CONCURRENT SCLERAL BUCKLE AND INTRAVITREAL BEVACIZUMAB FOR ADVANCED RETINOPATHY OF PREMATURITY-RELATED RETINAL DETACHMENT Rohan J. Shah, MD,*† Jose M. Garcia-Gonzalez, MD,†‡ Michael P. Blair, MD,†‡ John Galasso, MD, PhD,†‡ Michael J. Shapiro, MD†‡
Background: The preoperative use of intravitreal bevacizumab in Stage 4 or 5 retinopathy of prematurity (ROP) can reduce vascular endothelial growth factor load and bleeding risk; however, it can induce traction and exacerbate a tractional retinal detachment. Concurrent placement of a scleral buckle may reduce these risks and obviate future vitrectomy. Methods: A retrospective analysis of eyes treated for Stage 4 and 5 ROP with concurrent intravitreal bevacizumab and scleral buckle was performed. Retinal reattachment and need for vitrectomy were studied. Results: Thirteen eyes from 10 infants were treated with concurrent intravitreal bevacizumab and scleral buckle. Nine eyes were Stage 4a, 2 were Stage 4b, and 2 were Stage 5. All eyes with Stage 4 ROP achieved macular attachment at last follow-up. All the eyes with 4a ROP achieved retinal reattachment: 4 (44.4%) with buckle alone and 5 (55.6%) with subsequent vitrectomy. All 4 eyes with Stage 4b or 5 ROP required vitrectomy. Conclusion: Concurrent intravitreal bevacizumab and scleral buckle may serve as a bridge to vitrectomy and, in some instances, may obviate the need for subsequent intervention. RETINAL CASES & BRIEF REPORTS 10:183–186, 2016
sparing vitrectomy has become the mainstay of treatment for Stage 4 tractional retinal detachments related to ROP.2 High rates of favorable outcomes have been reported in some series, but they are not uniform. More recently, with the growing promise and utilization of antivascular endothelial growth factor (VEGF) agents such as bevacizumab (Avastin; Genentech Inc., San Francisco, CA) for diabetic retinopathy and age-related macular degeneration, off-label use of anti-VEGF therapy has been extended into the treatment regimen for ROP. Anti-VEGF effectiveness in ROP is likely explained by blockage of VEGF and regression of VEGF-induced vasoproliferation.3 The preoperative use of bevacizumab in eyes with Stage 4 or 5 ROP can induce regression of extraretinal fibrovascular proliferation (EFP) and decrease bleeding risk. However, doing so can cause contracture of
From the *Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Vanderbilt Eye Institute, Nashville, Tennessee; †University of Illinois at Chicago, Eye and Ear Infirmary, Chicago, Illinois; and ‡Retina Consultants, Ltd., Des Plaines, Illinois.
R
etinal detachment from retinopathy of prematurity (ROP) may occur despite appropriate peripheral ablative treatment in 12% of eyes.1 Since the natural history of Stage 4 and 5 ROP is blindness, surgical treatment of tractional elements is indicated. LensNone of the authors have any financial/conflicting interests to disclose. Reprint requests: Michael P. Blair, MD, Retina Consultants, Ltd., 2454 East Dempster Street, Ste 400, Des Plaines, IL 60016; e-mail: [email protected]
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the EFP, induce stronger tractional forces on the retina, and exacerbate a tractional retinal detachment.4,5 To reduce this risk, scleral buckle (SB) placement at the time of intravitreal bevacizumab injection can be used and serve as a bridge to planned subsequent vitrectomy. Owing to limited knowledge about the systemic consequences of anti-VEGF agents in premature infants, their use during the period of this study was mainly indicated when poor visualization (i.e., in setting of vitreous hemorrhage and/or prominent persistent tunica vasculosa lentis) limited sufficient laser therapy and when surgical success in advance ROP was threatened by the risk of hemorrhage from the persistence of vascular proliferation with retinal detachment.3,6,7 This study reports outcomes of combined SB and bevacizumab injection in treatment of ROP-related retinal detachments.
tion and #240 solid silicone encircling element placement were performed in a single setting, but eyes were included in the study if these procedures were performed within 2 weeks of each other. The band was lysed but left in situ 6 months to 12 months later to allow for eye growth. Exclusion criteria were any eyes that underwent vitrectomy before or concurrent with encerclage or anti-VEGF treatment. The primary outcome was defined as ultimate retinal reattachment, and secondary outcome was need for vitrectomy, which was performed if detachment persisted. Intravitreal bevacizumab injection was given at a concentration of 1.25 mg/0.05 mL. A total of 0.03 mL was injected 1 mm posterior to the limbus through the pars plicata unless this route was deemed unsafe in which case it was injected through the corneal limbus. Results
Patients Methods This study was approved by the University of Illinois at Chicago Institutional Review Board and encompassed a retrospective analysis of consecutive eyes that had been treated for Stage 4 and Stage 5 ROP. Inclusion criteria were those eyes that underwent bevacizumab injection and SB placement without concurrent vitrectomy. Generally, bevacizumab injec-
A total of 224 eyes of 112 patients were examined for ROP between 2006 and 2011. From this group, 13 eyes from 10 infants had tractional retinal detachment and were treated with bevacizumab and SB. All of the eyes, except one with Stage 4b ROP, which received bevacizumab 2 weeks after SB placement, underwent concurrent injection and SB placement. The preoperative data are delineated in Table 1. The average birth
Table 1. Patient Demographics and Surgical Outcomes of the 13 Eyes That Received Concurrent SB and Bevacizumab Treatment Birth Patient Weight (g)
Pregnancy Duration (weeks)
Eye
ROP Stage
Subsequent Procedures
4a 4a 4a 4a 4a 4a 4a 4a 4a 4b
— Vitrectomy — — Vitrectomy — Vitrectomy Vitrectomy Vitrectomy Bevacizumab OS*
1
878
24.85
2
652
23.00
3
850
24.00
660 622 624 1,228
24.43 24.71 25.00 30.00
OD OS OD OS OD OS OS OS OD OS
8
820
26.86
OD
4b
9
610
24.71
OS
5
10
652
25.00
OS
5
4 5 6 7*
Interval Between Final Macular Procedures Status — 10 days — — 1 month — 1 month 18 days 18 days 15 days
Final Retina Status
Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached with Residual peripheral temporal TRD† dragging Laser, then 1 week, then Attached Partial reattachment vitrectomy 2 weeks with residual temporal fold Bevacizumab, then 23 days, then Detached Partial reattachment Vx/Mx/Lx‡ 1 week Vitrectomy OS · 2 14 days, then Detached Partial reattachment 2 months
*Patient 7 received bevacizumab injection 15 days after SB placement. †Tractional retinal detachment. ‡Vitrectomy/membranectomy/lensectomy.
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185
Fig. 1. Patient 2 received concurrent SB and bevacizumab injection in both eyes and maintained attachment postoperatively: A and C. Retinal detachment with neovascularization and exudate, B and D. Resolved retinal detachment and neovascularization after SB and bevacizumab treatment.
weight of the patients was 760 g (range, 610–1,228 g). The average gestational age at the time of birth was 25.3 weeks (range, 23–30 weeks). Preoperative laser photocoagulation had been performed on all eyes, except for Patient 8, who received laser in the right eye
after treatment with bevacizumab and SB placement. Injections of bevacizumab were performed into the vitreous in all patients, except for the left eye of Patient 9 in which the injection was performed into the anterior chamber.
Fig. 2. Patient 3 received SB placement and bevacizumab injection in both eyes, and on postoperative examination, the retina achieved attachment in the left eye but was detached in the right eye and required vitrectomy 1 month later. Retcam photographs demonstrate: (A) Peripheral tractional retinal detachment with exudate and neovascularization of right eye, (B) Improved exudate and neovascularization after treatment with residual tractional retinal detachment requiring subsequent vitrectomy in the right eye, (C) Peripheral tractional retinal detachment of the left eye, and (D) Resolved tractional retinal detachment after treatment in the left eye.
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Of the 13 eyes, 9 (69.2%) were Stage 4a, 2 (15.4%) were Stage 4b, and 2 (15.4%) were Stage 5. Surgical results are delineated in Table 1. At most recent follow-up, retinal reattachment was achieved in all 9 eyes with Stage 4a ROP. Five (55.6%) of these eyes required vitrectomy after receiving bevacizumab and SB placement. The four remaining eyes (44.4%) did not require vitrectomy due to sustained retinal attachment after the initial treatment. Only partial retinal reattachment could be achieved in the 4 eyes with Stage 4b or Stage 5 disease, despite subsequent vitrectomy. On follow-up, the macula was attached in all Stage 4 ROP eyes (11/11) and was detached in the 2 eyes with Stage 5 disease. No retina worsened after release of encerclage. Figures 1 and 2 highlight surgical results of 2 patients who received concurrent SB and bevacizumab treatments.
formation and endophthalmitis. Furthermore, by reducing VEGF concentrations and providing improved support for fibrovascular traction, this treatment strategy could serve as an adjuvant for planned subsequent vitrectomy in eyes with highly active EFP. We do not intend this to be a replacement or even a comparison with vitrectomy, but simply to make the community aware that it can be a successful tool in the armamentarium, particularly when vitrectomy may be difficult, contraindicated, or lead to substantial bleeding due to active vascularity. Given the challenge in managing advanced cases of ROP, particularly those with prominent tunica vasculosa lentis and vascularly active EFP, this treatment approach may reduce fibrovascular traction after antiVEGF injection, reduce risks from intraocular surgery, and potentially improve anatomical and visual outcomes.
Discussion
Key words: bevacizumab, retinopathy of prematurity, scleral buckle, vitrectomy.
The preoperative use of bevacizumab for advanced ROP may help to improve vitrectomy results by decreasing EFP vascularity and thus intraopertive bleeding risk. However, its use may potentially increase the risk of traction from EFP and therefore increase tractional forces on the retina.8 Placement of a SB in advanced cases of ROP can relieve tractional forces on the retina from a tightly adherent hyaloid face.9,10 Thus to reduce the risk of EFP and tractional retinal detachment exacerbation from bevacizumab injection, a SB can be placed at the time of injection to reduce the increased tractional forces from contracting EFP on the retina before subsequent planned vitrectomy. This study demonstrated that this technique achieved macular attachment in 100% of Stage 4 detachments, although 64% also required subsequent vitrectomy. Surprisingly, our study also demonstrated that vitrectomy was unnecessary in 4 out of the 9 eyes with Stage 4a ROP. For Stage 4b and Stage 5 ROP, concurrent SB and bevacizumab treatments did not obviate the need for subsequent vitrectomy likely due to the severity of disease and advanced stages of retinal detachments. Limitations of our study include the retrospective nature and relatively the small number of eyes included. Despite these limitations, bevacizumab and SB may be useful as a bridge to vitrectomy and, in some instances of Stage 4a ROP, may obviate the need for subsequent intervention. Scleral buckle is certainly a relatively safe, easy, low-cost, and low technology procedure compared with vitrectomy. Additionally, SB may reduce the postoperative risk of cataract
References 1. Repka MX, Tung B, Good WV, et al. Outcomes of eyes developing retinal detachment during the early treatment for retinopathy of prematurity study (ETROP). Arch Ophthalmol 2006;124:24–30. 2. Capone A Jr, Trese MT. Lens-sparing vitreous surgery for tractional stage 4A retinopathy of prematurity retinal detachments. Ophthalmology 2001;108:2068–2070. 3. Micieli JA, Surkont M, Smith AF. A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol 2009;148:536–543. 4. Jan SY, Choi KS, Lee SJ. Delayed-onset retinal detachment after an intravitreal injection of ranibizumab for zone 1 plus retinopathy of prematurity. J AAPOS 2010;14:457–459. 5. Honda S, Hirabayashi H, Tsukahara Y, et al. Acute contraction of the proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2008;246:1061–1063. 6. Nazari H, Modarres M, Parvaresh MM, et al. Intravitreal bevacizumab in combination with laser therapy for the treatment of severe retinopathy of prematurity (ROP) associated with vitreous or retinal hemorrhage. Graefes Arch Clin Exp Ophthalmol 2010;248:1713–1718. 7. Lalwani GA, Berrocal AM, Murray TG, et al. Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity. Retina 2008;28:S13–S18. 8. Kuiper EJ, Van Nieuwenhoven FA, de Smet MD, et al. The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS One 2008;3:e2675. 9. Sears JE, Sonnie C. Anatomic success of lens-sparing vitrectomy with and without scleral buckle for stage 4 retinopathy of prematuriy. Am J Ophthalmol 2007;143:810–813. 10. Hinz BJ, de Juan E Jr, Repka MX. Scleral buckling surgery for active stage 4A retinopathy of prematurity. Ophthalmology 1998;105:1827–1830.
Background: The preoperative use of intravitreal bevacizumab in Stage 4 or 5 retinopathy of prematurity (ROP) can reduce vascular endothelial growth factor load and bleeding risk; however, it can induce traction and exacerbate a tractional retinal detachment. Concurrent placement of a scleral buckle may reduce these risks and obviate future vitrectomy. Methods: A retrospective analysis of eyes treated for Stage 4 and 5 ROP with concurrent intravitreal bevacizumab and scleral buckle was performed. Retinal reattachment and need for vitrectomy were studied. Results: Thirteen eyes from 10 infants were treated with concurrent intravitreal bevacizumab and scleral buckle. Nine eyes were Stage 4a, 2 were Stage 4b, and 2 were Stage 5. All eyes with Stage 4 ROP achieved macular attachment at last follow-up. All the eyes with 4a ROP achieved retinal reattachment: 4 (44.4%) with buckle alone and 5 (55.6%) with subsequent vitrectomy. All 4 eyes with Stage 4b or 5 ROP required vitrectomy. Conclusion: Concurrent intravitreal bevacizumab and scleral buckle may serve as a bridge to vitrectomy and, in some instances, may obviate the need for subsequent intervention. RETINAL CASES & BRIEF REPORTS 10:183–186, 2016
sparing vitrectomy has become the mainstay of treatment for Stage 4 tractional retinal detachments related to ROP.2 High rates of favorable outcomes have been reported in some series, but they are not uniform. More recently, with the growing promise and utilization of antivascular endothelial growth factor (VEGF) agents such as bevacizumab (Avastin; Genentech Inc., San Francisco, CA) for diabetic retinopathy and age-related macular degeneration, off-label use of anti-VEGF therapy has been extended into the treatment regimen for ROP. Anti-VEGF effectiveness in ROP is likely explained by blockage of VEGF and regression of VEGF-induced vasoproliferation.3 The preoperative use of bevacizumab in eyes with Stage 4 or 5 ROP can induce regression of extraretinal fibrovascular proliferation (EFP) and decrease bleeding risk. However, doing so can cause contracture of
From the *Department of Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Vanderbilt Eye Institute, Nashville, Tennessee; †University of Illinois at Chicago, Eye and Ear Infirmary, Chicago, Illinois; and ‡Retina Consultants, Ltd., Des Plaines, Illinois.
R
etinal detachment from retinopathy of prematurity (ROP) may occur despite appropriate peripheral ablative treatment in 12% of eyes.1 Since the natural history of Stage 4 and 5 ROP is blindness, surgical treatment of tractional elements is indicated. LensNone of the authors have any financial/conflicting interests to disclose. Reprint requests: Michael P. Blair, MD, Retina Consultants, Ltd., 2454 East Dempster Street, Ste 400, Des Plaines, IL 60016; e-mail: [email protected]
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the EFP, induce stronger tractional forces on the retina, and exacerbate a tractional retinal detachment.4,5 To reduce this risk, scleral buckle (SB) placement at the time of intravitreal bevacizumab injection can be used and serve as a bridge to planned subsequent vitrectomy. Owing to limited knowledge about the systemic consequences of anti-VEGF agents in premature infants, their use during the period of this study was mainly indicated when poor visualization (i.e., in setting of vitreous hemorrhage and/or prominent persistent tunica vasculosa lentis) limited sufficient laser therapy and when surgical success in advance ROP was threatened by the risk of hemorrhage from the persistence of vascular proliferation with retinal detachment.3,6,7 This study reports outcomes of combined SB and bevacizumab injection in treatment of ROP-related retinal detachments.
tion and #240 solid silicone encircling element placement were performed in a single setting, but eyes were included in the study if these procedures were performed within 2 weeks of each other. The band was lysed but left in situ 6 months to 12 months later to allow for eye growth. Exclusion criteria were any eyes that underwent vitrectomy before or concurrent with encerclage or anti-VEGF treatment. The primary outcome was defined as ultimate retinal reattachment, and secondary outcome was need for vitrectomy, which was performed if detachment persisted. Intravitreal bevacizumab injection was given at a concentration of 1.25 mg/0.05 mL. A total of 0.03 mL was injected 1 mm posterior to the limbus through the pars plicata unless this route was deemed unsafe in which case it was injected through the corneal limbus. Results
Patients Methods This study was approved by the University of Illinois at Chicago Institutional Review Board and encompassed a retrospective analysis of consecutive eyes that had been treated for Stage 4 and Stage 5 ROP. Inclusion criteria were those eyes that underwent bevacizumab injection and SB placement without concurrent vitrectomy. Generally, bevacizumab injec-
A total of 224 eyes of 112 patients were examined for ROP between 2006 and 2011. From this group, 13 eyes from 10 infants had tractional retinal detachment and were treated with bevacizumab and SB. All of the eyes, except one with Stage 4b ROP, which received bevacizumab 2 weeks after SB placement, underwent concurrent injection and SB placement. The preoperative data are delineated in Table 1. The average birth
Table 1. Patient Demographics and Surgical Outcomes of the 13 Eyes That Received Concurrent SB and Bevacizumab Treatment Birth Patient Weight (g)
Pregnancy Duration (weeks)
Eye
ROP Stage
Subsequent Procedures
4a 4a 4a 4a 4a 4a 4a 4a 4a 4b
— Vitrectomy — — Vitrectomy — Vitrectomy Vitrectomy Vitrectomy Bevacizumab OS*
1
878
24.85
2
652
23.00
3
850
24.00
660 622 624 1,228
24.43 24.71 25.00 30.00
OD OS OD OS OD OS OS OS OD OS
8
820
26.86
OD
4b
9
610
24.71
OS
5
10
652
25.00
OS
5
4 5 6 7*
Interval Between Final Macular Procedures Status — 10 days — — 1 month — 1 month 18 days 18 days 15 days
Final Retina Status
Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached Attached with Residual peripheral temporal TRD† dragging Laser, then 1 week, then Attached Partial reattachment vitrectomy 2 weeks with residual temporal fold Bevacizumab, then 23 days, then Detached Partial reattachment Vx/Mx/Lx‡ 1 week Vitrectomy OS · 2 14 days, then Detached Partial reattachment 2 months
*Patient 7 received bevacizumab injection 15 days after SB placement. †Tractional retinal detachment. ‡Vitrectomy/membranectomy/lensectomy.
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185
Fig. 1. Patient 2 received concurrent SB and bevacizumab injection in both eyes and maintained attachment postoperatively: A and C. Retinal detachment with neovascularization and exudate, B and D. Resolved retinal detachment and neovascularization after SB and bevacizumab treatment.
weight of the patients was 760 g (range, 610–1,228 g). The average gestational age at the time of birth was 25.3 weeks (range, 23–30 weeks). Preoperative laser photocoagulation had been performed on all eyes, except for Patient 8, who received laser in the right eye
after treatment with bevacizumab and SB placement. Injections of bevacizumab were performed into the vitreous in all patients, except for the left eye of Patient 9 in which the injection was performed into the anterior chamber.
Fig. 2. Patient 3 received SB placement and bevacizumab injection in both eyes, and on postoperative examination, the retina achieved attachment in the left eye but was detached in the right eye and required vitrectomy 1 month later. Retcam photographs demonstrate: (A) Peripheral tractional retinal detachment with exudate and neovascularization of right eye, (B) Improved exudate and neovascularization after treatment with residual tractional retinal detachment requiring subsequent vitrectomy in the right eye, (C) Peripheral tractional retinal detachment of the left eye, and (D) Resolved tractional retinal detachment after treatment in the left eye.
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Of the 13 eyes, 9 (69.2%) were Stage 4a, 2 (15.4%) were Stage 4b, and 2 (15.4%) were Stage 5. Surgical results are delineated in Table 1. At most recent follow-up, retinal reattachment was achieved in all 9 eyes with Stage 4a ROP. Five (55.6%) of these eyes required vitrectomy after receiving bevacizumab and SB placement. The four remaining eyes (44.4%) did not require vitrectomy due to sustained retinal attachment after the initial treatment. Only partial retinal reattachment could be achieved in the 4 eyes with Stage 4b or Stage 5 disease, despite subsequent vitrectomy. On follow-up, the macula was attached in all Stage 4 ROP eyes (11/11) and was detached in the 2 eyes with Stage 5 disease. No retina worsened after release of encerclage. Figures 1 and 2 highlight surgical results of 2 patients who received concurrent SB and bevacizumab treatments.
formation and endophthalmitis. Furthermore, by reducing VEGF concentrations and providing improved support for fibrovascular traction, this treatment strategy could serve as an adjuvant for planned subsequent vitrectomy in eyes with highly active EFP. We do not intend this to be a replacement or even a comparison with vitrectomy, but simply to make the community aware that it can be a successful tool in the armamentarium, particularly when vitrectomy may be difficult, contraindicated, or lead to substantial bleeding due to active vascularity. Given the challenge in managing advanced cases of ROP, particularly those with prominent tunica vasculosa lentis and vascularly active EFP, this treatment approach may reduce fibrovascular traction after antiVEGF injection, reduce risks from intraocular surgery, and potentially improve anatomical and visual outcomes.
Discussion
Key words: bevacizumab, retinopathy of prematurity, scleral buckle, vitrectomy.
The preoperative use of bevacizumab for advanced ROP may help to improve vitrectomy results by decreasing EFP vascularity and thus intraopertive bleeding risk. However, its use may potentially increase the risk of traction from EFP and therefore increase tractional forces on the retina.8 Placement of a SB in advanced cases of ROP can relieve tractional forces on the retina from a tightly adherent hyaloid face.9,10 Thus to reduce the risk of EFP and tractional retinal detachment exacerbation from bevacizumab injection, a SB can be placed at the time of injection to reduce the increased tractional forces from contracting EFP on the retina before subsequent planned vitrectomy. This study demonstrated that this technique achieved macular attachment in 100% of Stage 4 detachments, although 64% also required subsequent vitrectomy. Surprisingly, our study also demonstrated that vitrectomy was unnecessary in 4 out of the 9 eyes with Stage 4a ROP. For Stage 4b and Stage 5 ROP, concurrent SB and bevacizumab treatments did not obviate the need for subsequent vitrectomy likely due to the severity of disease and advanced stages of retinal detachments. Limitations of our study include the retrospective nature and relatively the small number of eyes included. Despite these limitations, bevacizumab and SB may be useful as a bridge to vitrectomy and, in some instances of Stage 4a ROP, may obviate the need for subsequent intervention. Scleral buckle is certainly a relatively safe, easy, low-cost, and low technology procedure compared with vitrectomy. Additionally, SB may reduce the postoperative risk of cataract
References 1. Repka MX, Tung B, Good WV, et al. Outcomes of eyes developing retinal detachment during the early treatment for retinopathy of prematurity study (ETROP). Arch Ophthalmol 2006;124:24–30. 2. Capone A Jr, Trese MT. Lens-sparing vitreous surgery for tractional stage 4A retinopathy of prematurity retinal detachments. Ophthalmology 2001;108:2068–2070. 3. Micieli JA, Surkont M, Smith AF. A systematic analysis of the off-label use of bevacizumab for severe retinopathy of prematurity. Am J Ophthalmol 2009;148:536–543. 4. Jan SY, Choi KS, Lee SJ. Delayed-onset retinal detachment after an intravitreal injection of ranibizumab for zone 1 plus retinopathy of prematurity. J AAPOS 2010;14:457–459. 5. Honda S, Hirabayashi H, Tsukahara Y, et al. Acute contraction of the proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2008;246:1061–1063. 6. Nazari H, Modarres M, Parvaresh MM, et al. Intravitreal bevacizumab in combination with laser therapy for the treatment of severe retinopathy of prematurity (ROP) associated with vitreous or retinal hemorrhage. Graefes Arch Clin Exp Ophthalmol 2010;248:1713–1718. 7. Lalwani GA, Berrocal AM, Murray TG, et al. Off-label use of intravitreal bevacizumab (Avastin) for salvage treatment in progressive threshold retinopathy of prematurity. Retina 2008;28:S13–S18. 8. Kuiper EJ, Van Nieuwenhoven FA, de Smet MD, et al. The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy. PLoS One 2008;3:e2675. 9. Sears JE, Sonnie C. Anatomic success of lens-sparing vitrectomy with and without scleral buckle for stage 4 retinopathy of prematuriy. Am J Ophthalmol 2007;143:810–813. 10. Hinz BJ, de Juan E Jr, Repka MX. Scleral buckling surgery for active stage 4A retinopathy of prematurity. Ophthalmology 1998;105:1827–1830.
