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A Randomized Trial of Atropine vs Patching for Treatment of Moderate Amblyopia in Children
The Pediatric Eye Disease Investigator Group
Arch Ophthalmol. 2002;120:268-278.
ABSTRACT
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Objective To compare patching and atropine as treatments for moderate amblyopia
in children younger than 7 years.
Methods In a randomized clinical trial, 419 children younger than 7 years with
amblyopia and visual acuity in the range of 20/40 to 20/100 were assigned
to receive either patching or atropine at 47 clinical sites.
Main Outcome Measure Visual acuity in the amblyopic eye and sound eye after 6 months.
Results Visual acuity in the amblyopic eye improved in both groups (improvement
from baseline to 6 months was 3.16 lines in the patching group and 2.84 lines
in the atropine group). Improvement was initially faster in the patching group,
but after 6 months, the difference in visual acuity between treatment groups
was small and clinically inconsequential (mean difference at 6 months, 0.034
logMAR units; 95% confidence interval, 0.005-0.064 logMAR units). The 6-month
acuity was 20/30 or better in the amblyopic eye and/or improved from baseline
by 3 or more lines in 79% of the patching group and 74% of the atropine group.
Both treatments were well tolerated, although atropine had a slightly higher
degree of acceptability on a parental questionnaire. More patients in the
atropine group than in the patching group had reduced acuity in the sound
eye at 6 months, but this did not persist with further follow-up.
Conclusion Atropine and patching produce improvement of similar magnitude, and
both are appropriate modalities for the initial treatment of moderate amblyopia
in children aged 3 to less than 7 years.
INTRODUCTION
AMBLYOPIA IS the most common cause of monocular visual impairment in
both children and young and middle-aged adults.1-3
Most cases are associated with strabismus, usually esotropia in infancy or
early childhood. Less frequently the cause is anisometropia (difference in
refractive error between the two eyes), a combination of strabismus and anisometropia,
or visual deprivation.4-5 About
25% of patients have a visual acuity in the amblyopic eye worse than 20/100,
and about 75% have an acuity of 20/100 or better.4, 6-8
Although some authors have reported benefits of treating amblyopia even in
adulthood,9-11
it is generally held that the response to treatment seems best when instituted
at an early age12-13 and is poor
after age 8 years.14-16
Occlusion therapy with patching of the sound eye has been the mainstay
of amblyopia treatment despite the lack of meaningful data demonstrating its
superiority compared with other modalities. Opinions vary on the number of
hours of patching per day that should be prescribed, ranging from a few hours
to all waking hours.17-18 Compliance
is often cited as a major problem because of patients' dislike of occlusion
owing to skin irritation and visual, social, and psychological reasons. Reported
rates of compliance range widely from 49% to 87%.4, 13, 18-25
Not unexpectedly, the success of occlusion therapy is reported to be dependent
on compliance.2, 26
Although less widely prescribed, pharmacologic penalization is an alternative
to occlusion therapy for amblyopia. This method involves the instillation
of a long-acting topical cycloplegic agent, such as atropine sulfate, into
the sound eye. The cycloplegia prevents accommodation, blurring the sound
eye at near fixation. When the sound eye is hyperopic, the penalization effect
is potentially augmented if less than full plus spectacle correction is prescribed
for the cyclopleged sound eye, effectively blurring its vision at both near
and distance fixation. Pharmacologic penaliza tion has generally been advocated
only for mild and moderate amblyopia (20/100 or better) because the blurring
effect on the sound eye may be insufficient when visual acuity in the amblyopic
eye is worse than 20/100.27-35
Clinical experience has found that pharmacologic penalization has a high acceptability
to patients and parents, and consequently high rates of compliance.33, 35
Despite the wealth of articles that have been written about amblyopia
therapy, the amount of meaningful data on the response to treatment is extremely
limited. In primarily retrospective studies, success rates (with varying definitions
of success) for treatment of moderate amblyopia in children have ranged from
about 40% to 90% for both patching and atropine.4, 13, 19, 26, 28, 31-33,35-44
Only a few studies have compared atropine and patching, all of which have
been either retrospective45 or, if prospective,
have had too small a sample size to provide meaningful data.34, 46
A treatment-related reduction in visual acuity in the sound eye has been reported
to occur rarely with both atropine and patching treatments and has usually
been reversible.28, 30, 32-35,44, 47-48
An unpublished survey of the Pediatric Eye Disease Investigator Group
conducted in 1997 found that for patients who met the eligibility criteria
for this trial, only 3% of the investigators prescribed atropine or some other
form of penalization therapy as their primary treatment modality, whereas
the other 97% prescribed patching. As a secondary treatment when patching
was unsuccessful, 41% prescribed penalization.
To determine optimal treatment for moderate amblyopia, we conducted
a randomized controlled clinical trial to assess whether treatment with atropine
drops was as effective as patching for this condition (20/40 to 20/100 in
the amblyopic eye) in children younger than 7 years who were able to complete
standardized optotype visual acuity testing.
PATIENTS AND METHODS
The study, supported through cooperative agreements with the National
Eye Institute of the National Institutes of Health (Bethesda, Md) was conducted
by the Pediatric Eye Disease Investigator Group at 47 clinical sites. The
protocol and informed consent forms were approved by institutional review
boards, and the parent or guardian (hereafter referred to as "parent") of
each study patient gave written informed consent. Study oversight was provided
by an independent data and safety monitoring committee.
PATIENT SELECTION
Eligibility testing included measurement of visual acuity in both eyes
using the Amblyopia Treatment Study visual acuity testing protocol (see "Examination
Procedures"), a cycloplegic refraction, an ocular examination, and an ocular
motility examination. Procedures were performed according to the investigator's
usual routine except for the visual acuity testing protocol. Visual acuity
testing was required to be performed within the 7 days prior to randomization;
the remainder of the examination could be completed within 2 months prior
to randomization.
Eligibility criteria for the trial included age younger than 7 years,
visual acuity in the amblyopic eye from 20/40 to 20/100, visual acuity in
the sound eye of 20/40 or better, intereye acuity difference of 3 or more
logMAR lines, the presence or history of an amblyogenic factor meeting study-specified
criteria for strabismus or anisometropia, and the wearing of optimal spectacle
correction for a minimum of 4 weeks at the time of enrollment (Table 1 has a complete list of the eligibility and exclusion criteria).
Details of the protocol for correction of refractive error have been published
previously.49
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Table 1. Eligibility and Exclusion Criteria*
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Based on a postrandomization review, 10 patients (3 in the patching
group and 7 in the atropine group) did not fully meet the visual acuity or
amblyogenic factor eligibility criterion: 1 patient had an amblyopic eye acuity
of 20/125, 4 had an intereye acuity difference less than 3 lines (1 of whom
had a 20/30 amblyopic eye acuity), and 5 were presumed to have amblyopia but
did not have a definite amblyogenic factor. These patients remained in the
study, and their data were included in the analyses.
SYNOPSIS OF STUDY DESIGN
After informed consent was obtained, each patient was randomly assigned
with equal probability to either the patching or atropine treatment group.
Randomization was accomplished on the study's Web site using a permuted-blocks
design of varying block sizes with a separate sequence of computer-generated
random numbers for each investigator.
Visual acuity in the amblyopic eye was the primary efficacy outcome
measure, and acuity in the sound eye was the primary safety outcome measure.
Protocol-specified follow-up visits were conducted after a period of 5 ±
2 weeks, 16 ± 2 weeks, and 26 ± 1 weeks (primary outcome). Additional
visits could be performed at the investigator's discretion. After the 6-month
outcome examination, patients continue to receive follow-up for an additional
18 months, during which there is no specific visit schedule except for the
requirement of at least 1 visit every 6 months.
TREATMENT PROTOCOLS
Both treatment groups followed a structured treatment protocol until
the 6-month outcome examination. Prior to this point, patients in the patching
group were not to be prescribed atropine, and patients in the atropine group
were not to be prescribed patching. A patient was considered to be successfully
treated with regard to the protocol when the amblyopic eye's visual acuity
was 20/30 or better or had improved 3 or more lines from baseline. If a treatment-related
decrease in the sound eye visual acuity (reverse amblyopia) was suspected,
treatment was at the investigator's discretion.
Patching Protocol
The patching protocol was designed to be similar to the investigator's
usual practice subject to the following stipulations: (1) the initial patching
time was a minimum of 6 hours per day (maximum, all waking hours); (2) assuming
that reverse amblyopia did not develop, this minimum remained in effect through
the 6-month outcome examination unless the criteria for successful treatment
were met; (3) if criteria for successful treatment were met, patching time
could be reduced but needed to be at least 7 hours per week as long as the
visual acuity in the amblyopic eye was 1 or more lines worse than that in
the sound eye; (4) if the visual acuity in the two eyes became equal, patching
could be discontinued; and (5) if criteria for successful treatment were not
met by the 16-week visit, and patching time had been less than 12 hours per
day, patching time was increased to 12 or more hours per day for 2 months
prior to the 6-month outcome examination. Adhesive skin patches provided by
the study (Coverlet Eye Occlusors; Beiersdorf-Jobst Inc, Rutherford College,
NC) were used unless there was skin allergy or irritation nonresponsive to
both local treatment with a skin emollient and a change in the brand of patch,
in which case a spectacle occluder could be prescribed.
Atropine Protocol
At enrollment, patients were prescribed 1 drop per day of atropine sulfate
1%, which was provided by the study. Sunglasses were also provided, with the
advice that they be worn with a hat when the child was in sunlight. Daily
atropine use was continued unless the visual acuity in the amblyopic eye met
criteria for successful treatment, in which case (at the investigator's discretion)
the frequency could be reduced to a minimum of 2 times a week and could be
discontinued if the acuities became equal in the two eyes. For patients with
hyperopia in the sound eye, if the amblyopic eye was not successfully treated
by the 16-week visit, the spectacle lens was reduced to plano for 2 months
prior to the 6-month outcome examination. If an allergy to atropine developed,
topical homatropine 5% could be substituted instead.
EXAMINATION PROCEDURES
At baseline and each protocol-specified visit, visual acuity was measured
in both eyes using the Amblyopia Treatment Study visual acuity testing protocol50 administered by a study-certified vision tester.
The test was administered either on the Baylor Video Acuity Tester or the
Electronic Visual Acuity Tester.51 The acuity
testing protocol consists of the presentation of single-surround HOTV optotypes
in 4 steps: a screening phase, followed by a first-threshold determination
(phase 1), reinforcement phase, and second-threshold determination (phase
2). In the screening phase, starting from either 20/100 or 20/400, a single
letter at each logMAR level is shown until one is missed. In phase 1, letters
are shown starting 2 logMAR levels above the missed level in screening to
determine the lowest level at which 3 of 3 or 3 of 4 letters are correctly
identified. In the reinforcement phase, to get the child with drifting attention
back on track, 3 larger letters are shown (but not scored) starting 2 levels
above the lowest correct level in phase 1. In phase 2, the child is given
a second chance on the last level missed in phase 1; if 3 of 3 or 3 of 4 are
correctly identified, the test continues at the next-smallest level until
a level is failed. When 2 letters are missed (of a maximum of 4 presentations),
testing stops. The visual acuity score is the lowest level passed in phase
1 or phase 2. Quality control measures for the visual acuity testing included
(1) a formal standardized training, certification, and recertification program;
(2) a calibration check of optotype size on the monitor prior to each masked
examination; and (3) a review of visual acuity testing score sheets at the
coordinating center to evaluate whether the protocol had been properly followed.
At the 5-week visit, a questionnaire designed to assess the effect of
amblyopia treatment on the child and parent (Amblyopia Treatment Index52) was completed by the parent. The questionnaire consists
of 18 items, each scored from 1 to 5, with 5 representing the most difficult.
Three subscales measured the adverse effects of treatment (8 items), difficulties
with compliance (5 items), and social stigma of treatment (3 items), with
internal consistency reliabilities of 0.86, 0.86, and 0.76, respectively.
Items were summed to compute each subscale score, then scaled to a common
range from 1 to 5.
At the 6-month outcome examination, visual acuity testing of the amblyopic
eye was conducted by a tester masked to the patient's treatment group. To
conceal the treatment group assignment, a patch was placed over the sound
eye by site staff prior to the examination to avoid unmasking either from
a dilated pupil due to atropine or from skin changes due to patching. For
patients receiving daily treatment, treatment was continued until the day
prior to the testing of the amblyopic eye's visual acuity. Outcome examination
testing also included the measurement of visual acuity in the sound eye and
assessment of ocular alignment using a simultaneous prism and cover test at
distance and near fixation. For patients in the patching group, this testing
typically was done on the same day as the amblyopic eye visual acuity testing,
whereas for patients in the atropine group, testing was performed at a second
visit after atropine had been discontinued for 7 days.
ADHERENCE TO THE TREATMENT PROTOCOL
Adherence to the treatment protocol by the patient was assessed by having
the parent maintain a calendar on which the treatment received each day was
logged. The calendars were reviewed at follow-up visits, and at each visit
the investigator made an assessment of the patient's adherence to the prescribed
treatment (excellent, 76%-100% of prescribed treatment completed; good, 51%-75%;
fair, 26%-50%; and poor, 25% or less). An average compliance score was computed
for each patient from the adherence assessment made at each visit while a
patient was on treatment (assigning a value of 4 for excellent, 3 for good,
2 for fair, and 1 for poor). The average scores were then used to categorize
each patient's adherence as excellent (>3.50), good (2.51-3.50), fair (1.51-2.50),
or poor ( 1.50).
At the coordinating center, each follow-up examination form was reviewed
to assess whether the investigator was properly prescribing the treatment
protocol, and feedback was provided to the investigator as indicated.
ADVERSE REACTIONS
At each study visit, the parent was asked about specific adverse effects
of treatment. For the patching group, this related to skin irritation. For
the atropine group, information was elicited at each visit on the development
of local adverse effects, such as ocular irritation, and systemic adverse
effects, such as dry skin and mouth, tachycardia, fever, flushing, and irritability.
Visual acuity in the sound eye at 6 months was the primary safety outcome.
For patients whose sound eye acuity was reduced from baseline (acuity<20/20
and decreased by 1 or more lines from baseline), subsequent follow-up data
were used to evaluate whether the decrease represented a real and/or permanent
reduction.
STATISTICAL METHODS
The sample size was based on whether the visual improvement at 6 months
with atropine was equivalent to that with patching. The equivalence limit,
which represents the end of the 95% confidence interval (CI) for the difference
in mean visual acuity between groups, was set to be 0.1 logMAR unit (a difference
of 0.1 logMAR unit is equivalent to 1 line of acuity). Monte Carlo simulations,
based on projected scenarios for the data, were used to establish a sample
size of 400 such that there would be at least 80% power, with an  level
of .05 for assessments of the treatment group differences in each of 3 subgroups
based on cause of amblyopia (strabismus, anisometropia, and combined-mechanism).
With this sample size, the power for the primary overall analysis was 99%.
The primary outcome was the 6-month amblyopic eye visual acuity score
in logMAR units. The treatment groups were compared in an analysis-of-covariance
model in which the logMAR acuity scores were adjusted for baseline acuity.
Patients were included in the primary analysis if they had a visual acuity
measurement in the amblyopic eye within the time window of the 6-month visit
or, in the absence of such a visit, if they had a visual acuity measurement
that was no more than 1 month before or 3 months after this window. Two additional
analyses were conducted on the 6-month amblyopic eye logMAR acuity scores:
one analysis included only patients who had an examination within the 6-month
window, and the other analysis included all patients using the method of last
observation carried forward to impute for missing data (for patients missing
the outcome examination, the visual acuity recorded at the last follow-up
examination was used; for patients with no follow-up, the baseline acuity
was used). Results of these 2 analyses were similar to the primary analysis
(data not shown). Interaction between baseline factors (cause of amblyopia,
age, and amblyopic eye acuity) and treatment group on the outcome acuity was
assessed by including interaction terms in the analysis-of-covariance models.
Methods used to analyze the amblyopic eye logMAR acuity scores at the 5-week
and 16-week visits paralleled the analysis conducted on the 6-month data.
Within treatment groups, the change in visual acuity from baseline was reported
in lines. Treatment group comparisons were reported as differences in logMAR
acuity.
A prespecified secondary outcome (treatment success) was defined as
a 6-month visual acuity of 20/30 or better and/or that had improved from baseline
by 3 or more lines. A patient was classified as a treatment failure if the
success criteria were not met or if the nonassigned treatment was received
for at least 1 week (ie, if a patient in the atropine group received patching
or a patient in the patching group received atropine). An exact 2-sided 95%
CI was computed for the difference in success percentages between the 2 groups.
Treatment group differences in the questionnaire subscale scores were
assessed with a Wilcoxon rank sum test. The treatment group difference in
the proportion of patients with a decreased 6-month visual acuity in the sound
eye was assessed with a Fisher exact test. Post-6-month sound eye visual acuity
results include data received at the coordinating center through December
31, 2001.
All analyses followed the intention-to-treat principle (ie, the treatment
group data were based on the randomization assignments, not on the actual
treatment received or whether the treatment protocol was followed). All reported P values are 2-tailed.
RESULTS
Between April 1999 and April 2001, 419 patients entered the trial, with
215 assigned to the patching group and 204 to the atropine group. The number
of patients enrolled per site ranged from 1 to 35 (median = 5 patients). The
mean ± SD age of the patients was 5.3 ± 1.1 years; 47% were
girls, and 83% were white. The mean visual acuity in the amblyopic eye at
enrollment was 0.53 logMAR units (approximately 20/63), with a mean difference
in acuity between eyes of 4.4 lines. The baseline characteristics of the 2
groups were similar (Table 2). Additional baseline data were reported previously.49
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Table 2. Baseline Characteristics According to Treatment Group*
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PATIENT FOLLOW-UP
The primary-outcome examination was completed by 97% of the patients
in the patching group and 95% in the atropine group (Figure 1). The vision tester was masked to treatment group for 97%
of these examinations (97% in the patching group and 98% in the atropine group).
Prior to the outcome examination, patients in each group had a similar number
of follow-up visits (mean ± SD number of visits, 2.6 ± 1.0 and
2.7 ± 1.1 in the patching and atropine groups, respectively; P = .52).
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Figure 1. Flowchart showing visit completion
and the timing of dropouts. Of the 208 patients in the patching group who
completed the 6-month outcome examination, 169 patients were in the 6-month
window (25-27 weeks), 7 were early (21 to <25 weeks), and 32 were late
(>27 to 40 weeks). Among the 7 patients with incomplete follow-up, 4 patients
were lost to follow-up, and 3 were withdrawn at the request of the parent.
Of the 194 patients in the atropine group who completed the 6-month outcome
examination, 164 patients were in the 6-month window (25-27 weeks), 5 were
early (21 to <25 weeks), and 25 were late (>27 to 40 weeks). Among the
10 patients with incomplete follow-up, 6 were lost to follow-up, and 4 were
withdrawn at the request of the parent.
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TREATMENT
Patching Group
The number of hours of patching prescribed at enrollment was 6 hours
in 43% of patients, 8 hours in 30%, 10 hours in 7%, and 12 or more hours in
20%. The maximum number of patching hours prescribed at any time prior to
the outcome examination was 6 or 7 hours in 30% of patients, 8 or 9 hours
in 27%, 10 or 11 hours in 10%, and 12 or more hours in 33%. For 80% of the
patients, the number of patching hours prescribed at baseline was the maximum
amount of patching prescribed during the 6-month follow-up period. For 26
patients, patching time during follow-up was increased from a lesser initial
amount to 12 or more hours per day. Six additional patients should have been
(but were not) prescribed at least 12 hours of patching per day as dictated
by the protocol for an incomplete response to a lesser amount of patching.
Patient adherence to the prescribed treatment was judged by the investigator
to be excellent in 49%, good in 34%, fair in 13%, and poor in 5% of patients.
A spectacle occluder was prescribed as a substitute for patching in 9 patients
who could not tolerate the skin patches. Four patients in the patching group
were switched to atropine prior to the primary-outcome examination because
of noncompliance with patching (parental decision in 2 cases and investigator's
decision in 2 cases).
Atropine Group
All patients were prescribed 1 drop of atropine 1% per day at baseline.
The amount of induced distance optical blur in the sound eye while the patient
was wearing spectacles (spherical equivalent of cycloplegic refraction minus
spherical equivalent of spectacle lens) was 0.50 diopter (D) or less for 66%
of patients, greater than 0.50 to 1.00 D for 19%, greater than 1.00 to 2.00
D for 14%, and greater than 2.00 D for 1%. A plano spectacle lens was prescribed
for the sound eye during follow-up for 56 patients, inducing distance optical
blur as defined previously of greater than 0.50 to 1.00 D for 3 patients,
greater than 1.00 to 2.00 D for 9, and greater than 2.00 D for 44 patients.
Four patients should have been (but were not) prescribed a plano lens for
the sound eye as dictated by the protocol for an incomplete response to atropine.
Patient adherence to the prescribed treatment was judged by the investigator
to be excellent in 78% of patients, good in 18%, fair in 3%, and poor in 1%.
Homatropine 5% was prescribed as a substitute in 2 patients who developed
an adverse reaction to atropine. Two patients in the atropine group were switched
to patching prior to the primary-outcome examination (parental decision in
both cases).
EFFECT OF TREATMENT ON VISUAL ACUITY IN THE AMBLYOPIC EYE
Substantial improvement in visual acuity from baseline to 6 months occurred
in both the patching group and the atropine group (Table 3). The mean change in visual acuity from baseline was 3.16
lines (95% CI, 2.95-3.37) in the patching group and 2.84 lines (95% CI, 2.61-3.07)
in the atropine group. The mean treatment group difference in the 6-month
logMAR acuity was 0.034 (95% CI, 0.005-0.064). Seventy-nine percent of the
patching group and 74% of the atropine group met our criteria for treatment
success (95% CI for difference in percentages, -4% to 13%).
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Table 3. Visual Acuity in the Amblyopic Eye at Outcome Examination
by Treatment Group*
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Although differences in amblyopic eye acuity between treatment groups
at 6 months were small, visual acuity in the amblyopic eye showed greater
initial improvement with patching than with atropine (Figure 2). At the 5-week visit, visual acuity had improved from
baseline by a mean of 2.22 lines in the patching group and 1.37 lines in the
atropine group (mean difference in logMAR acuity between groups, 0.087; 95%
CI, 0.060-0.113). By 16 weeks, the difference between groups had narrowed,
but the patching group still had slightly greater improvement (mean change
from baseline, 2.94 lines in the patching group and 2.42 lines in the atropine
group; mean difference in logMAR acuity between groups, 0.053; 95% CI, 0.026-0.080).
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Figure 2. Visual acuity results in each
treatment group for the amblyopic eye at the 5-week, 16-week, and 6-month
visits. A, Mean line change from baseline. B, Percentage of patients meeting
criteria for successful treatment (visual acuity of 20/30 or better and/or
3 or more lines of improvement from baseline). The point estimates and 95%
confidence intervals are shown.
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For all 3 causes of amblyopia (strabismus, anisometropia, and combined-mechanism)
and in subgroups based on patient age and baseline acuity in the amblyopic
eye, the effect of each treatment appeared consistent with the effect in the
overall group. In both treatment groups, all subgroups showed at least a 2.3-line
mean improvement in amblyopic eye acuity from baseline to the primary-outcome
examination. Statistically, there was no significant interaction between any
of these baseline factors and treatment group on the outcome acuity in the
amblyopic eye (P values for interaction were .68
for cause of amblyopia, .84 for age, and .59 for baseline amblyopic eye acuity).
EFFECT OF TREATMENT ON VISUAL ACUITY IN THE SOUND EYE
At the 6-month examination, visual acuity in the sound eye was decreased
from baseline by 1 line in 14 patients (7%) in the patching group and 30 patients
(15%) in the atropine group and by 2 or more lines in 3 patients (1%) and
17 patients (9%), respectively (P<.001). Only
1 patient (in the atropine group) was actively treated for a presumed treatment-related
decrease in sound eye acuity, with a return of visual acuity to its baseline
level.
In the atropine group, many of the excess cases of decreased sound eye
acuity appeared to be related to improper refractive correction combined with
a residual cycloplegic effect of the atropine (including 9 cases in which
the testing was done with a plano lens prescribed for therapeutic effect rather
than the proper lens), although data did not fully document this in all cases.
Among the 47 patients in the atropine group with a decrease of 1 or more lines
at 6 months, subsequent follow-up examinations were performed for 45. Visual
acuity on the subsequent testing was the same or better than that at baseline
in 40 of the 45 patients: 20 while still receiving atropine treatment (10
with the same refractive correction and 10 with a different refractive correction)
and 20 after atropine was discontinued (6 with the same refractive correction
and 14 with a different refractive correction). In the other 5 patients, acuity
on subsequent testing was decreased from baseline by 1 line (3 taking atropine;
2 not taking atropine). The 2 patients who have not had further follow-up
both had a 1-line decrease from baseline at 6 months.
Among the 17 patients in the patching group with a decreased sound eye
acuity, subsequent follow-up examinations were performed for 13. Visual acuity
on the subsequent testing was the same or better than that at baseline in
11 of the 13 patients; the other 2 had a 1-line decrease from baseline. The
4 patients who have not had further follow-up all had a 1-line decrease from
baseline at 6 months.
OTHER ADVERSE EFFECTS
In the patching group, mild skin irritation was reported at least once
for 41% of the patients, and moderate or severe irritation for an additional
6%.
In the atropine group, an ocular adverse effect was reported at least
once for 26% of patients, most commonly light sensitivity (18%), lid or conjunctival
irritation (4%), and eye pain or headache (2%). Facial flushing was reported
for 2 patients, one of whom continued taking atropine with no further problems
and one of whom was switched to homatropine.
During the 6-month treatment period, among patients with no history
of strabismus, a new distance ocular deviation of more than 8  developed
in 1 patient in the patching group (20- esotropia) and in 1 patient
in the atropine group (10- esotropia). Two patients in the patching
group and 3 patients in the atropine group had a preexisting esotropia that
increased by more than 10 (in 1 patient in the atropine group, this
occurred after a plano lens was prescribed for the sound eye). Among patients
with no distance ocular deviation at baseline, a small-angle strabismus (1-8 )
at distance fixation was noted at 6 months in 12 (12%) of 97 patients in the
patching group and 11 (12%) of 90 patients in the atropine group. Among patients
with a baseline 1- to 8- strabismus at distance fixation, no distance
deviation was noted at 6 months in 12 (24%) of 50 patients in the patching
group and 8 (17%) of 47 patients in the atropine group.
PARENT QUESTIONNAIRE
For patients completing the 5-week visit, the Amblyopia Treatment Index
was completed by 192 (92%) of the parents in the patching group and 181 (91%)
in the atropine group. In both treatment groups, the questionnaire results
indicated that treatment was well tolerated. However, the questionnaire scores
were consistently higher (worse) on all 3 subscales in the patching group
compared with the atropine group (adverse effects: median = 2.25 vs 2.00; P = .002; difficulty with compliance: median = 2.20 vs
1.80; P<.001; and social stigma: median = 3.00
vs 2.00; P<.001). The full questionnaire results
will be reported in a separate article.
COMMENT
We evaluated the comparative effectiveness of patching and atropine
as treatments for moderate amblyopia (visual acuity of 20/40 to 20/100) in
419 children younger than 7 years. The study, which was conducted in both
university and community-based practices, was designed to approximate clinical
practice, with the exceptions being (1) the use of randomization to determine
the treatment prescribed, and (2) the use of a standardized protocol to measure
visual acuity. Substantial improvement in the visual acuity of the amblyopic
eye occurred with both the patching and atropine treatment regimens. Improvement
was more rapid in the patching group, but by 6 months the difference in mean
visual acuity between groups was small (about one third of a line) and clinically
inconsequential. The difference between groups in the percentage of patients
meeting our criteria for successful treatment (visual acuity of 20/30 and/or
3 or more lines of improvement from baseline) was also small (79% in the patching
group vs 74% in the atropine group).
In the patching group, most patients received no more than 6 or 8 hours
of patching per day, and only 33% were treated for 12 or more hours per day.
In the atropine group, 15% of patients had more than +1.00 D of distance optical
blur in the sound eye at the start of treatment (comparing the lens correction
with the cycloplegic refraction), and an additional 25% were prescribed a
plano lens to maximize the optical blur during follow-up.
Both treatments were well tolerated, and few patients required alteration
of treatment because of adverse effects. One patient in each group developed
an esotropia greater than 8 that was not present at baseline. Approximately
equal numbers of patients manifested a small-angle strabismus ( 8 )
at 6 months that was not noted at baseline and a small-angle strabismus at
baseline that was not noted at 6 months; this likely reflects the variability
of testing for microtropia rather than a true improvement or worsening in
the ocular alignment related to treatment. Although no definite cases of a
persistent treatment-related decrease in the sound eye acuity occurred in
either group, more patients in the atropine group than the patching group
had a measured reduction of visual acuity in the sound eye at the 6-month
outcome examination. However, in nearly all cases with follow-up information
after the first 6 months, visual acuity in the sound eye returned to its prestudy
level; there were 5 patients in the atropine group and 2 patients in the patching
group in whom the sound eye acuity was 1 line worse than baseline at the last
follow-up visit. This is consistent with the variability of the testing50-51 and presumably does not represent
a true decrease. In many cases, the reduced sound eye acuity at 6 months was
likely related to the residual cycloplegic effect of atropine and/or an improper
refractive correction. Most of the patients were tested at 6 months with the
same refractive correction in use at study entry, not accounting for the possible
effect of 6 months of atropine treatment on undercorrected latent hyperopia.
Because the cycloplegic effect of even a single drop of atropine has been
reported to last for up to 14 days,53-54
in retrospect we should have discontinued atropine for longer than 7 days
before the 6-month visual acuity measurement. Thus, our data are inconclusive
about whether atropine may cause a treatment-related reduction of acuity in
the sound eye more often than patching. However, even if this is true, we
are reasonably confident that our cohort experienced no lasting adverse effect
on visual acuity of the sound eye. One potential concern with atropine use
would be the light exposure of the retina from the dilated pupil. Although
we provided sunglasses to our patients and recommended hat wear outdoors to
minimize the sunlight exposure, we believe that a few months of atropine use
does not have a deleterious effect on the retina. Atropine has been used long-term
to prevent the progression of myopia without an apparent adverse effect on
acuity,55-57 and
as noted previously, our post-6-month data do not suggest permanent impairment
in the sound eye acuity. We will be able to provide definitive long-term safety
data on the completion of 2-year follow-up. At that time we also will assess
differences between groups in stereoacuity and fusion.
The burden to administer amblyopia treatment in children falls on the
parent. One of the rationales for atropine use has been that it has a higher
degree of acceptability by patients and parents than patching.33, 35
This premise was supported in our parent questionnaire data obtained at the
5-week follow-up visit. However, whereas atropine was better accepted, the
treatment group differences, although highly statistically significant, were
small. In both groups, the questionnaire results indicated that the initial
month of treatment was usually well tolerated by the patient and parent.
We could identify no apparent sources of bias or confounding to explain
our findings. The follow-up visit rate was high in both groups, and missing
data from patients who dropped out of the study did not influence the interpretation
of the results. There was a slight imbalance in baseline visual acuity between
groups (the atropine group had slightly worse acuity), but this was accounted
for in analysis. Although the patients, parents, and investigators were unmasked
to the treatment group assignments, masking of the primary visual acuity outcome
measurement was achieved in 97% of cases. Visual acuity testing was performed
using a standardized protocol developed specifically for this study to ensure
consistency of testing across our many sites.50
The sample size for the trial was selected to have sufficient power to evaluate
the treatment effect in subgroups based on cause of amblyopia. As a result,
for the overall primary analysis, statistical power approached 100%. Thus,
it is unlikely that a substantially larger treatment group difference than
we found exists, and we can conclude with a high degree of confidence that
both patching and atropine produce an improvement in visual acuity of a similar
magnitude.
We could not ethically include an untreated control group in this trial.
Thus, our conclusion that both treatments improved visual acuity is based
on overwhelming clinical experience indicating that substantial improvement
of amblyopia rarely occurs without treatment, and the fact that the amount
of observed improvement (about 3 lines on average) substantially exceeded
any potential learning effect or age effect.50-51,58
The magnitude of the learning and age effects on the visual acuity of the
amblyopic eyes was likely similar to the observed improvement from baseline
to the 6-month outcome in acuity in the sound eyes of the patients in the
patching group (mean change, 0.6 lines). A slight overestimate of the amount
of improvement could also have occurred from including some patients with
anisometropia who were wearing their optimal spectacle correction for only
4 weeks at the time of enrollment. Such patients might have experienced some
on-study improvement due to the spectacles alone. Although this would not
have affected the relative treatment group comparison, it could have produced
a slight overestimate of the absolute amount of improvement experienced by
such patients in both treatment groups.
Improvement in the atropine group lagged behind that in the patching
group. It is possible that if our primary outcome had occurred at a time point
longer than 6 months, the atropine group might have shown further improvement,
perhaps achieving the same proportion of patients with 20/30 or better amblyopic
eye acuity as found in the patching group. In designing the trial, we recognized
that 6 months might be too short a time for the full benefit of atropine to
be manifested. However, we did not believe that it would be possible to sustain
patients who had persistent amblyopia in their treatment groups without permitting
changes in therapy beyond this 6-month time point. We also do not have the
data to determine whether initiating distance optical blur concomitant with
starting atropine therapy (by prescribing a plano spectacle lens for the sound
eye) would have produced a more rapid response than atropine alone. At the
end of 2-year follow-up, we will be able to determine whether there is any
advantage regarding visual acuity to the initiation of treatment with either
patching or atropine.
For the treatment protocols used in this study, the cost of the atropine
regimen is likely to be less than that of the patching regimen. Assuming a
cost of $0.35 per patch and the need to use an average of 1.5 patches a day,
the cost for 3 months of daily patching would be about $50 and for 6 months
about $100. A 15-mL bottle of atropine 1% costs about $10 and lasts for 6
months. With our protocol, about 25% of atropine-treated patients will need
to be prescribed a plano spectacle lens because of an inadequate response
to atropine alone. Assuming a cost of $50 for the lens, the cost of the atropine
plus the lens change is still less than that of a 6-month course of patching.
In translating our results into clinical practice, the findings must
be viewed in the context of the clinical profile of the cohort enrolled in
the study. The eligibility criteria for enrollment were broad, with the intention
to include most children with moderate strabismic and/or anisometropic amblyopia
(specifically excluding deprivational amblyopia and myopia) younger than 7
years who were developmentally able to perform optotype visual acuity testing.
This effectively set a lower age limit of about 3 years. To avoid including
prior treatment failures in the study, enrollment was restricted to children
who either had not been previously treated for amblyopia or had received no
more than 2 months of treatment in the prior 2 years. The visual acuity limit
for the amblyopic eye was set at 20/100 because atropine is not thought to
be as effective a treatment for worse acuities.33, 35
A 3-line difference in visual acuity between eyes was required (1) to assure
that a true reduction in acuity was present, and (2) to have a sufficient
depth of amblyopia to be able to assess improvement with treatment. Myopia
was an exclusion to assure visual blur at near fixation for patients in the
atropine group. In designing the trial to mirror a real-world situation, we
limited compliance aids to those commonly used in clinical practice: an instruction
sheet about treatment and a calendar to record the treatment received each
day. Nevertheless, we recognize that patients participating in a clinical
trial may differ from those in everyday practice, and our patients' level
of compliance may have been better than what may be achieved in the real world.
In summary, both atropine and patching are effective treatments for
moderate amblyopia in children aged 3 years to less than 7 years. Patching
has the potential advantages of a more rapid improvement in visual acuity
and possibly a slightly better acuity outcome, whereas atropine has the potential
advantages of easier administration and lower cost. Our data are inconclusive
about whether atropine may cause a transient treatment-related reduction of
visual acuity in the sound eye more often than patching. However, we are reasonably
confident that in our cohort, atropine did not have a lasting adverse effect
on the acuity of the sound eye. Because incomplete responders to one treatment
could later be given the other treatment, our results indicate that the initial
choice of patching or atropine can be made by the eye care provider and parent.
Both patching and atropine are appropriate modalities for the initial treatment
of moderate amblyopia in children.
AUTHOR INFORMATION
Submitted for publication November 9, 2001; final revision received
December 11, 2001; accepted December 14, 2001.
Supported by a cooperative agreement (EY11751) from the National Eye
Institute, Bethesda, Md.
The following companies provided materials at a discount for the study:
Precision Vision (near-acuity test), Stereo Optical Co Inc (stereoacuity tests),
Beiersdorf-Jobst Inc (Coverlet Eye Occlusors), and Bausch and Lomb Pharmaceuticals
Inc (atropine).
| The Pediatric Eye Disease Investigator Group
Clinical Sites
Listed in order of number of patients enrolled into the Amblyopia Treatment
Study 1, with city, state, site name, and number of patients in parentheses.
Personnel are listed as (I) for investigator, (C) for coordinator, and (V)
for visual acuity tester.
Gaithersburg, Md (36): Stephen R. Glaser (I),
Andrea M. Matazinski (C), David M. Sclar (V). Erie, Pa;
Pediatric Ophthalmology of Erie (33): Nicholas A. Sala (I), Chrissy
M. Vroman (C), Cindy E. Tanner (V). Dallas, Tex; Pediatric Ophthalmology PA and the Center for Adult Strabismus (26): David R. Stager, Sr (I), Priscilla M. Berry (I), David R. Stager,
Jr (I), Joost Felius (C), Jennifer A. Wilkerson (C), Maria Petrova Pesheva,
MD (C), Eileen E. Birch (V), Brett G. Jeffrey (V), Anna R. O'Connor (V). Providence, RI; Pediatric Ophthalmology and Strabismus Associates (25): David Robbins Tien (I), Glenn E. Bulan (I), Heidi C. Christ
(C), Lauren B. DeWaele (C), David A. Young (V). Calgary,
Alberta, Canada; Alberta Children's Hospital (24): William F. Astle
(I), Anna L. Ells (I), Cheryl R. Hayduk (C), Catriona I. Kerr (C), Mary S.
McAlester (C), Heather J. Peddie (C), Heather M. Vibert (C). Bethesda, Md; National Eye Institute (20): Richard W. Hertle (I), Susan
D. Mellow (C), Ed J. Fitzgibbon (V), Guy E. Foster (V). Anchorage, Alaska; Ophthalmic Associates (20): Robert W. Arnold (I),
Mary Diane Armitage (C), Nancy H. Brusseau (V). Milwaukee;
Medical College of Wisconsin (18): Mark S. Ruttum (I), Jane D. Kivlin
(I), Veronica R. Picard (C), Merelyn J. Chesner (V). Fullerton;
Southern California College of Optometry (17): Susan A. Cotter (I),
Carmen N. Barnhardt (I), Susan M. Shin (I), Raymond H. Chu (I), Lourdes Asiain
(C), Yvonne F. Flores (C), Gen Lee (C), John H. Lee (V), Sherene C. Fort (V),
Jennifer L. Slutsky (V). Houston; Texas Children's Hospital (14): Evelyn A. Paysse (I), David K. Coats (I), Kathryn M. Brady-McCreery
(I), Alma D. Sanchez (C), Viviana Correodor (C). Nashville,
Tenn; Vanderbilt Eye Center (13): Sean Donahue (I), Cindy Foss (C),
Julie A. Ozier (C), Ronald J. Biernacki (V), Evelyn Tomlinson (V). Portland, Ore; Casey Eye Institute (12): David T. Wheeler (I), Kimberley
A. Beaudet (C), Christin L. Bateman (V), Michele A. Hartwell (V). Sacramento, Calif; Permanente Medical Group (11): James B. Ruben (I),
Dipti Desai (C), Sue Ann Parrish (C), Tracy D. Louie (V). University of Alabama at Birmingham School of Optometry (10): Robert
P. Rutstein (I), Wendy L. Marsh-Tootle (I), Cathy H. Baldwin (C), Kristine
T. Becker (V). Baltimore, Md; Wilmer Institute (10):
Michael X. Repka (I), David G. Hunter (I), Jana S. Mattheu (C), Sheena O.
Broome (V), Carole R. Goodman (V). Indianapolis; Indiana
University Medical Center (9): Daniel E. Neely (I), David A. Plager
(I), Derek T. Sprunger (I), Donna J. Bates (C), Jay Galli (C), Michele E.
Whitaker (C). Fort Lauderdale, Fla; NOVA Southeastern University (9): Susanna M. Tamkins (I), Michele Gonzalez (C), Siby Jacobs (V). Baltimore, Md; Greater Baltimore Medical Center (7): Mary
Louise Z. Collins (I), Cheryl L. McCarus (C), Jaime N. Brown (V), Dorothy
B. Conlan (V). Atlanta, Ga; Emory Eye Center (7):
Scott R. Lambert (I), Lucy Yang (C), Alexander T. Elliott (V), Nicole Fallaha
(V). St Louis, Mo; Cardinal Glennon Children's Hospital (6): Oscar A. Cruz (I), Bradley V. Davitt (I), Susan A. Havertape
(C), Emily A. Miyazaki (C), Molly B. Bosch (C). Waterbury,
Conn; Ophthalmic Surgical Associates (6): Andrew J. Levada (I), Tabitha
L. Matchett (C), Angela Zimmerman Moya (C), Cara C. Mulligan (V), Shelley
K. Weiss (V), Holly J. Pelletier (V). Grand Rapids, Mich;
Pediatric Ophthalmology PC (6): Patrick J. Droste (I), Robert J. Peters
(I), Jan Hilbrands (C), Kelli A. Sheeran (V), Deborah K. Smith (V), Corrie
L. Vanraze-nswaay (U). Dallas; UT Southwestern Medical Center (6): David R. Weakley, Jr (I), Clare L. Dias (C). Wichita, Kan; Grene Vision Group (5): David A. Johnson (I), Ruth D.
James (C), Patti G. Claes (V), Kelli K. Drake (V). Rochester,
Minn; Mayo Clinic (5): Jonathan M. Holmes (I), Becky A. Nielsen (C),
Marcela Garcia (V), Rose M. Kroening (V), David A. Leske (V), Marna L. Levisen
(V), Deborah K. Miller (V), Debbie M. Priebe (V), Julie A. Spitzer (V). Philadelphia; Pennsylvania College of Optometry (5): Mitchell
M. Scheiman (I), Jo Ann T. Bailey (I), Kathleen T. Zinzer (V). Columbus; Ohio State University College of Optometry (5): Marjean T.
Kulp (I), Tracy L. Kitts (C), Michael J. Earley (V). Buffalo,
NY; Children's Hospital of Buffalo (4): Steven Awner (I), Scott E.
Olitsky (V). Lancaster, Pa; Family Eye Group/Eye Specialists
of Lancaster (4): David I. Silbert (I), Abbe E. Wagner (C), Kit M.
Castillo (V), Noelle S. Matta (V), Tracy L. Meshey (V), Paulette Myers-Ely
(V), Wendy L. Piper (V), Dena M. Scaringi (V), Pamela M. Snavely (V), Lori
J. Walker (V). Palm Harbor, Fla; Specialty Eye Care
(4): Christine L. Burns (I), Magda Barsoum-Homsy (I), Le Ila C. Lawrence (C). Chapel Hill; University of North Carolina, Department of Ophthalmology (4): David K. Wallace (I), Marguerite J. Sullivan (C). Tucson; University of Arizona (4): Joseph M. Miller (I), Toby Ann Aparisi
(C), Jenniffer Funk-Weyant (C), Megan Taylor (V), Sue Bulau (V). Iowa City; University of Iowa Hospitals and Clinics (4): William E.
Scott (I), Wanda I. Ottar-Pfeifer (C), Pamela J. Kutschke (V), Keith M. Wilken
(V). Minneapolis; University of Minnesota (4): C.
Gail Summers (I), Stephen P. Christiansen (I), Ann M. Holleschau (C), Sally
M. Cook (C), Jane D. LaVoie (V), Kim S. Merrill (V). Birmingham;
Alabama Ophthalmology Associates PC (3): Frederick J. Elsas (I), Thomas
H. Metz, Jr (I), Michelle L. Mizell (C), Stephanie O. Roberts Bennett (V). Norfolk; Eastern Virginia Medical School (3): Earl R. Crouch,
Jr (I), Kristen D. Ruark (C), Gaylord G. Ventura (V). Mexico
City, Mexico (3): Miguel Paciuc (I), Marina M. Schnadower (C), Cecilio
Velasco (V). Temple, Tex; Scott and White Ophthalmology (3): David C. Dries (I), V. Jeanne Vengco (C). Salt Lake City; University of Utah/Moran Eye Center (3): Richard J.
Olson (I), Robert O. Hoffman (I), Susan F. Bracken (C), Pat L. Remington (V),
Kimberly G. Yen (V). Asheville, NC; Asheville Eye Associates (2): Robert E. Wiggins, Jr (I), Sally A. Baumgartner (C), Mary Knecht
(V). Cincinnati, Ohio; Children's Hospital Medical Center (2): Constance E. West (I), Shelley L. Benson (C), Laurie A. Hahn-Parrott
(V), Walker E. Motley (V), Regina M. Poole (V). Philadelphia,
Pa; Children's Hospital of Philadelphia (2): Brian J. Forbes (I), Graham
E. Quinn (I), Melissa L. Ehnbom (V), Michelle C. Maturo (V), David R. Phillips
(V). Washington, DC; Children's National Medical Center (1): Marijean Michele Miller (I), Mitra Maybodi (I), Cori Greger (C). Canton; Eye Centers of Ohio (1): Elbert H. Magoon (I),
Paula A. Kannam (C), Lynn A. McAtee (C), Margie Andrews (V), Caroline M. Hoge
(V). Charleston; Medical University of South Carolina, Storm
Eye Institute (1): Richard A. Saunders (I), Judy P. Hoxie (C), Lisa
M. Langdale (C), Kimberly D. Lenhart (V). Boston, Mass;
New England College of Optometry (1): Bruce Moore (I), Erik M. Weissberg
(I). New York; State University of New York, College of
Optometry (1): Robert H. Duckman (I), David E. FitzGerald (I), Marilyn
Vricella (V).
Data Coordinating Center
Tampa, Fla: Roy W. Beck, Pamela S. Moke, R.
Clifford Blair, Stephen R. Cole, Raymond T. Kraker, Heidi A. Gillespie, Nicole
M. Boyle, Alisha N. Lawson, Julie A. Gillett, Shelly T. Mares, Brian B. Dale.
National Eye Institute
Bethesda, Md: Donald F. Everett.
Writing Committee
Roy W. Beck, Eileen E. Birch, Stephen R. Cole, Donald F. Everett, Richard
W. Hertle, Jonathan M. Holmes, Raymond T. Kraker, Michael X. Repka.
Pediatric Eye Disease Investigator Group Executive
Committee
Michael X. Repka (chair), Jonathan M. Holmes (vice-chair), Roy W. Beck,
Eileen E. Birch, Donald F. Everett, Pamela S. Moke.
Amblyopia Treatment Study 1 Steering Committee
Michael X. Repka, Roy W. Beck, Eileen E. Birch, Donald F. Everett, Richard
W. Hertle, Jonathan M. Holmes, Joseph M. Miller (1998-2000), Pamela S. Moke,
Graham E. Quinn (1998-2000), Richard A. Saunders (1998-2000), Kurt Simons
(1998-2000), Sue A. Cotter (2000-present), Mitchell M. Scheiman (2000-present).
Amblyopia Treatment Study 1 Publications Subcommittee
Joseph M. Miller, Graham E. Quinn, Richard A. Saunders.
Amblyopia Treatment Study 1 Operations Subcommittee
Susan A. Cotter (2000), Stephen R. Glaser, Maria P. Pesheva (2000),
Veronica R. Picard (2000-present), Nicholas A. Sala, D. Robbins Tien (2000-present).
Data and Safety Monitoring Committee
William Barlow (chair), Edward G. Buckley, Barry Davis, Velma Dobson,
John L. Keltner, Hana Osman, Earl A. Palmer, Dale L. Phelps.
|
|
Corresponding author: Roy W. Beck, MD, PhD, Jaeb Center for Health
Research, 3010 E 138th Ave, Suite 9, Tampa, FL 33613 (e-mail: rbeck{at}jaeb.org).
Reprints: PEDIG Data Coordinating Center, Jaeb Center for Health
Research.
From the Jaeb Center for Health Research, Tampa, Fla.
REFERENCES
| |
1. National Eye Institute Office of Biometry and Epidemiology. Report on the National Eye Institute's Visual Acuity
Impairment Survey Pilot Study. Washington, DC: Dept of Health and Human Services; 1984.
2. Simons K. Preschool vision screening: rationale, methodology and
outcome. Surv Ophthalmol. 1996;41:3-30.
FULL TEXT
|
ISI
| PUBMED
3. Attebo K, Mitchell P, Cumming R, Smith W, Jolly N, Sparkes R. Prevalence and causes of amblyopia in an adult population. Ophthalmology. 1998;105:154-159.
FULL TEXT
|
ISI
| PUBMED
4. Woodruff G, Hiscox F, Thompson JR, Smith LK. Factors affecting the outcome of children treated for amblyopia. Eye. 1994;8:627-631.
5. Shaw DE, Fielder AR, Minshull C, Rosenthal AR. Amblyopia: factors influencing age of presentation. Lancet. 1988;2:207-209.
FULL TEXT
|
ISI
| PUBMED
6. Köhler L, Stigmar G. Vision screening of four-year-old children. Acta Paediatr Scand. 1973;62:17-27.
ISI
| PUBMED
7. Winder S, Farquhar A, Nah GKM, Church WH, Rennie AGR. The outcome of orthoptic screening in Aberdeen in 1990. Br Orthopt J. 1996;53:36-38.
8. Bray LC, Clarke MP, Jarvis SN, Francis PM, Colver A. Preschool vision screening: a prospective comparative evaluation. Eye. 1996;10:714-718.
9. Meyer E, Mizrahi E, Perlman I. Amblyopia success index: a new method of quantitiative assessment of
treatment efficiency: application in a study of 473 anisometropic amblyopic
patients. Binocular Vis Q. 1991;6:83-90.
10. Wick B, Wingard M, Cotter S, Scheiman M. Anisometropic amblyopia: is the patient ever too old to treat? Optom Vis Sci. 1992;69:866-878.
FULL TEXT
|
ISI
| PUBMED
11. Kupfer C. Treatment of amblyopia ex anopsia in adults: a preliminary report of
seven cases. Am J Ophthalmol. 1957;43:918-922.
ISI
| PUBMED
12. Neumann E, Friedman Z, Abel-Peleg B. Prevention of strabismic amblyopia of early onset with special reference
to the optimal age for screening. J Pediatr Ophthalmol Strabismus. 1987;24:106-110.
PUBMED
13. Scott WE, Dickey CF. Stability of visual acuity in amblyopic patients after visual maturity. Graefes Arch Clin Exp Ophthalmol. 1988;226:154-157.
FULL TEXT
|
ISI
| PUBMED
14. Epelbaum M, Milleret C, Buisseret P, Dufier JL. The sensitive period for strabismic amblyopia in humans. Ophthalmology. 1993;100:323-327.
ISI
| PUBMED
15. Hardman Lea SJ, Loades J, Rubinstein MP. The sensitive period for anisometropic amblyopia. Eye. 1989;3:783-790.
16. Assaf AA. The sensitive period: transfer of fixation after occlusion for strabismic
amblyopia. Br J Ophthalmol. 1982;66:64-70.
FREE FULL TEXT
17. von Noorden GK. Binocular Vision and Ocular Motility: Theory and
Management of Strabismus. St Louis, Mo: Mosby–Year Book Inc; 1996.
18. Olson RJ, Scott WE. A practical approach to occlusion therapy for amblyopia. Semin Ophthalmol. 1997;12:161-165.
19. Oliver M, Neumann R, Chaimovitch Y, Gotesman N, Shimshoni M. Compliance and results of treatment for amblyopia in children more
than 8 years old. Am J Ophthalmol. 1986;102:340-345.
ISI
| PUBMED
20. Leach C. Compliance with occlusion therapy for strabismic and anisometropic
amblyopia: a pilot study. Binocular Vis Eye Muscle Surg Q. 1995;10:257-266.
21. Smith LK, Thompson JR, Woodruff G, Hiscox F. Factors affecting treatment compliance in amblyopia. J Pediatr Ophthalmol Strabismus. 1995;32:98-101.
ISI
| PUBMED
22. Williamson TH, Andrews R, Dutton GN, Murry G, Graham N. Assessment of an inner city visual screening programme for preschool
children. Br J Ophthalmol. 1995;79:1068-1073.
FREE FULL TEXT
23. Kivlin JD, Flynn JT. Therapy of anisometropic amblyopia. J Pediatr Ophthalmol Strabismus. 1981;18:47-56.
ISI
| PUBMED
24. Cleary M. Efficacy of occlusion for strabismic amblyopia: can an optimal duration
be identified? Br J Ophthalmol. 2000;84:572-578.
FREE FULL TEXT
25. Parkes LC. An investigation of the impact of occlusion therapy on children with
amblyopia, its effect on their families, and compliance with treatment. Br Orthopt J. 2001;58:30-37.
26. Hiscox F, Strong N, Thompson JR, Minshull C, Woodruff G. Occlusion for amblyopia: a comprehensive survey of outcome. Eye. 1992;6:300-304.
27. Pope LJ. Treatment of eccentric fixation without occlusion. Br Orthopt J. 1971;28:77-82.
28. Swann AP, Hunter CD. A survey of amblyopia treated by atropine occlusion. Br Orthopt J. 1974;31:65-69.
29. Haase W. Experiences with penalisation therapy. In: Moore S, Mein J, Stockbridge L, eds. Orthoptics:
Past, Present, Future. New York, NY: Stratton; 1975:105-111.
30. von Noorden GK, Milam JB. Penalization in the treatment of amblyopia. Am J Ophthalmol. 1979;88:511-518.
PUBMED
31. Ron A, Nawratzki I. Penalization treatment of amblyopia: a follow-up study of two years
in older children. J Pediatr Ophthalmol Strabismus. 1982;19:137-139.
PUBMED
32. North RV, Kelly ME. Atropine occlusion in the treatment of strabismic amblyopia and its
effect upon the non-amblyopic eye. Ophthalmic Physiol Opt. 1991;11:113-117.
FULL TEXT
|
ISI
| PUBMED
33. Repka MX, Ray JM. The efficacy of optical and pharmacological penalization. Ophthalmology. 1993;100:769-775.
ISI
| PUBMED
34. Foley-Nolan A, McCann A, O'Keefe M. Atropine penalisation vs occlusion as the primary treatment for amblyopia. Br J Ophthalmol. 1997;81:54-57.
FREE FULL TEXT
35. Simons K, Stein L, Sener EC, Vitale S, Guyton DL. Full-time atropine, intermittent atropine and optical penalization
and binocular outcome in treatment of strabismic amblyopia. Ophthalmology. 1997;104:2143-2155.
ISI
| PUBMED
36. Elder MJ. Occlusion therapy for strabismic amblyopia. Aust N Z J Ophthalmol. 1994;22:187-191.
FULL TEXT
|
ISI
| PUBMED
37. Newman DK, Hitchcock A, McCarthy H, Keast-Butler J, Moore AT. Preschool vision screening: outcome of children referred to the hospital
eye service. Br J Ophthalmol. 1996;80:1077-1082.
FREE FULL TEXT
38. Woodruff G, Hiscox F, Thompson JR, Smith LK. The presentation of children with amblyopia. Eye. 1994;8:623-626.
39. Fulton AB, Mayer DL. Esotropic children with amblyopia: effects of patching on acuity. Graefes Arch Clin Exp Ophthalmol. 1988;226:309-312.
FULL TEXT
|
ISI
| PUBMED
40. Scott WE, Stratton VB, Fabre J. Full-time occlusion therapy for amblyopia. Am Orthopt J. 1980;30:125-130.
41. Fletcher MC, Abbott W, Girar LJ, et al. Results of biostatistical study of the management of suppression amblyopia
by intensive pleoptics vs conventional patching. Am Orthopt J. 1969;19:8-30.
PUBMED
42. Gregersen E, Rindziunski E. "Conventional" occlusion in the treatment of squint amblyopia. A 10-year
follow-up. Acta Ophthalmol (Copenh). 1965;43:462-474.
PUBMED
43. Levartovsky S, Gottesman N, Shimshoni M, Oliver M. Factors affecting long-term results of successfully treated amblyopia:
age at beginning of treatment and age at cessation of monitoring. J Pediatr Ophthalmol Strabismus. 1992;29:219-223.
ISI
| PUBMED
44. Ron A, Nawratzki I. Penalization treatment of amblyopia. Metab Ophthalmol. 1978;2:151-153.
45. Simons K, Gotzler KC, Vitale S. Penalization vs part-time occlusion and binocular outcome in treatment
of strabismic amblyopia. Ophthalmology. 1997;104:2156-2160.
ISI
| PUBMED
46. Doran RML, Yarde S, Starbuck A. Comparison of treatment methods in strabismic amblyopia. In: Campos EC, ed. Strabismus and Ocular Motility
Disorders. London, England: Macmillan Press; 1990:51-59.
47. von Noorden GK. Occlusion therapy in amblyopia with eccentric fixation. Arch Ophthalmol. 1965;73:776-781.
FREE FULL TEXT
48. von Noorden GK. Amblyopia caused by unilateral atropinization. Ophthalmology. 1981;88:131-133.
ISI
| PUBMED
49. The Pediatric Eye Disease Investigator Group. The clinical profile of moderate amblyopia in children younger than
7 years. Arch Ophthalmol. 2002;120:281-287.
FREE FULL TEXT
50. Holmes JM, Beck RW, Repka MX, et al. The Amblyopia Treatment Study visual acuity testing protocol. Arch Ophthalmol. 2001;119:1345-1353.
FREE FULL TEXT
51. Moke PS, Turpin AH, Beck RW, et al. Computerized method of visual acuity testing: adaptation of the amblyopia
treatment study visual acuity testing protocol. Am J Ophthalmol. 2001;132:903-909.
FULL TEXT
|
ISI
| PUBMED
52. Cole SR, Beck RW, Moke PS, et al. The amblyopia treatment index. J AAPOS. 2001;5:250-254.
53. North RV, Kelly ME. A review of the uses and adverse effects of topical administration
of atropine. Ophthalmic Physiol Opt. 1987;7:109-114.
ISI
| PUBMED
54. Wolf AV, Hodge HC. Effects of atropine sulfate, methylatropine nitrate (metropine) and
homatropine hydrobromide on adult human eyes. Arch Ophthalmol. 1946;36:293-301.
FREE FULL TEXT
55. Kennedy RH, Dyer JA, Kennedy MA, et al. Reducing the progression of myopia with atropine: a long term cohort
study of Olmsted County students. Binocul Vis Strabismus Q. 2000;15:281-304.
PUBMED
56. Brodstein RS, Brodstein DE, Olson RJ, Hunt SC, Williams RR. The treatment of myopia with atropine and bifocals: a long-term prospective
study. Ophthalmology. 1984;91:1373-1379.
ISI
| PUBMED
57. Bedrossian RH. The effect of atropine on myopia. Ophthalmology. 1979;86:713-717.
ISI
| PUBMED
58. Fern KD, Manny RE. Visual acuity of the preschool child: a review. Am J Optom Physiol Opt. 1986;63:319-345.
ISI
| PUBMED
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