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Research Letters |

Fluorescein Angiography of Recurrent Retinopathy of Prematurity After Initial Intravitreous Bevacizumab Treatment FREE

Quan V. Hoang, MD, PhD; Daniel F. Kiernan, MD; Felix Y. Chau, MD; Michael J. Shapiro, MD; Michael P. Blair, MD
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago (Drs Hoang, Kiernan, Chau, Shapiro, and Blair); and Retina Consultants, Ltd, Des Plaines, Illinois (Dr Shapiro).


Arch Ophthalmol. 2010;128(8):1080-1081. doi:10.1001/archophthalmol.2010.145.
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Published online

Standard treatment for type 1 prethreshold retinopathy of prematurity (ROP) is laser ablation.1 A number of recent reports describe regression of ROP with intravitreous injection of the anti–vascular endothelial growth factor (VEGF) agent bevacizumab.26 We describe a premature boy diagnosed with type 1 prethreshold ROP who received bilateral intravitreous bevacizumab injections and demonstrated initial resolution. Two months later, clinical examination and fluorescein angiography demonstrated a circumferential vascular anastomotic pattern at the location of the initial stage 3 complex with radial vessels that continued peripherally toward a second, more anterior stage 3 complex. This was then successfully treated with laser photocoagulation.

A 26-week-gestation boy weighing 675 g at birth and with multiple medical problems was transferred to our institution for treatment of presumed type 1 prethreshold ROP in the setting of prominent tunica vasculosa lentis. Although initial examination disclosed immature vessels in zone 2, he quickly progressed to stage 3 with plus disease by age 34 weeks. Given the patient's critically ill health, the neonatology service recommended against prolonged sedation for laser therapy. Therefore, after an informed discussion with his parents, light intravenous sedation was administered to the infant and his eyelashes and conjunctival surfaces were prepared with 10% povidone-iodine topical solution. Intravitreous injections of bevacizumab (0.75 mg/0.025 mL) were administered bilaterally using a separate, sterile eyelid speculum for each eye. The infant was examined on postinjection day 1 and then weekly for 2 months. Within 2 weeks, examination identified regression of the lens-associated vessels, disappearance of extraretinal fibrovascular proliferation, and marked regression of plus disease. Subsequently, radial vessels grew anteriorly within the retina.

Two months after treatment, a second stage 3 complex developed anterior to the original stage 3 complex that had regressed, leaving a circumferential vascular anastomosis (Figure 1). Fluorescein angiography demonstrated anterior extraretinal fibrovascular proliferation with leakage and a more posterior circumferential vascular ring with associated telangiectasis but without leakage (Figure 2). Because the patient had become systemically stable enough for adequate sedation, conventional peripheral laser photocoagulation was administered to both eyes. Subsequent examination demonstrated bilateral cicatricial changes of the stage 3 complex over the next 3 weeks, with stabilization by 1 month after laser treatment without further vascular changes on follow-up.

Place holder to copy figure label and caption
Figure 1.

A second stage 3 complex (arrowheads) associated with plus disease developed anterior to the initial complex, which developed into a circumferential vascular anastomosis (arrows) with associated telangiectasis, evident on a RetCam color photograph (A) and a fluorescein angiogram (B).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

A wide-field RetCam fluorescein angiogram demonstrates a new stage 3 complex (arrowheads) anterior to the former complex, which has developed into a nonleaking, circumferential vascular anastomosis (arrows).

Graphic Jump Location

Evidence indicates that ROP may be a biphasic disease with an initial oxygen-induced vascular obliteration phase, followed by hypoxia-induced vessel proliferation.7 Anti-VEGF therapy may be effective in the second phase2 and as a single dose because there is theoretically only 1 burst of VEGF.8 This is in contrast to other ocular neovascular conditions, such as age-related macular degeneration and diabetic retinopathy, where aberrant VEGF production often recurs as a result of long-standing disease.

Supporting this, Mintz-Hittner and Kuffel3 reported that a single bilateral injection of bevacizumab in 22 eyes of 11 infants induced regression of acute ROP and allowed vascularization of the peripheral retina to resume. In contrast, another report5 described a 41-week-old boy with zone 1, stage 2 plus disease that initially responded to bevacizumab treatment, but recurrence developed 11 weeks later. This recurrence responded to a second bevacizumab injection, but the patient died soon afterward of systemic illness.

In our case, zone 2, stage 3 plus disease treated on day 64 of life responded markedly to intravitreous bevacizumab, but 2 months later a second, more anterior stage 3 complex developed. Although the occurrence of multiple ridges is well documented, it is a rare event compared with other patterns of ROP regression. To our knowledge, this is the first angiographic documentation of circumferential anastomosis at the bevacizumab-induced regression site with radial vessels progressing anteriorly to form a second stage 3 complex. The time course seems to indicate quiescence due to bevacizumab followed by reactivation from its waning effect. Although this case provides further evidence of the efficacy of bevacizumab as a treatment option for patients with ROP when laser treatment is not feasible, it also emphasizes that the angiogenic stimulus potentiating the sight-threatening complications of ROP may recur or persist after a single injection of an anti-VEGF agent. This case also provides further support that intravitreous bevacizumab does not necessarily inhibit subsequent retinal vascular development.3

Correspondence: Dr Blair, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 W Taylor Street, M/C 648, Chicago, IL 60612 (mblair2@uic.edu).

Author Contributions: Dr Blair had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: This work was supported by an unrestricted grant from Research to Prevent Blindness, New York, New York (Dr Blair).

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;121 (12) 1684- 1694
PubMed
Mintz-Hittner  HABest  LM Antivascular endothelial growth factor for retinopathy of prematurity. Curr Opin Pediatr 2009;21 (2) 182- 187
PubMed
Mintz-Hittner  HAKuffel  RR  Jr Intravitreal injection of bevacizumab (Avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II [published correction appears in Retina. 2008;28(9):1374]. Retina 2008;28 (6) 831- 838
PubMed
Quiroz-Mercado  HMartinez-Castellanos  MAHernandez-Rojas  MLSalazar-Teran  NChan  RV Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity [published correction appears in Retina. 2009;29(1):127]. Retina 2008;28 (3) ((suppl)) S19- S25
PubMed
Kong  LMintz-Hittner  HAPenland  RLKretzer  FLChévez-Barrios  P Intravitreous bevacizumab as anti–vascular endothelial growth factor therapy for retinopathy of prematurity: a morphologic study. Arch Ophthalmol 2008;126 (8) 1161- 1163
PubMed
Honda  SHirabayashi  HTsukahara  YNegi  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 (7) 1061- 1063
PubMed
Chen  JSmith  LE Retinopathy of prematurity. Angiogenesis 2007;10 (2) 133- 140
PubMed
Stone  JChan-Ling  TPe'er  JItin  AGnessin  HKeshet  E Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci 1996;37 (2) 290- 299
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

A second stage 3 complex (arrowheads) associated with plus disease developed anterior to the initial complex, which developed into a circumferential vascular anastomosis (arrows) with associated telangiectasis, evident on a RetCam color photograph (A) and a fluorescein angiogram (B).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

A wide-field RetCam fluorescein angiogram demonstrates a new stage 3 complex (arrowheads) anterior to the former complex, which has developed into a nonleaking, circumferential vascular anastomosis (arrows).

Graphic Jump Location

Tables

References

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;121 (12) 1684- 1694
PubMed
Mintz-Hittner  HABest  LM Antivascular endothelial growth factor for retinopathy of prematurity. Curr Opin Pediatr 2009;21 (2) 182- 187
PubMed
Mintz-Hittner  HAKuffel  RR  Jr Intravitreal injection of bevacizumab (Avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II [published correction appears in Retina. 2008;28(9):1374]. Retina 2008;28 (6) 831- 838
PubMed
Quiroz-Mercado  HMartinez-Castellanos  MAHernandez-Rojas  MLSalazar-Teran  NChan  RV Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity [published correction appears in Retina. 2009;29(1):127]. Retina 2008;28 (3) ((suppl)) S19- S25
PubMed
Kong  LMintz-Hittner  HAPenland  RLKretzer  FLChévez-Barrios  P Intravitreous bevacizumab as anti–vascular endothelial growth factor therapy for retinopathy of prematurity: a morphologic study. Arch Ophthalmol 2008;126 (8) 1161- 1163
PubMed
Honda  SHirabayashi  HTsukahara  YNegi  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 (7) 1061- 1063
PubMed
Chen  JSmith  LE Retinopathy of prematurity. Angiogenesis 2007;10 (2) 133- 140
PubMed
Stone  JChan-Ling  TPe'er  JItin  AGnessin  HKeshet  E Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity. Invest Ophthalmol Vis Sci 1996;37 (2) 290- 299
PubMed

Correspondence

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