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

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

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