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We Can Aim at Better Results in Coming Years—Reply

We Can Aim at Better Results in Coming Years—Reply In reply The design for the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity revolved around our desire to test whether cryotherapy would prevent blindness. With that concept in mind, we used a binary functional outcome of favorable vs unfavorable visual acuity. Visual acuity of 20/200 or worse is customarily classified as legal blindness. This was our unfavorable visual acuity outcome definition, which produced the semantic oddity of the term favorable to describe the opposite category, even though this would include eyes that were somewhat visually impaired. Thus, Jalali and Hussain correctly note that visual acuity in the range of 20/60 to 20/200 is not necessarily favorable in the usual sense of the word. Macular dragging, an intermediate outcome between structurally favorable and unfavorable, was categorized as favorable since macular morphology is relatively preserved. Dragged macula can produce pseudostrabismus by altering the angle κ, or it may induce anisometropia that would disrupt fusion and create true strabismus. Strabismus was not considered to be part of the definition of unfavorable functional outcome because it would have been impossible to separate out strabismus resulting from brain injury, or unrelated strabismus, within the research design that we used.1 Furthermore, the patients in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity only had 1 eye treated, and this situation does not translate into today's clinical practice of treating both eyes. Jalali and Hussein seem to suggest that intervention is needed before the eyes manifest retinopathy of prematurity (ROP) that can be classified in the usual way. I assume this would call for a nonsurgical, medical intervention using a strategy that may yet emerge from ongoing research. More explicitly, they suggest reanalyzing the study data to try to identify stages of disease where treatment results in outcomes of visual acuity of 20/40 or better. Such a subgroup analysis at 15 years would be fraught with inaccuracy, partly owing to missing data. Perhaps the information the doctors seek can be teased out of Table 6 in our 2002 article,2 which studied only eyes that did not have any surgical intervention and correlated visual acuity outcome with severity of ROP. This showed that the best visual acuity outcomes (20/40 or better) occurred in eyes that had no ROP, only zone III ROP, or zone II ROP that did not involve plus disease (as defined for clinical trial usage).3-5 It was noteworthy that even stage 3+ ROP had relatively good outcomes when it did not involve more than 4 clock-hour sectors.2 The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity study group also carried the analysis to a more detailed level wherein risk factors for unfavorable outcome were mathematically identified. (Stage of ROP is only 1 of those risk factors.) Using combined risk factors integrated into a mathematical algorithm, it is possible to assign the level of risk to an individual eye in an individual infant. This was the basis of the selection of eyes for experimental earlier intervention in the Early Treatment for Retinopathy of Prematurity study,6,7 which demonstrated how we can improve outcomes by intervening earlier in eyes that are identified as likely headed toward an unfavorable outcome. Improving outcomes overall not only reduces blindness in this high-risk population but also should have the desirable side effect of reducing other sequelae related to ROP, such as strabismus. When the intervention under consideration is as invasive as widespread ablation of the peripheral retina, medical ethics mandate that we make every effort to efficiently select eyes for treatment with methods like those used in the Early Treatment for Retinopathy of Prematurity study. It is now recommended to treat selected (high-risk) prethreshold eyes. Usually, but not always, this treatment will be used before threshold ROP occurs. Eyes with zone I or II ROP are now considered for treatment whenever there is Plus disease as judged by the presence of dilated and tortuous vessels in at least 2 quadrants of the posterior pole and by comparison with the research standard photograph,3-5 except for zone I eyes where stage 3 without Plus disease may also be treated. Less severe ROP may be followed up longer and considered for treatment if higher-risk severity develops.6 The Early Treatment for Retinopathy of Prematurity study guidelines represent a major advance toward our goal of efficiently selecting eyes for surgical treatment while allowing eyes with less threatening ROP to undergo spontaneous involution. Overall, this is a significant step toward achieving the better outcomes we all want. I thank Jalali and Hussain for their consideration of these details, and I certainly agree with the sentiment in their concluding sentence that even better treatment strategies are needed to further improve overall ocular and visual outcomes. Ablation of the peripheral retina should be applied only when there is a substantial risk of ocular damage from ROP since the therapy is known to carry some morbidity and may reduce the peripheral visual field.8 Because laser treatment is now recommended at a less mature phase of retinal vascular development, the possibility exists that effects on the peripheral visual field could be greater than they were when cryotherapy was applied at a more advanced disease state. In the future, as further follow-up of the Early Treatment for Retinopathy of Prematurity study cohort is conducted, we hope to learn whether peripheral visual field effects and other outcomes will differ from known cryotherapy effects. Correspondence: Dr Palmer, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239 (palmere@ohsu.edu). Financial Disclosure: None. Funding/Support: The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity was supported by a cooperative agreement with the National Eye Institute, National Institutes of Health, Bethesda, Md. Some of the participating centers, including the Casey Eye Institute, Oregon Health & Science University, Portland, also received indirect support through unrestricted grants from Research to Prevent Blindness, New York, NY. References 1. Bremer DLBaker JDFellows RHardy RJRogers GLPalmer EACryotherapy for Retinopathy of Prematurity Cooperative Group, Strabismus in premature infants in the first year of life. Arch Ophthalmol 1998;116329- 333PubMedGoogle ScholarCrossref 2. Cryotherapy for Retinopathy of Prematurity Cooperative Group, Multicenter trial of cryotherapy for retinopathy of prematurity: natural history ROP: ocular outcome at 5(1/2) years in premature infants with birth weights less than 1251 g. Arch Ophthalmol 2002;120595- 599PubMedGoogle ScholarCrossref 3. Cryotherapy for Retinopathy of Prematurity Cooperative Group, Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988;106471- 479PubMedGoogle ScholarCrossref 4. STOP-ROP Multicenter Study Group, Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial, I: primary outcomes. Pediatrics 2000;105295- 310PubMedGoogle ScholarCrossref 5. Good WVHardy RJDobson V et al. Early Treatment for Retinopathy of Prematurity Cooperative Group, The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics 2005;11615- 23PubMedGoogle ScholarCrossref 6. Early Treatment for Retinopathy of Prematurity Cooperative Group, Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;1211684- 1694PubMedGoogle ScholarCrossref 7. Hardy RJGood WVDobson V et al. Early Treatment for Retinopathy of Prematurity Cooperative Group, Multicenter trial of early treatment for retinopathy of prematurity: study design. Control Clin Trials 2004;25311- 325PubMedGoogle ScholarCrossref 8. Cryotherapy for Retinopathy of Prematurity Cooperative Group, Effect of retinal ablative therapy for threshold retinopathy of prematurity: results of Goldmann perimetry at age 10 years. Arch Ophthalmol 2001;1191120- 1125PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Ophthalmology American Medical Association

We Can Aim at Better Results in Coming Years—Reply

Palmer, Earl A.
Archives of Ophthalmology , Volume 124 (4) – Apr 1, 2006
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References (11)

Publisher
American Medical Association
Copyright
Copyright © 2006 American Medical Association. All Rights Reserved.
ISSN
0003-9950
eISSN
1538-3687
DOI
10.1001/archopht.124.4.605
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Abstract

In reply The design for the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity revolved around our desire to test whether cryotherapy would prevent blindness. With that concept in mind, we used a binary functional outcome of favorable vs unfavorable visual acuity. Visual acuity of 20/200 or worse is customarily classified as legal blindness. This was our unfavorable visual acuity outcome definition, which produced the semantic oddity of the term favorable to describe the opposite category, even though this would include eyes that were somewhat visually impaired. Thus, Jalali and Hussain correctly note that visual acuity in the range of 20/60 to 20/200 is not necessarily favorable in the usual sense of the word. Macular dragging, an intermediate outcome between structurally favorable and unfavorable, was categorized as favorable since macular morphology is relatively preserved. Dragged macula can produce pseudostrabismus by altering the angle κ, or it may induce anisometropia that would disrupt fusion and create true strabismus. Strabismus was not considered to be part of the definition of unfavorable functional outcome because it would have been impossible to separate out strabismus resulting from brain injury, or unrelated strabismus, within the research design that we used.1 Furthermore, the patients in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity only had 1 eye treated, and this situation does not translate into today's clinical practice of treating both eyes. Jalali and Hussein seem to suggest that intervention is needed before the eyes manifest retinopathy of prematurity (ROP) that can be classified in the usual way. I assume this would call for a nonsurgical, medical intervention using a strategy that may yet emerge from ongoing research. More explicitly, they suggest reanalyzing the study data to try to identify stages of disease where treatment results in outcomes of visual acuity of 20/40 or better. Such a subgroup analysis at 15 years would be fraught with inaccuracy, partly owing to missing data. Perhaps the information the doctors seek can be teased out of Table 6 in our 2002 article,2 which studied only eyes that did not have any surgical intervention and correlated visual acuity outcome with severity of ROP. This showed that the best visual acuity outcomes (20/40 or better) occurred in eyes that had no ROP, only zone III ROP, or zone II ROP that did not involve plus disease (as defined for clinical trial usage).3-5 It was noteworthy that even stage 3+ ROP had relatively good outcomes when it did not involve more than 4 clock-hour sectors.2 The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity study group also carried the analysis to a more detailed level wherein risk factors for unfavorable outcome were mathematically identified. (Stage of ROP is only 1 of those risk factors.) Using combined risk factors integrated into a mathematical algorithm, it is possible to assign the level of risk to an individual eye in an individual infant. This was the basis of the selection of eyes for experimental earlier intervention in the Early Treatment for Retinopathy of Prematurity study,6,7 which demonstrated how we can improve outcomes by intervening earlier in eyes that are identified as likely headed toward an unfavorable outcome. Improving outcomes overall not only reduces blindness in this high-risk population but also should have the desirable side effect of reducing other sequelae related to ROP, such as strabismus. When the intervention under consideration is as invasive as widespread ablation of the peripheral retina, medical ethics mandate that we make every effort to efficiently select eyes for treatment with methods like those used in the Early Treatment for Retinopathy of Prematurity study. It is now recommended to treat selected (high-risk) prethreshold eyes. Usually, but not always, this treatment will be used before threshold ROP occurs. Eyes with zone I or II ROP are now considered for treatment whenever there is Plus disease as judged by the presence of dilated and tortuous vessels in at least 2 quadrants of the posterior pole and by comparison with the research standard photograph,3-5 except for zone I eyes where stage 3 without Plus disease may also be treated. Less severe ROP may be followed up longer and considered for treatment if higher-risk severity develops.6 The Early Treatment for Retinopathy of Prematurity study guidelines represent a major advance toward our goal of efficiently selecting eyes for surgical treatment while allowing eyes with less threatening ROP to undergo spontaneous involution. Overall, this is a significant step toward achieving the better outcomes we all want. I thank Jalali and Hussain for their consideration of these details, and I certainly agree with the sentiment in their concluding sentence that even better treatment strategies are needed to further improve overall ocular and visual outcomes. Ablation of the peripheral retina should be applied only when there is a substantial risk of ocular damage from ROP since the therapy is known to carry some morbidity and may reduce the peripheral visual field.8 Because laser treatment is now recommended at a less mature phase of retinal vascular development, the possibility exists that effects on the peripheral visual field could be greater than they were when cryotherapy was applied at a more advanced disease state. In the future, as further follow-up of the Early Treatment for Retinopathy of Prematurity study cohort is conducted, we hope to learn whether peripheral visual field effects and other outcomes will differ from known cryotherapy effects. Correspondence: Dr Palmer, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239 (palmere@ohsu.edu). Financial Disclosure: None. Funding/Support: The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity was supported by a cooperative agreement with the National Eye Institute, National Institutes of Health, Bethesda, Md. Some of the participating centers, including the Casey Eye Institute, Oregon Health & Science University, Portland, also received indirect support through unrestricted grants from Research to Prevent Blindness, New York, NY. References 1. Bremer DLBaker JDFellows RHardy RJRogers GLPalmer EACryotherapy for Retinopathy of Prematurity Cooperative Group, Strabismus in premature infants in the first year of life. Arch Ophthalmol 1998;116329- 333PubMedGoogle ScholarCrossref 2. Cryotherapy for Retinopathy of Prematurity Cooperative Group, Multicenter trial of cryotherapy for retinopathy of prematurity: natural history ROP: ocular outcome at 5(1/2) years in premature infants with birth weights less than 1251 g. Arch Ophthalmol 2002;120595- 599PubMedGoogle ScholarCrossref 3. Cryotherapy for Retinopathy of Prematurity Cooperative Group, Multicenter trial of cryotherapy for retinopathy of prematurity: preliminary results. Arch Ophthalmol 1988;106471- 479PubMedGoogle ScholarCrossref 4. STOP-ROP Multicenter Study Group, Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial, I: primary outcomes. Pediatrics 2000;105295- 310PubMedGoogle ScholarCrossref 5. Good WVHardy RJDobson V et al. Early Treatment for Retinopathy of Prematurity Cooperative Group, The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics 2005;11615- 23PubMedGoogle ScholarCrossref 6. Early Treatment for Retinopathy of Prematurity Cooperative Group, Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;1211684- 1694PubMedGoogle ScholarCrossref 7. Hardy RJGood WVDobson V et al. Early Treatment for Retinopathy of Prematurity Cooperative Group, Multicenter trial of early treatment for retinopathy of prematurity: study design. Control Clin Trials 2004;25311- 325PubMedGoogle ScholarCrossref 8. Cryotherapy for Retinopathy of Prematurity Cooperative Group, Effect of retinal ablative therapy for threshold retinopathy of prematurity: results of Goldmann perimetry at age 10 years. Arch Ophthalmol 2001;1191120- 1125PubMedGoogle ScholarCrossref

Journal

Archives of Ophthalmology – American Medical Association

Published: Apr 1, 2006

Keywords: retinopathy of prematurity,cryotherapy,eye,strabismus,blindness

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