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Multicenter Trial of Cryotherapy for Retinopathy of Prematurity
Ophthalmological Outcomes at 10 Years
Cryotherapy for Retinopathy of Prematurity Cooperative Group
Arch Ophthalmol. 2001;119:1110-1118.
ABSTRACT
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Objective To evaluate outcomes at 10 years after randomization for eyes undergoing
cryotherapy vs eyes serving as controls, for patients enrolled in the Multicenter
Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP).
Methods The randomized cohort originally consisted of 291 preterm children with
birth weights less than 1251 g who developed a defined threshold of ROP severity
in one or both eyes. Patients with bilateral threshold ROP (n = 240) were
randomly assigned to receive cryotherapy to one eye and no cryotherapy to
the other eye. Those with ROP of less severity than threshold in the fellow
eye ("asymmetric"; n = 51) were randomly assigned to cryotherapy or no cryotherapy
in the eye with threshold ROP. Ten years later, a tester who was masked to
treatment status of each eye measured distance and near visual acuity, with
"unfavorable" outcome being 20/200 or worse. Patients also were evaluated
by study-certified ophthalmologists who assessed ROP residua primarily in
the posterior pole of the fundus, with unfavorable outcome being a posterior
retinal fold or worse.
Results For the 247 children examined, both functional and structural primary
outcomes showed fewer unfavorable outcomes in treated vs control eyes: 44.4%
vs 62.1% (P<.001) for distance visual acuity and
27.2% vs 47.9% (P<.001) for fundus status. Near
acuity results were similar to those for distance (42.5% vs 61.6%; P<.001). Total retinal detachments had continued to occur in control
eyes, increasing from 38.6% at 5 years to 41.4% at 10 years, while
treated eyes remained stable (at 22.0%). A previously disturbing subgroup
trend that more control eyes than treated eyes had visual acuity of 20/40
or better (in the 5-year report) was no longer present at 10 years;
eyes that received cryotherapy were found at least as likely as control eyes
to have 20/40 or better visual acuity.
Conclusions At 10 years, eyes that had received cryotherapy were much less likely
than control eyes to be blind. A previous trend for a higher proportion of
sighted control eyes than sighted treated eyes to show acuity in the normal
range was not confirmed. The results show long-term value from cryotherapy
in preserving visual acuity in eyes with threshold ROP.
INTRODUCTION
PREVIOUS REPORTS from follow-up examinations of the patients in the
Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP)
have demonstrated the beneficial effect of cryotherapy on eyes with threshold
ROP, defined as 5 contiguous or 8 cumulative clock hours of stage 3+ retinopathy
of prematurity (ROP) in zone I or II.1-6
In the most recent follow-up report, which presented results from the 5-year
examination,5 detailed analysis indicated that
cryotherapy—despite its benefit—did not seem to increase the chance
of attaining recognition visual acuity of 20/40 or better. There was even
a disturbing trend for fewer treated eyes than control eyes to achieve acuity
in this favorable range.5 The present report
extends the outcome assessment for these patients to 10 years of age, with
the addition of visual acuity measured for near fixation.
PATIENTS AND METHODS
PATIENTS
The subjects of this report are the 291 children who participated in
the randomized trial of cryotherapy. They were born prematurely between January
1, 1986, and November 30, 1987, had birth weights less than 1251 g, and developed
threshold ROP as neonates. Those who developed threshold ROP in both eyes
at the same time (bilateral threshold group; n = 240) were assigned at random
to receive cryotherapy to one eye and no cryotherapy to the other eye. If
threshold ROP had been reached in only one eye at the time of randomization
(asymmetric group; n = 51), that eye was randomly assigned to receive cryotherapy
or no cryotherapy. Randomization occurred at an average postmenstrual age
of 37.7 weeks2 (gestational + postnatal age),
ie, generally shortly before the typical due date of full-term birth (40 weeks).
Based on examinations performed approximately 10 years after randomization,
data were compiled for the present report.
Informed consents were obtained from parents prior to initial study
entry, prior to randomization, and prior to participation in the 5-
and 10-year follow-up phases of the study. Complete details concerning patients,
sample size determination, standardization of ROP classification, eligibility
for randomization, and cryotherapy technique are documented in previous publications.1-4
FUNCTIONAL OUTCOME: VISUAL ACUITY
The primary functional outcome, distance recognition visual acuity,
was evaluated by linear Snellen (letter) testing with the log of the minimum
angle of resolution (logMAR) visual acuity charts that were used in the Early
Treatment Diabetic Retinopathy Study (ETDRS) (Lighthouse, Inc, New York, NY).7 This chart is a modified version of the standard Snellen
chart. Because most ophthalmologists are familiar with the term Snellen to
describe letter recognition visual acuity testing, we have used this term
to refer to the chart, associated testing procedures, and results.5
Best-corrected distance and near monocular acuities were measured by
1 of 2 study-trained and certified testers who were masked to (1) the eye's
history of being randomized to cryotherapy vs control status, (2) the ophthalmologist's
assessment of visual function, and (3) the fundus outcome of the eye. Acuity
was estimated as the Snellen value of the line containing the smallest letter
size for which the child could identify correctly 3 of the 5 letters on the
line. Full details of testing parameters and techniques for distance acuity
testing have been reported previously.5
Prior to testing, each child was given a pretest requiring the binocular
identification of 10 individual letters 6 cm in height (at a distance of approximately
1.5 m) either by name or by matching to a lap board. If the child correctly
identified 9 of 10 consecutive letters, monocular distance Snellen testing
was undertaken using the distance ETDRS charts. Standard test distance was
4 m, but testing at 1 m or 50 cm was permitted if needed to obtain an acuity
measurement. Children who could not pass the pretest were developmentally
unable, were uncooperative, or had extremely low form-discrimination visual
capability.
Following distance visual acuity testing, near visual acuity was tested
using the Near ETDRS modified Snellen charts (Lighthouse, Inc). Standard test
distance was 40 cm, with a luminance of 10 or more candelas per square meter.
Testing at 20 cm or 10 cm was permitted, if needed to obtain an acuity measurement.
Near correction was provided in the event of aphakia, although such eyes typically
had poor acuity.
Children were tested while wearing their current glasses prescription
and usually prior to the cycloplegic refraction. If an eye's visual acuity
was worse than 20/40, and if the difference between the glasses correction
worn during acuity testing and the currently measured refractive error was
greater than 1.00 diopters (D) of myopia, greater than 3.5 D of hyperopia,
or greater than 1.5 D of astigmatism, then the acuity of that eye was retested
with appropriate correction in trial frames. If retesting was conducted after
cycloplegia, appropriate lenses were added to correct for test distances of
1 m or closer. In an attempt to avoid the need for formal retesting of children
whose myopia had progressed since they had received their glasses, the following
manifest refraction protocol was used for distance acuity testing. If distance
acuity was below 20/40, the vision tester placed a -0.75 D trial lens
power in front of the eye and remeasured acuity. If acuity did not improve
to at least 20/40, the trial lens power was increased to -1.50 D and
acuity was remeasured. The best recorded acuity was used in the subsequent
analysis.
Children were exempt from acuity testing if (1) the examining physician
judged the child to have no light perception in either eye and the parents
agreed that the child was behaviorally blind, or (2) the examining physician
and parents agreed that the child's binocular vision was only light perception
or worse and the child had either bilateral and total retinal detachment,
bilateral phthisis bulbi, or bilateral enucleation. History of retinal reattachment
surgery, including vitrectomy, was not an exclusion criterion.
STRUCTURAL OUTCOME
Each child underwent a standardized full comprehensive eye examination
performed by a study-certified ophthalmologist. At the conclusion of the examination,
the ophthalmologist summarized any residua of ROP that were observed in the
posterior retina,8 using the categories described
in Table 1.
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Table 1. Retinal Outcome Categories
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DATA ANALYSIS
A Mantel-Haenszel test9-11
was used for combined statistical analysis of the paired-sample data from
children with bilateral threshold disease and the independent-sample data
from children with asymmetric disease. When data from the subgroup of children
with bilateral threshold disease were analyzed by selected demographic characteristics,
the McNemar test for correlated proportions was used, as well as exact P values calculated from the binomial distribution.
Visual Acuity
For analysis of distance and near visual acuity data, favorable visual
acuity outcome was defined as Snellen scores of better than 20/200; scores
of 20/200 or worse were classified as unfavorable, as were eyes that were
exempted from acuity testing due to blindness. For a more detailed analysis,
eyes in the favorable category were divided into 3 visual acuity subgroups:
(1) better than or equal to 20/40, (2) worse than 20/40 but better than or
equal to 20/60, and (3) worse than 20/60 but better than 20/200. Eyes in the
unfavorable category were subdivided into those with and without quantifiable
acuity scores. Eyes with quantifiable acuity in the unfavorable category included
all those that could be assigned a specific acuity score of 20/200 or worse.
Since the closest distance at which children's distance acuity was permitted
to be tested was 0.5 m, the poorest quantifiable acuity score was 20/1600
(20/200 equivalent letters presented at 0.5 m). Eyes without quantifiable
acuity included those without light perception, those with light perception
only, those that were exempt from acuity testing due to complete blindness,
and those that were able to detect only the 2.2 cm–wide stripes of the
"low vision" Teller acuity card. The low vision card was not used to quantify
acuity but was presented at different distances and positions to detect the
presence of minimal pattern vision. For analyses of numerical acuity results,
scores were converted to logarithmic values.
Fundus
Eyes were categorized as having favorable or unfavorable outcomes, as
defined in Table 1. Favorable
fundus outcomes included eyes with a normal posterior pole appearance, as
well as eyes with certain abnormalities, ie, straightening of the temporal
retinal vascular arcade, macular ectopia, extramacular retinal fold, stage
4A partial retinal detachment,12 or abnormalities
anterior to the equator, such as scarring or retinoschisis. Essentially, unfavorable
fundus outcomes included eyes that had visibly damaged or optically obstructed
foveas, in addition to eyes that had total retinal detachment. Eyes that had
undergone retinal reattachment procedures such as vitrectomy or lensectomy
subsequent to total retinal detachment were categorized as having unfavorable
outcomes,13 regardless of the current appearance
of the posterior pole.
RESULTS
Of the original cohort of 291 children who participated in the randomized
trial, 36 (12.4%) died before the 10-year examination, the most recent death
occurring between the 4-year and 5-year examinations. All
but 8 of the remaining 255 children (97%) returned for the 10-year examination.
Of the 8 children who did not return, 4 were previously found blind in both
the treated and the control eyes, 1 with bilateral threshold disease had favorable
acuity and fundus outcomes in both eyes, 1 child had favorable acuity in the
treated eye and was blind in the control eye, and 2 had "asymmetric" (only
one eye randomized) control eyes with favorable acuity and fundus outcomes.
Of those 247 children who returned, 202 had a history of bilateral threshold
ROP and 45 had a history of asymmetric threshold ROP. Hence, results for 227
treated eyes and 222 control eyes were available for the present analysis.
The mean ± SD gestational age for the returning children was identical
to that of the full cohort (26.3 ± 1.8 weeks), and the mean birth weight
was virtually identical (799 ± 166 g vs 800 ± 165 g).2 The 10-year examination was scheduled 10 to 10
years after randomization, with the children at a median chronologic age of
10.5 years.
Distance Snellen acuity results were obtained for 144 treated and 106
control eyes, and near Snellen acuity results were obtained for 144 treated
and 105 control eyes. An additional 70 treated eyes and 105 control eyes that
were blind were included in the Snellen acuity results as blind and not further
quantifiable. Fundus outcome data were obtained from 217 treated and 215 control
eyes. Figure 1 shows the percentages
of treated and control eyes that had an unfavorable outcome. The data show
an overall reduction in unfavorable outcomes of 28.5% (P<.001) for distance acuity, 31.0% (P<.001)
for near acuity, and 43.2% (P<.001) for fundus
structure in eyes randomized to treatment, compared with control eyes. As
indicated in Table 2, there were
13 treated eyes and 11 control eyes that were not blind, yet could not be
tested with the Snellen acuity procedure. These were eyes of children who
could not pass the pretest for Snellen acuity testing because of neurodevelopmental
delay, lack of cooperation, or extremely poor form-discrimination visual capability.
Examination of functional visual outcomes of these eyes on a case-by-case
basis, taking into account grating (Teller card) results obtained at earlier
ages, suggested that it was unlikely that the results of these 13 treated
and 11 control eyes would change the conclusions obtained with Snellen testing.
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Percentages of control and treated eyes showing an unfavorable outcome
at the 10-year follow-up examination.
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Table 2. Visual Acuity Outcome at 10 Years*
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There were also 8 children who did not undergo examination of function
or structure at age 10 years. Examination of the data available from previous
evaluations of structural and functional outcomes of the eyes of these children
indicated consistency of outcomes with those of the much larger group of study
participants who were examined at 10 years.
SUBGROUPS
Data analysis in the majority subgroup of 202 children with bilateral
threshold ROP likewise showed a statistically significant reduction in percentage
of unfavorable outcomes among the treated eyes. Distance Snellen acuity test
results showed there were 51 such children with a favorable outcome in the
treated eye and an unfavorable outcome in the control eye, compared with 15
children who had the opposite discordant outcome of unfavorable in the treated
eye and favorable in the control eye (P<.001).
Results of near Snellen acuity testing in these bilateral threshold cases
showed there were 52 children with a favorable outcome in the treated eye
and unfavorable in the control eye, and 14 children with the opposite discordance
(P<.001). Paired comparison of distance and near acuity was examined using 
statistics for perfect agreement, for the categories in Table 2. The visual acuity agreement between these 2 test distances
was strong (for treated eyes, = 0.66; for control eyes, =
0.81; perfect agreement would be = 1.00). For fundus outcome, 46 children
had a favorable result in the treated eye and an unfavorable result in the
control eye, compared with 7 children who showed the opposite discordance
(P<.001). When analyses were restricted to eyes
with zone I ROP, an unfavorable visual acuity outcome was found in 94% (15/16)
of treated eyes and 94% (15/16) of control eyes, and an unfavorable structural
outcome was found in 88% (14/16) of treated eyes and 94% (15/16) control eyes.
Additional subgroup analyses indicated that the beneficial effect of
cryotherapy on both function and structure was independent of birth weight
category (<750 g, 750-999 g, or 1000-1250 g), sex, race, single or multiple
birth, or whether the child was born in a CRYO-ROP study hospital. As previously
reported,5 there was no evidence of a differential
treatment effect based on the extent of stage 3+ ROP at threshold (5 to 12
clock-hour sectors).
DETAILED ANALYSIS OF VISUAL ACUITY
Table 2 shows a more detailed
presentation of the distance and near Snellen acuity results. For distance
acuity, the percentage of eyes with visual acuity of 20/40 or better that
were treated with cryotherapy was similar to that of control eyes, 25.2% vs
23.7% for controls (P = .63). Data for eyes in the
unfavorable category were divided into measurable acuity worse than 20/200
vs designated blind, ie, acuity was too poor to be quantified. At this low
end of the spectrum of function, there were fewer treated eyes than control
eyes categorized as blind (32.7% vs 49.8%; P<.001).
For near acuity, the percentage of eyes with 20/40 or better was essentially
the same in the 2 treatment groups (22.4% for treated eyes and 22.7% for control
eyes; P = .96); and the percentage of blind eyes
was again lower in the treated group (32.7%) than in the control group (50.2%)
(P<.001).
FUNDUS DETAILS
In Table 3, data for eyes
with favorable structural outcome are divided into either essentially normal
posterior pole or mild abnormalities that included abnormally straightened
temporal retinal vessels and macular ectopia. Eyes with unfavorable structural
outcome are subgrouped into those with and without total retinal detachment.
There are more treated than control eyes with normal-appearing posterior poles
(53.5% vs 36.7%, respectively; P<.001), while
fewer treated than control eyes had total retinal detachment (21.7% vs 41.4%,
respectively; P<.001).
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Table 3. Retinal Structural Outcome Categories at 10 Years Based on
Most Severe ROP Residua*
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In addition to assigning the category score for ROP residua in the posterior
pole, the examining physician recorded detailed information about structure
and function for each eye. Table 4 presents these data for the children who had bilateral threshold ROP, in whom
one eye was treated and the other served as control. Outcome variables are
arranged approximately in the order in which they would be encountered during
a clinical examination. Results favored treatment for all variables in which
there was a significant difference between treated and control eyes.
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Table 4. Outcome Variables of Children With Bilateral Threshold ROP*
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COMMENT
The CRYO-ROP study primarily is devoted to the evaluation of the efficacy
and safety of cryotherapy for ROP. In recent years, retinal ablative therapy
for ROP in the United States has been performed far more often with laser
photocoagulation than with cryotherapy. It is likely that the results of the
CRYO-ROP study are relevant to laser treatment for severe ROP, because other
studies have suggested that results obtained with laser therapy are similar
to those with cryotherapy.14-19
Consistent with our previous reports,3-5
the results at age 10 years indicate a significantly beneficial effect of
cryotherapy on visual acuity (P<.001) and on the
anatomic status of the posterior pole of the fundus (P<.001)
in eyes that develop severe (defined threshold) ROP during the neonatal period.
A detailed list of findings from ophthalmologic examination (Table 4) supports the beneficial effects of cryotherapy for eyes
with threshold ROP. Despite the benefit from cryotherapy, treated threshold
eyes still have a substantial percentage of unfavorable functional outcomes
(44.4%); this reflects the severity of ROP at the time of randomization, as
well as the effect of neurological factors of prematurity that can affect
visual function, eg, hydrocephalus, intracerebral hemorrhage, and periventricular
leukomalacia20-21 with subsequent
optic atrophy or hypoplasia due to transsynaptic degeneration. Optic atrophy
occurred in similar proportion in both treated and control eyes that could
be assessed for this variable. Premature infants with enlarged cerebral ventricles
as a sequela of neonatal intracranial hemorrhage,22
as well as those with cystic periventricular leukomalacia, seem more likely
to have visual impairment on a neurological basis.23
Several authors have reviewed and discussed the association between ROP and
central nervous system sequelae,24-25
and severity of ROP is significantly correlated with functional neurodevelopmental
outcomes among our studied children.26
VISUAL ACUITY
Data collected at the 10-year examination provide a more complete assessment
of visual acuity than was obtained at earlier examinations, owing to a high
follow-up rate of 97% (247/255) and the increased maturity and cooperation
of the children. The visual acuity benefit of cryotherapy at 10 years is represented
by a decrease in the proportion of eyes with poor acuity ("legally blind"
at 20/200 or worse) and an increase in the proportion of eyes with acuity
better than 20/200.
In the highest vision category, the finding of similar percentages of
eyes with 20/40 or better visual acuity in both treated and control groups
at 10 years (Table 2) differs
from data for eyes examined at age 5 years.5
At 5 years, there were more control eyes than treated eyes with acuity
in the 20/40 or better range (13.4% vs 20.0%; P =
.06), raising the possibility of a detrimental effect of neonatal cryotherapy
on visual acuity outcome in the best-sighted group of eyes with a history
of threshold ROP. In the present report, the number of children who could
complete visual acuity testing with the ETDRS charts was increased over that
at 5 years, due to an increase in the proportion of children who could
pass the pretest from 86.5% at 5 years to 94.7% at 10 years, and to
an increase in the follow-up rate from 91.8% at 5 years to 96.9% at
10 years. With this increased sample size, the potential adverse effect of
cryotherapy on the development of normal visual acuity seen at the 5-year
examination was not confirmed, suggesting that cryotherapy did not damage
foveal acuity. Testers were not instructed to attempt acuity better than 20/40,
yet there were several treated and control eyes noted to have 20/20 acuity,
revealing that such good acuity is potentially achievable after threshold
ROP, with or without cryotherapy.
CHANGES IN ANATOMIC OUTCOMES
These 10-year outcome data provide evidence that both mild and severe
ocular structural defects in the randomized children do not necessarily remain
stable over time. Compared with previous data, we find that the net prevalence
of mild abnormalities (macular ectopia and partial retinal detachment sparing
the fovea) decreased slightly in both control and treated eyes. For control
eyes, the prevalence was 21.7% at 5 years and 15.3% at 10 years. In
eyes treated with cryotherapy, the proportion of eyes that have macular ectopia
as the worst ROP sequela decreased from 23.6% to 19.4% during this same period.
These changes are concordant with the increase in the rates of normal-appearing
posterior structural findings in control and treated eyes (from 32.9% at 5
years to 36.7% at 10 years for control eyes, and from 49.5% at 5 years
to 53.5% at 10 years for treated eyes). In the absence of photographic documentation,
it cannot be determined whether this represents true improvement in some cases,
or simply the random vacillations of judgment that are inherently associated
with equivocal findings.
Rates of total retinal detachment reported among the control eyes over
time were relatively stable at 3 months, 1 year, and 3 years (32.4%,
33.0%, and 34.1%, respectively), but an apparent increase at 5 years
(38.6%) continued at 10 years (41.4%). In contrast, among the treated eyes,
no appreciable trend toward increasing detachments was observed (3 months
[18.0%], 1 year [18.3%], 3 years [20.3%], 5 years [22.1%],
and 10 years [21.6%]).1-5
This comparison of treated vs control eyes suggests enduring benefit from
cryotherapy.
Late rhegmatogenous retinal detachments due to ROP tend to occur between
the ages of 5 and 15 years.27 Tasman28 stated that these most commonly occur at age 14 years,
compared with a mean age of 5.7 years for tractional or exudative detachments
from ROP. Such reports have provided no denominators with which to determine
the frequency of these acquired catastrophes. Continued follow-up beyond 10
years in our prospective cohort should permit estimates of late retinal detachment
rates in both treated and control eyes. Such data would bear on the need for
vigilant monitoring in clinical practice, and facilitate the prospective counseling
of patients.
Although the results we have presented and discussed are encouraging,
surgical treatment for threshold ROP does involve ablation of peripheral retina.
One would expect such eyes to demonstrate a reduction in visual field extent
even if retinal detachment is prevented. Indeed, several previous reports
of small studies have suggested that visual fields are constricted in eyes
of children who have undergone peripheral retinal cryotherapy or laser photocoagulation
for severe ROP.29-31
We previously reported results of white-sphere kinetic perimetry32
in a subset of the CRYO-ROP study population at the 5-year examination.33 The data showed an average visual field reduction
of approximately 6° in treated eyes compared with untreated control eyes
of patients who had sight in both their treated eye and control eye. Goldmann
perimetry was conducted as part of the 10-year CRYO-ROP study examination,
and a detailed analysis will be the subject of another report.
IMPLICATIONS
Even allowing for a modest constriction of visual field due to peripheral
retinal ablation, the risk-benefit ratio clearly favors treatment of the more
severe (threshold) cases of ROP. Our previously expressed concern about an
unanticipated adverse side effect of cryotherapy on visual acuity outcome5 is allayed by the finding at 10 years that cryotherapy
does not reduce the proportion of eyes that achieve acuity of 20/40 or better.
It appears that constriction of the peripheral visual field may represent
the only undesirable side effect likely to be seen during the first decade
of life following cryotherapy for threshold ROP.
Results from the CRYO-ROP study indicate that, even with treatment,
acuity outcomes for eyes with confirmed threshold ROP are favorable in only
slightly more than half of the eyes. Does this finding, in combination with
the acceptable level of adverse effects attributable to cryotherapy, and the
improved convenience of laser therapy,17 mean
that ophthalmologists should begin to intervene with treatment at a milder
disease category than the research-designed "threshold" that was used in the
CRYO-ROP study? Data from the CRYO-ROP study cannot answer this question,
but our natural outcome data34 do suggest that
treatment of milder ROP will result in the unnecessary treatment of a substantial
number of eyes. Because zone I ROP carries the possibility of rapid progression
to retinal detachment35 and showed a high proportion
of unfavorable functional and structural outcomes in the present study, a
certain clinical bias toward earlier treatment for zone I ROP is understandable.
Nevertheless, a randomized study of earlier intervention for zone I ROP did
not show it to be advantageous.36 The overwhelming
majority of eyes with ROP less severe than the threshold severity defined
and used for the CRYO-ROP study have good structural outcome and will likely
have good visual function.5, 34, 37
Thus, ophthalmologists who treat at any severity level less than that threshold
should recognize that their good success could be entirely due to the good
prognosis for these eyes, even without treatment.
Continuing well-designed research is needed to identify more effective
ways of preventing or treating ROP. One potential approach to therapy is to
use the known additional risk factors for individual infants beyond the classification
of the infant's ROP to predict the likelihood of reaching threshold severity.
These additional risk factors include "infant" variables such as birth weight
and gestational age, as well as the rate of progression of ROP in the eye.37 Based on such data, a multifactorial risk analysis
program (Risk Management of ROP; RM-ROP) has been developed that can predict
the likelihood for an eye to progress to threshold ROP and from there to an
unfavorable functional outcome.38 This program
can be downloaded from the Internet at http://www.sph.uth.tmc.edu/rmrop/. Even though the program is based on the actual historical and outcome
data of the CRYO-ROP study, it has not been adequately tested in a clinical
setting, and consequently must still be considered theoretical. Thus, while
the program may serve as a guideline for predicting progression of ROP, there
remain many "soft" factors, such as interexaminer variation in ROP classification
standards, the concordance of ROP severity between the 2 eyes, the current
state of vigor of the infant, and the attitude of the infant's family, that
must enter into the clinician's decision concerning the indications for treating
relatively advanced ROP.
The National Eye Institute has funded a study that uses a modified version
(RM-ROP2) of the risk analysis program, which predicts the likelihood of an
unfavorable structural outcome at several points during the clinical course
of ROP, from the onset of ROP throughout its progression. This new Early Treatment
for ROP study is designed to determine whether using this method to select
eyes for treatment prior to attainment of the classic threshold of severity
will improve outcomes in those eyes.
AUTHOR INFORMATION
The CRYO-ROP Cooperative Group
The CRYO-ROP investigators who participated during the 10-year examination
period are as follows:
Clinical Centers
The Children's Hospital, Birmingham, Ala: Frederick
J. Elsas, MD (principal investigator); Monica Collins, RN; John Jones, MD;
James A. Kimble, MD; Lanning Kline, MD; Douglas Witherspoon, MD (coinvestigators). University of California–Davis Medical Center, Sutter Memorial
Hospital, Sacramento: Alan M. Roth, MD (principal investigator); Byron
H. Demorest, MD (coinvestigator). Children's Hospital National
Medical Center, Georgetown University Medical Center, George Washington University
Medical Center, and Washington Hospital, Washington, DC: William S.
Gilbert, MD (principal investigator); David Plotsky, MD (coprincipal investigator);
Mohamad Jaafar, MD; A. Raymond Pilkerton, MD; Patricia Ann Mercer, MPA (coinvestigators). Jackson Memorial Hospital, Miami, Fla: R. Michael Siatkowski,
MD (principal investigator); John Clarkson, MD; Rose Anne Johnson, RN; John
Simon, MD; Jitka Zobal-Ratner, MD (coinvestigators). University
of Illinois Eye and Ear Infirmary, Chicago; Loyola University, Maywood, Ill;
and Lutheran General Hospital, Parkwood, Ill: Marilyn T. Miller, MD
(principal investigator); Cathleen Cronin, MD; Mark Daily, MD; Lawrence M.
Kaufman, MD, PhD; David Mittelman, MD; Nydia Santiago; Michael Shapiro, MD;
Kathleen Skuran, RN; Peggy Squires; Charles Vygantas, MD (coinvestigators). Riley Hospital, Wishard Memorial Hospital, and University Hospital,
Indianapolis, Ind: Forrest D. Ellis, MD (principal investigator); Donna
Bates; Eugene M. Helveston, MD (coinvestigators). University
of Louisville Hospital, Norton Kosair Children's Hospital, Louisville, Ky: Charles C. Barr, MD (principal investigator); Craig H. Douglas, MD;
Peggy H. Fishman, MD; Gregory K. Whittington, PsyS (coinvestigators). Tulane Medical Center, New Orleans, La: Robert A. Gordon,
MD (principal investigator); James G. Diamond, MD; Debbie Neff, LPN (coinvestigators). The Johns Hopkins Hospital, Baltimore, Md: Michael X. Repka,
MD (principal investigator); Julia A. Haller, MD; Stephen P. Kraft, MD; Jana
Mattheu, CO, COMT (coinvestigators). William Beaumont Hospital
and Children's Hospital of Michigan, Detroit: John D. Baker, MD (principal
investigator); Michael T. Trese, MD (coprincipal investigator); Patrick J.
Droste, MD; Patricia Manatrey, RN; John Roarty, MD (coinvestigators). Fairview-University Medical Center, Minneapolis, Minn:
C. Gail Summers, MD (principal investigator); Donna K. Knobloch; Jane D. Lavoie,
CO; Robert C. Ramsay, MD; Terri L. Young, MD (coinvestigators). Upstate New York Center: Rochester, University of Rochester: Dale L.
Phelps, MD (principal investigator); Hilary Camarda, BA; Ernest Guillet, MD;
Robert Olsen, MD; Donald Tingley, MD; Nancy Wood, CCRA (coinvestigators); Syracuse, Retina Research Institute of Central New York:
Paul Torrisi, MD (coprincipal investigator); Robert Hampton, MD; Walter Merriam,
MD (coinvestigators); Buffalo, Children's Hospital of Buffalo: James D. Reynolds, MD (coprincipal investigator); Steven Awner, MD
(coinvestigator). Duke Eye Center, Durham, NC: Edward
G. Buckley, MD (principal investigator); Malcolm M. Anderson, Jr, PA-C (coinvestigator). Children's Hospital Medical Center, University Hospital, Cincinnati,
Ohio: Miles J. Burke, MD (principal investigator); Judith C. Johnson,
RN (coinvestigator). Columbus Children's Hospital, Ohio
State University Hospital, Columbus, Ohio: Gary L. Rogers, MD (principal
investigator); Don L. Bremer, MD (coprincipal investigator); Rae R. Fellows,
MEd; Alan D. Letson, MD; Richard E. McClead, MD; Mary Lou Kachmer McGregor,
MD (coinvestigators). Casey Eye Institute, Oregon Health
Sciences University, Portland: Earl A. Palmer, MD (principal investigator);
Pat Bartholomew, BS (coinvestigator). Children's Hospital
of Philadelphia, Pa: Graham E. Quinn, MD (principal investigator);
Gary C. Brown, MD; Richard W. Hertle, MD; Joseph J. Kubacki, MD; Sheryl J.
Menacker, MD; Dennis L. Miller, BA; David B. Schaffer, MD; William Tasman,
MD; Martin C. Wilson, MD (coinvestigators). University of
Pittsburgh, The Eye and Ear Institute of Pittsburgh, Children's Hospital of
Pittsburgh, Pa: Kenneth P. Cheng, MD (principal investigator); Albert
W. Biglan, MD; John S. Davis, MD; Margaret Schramm, MS, MPH (coinvestigators). Medical University Hospital, Charleston, SC: Richard A.
Saunders, MD (principal investigator); Ettaleah Bluestein, MD (coinvestigator). Vanderbilt University Hospital, Nashville: Sean P. Donahue,
MD, PhD (principal investigator); Amy B. Law, RN; Robbin Sinatra, MD; Steven
Steele, RN (coinvestigators). Methodist Medical Center,
Parkland Memorial Hospital, St Paul Hospital, Medical City Dallas Hospital,
and Presbyterian Hospital, Dallas, Tex: Rand Spencer, MD (principal
investigator); Jean Arnwine; Priscilla M. Berry, MD; Joel N. Leffler, MD;
David R. Stager, MD (coinvestigators). University of Texas
Health Science Center–Medical Center, San Antonio: W. A. J. van
Heuven, MD (principal investigator); Bailey L. Lee, MD; Maria G. Montéz,
RN, MSHP (coinvestigators). University of Utah Hospital,
Salt Lake City: Robert O. Hoffman, MD (principal investigator); Susan
Bracken, RN; Andrew Jordan, MD; Michael Teske, MD (coinvestigators).
Resource Centers, Project Officers or Managers, Principal
Investigators, Study Chairman, Coinvestigators, and Testers
National Eye Institute, Bethesda, Md: Donald
F. Everett, MA (project officer). Casey Eye Institute, Oregon
Health Sciences University, Portland: Earl A. Palmer, MD (principal
investigator and study chairman); Carol P. Krom, BA; Sandra Newton (project
managers); Sherrianne Okawa, MSW; Kimberly Beaudet (national tracking coordinators). School of Public Health, Coordinating Center for Clinical Trials,
University of Texas Health Science Center, Houston: Robert J. Hardy,
PhD (principal investigator); Barry R. Davis, MD, PhD (coinvestigator); Betty
Tung, MS (project manager). University of Arizona School
of Medicine, Tucson: Velma Dobson, PhD (principal investigator); Graham
E. Quinn, MD (coinvestigator); Nicole Gidlewski; Victoria Myers (vision testers);
Erin Harvey, MA (project manager).
Committees
Executive Committee: Permanent members: Earl
A. Palmer, MD (chairman); Velma Dobson, PhD; Robert J. Hardy, PhD; Dale L.
Phelps, MD; Graham E. Quinn, MD; C. Gail Summers, MD. Ex-officio
members: Donald F. Everett, MA; Carol P. Krom, BA; Betty Tung, MS. Rotating members: Robert O. Hoffman, MD; Maria B. Montéz,
RN, MSHP; David Plotsky, MD (1995-1996). Jean Arnwine; John D. Baker, MD;
Charles C. Barr, MD (1996-1997). Greg Anderson, PA; James D. Reynolds, MD;
R. Michael Siatkowski, MD (1997-1998). Editorial Committee:
Chairman: Earl A. Palmer, MD. Members: Velma
Dobson, PhD; Robert J. Hardy, PhD; Dale L. Phelps, MD; Graham E. Quinn, MD;
C. Gail Summers, MD. Ex-officio members: Carol P.
Krom, BA; Betty Tung, MS.
Accepted for publication March 1, 2001.
The CRYO-ROP study is supported by a cooperative agreement (EY05874)
from the National Eye Institute, National Institutes of Health, US Department
of Health and Human Services, Bethesda, Md.
The paper was drafted by the Editorial Committee.
Corresponding author and reprints: Earl A. Palmer, MD, CRYO-ROP Headquarters,
Casey Eye Institute, Oregon Health Sciences University, 3375 SW Terwilliger
Blvd, Portland, OR 97201-4197 (e-mail: palmere{at}ohsu.edu).
From the Casey Eye Institute, Oregon Health Sciences University, Portland.
The authors have no affiliation with or financial interest in the subject
matter or materials discussed in the article (eg, employment, consultancies,
stock ownership, honoraria), with the exception of Velma Dobson, PhD, who
receives a small royalty from the sale of Teller acuity cards.
REFERENCES
| |
1. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: preliminary
results. Arch Ophthalmol. 1988;106:471-479.
ABSTRACT
2. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: three-month
outcome. Arch Ophthalmol. 1990;108:195-204.
ABSTRACT
3. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: one-year
outcome—structure and function. Arch Ophthalmol. 1990;108:1408-1416.
ABSTRACT
4. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: 3-year
outcome—structure and function. Arch Ophthalmol. 1993;111:339-344.
ABSTRACT
5. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity: Snellen
visual acuity and structural outcome at 5 years after randomization. Arch Ophthalmol. 1996;114:417-424.
ABSTRACT
6. Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;102:1130-1134.
ABSTRACT
7. Ferris III FL, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol. 1982;94:91-96.
ISI
| PUBMED
8. Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP). Manual of Procedures, Vol III, Phase III Follow-up
Study. Springfield, Va: National Technical Information Service; 1999. US
Dept of Commerce publication PB99-123010.
9. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies
of disease. J Natl Cancer Inst. 1959;22:719-748.
10. Hardy RJ, Davis BR. The design, analysis and monitoring of an ophthalmological clinical
trial. In: American Statistical Association: 1989 Proceedings
of Biopharmaceutical Section. Alexandria, Va: American Statistical
Association; 1989:248-253.
11. Hardy RJ, Davis BR, Palmer EA, Tung B. Statistical considerations in terminating randomization in the Multicenter
Trial of Cryotherapy for Retinopathy of Prematurity. Control Clin Trials. 1991;12:293-303.
FULL TEXT
|
ISI
| PUBMED
12. The International Committee for the Classification of the Late Stages
of Retinopathy of Prematurity. An international classification of retinopathy of prematurity, II. Arch Ophthalmol. 1987;105:906-912.
ISI
| PUBMED
13. Quinn GE, Dobson V, Barr CC, et al. Visual acuity in infants after vitrectomy for severe retinopathy of
prematurity. Ophthalmology. 1991;98:5-13.
ISI
| PUBMED
14. McNamara JA, Tasman W, Vander JF, Brown GC. Diode laser photocoagulation for retinopathy of prematurity: preliminary
results. Arch Ophthalmol. 1992;110:1714-1716.
ABSTRACT
15. Hunter DG, Repka MX. Diode laser photocoagulation for threshold retinopathy of prematurity:
a randomized study. Ophthalmology. 1993;100:238-244.
ISI
| PUBMED
16. Laser ROP Study Group. Laser therapy for retinopathy of prematurity [letter]. Arch Ophthalmol. 1994;112:154-156.
17. White JE, Repka MX. Randomized comparison of diode laser photocoagulation versus cryotherapy
for threshold retinopathy of prematurity: 3-year outcome. J Pediatr Ophthalmol Strabismus. 1997;34:83-87.
FULL TEXT
|
ISI
| PUBMED
18. O'Neil JW, Hutchinson AK, Saunders RA, Wilson ME. Acquired cataracts after argon laser photocoagulation for retinopathy
of prematurity. J AAPOS. 1998;2:48-51.
19. Connolly BP, McNamara JA, Sharma S, Regillo CD, Tasman W. A comparison of laser photocoagulation with trans-scleral cryotherapy
in the treatment of threshold retinopathy of prematurity. Ophthalmology. 1998;105:1628-1631.
FULL TEXT
|
ISI
| PUBMED
20. Phillips J, Christiansen SP, Ware G, Landers S, Kirby RS. Ocular morbidity in very low birth-weight infants with intraventricular
hemorrhage. Am J Ophthalmol. 1997;123:218-223.
ISI
| PUBMED
21. Jacobson L, Hellström A, Flodmark O. Large cups in normal-sized optic discs: a variant of optic nerve hypoplasia
in children with periventricular leukomalacia. Arch Ophthalmol. 1997;115:1263-1269.
ABSTRACT
22. Brown DR, Biglan AW, Stretavsky MMA. Retinopathy of prematurity: the relationship with intraventricular
hemorrhage and bronchopulmonary dysplasia. J Pediatr Ophthalmol Strabismus. 1990;27:268-271.
|
