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Cryotherapy for Active Retinopathy of Prematurity
Cryotherapy for Active Retinopathy of Prematurity WILLIAM TASMAN, MD, GARY C. BROWN, MD, DAVID B. SCHAFFER, MD, GRAHAM QUINN, MD, MICHAEL NAIDOFF, MD, WILLIAM E. BENSON, MD, GARY DIAMOND, MD
Abstract: Twenty-eight patients with bilateral symmetrical Stage 3 retinopathy of prematurity (ROP) and plus disease had one eye assigned to cryotherapy and the other to control. The majority of patients weighed under 1000 grams at birth and females outnumbered males by nearly a two-to-one ratio. Cryotherapy was generally performed at a gestational age of less than 40 weeks and a mean chronologie age of 10 weeks. Eleven patients showed improvement in both the treated and untreated eyes possibly due to variables among prematures not identified in the study. Eleven other patients experienced improvement in the treated eye and progression in the untreated eye. Using the binomial distribution on the latter group the P value was 0.0005 with a one-tailed hypothesis test and 0.001 with a two-tailed test, suggesting that in the sampled population cryotherapy appears to be preferred over no treatment. [Key words: cryotherapy, retinopathy of prematurity.] Ophthalmology 93:580-585, 1986
Several reports regarding cryotherapy in the treatment of retinopathy of prematurity (ROP) have appeared over the last several years. 1- 12 At the 1984 meeting of the American Academy of Ophthalmology we reported on 17 patients with bilateral symmetrical Stage 3 retinopathy of prematurity and plus disease who had one eye arbitrarily assigned to treatment and the other eye followed as a control. 13 Because of the small number of patients, no statistically significant conclusion could be drawn. Since that time an additional 11 patients have been similarly treated in a continuation of this study.
MATERIALS AND METHODS Twenty-eight eyes in 28 premature infants were treated with cryotherapy between January 1983 and May 1985 and follow-up ranged from 4 to 19 months. Two of the coauthors helped to develop the International ClassifiFrom the Retina Service, Wills Eye Hospital and Department of Ophthalmology at Thomas Jefferson University, Childrens Hospital of Philadelphia, Pennsylvania Hospital, Hospital of the University of Pennsylvania, Medical College of Pennsylvania, and Albert Einstein Medical Center. Presented at an Annual Meeting of the American Academy of Ophthalmology. Reprint requests to William Tasman, MD, Wills Eye Hospital, 9th & Walnut Streets, Philadelphia, PA 19107.
580
cation of Retinopathy of Prematurity in Calgary, Canada in September 1982. 14 They, along with other members of the committee, were asked to utilize the classification, and thus it became a cornerstone for classifying disease in this study. Accordingly, all of the treated eyes had reached Stage 3 of active ROP, and had plus disease and vascularization of the retina in Zone I or II (Fig 1). In addition, extraretinal fibrovascular proliferation was present for greater than five clock hours as suggested by the proposed collaborative study group (Fig 2). This differs from the collaborative study group in one respect, since threshold for treatment in that trial also includes eyes with eight interrupted hours of extraretinal fibrovascular proliferation. All of the infants had blood levels of Vitamin E between 1 and 2 mg per deciliter of blood, and were in nurseries with standard illumination. Infants were examined in the nursery generally between seven and nine weeks after birth as suggested by Palmer, 15 although on occasion exams as early as four weeks were performed. Either tropicamide 1% and phenylephrine 2.5% instilled three times every 15 minutes or homatropine 2% and phenylephrine 2.5% drops three hours, two hours, and one hour before examination were used for dilation. The latter drops were preferred for cryotherapy. Although the time of treatment upon reaching threshold was not precisely stipulated, in all cases treatment was performed within 48 hours. This followed a detailed discussion with the parents, at which time they were informed that no documented scientific evidence existed to prove
TASMAN, et al
• CRYOTHERAPY FOR ROP
Fig I. Top left, plus disease in an eye with Stage 3 retinopathy of prematurity. The veins are dilated and the arteries are tortuous. Fig 2. Top right, severe Stage 3 retinopathy of prematurity with extraretinal fibrovascular proliferation. Fig 3. Center left, cryotherapy is applied only to the avascular zone of retina (arrow). Fig 4. Center right, cryotherapy appearance one month after treatment. Fig 5. Bottom left, ridge before treatment. Bottom right, three months after treatment the ridge has regressed and vessels have grown into the avascular zone.
that treatment with cryotherapy was better than no treatment. Five infants were treated under general anesthesia, but the others received cryotherapy using local anesthesia consisting of 1h cc of subconjunctival 1% lidocaine or mepivicaine. Patients on respirators often also received pancuronium 0.1 mgm/kgm of body weight to paralyze eye movements. Those patients treated under general anes-
thesia usually had Zone I disease, which made it difficult to reach the anterior border of the ridge with cryotherapy without performing a limbal peritomy of the conjunctiva. In all cases the entire avascular zone of retina anterior to the ridge (Fig 3) was treated until the retina whitened. Care was taken to not freeze the overlying vitreous gel and the areas of extraretinal fibrovascular proliferation were left untouched. Pigmentary changes occurred in the 581
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fundus secondary to the cryotherapy, generally at five to ten days following treatment. At this time, areas of avascular retina not treated initially were identified and were frozen to create confluent chorioretinal scars if plus disease was still present (Fig 4). Signs of satisfactory response to cryotherapy included resolution of plus disease, usually within 14 days, flattening of the ridge, and gradual growth of normal retinal vessels into the treated avascular zone of retina (Fig 5). Failure of cryotherapy was characterized by persistence of plus disease and continued development of extraretinal fibrovascular proliferation leading to Stage 4 ROP. The end-point of the study was the anatomical appearance of the retina as determined by dragging to create a retinal fold involving the macula or, failing that, definite macular heterotopia. Results were analyzed from the standpoint of concordant and discordant pairs of eyes. The exact P values for the one-sided and two-sided test for patients who showed improvement in the treated eye and progression in the untreated eye were calculated using the binomial distribution.
RESULTS Among the 28 infants qualifying for cryotherapy, birthweights ranged from 480 grams to 1720 grams (mean, 885 grams). Eighteen patients were females and ten were males. Ten of the 11 most recently treated patients were analyzed from the standpoint of gestational age at birth and number of weeks until treatment (Table 1). The mean gestational age at the time of birth was 28.6 weeks and the majority of infants were treated at an average gestational age of 38.5 weeks. Thus, the mean interval of time between birth and cryotherapy was about 10 weeks chronologie age. Twenty-two of the 28 treated eyes (79%) showed resolution of retinopathy of prematurity, although five eyes required more than one treatment. Similarly, 6 of 28 treated eyes (21%) progressed and 5 of these developed retrolental membrane formation and closed funnel retinal detachment. However, in the 11 most recently treated patients none of the treated eyes deteriorated, and no therapeutic complications were encountered. Of the 28 untreated eyes, 12 resolved spontaneously (43%) and sixteen progressed (57%). When resolution occurred in the untreated eye it was generally slower than in the treated eye. Grouping results as concordant and discordant pairs of eyes in 28 patients, in 11 patients both the treated and untreated eye improved (Table 2). In 11 patients the treated eye improved and the untreated eye got worse, and in one patient the treated eye deteriorated while the untreated eye improved. Of the 11 patients who showed resolution of retinopathy of prematurity in the treated eye and progression in the untreated eye, 6 developed total retinal detachment in the 582
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Table 1. Gestational Age Patient No.
Gestational Age (weeks)
Gestational Age When Treated (weeks)
Chronologie Age When Treated (weeks)
29 26 27 26
39 38 35 36 40 36 39 40 44 38
10
1 2 3
4
5 6 7 8 9
28
26
31
35 30
10
28
12 8
10 12
10
8 5 14
10
Table 2. Concordant and Discordant Responses to Cryotherapy in 28 Patients Response Treated Treated Treated Treated Total
eye eye eye eye
better, better, worse, worse,
untreated eye better untreated eye worse untreated eye worse untreated eye better
No. Patients 11
11 5 1 28
untreated eye, and the other 5 developed dragging of the macula. The treated eyes in three of the six patients have been refracted and demonstrate a high myopia of about 9 diopters while a fourth patient who has also been refracted is mildly hyperopic. The one patient whose eye worsened after treatment is now 2 years old. She has about 5 diopt~rs of myopia in the untreated eye, and 7 diopters of myopia in the treated eye, which also has temporal displacement of the vessels and macular heterotopia, findings not present in the untreated eye. The treated eye is amblyopic, and patching of the fellow eye is currently being attempted. Three eyes were treated by scleral buckling. Two of these had previous cryotherapy and one of the two became reattached after surgery while the other did not. In the latter case the parents declined further surgery. A third eye, which had been an untreated control, responded satisfactorily to an encircling buckle, drainage of subretinal fluid, and cryotherapy. Two other eyes, one that had been treated and one that had been a control, were reattached following lensectomy and open sky vitrectomy. Unfortunately, the eye which had not originally been treated with cryotherapy subsequently developed reproliferation on the surface of the retina. Of the 28 patients, 12 showed a different response between the treated and untreated eye (Table 2). In 11 patients the treated eye improved and the condition of the untreated eye worsened. Using a one-sided hypothesis test on these 11 patients, testing the null hypothesis that the
TASMAN, et al
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untreated eye does at least as well as the treated eye in the population being sampled, vs. the alternative hypothesis that the untreated eye does worse than the treated eye in the population being sampled, we have a one-sided P value of0.0005. Using a two-sided hypothesis test, testing the null hypothesis that the untreated eye and treated eye behave similarly, vs. the alternative hypothesis that they do not behave similarly, we have a P value ofO.OOl. Thus, whether we are doing either a one- or two-tailed hypothesis test, we would, with P values of 0.0005 and 0.001, respectively, reject the null hypothesis and conclude that it appears in the population sampled that treatment appears to be preferred over no treatment.
11 patients who improved in both eyes demonstrated variables not identified by these observers. We hope that the collaborative trial on cryotherapy in ROP will be able to pinpoint such factors because of their larger numbers of babies and natural history documentation. In our previous report we stated that the role of cryotherapy in active retinopathy of prematurity still needs to be defined. With Pvalues of0.0005 and 0.001, we believe that the role of cryotherapy is an encouraging one, and that our data suggest that cryotherapy may be beneficial for preventing severe visual loss in a select group of eyes with active ROP. We now look forward to the results of the collaborative study on cryotherapy in ROP, so that a larger number of randomized eyes will be available to either complement or contradict our results.
DISCUSSION In our previous study, 12 of 17 patients (71%) were female and 5 (29%) were male. With the addition of 11 more patients the ratio of approximately 2 to 1 continues as evidenced by the fact that of 28 patients, 18 (64%) were female and 10 (36%) were male. The mean birthweight in this group of patients was well under 1000 grams, reaffirming the greater risk for ROP in small prematures. Gestationally, the retinal vessels reach the ora serrata nasally at eight months, but do not complete normal vascularization of the temporal retinal periphery until shortly after birth of the full-term infant. 16 Thus, it is not surprising that the majority of prematures in this study had not yet reached term when treated. The interval of time between birth and decision to treat in ten patients averaged ten weeks, or two and one-half months chronologie age, which is a slightly smaller window than the three months reported earlier. 13 Only one of the ten patients was over 40 weeks gestation when treated (Table 1). This suggests that premature infants should be examined by seven weeks, so that the opportunity to treat high-risk eyes is not lost. One treated eye in the first study, originally thought to have done better than the untreated eye over a longer follow-up, developed dragging of the retina that exceeded the dragging in the untreated eye. Of interest, however, is the observation that no progression of ROP occurred in the eleven most recently treated eyes. This contrasts with six treated eyes that worsened in the first study, a difference that may be attributable to more complete cryotherapy of the avascular zone of retina than in the earlier cases. The fact that 11 patients showed improvement in both the treated and untreated eye is difficult to explain statistically. In this study, the binomial distribution was used testing a one-sided and two-sided hypothesis on patients who demonstrated improvement in the treated eye and progression in the untreated eye. It may well be that the
REFERENCES 1. Yamashita Y. Studies on retinopathy of prematurity (Ill) Cryocautery for retinopathy of prematurity. Jpn J Clin Ophthalmol 1972; 26:38593. 2. Sasaki K, Yamashita Y, Maekawa T, Adachi T. Treatment of retinopathy of prematurity in active stage by cryocautery. Jpn J Ophthalmol1976; 20:384-95. 3. Takagi I. Treatment of acute retrolental fibroplasia. Acta Soc Ophthalmol Jpn 1978; 82:323-30. 4. Kingham JD. Acute retrolental fibroplasia; treatment by cryosurgery. Arch Ophthalmol1978; 96:2049-53. 5. Hindle NW, Leyton J. Prevention of cicatricial retrolental fibroplasia by cryotherapy. Can J Ophthalmol1978; 13:277-82. 6. Ben-Sira I, Nissenkom I, Grunwald E, Yassur Y. Treatment of acute retrolental fibroplasia by cryopexy. Br J Ophthalmol 1980; 64:75862. 7. Mousel OK, Hoyt CS. Cryotherapy for retinopathy of prematurity. Ophthalmology 1980; 87:1121-7. 8. Bert MD, Friedman MW, Ballard R. Combined cryosurgery and scleral buckling in acute proliferative retrolental fibroplasia. J Pediatr Ophthalmol Strabismus 1981; 18:9-12. 9. Hindle NW. Cryotherapy for retinopathy of prematurity to prevent retrolental fibroplasia. Can J Ophthalmol1982; 17:207-12. 10. Keith CG. Visual outcome and effect of treatment in stage Ill developing retrolental fibroplasia. Br J Ophthalmol1982; 66:446-9. 11. Mousel OK. Cryotherapy for retinopathy of prematurity; a personal retrospective. Ophthalmology 1985; 92:375-8. 12. Topilow HW, Ackerman AL, Wang FM. The treatment of advanced retinopathy of prematurity by cryotherapy and scleral buckling surgery. Ophthalmology 1985; 92:379-87. 13. Tasman W. Management of retinopathy of prematurity. Ophthalmology 1985; 92:995-9. 14. The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol1984; 102:1130-4. • 15. Palmer EA. Optimal timing of examination for acute retrolental fibroplasia. Ophthalmology 1981; 88:662-6. 16. Patz A, Payne JW. Retrolental fibroplasia. In: Duane TO, ed. Clinical Ophthalmology. Philadelphia: Harper & Row, 1982; Volume 3, Chapter 20.
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Discussion by Earl A. Palmer, MD The authors have been conducting an important investigation of cryotherapy for retinopathy of prematurity. Some weaknesses and unanswered questions in the present study need to be pointed out, not to detract from the value of these reports, but to indicate why cryotherapy cannot yet be considered as an established treatment for this disease and why a definitive collaborative study is still needed.
presumably the examiners who evaluated the outcome for the eyes were aware of which eye had received treatment, since this would ordinarily become obvious during indirect ophthalmoscopy. Masking by use of appropriate photographs would insure that identical outcome criteria were applied to the treated and control eyes.
SELECfiON OF PATIENTS
One principal outcome criterion is described as macular ectopia; an explanation of how this was defined is needed. Although each clinician among us has an idea of how this could be done, there is sometimes a surprising disparity of opinion on an issue such as this. Outcome was judged at varying times following treatment. The length of follow-up is 4 to 19 months, Dr. Tasman has informed me. ROP is a dynamic disease. The time of assessment for outcome is best standardized. Brief follow-up accounts for the fact that one eye in the earlier study worsened after the first publication, and the patient is now reclassified as an adverse discordant case. Because we lack enough information on what happens to these eyes later, the risk-limiting technique of applying cryotherapy to only one eye has been used in most studies.
It is not stated whether there was a check on the determination of the severity of retinopathy of prematurity (ROP), to control the consistency of criteria for selecting patients for cryotherapy. In particular, the determination of "plus disease" can be highly subjective. It would be helpful in this regard to have two examiners examine the patients independently. It was interesting that in the 1984 report, seven patients were excluded because they had developed retinal detachment in one eye, yet there is no mention of any exclusions from the added eleven patient since that first report. A comment on this apparent difference in the patient population during the time periods involved would be useful in assessing the consistency of patient selection over the 28 months of this study.
OUTCOME DETERMINATION
RESULTS RANDOMIZATION
In the more recent 11 patients, one must assume that the two eyes reached threshold for cryotherapy simultaneously. If not, then the two eyes were asymmetric and true randomization would be essential. Dr. Tasman has told me that the two eyes in all of the more recent eleven patients were quite symmetric, and that assignment oftreated versus control eye was done without regard to which eye was worse; however, a system for randomization was not used. Since the more recent 11 cases were not described as "randomized," but rather as "assigned," assurance is lacking that bias did not enter into the decision about which eye received cryotherapy. From a statistical and scientific standpoint, one must ask whether some unconscious bias toward treating the eye that looked even slightly worse or slightly better may have existed. One might assume that there would have been a tendency to treat the worse eye, and consequently that this bias should only increase the validity of the conclusions. It is not known, however, whether at this particular stage ofROP, the rate of progression has significance for the degree of cicatrization that ultimately develops. This highlights the fact that we do not know enough about the natural course of ROP. CONTROL OF BIAS
The statistical analysis in this report is accurate. The numbers are too small, however, to assess whether the results may be applicable to all subgroups; for example, by gender, birthweight, etc. Additionally, there are insufficient numbers of patients here to assess the safety of cryotherapy for ROP. If an extremely severe complication occurs only occasionally, will the strength of benefit justify that risk? It is important to recognize that while 28 patients were studied, the effective sample size of discordant cases includes only 12 patients, and statistical significance is based entirely on evaluation of these 12 discordant cases. If only a few more cases had gone the other way, statistical significance would be absent. TIMING OF EXAMINATIONS
The need to examine premature infants earlier than seven to nine weeks of age is governed by what, if anything, one plans to do as a result of the findings. For natural history studies, and for considering cryosurgical intervention, a first examination at about one month of age seems justified. However, since most American investigators in the field of ROP are unsatisfied with the evidence at hand as to the efficacy and safety of cryotherapy, it would seem unnecessary to routinely examine these infants earlier than age seven to nine weeks, unless an investigational procedure is being done and a research protocol requires it. The authors' suggestion that earlier examination be done "so that the opportunity to treat high risk eyes is not lost" implies an assumption as to the safety and efficacy of cryotherapy that may yet prove to be premature.
Whenever critically evaluating a study such as this, one seeks assurance that bias is controlled in every way possible. This may be accomplished through strict randomization, as noted above, as well as by masking the person who evaluates the results of treatment to be unaware of whether treatment was applied. Since there is no indication that this was the case in the present study,
MULTICENTER STUDY
From the Oregon Health Sciences University, Portland.
I have given some reasons why the present studies are inconclusive. I will now state why I believe that the Multicenter Trial
584
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of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) is urgently needed. CRYO-ROP will evaluate both the efficacy and the safety of this treatment procedure in a large number of cases. When failures occur, detailed information will be available for later analysis as to the possible reasons for this. By an analysis of the natural course of the disease in our study population, we hope to deduce indications for cryotherapy, should it prove safe and effective. These may be derived by noticing what happens to the eyes that do not receive cryotherapy. Through randomization and control of bias, statistically valid conclusions can be reached. Finally, more complete information is needed about the natural history of ROP. The multicenter study will provide this. Thus, our understanding will be increased not only about the use of cryotherapy, but also about the course of ROP in the population of patients in question, thereby facilitating the design of future studies. Ophthalmoscopy of premature infants ranks among the most difficult examinations that ophthalmologists are called upon to
make. The authors are to be congratulated for undertaking the studies described for us today. Trans-scleral cryotherapy in these patients is a technically demanding procedure and very tedious to carry out under direct visualization of the fundus. The effort involved in studying this form of therapy for ROP seems especially worthwhile when one recognizes the many decades oflife ahead for most of these young patients. The important implications of this pilot study of cryotherapy for ROP are, first, that cryotherapy does not always prevent blindness when applied as used in this study. Second, it is encouraging that we see little reason here to believe that cryotherapy is bad for these patients. Finally, this study gives further reason to hope that cryotherapy is beneficial in altering the course of ROP. It is this very hope for a useful therapy for this cruel disorder that mandates caution, lest our zeal obscure a bias that may lead to erroneous conclusions about investigational therapies. This pilot study provides an optimistic background as CRYOROP begins.
585
Abstract: Twenty-eight patients with bilateral symmetrical Stage 3 retinopathy of prematurity (ROP) and plus disease had one eye assigned to cryotherapy and the other to control. The majority of patients weighed under 1000 grams at birth and females outnumbered males by nearly a two-to-one ratio. Cryotherapy was generally performed at a gestational age of less than 40 weeks and a mean chronologie age of 10 weeks. Eleven patients showed improvement in both the treated and untreated eyes possibly due to variables among prematures not identified in the study. Eleven other patients experienced improvement in the treated eye and progression in the untreated eye. Using the binomial distribution on the latter group the P value was 0.0005 with a one-tailed hypothesis test and 0.001 with a two-tailed test, suggesting that in the sampled population cryotherapy appears to be preferred over no treatment. [Key words: cryotherapy, retinopathy of prematurity.] Ophthalmology 93:580-585, 1986
Several reports regarding cryotherapy in the treatment of retinopathy of prematurity (ROP) have appeared over the last several years. 1- 12 At the 1984 meeting of the American Academy of Ophthalmology we reported on 17 patients with bilateral symmetrical Stage 3 retinopathy of prematurity and plus disease who had one eye arbitrarily assigned to treatment and the other eye followed as a control. 13 Because of the small number of patients, no statistically significant conclusion could be drawn. Since that time an additional 11 patients have been similarly treated in a continuation of this study.
MATERIALS AND METHODS Twenty-eight eyes in 28 premature infants were treated with cryotherapy between January 1983 and May 1985 and follow-up ranged from 4 to 19 months. Two of the coauthors helped to develop the International ClassifiFrom the Retina Service, Wills Eye Hospital and Department of Ophthalmology at Thomas Jefferson University, Childrens Hospital of Philadelphia, Pennsylvania Hospital, Hospital of the University of Pennsylvania, Medical College of Pennsylvania, and Albert Einstein Medical Center. Presented at an Annual Meeting of the American Academy of Ophthalmology. Reprint requests to William Tasman, MD, Wills Eye Hospital, 9th & Walnut Streets, Philadelphia, PA 19107.
580
cation of Retinopathy of Prematurity in Calgary, Canada in September 1982. 14 They, along with other members of the committee, were asked to utilize the classification, and thus it became a cornerstone for classifying disease in this study. Accordingly, all of the treated eyes had reached Stage 3 of active ROP, and had plus disease and vascularization of the retina in Zone I or II (Fig 1). In addition, extraretinal fibrovascular proliferation was present for greater than five clock hours as suggested by the proposed collaborative study group (Fig 2). This differs from the collaborative study group in one respect, since threshold for treatment in that trial also includes eyes with eight interrupted hours of extraretinal fibrovascular proliferation. All of the infants had blood levels of Vitamin E between 1 and 2 mg per deciliter of blood, and were in nurseries with standard illumination. Infants were examined in the nursery generally between seven and nine weeks after birth as suggested by Palmer, 15 although on occasion exams as early as four weeks were performed. Either tropicamide 1% and phenylephrine 2.5% instilled three times every 15 minutes or homatropine 2% and phenylephrine 2.5% drops three hours, two hours, and one hour before examination were used for dilation. The latter drops were preferred for cryotherapy. Although the time of treatment upon reaching threshold was not precisely stipulated, in all cases treatment was performed within 48 hours. This followed a detailed discussion with the parents, at which time they were informed that no documented scientific evidence existed to prove
TASMAN, et al
• CRYOTHERAPY FOR ROP
Fig I. Top left, plus disease in an eye with Stage 3 retinopathy of prematurity. The veins are dilated and the arteries are tortuous. Fig 2. Top right, severe Stage 3 retinopathy of prematurity with extraretinal fibrovascular proliferation. Fig 3. Center left, cryotherapy is applied only to the avascular zone of retina (arrow). Fig 4. Center right, cryotherapy appearance one month after treatment. Fig 5. Bottom left, ridge before treatment. Bottom right, three months after treatment the ridge has regressed and vessels have grown into the avascular zone.
that treatment with cryotherapy was better than no treatment. Five infants were treated under general anesthesia, but the others received cryotherapy using local anesthesia consisting of 1h cc of subconjunctival 1% lidocaine or mepivicaine. Patients on respirators often also received pancuronium 0.1 mgm/kgm of body weight to paralyze eye movements. Those patients treated under general anes-
thesia usually had Zone I disease, which made it difficult to reach the anterior border of the ridge with cryotherapy without performing a limbal peritomy of the conjunctiva. In all cases the entire avascular zone of retina anterior to the ridge (Fig 3) was treated until the retina whitened. Care was taken to not freeze the overlying vitreous gel and the areas of extraretinal fibrovascular proliferation were left untouched. Pigmentary changes occurred in the 581
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fundus secondary to the cryotherapy, generally at five to ten days following treatment. At this time, areas of avascular retina not treated initially were identified and were frozen to create confluent chorioretinal scars if plus disease was still present (Fig 4). Signs of satisfactory response to cryotherapy included resolution of plus disease, usually within 14 days, flattening of the ridge, and gradual growth of normal retinal vessels into the treated avascular zone of retina (Fig 5). Failure of cryotherapy was characterized by persistence of plus disease and continued development of extraretinal fibrovascular proliferation leading to Stage 4 ROP. The end-point of the study was the anatomical appearance of the retina as determined by dragging to create a retinal fold involving the macula or, failing that, definite macular heterotopia. Results were analyzed from the standpoint of concordant and discordant pairs of eyes. The exact P values for the one-sided and two-sided test for patients who showed improvement in the treated eye and progression in the untreated eye were calculated using the binomial distribution.
RESULTS Among the 28 infants qualifying for cryotherapy, birthweights ranged from 480 grams to 1720 grams (mean, 885 grams). Eighteen patients were females and ten were males. Ten of the 11 most recently treated patients were analyzed from the standpoint of gestational age at birth and number of weeks until treatment (Table 1). The mean gestational age at the time of birth was 28.6 weeks and the majority of infants were treated at an average gestational age of 38.5 weeks. Thus, the mean interval of time between birth and cryotherapy was about 10 weeks chronologie age. Twenty-two of the 28 treated eyes (79%) showed resolution of retinopathy of prematurity, although five eyes required more than one treatment. Similarly, 6 of 28 treated eyes (21%) progressed and 5 of these developed retrolental membrane formation and closed funnel retinal detachment. However, in the 11 most recently treated patients none of the treated eyes deteriorated, and no therapeutic complications were encountered. Of the 28 untreated eyes, 12 resolved spontaneously (43%) and sixteen progressed (57%). When resolution occurred in the untreated eye it was generally slower than in the treated eye. Grouping results as concordant and discordant pairs of eyes in 28 patients, in 11 patients both the treated and untreated eye improved (Table 2). In 11 patients the treated eye improved and the untreated eye got worse, and in one patient the treated eye deteriorated while the untreated eye improved. Of the 11 patients who showed resolution of retinopathy of prematurity in the treated eye and progression in the untreated eye, 6 developed total retinal detachment in the 582
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Table 1. Gestational Age Patient No.
Gestational Age (weeks)
Gestational Age When Treated (weeks)
Chronologie Age When Treated (weeks)
29 26 27 26
39 38 35 36 40 36 39 40 44 38
10
1 2 3
4
5 6 7 8 9
28
26
31
35 30
10
28
12 8
10 12
10
8 5 14
10
Table 2. Concordant and Discordant Responses to Cryotherapy in 28 Patients Response Treated Treated Treated Treated Total
eye eye eye eye
better, better, worse, worse,
untreated eye better untreated eye worse untreated eye worse untreated eye better
No. Patients 11
11 5 1 28
untreated eye, and the other 5 developed dragging of the macula. The treated eyes in three of the six patients have been refracted and demonstrate a high myopia of about 9 diopters while a fourth patient who has also been refracted is mildly hyperopic. The one patient whose eye worsened after treatment is now 2 years old. She has about 5 diopt~rs of myopia in the untreated eye, and 7 diopters of myopia in the treated eye, which also has temporal displacement of the vessels and macular heterotopia, findings not present in the untreated eye. The treated eye is amblyopic, and patching of the fellow eye is currently being attempted. Three eyes were treated by scleral buckling. Two of these had previous cryotherapy and one of the two became reattached after surgery while the other did not. In the latter case the parents declined further surgery. A third eye, which had been an untreated control, responded satisfactorily to an encircling buckle, drainage of subretinal fluid, and cryotherapy. Two other eyes, one that had been treated and one that had been a control, were reattached following lensectomy and open sky vitrectomy. Unfortunately, the eye which had not originally been treated with cryotherapy subsequently developed reproliferation on the surface of the retina. Of the 28 patients, 12 showed a different response between the treated and untreated eye (Table 2). In 11 patients the treated eye improved and the condition of the untreated eye worsened. Using a one-sided hypothesis test on these 11 patients, testing the null hypothesis that the
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untreated eye does at least as well as the treated eye in the population being sampled, vs. the alternative hypothesis that the untreated eye does worse than the treated eye in the population being sampled, we have a one-sided P value of0.0005. Using a two-sided hypothesis test, testing the null hypothesis that the untreated eye and treated eye behave similarly, vs. the alternative hypothesis that they do not behave similarly, we have a P value ofO.OOl. Thus, whether we are doing either a one- or two-tailed hypothesis test, we would, with P values of 0.0005 and 0.001, respectively, reject the null hypothesis and conclude that it appears in the population sampled that treatment appears to be preferred over no treatment.
11 patients who improved in both eyes demonstrated variables not identified by these observers. We hope that the collaborative trial on cryotherapy in ROP will be able to pinpoint such factors because of their larger numbers of babies and natural history documentation. In our previous report we stated that the role of cryotherapy in active retinopathy of prematurity still needs to be defined. With Pvalues of0.0005 and 0.001, we believe that the role of cryotherapy is an encouraging one, and that our data suggest that cryotherapy may be beneficial for preventing severe visual loss in a select group of eyes with active ROP. We now look forward to the results of the collaborative study on cryotherapy in ROP, so that a larger number of randomized eyes will be available to either complement or contradict our results.
DISCUSSION In our previous study, 12 of 17 patients (71%) were female and 5 (29%) were male. With the addition of 11 more patients the ratio of approximately 2 to 1 continues as evidenced by the fact that of 28 patients, 18 (64%) were female and 10 (36%) were male. The mean birthweight in this group of patients was well under 1000 grams, reaffirming the greater risk for ROP in small prematures. Gestationally, the retinal vessels reach the ora serrata nasally at eight months, but do not complete normal vascularization of the temporal retinal periphery until shortly after birth of the full-term infant. 16 Thus, it is not surprising that the majority of prematures in this study had not yet reached term when treated. The interval of time between birth and decision to treat in ten patients averaged ten weeks, or two and one-half months chronologie age, which is a slightly smaller window than the three months reported earlier. 13 Only one of the ten patients was over 40 weeks gestation when treated (Table 1). This suggests that premature infants should be examined by seven weeks, so that the opportunity to treat high-risk eyes is not lost. One treated eye in the first study, originally thought to have done better than the untreated eye over a longer follow-up, developed dragging of the retina that exceeded the dragging in the untreated eye. Of interest, however, is the observation that no progression of ROP occurred in the eleven most recently treated eyes. This contrasts with six treated eyes that worsened in the first study, a difference that may be attributable to more complete cryotherapy of the avascular zone of retina than in the earlier cases. The fact that 11 patients showed improvement in both the treated and untreated eye is difficult to explain statistically. In this study, the binomial distribution was used testing a one-sided and two-sided hypothesis on patients who demonstrated improvement in the treated eye and progression in the untreated eye. It may well be that the
REFERENCES 1. Yamashita Y. Studies on retinopathy of prematurity (Ill) Cryocautery for retinopathy of prematurity. Jpn J Clin Ophthalmol 1972; 26:38593. 2. Sasaki K, Yamashita Y, Maekawa T, Adachi T. Treatment of retinopathy of prematurity in active stage by cryocautery. Jpn J Ophthalmol1976; 20:384-95. 3. Takagi I. Treatment of acute retrolental fibroplasia. Acta Soc Ophthalmol Jpn 1978; 82:323-30. 4. Kingham JD. Acute retrolental fibroplasia; treatment by cryosurgery. Arch Ophthalmol1978; 96:2049-53. 5. Hindle NW, Leyton J. Prevention of cicatricial retrolental fibroplasia by cryotherapy. Can J Ophthalmol1978; 13:277-82. 6. Ben-Sira I, Nissenkom I, Grunwald E, Yassur Y. Treatment of acute retrolental fibroplasia by cryopexy. Br J Ophthalmol 1980; 64:75862. 7. Mousel OK, Hoyt CS. Cryotherapy for retinopathy of prematurity. Ophthalmology 1980; 87:1121-7. 8. Bert MD, Friedman MW, Ballard R. Combined cryosurgery and scleral buckling in acute proliferative retrolental fibroplasia. J Pediatr Ophthalmol Strabismus 1981; 18:9-12. 9. Hindle NW. Cryotherapy for retinopathy of prematurity to prevent retrolental fibroplasia. Can J Ophthalmol1982; 17:207-12. 10. Keith CG. Visual outcome and effect of treatment in stage Ill developing retrolental fibroplasia. Br J Ophthalmol1982; 66:446-9. 11. Mousel OK. Cryotherapy for retinopathy of prematurity; a personal retrospective. Ophthalmology 1985; 92:375-8. 12. Topilow HW, Ackerman AL, Wang FM. The treatment of advanced retinopathy of prematurity by cryotherapy and scleral buckling surgery. Ophthalmology 1985; 92:379-87. 13. Tasman W. Management of retinopathy of prematurity. Ophthalmology 1985; 92:995-9. 14. The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol1984; 102:1130-4. • 15. Palmer EA. Optimal timing of examination for acute retrolental fibroplasia. Ophthalmology 1981; 88:662-6. 16. Patz A, Payne JW. Retrolental fibroplasia. In: Duane TO, ed. Clinical Ophthalmology. Philadelphia: Harper & Row, 1982; Volume 3, Chapter 20.
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Discussion by Earl A. Palmer, MD The authors have been conducting an important investigation of cryotherapy for retinopathy of prematurity. Some weaknesses and unanswered questions in the present study need to be pointed out, not to detract from the value of these reports, but to indicate why cryotherapy cannot yet be considered as an established treatment for this disease and why a definitive collaborative study is still needed.
presumably the examiners who evaluated the outcome for the eyes were aware of which eye had received treatment, since this would ordinarily become obvious during indirect ophthalmoscopy. Masking by use of appropriate photographs would insure that identical outcome criteria were applied to the treated and control eyes.
SELECfiON OF PATIENTS
One principal outcome criterion is described as macular ectopia; an explanation of how this was defined is needed. Although each clinician among us has an idea of how this could be done, there is sometimes a surprising disparity of opinion on an issue such as this. Outcome was judged at varying times following treatment. The length of follow-up is 4 to 19 months, Dr. Tasman has informed me. ROP is a dynamic disease. The time of assessment for outcome is best standardized. Brief follow-up accounts for the fact that one eye in the earlier study worsened after the first publication, and the patient is now reclassified as an adverse discordant case. Because we lack enough information on what happens to these eyes later, the risk-limiting technique of applying cryotherapy to only one eye has been used in most studies.
It is not stated whether there was a check on the determination of the severity of retinopathy of prematurity (ROP), to control the consistency of criteria for selecting patients for cryotherapy. In particular, the determination of "plus disease" can be highly subjective. It would be helpful in this regard to have two examiners examine the patients independently. It was interesting that in the 1984 report, seven patients were excluded because they had developed retinal detachment in one eye, yet there is no mention of any exclusions from the added eleven patient since that first report. A comment on this apparent difference in the patient population during the time periods involved would be useful in assessing the consistency of patient selection over the 28 months of this study.
OUTCOME DETERMINATION
RESULTS RANDOMIZATION
In the more recent 11 patients, one must assume that the two eyes reached threshold for cryotherapy simultaneously. If not, then the two eyes were asymmetric and true randomization would be essential. Dr. Tasman has told me that the two eyes in all of the more recent eleven patients were quite symmetric, and that assignment oftreated versus control eye was done without regard to which eye was worse; however, a system for randomization was not used. Since the more recent 11 cases were not described as "randomized," but rather as "assigned," assurance is lacking that bias did not enter into the decision about which eye received cryotherapy. From a statistical and scientific standpoint, one must ask whether some unconscious bias toward treating the eye that looked even slightly worse or slightly better may have existed. One might assume that there would have been a tendency to treat the worse eye, and consequently that this bias should only increase the validity of the conclusions. It is not known, however, whether at this particular stage ofROP, the rate of progression has significance for the degree of cicatrization that ultimately develops. This highlights the fact that we do not know enough about the natural course of ROP. CONTROL OF BIAS
The statistical analysis in this report is accurate. The numbers are too small, however, to assess whether the results may be applicable to all subgroups; for example, by gender, birthweight, etc. Additionally, there are insufficient numbers of patients here to assess the safety of cryotherapy for ROP. If an extremely severe complication occurs only occasionally, will the strength of benefit justify that risk? It is important to recognize that while 28 patients were studied, the effective sample size of discordant cases includes only 12 patients, and statistical significance is based entirely on evaluation of these 12 discordant cases. If only a few more cases had gone the other way, statistical significance would be absent. TIMING OF EXAMINATIONS
The need to examine premature infants earlier than seven to nine weeks of age is governed by what, if anything, one plans to do as a result of the findings. For natural history studies, and for considering cryosurgical intervention, a first examination at about one month of age seems justified. However, since most American investigators in the field of ROP are unsatisfied with the evidence at hand as to the efficacy and safety of cryotherapy, it would seem unnecessary to routinely examine these infants earlier than age seven to nine weeks, unless an investigational procedure is being done and a research protocol requires it. The authors' suggestion that earlier examination be done "so that the opportunity to treat high risk eyes is not lost" implies an assumption as to the safety and efficacy of cryotherapy that may yet prove to be premature.
Whenever critically evaluating a study such as this, one seeks assurance that bias is controlled in every way possible. This may be accomplished through strict randomization, as noted above, as well as by masking the person who evaluates the results of treatment to be unaware of whether treatment was applied. Since there is no indication that this was the case in the present study,
MULTICENTER STUDY
From the Oregon Health Sciences University, Portland.
I have given some reasons why the present studies are inconclusive. I will now state why I believe that the Multicenter Trial
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of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) is urgently needed. CRYO-ROP will evaluate both the efficacy and the safety of this treatment procedure in a large number of cases. When failures occur, detailed information will be available for later analysis as to the possible reasons for this. By an analysis of the natural course of the disease in our study population, we hope to deduce indications for cryotherapy, should it prove safe and effective. These may be derived by noticing what happens to the eyes that do not receive cryotherapy. Through randomization and control of bias, statistically valid conclusions can be reached. Finally, more complete information is needed about the natural history of ROP. The multicenter study will provide this. Thus, our understanding will be increased not only about the use of cryotherapy, but also about the course of ROP in the population of patients in question, thereby facilitating the design of future studies. Ophthalmoscopy of premature infants ranks among the most difficult examinations that ophthalmologists are called upon to
make. The authors are to be congratulated for undertaking the studies described for us today. Trans-scleral cryotherapy in these patients is a technically demanding procedure and very tedious to carry out under direct visualization of the fundus. The effort involved in studying this form of therapy for ROP seems especially worthwhile when one recognizes the many decades oflife ahead for most of these young patients. The important implications of this pilot study of cryotherapy for ROP are, first, that cryotherapy does not always prevent blindness when applied as used in this study. Second, it is encouraging that we see little reason here to believe that cryotherapy is bad for these patients. Finally, this study gives further reason to hope that cryotherapy is beneficial in altering the course of ROP. It is this very hope for a useful therapy for this cruel disorder that mandates caution, lest our zeal obscure a bias that may lead to erroneous conclusions about investigational therapies. This pilot study provides an optimistic background as CRYOROP begins.
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