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.

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.

This has been termed "peak-dose dyskinesia" (or I-D-I response, a shorthand
for "improvement-dyskinesia-improvement").

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").

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 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. 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. 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.

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").


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. 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.

Medication-related.

RLS seems distinct from akathisia, which is most often related to
underdosage or "wearing off" of the levodopa effect. 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.
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). 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. However, the specific neuronal systems involved
have yet to be determined.

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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