- Email: [email protected]
Effect of Early Vitreous Surgery for Aggressive Posterior Retinopathy of Prematurity Detected by Fundus Fluorescein Angiography
Effect of Early Vitreous Surgery for Aggressive Posterior Retinopathy of Prematurity Detected by Fundus Fluorescein Angiography Sachiko Nishina, MD, PhD, Tadashi Yokoi, MD, Tae Yokoi, MD, Yuri Kobayashi, MD, Miina Hiraoka, MD, Noriyuki Azuma, MD, PhD Objective: To assess the effect of early vitrectomy for aggressive posterior retinopathy of prematurity (APROP) using fundus fluorescein angiography. Design: Retrospective, observational case series. Participants: Eleven eyes of 7 patients with APROP that underwent early vitreous surgery. Methods: All eyes underwent vitrectomy with lensectomy that removed the vitreous gel around the fibrovascular proliferative tissue, but not the proliferative tissue when fibrovascular proliferation and retinal detachment occurred despite retinal photocoagulation. Fundus fluorescein angiography was performed before and after the early vitreous surgery. Main Outcome Measures: Dye leakage from the fibrovascular tissue, dilation and tortuosity of the retinal vasculature, and shunt vessels were evaluated by fundus fluorescein angiography. The status of the retinal reattachment was assessed postoperatively. Results: Nine eyes had severe dye leakage from the fibrovascular tissue and 2 eyes had moderate leakage seen by preoperative fluorescein angiography. Severe dilation and tortuosity of the retinal vessels were detected in 10 eyes and shunt vessels in 7 eyes. Six to 12 days after successful surgery, the retina reattached and dilation and tortuosity of the retinal vessels decreased substantially. Dye leakage diminished markedly in all eyes, resolved completely in 7 eyes, and was still apparent slightly in 4. At the final examination, fibrovascular proliferation and retinal detachment did not progress in any eyes; however, 2 eyes had a dragged or folded retina. Follow-up ranged from 6 to 19 months (mean, 9.2). Conclusions: Early vitrectomy that removes vitreous gel from around the proliferative tissue promptly reduces vascular activity and may limit progression of retinal detachment in APROP. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. Ophthalmology 2009;116:2442–2447 © 2009 by the American Academy of Ophthalmology.
The revised International Classification of Retinopathy of Prematurity (ROP)1 described aggressive posterior retinopathy of prematurity (APROP) and recognized it as an unusual form of ROP that rapidly progresses to a closed funnel of tractional retinal detachment within 1 or 2 weeks despite application of early, dense photocoagulation. The features and pathogenesis of this severe form of ROP have been investigated as type II ROP since 1974 in Japan.2,3 Identification of the initial signs of APROP and immediate application of dense, extensive laser photocoagulation to the nonvascularized retina and adjacent vascularized retina including the area of the shunting vessels are essential for treating APROP.2–5 Laser ablation performed early, densely, and repeatedly may transiently stabilize APROP; however, fibrovascular proliferation sometimes recurs in the area of the photocoagulation scars, and the tractional retinal detachment rapidly progresses.4 – 6 Recently, we have re-
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© 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
ported that early vitrectomy with lensectomy for APROP and early photocoagulation prevented progression of retinal detachment.5 Early vitreous surgery for APROP also was evaluated in another report.6 The aim of the surgery was not to remove the fibrovascular proliferative tissue, but to remove the surrounding vitreous gel along which the fibrovascular tissue grows. However, the mechanism by which the surgery stabilizes the retinopathy has not been clarified fully. Fundus fluorescein angiography for ROP, first performed by Flynn et al,7 is now available with a digital fundus camera, the RetCam 120 (Massie Research Laboratories, Inc., Pleasanton, CA), that can view a wide angle of the fundus including the periphery. With this camera, bedside fluorescein angiography can be performed easily to detect vascular areas of nonperfusion and early neovascularization of active retinopathy.8,9 ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2009.05.011
Nishina et al 䡠 Early Vitrectomy for APROP We conducted the current study to evaluate the preoperative status and the efficacy of early vitreous surgery for APROP using fundus fluorescein angiography with the Retcam 120.
Patients and Methods This study was approved by the institutional ethics committee; the parents of the patients provided informed consent before the infants were enrolled. Eleven eyes of 7 patients with APROP were studied. All eyes had undergone previous laser ablation at other clinics when the initial signs of APROP1–3 were identified, and laser was applied repeatedly and densely to the nonvascularized and adjacent vascularized retina. However, when laser treatment could not stop the progression of fibrovascular proliferation and tractional retinal detachment, the patients were referred immediately to our clinic at the National Center for Child Health and Development, Tokyo, Japan. All eyes underwent early vitrectomy with lensectomy as a second treatment performed by 1 surgeon (NA) in our clinic between December 2006 and March 2008. Three-port vitrectomy was performed using the Accurus 25-Gauge Surgical System (Alcon, Fort Worth, TX) and a small contact lens was designed for premature eyes. The details of the surgery have been described previously5 and are shown in online Video Clips 1 through 3 (available at http://aaojournal.org). We did not remove the fibrovascular tissue to avoid intraoperative bleeding, but we did remove the surrounding vitreous gel. Fluid–air exchange and endophotocoagulation were unnecessary, because no iatrogenic breaks occurred during the surgery. Fundus fluorescein angiography was performed within 2 days before the surgery and 6 to 12 days after the surgery. The pupils were dilated using 0.5% phenylephrine and 0.5% tropicamide eye drops instilled 3 times at 10-minute intervals 1 hour before the examination. A neonatal lid speculum and hydroxyethyl cellulose (Scopisol 15; Senju Pharmaceutical Co., Ltd., Osaka, Japan) were used to maintain the cornea– camera interface. The Retcam 120 was used to obtain color fundus photographs and perform fluorescein angiography using a blue excitation light source and the yellow filters in the system. The vital signs were monitored by a neonatologist during the procedure. Fundus fluorescein angiography was performed after administration of an intravenous dose of 0.1 ml/kg of 10% sodium fluorescein dye followed by a saline flush to obtain a bolus dose. Images of the posterior pole, peripheral retina, and fibrovascular tissue were recorded at 2-second intervals during all phases of the angiogram until 5 minutes. Dye leakage from the fibrovascular tissue, dilation and tortuosity of the vasculature, and shunt vessels were evaluated. The patients were followed for 6 to 19 months (mean, 9.2) postoperatively. Aphakic eyes were corrected with spectacles or contact lenses designed for premature babies about 2 weeks after surgery. The final anatomic outcomes were determined by binocular ophthalmoscopy and photography.
Results The characteristics of eyes that underwent early vitreous surgery for APROP and the results of fundus fluorescein angiography before and after surgery are shown in Table 1. The patients included 1 boy and 6 girls. The gestational ages at birth ranged from 23 to 28 weeks (mean, 25), and the birth weights ranged from 389 to 1194 g (mean, 734). The ROP extended to all 4 quadrants and underwent laser ablation within zone I in 9 eyes and to
posterior zone II in 2 eyes. The extent of the fibrovascular tissue ranged from 6 to 10 clock hours and all eyes had a tractional retinal detachment; the fovea was not involved (stage 4A) in 10 eyes and was involved (stage 4B) in 1 eye. The tip of the fibrovascular tissue was not attached to the vitreous base in any eyes. The postmenstrual ages at the time of vitreous surgery ranged from 35 to 41 weeks (mean, 38). Intraoperative complications did not develop in any eyes. Preoperative fundus fluorescein angiography showed severe dye leakage (the extent of dye leakage was 100%) from the fibrovascular tissue in 9 eyes and moderate leakage (the extent of leakage was ⬎70%) in 2 eyes. Severe dilation and tortuosity of the vasculature at the posterior pole were seen clearly in 10 eyes and the shunt vessels remained in 7 eyes. Six to 12 days after successful operations, the dye leakage decreased markedly in all eyes, that is, it resolved in 7 eyes (Figs 1 and 2) and was still apparent in 4 eyes (Fig 3). The extent of the fibrovascular tissue with residual dye leakage in the 4 eyes was ⬍50% of the preoperative findings. The dilation and tortuosity of vasculature also decreased in all eyes (Figs 1 to 3). Fluorescein did not cause any adverse effects. At the final examination, there was no progression of fibrovascular proliferation or retinal detachment in any eyes. Two eyes had a dragged or folded retina (Fig 3).
Discussion We perform vitrectomy with lensectomy in eyes with APROP as early as possible when fibrovascular tissue extends from the posterior retina to the posterior lens surface and causes a regional retinal detachment (stage 4A) despite sufficient laser ablation. Retinopathy of prematurity rapidly progresses to stage 5 within 1 to 2 weeks, when the growing fibrovascular tissue attaches to the posterior lens surface or the retina and ciliary body beneath the vitreous base. Thus, a wide-field vitrectomy with lensectomy to remove the vitreous gel between the fibrous tissue and vitreous base is needed to prevent progression of APROP.5 If the tip of the fibrovascular tissue has attached to the vitreous base, the tractional retinal detachment rapidly progresses to involve the fovea. In this case, cutting the fibrovascular tissue and removing the firm adhesion to the vitreous base are difficult without iatrogenic retinal breaks, resulting in retinal folds or a dragged retina as a result of the strong contraction of the residual fibrovascular tissue and no foveal formation.5 In the current series, all but 1 eye had stage 4A disease in which the fibrovascular tissue increased to 6 to 10 clock hours without attachment to the vitreous base. The eye with stage 4B also had 6 clock hours of fibrovascular tissue without attachment to the vitreous base. We successfully treated these eyes with vitrectomy and lensectomy to obtain retinal reattachment. Preoperative fundus fluorescein angiography showed extreme vascular activity based on extensive dye leakage from the fibrovascular tissue, dilation and tortuosity of the retinal vasculature at the posterior pole, and atypical shunt vessels. However, only 6 to 12 days after surgery, fluorescein angiography showed markedly decreased vascular activity and stabilized APROP. The dilation and tortuosity of the retinal vessels decreased, and the dye leakage from the fibrovascular tissue decreased substantially. These findings strongly support the effectiveness of early vitrectomy, not only for preventing fibrovascular pro-
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Ophthalmology Volume 116, Number 12, December 2009 Table 1. Characteristics of Eyes Undergoing Fundus Fluorescein Angiography
Patient
Gender
Gestational Age at Birth (wks)
Body Weight at Birth (g)
1
Female
26
906
2
Male
23
596
3 4 5 6
Female Female Female Female
24 28 28 23
647 1194 733 389
7
Female
24
670
Eye
Zone
Stage
Extent of FT (clock hours)
Right Left Right Left Left Left Left Right Left Right Left
I I I I I I I I I II II
4A 4A 4A 4A 4B 4A 4A 4A 4A 4A 4A
10 10 6 6 6 6 7 7 7 7 10
DR ⫽ dragging or folds of the retinal; FT ⫽ fibrovascular tissue; PMA ⫽ postmenstrual age. *Severe ⫽ extent of dye leakage was 100% of the FT; moderate ⫽ the extent of dye leakage was ⬎70% of the FT. † Decrease ⫽ the extent of dye leakage decreased by ⬍50% of the preoperative findings.
liferation but also for rapidly reducing the vascular activity in APROP. Consequently, early vitrectomy may limit the progression of tractional retinal detachment. The extent of the residual dye leakage from the fibrovascular tissue may indicate possible regrowth of fibrovascular tissue and recurrence of a tractional retinal detachment. In this series, the
extent of the remaining leakage was ⬍50% in all eyes without recurrence. These results raise some possibilities about the mechanism of the rapid reduction of vascular activity in APROP after vitrectomy. The first factor is that operative removal of the vitreous framework might reduce the tractional
Figure 1. The right eye of patient 6 (gestational age 23 weeks; birth weight, 389 g). A, Preoperatively, fibrovascular tissue grows in the photocoagulation scars with a hemorrhage between the 5 and 12 o’clock positions and a regional tractional retinal detachment has developed (stage 4A). B, Severe dye leakage from the fibrovascular tissue and dilation and tortuosity of the vasculature at the posterior pole are detected (at approximately 2 minutes and 30 seconds). C, Six days postoperatively, the retina has reattached without retinal dragging under residual fibrous tissue. D, The dye leakage has almost resolved and less dilation and tortuosity of the vasculature are seen (at approximately 4 minutes to show the most prominent leakage).
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Nishina et al 䡠 Early Vitrectomy for APROP (FA) before and after Surgery for Aggressive Posterior Retinopathy of Prematurity PMA at Vitrectomy (wks)
Preoperative Dye Leakage from FT*
Dilation and Tortuosity of Retinal Vasculature
Postoperative Day of FA
Postoperative Dye Leakage from FT†
Reduced Dilation and Tortuosity of Retinal Vasculature
Retinal Attachment (Final)
36 36 41 41 37 39 35 38 38 38 38
Severe Severe Severe Severe Severe Moderate Severe Severe Moderate Severe Severe
Severe Severe Severe Severe Severe Moderate Severe Severe Severe Severe Severe
12 12 6 6 11 11 7 6 6 7 7
None None None None Decrease None None None Decrease Decrease Decrease
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes, DR Yes, DR Yes Yes Yes Yes Yes
force of the fibrovascular tissue and suppress the growth of new vessels. Even after scleral buckling, the activity of the fibrovascular tissue seems to be attenuated.10 Decreased vitreous traction may allow the retinal pigment epithelium pump to absorb subretinal fluid, achieve retinal reattachment, and eliminate the stimulus for neovascularization.10,11 In vitro and animal studies have shown that traction and stretching of the vascular wall induces
changes in the retinal vasculature and may accelerate neovascularization with related integrins and other factors.12–14 However, scleral buckling has no effect on APROP, which is characterized by extensive, rapidly progressive retinopathy and is similar to florid diabetic retinopathy that requires full panretinal photocoagulation and early vitrectomy to prevent rapid progression of the tractional retinal detachment.15
Figure 2. The right eye of patient 1 (gestational age 26 weeks; birth weight, 906 g). A, Preoperatively, extreme fibrovascular tissue grows rapidly in the photocoagulation scars between the 9 and 7 o’clock positions and a tractional retinal detachment has developed (stage 4A). Dilation and tortuosity of the vasculature at the posterior pole, shunt vessels, and retinal and vitreous hemorrhages are seen. B, Severe dye leakage from the fibrovascular tissue is seen (at approximately 2 minutes and 30 seconds). C, Twelve days postoperatively, the retina has reattached without retinal dragging under residual fibrous tissue. D, The dye leakage has almost resolved and the dilation and tortuosity of vasculature have decreased (at approximately 4 minutes).
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Ophthalmology Volume 116, Number 12, December 2009
Figure 3. The left eye of patient 3 (gestational age 24 weeks; birth weight, 647 g). A, Preoperatively, fibrovascular tissue grows between the 2 and 8 o’clock positions and a tractional retinal detachment has developed involving the fovea (stage 4B). B, Severe dye leakage from the fibrovascular tissue is seen (at approximately 2 minutes and 30 seconds). C, Eleven days postoperatively, the retina has reattached with residual retinal folds. D, The dye leakage is reduced markedly with slight residual leakage (at approximately 4 minutes).
Vascular endothelial growth factor (VEGF) and other angiogenic factors contribute to the formation of neovascularization in ROP. Vitreous VEGF and stromal cell-derived factor 1␣ levels increase in eyes with active vascular stage 4 ROP.16 The second essential role of early vitrectomy for APROP may be that the operation washes out angiogenic factors such as VEGF and stromal cell-derived factor 1␣. Vitrectomy also seems to effectively remove the scaffold tissue and extracellular matrix that mediate angiogenesis.17 Recently, anti-VEGF treatment has been studied to treat ROP based on the efficacy of other angiogenic disorders such as age-related macular disease, proliferative diabetic retinopathy, and neovascular glaucoma. Intravitreal injection of bevacizumab (Avastin, Genentech, South San Francisco, CA), a recombinant humanized anti-VEGF monoclonal antibody, has been investigated for severe ROP including APROP.18 –20 The drug seems to effectively reduce vascular activity including the tunica vasculosa lentis, dilation and tortuosity of the retinal vessels, and neovascular proliferation with laser photocoagulation in early stage APROP.18,19 Bevacizumab also may have an effect on stage 4 ROP; however, in eyes with advanced ROP, the drug cannot sufficiently reduce the vascular activity of the fibrous tissue and prevent the rapid progression of the tractional retinal detachment without vitrectomy.20 Most important, the optimal dose of bevacizumab that preserves the normal neuroretinal development has not been determined in human ROP.19 –22 Severe ischemic retinopathies,
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including APROP and florid diabetic retinopathy, are followed by marked overproduction of VEGF and other angiogenic factors that lead to abnormal vascularization. Thus, 1 injection of a safe dose of bevacizumab probably cannot prevent rapid progression of the disease. Meanwhile, an intravitreal injection of bevacizumab is problematic for APROP, which is characterized by prominent fibrovascular proliferative tissue, because the drug may cause strong contraction of the fibrous tissue in advanced ROP.23 Early vitrectomy has a substantial effect on APROP, presumably by washing out VEGF and other angiogenic factors resulting in prompt declines in vascular activity. The positive effect on the disease may result from the complete removal of the vitreous tractional force and washing out of the VEGF and other angiogenic factors simultaneously. It is uncertain if vitrectomy can convert the active vascular stage to the inactive cicatricial stage via a change in cytokine release or if the APROP may progress spontaneously to cicatrization because of the reduced scaffolding area for the fibrovascular tissue. Further investigation is needed to clarify the mechanism of the rapid conversion of APROP to cicatrization after vitrectomy. The current study had some limitations in that it was not randomized, controlled, or prospective to clarify whether vitrectomy with lensectomy is more appropriate to treat eyes with stage 4A APROP. Lens preservation is important to promote visual development; however, lensectomy may be necessary when the fibrovascular tissue rapidly grows to
Nishina et al 䡠 Early Vitrectomy for APROP the vitreous base in APROP. Further investigation also is needed to obtain long-term functional outcomes of early vitrectomy for APROP with continuous management of aphakic eyes.
References 1. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005;123:991–9. 2. Uemura Y, Tsukahara I, Nagata M, et al. Diagnostic and therapeutic criteria for retinopathy of prematurity [in Japanese]. Committee’s Report Appointed by the Japanese Ministry of Health and Welfare. Tokyo, Japan: Japanese Ministry of Health and Welfare, 1974. Nippon no Ganka 1975;46:553–9. 3. Morizane H. Initial sign and clinical course of the most severe form of acute proliferative retrolental fibroplasia (type II) [in Japanese]. Nippon Ganka Gakkai Zasshi 1976;80:54 – 61. 4. Vinekar A, Trese MT, Capone A Jr, Photographic Screening for Retinopathy of Prematurity (PHOTO-ROP) Cooperative Group. Evolution of retinal detachment in posterior retinopathy of prematurity: impact on treatment approach. Am J Ophthalmol 2008;145:548 –55. 5. Azuma N, Ishikawa K, Hama Y, et al. Early vitreous surgery for aggressive posterior retinopathy of prematurity. Am J Ophthalmol 2006;142:636 – 43. 6. Micelli Ferrari T, Furino C, Lorusso VV, et al. Three-port lens-sparing vitrectomy for aggressive posterior retinopathy of prematurity: early surgery before tractional retinal detachment appearance. Eur J Ophthalmol 2007;17:785–9. 7. Flynn JT, Cassady J, Essner D, et al. Fluorescein angiography in retrolental fibroplasia: experience from 1969 –1977. Ophthalmology 1979;86:1700 –23. 8. Ng EY, Lanigan B, O’Keefe M. Fundus fluorescein angiography in the screening for and management of retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 2006;43:85–90. 9. Azad R, Chandra P, Khan MA, Darswal A. Role of intravenous fluorescein angiography in early detection and regression of retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 2008;45:36 –9. 10. Hinz BJ, de Juan E Jr, Repka MX. Scleral buckling surgery for active stage 4A retinopathy of prematurity. Ophthalmology 1998;105:1827–30. 11. Trese MT. Scleral buckling for retinopathy of prematurity. Ophthalmology 1994;101:23– 6.
12. Yamashita H, Hori S, Yamamoto T. Effect of traction on the vasculature of chorioallantoic membranes of chick embryos. Invest Ophthalmol Vis Sci 1989;30:778 – 82. 13. Wilkinson-Berka JL, Jones D, Taylor G, et al. SB-267268, a nonpeptidic antagonist of alpha(v)beta3 and alpha(v)beta5 integrins, reduced angiogenesis and VEGF expression in a mouse model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 2006;47:1600 –5. 14. Albinsson S, Hellstrand P. Integration of signal pathways for stretch-dependent growth and differentiation in vascular smooth muscle. Am J Physiol Cell Physiol 2007;293:C772– 82. 15. Favard C, Guyot-Argenton C, Assouline M, et al. Full panretinal photocoagulation and early vitrectomy improve prognosis of florid diabetic retinopathy. Ophthalmology 1996;103:561–74. 16. Sonmez K, Drenser KA, Capone A Jr, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology 2008;115:1065–70. 17. Krishnan L, Hoying JB, Nguyen H, et al. Interaction of angiogenic microvessels with the extracellular matrix. Am J Physiol Heart Circ Physiol 2007;293:H3650 – 8. 18. Chung EJ, Kim JH, Ahn HS, Koh HJ. Combination of laser photocoagulation and intravitreal bevacizumab (Avastin) for aggressive zone I retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2007;245:1727–30. 19. Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging 2007;38:233–7. 20. Kusaka S, Shima C, Wada K, et al. Efficacy of intravitreal injection of bevacizumab for severe retinopathy of prematurity: a pilot study. Br J Ophthalmol 2008;92:1450 –5. 21. Kong L, Mintz-Hittner HA, Penland RL, et al. Intravitreal bevacizumab as anti-vascular endothelial growth factor therapy for retinopathy of prematurity: a morphologic study [letter]. Arch Ophthalmol 2008;126:1161–3. 22. Geisen P, Peterson LJ, Martiniuk D, et al. Neutralizing antibody to VEGF reduces intravitreous neovascularization and may not interfere with ongoing intraretinal vascularization in a rat model of retinopathy of prematurity. Mol Vis [serial online] 2008;14:345–57. Available at: http://www.molvis.org/ molvis/v14/a43/. Accessed April 22, 2009. 23. Honda S, Hirabayashi H, Tsukahara Y, Negi A. Acute contraction of the proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2008;246:1061–3.
Footnotes and Financial Disclosures Originally received: December 15, 2008. Final revision: May 7, 2009. Accepted: May 7, 2009. Available online: October 8, 2009.
Supported by Grants of Research for Disorders of Sensory Organs from the Ministry of Health Welfare and Labor, Japan. Manuscript no. 2008-1501.
The Department of Ophthalmology, National Center for Child Health and Development, Tokyo, Japan. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Correspondence: Noriyuki Azuma, MD, PhD, Department of Ophthalmology, National Center for Child Health and Development, 2-10-1 Ohkura, Setagaya-ku, Tokyo, 157-8535, Japan. E-mail: [email protected].
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The revised International Classification of Retinopathy of Prematurity (ROP)1 described aggressive posterior retinopathy of prematurity (APROP) and recognized it as an unusual form of ROP that rapidly progresses to a closed funnel of tractional retinal detachment within 1 or 2 weeks despite application of early, dense photocoagulation. The features and pathogenesis of this severe form of ROP have been investigated as type II ROP since 1974 in Japan.2,3 Identification of the initial signs of APROP and immediate application of dense, extensive laser photocoagulation to the nonvascularized retina and adjacent vascularized retina including the area of the shunting vessels are essential for treating APROP.2–5 Laser ablation performed early, densely, and repeatedly may transiently stabilize APROP; however, fibrovascular proliferation sometimes recurs in the area of the photocoagulation scars, and the tractional retinal detachment rapidly progresses.4 – 6 Recently, we have re-
2442
© 2009 by the American Academy of Ophthalmology Published by Elsevier Inc.
ported that early vitrectomy with lensectomy for APROP and early photocoagulation prevented progression of retinal detachment.5 Early vitreous surgery for APROP also was evaluated in another report.6 The aim of the surgery was not to remove the fibrovascular proliferative tissue, but to remove the surrounding vitreous gel along which the fibrovascular tissue grows. However, the mechanism by which the surgery stabilizes the retinopathy has not been clarified fully. Fundus fluorescein angiography for ROP, first performed by Flynn et al,7 is now available with a digital fundus camera, the RetCam 120 (Massie Research Laboratories, Inc., Pleasanton, CA), that can view a wide angle of the fundus including the periphery. With this camera, bedside fluorescein angiography can be performed easily to detect vascular areas of nonperfusion and early neovascularization of active retinopathy.8,9 ISSN 0161-6420/09/$–see front matter doi:10.1016/j.ophtha.2009.05.011
Nishina et al 䡠 Early Vitrectomy for APROP We conducted the current study to evaluate the preoperative status and the efficacy of early vitreous surgery for APROP using fundus fluorescein angiography with the Retcam 120.
Patients and Methods This study was approved by the institutional ethics committee; the parents of the patients provided informed consent before the infants were enrolled. Eleven eyes of 7 patients with APROP were studied. All eyes had undergone previous laser ablation at other clinics when the initial signs of APROP1–3 were identified, and laser was applied repeatedly and densely to the nonvascularized and adjacent vascularized retina. However, when laser treatment could not stop the progression of fibrovascular proliferation and tractional retinal detachment, the patients were referred immediately to our clinic at the National Center for Child Health and Development, Tokyo, Japan. All eyes underwent early vitrectomy with lensectomy as a second treatment performed by 1 surgeon (NA) in our clinic between December 2006 and March 2008. Three-port vitrectomy was performed using the Accurus 25-Gauge Surgical System (Alcon, Fort Worth, TX) and a small contact lens was designed for premature eyes. The details of the surgery have been described previously5 and are shown in online Video Clips 1 through 3 (available at http://aaojournal.org). We did not remove the fibrovascular tissue to avoid intraoperative bleeding, but we did remove the surrounding vitreous gel. Fluid–air exchange and endophotocoagulation were unnecessary, because no iatrogenic breaks occurred during the surgery. Fundus fluorescein angiography was performed within 2 days before the surgery and 6 to 12 days after the surgery. The pupils were dilated using 0.5% phenylephrine and 0.5% tropicamide eye drops instilled 3 times at 10-minute intervals 1 hour before the examination. A neonatal lid speculum and hydroxyethyl cellulose (Scopisol 15; Senju Pharmaceutical Co., Ltd., Osaka, Japan) were used to maintain the cornea– camera interface. The Retcam 120 was used to obtain color fundus photographs and perform fluorescein angiography using a blue excitation light source and the yellow filters in the system. The vital signs were monitored by a neonatologist during the procedure. Fundus fluorescein angiography was performed after administration of an intravenous dose of 0.1 ml/kg of 10% sodium fluorescein dye followed by a saline flush to obtain a bolus dose. Images of the posterior pole, peripheral retina, and fibrovascular tissue were recorded at 2-second intervals during all phases of the angiogram until 5 minutes. Dye leakage from the fibrovascular tissue, dilation and tortuosity of the vasculature, and shunt vessels were evaluated. The patients were followed for 6 to 19 months (mean, 9.2) postoperatively. Aphakic eyes were corrected with spectacles or contact lenses designed for premature babies about 2 weeks after surgery. The final anatomic outcomes were determined by binocular ophthalmoscopy and photography.
Results The characteristics of eyes that underwent early vitreous surgery for APROP and the results of fundus fluorescein angiography before and after surgery are shown in Table 1. The patients included 1 boy and 6 girls. The gestational ages at birth ranged from 23 to 28 weeks (mean, 25), and the birth weights ranged from 389 to 1194 g (mean, 734). The ROP extended to all 4 quadrants and underwent laser ablation within zone I in 9 eyes and to
posterior zone II in 2 eyes. The extent of the fibrovascular tissue ranged from 6 to 10 clock hours and all eyes had a tractional retinal detachment; the fovea was not involved (stage 4A) in 10 eyes and was involved (stage 4B) in 1 eye. The tip of the fibrovascular tissue was not attached to the vitreous base in any eyes. The postmenstrual ages at the time of vitreous surgery ranged from 35 to 41 weeks (mean, 38). Intraoperative complications did not develop in any eyes. Preoperative fundus fluorescein angiography showed severe dye leakage (the extent of dye leakage was 100%) from the fibrovascular tissue in 9 eyes and moderate leakage (the extent of leakage was ⬎70%) in 2 eyes. Severe dilation and tortuosity of the vasculature at the posterior pole were seen clearly in 10 eyes and the shunt vessels remained in 7 eyes. Six to 12 days after successful operations, the dye leakage decreased markedly in all eyes, that is, it resolved in 7 eyes (Figs 1 and 2) and was still apparent in 4 eyes (Fig 3). The extent of the fibrovascular tissue with residual dye leakage in the 4 eyes was ⬍50% of the preoperative findings. The dilation and tortuosity of vasculature also decreased in all eyes (Figs 1 to 3). Fluorescein did not cause any adverse effects. At the final examination, there was no progression of fibrovascular proliferation or retinal detachment in any eyes. Two eyes had a dragged or folded retina (Fig 3).
Discussion We perform vitrectomy with lensectomy in eyes with APROP as early as possible when fibrovascular tissue extends from the posterior retina to the posterior lens surface and causes a regional retinal detachment (stage 4A) despite sufficient laser ablation. Retinopathy of prematurity rapidly progresses to stage 5 within 1 to 2 weeks, when the growing fibrovascular tissue attaches to the posterior lens surface or the retina and ciliary body beneath the vitreous base. Thus, a wide-field vitrectomy with lensectomy to remove the vitreous gel between the fibrous tissue and vitreous base is needed to prevent progression of APROP.5 If the tip of the fibrovascular tissue has attached to the vitreous base, the tractional retinal detachment rapidly progresses to involve the fovea. In this case, cutting the fibrovascular tissue and removing the firm adhesion to the vitreous base are difficult without iatrogenic retinal breaks, resulting in retinal folds or a dragged retina as a result of the strong contraction of the residual fibrovascular tissue and no foveal formation.5 In the current series, all but 1 eye had stage 4A disease in which the fibrovascular tissue increased to 6 to 10 clock hours without attachment to the vitreous base. The eye with stage 4B also had 6 clock hours of fibrovascular tissue without attachment to the vitreous base. We successfully treated these eyes with vitrectomy and lensectomy to obtain retinal reattachment. Preoperative fundus fluorescein angiography showed extreme vascular activity based on extensive dye leakage from the fibrovascular tissue, dilation and tortuosity of the retinal vasculature at the posterior pole, and atypical shunt vessels. However, only 6 to 12 days after surgery, fluorescein angiography showed markedly decreased vascular activity and stabilized APROP. The dilation and tortuosity of the retinal vessels decreased, and the dye leakage from the fibrovascular tissue decreased substantially. These findings strongly support the effectiveness of early vitrectomy, not only for preventing fibrovascular pro-
2443
Ophthalmology Volume 116, Number 12, December 2009 Table 1. Characteristics of Eyes Undergoing Fundus Fluorescein Angiography
Patient
Gender
Gestational Age at Birth (wks)
Body Weight at Birth (g)
1
Female
26
906
2
Male
23
596
3 4 5 6
Female Female Female Female
24 28 28 23
647 1194 733 389
7
Female
24
670
Eye
Zone
Stage
Extent of FT (clock hours)
Right Left Right Left Left Left Left Right Left Right Left
I I I I I I I I I II II
4A 4A 4A 4A 4B 4A 4A 4A 4A 4A 4A
10 10 6 6 6 6 7 7 7 7 10
DR ⫽ dragging or folds of the retinal; FT ⫽ fibrovascular tissue; PMA ⫽ postmenstrual age. *Severe ⫽ extent of dye leakage was 100% of the FT; moderate ⫽ the extent of dye leakage was ⬎70% of the FT. † Decrease ⫽ the extent of dye leakage decreased by ⬍50% of the preoperative findings.
liferation but also for rapidly reducing the vascular activity in APROP. Consequently, early vitrectomy may limit the progression of tractional retinal detachment. The extent of the residual dye leakage from the fibrovascular tissue may indicate possible regrowth of fibrovascular tissue and recurrence of a tractional retinal detachment. In this series, the
extent of the remaining leakage was ⬍50% in all eyes without recurrence. These results raise some possibilities about the mechanism of the rapid reduction of vascular activity in APROP after vitrectomy. The first factor is that operative removal of the vitreous framework might reduce the tractional
Figure 1. The right eye of patient 6 (gestational age 23 weeks; birth weight, 389 g). A, Preoperatively, fibrovascular tissue grows in the photocoagulation scars with a hemorrhage between the 5 and 12 o’clock positions and a regional tractional retinal detachment has developed (stage 4A). B, Severe dye leakage from the fibrovascular tissue and dilation and tortuosity of the vasculature at the posterior pole are detected (at approximately 2 minutes and 30 seconds). C, Six days postoperatively, the retina has reattached without retinal dragging under residual fibrous tissue. D, The dye leakage has almost resolved and less dilation and tortuosity of the vasculature are seen (at approximately 4 minutes to show the most prominent leakage).
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Nishina et al 䡠 Early Vitrectomy for APROP (FA) before and after Surgery for Aggressive Posterior Retinopathy of Prematurity PMA at Vitrectomy (wks)
Preoperative Dye Leakage from FT*
Dilation and Tortuosity of Retinal Vasculature
Postoperative Day of FA
Postoperative Dye Leakage from FT†
Reduced Dilation and Tortuosity of Retinal Vasculature
Retinal Attachment (Final)
36 36 41 41 37 39 35 38 38 38 38
Severe Severe Severe Severe Severe Moderate Severe Severe Moderate Severe Severe
Severe Severe Severe Severe Severe Moderate Severe Severe Severe Severe Severe
12 12 6 6 11 11 7 6 6 7 7
None None None None Decrease None None None Decrease Decrease Decrease
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes Yes, DR Yes, DR Yes Yes Yes Yes Yes
force of the fibrovascular tissue and suppress the growth of new vessels. Even after scleral buckling, the activity of the fibrovascular tissue seems to be attenuated.10 Decreased vitreous traction may allow the retinal pigment epithelium pump to absorb subretinal fluid, achieve retinal reattachment, and eliminate the stimulus for neovascularization.10,11 In vitro and animal studies have shown that traction and stretching of the vascular wall induces
changes in the retinal vasculature and may accelerate neovascularization with related integrins and other factors.12–14 However, scleral buckling has no effect on APROP, which is characterized by extensive, rapidly progressive retinopathy and is similar to florid diabetic retinopathy that requires full panretinal photocoagulation and early vitrectomy to prevent rapid progression of the tractional retinal detachment.15
Figure 2. The right eye of patient 1 (gestational age 26 weeks; birth weight, 906 g). A, Preoperatively, extreme fibrovascular tissue grows rapidly in the photocoagulation scars between the 9 and 7 o’clock positions and a tractional retinal detachment has developed (stage 4A). Dilation and tortuosity of the vasculature at the posterior pole, shunt vessels, and retinal and vitreous hemorrhages are seen. B, Severe dye leakage from the fibrovascular tissue is seen (at approximately 2 minutes and 30 seconds). C, Twelve days postoperatively, the retina has reattached without retinal dragging under residual fibrous tissue. D, The dye leakage has almost resolved and the dilation and tortuosity of vasculature have decreased (at approximately 4 minutes).
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Figure 3. The left eye of patient 3 (gestational age 24 weeks; birth weight, 647 g). A, Preoperatively, fibrovascular tissue grows between the 2 and 8 o’clock positions and a tractional retinal detachment has developed involving the fovea (stage 4B). B, Severe dye leakage from the fibrovascular tissue is seen (at approximately 2 minutes and 30 seconds). C, Eleven days postoperatively, the retina has reattached with residual retinal folds. D, The dye leakage is reduced markedly with slight residual leakage (at approximately 4 minutes).
Vascular endothelial growth factor (VEGF) and other angiogenic factors contribute to the formation of neovascularization in ROP. Vitreous VEGF and stromal cell-derived factor 1␣ levels increase in eyes with active vascular stage 4 ROP.16 The second essential role of early vitrectomy for APROP may be that the operation washes out angiogenic factors such as VEGF and stromal cell-derived factor 1␣. Vitrectomy also seems to effectively remove the scaffold tissue and extracellular matrix that mediate angiogenesis.17 Recently, anti-VEGF treatment has been studied to treat ROP based on the efficacy of other angiogenic disorders such as age-related macular disease, proliferative diabetic retinopathy, and neovascular glaucoma. Intravitreal injection of bevacizumab (Avastin, Genentech, South San Francisco, CA), a recombinant humanized anti-VEGF monoclonal antibody, has been investigated for severe ROP including APROP.18 –20 The drug seems to effectively reduce vascular activity including the tunica vasculosa lentis, dilation and tortuosity of the retinal vessels, and neovascular proliferation with laser photocoagulation in early stage APROP.18,19 Bevacizumab also may have an effect on stage 4 ROP; however, in eyes with advanced ROP, the drug cannot sufficiently reduce the vascular activity of the fibrous tissue and prevent the rapid progression of the tractional retinal detachment without vitrectomy.20 Most important, the optimal dose of bevacizumab that preserves the normal neuroretinal development has not been determined in human ROP.19 –22 Severe ischemic retinopathies,
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including APROP and florid diabetic retinopathy, are followed by marked overproduction of VEGF and other angiogenic factors that lead to abnormal vascularization. Thus, 1 injection of a safe dose of bevacizumab probably cannot prevent rapid progression of the disease. Meanwhile, an intravitreal injection of bevacizumab is problematic for APROP, which is characterized by prominent fibrovascular proliferative tissue, because the drug may cause strong contraction of the fibrous tissue in advanced ROP.23 Early vitrectomy has a substantial effect on APROP, presumably by washing out VEGF and other angiogenic factors resulting in prompt declines in vascular activity. The positive effect on the disease may result from the complete removal of the vitreous tractional force and washing out of the VEGF and other angiogenic factors simultaneously. It is uncertain if vitrectomy can convert the active vascular stage to the inactive cicatricial stage via a change in cytokine release or if the APROP may progress spontaneously to cicatrization because of the reduced scaffolding area for the fibrovascular tissue. Further investigation is needed to clarify the mechanism of the rapid conversion of APROP to cicatrization after vitrectomy. The current study had some limitations in that it was not randomized, controlled, or prospective to clarify whether vitrectomy with lensectomy is more appropriate to treat eyes with stage 4A APROP. Lens preservation is important to promote visual development; however, lensectomy may be necessary when the fibrovascular tissue rapidly grows to
Nishina et al 䡠 Early Vitrectomy for APROP the vitreous base in APROP. Further investigation also is needed to obtain long-term functional outcomes of early vitrectomy for APROP with continuous management of aphakic eyes.
References 1. International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005;123:991–9. 2. Uemura Y, Tsukahara I, Nagata M, et al. Diagnostic and therapeutic criteria for retinopathy of prematurity [in Japanese]. Committee’s Report Appointed by the Japanese Ministry of Health and Welfare. Tokyo, Japan: Japanese Ministry of Health and Welfare, 1974. Nippon no Ganka 1975;46:553–9. 3. Morizane H. Initial sign and clinical course of the most severe form of acute proliferative retrolental fibroplasia (type II) [in Japanese]. Nippon Ganka Gakkai Zasshi 1976;80:54 – 61. 4. Vinekar A, Trese MT, Capone A Jr, Photographic Screening for Retinopathy of Prematurity (PHOTO-ROP) Cooperative Group. Evolution of retinal detachment in posterior retinopathy of prematurity: impact on treatment approach. Am J Ophthalmol 2008;145:548 –55. 5. Azuma N, Ishikawa K, Hama Y, et al. Early vitreous surgery for aggressive posterior retinopathy of prematurity. Am J Ophthalmol 2006;142:636 – 43. 6. Micelli Ferrari T, Furino C, Lorusso VV, et al. Three-port lens-sparing vitrectomy for aggressive posterior retinopathy of prematurity: early surgery before tractional retinal detachment appearance. Eur J Ophthalmol 2007;17:785–9. 7. Flynn JT, Cassady J, Essner D, et al. Fluorescein angiography in retrolental fibroplasia: experience from 1969 –1977. Ophthalmology 1979;86:1700 –23. 8. Ng EY, Lanigan B, O’Keefe M. Fundus fluorescein angiography in the screening for and management of retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 2006;43:85–90. 9. Azad R, Chandra P, Khan MA, Darswal A. Role of intravenous fluorescein angiography in early detection and regression of retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 2008;45:36 –9. 10. Hinz BJ, de Juan E Jr, Repka MX. Scleral buckling surgery for active stage 4A retinopathy of prematurity. Ophthalmology 1998;105:1827–30. 11. Trese MT. Scleral buckling for retinopathy of prematurity. Ophthalmology 1994;101:23– 6.
12. Yamashita H, Hori S, Yamamoto T. Effect of traction on the vasculature of chorioallantoic membranes of chick embryos. Invest Ophthalmol Vis Sci 1989;30:778 – 82. 13. Wilkinson-Berka JL, Jones D, Taylor G, et al. SB-267268, a nonpeptidic antagonist of alpha(v)beta3 and alpha(v)beta5 integrins, reduced angiogenesis and VEGF expression in a mouse model of retinopathy of prematurity. Invest Ophthalmol Vis Sci 2006;47:1600 –5. 14. Albinsson S, Hellstrand P. Integration of signal pathways for stretch-dependent growth and differentiation in vascular smooth muscle. Am J Physiol Cell Physiol 2007;293:C772– 82. 15. Favard C, Guyot-Argenton C, Assouline M, et al. Full panretinal photocoagulation and early vitrectomy improve prognosis of florid diabetic retinopathy. Ophthalmology 1996;103:561–74. 16. Sonmez K, Drenser KA, Capone A Jr, Trese MT. Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology 2008;115:1065–70. 17. Krishnan L, Hoying JB, Nguyen H, et al. Interaction of angiogenic microvessels with the extracellular matrix. Am J Physiol Heart Circ Physiol 2007;293:H3650 – 8. 18. Chung EJ, Kim JH, Ahn HS, Koh HJ. Combination of laser photocoagulation and intravitreal bevacizumab (Avastin) for aggressive zone I retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2007;245:1727–30. 19. Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging 2007;38:233–7. 20. Kusaka S, Shima C, Wada K, et al. Efficacy of intravitreal injection of bevacizumab for severe retinopathy of prematurity: a pilot study. Br J Ophthalmol 2008;92:1450 –5. 21. Kong L, Mintz-Hittner HA, Penland RL, et al. Intravitreal bevacizumab as anti-vascular endothelial growth factor therapy for retinopathy of prematurity: a morphologic study [letter]. Arch Ophthalmol 2008;126:1161–3. 22. Geisen P, Peterson LJ, Martiniuk D, et al. Neutralizing antibody to VEGF reduces intravitreous neovascularization and may not interfere with ongoing intraretinal vascularization in a rat model of retinopathy of prematurity. Mol Vis [serial online] 2008;14:345–57. Available at: http://www.molvis.org/ molvis/v14/a43/. Accessed April 22, 2009. 23. Honda S, Hirabayashi H, Tsukahara Y, Negi A. Acute contraction of the proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2008;246:1061–3.
Footnotes and Financial Disclosures Originally received: December 15, 2008. Final revision: May 7, 2009. Accepted: May 7, 2009. Available online: October 8, 2009.
Supported by Grants of Research for Disorders of Sensory Organs from the Ministry of Health Welfare and Labor, Japan. Manuscript no. 2008-1501.
The Department of Ophthalmology, National Center for Child Health and Development, Tokyo, Japan. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.
Correspondence: Noriyuki Azuma, MD, PhD, Department of Ophthalmology, National Center for Child Health and Development, 2-10-1 Ohkura, Setagaya-ku, Tokyo, 157-8535, Japan. E-mail: [email protected].
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