Download Levodopa/carbidopa for childhood amblyopia.

Levodopa/Carbidopa for Childhood Amblyopia
Lawrence E. Leguire,* Gary L. Rogers,* Don L. Bremer*
Philip D. Walson,^ and Mary Lou McGregor*
Purpose. To evaluate the efficacy and tolerance of two low doses of levodopa/carbidopa (25/
6.25 mg, 50/12.5 mg) and placebo (Turns) in 20 children with amblyopia between the ages of 4
and 14 years.
Methods. A double-masked placebo-controlled randomized 8-hour study was performed during which subjects received one of two doses of levodopa/carbidopa or placebo, combined
with occlusion of the dominant eye. Visual acuity was measured at baseline and at 1 and 5
hours after capsule ingestion. Tolerance was assessed by questionnaire and physical examination.
Results. Visual acuity significantly improved by one line, from an overall average of 20/121 to
20/96, in the amblyopic eyes of both groups that received levodopa/carbidopa. Visual acuity
did not significantly change in the placebo group. Tolerance was similar among all three
groups.
Conclusion. Average dose levels of 0.95/0.24 mg/kg and 1.94/0.49 mg/kg of levodopa/carbidopa were found to be well tolerated and efficacious at temporarily improving visual acuity in
amblyopic eyes of children. Invest Ophthalmol Vis Sci. 1993;34:3090-3095.
JYecently, Gottlob and Stangler-Zuschrott 1 found
that a 200 mg/50 mg dose of levodopa/benzerazide
temporarily improved contrast sensitivity and decreased scotoma size in the amblyopic eyes of nine
adults. Based on these initial findings, Leguire and
colleagues2 undertook a single-dose pilot study of the
effects of levodopa/carbidopa on visual function in
five children with amblyopia between the ages of 7 and
12 years and in two normal adults. Dose was dependent on body weight and averaged 4 mg/kg for the
amblyopic subjects. Leguire et al2 used several tests of
visual function including Snellen visual acuity, which
was measured at baseline and at 1 and 5 hours after
drug ingestion. The results revealed that 1 hour after
drug ingestion Snellen visual acuity in the amblyopic
eyes improved by about 50% from a mean of 20/159
to 20/83. Snellen visual acuity decreased to 20/103 5
hours after drug ingestion. Snellen visual acuity remainded stable in the normal subjects. Unfortunately,
three of five amblyopic children and one normal adult
experienced one or two episodes of transient nausea
and emesis as side effects.
Although the Snellen visual acuity results of the
pilot study were encouraging, the high prevalence of
nausea and emesis would preclude the study dose as an
initial therapeutic dose. The purpose of the current
study is to determine whether a much smaller dose of
levodopa/carbidopa, when combined with occlusion
therapy, could be used, which would improve visual
function yet minimize adverse side effects such as nausea and emesis.
METHODS
From the *Departmenl of Ophthalmology, and the f Division of Pharmacology/
Toxicology, Children's Hospital, Columbus, Ohio.
Supported in part, by the Knights Templar Eye Foundation, Inc., the Ohio Lion 's
Eye Research Foundation and Children's Hospital Research Foundation. Some of
these results were presented to the Association for Research in Vision and
Ophthalmology, Sarasota, FL, 1992.
Submitted for publication November 2, 1992; accepted March 24, 1993.
Proprietary interest category: N.
Reprint requests: Lawrence E. Leguire, Department of Ophthalmology, Children's
Hospital, 700 Children's Drive, Columbus, Ohio 43205
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Subjects
Twenty amblyopic children participated in the study.
Detailed subject information is listed in Table 1. Two
additional subjects were recruited for the study; however, because the subjects did not know the alphabet
they could not complete the visual acuity test at base-
Investigative Ophthalmology & Visual Science, October 1993, Vol. 34, No. 11
Copyright © Association for Research in Vision and Ophthalmology
Levodopa/Carbidopa for Childhood Amblyopia
TABLE l.
Subject No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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Detailed Subject Information
Age (yr)
Gender
6.85
14.92
9.70
6.50
10.67
4.67
12.25
5.75
6.50
9.00
12.92
5.85
9.85
7.85
8.33
8.50
5.42
13.20
10.25
6.92
F
F
F
F
F
F
M
F
M
M
F
M
F
M
M
F
M
F
M
M
Type of
Amblyopia
AA
SA
ASA
SA
AA
AA
SA
AA
DA
AA
SA
AA
AA
SA
AA
AA
ASA
ASA
SA
SA
Weight (kg)
25
55
27
23.6
22
15.9
66.1
20
20.9
22.9
52.3
24.8
30.2
23
23.4
26.4
17.1
48.9
45.2
24.1
AA: Anisometropic; SA: strabismic; ASA: anisometropic with strabismus; DA: deprivational.
line and were dropped from the study. The subjects
were considered either stable amblyopes (subjects who
did not respond to occlusion or penalization therapy
because of age) or difncult-to-treat amblyopes
(younger than 9 years but did not comply with occlusion or penalization). Because of concern and limited
available knowledge about the side effects and tolerance of levodopa/carbidopa in children, the number
of subjects in the current study was determined to be
the minimum required to reach statistical significance
(0.05) of a change in visual acuity. The tenets of the
Declaration of Helsinki were followed. The study protocol was approved by the Human Subjects Committee at Children's Hospital, Columbus, Ohio. Fully informed signed consent was obtained from at least one
parent and assent was obtained from each child before
the start of the study.
Design and Procedures
Each subject was instructed to have an empty stomach
when they arrived at the Eye Clinic at Children's Hospital, Columbus, Ohio at 8:00 AM; however, fruit juice
was allowed. In the current study we chose to measure
visual acuity because in a pilot study2 it was found that
levodopa/carbidopa had a greater effect on visual
acuity than on contrast sensitivity, pattern visual
evoked responses or stereoacuity. Following baseline
visual acuity (described later), the subject's dominant
eye was occluded throughout the study except for the
vision tests.
The subjects and parents were taken to the Clinical Study Center where a study nurse obtained base-
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line information including blood pressure, heart rate,
and respiration, and the subject was asked how he/she
felt. Some of the subjects volunteered for a pharmacokinetic portion of the study, which was undertaken as
previously described.2 However, the pharmacokinetic
profiles have not been undertaken to date and will be
reported elsewhere. After all baseline measures were
taken the subject was given a capsule to take by mouth
that contained one of two doses (25 mg or 50 mg) of
levodopa (Sinemet; Merck, Sharp and Dohme, West
Point, PA) with 25% carbidopa (6.25 mg or 12.5 mg,
respectively) or placebo (1/4 tab of Turns, [Smith
Kline Beecham, Philadelphia, PA]). The capsules were
filled and randomized by pharmacy department personnel thus masking all study/test personnel and all
subjects as to the contents of each capsule. For a few
of the youngest subjects the capsule had to be crushed
to be swallowed; however, because the placebo (Turns)
and levodopa/carbidopa were the same color the
crushing of the capsule did not unmask the study
nurse.
Tolerance information was collected at baseline
and every half hour for the first 3 hours after capsule
ingestion and every hour thereafter until the end of
the 8-hour study. Two hours after capsule ingestion
the subject was given a low-protein meal that typically
included clear soup, salad, fruit, fruit juice, and cake
or pie. At the end of the study the subject was required
to consume 8 ounces of Sustacal (Bristol-Myers
Squibb Co., Evansville, IN), a high protein drink,
which theoretically3 would reduce further uptake of
the levodopa/carbidopa into the brain. The next day a
study nurse called the family to check on any side effects experienced after the subject left the study
center. None were reported.
Visual Acuity
Visual acuity, as designated by log Snellen fraction,
was measured with full optical correction at baseline
and at one and five hours after capsule ingestion. Visual acuity was measured with three different Early
Treatment Diabetic Retinopathy Study (ETDRS)
acuity charts4 at a viewing distance of 6 m. The acuity
chart was illuminated by a Kodak carousel projector
and had a mean luminance of 216.7 cd/m2. A different
chart was used for each of the three test sessions under
forced choice conditions; therefore, memorization of
letters from test session to test session was not possible. The amblyopic eye was always tested first and thus
any changes evident in the amblyopic eye could not
have been attributable to letter memorization within a
session. Also, because all subjects were occluded
throughout the study, changes in acuity in the amblyopic eye between groups could not be attributable to
occlusion, per se. Each subject was required to read
each letter on each line until a majority of the letters
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Investigative Ophthalmology & Visual Science, October 1993, Vol. 34, No. 11
on a given line were missed. The examiner held the tip
of a yard stick below each letter to be read, and started
approximately two lines above the subject's previously
reported visual acuity level. In the event that the subject said that he could not see or identify the letter(s),
the subject was instructed to give his best guess. Such
forced choice procedures would minimize learning
and criterion shifts within and between test sessions.
In the event that the subject could not correctly
identify all the letters on the top line at the viewing
distance of 6 m, the chart was moved to a 3-m viewing
distance for testing the amblyopic eye. Four subjects
could not undertake the ETDRS acuity test because
they did not know the whole alphabet and, instead,
visual acuity was measured with the HOTV (Goodlite
Co., Forrest Park, IL) visual acuity test at a viewing
distance of 6 m under forced choice conditions.
RESULTS
Individual Visual Acuity Data
Figures 1A to 1C depict log Snellen fractions for the
dominant and amblyopic eyes for persons in the placebo (Fig. 1A), 25/6.25 mg (Fig. IB) and 50/12.5 mg
(Fig. 1C) levodopa/carbidopa groups. For persons in
all three groups, log Snellen fraction in the dominant
eye appeared very stable at about 0.0 (20/20) during
the three test trials. In the amblyopic eye, at baseline
(trial 1) there was a wide range of log Snellen fractions
for each group of subjects.
In all three groups, after capsule ingestion, subjects exhibited various amounts of decrease (improvement) in log Snellen fraction in the amblyopic eye between baseline and the two follow-up trials. In the placebo group, the greatest improvement in log Snellen
fraction, regardless of follow-up trial, was 0.15 (1.5
lines) and averaged 0.063 (SD = 0.073), which was not
significantly different from 0 (1 sample t = 2.13, df =
5, P > 0.05). One subject in the placebo group did not
exhibit a decrease in log Snellen fraction from baseline, in either follow-up trial, and had a minimum increase in log Snellen fraction of 0.06. In the 25/6.25
mg levodopa/carbidopa group, the greatest improvement in log Snellen fraction, regardless of follow-up
trial, was 0.24 (2.4 lines) and averaged 0.143 (SD =
0.079), which was significantly different from 0 (1 sample t = 4.42, df = 5, P < 0.01). In the 50/12.5 mg
levodopa/carbidopa group, the greatest improvement
in log Snellen fraction, regardless of follow-up trial,
was 0.38 (3.8 lines) and averaged 0.125 (SD = 0.124),
which was significantly different from 0 (1 sample t =
2.85, df = 7, P < 0.03). Therefore, when comparing
individual data among groups, there appears to be
some evidence of a dose-response relationship with
the largest improvement in the 50/12.5 mg levodopa/
carbidopa group and the smallest improvement in the
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A. PLACEBO
PLACEBO
Dominant Eya
Amblyoplo Eya
1.40
120 '
1.00
oeo '
0.6O '
0.40 '
020 '
0.00
B. 26/6.26 mg
»T
Time
3
Trial
26/6.25 mg
Dominant Eya
Amblyoplo Eya
1.00 •
1.40
0.80 •
120
0.60 •
1.00
0.40 •
oso
020 •
0.60
OXIO
0.40
•
-020 •
-0.40
sir
Time
3
Trial
«T Time
3 Trial
C. 50/12.5 mg
60/12.5 mg
Dominant Eya
Amblyoplo Eya
1.00
•
0.80
•
0.60
•
o
0.40
•
o
1.40
e
JO
120 •
1.00 '
OSO '
020 •
0X10
-O20
•
•
=
aeo'
W
0.40 •
O
-0.40
Time
Trial .
020 '
0.00
ST Time
3 Trial
FIGURE 1. Log Snellen fraction in the dominant (left) and
amblyopic (right) eyes is plotted as a function of trial number
and test time for individual subjects in the placebo (A), 25/
6.25 mg (B), and 50/12.5 mg (C) levodopa/carbidopa
groups. In each graph, a log Snellen fraction of 0.0 represents 20/20 Snellen visual acuity and 1.00 represents 20/
200 Snellen visual acuity. Different symbols have been used
to clarify each subject's change in log Snellen fraction over
time.
placebo group, with the 25/6.25 mg levodopa/carbidopa group falling between the two extremes.
Grouped Visual Acuity Data
Based on the results of the original pilot study2 we
predicted that each levodopa/carbidopa group would
exhibit an improvement in visual acuity in the amblyopic eye. Table 2 depicts the log Snellen fractions
(means and standard deviations) for the three groups
of subjects (placebo, 25/6.25 mg levodopa/carbidopa,
50/12.5 mg levodopa/carbidopa) at baseline and at 1
and 5 hours after capsule ingestion. Statistical probability levels are based on one- or two-tailed paired t
Levodopa/Carbidopa for Childhood Amblyopia
TABLE
3093
2. Grouped Visual Acuity Data
Placebo
25/6.25 mg
Baseline
1 hour
5 hours
.83 (.24)
.77 (.24)
.83 (.26)
50/12.5 mg
(n =•6)
(n = 6)
Ambly
Dom
Ambly
.03 (.21)
- . 0 1 (•21)
- . 0 1 (.22)
.89 (.14)
.81 (.13)
.79 (.16)*
All Levodopa/Carbidopa
Subjects 25/6.25 mg and
50/12.5 mg
(n = 8)
- . 0 5 (.15)
.01 (.17)§
- . 0 5 (.20)
(n = 14)
Ambly
Dom
Ambly
Dom
.69 (.27)
.64 (.29)*
.60 (.24)*
- . 0 4 (.15)
- . 0 6 (.15)
- . 0 8 (.16)
.78 (.24)
.71 (.24)f
.68 (.23)t
- . 0 5 (.14)
- . 0 3 (.15)
- . 0 7 (.17)
Dom
* P< .05
f P < .01
X P < .005
§ P < .02
tests, dependent on the predictions derived from the
pilot study. Note that the log Snellen fraction remained stable in the placebo group at about 0.83 (20/
135) in the amblyopic eye and about 0.0 (20/20) in the
dominant eye. In the 25/6.25 mg levodopa/carbidopa
group, log Snellen fraction in the amblyopic eye improved by 0.1 (one line), from 0.89 (20/155) to 0.79
(20/123) (paired t = 2.68, df = 5, 1 tailed P < 0.05) 5
hours after capsule ingestion. In the 50/12.5 mg levodopa/carbidopa group, log Snellen fraction improved
from 0.69 (20/98) to 0.64 (20/87) 1 hour after capsule ingestion (paired t = 2.12, df = 7, 1-tailed P <
0.05) and improved to 0.60 (20/80) 5 hours after capsule ingestion (paired t = 1.92, df = 7, 1-tailed P <
0.05). Therefore, in comparing the 25/6.25 mg and
50/12.5 mg groups it appears that a higher dose of
levodopa/carbidopa yielded a more rapid change in
visual acuity. When the subjects in the 25/6.25 mg and
50/12.5 mg levodopa/carbidopa groups were combined, the 14 subjects who received levodopa/carbidopa showed a significant improvement in log Snellen
fraction in the amblyopic eye from 0.78 (20/121) to
0.71 (20/103) at 1 hour (paired t = 2.85, df = 13,
1-tailed P < 0.01) and to 0.68 (20/96) at 5 hours
(paired t = 3.09, df = 13, 1-tailed P < 0.01) after
capsule ingestion.
The subjects who received levodopa/carbidopa
included five children with strabismic amblyopia and
seven children with anisometropic amblyopia (the
other two included a combined anisometropic/strabismic amblyope and a deprivational amblyope). The
children with strabismic amblyopia had a mean change
in log Snellen fraction of 0.08 and the ones with anisometropic amblyopia had a mean change in log Snellen
fraction of 0.16. Although the difference in change in
log Snellen fraction was not statistically significant,
there appears to be a clear trend toward the subjects
with anisometropic amblyopia having a greater improvement in log Snellen fraction with levodopa/carbidopa.
There was no significant correlation between the
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subject's age and maximum amount of change in log
Snellen fraction (R = 0.07) or between dose based on
body weight (mg/kg) and maximum amount of change
in log Snellen fraction (R = 0.23).
The log Snellen fraction in the dominant eye of
the subjects in the 50/12.5 mg levodopa/carbidopa
group remained stable at about — 0.05 (20/18). However, the dominant eye of the subjects in the 25/6.25
mg levodopa/carbidopa group exhibited a small but
significant increase in log Snellen fraction from — 0.05
(20/18) to 0.01 (20/20) 1 hour after capsule ingestion
(paired t = 3.48, P < 0.02). The increase in log Snellen
fraction was not present 5 hours after levodopa/carbidopa ingestion and was not evident in the combined
data.
Side Effects
Table 3 depicts the number and percentage of reported symptoms from the three groups of subjects.
The number and percentages are based on ten reporting periods multiplied by the number of subjects in the
respective group. Therefore, the maximum number of
reports would have been 60, 60, and 80 for the placebo, 25/6.25 mg, and 50/12.5 mg levodopa/carbidopa groups, respectively.
Overall, the number of symptoms appeared similar among the three groups. One subject in the 50/
12.5 mg levodopa/carbidopa group experienced two
TABLE
3. Symptoms: Total Number (%)
Placebo
(n = 6)
25/6.25 mg
(n = 6)
17(28%)
6 (9%)
3 (4%)
1 (1%)
Irritable
10(17%)
2 (3%)
2 (3%)
3 (5%)
Legs hurt
Cold
Tired/Sleepy
Dizzy
Nausea
Headache
Other
* With emesis (X2).
50/12.5 mg
(n = 8)
36 (45%)
1 (1%)*
Hot (X2)
Earache (X2)
Sore throat
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Investigative Ophthalmology & Visual Science, October 1993, Vol. 34, No. 11
transient episodes of nausea and emesis. This subject
received 2/0.5 mg/kg of levodopa/carbidopa while on
average the group received 1.94/0.49 mg/kg (range:
0.76/0.19 to 3.14/0.49 mg/kg). However, these findings are complicated in that the subject's mother continually asked the subject if she was going to get sick,
shortly after capsule ingestion and long before the
subject experienced any symptoms. (Nausea and vomiting are listed as a possible side effects on the consent
form.)
The most prevalent side effect reported in the
study was tiredness and sleepiness. This "side effect"
of the study was probably the result of the length of
the study. Most of the time the subjects and parents
were waiting for the next test session or examination
and they occupied their time by watching videotaped
movies in the Clinical Study Center.
The three groups of subjects had similar respiration, heart rate, and blood pressure at baseline and
throughout the study session. In addition, the one
subject who experienced nausea and emesis did not
demonstrate any noticeable change in blood pressure,
respiration, or heart rate associated with the emesis.
DISCUSSION
The current study revealed that 25/6.25 mg or 50/
12.5 mg of levodopa/carbidopa significantly improved visual acuity by one line, from 20/121 to 20/
96, in the amblyopic eyes of previously stable or difficult-to-treat children with amblyopia. Visual acuity did
not change significantly in a similar group of amblyopic subjects who received placebo. In the original
pilot study2 it was found that 100/25 mg to 200/50 mg
of levodopa/carbidopa, depending on body weight
and which averaged 4.0/1.0 mg/kg, improved visual
acuity by about 0.3 log Snellen fractions or about 3
lines on the ETDRS acuity charts. In the pilot study a
traditional Snellen visual acuity chart was used, with
unequal letter size changes between lines, and on that
chart there was a 1.5 line change in visual acuity.
Therefore, some caution is noted in comparing the
two studies. The combined results of the two studies,
however, are suggestive of a dose-response relationship between levodopa/carbidopa and visual acuity;
with a higher dose yielding a greater improvement in
visual acuity. Also suggestive of a dose-response relationship was the finding that the greatest individual
improvement in log Snellen fraction occurred in the
50/12.5 mg levodopa/carbidopa group (0.38), followed by 0.24 in the 25/6.25 mg levodopa/carbidopa
group and 0.15 in the placebo group. A significant
dose-response correlation was not found in the
current study probably because of the relatively small
difference in dose between levodopa/carbidopa
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groups and because of the small change in visual acuity
observed. The small change in visual acuity found with
levodopa/carbidopa, however, was by design: our major aim was to find a low dose of levodopa/carbidopa
that would minimize side effects yet reveal some improvement in vision.
The current study doses of 25/6.25 mg and 50/
12.5 mg reflect an average of 0.95/0.24 mg/kg and
1.94/0.49 mg/kg body weight, respectively. At these
average single-dose levels one of 14 subjects experienced nausea with emesis, and that subject had received 2.0/.5 mg/kg of levodopa/carbidopa. In the
original pilot study2 in which five amblyopic subjects
received an average 4.0/1.0 mg/kg of levodopa/carbidopa, three subjects experienced nausea with emesis.
Therefore, given the current results and those of the
pilot study, it would seem reasonable in future studies
to provide an upper limit in the initial dose of about
1.5/.38 mg/kg of levodopa/carbidopa to minimize
nausea with emesis and yet yield an improvement in
visual acuity. At the same time, however, it is important to note that the current and pilot studies were
performed on subjects with an empty stomach. As a
consequence, a higher initial dose could be considered
if the levodopa/carbidopa is taken after the ingestion
of food.
The emphasis of the current endeavor is to determine the feasibility of augmenting occlusion therapy
with levodopa/carbidopa. In this regard, in the
current study all subjects were occluded throughout
the 8-hour study. Because both the placebo and levodopa/carbidopa groups were occluded, the improvement in visual acuity seen in the levodopa/carbidopa
group could not be attributable to occlusion, per se.
The current results support the hypothesis that levodopa/carbidopa could be tolerated by children with
amblyopia and support the possibility that levodopa/
carbidopa could be used to augment occlusion
therapy.
One reason it may be important to study the augmentation of occlusion therapy with levodopa/carbidopa is patient compliance with occlusion. When occlusion is first implemented on a child with active amblyopia, the success of occlusion therapy is dependent
on compliance. And, from a clinical perspective, compliance depends on the child's initial visual acuity in
the amblyopic eye. Children with deep amblyopia, say
worse than 20/100, are less likely to comply with occlusion than children with mild amblyopia. When the
child with deep amblyopia has his dominant eye occluded, he does not have functional vision with the
amblyopic eye, finds it difficult to watch television,
play games, or do class work or homework. If levodopa/carbidopa can be used to improve visual acuity
such that functional vision can be achieved by the
Levodopa/Carbidopa for Childhood Amblyopia
amblyopic eye then compliance could be increased
and the success of occlusion therapy might be improved. Thus an avenue for future research would be
to undertake a systematic investigation into the influence of levodopa/carbidopa on occlusion compliance.
Finally, it is important to note that many of the
subjects in the current study were beyond the age
where occlusion therapy is effective in amblyopia.
Given that these older amblyopes also exhibited improved visual acuity with levodopa/carbidopa raises
the possibility that older children and even adults
could benefit from levodopa/carbidopa therapy. Indeed, preliminary evidence suggests that amblyopic
adults could exhibit an improved and maintained visual acuity in the amblyopic eye following one week of
levodopa therapy alone5. Likewise, our research
group has found preliminary evidence that 3 weeks of
part-time occlusion combined with levodopa/carbidopa can yield improved and maintained visual acuity
and contrast sensitivity in the amblyopic eyes of older
children (unpublished data). Overall, the improved visual function observed in amblyopic children26 and in
amblyopic adults15 with levodopa therapy is very encouraging and warrants further study.
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3095
Key Words
amblyopia, levodopa, strabismus, anisometropia, sinemet
References
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2. Leguire LE, Rogers GL, Bremer DL, Walson P, Neff
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3. Nutt JG, Woodward WR, Hammerstad JP, Carter JH,
Anderson JL. The "on-off" phenomenon in Parkinson's disease: relation to levodopa absorption and
transport. NEnglJMed. 1984;310:483-488.
4. Ferris FL, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. AmJ Ophthalmol. 1982;94:91-96.
5. Gottlob I, Charlier J, Reinecke RD. Visual acuities and
scotomas after one week of levodopa administration
in amblyopic patients. Invest Ophthalmol Vis Sci.
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6. Leguire LE, Rogers GL, Bremer DL, Walson P. Double masked placebo controlled randomized trial of levodopa for childhood amblyopia. Invest Ophthalmol
Vis Sci Suppl. 1992;33(suppl):742.