An Algorithm For The Management Of Parkinson's Disease, a supplement of
the American Academy of Neurology. Reprinted in Neurology 1994;44:S1-S52.
Editors: William Koller, M.D. Ph.D
         Dee Silver, M.D.
         Abraham Lieberman, M.D.

The text of the Algorithm is contained in four messages, which includes
this Foreword.

This is a significant work, in that it includes the medical approach
to treating problems that Parkinson's disease sufferers endure. It is
comforting to know that as the disease progresses, answers to tomorrows
"opportunities" have answers, today.

This document can be more effective and manageable if printed rather than
read online. Print the document using the Courier font on your printer.
Import all five messages into one document. Then print the document.

The tables will line up if 12 point type is used.

There are 165 references in this document, of which I reproduced 18. I can
look up the references for those interested, on a case by case basis or
you can find them in Neurology, December 94 edition, supplement, at your
medical library.

The breakouts are not included. The breakouts were just a graphical
representation of what the text covered. The two Tables included, provided
more information than was in the text.

EARLY PARKINSON'S DISEASE

NONPHARMACOLOGIC INTERVENTION

 The optimal approach to the management of early PD includes
both pharmacologic and non-pharmacologic treatments. The best
results will be  achieved by addressing all the patient's needs.
A good attitude on the  part of the patient, a strong support
system, and an experienced treating physician are all essential
components for a successful outcome.  Attention should not be
focused solely on pharmacologic therapy. A team approach and a
variety of therapeutic interventions are essential to optimal
management  (breakout 1).

GROUP SUPPORT. Patients and their families need help adapting to
living with a chronic, progressive illness. Support groups offer
psychologic and social  benefits to both patient and family.
 Patients with PD benefit greatly from interaction with each
other. Initially, individuals often tend to feel they are the
only ones with this disease. Both the patient and the patient's
family can benefit from  participation in support groups. A
national organization, the American  Parkinson Disease
Association (APDA), has chapters in most cities. Many of  these
groups meet on a monthly basis for discussion among themselves
and,  often, presentations by various professionals. The
clinician should advise patients of the APDA's existence and
encourage their participation.
 Because some patients with early disease might become discouraged
when exposed to patients with more advanced disease, special APDA
groups for  individuals with young-onset PD have been formed to
address their unique needs.
 Families of patients with PD also can benefit from group
support. All family members are affected when a loved one is
stricken by this disease, and they can react dysfunctionally if
they do not have access to educational and support resources.

EDUCATION. Support groups provide practical information
regarding PD. They  often address issues such as the need for
grab bars in the bathroom, a  trapeze over the head of the bed,
and velcro closures on clothing, which  often are not mentioned
by the physician. Patients who know as much as  possible about
their disease will receive the best treatment. PD newsletters
from such national organizations as the United Parkinson's
Foundation, the  National Parkinson Foundation, and the APDA
provide the education that  allows patients to become advocates
for their own causes.
 Information regarding available support organizations can be
obtained by contacting:

The American Parkinson Disease Association, Inc.
60 Bay Street, Suite 401
Staten Island, NY 10301

(800) 223-2732

National Parkinson Foundation, Inc.
1501 N.W. 9th Avenue, Bob Hope Road
Miami, FL 33136-1494

(800) 433-7022

Parkinson's Disease Foundation
650 W, 168th Street
New York, NY 10032

(212) 923-4700; (800) 457-6676

United Parkinson's Foundation
833 W. Washington Boulevard
Chicago, IL 60607

(312) 733-1893

 The book Parkinson's Disease: A Guide for Patient and Family,
by R.C. Duvoisin[1] also provides excellent information. The
physician should let patients know about these invaluable
educational resources.

EXERCISE. Daily exercise is one of the most beneficial things a
patient can do for himself, can consist of stretching, walking,
swimming or any activity the patient enjoys and will do
regularly. More formal cardiovascular programs also are
beneficial. Physicians should strongly encourage their patients
to exercise.
1
NUTRITION: Patients with PD are at risk for nutritional
disturbances for many reasons. Good nutrition is therefore
essential to their overall well-being. Although no specific diet
is required, patients should receive sufficient fiber and fluids
to prevent constipation and enough calcium to avoid
osteoporosis. Patients often will ask about the amount of
protein needed in their diet, This is a concern only in
individuals who are taking levodopa and experiencing erratic
responses. It is not usually an issue in early PD.

PHARMACOLOGIC INTERVENTION

 Once the diagnosis of PD has been made, the next decision is
whether a patient should receive antiparkinsonian medication
(breakout 2).[2-6] Before the evidence of selegiline's possible
role as a putative neuroprotective agent emerged, the decision
to treat or not to treat PD was based solely on the degree of a
patient's functional impairment,[3-6] which in turn depended
upon the particular symptoms the patient had (tremor,
bradykinesia, gait impairment); whether the symptoms affected
the dominant hand, nondominant hand, or both; and whether the
patient was or was not working. If a neuroprotective therapy is
definitely proven, then it should be started as soon as the
diagnosis can he made.
 Once the degree of functional impairment is established, factors
that affect a patient's ability to tolerate antiparkinsonian
medication should be ascertained. One of the most important of
these factors is whether the patient has cognitive impairment.
 Although these issues may seem straight forward, the decision
to treat or not to treat is not easily reached, Assessing the
severity of parkinsonian symptoms, functional impairment, and
cognitive impairment is difficult.[6]

FUNCTIONAL IMPAIRMENT. The presence of parkinsonian symptoms or
functional impairment is implicit in diagnosing PD.[7-8] If no
symptoms or functional impairment were present, obviously the
patient would not have come or been brought to a physician.
Therefore, the issue is not whether functional impairment is
present, but it is a question of degree and how the impairment
can be assessed.
 Patients are most often aware of tremor, slowness of movement,
and gait impairment.[3-4] In most patients with early PD, the
disease is predominantly unilateral, so that the degree of
functional impairment often depends on which hand
is affected. Thus, a patient with early PD with micrographia
will have more functional impairment than a patient at the same
stage of illness who has bradykinesia involving the nondominant,
non-writing band. As a result, patients with symptoms involving
the dominant hand are more likely to seek treatment. PD in
patients with early midline symptoms, manifested as gait
impairment or postural instability, may evolve into a
Parkinsonism Plus Syndrome (progressive supranuclear palsy and
multiple system atrophies).[9] At the time of diagnosis however,
it may be impossible to distinguish a patient with Parkinsonism
Plus Syndrome from one with PD. However, the initial
pharmacologic approach is the same in these parkinsonian
syndromes.
 Parkinsonian patients with symptoms of gait impairment or
postural instability-manifested as festination, freezing,
and impaired turning--should be treated. These symptoms can
lead to falls and serious injury. Gait impairment and postural
instability, if caused by early PD, are likely to respond to
dopaminergic therapy. In advanced PD these symptoms may not respond
as well to dopaminergic therapy. It is therefore conceivable that
different mechanisms underlie these symptoms in early PD vs
advanced PD.[10]
 Tremor is present in approximately 70% of patients with PD.[2]
The tremor is usually asymmetric and present at rest. Therefore,
unlike a tremor that manifests itself during movement, the tremor
of PD, per se, is less likely to result in functional impairment.
In some patients the rest tremors are associated with subjective
distress, ''like a motor running all the time," and these tremors
can be as disabling as a tremor that impairs motor skills. The
resting tremor of PD may respond to carbidopa-levodopa, provided
the dosage is high enough. For refractory cases of severe PD
tremor, stereotactic thalamotomy is an effective option.
 The single most important social factor that determines whether
or not a symptom will result in functional disability that
requires treatment with carbidopa-levodopa is whether or not
the patient is working.[10,11] All things being equal,
bradykinesia severe enough to cause marked slowing in walking
and handling utensils is more likely to result in disability
in someone who is working than someone who is not. Patients with
PD who are working have to perform under a more strict time
frame, and their symptoms can impair job performance.
 The Activities of Daily Living (ADL) scale of the United
Parkinson Disease Rating Scale (UPDRS) is the most useful
and uniform way to assess disability.[2] The ADL scale
evaluates speech, salivation, swallowing, handwriting,
cutting food, handling utensils, hygiene, tuning in bed,
falling, freezing, walking, tremor, and sensory symptoms.
Careful questioning with the ADL scale as a framework often
provide insight into how particular symptoms result in
disability and provides a means of monitoring Parkinsonism over
time.

COGNITIVE IMPAIRMENT: Cognitive impairment is an important
modifier in determining pharmacologic intervention. Overt or
subclinical cognitive impairment can alter a patient's response
to antiparkinsonian drugs, especially anticholinergics and
amantadine. In these patients, pharmacologic intervention can
superimpose a toxic delirium on a substrate of disease related
impairment. Cognitive impairment also can affect pharmacologic
intervention indirectly. Patients with cognitive impairment may
not perceive symptoms as acutely as patients without it. Such
patients, although functionally impaired, sometimes insist they
require no treatment. For symptoms such as tremor or
bradykinesia, it may be best not to override the patient's
wishes; but for gait impairment and postural instability, with
their potential for serious disability, it may be necessary to
do so. Such a decision obviously will be made with the approval
of the patient's spouse and family.
 A related problem is affective disorders. Perception of
impairment is often more exaggerated with patients who are
anxious and depressed than those who are not. In some of these
patients, counseling and antidepressants may be as effective as
or more effective than antiparkinsonian drugs. Dementia occurs
in 30 to 70% of patients with PD, depending on their age and
duration of disease.[12-15] How much of this dementia is
disease-specific and how much comes from an overlap between PD
and Alzheimer's disease is debated. Dementia is common in early
PD, although mild cognitive impairment maybe common.[4,5]
It is difficult to assess mild cognitive impairment and to
distinguish it from a personality change, anxiety, depression, or
preclinical dementia. Behavioral abnormalities, such as getting
lost in familiar surroundings, failing to balance a checkbook,
or personality changes, may be better indicators of cognitive
impairment than cognitive testing in early PD. Thus, a patient
who was confident, extroverted, and assertive and becomes
uncertain, introverted, and cautious may be cognitively impaired
in the absence of depression.
 The Mini-Mental State Examination (MMSE) is a simple means of
measuring cognitive impairment. It assesses temporal and spatial
orientation; digit span; and the ability to express and
understand language, to follow commands, to remember, and
to complete constructions. An abnormal MMSE suggests cognitive
impairment but is not diagnostic of dementia. Conversely, a
normal test does not exclude cognitive impairment.

NEUROPROTECTION. Until recently, all treatment of PD was
symptomatic. Little was known about neuroprotection; slowing
disease progression. A retrospective review of parkinsonian
patients who were treated with the MAO-B inhibitor selegiline
(formerly known as deprenyl), however, suggested that this drug
may be a neuroprotective agent.[17] Research subsequently showed
that selegiline, by inhibiting MAO-B, prevented the development
of MPTP-induced parkinsonism.[16] This suggested that selegiline
may be able to slow the progression of PD, possibly by reducing
the generation of toxic free radicals.
 The hypothesis that selegiline may delay the progression of PD
was tested in four prospective studies of patients with newly
diagnosed PD who were not receiving carbidopa-levodopa.[10,11,18,19]
Patients in these studies were randomly assigned to either
selegiline, 10 mg per day, or placebo and were followed until
they required carbidopa-levodopa treatment. In all four studies
selegiline slowed the rate of symptom development and delayed
the need for carbidopa-levodopa by 50%. In all four studies however,
selegiline was shown to have a symptomatic effect-which may be
related to either its ability to block dopamine degradation in
glial cells and neurons, thereby raising intracellular dopamine;
or its ability to block dopamine reuptake, thereby raising
levels of extracellular dopamine.[20-21]
 The symptomatic improvement could be related to an indirect
effect of selegiline on dopamine receptors.[22] This symptomatic
effect remains the focus of unresolved debate. Some think the
symptomatic improvement is sufficient to obviate the need to
invoke a neuroprotective effect as its mechanism of action.[23]
Others believe symptomatic improvement is not extensive enough to
explain this effect.[10] A retrospective postmortem study
demonstrated greater preservation of dopaminergic neurons
selegiline treated patients than in those not treated with the
drug.[24] Several other studies indicate selegiline may rescue
dopaminergic neurons through a trophic effect, independent of
inhibition of MAO-B.[25-26]
 The delay in the progression of PD symptoms and the paucity of
side effects associated with selegiline makes it a useful drug
for initiating treatment in PD regardless of whether it exerts
neuroprotective effect. Some clinicians think it is reasonable
to continue selegiline once it has been started. If selegiline
is later shown not to have a neuroprotective effect, little harm
will have been done. If, on the other hand, the drug is later
shown to have such an effect, patients who did not receive it
may have needlessly suffered a greater loss of neurons than
those who did.

AGE CONSIDERATIONS

 The choice of drugs used in the treatment of PD is determined
in part by the relative chronologic and biologic age of the
patient. Age 60 is used here as an arbitrary cutoff (breakouts
3A and 3B)

AMANTADINE. Patients <6O years of age. Amantadine is an
antiviral agent discovered by chance to have antiparkinson
activity.[27] Its principal mechanism of action has not been
established, but it is known to increase dopamine release, block
dopamine reuptake, stimulate dopamine receptors, [28-29]
and-based on its clinical effects-to have peripheral
anticholinergic properties.[30] In uncontrolled studios, two
thirds of patients receiving amantadine monotherapy showed
improvement in akinesia, rigidity, and tremor.[27,31] Amantadine
appears to be more effective than anticholinergic drugs with
regard to akinesia and rigidity[32] but is less effective with
regard to tremor.[33]
 Placebo-controlled studies have confirmed improvement in all
of the cardinal manifestations of PD.[34,35] Benefit from
amantadine is transient in some patients,[36,37] with one third
of patients showing reduced benefit within 4 to 8 weeks of
initiation of treatment.[27] In some studies, however,
the benefit has been sustained for as long as 1 year.[32]
 Amantadine is best used as short-term monotherapy for a period
of 6 to 12 months in the treatment of patients with mild to
moderate parkinsonism. Response frequently correlates with
response to levodopa,[32] making it particularly suitable for
use before levodopa. If its effect wanes and other
antiparkinsonian medications are added, amantadine should be
discontinued to avoid unnecessary polypharmacy. Gradual
withdrawal is recommended to prevent acute exacerbation of
parkinsonian symptoms.
 Amantadine provides either modest or no significant additional
benefit when added to levodopa treatment.[29,38,39] Addition of
levodopa to amantadine treatment however, produces a significant
improvement.[38,40]
 Amantadine has a plasma half-life of 10 to 28.5 hours and can be
administered twice daily in dosages of 100 to 300 mg daily.
Larger dosages provide no additional benefit[41] and increase
the likelihood of adverse effects.
 This drug's major advantage is a low incidence of side effects
but, since it is excreted largely unchanged in the urine, it should
be used with caution in patients with renal failure. Peripheral
vascular side effects include livedo reticularis and ankle edema,
but these are rarely severe enough to limit treatment. Confusion,
hallucinations, insomnia, and nightmares can occur but are less
common in patients aged 60 years or less, and they are more likely to
occur when amantadine is used in combination with other
antiparkinsonian drugs. Dry mouth and blurred vision are
presumed to be peripheral anticholinergic side effects, but they
seem to occur more commonly when amantadine is given in
combination with anticholinergic drugs.
 In summary, amantadine is indicated for early treatment of PD in
patients 60 years of age or less who have mild akinesia and rigidity
and in whom tremor is not a major problem. Its therapeutic effects are
relatively mild and might be limited in duration, but its low
potential for side effects makes it particularly useful for
early administration.
 Patients >60 years of age. Amantadine may be used as early
monotherapy for patients over age 60 with the same guidelines
as for patients under aged 60 and under. Since the use of
anticholinergic drugs is discouraged in this age group
(discussion to follow), amantadine fills the need for a
mild antiparkinsonian drug with low risk for adverse cognitive
effects. Nonetheless, the risk for cognitive impairment with
amantadine use is greater at this age, and appropriate caution
should be exercised In patients older than 60 years of age, an
initial dose of 100 mg once daily should be administered for 1
week before increasing to 100 mg bid. Doses higher than 200 mg
daily are discouraged in this age group

ANTICHOLINERGIC DRUGS. A balanced interaction exists between
effects of dopamine and acetylcholine in the basal ganglia. In
PD, dopamine depletion results in a state of cholinergic
sensitivity, so that cholinergic drugs exacerbate and
anticholinergic drugs improve parkinsonian symptoms.[42]
Centrally acting anticholinergic drugs, such as trihexyphenidyl
and benztropine, continue to occupy a useful place in the
treatment of PD in the era of levodopa and dopamine
agonists.[30] Although some anticholinergic drugs (e.g.,
benztropine) might augment the dopamine effect by inhibiting
striatal presynaptic reuptake of dopamine, it is uncertain
whether or not this contributes significantly to their mechanism
of action.
 Patients <60 years of age. Anticholinergic drugs should be
considered for early monotherapy in patients 60 years
of age or younger. Patients with tremor-predominant parkinsonism
who are not significantly disturbed by akinesia are particularly
good candidates for this approach. In many early studies,
anticholinergic drugs were reported to be more effective for
tremor and rigidity than for akinesia. Although this
differential effect of anticholinergic drugs on specific
parkinsonian signs has never been adequately studied and is not
universally accepted,[43] contemporary clinical experience has
been that anticholinergic drugs are useful for resting tremor
but of little value in the treatment of akinesia or impaired
postural reflexes.[44]
 Trihexyphenidyl is the most widely used anticholinergic drug,
but little evidence suggests that one drug in this class is
superior to another in terms of either therapeutic efficacy
or side effects. Trihexyphenidyl is initiated at 0.5 to 1.0 mg
twice daily and increased gradually to a dosage of 2 to 3 mg
three times daily. Benztropine is given in dosages of 0.5 to
1.0 mg twice daily.
 As with amantadine, anticholinergic drugs should be
discontinued gradually to avoid acute exacerbation of
parkinsonism,[45] even in patients in whom clinical response
does not appear significant. Adverse side effects of
anticholinergic drugs are common and often limit their use,
irrespective of the patient's age. Peripheral antimuscarinic
effects include dry mouth, blurred vision, constipation, nausea,
urinary retention, impaired sweating, and tachycardia. Particular
caution should be exercised in the presence of prostatic
hypertrophy or closed-angle glaucoma. Mild peripheral effects,
such as dry mouth and blurred vision, often subside with continued
treatment and do not limit therapy. CNS effects-such as sedation,
dysphoric effects, memory impairment, acute confusion, and
hallucinations-are much more troublesome and usually require
discontinuation of medication.
 Both advanced age and dementia are risk factors for CNS toxicity;
therefore, the use of anticholinergic drugs should be limited to
patients aged 60 or younger. Even in patients without obvious
cognitive side effects, improvement in short-term and long-term
memory has been demonstrated after withdrawal of anticholinergic
drugs.[30]
 In summary, anticholinergic drugs are useful for the early
treatment of PD in patients 60 years of age or younger in
whom resting tremor is the predominant symptom. Because of the
high incidence of peripheral and CNS side effects associated
with these drugs, their use in patients without tremor and in
patients above age 60 or with dementia is not recommended.
 Patients >60 years of age. As discussed previously, the routine
administration of anticholinergic drugs to patients above age 60
is not recommended. Nevertheless, these agents might be useful
against specific symptoms in these patients, such as resting
tremor that has been resistant to other treatment. If sialorrhea
is to be treated with an anticholinergic drug in this
population, one which acts peripherally, such as propantheline,
should be considered to avoid CNS toxicity.

DOPAMINE AGONISTS. Dopamine agonists offer the theoretic
advantage of exerting a direct action on striatal dopamine
receptors, which does not require presynaptic uptake and
synaptic release by degenerating dopaminergic nerve terminals.
In addition, they do not require metabolic conversion to exert
their effects, and their absorption and transport into the brain
are not influenced by circulating plasma amino acids.
Traditionally, dopamine agonists have been developed and used
largely for the treatment of patients with declining response to
levodopa, motor fluctuations, dyskinesias, or other adverse
levodopa effects. The early use of dopamine agonists as a
levodopa-sparing strategy-to reduce or delay long-term levodopa
complications-recently has been suggested.[46]
 In a widely cited, uncontrolled, retrospective study, patients
treated with bromocriptine and levodopa showed equivalent
therapeutic benefit with fewer motor fluctuations and dyskinesias
than patients treated with levodopa alone.[47] A prospective trial
from the same center, comparing patients treated with lisuride,
lisuride plus levodopa, or levodopa also showed fewer fluctuations in
lisuride-treated patients than patients receiving levodopa
alone.[48] However, a double-blind, randomized, prospective
study of a small number of patients-comparing early combination
therapy with levodopa monotherapy-showed no significant
differences in frequency of long-term levodopa fluctuations
after 4 years of treatment.[49] Results of a similar but larger
prospective study comparing levodopa with combination therapy
have not yet been published.
 Despite the lack of definitive data on the comparative advantages
of levodopa and combination therapy,[50] the early use of dopamine
agonists is increasingly advocated as a levodopa-sparing strategy,
to delay or reduce the incidence and severity of long-term levodopa
fluctuations and dyskinesias,[51-52] and possibly to reduce oxidative
stress from free radicals generated by high-dose levodopa replacement
therapy.[53]
 Bromocriptine and pergolide are the only dopamine
agonists currently available for use in the United States.
Bromocriptine has both presynaptic and postsynaptic effects and
stimulates D2 receptors. It is started in low doses with close
monitoring for such side effects as hypotension, nausea,
vomiting, hallucinations, peripheral vasoconstriction, and
erythromelalgia. Bromocriptine is initiated at 1.25 mg daily and
titrated slowly, according to response, to a level of 10 to 25
mg daily. Some patients, however, might require dosages as high
as 50 to 75 mg daily. As bromocriptine is titrated upward, the
dosage of levodopa is usually lowered to reduce dopaminergic
toxicity.
 Pergolide does not have presynaptic effects and
stimulates both D1 and D2 receptors. It is more potent than
bromocriptine by a factor of 10 and has a longer duration of
action. It is initiated with 0.05 mg daily and titrated slowly
over several weeks to a dose of 2 to 3 mg daily. Further
increases in dosage might be considered, if needed, to a maximum
of 5 mg daily. Although pergolide's therapeutic efficacy is
similar to that of bromocriptine, pergolide may be beneficial
for some patients in whom bromocriptine therapy fails because it
does not produce a clinical response or cause intolerable side
effects.[54,55]
 Patients <60 years of age. Dopamine agonist monotherapy may be
considered for mild parkinsonian symptoms in patients aged 60 years
and below, but it produces suboptimal benefit in many patients.
Even when it is effective, its benefit might wane after several
months.[47-49,51] We therefore recommend that in most cases,
dopamine agonists be held in reserve until after initiation of
levodopa, when they can be used instead of increasing levodopa
dosages for management of increased parkinsonian disability.
[51,52,54] It is not yet known whether this approach will reduce
or delay the incidence of long-term levodopa fluctuations, but
the issue is expected to be resolved by studies currently in progress.
 Patients >60 years of age. The rationale for dopamine agonists in
patients over age 60 is similar to that for its use in younger
patients. The aim is to reduce cumulative exposure to levodopa and
thereby possibly reduce long-term side effects. Controversy remains,
however, as to whether cumulative levodopa exposure over the long
term has any adverse consequences. It is recommended that levodopa be
initiated first and that when the levodopa requirement exceeds
600 mg daily, a dopamine agonist be added according to the
regimen described previously.

LEVODOPA. Levodopa is the most effective drug available for the
treatment of early PD, and patients who fail to respond to it
are highly unlikely to respond to dopamine agonists.[52] Despite
a good initial response, however, approximately 50% of patients
experience motor fluctuations, such as "wearing-off" effect,
unpredictable "on-off" effects, dyskinesias, and dystonias
within 6 years of levodopa's initiation.
 Patients <60 years of age. The treatment of patients with
young-onset PD, who show earlier and more frequent appearance
of severe motor fluctuations and involuntary movements, is
particularly problematic with regard to the adverse effects of
long-term levodopa use.[56,57] Some practitioners have expressed the
concern that levodopa fluctuations and dyskinesias are related
more to the duration of levodopa treatment than to the duration
and severity of the disease,[56,58,59] Therefore, proponents of
this theory have recommended that levodopa treatment be withheld
until the appearance of significant limitations in activities of
daily living and job performance. Other clinicians, however,
contend that because no evidence proves that levodopa therapy is
directly responsible for these late effects, delay of treatment
unnecessarily deprives patients of improved function during the
early phase of the disease.[60] Despite this unresolved
controversy, most practitioners agree that treatment with
levodopa should be initiated when the disease markedly impairs
job performance or activities of daily living.[61]
 Another possibility is that the form of levodopa delivery plays a role
in the development of fluctuations and dyskinesias.[61] In
experimental animals, continuous and intermittent administration
of dopamine agonists exert different and frequently opposite
effects on dopamine-mediated behavior.[62] In several recent
studies, chronic, intermittent levodopa administration produced
greater dopamine-mediated behavioral supersensitivity than
continuous treatment, although this has not been confirmed by
all studies.[63,64]
 Some research has suggested that chronic intermittent therapy
is less physiologic than continuous treatment and might result
in postsynaptic changes that affect the response to levodopa
treatment.[64] These dopamine receptor changes might then cause
a narrowing of the therapeutic window and steepening of the
dose-response curve, resulting in a fluctuating levodopa
response.[65]
 Dopamine replacement treatments that provide stable stimulation
of dopamine receptors might possibly avoid the appearance of motor
fluctuations.[65,66] For this reason, the use of
sustained-release formulations of levodopa for initiation of
therapy has been advocated increasingly, although their ability
to produce predictably smooth plasma levodopa levels[66] and
prevent motor fluctuations has not been proven.[67] In Europe,
the sustained-release benserazide-levodopa formulation utilizes
the decarboxylase inhibitor benserazide rather than carbidopa.
The drug is sold under the trade name Madopar. One randomized,
double-blind study comparing sustained-release
benserazide-levodopa with standard benserazide-levodopa in a
relatively small number of patients showed fewer fluctuations
and dyskinesias in patients on the sustained-release preparation
2 years after treatment began.[68] More definitive information
on the potential advantage of the early use of sustained-release
carbidopa-levodopa should emerge froin an ongoing clinical
trial, in which patients are randomized to either immediate, or
sustained-release carbidopa-levodopa.[67]
 We typically introduce levodopa therapy in the form of sustained-release
carbidopa-levodopa in patients who are beginning to experience
significant disability in activities of daily living or
professional activities. Determination of what constitutes
significant disability must be made on a case-by-case basis.
Once this decision has been reached, the issue of dosage must be
addressed. No available prospective, controlled studies have
compared low-dose with higher-dose levodopa treatment, and
uncontrolled studies have yielded conflicting results regarding
the effect of dosage on incidence of fluctuations.[69,70]
 Experimental studies of alternate-day[71] and oral-pulse[72]
levodopa therapy in early FD have been carried out in an effort
to reduce total levodopa exposure. These approaches, however,
are of unproven long-term benefit arid expose the patient to the
potential adverse effects of intermittent rather than continuous
treatment, which might be less desirable.
 Sustained-release carbidopa-levodopa should be initiated at
25/100 mg or 50/200 mg twice daily given early morning and early
to midafternoon. If delayed onset of effect ("kick-in" time) and
lack of sufficient peak effect are problematic, then standard
carbidopa-levodopa may be introduced. A relatively low dose of
200 to 400 mg of levodopa should be maintained until progressively
disabling symptoms require an increase in dosage or dosing
frequency. When a daily dose of 500 to 800 mg of levodopa is reached, the
addition of a dopamine agonist is favored over further increases
in the levodopa dosage.
 Patients >60 years of age. The concern for long-term adverse
effects of levodopa are not as great for patients above age 60,
in whom the incidence and severity of motor fluctuations and
dyskinesias appears to be diminished.[57] Since anticholinergic
drugs are discouraged in patients older than age 60 and dopamine
agonist monotherapy is unlikely to be of sufficient long-term
benefit, carbidopa-levodopa is likely to be required earlier
in this age group. As in patients 60 years or younger,
sustained-release carbidopa-levodopa is recommended, but an early
trial with standard carbidopa-levodopa should be considered if
the response to the sustained-release preparation is suboptimal.
 The incidence of CNS side effects, such as hallucinations,
confusion, and psychosis, is higher among patients in this age
group, and appropriate caution should be exercised in determining
dosage and in combining carbidopa-levodopa with other medications
that exert CNS effects.

ADVANCING PARKINSON'S DISEASE

DYSAUTONOMIAS

CONSTIPATION. Pfeiffer and his colleagues have emphasized the
importance of considering two distinct processes responsible for
normal stool expulsion.[73-75] First, stool moves through the
colon by the sequential contraction of muscles within the
intestinal wall. Intrinsic enteric neurons regulate this
muscular activity. Second, parasympathetic afferent and efferent
fibers mediate the excitatory and inhibitory input to the colon.
 In patients with PD, Lewy bodies have been found within
degenerating colonic neurons (myenteric plexus); the primary
clinical correlate is slowed stool transit time related to
impaired colonic muscle contraction. In a second syndrome,
colonic transit time may or may not be normal, but the primary
abnormality is in defecation. Parkinsonian patients are unable
to straighten the anorectal angle on straining, accentuating its
flap valve action and resulting in an obstruction to the passage
of stool. It has been suggested that this paradoxical
contraction of the pelvic musculature is dystonic in nature and
correlates with the progression of PD. In support of this
argument, apomorphine has been shown to alleviate this
defecatory problem in some patients with PD.[76] Other disorders
associated with constipation in patients with PD include
megacolon and sigmoid volvulus.
 Management (breakout 4). Dietary modification aimed at
increasing bulk and softening the stool should be the first
strategy for constipation, and ultimately the most efficacious,
in patients with PD. They must be encouraged to drink at least
eight glasses of water each day. Low-fiber foods, such as many
breads and cakes need to be reduced, and bananas must be
eliminated from the diet. At least two meals per day should
include high-fiber raw vegetables. Carrots, cauliflower, and
broccoli are good choices. Oat bran as a hot cereal (Quaker Oats
bran) adds significant fiber to the diet, especially when
one-fourth to one-third cup is used in the morning. As a morning
meal, it reduces the amount of protein, adds bulk, and helps
stimulate the gastrocolic reflex.
 Increasing physical activity is also helpful. Although vigorous
exercise is not necessary, just doing a few pushups, situps, or
isometric exercises is not enough. Patients must be encouraged to
walk as much as several miles a day, if possible, or swim regularly.
 If stools remain hard despite the measures outlined above, stool
softeners such as docusate, given with each meal can be useful.
Lactulose, 10 to 20 g per day, may benefit some patients. Patients
are warned that the results with any method of softening stool will
not be immediate and that persistence with dietary and pharmacologic
measures is necessary.
 Since anticholinergic agents decrease bowel motility, stopping such
drugs can be useful for alleviating constipation, but this is often
at the price of increased parkinsonism. The next step is a trial of
cisapride (a cholinomimetic agent) which increases intestinal
motility.[77] Even at the usual dosage of 5 mg bid, it is important
to watch for occasional worsening of Parkinson's signs and symptoms.
Mild laxatives such as milk of magnesia or enemas should be a last
resort and used sparingly-perhaps no more than once a week as
part of an overall bowel regimen-but in some patients enemas may
be necessary. Apomorphine injection may provide enough benefit
to permit successful defecation.

URINARY PROBLEMS. The neuro-anatomic substrate for normal
voiding is widespread. The detrusor motor area in the frontal
lobes connects with a similar functional region in the
pontomesencephalic reticular formation. Input from the basal
ganglia to this cortico-mesencephalic loop depresses detrusor
contraction; hypothalamic input increases detrusor contraction.
Peripherally the detrusor is innervated via sacral
parasympathetic neurons, a pathway that is facilitated by
noradrenergic neurons in the locus ceruleus. Seemingly more
important for patients with PD, however, is the loss of
dopaminergic output from the substantia nigra, which appears to
increase detrusor hyperreflexia. Most patients with PD suffer
from detrusor hyperactivity. Relatively few have detrusor
hypoactivity or urethral sphincter dysfunction.
 Common symptoms in PD patients that result from detrusor
hyperactivity include urgency, frequency, and nocturia. Nocturia
is the most common and usually the earliest complaint, only much
later followed by daytime symptoms. In fact, if daytime frequency
or urgency occurs as an initial complaint, causes from mechanical outlet
obstructions, such as prostatic hypertrophy, must be considered.
 Management (breakout 5) Many patients can reduce nighttime
frequency by the simple expedient of reducing liquid intake in
the evening (no liquids after supper). If this nonpharmacologic
intervention is ineffective, peripherally acting
anticholinergics, such as oxybutynin or propantheline, can be
tried. Oxybutynin, 5 to 10 mg, can be administered at bedtime
only or on a tid basis. Propantheline, 7.5 to 15 mg, may also
work well at bedtime or on a tid schedule. If anticholinergics
prove ineffective, hyoscyamine, a parasympatholytic agent, may
work on a qid regimen or at night only (0.15 to 0.30 mg). A
trial of desmopressin, administered at night in escalating doses
(usually 10 to 20 micro g) as an intranasal spray, may work for
otherwise refractory cases.
 Anticholinergic agents, used in the treatment of detrusor
hyperactivity, reduce detrusor contractions, an effect that
may worsen voiding problems in patients with detrusor hypoactivity
or outlet obstruction. Detrusor hyporeflexia, producing incomplete
bladder emptying and urinary frequency, may respond to a reduction
in the dosage of an anticholinergic antiparkinsonian medication
when that is the cause. It is therefore essential that PD patients
with urinary dysfunction have urologic evaluations that include
recording of bladder and sphincter pressure, sphincter
electromyography, and fluoroscopy and that these tests be performed
only by a urologist familiar with their interpretation.
 When cystometric studies reveal a hypoactive detrusor, benefit
may be obtained from alpha adrenergic-blocking agents such as
phenoxybenzamine or prazosin, which decrease tone in the bladder neck.
Unfortunately, these agents can exacerbate or cause orthostatic
hypotension and cardiac arrhythmias and should be used with
caution in patients with PD. Drugs that relax striated
muscle--such as diazepam, baclofen, or dantrolene--can
ocasionally be effective when the external sphincter is
hyperreflexic. Intermittent catheterization is necessary with
myogenic overdystension. Any deterioration in voiding pattern
(even in the absence of dysuria) should raise the concern of
infection, which should be treated promptly.[78]

SEXUAL PROBLEMS. Little attention has been paid to the sexual
dysfunction common in patients with PD. Most treatment is aimed
at impotence in men, with virtually nothing being known about
the sexual function of women with PD. In men, the most common
problem is achieving or sustaining an erection.
 Management (breakout 6). Propranolol or other beta-adrenergic blockers,
sometimes used to control postural or action tremor in patients
with PD, are common offenders. Other possible problem drugs
include antihypertensives (alpha-adrenergic blockers such as
clonidine, methyldopa, and guanfacine). Guanethidine, although
less frequently used, is a potential offender, as are thiazide
diuretics, anxiolytics, digoxin, and cimetidine.
 Looking for depression is often rewarding; medical evaluation
is mandatory but rarely helpful. Although depression is a frequent
cause of sexual dysfunction, it is noteworthy that antidepressant drugs
(particularly the serotonin uptake inhibitors fluoxetine,
paroxetine, sertraline) can cause impotence. Tricyclics also
have been implicated as a less frequent cause of impotence.
Depressed patients should be treated with either tricyclic
antidepressants or serotonin uptake inhibitors, despite the
problems described above. Tricyclics (with anticholinergic
properties) have the added advantage of alleviating some of the
parkinsonian symptoms, but the best approach is to use the most
efficacious drug to lift depression in a given patient. Some
patients with anxiety- or stress-associated sexual dysfunction
benefit from low-dose anxiolytics.
 Endocrine function can be ascertained with serum levels of
prolactin testosterone, and luteinizing hormone and studies of
thyroid function. If no medical or psychologic reasons seem to
be causing impotence, one can try yohimbine, 5 mg tid for 1 month.
Further treatment, under consultation with an expert urologist,
can include local injection of phentolamine(an alpha-adrenergic
blocker) and papaverine. This combination provides a short-term
vasodilator effect by acting on smooth muscle. More invasive
approaches, such as implants, are less easily accepted by patients and
treating physicians. Previously untreated patients may find that
starting treatment with levodopa can help sexual dysfunction,
probably by alleviating bradykinesia and increasing desire. In
fact, some patients on high doses of antiparkinsonian agents
become hypersexual, even in the face of inability to perform.

ORTHOSTATIC HYPOTENSION. The anatomic site responsible for
orthostatic hypotension (OH) patients with PD are probably
heterogeneous, since no consistency in abnormalities has been
reported. Sympathetic efferent dysfunction in some patients can
be inferred from a failure to increase heart rate with falling
blood pressure and the lack of blood pressure overshoot with
Valsalva. Abnormalities of renin and inadequate increases in
serum norepinephrine on standing may be contributory factors. A
central autonomic defect may be involved, as suggested by an
increased pressor response to norepinephuine patients with PD.
The finding of Lewy bodies in the hypothalamus of these patients
support such an etiology in some. More likely in most patients
however, is a generalized sympathetic degeneration from Lewy
body disease causing cell loss in the sympathetic ganglia.[78]
 Management (breakout 7). OH, although not uncommon in patients
with PD, should be treated only in those who are symptomatic.
Levodopa or dopamine receptor agonists exacerbate OH, the latter
especially during the first weeks of treatment.
 Many patients who have been on antihypertensive drugs begin to
experience OH with progression of PD. They often can tolerate a
reduction in or cessation of their antihypertensive medications.
In those patients who are not taking antihypertensives, the first
step in treating OH should be the addition of salt and fluids to the
diet. Higher salt intake can be achieved by deliberately adding
salt to food at the table (as opposed to adding it in the
cooking process) so that other family members do not get
additional unnecessary salt. Salt tablets, up to 2 g per day,
are another alternative. Compressive stockings and behavior
modification should be used in conjunction with increased salt
and fluid intake. Knee-high stockings are less effective than
thigh-high ones, but the former are preferable because of
increased compliance. Practitioners can teach patients behavior
modification that reduces OH, such as getting up slowly and
sleeping with the head tilted.
 For parkinsonian patients with OH, fludrocortisone (a salt-retaining
steroid) can be started in doses of 0.1 rug per day and titrated
upwards in 0.1 mg increments up to 0.3 mg tid. Patients taking it
should be monitored for possible congestive heart failure and supine
hypertension, however Indomethacin, 25 mg tid is not as
effective as fludrocortisone but is more easily tolerated. It
probably works by inhibiting vasodilating prostaglandins.
Midodrine, 5 to 10 mg qid, is an investigational
alpha-adrenergic agonist that is particularly effective in some
patients. In evaluating patients with "dizziness" OH should be
distinguished from complaints caused by postural instability
visualmotor dysfunction, or multiple sensory deficits.[79]

THERMOREGULATION. The neurochemical and anatomic regulation of
temperature is complex and poorly understood. Preoptic and
hypothalamic areas appear to have thermoregulatory function.
Noradrenergic, serotonergic, and cholinergic systems have an
incompletely understood role in thermal homeostatais. Sweating
is mediated by efferent sympathetic cholinergic fibers, which
may be damaged in PD. Lewy bodies and cell loss in the
hypothalamus have been implicated in PD-associated sweating
abnormalities.
 Management (breakout 8). Abnormal sensations of heat or cold,
impaired sweating responses, and hypothermia all can occur in
the untreated patient. Excessive sweating of the head and neck
in response to external heat has been associated with poor heat
dissipation. Some of these phenomena disappear with levodopa
treatment, which suggests a role for central dopaminergic systems
in thermoregulation.[80] Severe drenching sweats occur as an
end-of-dose "off" phenomenon in patients with motor fluctuations,
further supporting a role for dopamine systems in vasomotor tone
and heat regulation. Dopamine agonist therapy may be of benefit to
such patients.
 Although peak-dose chorea can cause sweating, it is rarely if ever
as severe as that seen in the "off' state For patients who experience it,
however, a reduction in the dopaminergic medications may help
but often at the price of more "off" time. These patients are
more likely to respond to beta-adrenergic blockers than are
patients with "off"-period sweating.
 Severe hyperpyrexia after levodopa withdrawal resembles the
neureleptic malignant syndrome and needs to be treated promptly
with reinstitution of dopaminergic agents.
 Other causes of excessive sweating must not be neglected simply
because the patient has PD. Benign sweating can occur with either
a visual, olfactory or gustatory stimulus. Ethanol and aspirin in
high doses also can cause increased intermittent sweats. Therefore,
taking a thorough history usually will clarify these situations
Thyrotoxicosis and postmenopausal states need to be considered and
appropriate endocrine evaluation initiated. Finally, chronic
infections such as tuberculosis must not be forgotten in the
differential diagnosis.

PAIN. The mechanisms responsible for pain in PD are unclear and
probably not the same in all patients. It can be mediated via
peripheral somatic or autonomic afferent nerves. Selective
autonomic block, however, does not seem to reduce the pain in
PD, and signs of autonomic disturbance are not usually present.
Since many of these syndromes are associated with dystonia, one
possible site for the origin of PD-associated pain is afferent
nerve fibers within the dystonic muscles. A spinal cord or
cerebral origin for some pains is suggested by the
pseudoradicular pattern seen in some patients. Many pain
syndromes occur in the "off" state only, suggesting a role for
dopamine-containing cells in the diencephalon,[81] which
terminate on receptors in the dorsal horn and intermediolateral
column.[82,83] Sensory symptoms often appear neuritic in
character, including paresthesias, burning dysesthsisa, coldness
or numbness, and deep aching.[84] The legs are more often
involved than the arms; face and neck are rarely involved.[85]
Akathisia sometimes is present. Pain is often, but not always,
worse on the side of worse parkinsonism.[86]
 Management (breakout 9) Pain related to parkinsonism often responds to
adjustment of antiparkinsonian medications. Most often, it is
linked to levodopa "off" states or insufficient levodopa dosage;
thus, optimizing medications (as described later) can be
gratifying. Other causes for radicular pain and neuropathy need
to be evaluated when appropriate. Pain related to arthritis is
not uncommon in elderly patients with PD.[87]

DYSPHAGIA. Significant dysphagia in patients with PD is usually;
But not always, related to the severity of disease and occurs in
up to 40% of patients. direct involvement of oropharangeal
muscles is suggested by the observance that many patients suffer
severe dysphagia only when "off," a situation that improves
dramatically as soon as a dose of levodopa becomes effective
Swallowing abnormalities include abnormal lingual control and
inability to pass a bolus of food backward into the pharynx.
Silent aspiration with repetitive reflux of food from the
vallecula and pyriform sinuses into the oral cavity are a
significant problem. Retention of food and pills in the
vallecula are another contributory cause of erratic levodopa
absorption, and therefore, a secondary cause of dysphagia.
Esophageal dysmotility occurs in as many as 70% of patients but
also is present in a significant number of controls.[88,89]
 Management (breakout 10). Soft diets help most types of
dysphagia by making It easier to move food in the mouth and
esophagus. Soft food also decreases aspiration by reducing the
need for separate liquid intake, since liquids often cause more
aspiration than solids. Since dysphagia is usually decreased
dramatically during "on" times, the best strategy is to increase
"on" time with additional dopaminergic medications, if possible.
Increased "off" time, however; is not a realistic goal for many
patients. All patients should eat only during an "on" period.
Feeding gastrostomies or jejunostomies are a last resort and are
rarely necessary in patients with idiopathic PD; but when
needed, these procedures provide the benefit of allowing more
normal intake of food and medication.

SEBORRHEA. Excessive secretion of oil by sebaceous glands is
common in PD.
 Management (breakout 11) 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.[90,91] 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%).[92] Extrinsic factors are environmental elements that may
cause an individual to fall. Environmental factors account for
30 to 50% of falls in elderly individuals.[92]
 Falling is a significant problem in PD (breakout 12).[93-95] 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.[95] Mental
status changes, OH, dyskinesias, and age-related physical
changes are other possible factors.[96-100]

POSTURAL INSTABILITY. Postural instability often responds poorly
to drug therapy especially with advanced disease. Although
postural instability improves with the administration of
levodopa[94]--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.[101] 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,[102] may work for some patients. Having someone
rhythmically pull or push or passively elevate the patient's
knee also can help,[102] 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%.[103] At times, PD may be
accompanied by Alzheimer's disease, Cognitive impairment is an
independent risk factor for falls in the elderly.[90] 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.[90] If clinical signs and symptoms suggest any other
neurologic condition, a detailed workup should be performed.
Aging,[104] arthritis, physical inactivity and cardiac
disease[105] 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.[106] Decreased muscle strength in the lower limbs is
associated with falling[107,108] and mortality[109,110] 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.111 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.[90] The total number of medications used appears to
be directly related to the risk of falls.[111]

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.[112]
 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.[90] 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,[90,111] 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.[113] 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.[113] 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 (breakout 13) 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 (breakout 14).
 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;[114] 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 bromoctiptine 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[115] 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 (breakout 15).
 Substituting sustained-release caribidopa-levodopa for the
standard formulation typically will add 60 to 90 minutes to
the response duration.[116] 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.[116] 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[117]
or pergolide.[118] 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.[119] 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.[119] 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[115] 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.[120] 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.[120] 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 (breakout 16). Large neutral amino acid breakdown
products of dietary protein, which inhibit levodopa transport,[121]
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.[122]
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.[120]
 Liquid carbidopa-levodopa may allow more consistent and reliable
control of parkinsonism and is worth considering in patients with
erratic control of their condition.[7] 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 (breakout 17). 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.[123] 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[123]; 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).

DYSKINESIAS. Dyskinesias can be drug or disease-related. If they
include a prominent component of chorea, medications are
implicated. If they are exclusively dystonic, this could either
be caused by a disease-related condition or secondary to
medications. Thus, dyskinesias an more appropriately addressed
by separating them into those that are choreiform/choreodystonic
vs those that are exclusively dystonic.(breakout 18).

 Choreiform /choredystonic. Chorea in the context of PD is
invariably related to medications, Frequently, a prominent
dystonic component is seen in conjunction with the chorea; hence
the term, "choreodystonic."
 These choreodystonic dyskinesias occur in two patterns. The most
common form is seen at the time of peak levodopa effect and has
been termed "peak-dose dyskinesia" (or I-D-I response, a
shorthand for "improvement-dyskinesia-improvement").[124] The
first and most obvious approach to this problem is to modestly
lower the individual uses of carbidopa-levodopa (eg, 25-mg
decrements), Unfortunately, many patients have a very narrow
therapeutic window, and even a small levodopa decrement can
result in transition from a dyskinetic state to a relative "off"
state. In this circumstance, one may consider adding or
increasing a dopamine agonist medication (bromocriptine or
pergolide), which allows a slightly tighter titration of the
response. Patients who swing dramatically from severe dyskinesia
and who have a short-duration response to the "off" state may
find liquid carbidopa-levodopa to be a better option, with
benefits and drawbacks as described above.
 Choreodystonic dyskinesias are also seen in a second distinct pattern,
in which these adventitious movements occur just at the beginning and
again at the end of the levodopa response cycle. This has been
termed "diphasic dyskinesia" or D-I-D response, a shorthand for
"dyskinesia-improvement-dyskinesia").[124] This pattern is much
less common than peak-dose dyskinesia and is often difficult to
diagnose because the pattern may not he obvious, either to the
patient or the clinician, The end-of-dose period of dyskinesias
is typically more prolonged and troublesome than the initial
dyskinetic period of the levodopa cycle.
 Although this D-I-D pattern can be very difficult to treat, it may
respond to simple measures if the dyskinesias are relatively mild.
First, more frequent dosing of carbidopa-levodopa may allow a more
continuous "on" state without periodically cycling through the
dyskinetic phases. Obviously the timing of the doses should he
based on the carbidopa-levodopa response duration. In a similar
strategy to the one for treating "wearing-off" problems, a
sustained-release formulation of carbidopa-levodopa may be
substituted for the standard formulation, The addition of
dopamine agonist therapy close titration, using liquid
carbidopa-levodopa, may be options for some patients. Finally,
subcutaneous apomorphine may provide a route of escape from the
dyskinetic phase. The use of subcutaneous apomorphine (as
described before) allows time for the next dose of
carbidopa-levodopa to become clinically effective.
 Occasional patients experience severe choreodystonic dyskinesias
with a diphasic pattern, this can be very difficult to treat
effectively. The initial descriptions of this clinical
pattern[124] documented the failure of carbidopa-levodopa
dosages administered at short intervals around the clock to
effectively treat this problem. Although several
carbidopa-levodopa doses at short intervals can successfully
defer the end-of-dose dyskinetic period, this strategy fails
after approximately tour to five overlapping doses.[124] At this
point, patients typically begin to experience a sense of drug
intoxication and, furthermore, note a decreasing threshold for
dyskinesias with an inability to suppress them, despite even
larger doses of carbidopa-levodopa.
 For the diphasic dyskinesia pattern to become obvious, the levodopa
dose must be adequate; too low a dose will simply result in
dyskinesias, whereas a higher dose allows the full pattern to
develop[124] The usual dosages of carbidopa-levodopa used to treat
conventional parkinsonian motor problems are adequate for
demonstration of the diphasic dyskinesia pattern (ie, 100 to 250
mg of levodopa). Typically, it is the end-of-dose dyskinetic period
rather than the initial dyskinetic phase that is the more troublesome
and sustained. It tends to occur at a fairly well-defined portion of
the levodopa response cycle, usually 2 to 8 hours after a single
dose of carbidopa-levodopa. One treatment strategy is to overlap
four to five doses of carbidopa-levodopa at intervals that are
just long enough to preclude the development of the dyskinetic
phase at the end of each dosage cycle[124] After the last dose,
however, patients will cycle through the dyskinetic phase but at
a relatively predictable time. Thus, they can arrange to be at
home-and perhaps self administer a mild, short-acting
tranquilizer such as alprazolam--during the time the dyskinetic
period is expected.
 Once they have cycled through this dyskinetic period, patients
typically experience adequate control of their parkinsonian motor
symptoms for the remainder of the day, although control is not
quite as good as during the time of peak levodopa response. This
control typically continues overnight and into the next morning.
If left untreated, patients usually start to experience increasing
motor manifestations of parkinsonism by mid to late morning, at
which time they can again restart their levodopa cycle, taking
four to five overlapping doses. Thus, with this strategy patients
can attain good control of their parkinsonian symptoms for several midday
hours and adequate control during other portions of the day,
once they have cycled through their last dyskinetic period.
 An alternative strategy for treating the severe diphasic
choreodystonic dyskinesias is to switch the patient to dopamine
agonist monotherapy (bromocriptine or pergolide). The transition
can be difficult, as the dopamine agonist must be slowly
introduced and the carbidopa-levodopa dosages concomitantly
decreased. Eventually, as patients make the transition to
bromocriptine or pergolide alone, they often will find that
their parkinsonism is not as well controlled as with
carbidopa-levodopa. The dyskinetic periods may be absent or
substantially reduced in severity, however. To be effective, the
bromocriptine or pergolide doses usually need to be higher than
those employed when these drugs are used as adjunctive therapy
with carbidopa-levodopa. For monotherapy, the usual range is 30
to 60 mg of bromocriptine or 3.0 to 6.0 mg of pergolide as
monotherapy.
 Exacerbated by anxiety. Regardless of the type or pattern.
choreodystonic dyskinesias can be unmasked or worsened by anxiety-
provoking situations. If this is a frequent problem for the patient,
intervention directed at neuropsychiatric issues may be appropriate.
 Dystonic movements. Dystonia in the absence of chorea is common in PD
and can be caused by the disease process, per se, rather than a
medication effect. Dystonia is commonly related to drug action, however.
Prototypic is the isolated dystonic deviation of the toes or cramping of
the legs that occasionally occurs in undertreated patients.
Often, this will occur with other signs of undertreated
parkinsonism. In this case, the usual strategies for improving
PD motor control are appropriate.
 In certain patients, painful dystonia of the lower extremities is
particularly a problem upon awakening in the morning (early morning
foot dystonia), before the initial morning dose of carbidopa-levodopa
can take effect. One option is to administer a dose of CR
carbidopa-levodopa at bedtime. The effects may not be sufficiently
long-lasting to carry the patient to the following morning, however.
Administration of a dose of carbidopa-levodopa in the early
morning, before the patient is scheduled to rise from bed, can
be effective but requires the patient to set an alarm to awaken.
The addition of bromocriptine or pergolide, with their
longer-lasting effects, also may prove beneficial, particularly
if one of the doses is administered at bedtime.
 Some patients experience painful or uncomfortable dystonia at the
end of their levodopa response cycle. Several options are available, as
described in the section "Optimal peak response but "wearing
off." This is also one circumstance, apart from tremor, in which
an anticholinergic drug may be helpful. Lithium may be helpful
for painful "off"-period dystonia and can be tried when all
other methods have failed. Botulinum toxin injection can be used
to treat sustained focal dystonias of the foot. In some patients
dystonia may be secondary to their medications. If it is present
at the time of peak levodopa effect, a reduction in the
individual doses of carbidopa-levodopa should result in
resolution. If it occurs during the "off" period as a
"wearing-off" phenomenon, strategies can be employed to increase
"on"  time (see the section "Optimal response but wearing off").

NEUROPSYCHIATRIC PROBLEMS

 The neuropsychiatric manifestations of PD and of the
medications used to treat it can be ever more disabling than the
motoric dysfunction seen in this illness. In approaching the
management of this group of symptoms, it is important to keep in
mind that some of them, such as hallucinations, usually are
induced by medication, while others, such as depression and
"off"-period anxiety, typically are not directly related to
drugs. Still a third group of neuropsychiatric symptoms, most
notably memory loss, confusion, ant agitation occur independent
of medication in some patients but can be caused or exacerbated
by antiparkinsonian agents in others. Thus, in devising a
rational approach to the treatment of these behavioral
syndromes, a critical decision must be made as to whether to add
psychoactive medications, reduce the dosage of antiparkinsonian
agents, or do both.

COGNITIVE IMPAIRMENT. The incidence of dementia in patients with
PD has been variously estimated, but most studies place it in
the range of 15 to 20%[125,126] in a typical clinic population.
Its prevalence increases with disease duration and with
advancing age and contributes to mortality. In one recent
study,[125] dementia developed in 65% of patients with PD by the
time they reached 85 years of age. Memory loss is one of the
most noticeable manifestations of dementia in patients with
PD.[127] Some patients also manifest the phenomenon of
bradyphrenia a slowing of cognitive processes that is out of
proportion to their general level of cognitive function.[128]
Not only does primary dementia appear in patients with PO but
these individuals especially those over age 65, may also suffer
from other dementing illnesses, such as Alzheimer's disease or
multi-infarct dementia.
 Unlike drug-induced cognitive symptoms, those caused by PD itself
are not amenable to therapy (breakout 19). However, parkinsonian
patients with dementia are especially prone to experience further
memory loss or confusion when treated with antiparkinsonian drugs.
As I will discuss, reduction or cessation of these drugs is a valid
therapeutic option in this circumstance.
 Drug-induced cognitive impairment can take the form of impaired
memory or confusion. Memory deficit as a manifestation of
antiparkinsonian drugs is almost always caused by agents having
anticholinergic properties--most notably drugs such as trihexyphenidyl
or benztropine, but also agents such as amantadine and the tricyclic
antidepressants. This effect appears to be especially prominent in the
elderly, which suggests that the primary antiparkinsonian anticholinergic
drugs should be avoided in this group and that even these agents
with milder anticholinergic effects should he used with great
caution.
 The management of medication-induced memory deficit
consists of reducing or elimination the offending medication. In
patients who take more than one class of anticholinergic
preparation, the agent with the most potent anticholinergic
properties-the anticholinergic antiparkinsonian agents-should be
eliminated or reduced first, followed by the tricyclic
antidepressants and finally amantadine. A tricyclic
antidepressant such as amitriptyline occasionally can be
replaced with one with less anticholinergic potency, such as
nortriptyline, but just as often, total discontinuance of drugs
with any anticholinergic effect, however mild, is required.
 Confusion can be induced by anticholinergic medications and by
those which are dopaminergic, as well. Thus, selegiline, the
dopamine agonists (bromocriptine and pergolide), and
carbidopa-levodopa must be considered as potential causes of
this symptom. When confusion develops in a patient taking
several of these preparations, a decision must be made as to
which should be discontinued or reduced first. A reasonable
guideline is to discontinue first the agent that has the
greatest potential for causing confusion but has a relatively
smaller impact on the motoric symptoms of PD. In this approach,
the anticholinergic preparations should he the first to be
discontinued, followed by selegiline, tricyclic antidepressants,
amantadine, and then the dopamine agonists. If confusion
persists despite discontinuance of these preparations, or if the
patient has not been receiving any of them, the
carbidopa-levodopa dosage must then be reduced.
 In most patients with moderate to advanced PD, total discontinuance of
carbidopa-levodopa is not feasible because of the reemergence of
severely disabling motoric symptoms. Instead, a gradual downward
titration of dosage is recommended, aiming at an amount low
enough to relieve confusion but high enough to provide some
benefit for motor skills and ambulation. Unfortunately, in some
patients confusion is a direct consequence of the disease
process and no medication adjustment is adequate to reduce these
symptoms.

PSYCHOSIS. Psychosis in PD can take many forms[129] and is
almost always drug-induced. Two of the most common psychotic
manifestations are vivid dreams and hallucinations (breakout
20). The management of the former is handled in the "Sleep
disorders" algorithm. The latter is covered under a separate
heading in the "Neuropsychiatric problems" algorithm.

BEHAVIORAL IMPAIRMENT. Behavioral impairment in PD can take the
form of agitation, depression, anxiety, and panic attacks
(breakout 21).
 Agitation. Agitation can occur spontaneously in
PD or result from virtually any of the antiparkinsonian
medications.
 * Primary. The treatment of agitation, when it
occurs without relation to antiparkinsonian medication, involves
the administration of anxiolytic agents. The benzodiazepines,
especially alprazolam, are particularly useful. Diazepam and
lorazepam can he used for this purpose, as well. Buspirone, a
5-HTia serotonin agonist, is also an effective anxiolytic, but
because of its dopamine-blocking potential it probably should
not be the first agent used in a patient with PD.
 * Medication induced. When it appears that agitation is an adverse
effect of medication, adjunctive antiparkinsonian agents should be
discontinued in order of their potential to have caused this
syndrome. Selegiline, especially in a patient already receiving
levodopa, should be discontinued first, followed by amantadine,
dopamine agonists, and anticholinergic agents. It is worth
noting because of their profound effect on cognitive processes,
are the first to be discontinued when memory loss is the target
symptom but are among the last to be discontinued when agitation
is the problem. If none of these preparations is in use, or if
all have been discontinued without improvement in agitation,
then carbidopa-levodopa must be carefully titrated downward, in
hope of improving agitation without allowing the reemergence of
serious motor disability.; In addition to these measures, a
careful review should be made of other non-PD medications that
may have the potential to produce or enhance agitation.
 Certain patients who are receiving inadequate dosages of dopaminergic
medications or who are experiencing "wearing off" of the
levodopa effect become very anxious and might appear agitated.
This must be distinguished from primary agitation.
 Depression. Depression is extremely common in PD. In a recent study the
incidence of depression in PD was found to be 47%.[130] The
diagnosis of an affective disorder in PD can be difficult,
however, because many of the clinical manifestations of
depression--such as slowness, poor concentration, sleep
disturbance, and loss of energy--can be signs of PD itself.
Starkstein et al.[131] confirmed that motor retardation, loss of
energy, and early morning awakening were no more common in
nondepressed than depressed patients with PD. On the other hand,
depressive symptoms--such as worrying, brooding, loss of
interest, suicidal tendencies, social withdrawal, loss of
libido, and initial or middle insomnia--among others, were more
common in depressed than nondepressed patients.
 Having made a diagnosis of depression, it is important to recognize
that in some patients, mood changes occur in synchrony with motor
fluctuations, resulting in the patient's feeling depressed only
when he or she is in an "off" state.[132] In this circumstance,
management consists of techniques to reduce motor fluctuations
(see the "Motor problems" section of the algorithm). In
parkinsonian patients with sustained depression, a variety of
therapeutic approaches can be used. In some situations
counseling serves as an important adjunct to other therapies,
but a major depressive disorder usually requires pharmacologic
therapies, physiologic therapies, or both.
 The tricyclic antidepressant medications are a mainstay of
pharmacotherapy for these patients.[133] Amitriptyline is among the
least expensive of this class of agents. Its sedative properties
can be a distinct advantage when it is administered at bedtime to
patients with disturbed sleep. The anticholinergic and
orthostatic side effects of this drug, however, will often limit
its effectiveness or prevent its use, especially in elderly
patients or those with moderately severe PD. Nortriptyline is
often a better choice, given its lower anticholinergic potency.
An initial dose of 20 to 40 mg is appropriate, with the ultimate
dosage seldom exceeding 100 mg per day in the PD population.
While it is not as sedating as amitriptyline, nortriptyline is
still useful in encouraging sleep when given as a bedtime
dosage. The selective serotonin reuptake inhibitors--such as
fluoxetine, sertraline, and paroxetine also are employed frequently for treatment of depression in patients with PD. These agents are activating rather than sedating in their action, which might be desirable in certain
patients. The dosages for the treatment of depression in PD are
the same as those for non-PD-associated depression (eg, 20 mg
daily for fluoxetine). Some concern has been raised that the
symptoms of PD could worsen after fluoxetine treatment, but this
is not a common problem.[134] The potential does exist, however,
for an adverse interaction between selective serotonin reuptake
inhibitors and selegiline and concurrent use usually is
discouraged.[135]
 Electroconvulsive therapy (ECT) is another treatment modality
available for the therapy of depression in PD.[136] Typically,
ECT is considered either for severe depression that is unresponsive
to medical therapy or for temporary amelioration of severe
depressive symptoms during the 1- to 3-week latency before
antidepressant drugs take effect. A fringe benefit of this approach
is that transient improvement might occur in the motor signs of PD,
as well.[137]
 Anxiety and panic reactions. Like depression anxiety or
panic might appear predominantly during "off" periods in some patients
but in others can be present throughout the day, irrespective of
control of parkinsonian symptoms. Using DSM-III-R criteria, a
recent study found that 38% of PD patients manifested clinically
significant anxiety.[138] When anxiety occurs predominantly
during "off" periods, its intensity tends to parallel the
difference in motoric function between the "on" and "off"
states.[139] In patients who experience anxiety largely while
"off," therapeutic attention first should be directed to
improving fluctuations in motor performance before considering
pharmacologic intervention. In patients who suffer persistent
anxiety or whose fluctuations cannot be sufficiently controlled
to improve their "off"-period anxiety, anxiolytic drugs are
indicated. The most useful agents for this purpose are the
benzodiazepines, such as diazepam, alprazolam, and lorazepam.
Typical dosages for this purpose are 0.5 to 1 mg three times
daily for alprazolam or 2.5 to 5 mg four times daily for
diazepam. Still lower dosages are often required at the
initiation of therapy in the elderly.
 For patients who do not benefit from the benzodiazepines, imipramine
or buspirone can be considered, but it must be recognized that the
former agent can have undesirable side effects, such as confusion or
hypotension, and that the latter has mild dopamine-blocking
properties.
 Panic disorder consists of a severe state of anxiety that occurs
episodically and is characterized by a variety of psychologic, a
utonomic, and somatic symptoms. These include, among others,
breathlessness, nausea and vomiting, diaphoresis, dizziness, choking,
and the fear of dying or going insane. In occasional patients, such
symptoms coincide with their levodopa "off" states. For these
individuals, dosage adjustment of their antiparkinsonian drugs,
as described in the section, "Motor problems," is the appropriate
treatment. In other patients, treatment directed at panic disorder,
per se, is necessary. Benzodiazepines also may be useful in these
cases, but higher dosages may be required to achieve the desired result.
A specific benzodiazepine, clonazepam, may be especially useful in
panic disorder. Should these agents be ineffective, the
serotonin reuptake inhibitors can also be used to good
advantage. For refractory cases, ECT may be effective.

HALLUCINATIONS. Treatment related psychosis can cause severe
disability in a patient with PD. Both anticholinergic and
dopaminergic antiparkinsonian medications can induce psychotic
symptoms, such as paranoia and hallucinations (breakout 22).

 Medication-induced. When related to dopaminergic agents, this
complex of symptoms presumably results from stimulation of
mesolimbic dopamine receptors. It has been estimated that the
overall incidence of hallucinosis in levodopa-treated PD
patients is 20%.[129] In these patients, the earliest sign of
psychosis is often the appearance of restlessness, vivid dreams,
and nightmares. More advanced symptomatology consists of
hallucinations and paranoid ideation. With further progression,
a state of delirium can develop. Hallucinations that develop
under these circumstances are usually visual and more common at
night. They are typically nonthreatening and often involve
family members (alive or deceased) or nonferocious animals such
as cats or dogs.
 As is the case with other treatment-related neuropsychiatric side
effects, reduction or discontinuance of potentially causative
medications should be the first means of therapy starting with
those adjunctive agents that have relatively less efficacy in the
treatment of the motor symptoms of PD. Thus, selegiline or
amantadine should be the first agents to be discontinued, followed
by anticholinergic agents and then the dopamine agonists. Next, if
needed, carbidopa-levodopa should be titrated downward to the point
of improvement in psychotic symptomatology, but at the same time this
improvement must be balanced against the inevitable reemergence of
bradykinesia, rigidity, or tremor. If hallucinations are
predominantly nocturnal, an attempt should be made to remove or
reduce dosing of antiparkinsonian agents administered in the
late evening or at bedtime.
 When hallucinations persist despite the maximally tolerated reduction
of antiparkinsonian medication, pharmacologic antipsychotic therapy is
indicated. Neuroleptic agents are the most effective drugs for this
purpose, but most of these preparations--such as haloperidol,
perphenazine, or chlorpromazine--are potent dopamine blockers
whose potential for inducing parkinsonian symptoms limits their
usefulness. Low-potency neuroleptic agents, however, can be very
useful for treating hallucinosis in patients with PD. Three such
agents are thioridizine, molindone, and risporidone. These drugs
often can be used at low dosages (eg, 20 to 30 mg per day for
thioridizine or 0.5 to 1 mg per day for risporidone), with
little or no noticeable effect on parkinsonian symptoms but with
clear improvement in hallucinations. This approach is especially
useful for patients who have vivid dreams nightmares, or
nocturnal hallucinations, it whom the drug can be administered
late in the evening or at bedtime. It should be noted that among
these three low-potency neuroleptics, risperidone is relatively
new. Significant experience with its use in patients with PD has
not yet been accumulated.
 The most potent neuroleptic agent that can be used without fear of
worsening parkinsonian symptoms is clozapine.[141,142] This atypical
neuroleptic is a less potent blocker of striatal dopamine receptors
than other drugs in its class and it appears to be specific for the
subclass of dopamine-receptor mediated psychosis. The dosages required to
treat dopaminergic-induced hallucinosis are much lower than
those required in schizophrenia. A starting dose of 12.5 mg at
bedtime is appropriate. If upward titration is required in
patients with PD, the final dosage seldom exceeds 50 mg per day.
Even at these low dosages, side effects such as sedation and
hypotension are seen.
 One additional approach to the treatment of levodopa-induced
hallucinosis is the use of the serotonin antagonist ondansetron.[143]
Early experience indicates that this agent may be effective for this
purpose, but high cost may inhibit its use except under extreme
circumstances.
 Other medical conditions. If psychiatric symptoms in a patient with
PD are unrelated to antiparkinsonian medications or represent
activation of an underlying, preexistent psychotic disorder,
larger dosages of clozapine likely will be required. Additional
side effects may be seen with higher dosages, most notably
severe sialorrhea and the induction of seizures. The most
serious complication, agranulocytosis, is not dose-related and
occurs in approximately 2% of patients who receive this agent.

SLEEP DISORDERS

One of the most common problems for patients with moderate to
advanced PD is disruption of normal sleep patterns.[144-146] In
his initial monograph, James Parkinson recognized sleep
disturbance as an important component of paralysis agitans.[147]
While poor sleep is common in the elderly, patients with PD have
a unique set of difficulties that require accurate diagnosis and
often improve with correct intervention.
 The physiologic basis for disrupted sleep arises from three
neurotransmitter systems. Nigral dopamine cell loss causes poor
mobility, while dorsal raphe serotonergic cell loss and locus ceruleus
noradrenergic cell loss contribute to depression and sleep cycle
disruption.[148,149] (See the algorithm and the corresponding
text for specific symptom management.)

INSOMNIA. The first branch point of the sleep disorder portion
of the algorithm covers difficulty with sleep initiation and
sleep maintenance (breakout 23). Initiation and maintenance
problems may be primary sleep disorders or be associated with
dementia, secondary to PD mobility impairment or tremor, or may
result from medication-induced dyskinesia or depression.
 Idiopathic insomnia. Inability to fall asleep is common among
patients with PD. A diagnosis of idiopathic insomnia usually is
made clear by the initial description, although a diary can
provide useful information. Evaluation may include all-night
polysomnography (PSG) in select patients. Patients should he
asked about their ability to turn over in bed or adjust sheets
without assistance, frequency of nocturia, and occurrence of
nightmares. If the bed partner reports any unusual behaviors by
the patient (eg, semipurposeful actions, aggression, wandering),
PSG may reveal REM Behavior Disorder (RBD). This syndrome is
most frequent in older males with neurologic illness and may
result in injury to patient or spouse. Case reports of RBD and
PD are in the literature and in our clinical practice. RBD in
patients with PD may he treated with low-close clonazepam (0.25
to 1.0 mg nightly).
 Pharmacologic options for idiopathic insomnia are listed in table 1,
along with typical dosages. Long-term use of sedative hypnotics is
generally not good practice, as physical dependence and cognitive
side effects are common. Pharmacologic profiles and side effects of these
medications are discussed in a recent review.[151]
 Nocturnal PD symptoms. Attention should be directed first to any PD
symptoms or motor fluctuation.[152] Trouble getting comfortable or
turning in bed often is caused by underdosage of dopaminergic
medications or "wearing off" of their effects. One of the
long-acting levodopa preparations carbidopa-levodopa CR 50/200
or CR 25/100) at bedtime may be an appropriate treatment for
certain of these patients.[153] Alternatively, dopamine agonists
such as pergolide or bromocriptine may be employed. These
agents, because of their longer half-lives, also have the
advantage of reducing early morning dystonia.
 Occasionally, dyskinesias interfere with normal sleep. If such is
the case, bedtime dopaminergic dosages should be decreased. Physical aids
such as satin sheets for greater ease of movement and condom
catheters may he helpful.
 Medication-induced. If patients are taking selegiline twice daily,
the second dose should be given no later than noon. If that is already
the practice, consider elimination of the second dose or discontinuation
of the drug altogether. Insomnia is not uncommon with selegiline and this
may result from the amphetamine metabolites of the parent
compound. Amantadine may also produce insomnia because of its
stimulatory effects. Dosage reduction or drug discontinuation
should he considered.
 Dementia associated with PD. (See sleep-related problems within the
"Dementia" sections to follow.) Depression. Patients with insomnia
should be questioned about possible depression and, if indicated, a
treatment program initiated. Such a program may include increased daytime
activities, counseling, or antidepressant medications.  The
soporific effects of tricyclic agents often work to promote
sleep onset and sleep consolidation. Typical choices include
amitriptyline or nortriptyline at 10 to 25 mg at bedtime.
Maximum dosages are usually less than 100 mg, because of the
higher frequency of side effects in elderly patients.

----------------------------------------------------------------
Table 1. Medications used for the short-term treatment of
insomnia (dose at bedtime)

Diphenhydramine   25-75 mg

Chloral hydrate   250-750 mg

Tricyclic agents  10-100 mg

Temazepam         15-30 mg

Diazepam          1-5 mg

Clonazepam        0.5-1 mg

Zolpidem          10 mg

----------------------------------------------------------------
EXCESSIVE DAYTIME SLEEPINESS. Many factors contribute to
daytime sleepiness (breakout 24). For the person with PD,
several common problems emerge as outlined in the table 2.
 Depression. If untreated depression exists, then treatment with
an alerting antidepressant (eg, bupropion, 75 to 300 mg per day
in divided doses) or low bedtime doses of a tricyclic may help
to alleviate daytime sleepiness (see subsection on depression
under "Behavioral impairment" in the "Neuropsychiatric problems"
section). Often, depression in patients with PD lacks some of
the classic vegetative signs and may be mistaken as
bradykinesia. Psychologic assessment or an empiric trial of
medical therapy is warranted. Electroencephalography may reveal
reduced sleep latency in PD patients with depression.[154]
 Medication-induced. Perhaps the most simple form of daytime
sleepiness to address is medication-induced. Use of anxiolytics
or other sedating agents should be minimized during the day.
Levodopa-induced sleepiness is a well-characterized but uncommon
phenomenon. Patients with moderate to advanced stages of PD
sometimes describe the overwhelming urge to sleep as a dose of
levodopa takes effect. This may occur more often with
sustained-release carbidopa-levodopa. The mechanism for this
effect is unclear, although stimulation of dopamine receptors
may induce sleep at low levels.[155] Perhaps the more gradual
onset of the CR formulation is responsible for this phenomenon.
One occasionally can reduce this effect by switching from a CR
to a short-acting form of carbidopa-levodopa during the daytime.

----------------------------------------------------------------
Table 2. Causes of excessive daytime sleepiness
         associated with Parkinson's disease

         Drug-induced

         Levodopa
         Anxiotytics
         Antidepressants
         Selegiline-induced insomnia

         Primary steep disorder

         Obstructive sleep apnea
         Restless leg syndrome
         Periodic limb movements of sleep
         REM behavior disorder

         Endocrine dysfunction (eg hypoparathyroidism)

         Circadian cycle disruption with dementia
         PD, lack of zeitgebers

-----------------------------------------------------------------
 Dementia. Disruption of normal circadia rhythms occurs with the
dementia of PD when patients lose the normal environmental an
temporal clues, or "zeitgebers" about time passage.[156] This
problem is common in nursing homes and other institutional
settings. In all patients, sleep hygiene should be reviewed. For
some, restoration of consistent schedules (eg lights out, meals,
medication times, exposure to sunlight) is adequate for
normalizing circadian cycles.
 Idiopathic. Nighttime insomnia should be corrected if possible.
Other primary sleep disorders, such as obstructive sleep apnea[157]
or narcolepsy should be evaluated with appropriate PSG and mean sleep
latency testing studies. Treatment with methylphenidate, 5 to 10 mg
one to two times daily, or selegiline, 5 mg at morning and noon, can be
beneficial. Occasionally, caffeine (as coffee or tablets, 100 to
200 mg per day) produces increased alertness.
 Hypothyroidism and other metabolic causes for excessive daytime
sleepiness should he investigated,

NIGHTMARES. Nightmares can be induced by medications, a
precursor of dementia, or idiopathic (breakout 25).
 Medication induced. Dopaminergic medications frequently induce vivid
dreams. In fact, patients with PD often note a return of
previously absent dreaming shortly after initiation of
carbidopa-levodopa therapy. It is only after several years of
treatment, with higher dosages of levodopa, that vivid dreams
become problematic, Simple reductions in nighttime dopaminergic
drugs should alleviate the nightmares, Elimination or reduction
of tricyclic medications also can be beneficial. A distinction
between vivid dreams and RBD may be important in certain
patients, Manifestations of the former are reported by the
patient, whereas complaints relating to RBD typically are voiced
by the bed partner.
 Dementia, Increasing nightmares are harbingers of cognitive impairment
and possible daytime drug-induced psychosis. If optimal motor function
can only be obtained with dopaminergic dosages that produce psychosis,
treatment with low-dose clozapine may produce a striking
benefit.[158,159] This drug is associated with a 1 to 2% risk of
neutropenia (and death from overwhelming infection), Therefore,
weekly monitoring of the white blood count is mandatory.[160]
The dosage of clozapine is much lower than that used for
schizophrenia. Typically, 12.5 mg is prescribed nightly. The
maximum dose is 75 mg nightly but most patients do quite well in
the 12.5- to 25-mg range. Some patients require treatment only
three to four nights per week, The most common side effects
associated with clozapine are lethargy and hypotension, with the
former most often seen in patients with frank dementia.
Alternative antipsychotics can be employed. Those with the least
specific D2 receptor blockade produce less exacerbation of
parkinsonism. Molindone, 5 to 25 mg nightly, or thioridazine, 10
to 50 mg nightly has been used for many years to this end,
Little experience has been gained with the recently released
drug risperidone.
 Idiopathic. If aggressive behavior or wandering occurs during sleep
PSG may confirm RBD and appropriate treatment can be started, If RBD
is not present on PSG, then reduction of dopaminergic medications is
often necessary.

RESTLESS LEG SYNDROME AND PERIODIC LIMB MOVEMENTS OF SLEEP. This
primary sleep disorder has such high prevalence in the PD
population that all clinicians should be aware of its varied
manifestations.[161] Restless leg syndrome (RLS) consists of
uncomfortable sensations in the legs (eg parasthesias, aches
cramping, and an overwhelming need to move or walk). Symptoms
are at the worst in the evening or when the patient attempts to
rest, and they transiently improve while the patient is walking,
stretching, or exercising. RLS can be related to medications
being taken, a symptom of PD itself, or idiopathic (breakout
26).
 Medication-related. RLS seems distinct from akathisia,
which is most often related to underdosage or "wearing off" of
the levodopa effect.[162] If akathisia is suspected, then
adjustment of antiparkinsonian medications is appropriate.
Simply increasing carbidopa-levodopa doses at bedtime (the CR
forms are particularly useful) maybe beneficial. It remains
unclear whether or not PD-related leg restlessness should be
considered idiopathic RLS. Clozapine has been reported to reduce
akathisia.[163] Differential diagnosis also should include
nocturnal dyskinesia. This may be reduced by lowering bedtime
doses of dopaminergic medications.
 Idiopathic. Approximately 50% of patients with RLS have associated
periodic limb movements of sleep (PLMS).[161] Termed "nocturnal
myoclonus" in the past-perhaps inappropriately-this syndrome can be
so mild as to be detectable only with PSG or so severe that it forces bed
partners to sleep in separate rooms. The movements resemble
fragments of the triple flexion or Babinski reflex. They last
0.5 to 6 seconds and occur every 20 to 40 seconds. These
movements can profoundly disrupt normal sleep architecture and
produce insomnia and excessive daytime sleepiness. The dramatic
response to levodopa and dopaminometic medications implies
reduced dopamine activity in the brain or spiral cord. [164]
However, the specific neuronal systems involved have yet to be
determined.[165] Regardless, it is clear that patient symptoms
worsen with insufficient carbidopa-levodopa treatment and are
relieved with increased medication. In particular,
sustained-release carbidopa-levodopa can effectively halt RLS
symptoms and markedly reduce PLMS. Unfortunately, overflow of
RLS symptoms into the daytime is often a problem with levodopa
therapy and requires additional doses during the waking hours. A
long-acting dopamine agonist, such as pergolide, is an effective
alternative in many patients. Other treatment options include
low-dose clonazepam or opiates (eg, codeine, 30 to 60 mg
nightly). Tricyclic agents may exacerbate RLS and PLMS.
 For nocturnal symptoms, direct attention to any Parkinson's disease
symptoms or motor fluctuation. One of the long-acting levodopa
preparations at bedtime may be an appropriate. Alternatively
dopamine agonists may be employed.
 If dyskinesias interfere with normal sleep, bedtime dopaminergic
dosages should be decreased. If insomnia is medication-induced and
patients are taking selegiline twice daily, the second dose should be
given no later than noon. If this is already the practice, consider
elimination of the second dose or discontinuation of the drug altogether.
 Patients with insomnia should be questioned about possible
depression and, if indicated, a treatment program initiated.
 The most simple form of daytime sleepiness to address is
medication-induced. Use of anxiolytics or other sedating agents
should be minimized during the day. Patients with moderate to
advanced stages of Parkinson's disease may describe an
overwhelming urge to sleep as a dose of levodopa takes effect.
This effect can occasionally be reduced by switching from a CR
to a short-acting form of carbidopa-levodopa during the daytime.
 Disruption of normal circadian rhythms occurs with the dementia
of Parkinson's disease when patients lose the normal
environmental and temporal clues about time passage. For some,
restoration of consistent schedules is adequate for normalizing
circadian cycles.
 Nighttime insomnia should be corrected if possible. Other primary
sleep disorders should he evaluated with appropriate polysomnongraphy
and mean sleep latency testing studies. Treatment with methylphenidate
or selegiline can be beneficial. Occasionally caffeine produces
increased alertness.

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