Ocular Cosmesis in
Retinopathy of Prematurity
Gail Summers, MD; Dale L. Phelps, MD; Betty Tung, MS; Earl A. Palmer, for the Cryotherapy for Retinopathy of Prematurity Cooperative Group
\s=b\ We report the externally apparent outcome in the natural history cohort (n=4099) that was followed up prospectively in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. The overall incidence of an adverse cosmetic outcome in the survivors who were examined 12 months post term (n=2759) was 15.1%. Adverse cosmetic outcomes included strabismus (12.8%), nystagmus (3.3%), total retrolental membrane (1%), epiphora (0.6%), corneal opacity (0.6%), cataract (0.3%), and episcleral hyperemia (0.3%). A comparable subgroup examined 24 months post term showed strabismus
(14.4%), nystagmus (2.2%), epiphora (0.5%), corneal opacity (0.7%), cataract (0.5%), episcleral hyperemia (0.5%), lid fissure asymmetry (2.4%), and corneal diameter asymmetry (2.0%). The rate of adverse aesthetic outcome was greatest in eyes that had developed more severe acute retinopathy of prematurity and an unfavorable structural outcome. In patients with bilateral threshold retinopathy of prematurity who underwent no therapeutic ocular procedures, other than randomized assignment to undergo cryotherapy in one eye, more frequent adverse cosmetic outcomes were found in the untreated eyes.
{Arch Ophthalmol. 1992;110:1092-1097)
IXTith advances in medical technology, ^ the survival rate for very-low-
birth-weight infants has improved. These infants
are
at
greatest risk for
developing retinopathy of prematurity (ROP); therefore, the number of pa¬
tients with ROP and its associated man¬ ifestations is increasing.17 The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYOROP) has shown that cryotherapy ap¬ plied to eyes with severe ROP can
MD;
reduce the occurrence of an unfavorable structural outcome at 12 months by 45.8%. A similar benefit for visual func¬ tion has also been described.8 However, the disease cannot be completely elim¬ inated at this time, and complications associated with ROP continue to be ob¬ served. Furthermore, the long-term ef¬ fects of treatment on ocular status re¬ main to be defined. The most important consequence of progressive ROP is visual impairment. However, an adverse cosmetic outcome can compound the patient's disability by interfering with psychosocial devel¬ opment. Interpersonal bonding and de¬ velopment of emotional maturity can be impaired due to unfavorable reactions from others.912 Indeed, the opportunity for successful early interpersonal inter¬ actions can actually play a greater role in a child's level of functioning than does his or her level of vision.13 Thus, abnor¬ mal ocular features that are externally visible can add to the burden of ROP, through their influence on the child's
psychological development. While the primary goal of the CRYOROP study was to evaluate the safety and efficacy of cryotherapy for severe ROP, additional prospective data have been collected from this large group of infants with a birth weight less than
1251 g. Included within these data are observations that permit evaluation of the external appearance of infants with varying levels of ROP, including those infants who were randomized to un¬
dergo cryotherapy. Herein, we present
the ocular cosmetic outcome results in the natural history population of pre¬ mature infants who were examined 12 and 24 months post term and examine the potential effect of cryotherapy on that outcome. PATIENTS AND METHODS
Accepted
publication March 3, 1992. From the Department of Ophthalmology, University of Minnesota, Minneapolis (Dr Summers); the Department of Pediatrics and Ophthalmology, University of Rochester (NY) (Dr Phelps); the School of Public Health, University of Texas at Houston (Ms Tung); and the Department of Ophthalmology and Pediatrics, Oregon Health Sciences University, Portland, Ore (Dr Palmer). Presented in part at the meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Fla, May 2, 1991. Reprint requests to CRYO-ROP Headquarters, The Oregon Health Sciences University, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, for
OR 97201-4197 (Dr Palmer).
Patients enrolled in the CRYO-ROP study included infants with a birth weight less than 1251 g who were born between January 1, 1986, and November 30, 1987, and followed up at one of the 23 participat¬ ing centers. Of 9751 patients admitted to participating neonatal intensive care units, a subgroup of 4099 infants was defined as the "natural history cohort."14'15 Enroll¬ ment into this cohort required that the infant survive up to 28 days, that consent to participation in the study was obtained, that the infants have no serious ocular
anomaly
or
major systemic malformations,
and that they undergo a first eye exami¬ nation by a certified study ophthalmologist by 49 days after birth. The schedule of eye examinations in the nursery has been pre¬ viously described.1116 Stage of ROP was defined by the International Classification of ROP.17 When an eye developed a level of ROP previously defined as the thresh¬ old for treatment16 (218 patients), random¬ ization was made to the cryotherapy or control group. Another 73 patients with threshold disease were referred for ran¬ domization in the cryotherapy trial and are part of the study population previously re¬ ported.8'15·16 They are not included in this report because they were not eligible for participation in the natural history cohort according to the inclusion criteria listed above. Informed consent was obtained prior to entry into the natural history study and again prior to randomization. Although data from fundus photographs of randomized participants were examined in previous reports,8'14·16 the findings of exam¬ ining ophthalmologists were used for data analysis in the present report. Of the 4099 participants in the natural history cohort, 3835 survived until the examination at 12 months post term. An effort was made to examine each of these participants at one of the 23 participating centers. Due to budget¬ ary constraints, the entire population could not be reexamined at annual intervals after this 12-month examination. However, a sub¬ group of the natural history cohort (1208 pa¬ tients) was selected for follow-up at 24 months post term. This group consisted of infants who were enrolled at five of the 23 participating centers. After the 12-month examination, these centers were designated "natural history centers." In addition, all of the remaining randomized patients were fol¬ lowed up at the other 18 participating cen¬ ters. Our report includes all patients in the natural history cohort, as defined above, who were examined at the 12- and 24-month out¬ come times. Both monocular and interocular variables were identified as adverse cosmetic out¬ comes. The monocular variables (total retro¬ lental membrane, epiphora, corneal opacity, cataract, and episcleral hyperemia) de¬ scribed the cosmetic result in an individual eye. The interocular (binocular) variables required the assessment of one eye com¬ pared with the other eye and included stra¬ bismus, nystagmus, lid fissure asymmetry, and corneal diameter asymmetry. The latter two variables were assessed by external in¬ spection at the time of the clinical examina¬ tion. The investigator indicated whether the lid fissures and corneal diameters were sym¬ metric or asymmetric; if they were asym¬ metric, the side with the smaller diameter was indicated. Actual measurements of lid fissures and corneal diameters were not re-
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corded in the study data. Although microphthalmos may have accounted for the smaller lid fissure and corneal diameter, ax¬ ial lengths were not recorded in the study data. Most variables were recorded at both the 12- and 24-month examinations. A complete retrolental membrane was not specifically recorded at the 24-month ex¬ amination, and asymmetric corneal diameTable 1.—Natural
Group patients enrolled in natural history cohort (n=4099)_
ters and lid fissures were recorded only at the 24-month examination. The incidence of any of these features that could contrib¬ ute to an adverse cosmetic outcome was
examined. The effects of both the severity of ROP at its maximum acute stage and the final structural outcome on cosmetic outcome were determined. Finally, the ef¬ fect of cryotherapy on cosmetic outcome was studied.
History Population
Mean±SD Birth Weight, g
Mean±SD Gestational Age, wk
954 ±185
27.9±2.2
Total
12-mo Examination
Natural history cohort at 23 participating centers
(n=2759)_
952±184
27.8±2.2
953±188 24-mo Examination
27.7±2.3
954±186
27.8±2.3
Natural history cohort at 5 "natural history centers"
(n=982)_
Natural history cohort at 5 "natural history centers"
(n=993)
RESULTS Patient Population
Of the 4099 patients enrolled in the natural history cohort, 3835 survived until the 12-month examination, and 2759 (72%) of these patients returned for follow-up examination. In the sub¬ group of the natural history cohort that was followed up at one of the five nat¬ ural history centers, 982 (81%) returned at 12 months. This subgroup represents 30% of the total population available for follow-up, and their birth weights and gestational ages were similar to the to¬ tal natural history cohort (Table 1). At 24 months, 993 (82%) of the 1208 pa¬ tients in the natural history cohort fol¬ lowed up at the five natural history centers returned for follow-up exami¬ nation. Their birth weights and gesta¬ tional ages were also similar to the overall natural history group. Data for the natural history subgroup are there¬ fore presumed to accurately reflect the entire natural history cohort.
Table 2.—Incidence of Adverse Cosmetic Outcome* 12-mo Examination 24-mo Examination
History Population
History Subgroup
Total Natural Adverse Cosmetic Outcome Monocular outcome Total retrolental membrane
Epiphora Corneal opacity Cataract
Episcleral hyperemia Interocular outcome Strabismus
Nystagmus Lid fissure asymmetry Corneal diameter asymmetry *UG indicates number of
Table
patients/eyes
I% Present n=5518 1.0 0.6 0.6 0.3 0.3 n=2759 12.8 3.3 NR NR in which examiner
I% Present n=1964 1.0 0.7 0.6 0.4 0.2 n=982 11.7 2.9 NR NR
UG 43
13
40 49
was
History Subgroup
Natural
unable to
3.—Relationship of Retinopathy of Prematurity (ROP)
grade
the
Natural I
UG
% Present n=198i NR
15
0.5 0.7 0.5 0.5 n=993 14.4 2.2 2.4 2.0
13 26
particular outcome; NR,
to 12-Month Cosmetic Outcome
UG
31
not recorded.
by International
Classification of ROP*
Zone 2 Outcome
Zone 1 ROP
i
I
Stage 3+
Stage 3
Stage
2
Stage
1
Monocular outcome (n=5518) Total retrolental membrane
Zone 3
Other
No ROP
0 0 0 0 (n=52) 16(20.8) 34(7.7) 1(0.2) 1(0.1) 4(0.9) 3(0.3) 5(0.5) 2(0.3) 1(2.3) 16(0.8) Epiphora (n=34)_1 (1.2)_2(0.4) Corneal opacity (n=31)_5(6.1) 22(4.7) 1(0.2) 3(0.3) 0_0_0_0_ Cataract (n=18) 2 (2.4)_12(2.6) 0 0 0 1(0.1) 2(0.1) 1(0.2) Episcleral hyperemia (n=17)_6(7.1)_6(1.3) (0.1)_0_0_0_4(0.2) 0_1 Interocular outcome (n=2759) Strabismus (n=347) 102(43.4) 37(15.7) 57(11.8) 47(9.5) 39(12.3) 1(4.5) 50(5.6) 14(36.8) 0 41(18.3) 10(4.2) 10(2.1) 2(0.4) 6(1.9) 5(0.6) Nystagmus (n=89) _15(36.6) 0 0 0 0 2(1.1) 1(0.9) Eyelid fissure asymmetry (n=24)t _6(35.3) 15(20.0) Corneal diameter asymmetry (n=20)t 0 0 0 4(23.5) 15(20.0) 1(0.6) *Values are number (percent). Percentages indicate prevalence of the adverse cosmetic outcome for each specified level of ROP after the "unable to grade" patients/eyes are removed from the denominator. tData from subgroup at 24 months (n=993).
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Table
Ocular Structural Outcome 12
Monocular Cosmetic Outcome Corneal opacity Present Absent Unable to grade Cataract Present Absent Unable to grade
-1
Unfavorable!
Favorable
3(0.1)
Episcleral hyperemia Present Absent Unable to
24
mo
121
6(0.1)
10(7.1)
5339
130
9
6(0.1)
-1
2(0.1)
11
1934
5
(6.2)
9
(28.9) 27
(0.3)
3
1931
(8.6) 32
(0.5)
1
1927
137
5339
Unfavorable!
Favorable
(17.1)
25
5342
mo
I
(2.9) 34
grade
Epiphora
1
32 (0.6) 5309
Present Absent
Unable to grade Narrower eyelid fissure Present Absent Unable to grade Smaller corneal diameter Present Absent Unable to grade
(0.7)
7
2
(5.4) 35
more.
9
(0.5)
13
(31.7)
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
1930
29
NR
NR
0
0
1927
6
*NR indicates not recorded. Values are number (percent). fUnfavorable structural outcome includes total retinal detachment and ing macula or retinal fold.
Table
(0.4)
1928
145
28
(0.3)
partial
12
(29.3)
retinal detachment involv¬
5.—Relationship of Bilateral Threshold Retinopathy of Prematurity to Cosmetic Outcome* 12 mo
Cosmetic Outcome Total retrolental membrane Corneal opacity Cataract
24
mo
Treated
Control
Treated
Control
(n=110)
(n=110)
(n=103)
(n=103)
Present
UG
Present 14
NR
NR NR
NR NR
" UG
Present NR
UG
Present NR
UG
Episcleral hyperemia Epiphora Narrower lid fissure Smaller corneal diameter
NR
*NR indicates not recorded; UG, unable to
NR NR
14
15
grade.
Incidence of Adverse Cosmetic Outcome
The incidence of an adverse cosmetic patients in the natural his¬ tory cohort at 12 and 24 months is pre¬ sented in Table 2. The 12-month data are presented for the entire natural history cohort and for the subgroup that was followed up at the five natural his¬ tory centers. The 24-month data repre¬ sent the natural history subgroup. The denominator for the percent with an unfavorable outcome includes only outcome for
cohort followed up at the five natural history centers was similar to that of the total population. In addition, similar cosmetic outcome results at the 24-month examination were found within this subgroup. The most common adverse externally evident outcome was strabismus (12.8% of the total natural history population at 12 months and 14.4% of the natural his¬ tory subgroup examined at 24 months). Analysis showed a trend for the inci¬ dence of strabismus to increase in those patients with lower birth weights and gestational ages: 20.0% for those weigh¬ ing less than 750 g, 12.6% for those weighing 750 to 999 g, and 10.4% for those weighing 1000 to 1250 g, and 16.1% for those born at 27 weeks' ges¬ tation or less, 10.2% for those born at 28 to 31 weeks' gestation, and 9.6% for those born at 32 weeks' gestation or
history
4.—Relationship of Structural Outcome of Retinopathy of Prematurity to Cosmetic Outcome*
those eyes (monocular variables) or pa¬ tients (interocular variables) for whom an assessment was made by an investi¬ gator. Some variables could not be graded due to lack of patient coopera¬ tion for accurate examination, reduced media clarity, or previous enucleation (one eye). These eyes/patients are indi¬ cated in the columns in Table 2 labeled "unable to grade" and have been ex¬ cluded from the denominator. At 12 months, the incidence of an ad¬ verse cosmetic outcome in the natural
An additional five patients with vi¬ sion in both eyes showed temporal mac¬ ular heterotopia in one or both eyes, which often gives the cosmetic appear¬ ance of strabismus, despite the absence of true strabismus on alternate cover testing. The temporal displacement of the macula causes nasal displacement of the anterior visual axis (positive angle kappa), giving the appearance of ex-
otropia.
Because patients with bilateral threshold ROP had only one eye treated with cryotherapy, this could potentially contribute to an increase in the incidence of strabismus in this population. When the randomized pa¬ tients were excluded from data analy¬ sis, strabismus occurred in 10.3% of the natural history population at 12 months (n=2577). The birth weights and gestational ages were slightly greater for this group (mean [±SD] birth weight, 962±181 g; mean [±SD] gestational age, 28.0±2.2 weeks), and the incidence of strabismus was as follows: 13.8% for infants weighing less than 750 g, 10.1% for those weighing 750 to 999 g, and 9.5% for those weighing 1000 to 1250 g, and 11.7% for those born at 27 weeks' gestation or less, 9.3% for those born at 28 to 31 weeks' gestation, and 9.7% for those born at 32 weeks' gestation or more. These data show a lower incidence of strabismus in the groups with lower birth weights and lower gestational ages compared with the total natural history population (above). This reduction reflects the predominance of the randomized pop¬ ulation in these groups with lower birth weights and lower gestational ages and their exclusion in these later data.
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examiner judge that epiphora was re¬ lated to ROP, presumably related to the associated complications of glaucoma or corneal opacity causing photosensitivity and tearing. A similar relationship was noted in the subgroup at 12 and 24 months.
Relationship to Structural Outcome Table 4
presents the relationship be¬
tween structural outcome and an ad¬ verse cosmetic outcome at 12 and 24
Fig 1.—Retrolental mass and shallow ante¬ rior chamber due to stage 5 retinopathy of prematurity result in an unsatisfactory cos¬ metic appearance.
Fig 2.—Dense corneal opacity obscures a portion of the pupil in an eye with a retrolen¬ tal membrane due to retinopathy of prematu¬ rity.
months in this natural history cohort. An unfavorable structural outcome de¬ termined by physician examination is defined in the CRYO-ROP study as a total retinal detachment, retrolental mass, a partial retinal detachment in¬ volving zone 1, or a retinal fold involv¬ ing the macula.16 Eyes with other fundus appearances were considered to have a favorable structural outcome; this included eyes with macular heterotopia, less severe residual ROP, and an absence of fundus abnormalities. The percent unfavorable is calculated as the number with the cosmetic outcome variable present as a portion of the to¬ tal number of eyes (with cosmetic out¬ come present or absent) with an unfa¬ vorable structural outcome. Eyes with an unfavorable structural outcome showed an increased rate of corneal opacity, cataract, and episcleral hyperemia at both the 12- and 24-month examinations. Epiphora was the only cosmetic outcome variable that was not directly related to an unfavorable struc¬ tural outcome at 12 months, but a rela¬ tionship between epiphora and unfavor¬ able structural outcome was seen at 24 months. At the 24-month examination, an unfavorable structural outcome was more likely to be associated with a nar¬ rower lid fissure and smaller corneal diameter. Most of the eyes with a nar¬ rower lid fissure also had a smaller cor¬ neal diameter. All but two of these eyes had total retinal detachment. Effect of
Fig 3.—Spectacle magnification improves the aesthetic appearance of a patient microphthalmic left eye that is blind due to stage 5 retinopathy of prematurity.
Relationship to Acute
ROP
Table 3 shows the relationship be¬ tween an adverse cosmetic outcome and the most severe documented level of acute ROP. A few infants had an ad¬ verse cosmetic outcome despite lack of documented ROP. Some infants were not examined at the defined intervals due to poor medical status; in other cases, media haze prevented documen¬ tation of the presence or absence of
with
a
ROP. The data listed in the column in Table 3 labeled "other" reflect infants found to have regressing ROP even though active ROP was not previously seen. A more posterior location and a higher stage of ROP indicate more severe structural disease. In Table 3, a direct relationship between all the ad¬ verse cosmetic outcomes, except epi¬ phora, and the severity of ROP is dem¬ onstrated. In only three eyes did the
Cryotherapy
Table 5 compares the cosmetic out¬ come in treated and control eyes. In this analysis, data from patients with bilat¬ eral threshold ROP were examined for the effect of cryotherapy on ocular cosmesis. Because additional ocular sur¬ gery is a confounding variable, data from patients who underwent eye sur¬ gery other than cryotherapy were ex¬ cluded from this analysis. Of the 218 patients with threshold disease in the natural history cohort, 180 had bilateral threshold ROP, with one eye random¬ ized to receive cryotherapy. Twentytwo patients died before the 12-month examination, and 148 returned for follow-up examination 12 months after
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Fig 4.—The placement of a scierai shell over a microphthalmic left eye improves the appear¬ of a patient with stage 5 retinopathy of prematurity.
ance
cryotherapy; 110 ofthose returning had undergone other ocular procedures (eg, scierai buckling or vitrectomy) in either eye. One hundred forty patients in the natural history cohort with bilat¬
COMMENT
not
eral threshold disease returned for follow-up examination at 24 months, and 103 of these had not undergone other therapeutic ocular procedures. These patients (n=110 at 12 months and n=103 at 24 months) were examined for the effect of cryotherapy on cosmetic outcome.
The cosmetic outcome results for these matched pairs of eyes in patients in the natural history cohort with bilat¬ eral threshold ROP (one eye random¬ ized to treatment with cryotherapy and no other invasive ocular treatment for either eye) are presented in Table 5. The results at 12 and 24 months are listed for each outcome variable, except for those that are indicated as not being specifically recorded on the data entry form. An increased rate of adverse cos¬ metic outcome is seen in the untreated (control) eyes at both 12 and 24 months. At the 24-month examination, the rate of narrower lid fissure and smaller cor¬ neal diameter is greater for the control eyes.
The importance of a cosmetically vis¬ ible abnormality depends on the extent of the abnormality, the social setting in which it is noticed, and the awareness and bias of the observer. We have examined the incidence of various ad¬ verse cosmetic outcomes in a large group of very-low-birth-weight infants who were prospectively examined by certified study ophthalmologists. While reports of aesthetically relevant com¬ plications of ROP have described mi-
crophthalmos, ptosis, nystagmus, cata¬
ract, strabismus, and phthisis,18"22 we believe that this is the first report spe¬
cifically addressing the incidence of cos¬
metic outcome of ROP. The CRYOROP study has shown that cryotherapy reduces the rate of an unfavorable structural and functional outcome at 12 months. The data presented herein show that cryotherapy also reduces the rate of an adverse cosmetic outcome. Although cryotherapy does not prevent externally visible ocular sequelae, eyes with threshold ROP that were treated with cryotherapy are less likely to ap¬ pear abnormal than untreated eyes with a similar level of ROP.
While the primary consequence of strabismus is disruption of binocularity, the cosmetic effect is addressed in this report. Strabismus was the most com¬ mon externally visible outcome in this group of premature infants, occurring at a rate of 12.8% at the 1-year exami¬ nation and 14.4% in the subgroup at the 2-year examination. The rate is slightly lower when infants who did not reach threshold were eliminated from the study group (see the "Results" section). Because strabismus is a binocular ab¬ normality, it is possible that the inci¬ dence of strabismus in the randomized group would have been different if both eyes had received cryotherapy. An ad¬ ditional five patients showed temporal macular heterotopia, which can cause pseudostrabismus. This structural dis¬ tortion alters the angle kappa and pro¬ duces the cosmetic appearance of an exotropia for temporal ectopia, even in the absence of true strabismus.23 Other investigators have also noted an in¬ creased frequency of strabismus in pre¬ mature infants.2426 Strabismus findings in the CRYO-ROP study will be further documented in a future publication. Lid fissure asymmetry is most often recognized as monocular or asymmetric blepharoptosis. Fledelius20 has re¬ ported a prevalence of 2% for congeni¬ tal ptosis in 302 infants with a birth weight less than 2500 g. However, asymmetric lid fissures in the present study were directly related to corneal diameter asymmetry and to an unfavor¬ able structural outcome (Table 4). This suggests that the lid abnormality in most of our cases represented a pseudoptosis due to enophthalmos and microphthalmos, although axial length was not recorded. Because corneal di¬ ameter asymmetry was recorded only at the 24-month examination, the data do not allow an explanation of whether microphthalmos, enophthalmos, and fis¬ sure narrowing are due to local arrest of growth and development or to globe shrinkage following the development of advanced cicatricial ROP. Transient lens opacities have been reported in premature newborns,27,28 but these are not usually considered to be visually or cosmetically important. However, postnatal cataracts have been reported to occur at a rate of 0.3% in a series of 1000 infants with a birth weight less than 1260 g29; a similar inci¬ dence was found in the present study.
Certainly,
some
cataracts, particularly
those involving the anterior portion of the lens, can produce an aesthetically unsatisfactory appearance. Leukokoria is an externally visible abnormality that may be caused by various structural abnormalities, including not only cata-
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ract but also retrolental mass
(Fig 1), as
recorded herein. Corneal opacities may be sufficiently dense to present a cosmetic abnormal¬ ity (Fig 2). The rate of corneal opacity was highest in the eyes with an unfa¬ vorable structural outcome (Table 4). Another report from the CRYO-ROP
Cooperative Group suggested no change in the rate of corneal opacity in
eyes with
stage 5 ROP in which vitrec-
performed.30 Methods to improve the external ap¬
tomy
eyelid on the side of the enophthalmic orbit has been recom¬ mended to improve cosmesis, but none of the patients in the present study had undergone lid surgery by the time of the elevate the
24-month examination. Another poten¬ tial method to improve cosmesis in mi¬ crophthalmos is volume expansion.31 Use of this technique in patients with ROP has not been described, to our
knowledge.
Medical literature
was
following severe ROP include optical magnification of the blind, microphthalmic eye with a less myopic or more hyperopic correction than the con¬ tralateral spectacle lens (Fig 3). This method involves placement of various trial lenses in front of the blind, microphthalmic eye to minimize the ap¬ parent difference in sizes of the globes. A scierai shell fit over a phthisical eye can also improve the aesthetic appear¬ ance (Fig 4). Blepharoptosis surgery to pearance
on
ROP is under¬
standably focused on management of the premature infant and treatment of ROP to improve the ocular structural and functional outcome. However, rec¬ ognition of the cosmetic abnormalities associated with ROP and the treatment alternatives in the management of these problems remain important to the child's development. The negative emo¬ tional reactions to the blind are well de¬ scribed,9'12,32 but the reactions to more subtle aesthetic abnormalities, such as corneal opacity or cataract, are not well
defined. Parental expectations for a child with abnormal ocular features may be reduced. Positive interpersonal relationships are necessary for psy¬ chosocial maturation, and abnormal cos¬ mesis can interfere with these rela¬ tionships. Later, particularly in adoles¬ cence, an adverse cosmetic outcome can affect the child's self-image.33·34 Herein, we have defined the incidence of cos¬ metic abnormalities in a very-low-birthweight population. In addition, we have shown that there do not appear to be externally visible adverse side effects of cryotherapy that would deter its use in patients with threshold ROP. Future efforts should be devoted to under¬ standing how external appearance in¬ fluences the social, educational, and de¬ velopmental maturation of the pre¬ mature child. This investigation was supported by cooperative agreement U01 E405874 from the National Eye Insti¬ tute, National Institutes of Health, Bethesda, Md. Pat Wallace, of the Casey Eye Institute, Portland, Ore, provided photographic assistance for Fig 4.
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Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Oph-
thalmol. 1984;102:1130-1134. 18. Hallenbeck J. Pseudo-retardation in retrolental fibroplasia. The New Outlook for the Blind.
1954;48:301-307. 19. Gitter KA, Meyer D, White RH Jr, Ortolan G, Sarin LK. Ultrasonic aid in the evaluation of leucocoria. Am J Ophthalmol. 1968;65:190-195. 20. Fledelius H. Prematurity and the eye: ophthalmic 10-year follow-up of children of low and
weight. Acta Ophthalmol Suppl (Copenh). 1976;128:11-245. 21. Harris GS. Retinopathy of prematurity and retinal detachment. Can J Ophthalmol. 1976;11:21\x=req-\ normal birth
25.
22.
Kelly SP,
Fielder AR. Microcornea associ-
ated with retinopathy of prematurity. Br J Ophthalmol. 1987;71:201-203. 23. Foster RS, Metz HS, Jampolsky A. Strabismus and pseudostrabismus with retrolental fibroplasia. Am J Ophthalmol. 1975;79:985-989. 24. Kushner BJ. Strabismus and amblyopia associated with regressed retinopathy of prematurity. Arch Ophthalmol. 1982;100:256-261. 25. Schaffer DB, Quinn GE, Johnson L. Sequelae of arrested mild retinopathy of prematurity. Arch
Ophthalmol. 1984;102:373-376.
26. Snir M, Nissenkorn I, Sherf I, Cohen S, Ben Sira I. Visual acuity, strabismus and amblyopia in premature babies with and without retinopathy of prematurity. Ann Ophthalmol. 1988;20:256-258. 27. McCormick AQ. Transient cataracts in premature infants: a new clinical entity. Can J Ophthalmol. 1968;3:202-206. 28. Alden ER, Kalina RE, Hodson WA. Transient cataracts in low-birth-weight infants. J Pediatr.
1973;82:314-318.
29. Guy LP. Postnatal cataracts in premature infants. Am J Ophthalmol. 1954;38:65-68. 30. Quinn GE, Dobson V, Barr CC, et al. Visual acuity in infants after vitrectomy for severe retinopathy of prematurity. Ophthalmology. 1991;98:5-13. 31. Cahill KV, Burns JA. Volume augmentation of the anophthalmic orbit with cross-linked collagen (Zyplast). Arch Ophthalmol. 1989;107:1684-1686. 32. Van Hasselt VB. Social adaptation in the blind. Clin Psychol Rev. 1983;3:87-102. 33. Kent D. Finding a way through the rough years: how blind girls survive adolescence. J Vis Impairment Blindness. 1983;77:247-250. 34. Van Hasselt VB, Hersen M, Kazdin AE. Assessment of social skills in visually-handicapped adolescents. Behav Res Ther. 1985;23:53-63.
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Retinopathy of Prematurity
Gail Summers, MD; Dale L. Phelps, MD; Betty Tung, MS; Earl A. Palmer, for the Cryotherapy for Retinopathy of Prematurity Cooperative Group
\s=b\ We report the externally apparent outcome in the natural history cohort (n=4099) that was followed up prospectively in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity. The overall incidence of an adverse cosmetic outcome in the survivors who were examined 12 months post term (n=2759) was 15.1%. Adverse cosmetic outcomes included strabismus (12.8%), nystagmus (3.3%), total retrolental membrane (1%), epiphora (0.6%), corneal opacity (0.6%), cataract (0.3%), and episcleral hyperemia (0.3%). A comparable subgroup examined 24 months post term showed strabismus
(14.4%), nystagmus (2.2%), epiphora (0.5%), corneal opacity (0.7%), cataract (0.5%), episcleral hyperemia (0.5%), lid fissure asymmetry (2.4%), and corneal diameter asymmetry (2.0%). The rate of adverse aesthetic outcome was greatest in eyes that had developed more severe acute retinopathy of prematurity and an unfavorable structural outcome. In patients with bilateral threshold retinopathy of prematurity who underwent no therapeutic ocular procedures, other than randomized assignment to undergo cryotherapy in one eye, more frequent adverse cosmetic outcomes were found in the untreated eyes.
{Arch Ophthalmol. 1992;110:1092-1097)
IXTith advances in medical technology, ^ the survival rate for very-low-
birth-weight infants has improved. These infants
are
at
greatest risk for
developing retinopathy of prematurity (ROP); therefore, the number of pa¬
tients with ROP and its associated man¬ ifestations is increasing.17 The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYOROP) has shown that cryotherapy ap¬ plied to eyes with severe ROP can
MD;
reduce the occurrence of an unfavorable structural outcome at 12 months by 45.8%. A similar benefit for visual func¬ tion has also been described.8 However, the disease cannot be completely elim¬ inated at this time, and complications associated with ROP continue to be ob¬ served. Furthermore, the long-term ef¬ fects of treatment on ocular status re¬ main to be defined. The most important consequence of progressive ROP is visual impairment. However, an adverse cosmetic outcome can compound the patient's disability by interfering with psychosocial devel¬ opment. Interpersonal bonding and de¬ velopment of emotional maturity can be impaired due to unfavorable reactions from others.912 Indeed, the opportunity for successful early interpersonal inter¬ actions can actually play a greater role in a child's level of functioning than does his or her level of vision.13 Thus, abnor¬ mal ocular features that are externally visible can add to the burden of ROP, through their influence on the child's
psychological development. While the primary goal of the CRYOROP study was to evaluate the safety and efficacy of cryotherapy for severe ROP, additional prospective data have been collected from this large group of infants with a birth weight less than
1251 g. Included within these data are observations that permit evaluation of the external appearance of infants with varying levels of ROP, including those infants who were randomized to un¬
dergo cryotherapy. Herein, we present
the ocular cosmetic outcome results in the natural history population of pre¬ mature infants who were examined 12 and 24 months post term and examine the potential effect of cryotherapy on that outcome. PATIENTS AND METHODS
Accepted
publication March 3, 1992. From the Department of Ophthalmology, University of Minnesota, Minneapolis (Dr Summers); the Department of Pediatrics and Ophthalmology, University of Rochester (NY) (Dr Phelps); the School of Public Health, University of Texas at Houston (Ms Tung); and the Department of Ophthalmology and Pediatrics, Oregon Health Sciences University, Portland, Ore (Dr Palmer). Presented in part at the meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Fla, May 2, 1991. Reprint requests to CRYO-ROP Headquarters, The Oregon Health Sciences University, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, for
OR 97201-4197 (Dr Palmer).
Patients enrolled in the CRYO-ROP study included infants with a birth weight less than 1251 g who were born between January 1, 1986, and November 30, 1987, and followed up at one of the 23 participat¬ ing centers. Of 9751 patients admitted to participating neonatal intensive care units, a subgroup of 4099 infants was defined as the "natural history cohort."14'15 Enroll¬ ment into this cohort required that the infant survive up to 28 days, that consent to participation in the study was obtained, that the infants have no serious ocular
anomaly
or
major systemic malformations,
and that they undergo a first eye exami¬ nation by a certified study ophthalmologist by 49 days after birth. The schedule of eye examinations in the nursery has been pre¬ viously described.1116 Stage of ROP was defined by the International Classification of ROP.17 When an eye developed a level of ROP previously defined as the thresh¬ old for treatment16 (218 patients), random¬ ization was made to the cryotherapy or control group. Another 73 patients with threshold disease were referred for ran¬ domization in the cryotherapy trial and are part of the study population previously re¬ ported.8'15·16 They are not included in this report because they were not eligible for participation in the natural history cohort according to the inclusion criteria listed above. Informed consent was obtained prior to entry into the natural history study and again prior to randomization. Although data from fundus photographs of randomized participants were examined in previous reports,8'14·16 the findings of exam¬ ining ophthalmologists were used for data analysis in the present report. Of the 4099 participants in the natural history cohort, 3835 survived until the examination at 12 months post term. An effort was made to examine each of these participants at one of the 23 participating centers. Due to budget¬ ary constraints, the entire population could not be reexamined at annual intervals after this 12-month examination. However, a sub¬ group of the natural history cohort (1208 pa¬ tients) was selected for follow-up at 24 months post term. This group consisted of infants who were enrolled at five of the 23 participating centers. After the 12-month examination, these centers were designated "natural history centers." In addition, all of the remaining randomized patients were fol¬ lowed up at the other 18 participating cen¬ ters. Our report includes all patients in the natural history cohort, as defined above, who were examined at the 12- and 24-month out¬ come times. Both monocular and interocular variables were identified as adverse cosmetic out¬ comes. The monocular variables (total retro¬ lental membrane, epiphora, corneal opacity, cataract, and episcleral hyperemia) de¬ scribed the cosmetic result in an individual eye. The interocular (binocular) variables required the assessment of one eye com¬ pared with the other eye and included stra¬ bismus, nystagmus, lid fissure asymmetry, and corneal diameter asymmetry. The latter two variables were assessed by external in¬ spection at the time of the clinical examina¬ tion. The investigator indicated whether the lid fissures and corneal diameters were sym¬ metric or asymmetric; if they were asym¬ metric, the side with the smaller diameter was indicated. Actual measurements of lid fissures and corneal diameters were not re-
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corded in the study data. Although microphthalmos may have accounted for the smaller lid fissure and corneal diameter, ax¬ ial lengths were not recorded in the study data. Most variables were recorded at both the 12- and 24-month examinations. A complete retrolental membrane was not specifically recorded at the 24-month ex¬ amination, and asymmetric corneal diameTable 1.—Natural
Group patients enrolled in natural history cohort (n=4099)_
ters and lid fissures were recorded only at the 24-month examination. The incidence of any of these features that could contrib¬ ute to an adverse cosmetic outcome was
examined. The effects of both the severity of ROP at its maximum acute stage and the final structural outcome on cosmetic outcome were determined. Finally, the ef¬ fect of cryotherapy on cosmetic outcome was studied.
History Population
Mean±SD Birth Weight, g
Mean±SD Gestational Age, wk
954 ±185
27.9±2.2
Total
12-mo Examination
Natural history cohort at 23 participating centers
(n=2759)_
952±184
27.8±2.2
953±188 24-mo Examination
27.7±2.3
954±186
27.8±2.3
Natural history cohort at 5 "natural history centers"
(n=982)_
Natural history cohort at 5 "natural history centers"
(n=993)
RESULTS Patient Population
Of the 4099 patients enrolled in the natural history cohort, 3835 survived until the 12-month examination, and 2759 (72%) of these patients returned for follow-up examination. In the sub¬ group of the natural history cohort that was followed up at one of the five nat¬ ural history centers, 982 (81%) returned at 12 months. This subgroup represents 30% of the total population available for follow-up, and their birth weights and gestational ages were similar to the to¬ tal natural history cohort (Table 1). At 24 months, 993 (82%) of the 1208 pa¬ tients in the natural history cohort fol¬ lowed up at the five natural history centers returned for follow-up exami¬ nation. Their birth weights and gesta¬ tional ages were also similar to the overall natural history group. Data for the natural history subgroup are there¬ fore presumed to accurately reflect the entire natural history cohort.
Table 2.—Incidence of Adverse Cosmetic Outcome* 12-mo Examination 24-mo Examination
History Population
History Subgroup
Total Natural Adverse Cosmetic Outcome Monocular outcome Total retrolental membrane
Epiphora Corneal opacity Cataract
Episcleral hyperemia Interocular outcome Strabismus
Nystagmus Lid fissure asymmetry Corneal diameter asymmetry *UG indicates number of
Table
patients/eyes
I% Present n=5518 1.0 0.6 0.6 0.3 0.3 n=2759 12.8 3.3 NR NR in which examiner
I% Present n=1964 1.0 0.7 0.6 0.4 0.2 n=982 11.7 2.9 NR NR
UG 43
13
40 49
was
History Subgroup
Natural
unable to
3.—Relationship of Retinopathy of Prematurity (ROP)
grade
the
Natural I
UG
% Present n=198i NR
15
0.5 0.7 0.5 0.5 n=993 14.4 2.2 2.4 2.0
13 26
particular outcome; NR,
to 12-Month Cosmetic Outcome
UG
31
not recorded.
by International
Classification of ROP*
Zone 2 Outcome
Zone 1 ROP
i
I
Stage 3+
Stage 3
Stage
2
Stage
1
Monocular outcome (n=5518) Total retrolental membrane
Zone 3
Other
No ROP
0 0 0 0 (n=52) 16(20.8) 34(7.7) 1(0.2) 1(0.1) 4(0.9) 3(0.3) 5(0.5) 2(0.3) 1(2.3) 16(0.8) Epiphora (n=34)_1 (1.2)_2(0.4) Corneal opacity (n=31)_5(6.1) 22(4.7) 1(0.2) 3(0.3) 0_0_0_0_ Cataract (n=18) 2 (2.4)_12(2.6) 0 0 0 1(0.1) 2(0.1) 1(0.2) Episcleral hyperemia (n=17)_6(7.1)_6(1.3) (0.1)_0_0_0_4(0.2) 0_1 Interocular outcome (n=2759) Strabismus (n=347) 102(43.4) 37(15.7) 57(11.8) 47(9.5) 39(12.3) 1(4.5) 50(5.6) 14(36.8) 0 41(18.3) 10(4.2) 10(2.1) 2(0.4) 6(1.9) 5(0.6) Nystagmus (n=89) _15(36.6) 0 0 0 0 2(1.1) 1(0.9) Eyelid fissure asymmetry (n=24)t _6(35.3) 15(20.0) Corneal diameter asymmetry (n=20)t 0 0 0 4(23.5) 15(20.0) 1(0.6) *Values are number (percent). Percentages indicate prevalence of the adverse cosmetic outcome for each specified level of ROP after the "unable to grade" patients/eyes are removed from the denominator. tData from subgroup at 24 months (n=993).
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Table
Ocular Structural Outcome 12
Monocular Cosmetic Outcome Corneal opacity Present Absent Unable to grade Cataract Present Absent Unable to grade
-1
Unfavorable!
Favorable
3(0.1)
Episcleral hyperemia Present Absent Unable to
24
mo
121
6(0.1)
10(7.1)
5339
130
9
6(0.1)
-1
2(0.1)
11
1934
5
(6.2)
9
(28.9) 27
(0.3)
3
1931
(8.6) 32
(0.5)
1
1927
137
5339
Unfavorable!
Favorable
(17.1)
25
5342
mo
I
(2.9) 34
grade
Epiphora
1
32 (0.6) 5309
Present Absent
Unable to grade Narrower eyelid fissure Present Absent Unable to grade Smaller corneal diameter Present Absent Unable to grade
(0.7)
7
2
(5.4) 35
more.
9
(0.5)
13
(31.7)
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
1930
29
NR
NR
0
0
1927
6
*NR indicates not recorded. Values are number (percent). fUnfavorable structural outcome includes total retinal detachment and ing macula or retinal fold.
Table
(0.4)
1928
145
28
(0.3)
partial
12
(29.3)
retinal detachment involv¬
5.—Relationship of Bilateral Threshold Retinopathy of Prematurity to Cosmetic Outcome* 12 mo
Cosmetic Outcome Total retrolental membrane Corneal opacity Cataract
24
mo
Treated
Control
Treated
Control
(n=110)
(n=110)
(n=103)
(n=103)
Present
UG
Present 14
NR
NR NR
NR NR
" UG
Present NR
UG
Present NR
UG
Episcleral hyperemia Epiphora Narrower lid fissure Smaller corneal diameter
NR
*NR indicates not recorded; UG, unable to
NR NR
14
15
grade.
Incidence of Adverse Cosmetic Outcome
The incidence of an adverse cosmetic patients in the natural his¬ tory cohort at 12 and 24 months is pre¬ sented in Table 2. The 12-month data are presented for the entire natural history cohort and for the subgroup that was followed up at the five natural his¬ tory centers. The 24-month data repre¬ sent the natural history subgroup. The denominator for the percent with an unfavorable outcome includes only outcome for
cohort followed up at the five natural history centers was similar to that of the total population. In addition, similar cosmetic outcome results at the 24-month examination were found within this subgroup. The most common adverse externally evident outcome was strabismus (12.8% of the total natural history population at 12 months and 14.4% of the natural his¬ tory subgroup examined at 24 months). Analysis showed a trend for the inci¬ dence of strabismus to increase in those patients with lower birth weights and gestational ages: 20.0% for those weigh¬ ing less than 750 g, 12.6% for those weighing 750 to 999 g, and 10.4% for those weighing 1000 to 1250 g, and 16.1% for those born at 27 weeks' ges¬ tation or less, 10.2% for those born at 28 to 31 weeks' gestation, and 9.6% for those born at 32 weeks' gestation or
history
4.—Relationship of Structural Outcome of Retinopathy of Prematurity to Cosmetic Outcome*
those eyes (monocular variables) or pa¬ tients (interocular variables) for whom an assessment was made by an investi¬ gator. Some variables could not be graded due to lack of patient coopera¬ tion for accurate examination, reduced media clarity, or previous enucleation (one eye). These eyes/patients are indi¬ cated in the columns in Table 2 labeled "unable to grade" and have been ex¬ cluded from the denominator. At 12 months, the incidence of an ad¬ verse cosmetic outcome in the natural
An additional five patients with vi¬ sion in both eyes showed temporal mac¬ ular heterotopia in one or both eyes, which often gives the cosmetic appear¬ ance of strabismus, despite the absence of true strabismus on alternate cover testing. The temporal displacement of the macula causes nasal displacement of the anterior visual axis (positive angle kappa), giving the appearance of ex-
otropia.
Because patients with bilateral threshold ROP had only one eye treated with cryotherapy, this could potentially contribute to an increase in the incidence of strabismus in this population. When the randomized pa¬ tients were excluded from data analy¬ sis, strabismus occurred in 10.3% of the natural history population at 12 months (n=2577). The birth weights and gestational ages were slightly greater for this group (mean [±SD] birth weight, 962±181 g; mean [±SD] gestational age, 28.0±2.2 weeks), and the incidence of strabismus was as follows: 13.8% for infants weighing less than 750 g, 10.1% for those weighing 750 to 999 g, and 9.5% for those weighing 1000 to 1250 g, and 11.7% for those born at 27 weeks' gestation or less, 9.3% for those born at 28 to 31 weeks' gestation, and 9.7% for those born at 32 weeks' gestation or more. These data show a lower incidence of strabismus in the groups with lower birth weights and lower gestational ages compared with the total natural history population (above). This reduction reflects the predominance of the randomized pop¬ ulation in these groups with lower birth weights and lower gestational ages and their exclusion in these later data.
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examiner judge that epiphora was re¬ lated to ROP, presumably related to the associated complications of glaucoma or corneal opacity causing photosensitivity and tearing. A similar relationship was noted in the subgroup at 12 and 24 months.
Relationship to Structural Outcome Table 4
presents the relationship be¬
tween structural outcome and an ad¬ verse cosmetic outcome at 12 and 24
Fig 1.—Retrolental mass and shallow ante¬ rior chamber due to stage 5 retinopathy of prematurity result in an unsatisfactory cos¬ metic appearance.
Fig 2.—Dense corneal opacity obscures a portion of the pupil in an eye with a retrolen¬ tal membrane due to retinopathy of prematu¬ rity.
months in this natural history cohort. An unfavorable structural outcome de¬ termined by physician examination is defined in the CRYO-ROP study as a total retinal detachment, retrolental mass, a partial retinal detachment in¬ volving zone 1, or a retinal fold involv¬ ing the macula.16 Eyes with other fundus appearances were considered to have a favorable structural outcome; this included eyes with macular heterotopia, less severe residual ROP, and an absence of fundus abnormalities. The percent unfavorable is calculated as the number with the cosmetic outcome variable present as a portion of the to¬ tal number of eyes (with cosmetic out¬ come present or absent) with an unfa¬ vorable structural outcome. Eyes with an unfavorable structural outcome showed an increased rate of corneal opacity, cataract, and episcleral hyperemia at both the 12- and 24-month examinations. Epiphora was the only cosmetic outcome variable that was not directly related to an unfavorable struc¬ tural outcome at 12 months, but a rela¬ tionship between epiphora and unfavor¬ able structural outcome was seen at 24 months. At the 24-month examination, an unfavorable structural outcome was more likely to be associated with a nar¬ rower lid fissure and smaller corneal diameter. Most of the eyes with a nar¬ rower lid fissure also had a smaller cor¬ neal diameter. All but two of these eyes had total retinal detachment. Effect of
Fig 3.—Spectacle magnification improves the aesthetic appearance of a patient microphthalmic left eye that is blind due to stage 5 retinopathy of prematurity.
Relationship to Acute
ROP
Table 3 shows the relationship be¬ tween an adverse cosmetic outcome and the most severe documented level of acute ROP. A few infants had an ad¬ verse cosmetic outcome despite lack of documented ROP. Some infants were not examined at the defined intervals due to poor medical status; in other cases, media haze prevented documen¬ tation of the presence or absence of
with
a
ROP. The data listed in the column in Table 3 labeled "other" reflect infants found to have regressing ROP even though active ROP was not previously seen. A more posterior location and a higher stage of ROP indicate more severe structural disease. In Table 3, a direct relationship between all the ad¬ verse cosmetic outcomes, except epi¬ phora, and the severity of ROP is dem¬ onstrated. In only three eyes did the
Cryotherapy
Table 5 compares the cosmetic out¬ come in treated and control eyes. In this analysis, data from patients with bilat¬ eral threshold ROP were examined for the effect of cryotherapy on ocular cosmesis. Because additional ocular sur¬ gery is a confounding variable, data from patients who underwent eye sur¬ gery other than cryotherapy were ex¬ cluded from this analysis. Of the 218 patients with threshold disease in the natural history cohort, 180 had bilateral threshold ROP, with one eye random¬ ized to receive cryotherapy. Twentytwo patients died before the 12-month examination, and 148 returned for follow-up examination 12 months after
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Fig 4.—The placement of a scierai shell over a microphthalmic left eye improves the appear¬ of a patient with stage 5 retinopathy of prematurity.
ance
cryotherapy; 110 ofthose returning had undergone other ocular procedures (eg, scierai buckling or vitrectomy) in either eye. One hundred forty patients in the natural history cohort with bilat¬
COMMENT
not
eral threshold disease returned for follow-up examination at 24 months, and 103 of these had not undergone other therapeutic ocular procedures. These patients (n=110 at 12 months and n=103 at 24 months) were examined for the effect of cryotherapy on cosmetic outcome.
The cosmetic outcome results for these matched pairs of eyes in patients in the natural history cohort with bilat¬ eral threshold ROP (one eye random¬ ized to treatment with cryotherapy and no other invasive ocular treatment for either eye) are presented in Table 5. The results at 12 and 24 months are listed for each outcome variable, except for those that are indicated as not being specifically recorded on the data entry form. An increased rate of adverse cos¬ metic outcome is seen in the untreated (control) eyes at both 12 and 24 months. At the 24-month examination, the rate of narrower lid fissure and smaller cor¬ neal diameter is greater for the control eyes.
The importance of a cosmetically vis¬ ible abnormality depends on the extent of the abnormality, the social setting in which it is noticed, and the awareness and bias of the observer. We have examined the incidence of various ad¬ verse cosmetic outcomes in a large group of very-low-birth-weight infants who were prospectively examined by certified study ophthalmologists. While reports of aesthetically relevant com¬ plications of ROP have described mi-
crophthalmos, ptosis, nystagmus, cata¬
ract, strabismus, and phthisis,18"22 we believe that this is the first report spe¬
cifically addressing the incidence of cos¬
metic outcome of ROP. The CRYOROP study has shown that cryotherapy reduces the rate of an unfavorable structural and functional outcome at 12 months. The data presented herein show that cryotherapy also reduces the rate of an adverse cosmetic outcome. Although cryotherapy does not prevent externally visible ocular sequelae, eyes with threshold ROP that were treated with cryotherapy are less likely to ap¬ pear abnormal than untreated eyes with a similar level of ROP.
While the primary consequence of strabismus is disruption of binocularity, the cosmetic effect is addressed in this report. Strabismus was the most com¬ mon externally visible outcome in this group of premature infants, occurring at a rate of 12.8% at the 1-year exami¬ nation and 14.4% in the subgroup at the 2-year examination. The rate is slightly lower when infants who did not reach threshold were eliminated from the study group (see the "Results" section). Because strabismus is a binocular ab¬ normality, it is possible that the inci¬ dence of strabismus in the randomized group would have been different if both eyes had received cryotherapy. An ad¬ ditional five patients showed temporal macular heterotopia, which can cause pseudostrabismus. This structural dis¬ tortion alters the angle kappa and pro¬ duces the cosmetic appearance of an exotropia for temporal ectopia, even in the absence of true strabismus.23 Other investigators have also noted an in¬ creased frequency of strabismus in pre¬ mature infants.2426 Strabismus findings in the CRYO-ROP study will be further documented in a future publication. Lid fissure asymmetry is most often recognized as monocular or asymmetric blepharoptosis. Fledelius20 has re¬ ported a prevalence of 2% for congeni¬ tal ptosis in 302 infants with a birth weight less than 2500 g. However, asymmetric lid fissures in the present study were directly related to corneal diameter asymmetry and to an unfavor¬ able structural outcome (Table 4). This suggests that the lid abnormality in most of our cases represented a pseudoptosis due to enophthalmos and microphthalmos, although axial length was not recorded. Because corneal di¬ ameter asymmetry was recorded only at the 24-month examination, the data do not allow an explanation of whether microphthalmos, enophthalmos, and fis¬ sure narrowing are due to local arrest of growth and development or to globe shrinkage following the development of advanced cicatricial ROP. Transient lens opacities have been reported in premature newborns,27,28 but these are not usually considered to be visually or cosmetically important. However, postnatal cataracts have been reported to occur at a rate of 0.3% in a series of 1000 infants with a birth weight less than 1260 g29; a similar inci¬ dence was found in the present study.
Certainly,
some
cataracts, particularly
those involving the anterior portion of the lens, can produce an aesthetically unsatisfactory appearance. Leukokoria is an externally visible abnormality that may be caused by various structural abnormalities, including not only cata-
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ract but also retrolental mass
(Fig 1), as
recorded herein. Corneal opacities may be sufficiently dense to present a cosmetic abnormal¬ ity (Fig 2). The rate of corneal opacity was highest in the eyes with an unfa¬ vorable structural outcome (Table 4). Another report from the CRYO-ROP
Cooperative Group suggested no change in the rate of corneal opacity in
eyes with
stage 5 ROP in which vitrec-
performed.30 Methods to improve the external ap¬
tomy
eyelid on the side of the enophthalmic orbit has been recom¬ mended to improve cosmesis, but none of the patients in the present study had undergone lid surgery by the time of the elevate the
24-month examination. Another poten¬ tial method to improve cosmesis in mi¬ crophthalmos is volume expansion.31 Use of this technique in patients with ROP has not been described, to our
knowledge.
Medical literature
was
following severe ROP include optical magnification of the blind, microphthalmic eye with a less myopic or more hyperopic correction than the con¬ tralateral spectacle lens (Fig 3). This method involves placement of various trial lenses in front of the blind, microphthalmic eye to minimize the ap¬ parent difference in sizes of the globes. A scierai shell fit over a phthisical eye can also improve the aesthetic appear¬ ance (Fig 4). Blepharoptosis surgery to pearance
on
ROP is under¬
standably focused on management of the premature infant and treatment of ROP to improve the ocular structural and functional outcome. However, rec¬ ognition of the cosmetic abnormalities associated with ROP and the treatment alternatives in the management of these problems remain important to the child's development. The negative emo¬ tional reactions to the blind are well de¬ scribed,9'12,32 but the reactions to more subtle aesthetic abnormalities, such as corneal opacity or cataract, are not well
defined. Parental expectations for a child with abnormal ocular features may be reduced. Positive interpersonal relationships are necessary for psy¬ chosocial maturation, and abnormal cos¬ mesis can interfere with these rela¬ tionships. Later, particularly in adoles¬ cence, an adverse cosmetic outcome can affect the child's self-image.33·34 Herein, we have defined the incidence of cos¬ metic abnormalities in a very-low-birthweight population. In addition, we have shown that there do not appear to be externally visible adverse side effects of cryotherapy that would deter its use in patients with threshold ROP. Future efforts should be devoted to under¬ standing how external appearance in¬ fluences the social, educational, and de¬ velopmental maturation of the pre¬ mature child. This investigation was supported by cooperative agreement U01 E405874 from the National Eye Insti¬ tute, National Institutes of Health, Bethesda, Md. Pat Wallace, of the Casey Eye Institute, Portland, Ore, provided photographic assistance for Fig 4.
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