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Benefits of monitoring plasma levodopa in Parkinson's disease patients with drug-induced chorea.

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Benefits of Monitoring Plasma
Levodopa in Padunson’s Disease Patients
with Drug-induced Chorea
Jacob I. Sage, MD, Margery H. Mark, MD, Denise M. McHale, MD, Patricia K. Sonsalla, PhD,
and Dawn Vitagliano, BA
We studied the temporal patterns of chorea and plasma levodopa profiles in 30 patients with Parkinson’s disease whose
motor fluctuations were difficult to characterize and treat on the basis of observation alone. We were able to determine
whether chorea was associated with high levodopa concentrations or low levodopa concentrations or both. We found
the following patterns of levodopa-associatedchorea: chorea due to inadequate levodopa levels, chorea due to biphasic
levodopa absorption, chorea associated with either rapid or slow levodopa absorption, and chorea due to long-duration
levodopa absorption mimicking a sustained-release preparation. Seven patients benefited after their dosing schedules
were rearranged as a result of information gained from monitoring. We conclude that any patient with levodopaassociated chorea who cannot be regulated on the basis of observation alone should be studied with simultaneous
plasma levodopa measurements and clinical monitoring to detect an unusual plasma levodopa pattern that may be
improved by adjustment of dosing schedule.
Sage JI, Mark MH, McHale DM, Sonsalla PK, Vitagliano D. Benefits of monitoring plasma levodopa in
Parkinson’s disease patients with drug-induced chorea. Ann Neurol 1991;29:623-628
The long-term use of levodopa (LD) and other agents
in patients with Parkinson’s disease (PD) has resulted
in an increasing number of patients with severe,
treatment-related motor fluctuations { 11. In this report,
we describe some of the difficulties inherent in the
clinical analysis of severe motor fluctuations, which
bear on the choice of treatment strategies, and demonstrate the practical usefulness of serial plasma LD measurements in treating these patients. We emphasize the
variability of LD absorption as a cause of motor fluctuations in patients with advanced PD.
The successful treatment of motor fluctuations in
parkinsonian patients on long-term LD therapy can be
a complex and elusive objective. Although patients
with end-ofdose wearing-off may respond well to
the addition of direct-acting dopamine receptor agonists, deprenyl, controlled-release LD (Sinemet CR;
Dupont-Merck Pharmaceuticals, Wilmington, DE), or
increasing the frequency of LD administration alone,
those fluctuators with complex or unpredictable patterns require judicious rearrangement of LD dose and
frequency. Because these patients depend on adequate
plasma LD levels for a symptomatic response, the aim
of therapy is to find a dosing schedule that achieves
plasma LD concentrations within a therapeutic range
and minimizes highs and lows {Z, 31.
For some patients with complex fluctuations, successful LD dosing schedules can be achieved by observation alone. The concomitant antiparkinsonian effect
of a given LD dose is usually sufficient to discriminate
dyskinesias associated with excessive levels of LD
from those related to low concentrations of LD. Wellrecognized patterns such as I-D-I (improvementdyslunesias-improvement) or D-I-D (dyskinesiasimprovement-dyskinesias) associated with the usual
plasma LD profiles of standard LD preparations generally provide adequate information on which to base
rational dosing changes {4}. In those patients with dystonia, recognizable dystonic patterns are also helpful in
adjusting LD dose and frequency {4, 53.
Unfortunately, a number of patients with complex
fluctuations do not have discernible patterns on clinical
grounds alone. A frequent problem is distinguishing
between D-I-D and I-D-I patterns of response, that is,
in discerning chorea related to low plasma LD concentrations from that related to high plasma LD concentrations. ‘‘Low dopa chorea” (LDC) is defined as chorea
that begins at a certain threshold plasma LD concentra-
From the Department of Neurology, University of Medicine and
Dentistry of New Jersey, Robert Wood Johnson Medical School,
New Brunswick, NJ.
Received Jul 25, 1990, and in revised form Oct 11 and Dec 14.
Accepted for publication Dec 16, 1990.
Address correspondence to Dr Sage, Department of Neurology,
UMDNJ-Robert Wood Johnson Medical School, CN-19, New
Brunswick, NJ 08903.
Copyright 0 1991 by the American Neurological Association
0 ’0
” , . , . , .
-2 hr
. ,
Fig 1. Patient 1. Relationship of Sinemet dose, plasma levodopu
(LO) concentration. and chorea. Afternoon chorea and dystonia
suggesting peak LD dose effec-t was actually a result of inadequate pkuma LD concentrations.
tion but then disappears above another higher threshold concentration. “High dopa chorea” ( H D C ) is defined as chorea that occurs above a specific threshold
plasma LD concentration, continues t o worsen as the
plasma LD increases, and disappears w h e n plasma LD
declines below a second (usually lower) threshold. We
will describe examples in which the clinical response
and t h e pharmacokinetics of standard LD preparations
were sufficiently unusual that serial measurements of
plasma LD, simultaneous with clinical examinations,
were required t o establish the correct pattern of chorea
and adjust cherapy appropriately.
Patients and Methods
Thirty patients with advanced PD and functionally limiting
chorea were studied. In none did the antiparkinsonian effect
of a given LD dose predictably correlate with the presence
or absence of chorea, and therefore, it could not be used to
differentiate H D C from LDC. Twenty of these patients also
had complex patterns of LD-associated dystonia as described
previously [5]. Characteristics of the patient population were
as follows: age, 64 11 years; duration of PD, 12 ? 5 years;
duration of Sinemet treatment, 10 ? 4 years; duration of
motor fluctuations, 5 k 4 years; LD dose (as Sinemet), 1,2 17
k 1,295 mg/day. Twenty-one patients were evaluated on
standard Sinemet alone, 3 patients were evaluated on Sinemet CR only, and 6 patients were evaluated on standard
Sinemet and subsequently on Sinemet CR. Previously, every
624 Annals of Neurology Vol 29 No 6 June 1991
TIME (hours)
4 4
2 hr
TIME (hours)
F i g 2. Patient 2. Relationship of Sinemet dose, plasma levodopa
(LO) concentration, and chorea. Chorea suggesting “high dopa
chorea” occurring approximately 1 hour after some doses of Sinemet was, in fact, “low dopa chorea” due to slow LD absorption.
effort had been made to reduce each patient’s chorea. These
efforts included rearrangement of Sinemet dose and frequency based on clinical observation and questioning, or
instituting or changing dopamine agonist (24 patients), anticholinergic (28 patients), amantadine hydrochloride (17 patients), or deprenyl(22 patients) therapy with adjustment of
concomitant LD dosage where appropriate. Patients were
rated for clinical features of parkinsonism using a modified
Unified Parkinson Disease Scale (0 = normal mobility, 116
= severe parkinsonism) and for chorea (0 = no chorea, 52
= severe chorea), although for the purposes of this study,
only the ratings for chorea are reported (Figs 1-5).
After informed consent was obtained, patients were followed in the neurology department observation unit from 9
AM to 5 PM for 1 to 4 days. Patients took Sinemet at the
usual dose and frequency, and most were rated approximately hourly for parkinsonism and chorea, although the
frequency of measurement was often tadored to individual
patients. Simultaneously, blood was drawn for plasma LD
determinations. Plasma LD levels were measured as previously described [5}. The thresholds and windows for H D C
and LDC were generated by inspection of curves representing clinical state and interpolation of the plasma LD profiles.
Numbers are reported as mean ? SD. When patients were
studied over multiple dosing cycles, data from all the dosing
cycles were used to generate the final means.
: : o
TIME (hours)
37.511 5 0
-1 hr
TIME (hours)
Fig 3. Patient 3. Relationship of Sinemet dose, pkzsma levodopa
(LO) concentration, and chorea. Constant chorea during each
LD dosing cycle suggesting a combination of “high dopa chorea”
(HDCi and “low dopa chorea” was actually HDC resulting
fmm long-duration suprathreshold LD concentrati0n.r.
Fig 4. Patient 4. Relationship of Sinemet dose. plasma levodopa
(LO) concentration, and chorea. Biphasic chorea associated with
pronounced freezing suggesting a dyskine.rias-im~rovementdyskinesia.i response was actually due t o a biphasic absorption
Twenty-seven patients on standard Sinemet preparations received the drug at a mean frequency of 2.9 5
0.8 hours (range, 2-5 hours). The time to peak plasma
LD concentration after a given dose was 0.9 2 0.6
hours (range, 0.25-2.5 hours). The time for plasma
LD concentration to return to baseline in the patients
for whom an exact time could be measured was 2.5
0.9 hours (range, 0.75-5 hours). For 9 patients on
Sinemet CR, mean frequency of dosing was 3.0 +- 0.7
hours (range, 2-4 hours). The time to peak plasma LD
concentration after a dose was 1.3 k 0.8 hours (range,
0.5-2.5 hours). The time for plasma LD to return to
baseline in the patients for whom an exact time could
be measured was 2.5 +- 0.8 hours (range, 1.5 to >4
hours). Eighteen patients exhibited HDC. The mean
plasma LD concentration above which H D C occurred
was 1.7 i 1.3 Fg/ml (range, 0.5-5 Fg/ml). Eleven
patients exhibited LDC. LDC occurred between
plasma LD concentrations of 1.2 -f- 1.1 pg/mi (range,
0.5-4 Fg/ml) and 2.0 2 1.2 Fg/ml (range, 1-5 Fg/
ml). One patient had both H D C and LDC. Both H D C
and LDC occurred regardless of whether plasma LD
concentrations were rising or falling and were depen-
dent only on the actual plasma LD levels. The thresholds for LDC and H D C are specific for individual
patients. The absolute plasma LD concentrations,
however, cannot be compared between patients.
Seven patients improved after their Sinemet dosing
schedules were rearranged as a direct result of information gained from monitoring. Three patients exhibited
LDC and 4 had HDC. Among these 7 patients, 5 specific patterns were recognized. For each pattern, an
example is presented of the clinical profile, initial impression, results of monitoring, and subsequent medication changes.
LDC: lmdequate Plasma Levodopa Concentration
PATIENT 1. O n standard Sinemet (50/500 mg) every
2 hours from 7 AM to 9 PM, fluctuations were characterized by good antiparkinsonian control for most of
the day but with limb chorea and facial dystonia in the
afternoons. Neither increasing the Sinemet interdose
interval to as much as 4 hours, nor decreasing the individual dose to as low as 25/100 mg, diminished the
chorea or dystonia. Facial dystonia and chorea occurring between 1 and 2 hours after a Sinemet dose
justified the initial impression that the symptoms were
Sage et al: L-Dopa in Drug-induced Chorea
dose and continuing until the next dose. Neither increasing the dose to 35/350 mg, decreasing the dose
to 20/200 mg, nor increasing the dosing frequency to
2 hours diminished the chorea. The fluctuation pattern
was compatible with LDC in combination with HDC.
Failure to reduce chorea by decreasing the dose to
201200 mg also supported this conclusion. Monitoring
revealed plasma LD concentrations that rose to a maximum within 30 minutes of the Sinemet dose and plateaued at this level for at least 4 hours (see Fig 3). The
Sinemet dose was therefore gradually reduced to 101
100 mg every 4 hours, which reduced the patient’s
chorea without adversely affecting “on” time.
TIME (hours)
Fig 5 . Patient 5 . Relationship of Sinemet dose, plasma levodopa
(LD) concentration, and chorea. Chorea occuwing within 10 t o
I5 minutes of some Sinemet doses snggesting “low dopa chorea”
actually resulted from vwy rapid absorption of LD.
related to peak dose effect. Plasma LD concentrations
in the afternoon were consistently low, reflecting poor
LD absorption (see Fig 1). Increasing the afternoon
Sinemet to an hourly schedule ameliorated both the
chorea and dystonia.
LDC: S l w Leyodopa Absorption
PATIENT 2. Standard Sinemet (25/250 mg) given every 3 hours produced chorea lasting about 1 hour beginning 1 hour after most doses. The timing of chorea
suggested HDC. Monitoring revealed a slow LD absorption pattern with a peak (plasma LD, 9.1 pg/ml)
at 2 hours (see Fig 2). The patient maintained relatively
high plasma LD concentrations by his second or third
dose of the day and required levels greater than 5 pg/
ml to be free of chorea. The patient increased the rate
of LD absorption to produce a peak concentration by
0.75 hours by crushing the tablet and suspending it in
water before swallowing it. He kept the dosing frequency the same, and his response was favorable.
H D C : Long-Duration Suprathreshold
LD Concentrations
PATIENT 3. On standard Sinemet (25/250 mg) every
4 hours from 9 AM until 9 PM, fluctuations were characterized by chorea beginning 30 minutes after each
626 Annals of Neurology Vol 29 No 6 June 1991
HDC: Biphasic Levodopa Absorption
PATIENT 4. Standard Sinemet (37.5/150 mg) given
every 3.5 hours produced severe chorea within 15 minutes, associated with pronounced freezing (start hesitation). Within 30 minutes, the chorea had subsided although it had not disappeared and the freezing was
gone. Both reappeared at maximum severity at 2.5
hours after the dose but again subsided within 30 minutes. A range of Sinemet doses between 10/100 and
20/200 mg did not alleviate the problem, nor did
shortening the interval between doses to as much as
every 2 hours. Freezing associated with chorea in a
biphasic pattern suggested a D-I-D response, which
justified the increase in Sinemet dose and frequency.
Monitoring revealed biphasic LD concentration peaks
at 0.25 and 2.5 hours, which corresponded to the periods of maximum chorea and paradoxical peak-dose
freezing (see Fig 4). The dose was reduced back to 101
100 mg,the smallest dose that allowed the patient to
achieve the “on” state, with some but not complete
abatement of dyskinesia and freezing.
H D C : Rapid Levodopa Absorption
PATIENT 5. Standard Sinemet (37.5/375 mg) at intervals of 2 to 3 hours produced severe chorea that
began within 10 to 15 minutes after some doses and
that decreased rapidly. At other times, chorea began
1.5 hours after the dose but also decreased rapidly.
The variable response was compatible with a peak dose
effect with occasional rapid absorption, a low dose effect with occasional episodes of slow absorption, or
some combination of both. Peak LD concentrations
occurred at variable times after each dose from less
than 15 minutes up to 1 hour (see Fig 5). In every
instance, chorea was associated with peak LD concentrations. Reducing the dose to 25/250 mg produced
amelioration of chorea with increased “off” time, but
the overall effect was preferred by the patient.
There is increasing evidence that fluctuations in LD
responsiveness in patients with Parkinson’s disease are
due both to postsynaptic changes (6-8) and to variations of drug delivery at the striatal dopamine receptor
{9-131. Experience with the patients reported here
provides further evidence that variable LD absorption
patterns are an important cause of motor fluctuations in
patients with advanced Parkinson’s disease [6}. Using
standard LD preparations, absorption to peak varies
from as little as 10 to 15 minutes to as much as 2.5 hours.
Therefore, although summing the absorption patterns
over many patients taking standard Sinemet produces
a fairly consistent mean time to peak C14, 15) of between 0.5 and 1.0 hour, the patient or physician will
have difficulty interpreting an individual pattern over
a manageable time interval. The use of controlledrelease LD preparations adds even more complexity to
the analysis. Given this chaotic situation, it becomes
extremely difficult to predict the correct patterns of
chorea in some of these patients if timing of chorea is
the major criterion for diagnosis. In other words, it
may become impossible to distinguish LDC from H D C
responses on clinical grounds alone.
Not only is there variability of temporal LD absorption patterns between patients, there is significant variability when multiple dosing cycles are studied in a
single patient on the same LD formulation. This chaotic picture is clarified by the operational definitions
of LDC and HDC. An individual patient’s observable
clinical response to LD (whether H D C or LDC) is relatively constant within the usual range of plasma LD
concentrations, that is, most patients consistently have
either H D C or LDC. Only 1 patient in this study had
both types of chorea. Therefore, in difficult cases, once
an individual patient’s type of chorea is established with
a plasma LD profile, physicians and patients can afterward make rational judgments about changes in LD
dosing and schedules based on clinical responses alone.
Regardless of the timing of chorea, patients will almost
always then be able to predict whether hyperkinetic
movements mean too much or too little LD and can
take or withhold medication as indicated.
It should be noted that the clinical situation described here is unusual because the timing of chorea is
not generally the major criterion for distinguishing
“on” or “off‘ state. In most patients, mobility is crucial
and that alone determines medication adjustments.
Furthermore, for many patients, chorea is not functionally disabling. In contrast to the more usual situation,
every patient described here had at least some periods
of chorea when “on,” which were an important disabling feature of the illness. The antiparkinsonian effect of a dose, therefore, could not be used to distinguish H D C from LDC. In many patients, patterns of
dystonia are also helpful in discerning H D C from
LDC. Foot dystonia is often associated with inadequate
LD concentrations, whereas facial dystonia occurs with
peak levels 116). Unfortunately, these patterns do not
always hold true in complex patients (5} and their association with chorea can sometimes lead to even more
difficulty in separating H D C from LDC.
Although LD-associated dyskinesias include both
chorea and dystonia, the present data support the suggestion that they be considered distinct from one another (17). Both H D C and LDC were related only to
individual plasma LD levels that presumably reflected
cisternal cerebrospinal fluid concentrations [IS}. An
expected but variable lag between plasma level and
clinical response is noted (19); this is demonstrated by
the observation that the second threshold seen in the
HDC pattern is often lower than the initial threshold.
Furthermore, LD-associated chorea is never seen at
plasma LD concentrations of zero. In contrast, dystonia
can be related to both plasma LD levels and to whether
the plasma LD concentration is rising or falling (51.
The most severe form of dystonia is seen at troughs as
LD concentration falls from a peak {5). Early morning
dystonia often occurs many hours after a patient’s last
LD dose, presumably reflecting minimal dopamine receptor stimulation in the advanced patient. These observations suggest that chorea is a pharmacologically
simpler phenomenon than dystonia, the former perhaps uniquely dependent on D,-receptor stimulation
C1, 20,2 1); whereas dystonia may depend on the more
complex interaction among Dl-, DZ- {21], or D,receptors [22, 233.
The present study emphasizes that the D-I-D temporal pattern is a somewhat misleading description in
patients who have severe fluctuations. In these patients,
the dyskinesia does not always precede improvement
in the parkinsonian symptoms and signs. When chorea
obviously precedes the antiparkinsonian effect of a
given dose, recognition of the D-I-D pattern is easy,
as noted here. Chorea and improvement may occur
together, however, or chorea may begin shortly after
the onset of the antiparkinsonian benefit, as in the patients with LDC described here. It is precisely because
dyskinesias do not always precede improvement in the
D-I-D pattern that it is difficult to distinguish I-D-I
from D-I-D responses in these patients. This may also
explain why the D-I-D pattern is believed to be so
much rarer than the present study suggests. Without
simultaneous plasma LD levels, the D-I-D pattern may
be confused with an I-D-I response. For this reason,
we prefer the designations LDC or H D C as more appropriate, both in describing the actual situation and in
indicating the direction of therapeutic intervention.
Our experience demonstrates that serial plasma LD
monitoring is a useful way to study some patients and
also help some patients reduce motor fluctuations. Unusual patterns such as inadequate LD levels, biphasic
LD absorption, chorea associated with either rapid or
slow LD absorption, and sustained LD absorption were
detected. Seven of 30 patients benefited as a result of
Sage et al: L-Dopa in Drug-induced Chorea
our ability to distinguish HDC from LDC. We conclude that any patient with PD and LD-associated chorea, who cannot adequately be regulated on the basis of
observation alone, should be studied with simultaneous
plasma LD measurements and clinical monitoring.
This paper was presented in part at the 115th Annual Meeting of
the American Neurological Association, Atlanta, GA, October 1990.
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