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
 
----Start of An Algorithm For The Management Of 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.
 
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.
 
 
John Cottingham         NEW ADDRESS:          [log in to unmask]