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Response to Levodopa Treatment in Dopa-Responsive Dystonia
John G. Nutt, MD;
Torbjoern G. Nygaard, MD
Arch Neurol. 2001;58:905-910.
ABSTRACT
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Background Dopa-responsive dystonia (DRD) is similar to Parkinson disease in that
both disorders have impaired dopamine synthesis and respond to levodopa treatment.
Dopa-responsive dystonia differs in that dopamine storage is intact in contrast
to Parkinson disease in which it is markedly reduced.
Objective To examine the short- and long-duration responses to levodopa dosing
in subjects with DRD.
Methods The response to brief infusions of levodopa was examined in 4 subjects
with DRD and the effects of withdrawal of levodopa for 3 to 7 days studied
in the 3 subjects receiving long-term levodopa therapy. Motor function was
measured with tapping speed, Unified Parkinson's Disease Rating Scale motor
score, and global dystonia score.
Results The short-duration response to levodopa dosing seems to develop more
slowly and persists longer in subjects with DRD than in subjects with Parkinson
disease. Withdrawal of levodopa leads to a gradual decline in tapping speed
and reemergence of dystonia over several days, similar to the rate of decay
of motor function in Parkinson disease. The short- and long-duration responses
were not clearly differentiated in DRD.
Conclusions This pilot study suggests that retained dopamine storage in DRD may
prolong the short-duration response and blur the distinction of the short-
and long-duration responses. The decline in motor function in DRD on withdrawal
of long-term levodopa therapy resembles that in Parkinson disease, suggesting
that a long-duration response, if it exists in DRD, is unrelated to dopamine
storage.
INTRODUCTION
DOPA-RESPONSIVE dystonia (DRD) is generally an autosomal dominant disorder
manifest as dystonia and particularly in older patients, as parkinsonism.1 Most cases of DRD are related to a mutation in GTP
cyclohydrolase I, impairing the production of tetrahydrobiopterin, an essential
cofactor for tyrosine and tryptophan hydroxylases.2
Consequently, synthesis of dopamine is compromised in DRD3, 4
as it is idiopathic Parkinson disease (PD).5
Consistent with this neurochemical pathology, both DRD and PD respond to the
dopamine precursor levodopa.6
Dopamine storage is normal in DRD, as judged by positron emission tomographic
studies with fluorodopa and biochemical studies of markers for dopamine nerve
terminals.4, 7 In contrast, in
PD, dopamine storage and dopamine nerve terminals are reduced.8, 9
The importance of impaired dopamine storage to the response to exogenous levodopa
treatment in PD is unknown. Storage may influence the duration of the short-duration
response, an immediate response to levodopa dosing measured in hours.10 The "storage hypothesis" proposes that development
of motor fluctuations in PD is due to reduction in the duration of response
to each dose of levodopa caused by the progressive loss of dopamine nerve
terminals and dopamine storage capacity.11, 12
Storage of dopamine synthesized from exogenous levodopa treatment has
also been proposed to be the basis of the long-duration response.10, 13, 14 The long-duration
response is a therapeutic effect that builds up over days with repeated levodopa
dosing and likewise decays over days on cessation of levodopa treatment.10 Diminishing storage capacity could reduce the magnitude
of the long-duration response or speed its decline on stopping levodopa treatment.
This study examined the short- and long-duration responses to levodopa
treatment in subjects with DRD and, by comparison with the responses in subjects
with PD, to deduce how dopamine storage affects the motor response to exogenous
levodopa treatment.
SUBJECTS AND METHODS
SUBJECTS
Three subjects with DRD and 1 asymptomatic mutation carrier participated
in these studies after giving informed consent to a protocol approved by the
Oregon Health Sciences University institutional review board and the General
Clinical Research Center (GCRC) Advisory Committee, Portland. Subject 1 was
the proband in a previous report of DRD15 and
her family has been included in other studies of DRD.4, 7
Subject 2 had the DRD phenotype and a similarly affected daughter. Subjects
3 and 4 were third-degree relatives whose family has been included in previous
studies of DRD.1, 16, 17, 18
The subjects' clinical features are described in Table 1. Subject 3 had also participated in another study of the
effects of levodopa treatment withdrawal.13
Data from 18 subjects with PD who were studied after 1 year of long-term levodopa
therapy19 are included for comparison.
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Table 1. Characteristics of 4 Study Subjects*
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PROTOCOL
Three subjects were admitted to the Oregon Health Sciences University
GCRC for 6 days; the fourth subject was admitted for 38 hours on 2 occasions
separated by 1 week. Subjects received a 2-hour infusion of levodopa (1 mg/kg
per hour) with concomitant oral carbidopa on the first GCRC day and a second
infusion 4 to 8 days later. No levodopa was administered between the 2 infusions
(ie, a "levodopa holiday"). Bradykinesia was monitored by the speed of tapping
2 manual counters 20 cm apart20 at half to
hourly intervals throughout the waking day (7 AM-10 PM). The motor Unified
Parkinson's Disease Rating Scale21 and dystonia
were monitored by the investigators 3 times per day. This protocol is identical
to the protocol we have used to investigate the short- and long-duration responses
in PD.19
The baseline tapping rate was the mean of 2 or 3 determinations obtained
in the hour before each infusion. The latency of the short-duration response
to levodopa treatment was the time from the beginning of the infusion until
the tapping rate increased 10% over the baseline tapping rate. The duration
of response was the time that the tapping rate exceeded baseline by 10%. The
peak response was the mean of the 3 consecutive highest tapping scores. The
time to peak response was the time from the beginning of the infusion to the
first of the 3 consecutive highest tapping rates. A short-duration response
was considered absent if the tapping rate did not increase by 10%. The long-duration
response was considered the decrement in tapping speed from the baseline scores
(8-9 AM) prior to the first infusion of levodopa to the 8 to 9 AM scores on
the morning of the second infusion which marked the end of the levodopa holiday.
RESULTS
CLINICAL MANIFESTATIONS
Subjects 1 and 4 had mild parkinsonism as evidenced by the Unified Parkinson's
Disease Rating Scale motor scores and baseline tapping rates on the first
GCRC day that were 2.5 (subject 1) and 1.8 (subject 4) SDs below the average
tapping rate of age-matched normal control subjects.22
The Unified Parkinson's Disease Rating Scale motor score increased, tapping
rate declined, and dystonia appeared in subject 1 when levodopa was withdrawn
(Table 2). Subject 4 had never
previously received levodopa treatment and, therefore, the Unified Parkinson's
Disease Rating Scale motor score and tapping speed did not deteriorate during
the GCRC admission. She did not have dystonia (Table 2).
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Table 2. Effects of Levodopa Holiday*
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Subjects 2 and 3 primarily manifest dystonia that only became evident
with the withdrawal of levodopa treatment. The baseline tapping speeds in
subjects 2 and 3 were initially faster than average normal controls.22 Tapping speed deteriorated primarily in 1 hand in
each subject on the withdrawal of levodopa treatment, but improved in both
hands when levodopa treatment was restarted (Table 2). There was no clearly more-affected side in either subject
so the asymmetric deterioration in tapping could not be related to asymmetric
disease as commonly seen in idiopathic PD.
The averages of the 8 to 9 AM tapping rates in right and left hands
for each subject at the beginning of the levodopa holiday (mean, 151 taps
per minute), at the end of the levodopa holiday (138 taps per minute) and
the day after the second infusion of levodopa (161 taps per minute) (Table 2) were compared by analysis of variance
with repeated measures. The 3 days differed (P =
.02) with a statistically significant difference between the tapping rates
at the end of the levodopa holiday and the day after the holiday when the
administration of levodopa treatment had been restarted (P<.05, Student-Newman-Keuls test).
SHORT-DURATION RESPONSE
Following the first infusion, a short-duration response, defined as
a 10% or greater increase in tapping speed to a 2 mg/kg dose of levodopa administered
at a constant infusion rate over 2 hours, was only evident in subject 2. The
response magnitude (27 taps per minute) and response duration (2.0 hours)
in the right hand were very similar to the mean responses in patients with
idiopathic PD (Table 3).
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Table 3. Response to Infusions of Levodopa
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The second infusion of 2 mg/kg was administered when subjects 1 through
3 had been without levodopa treatment for 3 to 8 days. Levodopa-naive subject
4 was administered 2 mg/kg of levodopa as a 6-hour instead of a 2-hour infusion
because she experienced nausea and vomiting with the first infusion. Subjects
1, 2, and 4 had a measurable response to the second infusion of levodopa.
Subject 3 did not acutely respond to the second infusion but tapping was faster
the next day after an additional oral dose of 10 mg/100 mg carbidopa/levodopa,
respectively, was administered 9 hours after the infusion of levodopa (Figure 1).
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Tapping speeds in 4 subjects with dopa-responsive dystonia (DRD)
(upper 4 panels) and mean of 18 subjects with Parkinson disease (PD) (bottom
panel). Large arrows indicate the times of levodopa infusions; small arrows,
oral doses of levodopa. No levodopa treatment was administered between the
large arrows (ie, "levodopa holiday").
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The time course of the immediate (presumed to be a short-duration) response
seemed to be different in subjects with DRD compared with subjects with PD.
The peak effect was slightly delayed in subject 1 but persisted for 10.5 hours
when she received an oral dose of levodopa (Figure 1). Subject 2 had 4.5 hours of greater than 10% improvement
in tapping with the administration of levodopa that waned slightly in the
evening. The next morning with no further levodopa doses, tapping speed exceeded
the previous morning preinfusion baseline by more than 10% (Figure 1). Subject 3 had a brief improvement in dystonia, but no
improvement in tapping with the infusion of levodopa. It was not until the
next day and following an additional administration of 10 mg/100 mg carbidopa/levodopa,
respectively, dose in the evening that the improvement in tapping speed was
evident (Figure 1). Subject 4 had
no response to a 2-hour infusion on day 1, but 5 days later, the same amount
of levodopa administered over 6 hours produced a definite response that was
even larger the next day despite no additional administration of levodopa
(Figure 1).
For comparison, the mean response to an infusion of levodopa after a
3-day levodopa holiday in 18 subjects with PD receiving long-term levodopa
treatment for 1 year is shown in Figure 1. The response in subjects with PD differed in that there was a
rapid onset of the short-duration response and a rapid return to the preinfusion
baseline.
LONG-DURATION RESPONSE
The long-duration response is a deterioration in motor function that
appears over days on withdrawal of levodopa treatment in subjects with PD.
The 3 subjects receiving long-term levodopa therapy had a decline in tapping
speed and reemergence of dystonia over 3 to 8 days without levodopa. The temporal
pattern resembled the rate of deterioration of the long-duration response
in PD (Table 2 and Figure 1). Dystonia was primarily in the legs and did not account
for the deterioration in tapping speed. The fourth subject, who had not been
receiving long-term levodopa therapy, had no deterioration in tapping speed
during the GCRC admission suggesting that the slowing of tapping speed in
the other subjects was due to levodopa withdrawal.
DIURNAL MOTOR VARIATION
Subjects 1 through 3 reported diurnal variation or sleep benefit was
present prior to starting long-term therapy with levodopa and disappeared
during levodopa treatment. Diurnal variation reappeared in subjects 1 and
3, manifested by slowing in tapping and severity of dystonia at the end of
the day during levodopa withdrawal.
COMMENT
SHORTCOMINGS
It is first worth mentioning the shortcomings of this study. Only 4
subjects with varied clinical manifestations were studied. Clinical scoring
of dystonia was not done with a frequency to allow precise determination of
time course of this sign. Despite these problems, the patterns of response
to levodopa treatment in these 4 subjects were similar and allow tentative
conclusions about the levodopa responses in DRD. Finally, we assume that dopamine
storage is responsible for differences in levodopa responses between DRD and
PD; other factors could also be important.
SHORT-DURATION RESPONSE
Only in subject 2 did the first infusion of levodopa produce a clinically
apparent response. The lack of a response to a brief infusion in the other
3 subjects is consistent with the clinical impression that patients with DRD
do not have motor fluctuations despite prolonged treatment with levodopa.6, 13
The short-duration response to the second infusion in the subjects with
DRD differed from that of the subjects with PD in several ways. First, the
onset of the clinical response to the infusions of levodopa was delayed in
subjects 1, 3, and 4. In PD, the response to the infusions of levodopa is
generally prompt, and even in de novo subjects, appears within several hours
of beginning the infusion.19 However, the latency
to response to levodopa is shorter in fluctuating than in de novo and subjects
with stable PD,23, 24 an observation
that has been attributed to loss of dopamine storage capacity.24
This explanation would be consistent with our findings in subjects with DRD.
Development of supersensitivity in subjects with PD is an alternative explanation
for shortened latency in more severely affected patients.10
Second, the responses of subjects 3 and 4 suggest that in DRD the exposure
to levodopa must be longer for its clinical effects to develop. In subject
3, two doses of levodopa and a night's sleep abolished dystonia and reestablished
her normal tapping rate. In subject 4, the initial 2-mg/kg dose administered
as a 2-hour infusion had no effect but 4 days later, the same dose administered
over 6 hours produced an increase in tapping rate. The increase in tapping
was even greater the next morning, although she received no further levodopa
doses.
Third, the duration of the response to levodopa was prolonged in subjects
with DRD after the levodopa holiday. Twenty-four hours after the infusion
and with no further administration of oral levodopa, tapping speeds of subjects
2 and 4 had not returned to the baseline rates prior to the infusion. The
response in subject 1 lasted at least 10 hours after the second infusion.
This is in contrast to PD in which the subjects tapping speed generally returned
to the preinfusion baseline within 4 hours after the infusion.
Our results suggest that intact dopamine storage substantially alters
the short-duration response to exogenous levodopa treatment. This is consistent
with the clinical observations that subjects with DRD require small daily
doses of levodopa treatment and rarely develop motor fluctuations and dyskinesia,6, 25 adverse effects that eventually plague
most subjects with PD who respond to levodopa treatment.
LONG-DURATION RESPONSE
The long-duration response to levodopa treatment, a therapeutic action
that decays over days after withdrawal of long-term administered levodopa,
was apparent in the 3 subjects with DRD who were receiving long-term levodopa
therapy. In all, withdrawal of levodopa for 3 to 8 days caused the reemergence
of dystonia and slowing in tapping. The rate at which the clinical signs reappeared
was similar to the rate at which parkinsonism worsens on withdrawal of levodopa
in subjects with PD.19, 26 Our
results confirmed the results of Dewey et al13
who also found that dystonia reappeared 29 to 38 hours after withdrawal of
levodopa treatment in 3 subjects with DRD.
The mechanism underlying the long-duration response is unknown. One
hypothesis is that presynaptic dopamine storage is responsible.10, 27
If this were the case, one might expect that subjects with DRD with intact
storage would have a longer long-duration response than would subjects with
PD. However, our data and the study results of Dewey et al13
suggest that this is not the case. Also, the long-duration response was of
similar magnitude to that of subjects with PD—certainly not larger as
might be postulated if dopamine storage in remaining dopamine nerve terminals
was responsible for the long-duration response. These observations implicate
a postsynaptic origin for the long-duration response.
Other evidence favors a postsynaptic mechanism for the long-duration
response. Ropinirole, a D2 and D3 dopamine receptor agonist, can produce a
long-duration response in de novo subjects with PD.28
Apomorphine, a D1 and D2 dopamine receptor agonist, can sustain the long-duration
response in some subjects with advanced PD in whom levodopa treatment is withdrawn
for 3 or 4 days.29
SHORT-DURATION VS LONG-DURATION RESPONSES IN DRD
As must be apparent from the discussion above, the concept of a short-
and long-duration response in DRD is on less solid footing than in idiopathic
PD. In PD, the time courses of the short- and long-duration responses are
markedly different and a short infusion of levodopa does not restore the long-duration
response.26 The apparent persistence of the
short-duration response into the next day in at least 2 of our subjects with
DRD suggests that the motor deterioration with levodopa withdrawal could be
just loss of the short-duration response. That is, there is no long-duration
response in DRD; decline in motor function with levodopa withdrawal is the
wearing off of a prolonged short-duration response in DRD.
Alternatively, one could postulate that there is no short-duration response,
just a long-duration response. The slow buildup in the response to levodopa
treatment over 24 hours in our subjects with DRD could be superficially consistent
with this interpretation. However, development of a long-duration response
over 24 hours is much more rapid than what is observed in PD.14, 28, 30
DIURNAL MOTOR PATTERN
Diurnal motor patterns manifest by declining motor function during the
day and improvement by sleep were not apparent in subjects 1, 2, and 3 during
long-term levodopa therapy but reappeared in subjects 1 and 3 during the levodopa
holiday. This pattern is similar to, but generally more marked than, the diurnal
motor pattern seen in PD and identified as sleep benefit.31, 32, 33
It suggests that the diurnal motor pattern is a clinical marker of impaired
dopaminergic neurotransmission.
AUTHOR INFORMATION
Accepted for publication December 22, 2000.
This investigation was supported in part by grant R01 NS 21062 from
the National Institute of Neurological Disorders and Stroke, Bethesda, Md
(Dr Nutt), Clinical Research Center grant RR 000 334 from the National
Institutes of Health, Bethesda, and the National Parkinson Foundation, Miami,
Fla (Dr Nutt).
We thank the subjects for taking time out of their busy lives to participate
in a demanding protocol, the GCRC nurses for careful execution of the protocol,
Eric Lea for preparing the illustration, and Karen Landey for preparation
of the manuscript.
From the Departments of Neurology and Physiology and Pharmacology,
Oregon Health Sciences University, Portland (Dr Nutt); Department of Neurology,
East Orange Veterans Affairs Medical Center, East Orange, NJ (Dr Nygaard);
and the Department of Neurosciences, University of Medicine and Dentistry–New
Jersey Medical School, Newark, NJ (Dr Nygaard).
Corresponding author: John G. Nutt, MD, Department of Neurology,
OP 32, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland,
OR 97201-3098.
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