Article

Fluorescein Angiography for Eyes With ROP Treated With Anti-VEGF

Appropriate imaging can guide treatment.

Fluorescein Angiography for Eyes With ROP Treated With Anti-VEGF

Appropriate imaging can guide treatment.

SAMIR N. PATEL, BS • R.V. PAUL CHAN, MD • MICHAEL A. KLUFAS, MD

Retinopathy of prematurity (ROP) continues to be a leading cause of blindness in children, particularly in middle-income countries, despite advances in our understanding and treatment of the disease. Laser photocoagulation has historically been the gold standard treatment for ROP,1 but the management of ROP continues to evolve with the emergence of anti-VEGF drugs.

Since the introduction of these drugs for the management of ROP, there has been a significant effort to elucidate the potential role of anti-VEGF agents for ROP; however, controversy persists regarding the ideal treatment regimen and potential adverse events of the drugs.

The pathogenesis of ROP has been described, and it ultimately leads to VEGF overexpression inducing neovascularization.2 The key pathologic feature in ROP, local ischemia with subsequent retinal neovascularization, has common features with other vasoproliferative disorders, such as diabetic retinopathy. In DR, anti-VEGF agents are widely used to treat the disease.

In ROP, anti-VEGF agents have several potential advantages over traditional laser therapy, but one of most apparent benefits is sparing of peripheral retinal ablation.3 Other potential benefits over laser therapy include less myopia and less time involved to administer the treatment, which are paramount in developing countries where physician resources are limited.4

Samir N. Patel, BS, is a fourth-year medical student at the Weill Cornell Medical Center in New York, NY. R.V. Paul Chan, MD, is professor and vice chair of ophthalmology and director of the Pediatric Retina and ROP Service of the Illinois Eye and Ear Infirmary at the University of Illinois at Chicago. Michael A. Klufas, MD, is a second-year resident at the Jules Stein Eye Institute of the University of California-Los Angeles. The authors report no financial interests in any product mentioned in this article. Dr. Chan can be reached via e-mail at rvpchan@gmail.com.

CURRENT ROLE OF ANTI-VEGF IN ROP

Bevacizumab (Avastin, Genentech, South San Francisco, CA) has been reported as a treatment for ROP since 2007, and its use has been increasing, although there is renewed interest in the use of ranibizumab (Lucentis, Genentech)5,6 and pegaptanib sodium (Macugen, Valeant, Bridgewater, NJ).7,8

In 2011, the BEAT-ROP study reported the prospective use of primary intravitreal bevacizumab for zone I/posterior zone II, stage 3 ROP with plus disease. The study noted a significantly higher rate of recurrence in zone I disease with conventional laser therapy, compared with intravitreal bevacizumab monotherapy.9 To date, the study has been one of the few prospective studies of the use of anti-VEGF for ROP because most other studies have predominantly been retrospective in nature.

Since then, the use of anti-VEGF drugs in eyes with treatment-requiring ROP has rapidly spread around the world, with a recent meta-analysis noting that more than 55 clinical studies, assessing more than 1,400 eyes, have reported on the use of VEGF therapies for ROP.10,11

However, despite these reports, significant concerns remain regarding local and systemic adverse events when using anti-VEGF agents in infants. All anti-VEGF agents used for the treatment of ROP are off-label at this time, with package inserts stating “the safety and effectiveness in pediatric patients has not been established.” No study, including the BEAT-ROP study,9 has been adequately powered to evaluate the safety of these compounds in neonates.

Previous studies have noted that intravitreal bevacizumab in eyes with ROP results in systemic absorption of the drug and a reduction in circulating systemic VEGF levels at up to eight weeks.12-14 Other reports have indicated that other anti-VEGF agents, such as ranibizumab, may only suppress systemic VEGF levels for one day postinjection, suggesting that this agent may result in fewer potential systemic side effects.15

In a meta-analysis assessing systemic complications in 585 patients, eight patients (1.4%) reported systemic complications after intravitreal injection; however, none of these complications were associated with treatment with anti-VEGF agents.10

Particular Concerns in Neonates

Compared to the adult population using anti-VEGF agents, there is a greater concern regarding the systemic absorption of the drugs in developing infants. Additionally, in children who fail laser therapy, there may be a more disrupted retinal-blood barrier if anti-VEGF treatment is used, resulting in potentially increased systemic absorption.

VEGF has been implicated as an important neuronal protectant under ischemic conditions,16 and it is particularly important for the survival of retinal neurons17 and maintenance of the retinal pigment epithelium. VEGF is also involved in the development of many organ systems, including the liver, kidneys, and lungs. Neonates with ROP often have other systemic comorbidities, particularly poor lung maturation, which further elevates the systemic concerns of anti-VEGF agents.

Local ocular adverse events are a potential complication of all intravitreal injections. In a meta-analysis of 882 eyes, 55 eyes (6.2%) developed an ocular complication requiring retreatment.10 The reasons for retreatment were recurrent neovascularization in 32 cases (58.2%), retinal hemorrhage in 10 cases (18.2%), retinal detachment in nine cases (16.4%), partial retinal detachment in one case (1.8%), macular dragging in two cases (3.6%), and persistent plus disease in one case (1.8%).

FA IN PEDIATRIC RETINA

Fluorescein angiography is a valuable tool for evaluation of the chorioretinal vasculature in vasoproliferative disorders, such as DR18 and exudative age-related macular degeneration19 in adults.

Given that ROP presents with retinal ischemia and retinal neovascularization, it has common features with other vasoproliferative disorders. Therefore, techniques such as FA could play a central role in better understanding the pathogenesis of ROP.

Fluorescein angiography was initially used to study retrolental fibroplasia by Flynn and colleagues in the 1960s. These investigators noted that FA could identify late complications of ROP and changes that were not visible on clinical examination. These angiograms were obtained using a Zeiss fundus camera (Carl Zeiss Meditec, Dublin, CA), but because this fundus camera was cumbersome to use in the pediatric population, subsequent use of FAs in ROP was limited.

With the introduction of imaging technology better suited for the pediatric population, bedside FA imaging for neonates has evolved to become a viable complement to fundus imaging and clinical examination. FA already has an important role in the evaluation and management of pediatric vascular disorders, including Coats’ disease,20-22 choroidal neovascular membranes,23-25 sickle cell retinopathy,26,27 and ocular tumors.28

Fluorescein angiography appears to be safe in children including neonates with ROP, with no adverse effects reported in several series.29-34 FA may be performed at the bedside in the neonatal ICU, where neonates are closely monitored by the medical team, as well as during exams under anesthesia when clinically indicated.

The role of FA, however, in the diagnosis of ROP remains unclear. Most current studies of FA in ROP have been predominately descriptive, which may limit their clinical impact and conclusions.29,32,33,35-37

In 2006, Ng and colleagues published a case series of 23 patients receiving serial FAs, and they demonstrated that clear angiograms could be obtained as part of an ROP screening paradigm.29 Further, they noted that some vascular pathologies, including arteriovenous tufts and bays within irregular ridges, were observed on angiograms but could not be seen on indirect ophthalmoscopy.

Similar vascular features were notable in an atlas of FA findings in 22 eyes undergoing laser treatment for ROP such that FA was useful to distinguish the deceptively featureless zone I junction between the vascularized and nonvascularized retina.31

Similar studies have suggested that FA could improve the diagnosis of zone in ROP,32,33 and recent evidence has noted that, among ROP experts, supplementation of color fundus photographs with FA may improve the accuracy for certain classifications of ROP, including zone I and stage 3.38,39 FA has also been shown to identify aberrant vascular pathologies in infants with aggressive posterior ROP by identifying capillary nonperfusion and shunting in the vascularized retina.35

FA Combined With Anti-VEGF

Fluorescein angiography has recently been used in infants with ROP treated with anti-VEGF agents as a means to monitor vascular patterns after treatment and to identify late recurrence of disease. FA may allow for better visualization of vascularization, particularly in the periphery of the retina. To date, several studies have reported the FA findings in infants with ROP treated with anti-VEGF agents.36,37,40

In 2014, Tahija and colleagues retrospectively reviewed a cohort of 20 eyes and noted that FA demonstrated incomplete vascularization in nearly half the eyes between 27 to 224 weeks after the last bevacizumab injection.37

Common FA findings in these patients included irregular branching of large arterioles and circumferential vessel formation. Furthermore, nine of 20 eyes in this study were noted to have FA dye leakage within the vascular-avascular junction, which some have noted to be a significant sign of ROP progression.33

In a single randomized controlled trial of bevacizumab vs laser therapy in infants with type 1 ROP, Lepore and colleagues40 also noted similar abnormalities at the junction of the vascular and avascular retina in FAs nine months after treatment with anti-VEGF therapy.

Even within the vascularized retina, FAs post–anti-VEGF therapy noted loss of retinal capillary beds at the posterior pole. Additionally, macular abnormalities, such as the absence of the foveal avascular zone or hyperfluorescent lesions in the posterior pole, were more likely to persist in the bevacizumab treatment arm (Figure, page 45).

Figure. Fundus imaging and fluorescein angiography of an infant over 18 months after intravitreal bevacizumab treatment. A) Wideangle RetCam fundus photo of the left eye shows regressed plus disease. B) Fluorescein angiography of the left eye highlights the retinal vasculature in the posterior pole. C) Fluorescein angiography of the left eye reveals vascular shunts and peripheral nonperfusion (arrows). D) Fluorescein angiography of the contralateral right eye also displays areas of peripheral nonperfusion (arrows). There was no evidence of retinal neovascularization in either eye.

The abnormal arteriolar branching noted on FAs of these bevacizumab-treated eyes may indicate continued abnormal vascular development, and the implications of this finding in the long term are unknown. Similar findings on pretreatment FAs of differential branching at the vascular-avascular junction and hypoperfused retinal areas with “cotton-wool–like” spots were noted in a study by Henaine-Berra and colleagues.36 However, on the post-treatment FAs, the group noted rapid and complete regression of neovascularization in all cases, with vascularization continuing to grow toward the periphery.

In these studies presented, all of the infants received a pretreatment FA, but the timing of FA post-treatment was variable. Henaine-Berra et al obtained post-treatment FAs at one month and then on a PRN basis, while Lepore et al obtained post-treatment FAs every two weeks until discharge.

The optimal frequency of FA imaging in this population remains unclear. For normal vascular development, by a postconception age of 36 weeks, nearly 50% of infants with no ROP may have vessels that end in zone III, and for those at a postconception age of 40 weeks, more than 90% may have vascularization in zone III.41

Questions and Concerns

More frequent FA imaging is especially concerning if infants are receiving these examinations under general anesthesia. Indeed, many physicians commonly obtain FAs in the NICU without sedation or intubation, but they also obtain them in the operating room under sedation. Additional considerations also include the reliability of the family to adhere to follow-up appointments.

The etiology of the persistent avascular peripheral retina of these babies treated with anti-VEGF therapy remains unclear. Are these changes we are seeing secondary to disease progression? Would these characteristics be noted if a different anti-VEGF drug was used? Is there a level of under/overtreatment?

To further confound the issue, recent evidence has noted that there may be a baseline level of normal peripheral retinal nonperfusion in these children with presumed normal retinas.42 These questions remain as we further elucidate the role of anti-VEGF therapy in the management of ROP.

CONCLUSION

In the era of multimodal imaging, FA is playing an emerging role in guiding the management of ROP in the anti-VEGF era. FA may have utility in characterizing vascular maturation after intravitreal anti-VEGF therapy. Prospective multicenter studies assessing the long-term role of FA in this population are warranted. RP

REFERENCES

1. 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;121:1684-1694.

2. Hartnett ME, Penn JS. Mechanisms and management of retinopathy of prematurity. N Engl J Med. 2012;367:2515-2526.

3. Mintz-Hittner HA. Treatment of retinopathy of prematurity with vascular endothelial growth factor inhibitors. Early Hum Dev. 2012;88:937-941.

4. Harder BC, Schlichtenbrede FC, von Baltz S, Jendritza W, Jendritza B, Jonas JB. Intravitreal bevacizumab for retinopathy of prematurity: refractive error results. Am J Ophthalmol. 2013;155:1119-1124.

5. Castellanos MA, Schwartz S, Garcia-Aguirre G, Quiroz-Mercado H. Short-term outcome after intravitreal ranibizumab injections for the treatment of retinopathy of prematurity. Br J Ophthalmol. 2013;97:816-819.

6. Lin CJ, Chen SN, Hwang JF. Intravitreal ranibizumab as salvage therapy in an extremely low-birth-weight infant with rush type retinopathy of prematurity. Oman J Ophthalmol. 2012;5:184-186.

7. Autrata R, Krejcirova I, Senkova K, Holousova M, Dolezel Z, Borek I. Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone I and posterior zone II. Eur J Ophthalmol. 2012;22:687-694.

8. Autrata R, Senkova K, Holousova M, Krejcirova I, Dolezel Z, Borek I. [Effects of intravitreal pegaptanib or bevacizumab and laser in treatment of threshold retinopathy of prematurity in zone I and posterior zone II--four years results]. Cesk Slov Oftalmol. 2012;68:29-36.

9. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364:603-615.

10. Pertl L, Steinwender G, Mayer C, et al. A systematic review and meta-analysis on the safety of vascular endothelial growth factor (VEGF) inhibitors for the treatment of retinopathy of prematurity. PLoS ONE. 2015;10:e0129383.

11. Klufas MA, Chan RV. Intravitreal anti-VEGF therapy as a treatment for retinopathy of prematurity: what we know after 7 years. J Pediatr Ophthalmol Strabismus. 2015;52:77-84.

12. Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and aascular endothelial growth factor in infants with retinopathy of prematurity. Am J Ophthalmol. 2012;153:327-333.

13. Hård A-L, Hellström A. On safety, pharmacokinetics and dosage of bevacizumab in ROP treatment – a review. Acta Paediatrica. 2011;100:1523-1527.

14. Wu WC, Lien R, Liao PJ, et al. Serum levels of vascular endothelial growth factor and related factors after intravitreous bevacizumab injection for retinopathy of prematurity. JAMA Ophthalmol. 2015;133:391-397.

15. Zhou Y, Jiang Y, Bai Y, Wen J, Chen L. Vascular endothelial growth factor plasma levels before and after treatment of retinopathy of prematurity with ranibizumab. Graefes Arch Clin Exp Ophthalmol. 2015 Apr 6. [Epub ahead of print]

16. Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol. 2007;171:53-67.

17. Saint-Geniez M, Maharaj ASR, Walshe TE, et al. Endogenous VEGF is required for visual function: evidence for a survival role on Müller cells and photoreceptors. PLoS ONE 2008;3:e3554.

18. Classification of diabetic retinopathy from fluorescein angiograms. ETDRS report number 11. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98:807-922.

19. Mokwa NF, Ristau T, Keane PA, Kirchhof B, Sadda SR, Liakopoulos S. Grading of age-related macular degeneration: comparison between color fundus photography, fluorescein angiography, and spectral domain optical coherence tomography. J Ophthalmol. 2013;2013:385915.

20. Blair MP, Ulrich JN, Elizabeth Hartnett M, Shapiro MJ. Peripheral retinal nonperfusion in fellow eyes in coats disease. Retina. 2013;33:1694-1699.

21. Koozekanani DD, Connor TB Jr, Wirostko WJ. RetCam II fluorescein angiography to guide treatment and diagnosis of Coats disease. Ophthalmic Surg Lasers Imaging. 2010 Mar 9:1-3.

22. Zheng XX, Jiang YR. The effect of intravitreal bevacizumab injection as the initial treatment for Coats’ disease. Graefes Arch Clin Exp Ophthalmol. 2014;252:35-42.

23. Giansanti F, Virgili G, Varano M, et al. Photodynamic therapy for choroidal neovascularization in pediatric patients. Retina. 2005;25:590-596.

24. Kim R, Kim YC. Intravitreal ranibizumab injection for idiopathic choroidal neovascularization in children. Semin Ophthalmol. 2014;29:178-181.

25. Kohly RP, Muni RH, Kertes PJ, Lam WC. Management of pediatric choroidal neovascular membranes with intravitreal anti-VEGF agents: a retrospective consecutive case series. Can J Ophthalmol. 2011;46:46-50.

26. Gill HS, Lam WC. A screening strategy for the detection of sickle cell retinopathy in pediatric patients. Can J Ophthalmol. 2008;43:188-191.

27. Hero M, Harding SP, Riva CE, Winstanley PA, Peshu N, Marsh K. Photographic and angiographic characterization of the retina of Kenyan children with severe malaria. Arch Ophthalmol. 1997;115:997-1003.

28. Shields JA, Reichstein D, Mashayekhi A, Shields CL. Retinal vasoproliferative tumors in ocular conditions of childhood. J AAPOS. 2012;16:6-9.

29. 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.

30. 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;45:36-39.

31. Lepore D, Molle F, Pagliara MM, et al. Atlas of fluorescein angiographic findings in eyes undergoing laser for retinopathy of prematurity. Ophthalmology. 2011;118:168-175.

32. Zepeda-Romero LC, Oregon-Miranda AA, Lizarraga-Barron DS, Gutierrez-Camarena O, Meza-Anguiano A, Gutierrez-Padilla JA. Early retinopathy of prematurity findings identified with fluorescein angiography. Graefes Arch Clin Exp Ophthalmol. 2013;251:2093-2097.

33. Purcaro V, Baldascino A, Papacci P, et al. Fluorescein angiography and retinal vascular development in premature infants. J Matern Fetal Neonatal Med. 2012;25(Suppl 3):53-56.

34. Flynn JT, Cassady J, Essner D, et al. Fluorescein angiography in retrolental fibroplasia: experience from 1969-1977. Ophthalmology. 1979;86:1700-1723.

35. Yokoi T, Hiraoka M, Miyamoto M, et al. Vascular abnormalities in aggressive posterior retinopathy of prematurity detected by fluorescein angiography. Ophthalmology. 2009;116:1377-1382.

36. Henaine-Berra A, Garcia-Aguirre G, Quiroz-Mercado H, Martinez-Castellanos MA. Retinal fluorescein angiographic changes following intravitreal anti-VEGF therapy. J AAPOS. 2014;18:120-123.

37. Tahija SG, Hersetyati R, Lam GC, Kusaka S, McMenamin PG. Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. Br J Ophthalmol. 2014;98:507-512.

38. Patel SN, Klufas MA, Ryan MC, et al. Color fundus photography versus fluorescein angiography in identification of the macular center and zone in retinopathy of prematurity. Am J Ophthalmol. 2015;159:950-957.

39. Klufas MA, Patel SN, Ryan MC, et al. Influence of fluorescein angiography on the diagnosis and management of retinopathy of prematurity. Ophthalmology. 2015;122:1601-1508.

40. Lepore D, Quinn GE, Molle F, et al. Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings. Ophthalmology. 2014;121:2212-2219.

41. Palmer EA, Flynn JT, Hardy RJ, et al. Incidence and early course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology. 1991;98:1628-1640.

42. Avery RL. What is the evidence for systemic effects of intravitreal anti-VEGF agents, and should we be concerned? Br J Ophthalmol. 2014;98:i7-i10.