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--
 
 
 
John Cottingham         NEW ADDRESS:          [log in to unmask]