alteration of the distribution of body weight, walking sideways, rocking
movements of the body, stamping feet, walking briskly, taking longer steps,
consciously lifting one limb higher and sliding one foot backwards then
throwing it forwards, may work for some patients.

Having someone rhythmically pull or push or passively elevate the patient's
knee also can help, Verbal or auditory stimuli that are used include
marching like a soldier to commands, walking or dancing to music, sudden
clapping of hands and swearing.

Visual stimuli include stepping over objects such as the handle of a
walking stick, another person's foot, or carpet patterns; watching other
people walk; and imagining white lines to step over.


DEMENTIA

The proportion of patients with PD who are also demented is approximately
15 to 2O%. At times, PD may be accompanied by Alzheimer's disease,
Cognitive impairment is an independent risk factor for falls in the
elderly. Hence, parkinsonian patients with dementia have an even higher
risk of falls. Patients and their families should be educated about the
increased risk of falls, and occasionally these patients may benefit with
gait training and physical therapy.


OTHER NEUROLOGIC DEFICITS

Patients with PD can have associated neurologic conditions that may
increase their risk of falls.

These conditions include myopathy, cervical degenerative disease, normal
pressure hydrocephalus, lower back problems, multiple sensory deficits (eg,
visual, vestibular, proprioceptive), cerebellar deficits, and other
deficits caused by strokes. If clinical signs and symptoms suggest any
other neurologic condition, a detailed workup should be performed.

Aging, arthritis, physical inactivity and cardiac disease in the elderly
also should be considered as causes of muscle weakness. It often is
overlooked/in elderly patients because examiners are often too "generous"
to grade their muscle strength.

Decreased muscle strength in the lower limbs is associated with falling and
mortality among the elderly. Physical therapy plays an important role in
strengthening weakened muscles and improving stability and gait.


OTHER MEDICAL CAUSES

Acute illness, such as pneumonia, and the worsening of chronic conditions,
such as congestive heart failure, can precipitate falls. Stable
parkinsonian patients who suddenly begin to have falls or an acute increase
in the frequency of falls should undergo complete medical evaluation.

Medications can contribute to falls by causing volume depletion, OH,
fatigue, impaired mental alertness, or other unknown mechanisms. The total
number of medications used appears to be directly related to the risk of
falls.


RECOMMENDATIONS

Every patient with PD who is experiencing falls should have a home safety
evaluation performed by a trained therapist. The ability to avoid falls
decreases with age, because of changes in posture, body-orienting reflexes,
muscle strength, and decreased height of steppage.

Extrinsic factors that contribute to the tendency to fall could include
poor lighting, torn carpet, loose rugs, slippery surfaces, small objects on
the floor, inappropriate furniture, and unsafe stairs. Adaptive equipment,
such as walkers, if inappropriately used, also will increase the risk of
falling. As the chances of falling are proportional to the number of risk
factors, everything possible should be done to correct environmental factors.

Not all risk factors are correctable and even after optimal treatment some
patients continue to experience falls. Prevention is the best strategy, but
an occasional patient may be safest using a wheelchair on a permanent basis.


MOTOR PROBLEMS

During the early stages of PD, the clinical responses to levodopa therapy
are stable and characterized by a "long-duration" pattern. Patients with
early disease require several days to plateau following a change in their
levodopa dosage. Once plateaued, they experience no clinical variability,
even if doses are late or skipped. If levodopa is stopped, it may take up
to a week to return to the pre-levodopa baseline.

In contrast, with advancement of PD, the levodopa response shifts to a
"short-duration" pattern. Patients with advanced disease experience
clinical motor fluctuations that reflect ever-changing brain levodopa levels.

Knowledge of the individual patient's short-duration levodopa response
pattern is often crucial to arriving at the correct treatment advice. The
short-duration response typically develops, plateaus, and abates over
several hours after a single dose of levodopa.

The plateau phase of clinical improvement ("on") typically peaks about 45
to 90 minutes after administration of the standard formulation of
carbidopa-levodopa and 60 to 150 minutes after the controlled- release CR)
formulation.

Rare patients with delayed gastric emptying may have a somewhat more
delayed response. The clinician should focus on the adequacy of the peak
response, the duration of that response, and the time that the dyskinesias
are manifest in the response cycle. This often can be determined from the
history but may require observation in the office.


NO RESPONSE

A few patients with parkinsonism will experience no beneficial response to
carbidopa-levodopa in any dose. Such patients with parkinsonian symptoms
probably do not have PD but rather striatonigral degeneration or some other
similar condition in which the pathology is beyond the substantia nigra,
involving other portions of the extrapyramidal motor system.

An adequate trial of medication must be employed before concluding that the
patient is a nonresponder.

Management.

Patients who fail to respond to lower dosages of carbidopa-levodopa can
have the dosage gradually raised, with the standard rather than the CR
preparation for the purposes of this trial. Patients should be instructed
to take their doses on an empty stomach. to make certain the poor response
is not secondary to the inhibitary effects of dietary protein.

Once the dosage has been slowly pushed up to approximately 1,200 mg per day
(eg, 300 mg four times daily) with no response, it would then be reasonable
to conclude that carbidopa- levodopa therapy is not beneficial.

Since the long-duration levodopa response takes several days to become
fully manifest, patients should be maintained on the higher doses for
approximately 1 week to allow the full effects to occur.

Certain patients being seen in the office who report no response to
levodopa may be challenged with a somewhat larger dose than they have been
taking. If there is still no response, however, this strategy should not
preclude going ahead with a trial of chronic administration of higher doses
of carbidopa-levodopa, since some patients manifest a long-duration effect
that will not be seen after one or two doses.

Obviously, the aforementioned strategies pertain to patients who simply
fail to respond to carbidopa-levodopa rather than those who cannot tolerate
this medication, for whom other strategies may apply. Patients who fail to
respond to very high doses of carbidopa-levodopa are unlikely to respond to
dopamine agonist medications either, although some clinicians choose to try
these nonetheless. Patients who fail to respond to levodopa and whose
primary problem is tremor or dystonia can he given a trial of
anticholinergic therapy {eg, trihexyphenidyl, benztropine).


SUBOPTIMAL PEAK RESPONSE

Patients who experience suboptimal motor control at the time of peak effect
of levodopa can have their response potentiated in a variety of ways.

The simplest approach is to raise the individual doses of levodopa (with
carbidopa) by small and gradual increments until improvement develops. The
point of diminishing returns is at approximately 250 mg of levodopa per
dose of the standard formulation and 400 mg of the CR formulation. Rare
patients may require slightly higher doses for maximum effect.

Although no compelling evidence points to levodopa toxicity, some concerns
do exist; hence, some clinicians have favored keeping the levodopa dosage
lower and instead adding or increasing one of the two available adjunctive
dopamine agonist drugs, bromocriptine or pergolide. A minimum total daily
dose of 15 mg of bromocriptine or 1.5 mg of pergolide (divided) is usually
necessary to achieve a minimally clinically significant effect.

Selegiline also will potentiate the peak effect of levodopa therapy by
inhibiting MAO-B, one enzymatic route of dopamine degradation.

If tremor is prominent, the addition of an anticholinergic drug, such as
trihexyphenidyl or benztropine, may be helpful, if tolerated. Amantadine is
also mildly beneficial as an adjunctive drug in this situation.

Unfortunately occasional patients experience side effects that limit the
dosage of medications that can be administered. These include
hallucinations, psychosis, confusion, nightmares, and dyskinesias, which
can be induced or exacerbated by levodopa, dopamine agonists, or selegiline.

Anticholinergic drugs have their own side-effect spectrum that includes
memory impairment, hallucinations, psychosis, constipation, urinary
hesitancy, and visual blurring.


OPTIMAL PEAK RESPONSE BUT "WEARING OFF"

Adjustment of medications to obtain an optimal peak effect generally is the
initial strategy. Subsequently, the focus shifts to the levodopa response
duration. Patients with "wearing off" of their levodopa effect before the
next dose may respond to one of several strategies.

Substituting sustained-release caribidopa-levodopa for the standard
formulation typically will add 60 to 90 minutes to the response duration.
Although there is not a direct milligram to milligram correspondence
between the standard and CR formulations of carbidopa-levodopa, simple
dosing guidelines allow a rapid transition.

In converting to the CR formulation, the individual doses must be 30 to 50%
higher to achieve the same peak effect. The interval between doses is
adjusted to correspond with the estimated response duration.

Simply shortening the interval between carbidopa-levodopa doses (standard
or CR formulation) is a common sense strategy for countering "wearing-off"
effects. Optimally, the next dose should be given just before the effects
from the last dose have worn off.

Patients with short-duration responses often respond well to adjunctive
dopamine agonist therapy with bromocriptine or pergolide. The dosage is
started at subtherapeutic levels (1.25 mg of bromocriptine or 0.05 mg of
pergolide daily), and hence the levodopa dosage should be maintained until
a clinical response develops. Subsequently, the levodopa dosage can be
gradually lowered as the clinical effects from bromocriptine or pergolide
become apparent.

The clinically effective range of dosages is approximately 15 to 50 mg of
bromocriptine or 1.5 to 5.0 mg of pergolide daily (divided). Occasionally,
switching from one dopamine agonist to another (eg, bromocriptine to
pergolide using a 10-to-1 potency ratio is helpful). The expense of the
highest doses of these drugs may be prohibitive, however, for certain
patients.

In patients with severe fluctuations, if titration cannot be adequately
achieved with the above measures, transition to liquid carbidopa-levodopa
may be considered.

Very close titration is possible with this strategy, resulting both in less
"off" time and potentially fewer dyskinesias (see below) The disadvantages
are: a much shorter response duration (60 to 90 minutes), the requirement
for the patient to prepare the liquid formulation, and the lack of
stability of levodopa in solution. This last problem is countered by adding
ascorbic acid for stabilization, but even then, the liquid preparation
cannot be carried over from one day to the next.

The usual mixture is prepared by pulverizing with mortar and pestle, ten
25/100 standard carbidopa-levodopa tablets and 2 g of ascorbic acid, which
are then added to 1 liter of tap water.

The transition from tablet to liquid carbidopa-levodopa is made by
administering small levodopa doses at 60- to 90-minute intervals, with the
total daily dose similar to that given with tablets; further titration is
based on the response.

Several investigational drugs are under development for treatment of
response fluctuations. These include novel dopamine agonists,
catechol-O-methyl transferase inhibitors, and selective MAO inhibitors.
Patients who experience fluctuations may wish to take advantage of the
opportunities for entry into investigational protocols, which are available
at many major medical centers.

The addition of amantadine or selegiline also may result in mildly improved
control of short-duration levodopa responses.

If tremor is a significant problem, anticholinergic drugs (eg,
trihexyphenidyl, benztropine) are an appropriate option, although
anticholinergic side effects often limit their utility, especially in the
elderly "Off"-phase dystonia also may respond to anticholinergic medications.

Subcutaneous apomorphine is favored by some clinicians outside the United
States as rescue therapy for patients caught in a levodopa "off" state. The
response is rapid, developing in approximately 3.5 to 12.5 minutes and
returning the patient to an "on" state comparable to their peak response
with levodopa. Although the response is brief (approximately 1 hour), it
allows time for the patient's next dose of carbidopa-levodopa to take
effect. Apomorphine's potential emetic effect necessitates concomitant use
of domperidone, an investigational antiemetic drug that does not cross the
blood-brain barrier and hence does not exacerbate parkinsonism. Domperidone
is available by prescription in most countries outside the United States.


OPTIMAL PEAK RESPONSE BUT UNPREDICTABLE "OFF"

Most PD patients with fluctuations and intermittent loss of their levodopa
effect have predictable "off" periods, although they may not perceive the
pattern. To establish the pattern, it may be necessary to have the patient
come to the office in the "off" state and then serially observe him as he
cycles through the "on" response. Unfortunately, occasional patients suffer
from lack of predictability of their "off" states, including premature
"wearing-off" and skipped-dose effects.

Management.

Large neutral amino acid breakdown products of dietary protein, which
inhibit levodopa transport, may be a major factor in certain patients.
Specific inquiry is necessary to establish the extent of meal effects.

In appropriate patients, redistribution of dietary protein can prove
beneficial. Consuming most of the daily protein requirement during only one
meal (often supper) may allow better responses after the other meals of the
day. A dietitian should be involved in such modifications to assure that
the minimum daily protein requirement continues to be met.

Adjunctive dopamine agonist therapy (bromocriptine, pergolide) may be
particularly beneficial in patients with unpredictable "off" states.
Delivery of these drugs to the brain does not appear to be compromised by
meals and the response durations exceed those with levodopa.

Patients with unpredictable "off" periods sometimes get intermittently
"trapped" in this state. Subcutaneously administered apomorphine and the
adjunct antiemetic domperidone, where available can be an effective rescue
therapy for such patients.

Liquid carbidopa-levodopa may allow more consistent and reliable control of
parkinsonism and is worth considering in patients with erratic control of
their condition. As discussed patients must be willing to accept the
inconvenience of very frequent dosing (every 60 to 90 minutes) and daily
preparation. Patients with unpredictable "off" states also may be
appropriate candidates for many of the investigational protocols available
at certain major medical centers.


FREEZING (MOTOR BLOCKS)

Hesitancy or freezing of motor behavior can occur with any movement but is
most apparent and troublesome to PD patients when it involves gait. In some
patients, freezing is a manifestation of either an inadequate or an
excessive dopamine effect. In certain other patients, it occurs independent
of medications and is refractory to manipulation of dopamine.

Management.

Attention to the timing of freezing in the levodopa response cycle
determines the treatment strategy.

Freezing in conjunction with other prominent signs of parkinsonism during
the time of peak levodopa effect suggests an underdosed state that may
respond to larger individual doses of carbidopa-levodopa and other
strategies described in the section, "Suboptimal peak response."

Patients whose freezing is confined to their levodopa "off" states are
often particularly responsive to more aggressive medical treatment, using
the strategies outlined under "Optimal peak dose but wearing off."

Although freezing may not respond as consistently to dopamine therapy as
other motor manifestations, it certainly can be controlled with drugs in
some patients.

Patients who already are receiving maximal medical treatment yet display
freezing, even during their peak levodopa response times, present the most
troublesome management problem. This scenario is most common in patients on
adjunctive dopamine agonist therapy (bromocriptine or pergolide),
particularly if higher doses are employed. These patients may note
improvement within a day or a few days after a 50% reduction in their
dopamine agonist drug is tried. Further tapering reductions are appropriate
in certain patients. A trial of levodopa dosage reduction or
discontinuation of selegiline-which has the same effect as lowering
levodopa dosage-may also be done on a trial basis.

Occasional patients improve with increased levodopa dosages, even if other
signs of parkinsonism appear optimally controlled. Hence, a brief trial of
incremental levodopa dosing may be indicated in some patients. Certain
patients with refractory motor blocks may he candidates for clinical trials
at major medical centers.

Regardless of the cause, gait freezing and similar motor blocks can be
overcome by certain tricks that involve the use of sensory or mental
imagery cues.

A patient unable to initiate the first step (freezing) often can circumvent
this gait inhibition by one of several strategies, such as:
-stepping toward a target on the ground;
-stepping over a cane laid on the floor in front of the foot; or
-taking the first steps with a stiff-legged,long-striding military gait.

The general idea is to implement a conscious motor program to substitute
for the malfunctioning subconscious automatic motor program. After
experimenting with different ploys, patients typically find at least one
strategy that is helpful.

Anxiety can exacerbate the tendency for motor blocks/freezing, If this is a
major factor, measures aimed directly at treating the anxiety state may he
appropriate (see the "Behavior impairment" subsection of the
"Neuropsychiatric problems" section).

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