Aggressive posterior retinopathy of prematurity (APROP) is a severe and rare form of retinopathy of prematurity (ROP), which is characterized by rapid progression to retinal detachment and diagnosed by the posterior location, prominence of plus disease, and ill-defined nature of the retinopathy.1 Anti-vascular endothelial growth factor (VEGF) drugs, specifically intravitreal bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA), have been successfully employed alone and in combination with other treatment methods to treat APROP.2,3
In this case report, we demonstrate the continued development of the fovea and foveal avascular zone (FAZ) after multiple IVB treatments for APROP.
A 1,310 g male twin born at 31 weeks postmenstrual age (PMA) through in vitro fertilization was noted at 33 weeks PMA to have significant plus disease, undeveloped fovea, circumferential vessels, extensive areas of avascular retina, arteriovenous shunting, and retinal hemorrhages in both eyes consistent with APROP in zone 1 (Figures 1a and 1b). IVB 0.625 mg/0.025 mL was injected in both eyes with a 30-gauge needle at 0.75 mm posterior to the limbus. One week after the IVB injection, the right eye showed reduced retinal vascular dilation and tortuosity. The left eye progressed to retinal detachment, requiring multiple surgical interventions.
(a) Right eye at 33 weeks postmenstrual age (PMA), fundus image showing aggressive posterior retinopathy of prematurity (APROP) in zone I. (b) Left eye at 33 weeks PMA, fundus image showing APROP in zone I. Venous dilatation and arteriolar tortuosity of the posterior retinal vessels, undeveloped fovea, circumferential vessels, extensive areas of avascular retina, arteriovenous shunting, retinal hemorrhages in both eyes. (c) Right eye at 37 weeks PMA, fluorescein angiography (FA) image showing perifoveal capillary ring and nearly complete foveal avascular zone (FAZ), large areas of avascular retina, mild leakage at the junction between vascular and avascular retina, arteriolar-venular shunts between vessel arcades at vascular retina. (d) Right eye at 45 weeks PMA, FA image showing complete foveal capillary ring and FAZ, hyperfluorescent foci especially at temporal perifoveal area, arteriolar-venular shunts between vessel arcades at vascular retina, finger shaped vessels. (e) Right eye at 45 weeks PMA, FA image showing persistent leakage at vascularized/avascular junction due to vascular extra-retinal proliferation and chorioretinal scar-related laser treatment at zone 2 and zone 3. (f) Right eye at 54 weeks PMA, FA image showing no activation and chorioretinal scar related laser treatment at the border of zone 1. (g) Right eye at 78 weeks PMA, optical coherence tomography image showing persistent inner retinal layer and normal outer retinal layer at the foveal center, shallow foveal pit, and slightly dome-shaped macula.
At 37 weeks PMA, fluorescein angiography (FA) was performed using 10% fluorescein at a dose of 0.1 mL/kg. On FA, early foveal vascular development was observed. The perifoveal capillary ring was telangiectatic and slightly incomplete with a large FAZ (Figure 1c). Diode laser photocoagulation (LPC) (OcuLight SLx Infrared 810 nm Laser; Iridex, Mountain View, CA) was performed to the peripheral avascular retina, sparing the avascular temporal macula.
At 45 weeks PMA, the foveal capillary ring and FAZ were complete (Figure 1d). However, due to the recurrence of vascular extra-retinal proliferation, additional LPC was applied to the temporal macula and a second dose of 0.625 mg IVB was injected in the right eye (Figure 1e).
At 54 weeks PMA, a fully developed foveal capillary ring was observed on FA without disease reactivation (Figure 1f). At the last exam, performed at 78 weeks PMA, optical coherence tomography (OCT) (Envisu C2300 and R2310; Bioptigen, Durham, NC) imaging of the right eye showed interim development of persistent inner retinal layer (IRL) and normal outer retinal layers (ORLs) at the fovea, shallow foveal pit, and slightly dome-shaped macula. OCT of the right eye is displayed in Figure 1g.
APROP is a severe form of ROP that can progress rapidly to retinal detachment. Diagnostic criteria include posterior location, prominence of plus disease, shunt vessels, flat neovascularization, and ill-defined nature of retinopathy.1,2
Laser photocoagulation is a standard treatment for ROP but is destructive. IVB is nondestructive, allows vessels to advance toward the peripheral retina, and has been used as an alternative treatment for ROP since 2007.3,4 Moreover, the incidence of unfavorable outcomes with LPC in zone 1 of ROP is higher than that of IVB.5
Foveal development begins as early as 22 weeks PMA and continues into childhood.6 The fovea at preterm birth has an immature appearance with a shallow foveal pit, persistent IRLs at the foveal center, and thin ORLs.7 Persistent inner retinal layers at the foveal center are a hallmark of retinal immaturity.8 Mintz-Hittner et al.9 hypothesized that infants born at 36 weeks gestational age or greater develop a normal FAZ, whereas infants born at less than 30 weeks' gestational age develop a smaller or absent FAZ. Villegas et al.10 showed that patients with a history of ROP appear to have a high frequency of macular morphological abnormalities on OCT, including retention of IRLs and absent foveal depression.
The effect of IVB and LPC on foveal development has not been well described. Vogel et al.11 monitored foveal development in infants treated with IVB or LPC. They found that IVB was associated with more rapid ORL thickening, whereas LPC was associated with earlier IRL extrusion. They theorized that the differences in VEGF expression may explain these findings. Clark et al.12 investigated macular thickness and foveal development in treated and untreated fellow eyes of infants who underwent unilateral IVB. They found small but nonsignificant differences in foveal development and thickness in eyes treated with IVB compared to fellow eyes without notable visual acuity (VA) differences. In our patient, evaluation of foveal anatomy with OCT revealed persistent IRLs and normal ORLs at the foveal center and a shallow foveal pit, which are likely due to retinal immaturity. IVB or LPC may also contribute to this process.
There has been concern that IVB, as an inhibitor of angiogenesis, can disrupt foveal development or may cause foveal hypoplasia. Henaine-Berra et al.13 observed development of the FAZ in 25 eyes (53%) beginning at 1 month after IVB therapy. In another study, Lepore et al.14 reported that the absence of FAZ persisted in the eyes treated with bevacizumab more frequently than in eyes treated with laser. Yourey et al.15 reported that VEGF has multiple functions beyond angiogenesis, including promotion of retinal photoreceptor proliferation and survival. Nonetheless, we chose IVB therapy to avoid ablation of an undeveloped fovea. Continued examination showed growth of macular vessels, despite irregular orientation, and development of the foveal vascular ring with FAZ. This suggests that formation of the FAZ and foveal vascular ring may be facilitated by mediators other than VEGF. Irregular development of macular vessels may be due to IVB treatment or retinal immaturity.
In conclusion, treatment of APROP with undeveloped fovea can add complexity. Although bevacizumab is an inhibitor of angiogenesis and delays vascular development, this may not be determinative of the visual outcome. Retinal development has resilience that may compensate for the early disturbance, resulting in a surprisingly normal late outcome. Further study of patients with APROP are still needed to correlate the early effects of IVB and LPC treatments on foveal anatomy and VA.
- International Committee for the Classification of Retinopathy of Prematurity. The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123(7):991–999. doi:10.1001/archopht.123.7.991 [CrossRef]
- Travassos A, Teixeira S, Ferreira P, et al. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Ophthalmic Surg Lasers Imaging. 2007;38(3):233–237.
- Nazari H, Modarres M, Parvaresh MM, Ghasemi Falavarjani K. 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 Opthamol. 2010;248(12):1713–1718. doi:10.1007/s00417-010-1430-x [CrossRef]
- Mintz-Hittner HA. Treatment of retinopathy of prematurity with vascular endothelial growth factor inhibitors. Early Hum Dev, 2012;88(12):937–941. doi:10.1016/j.earlhumdev.2012.09.019 [CrossRef]
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- Hendrickson A, Possin D, Vajzovic L, Toth C. Histologic development of the human fovea from midgestation to maturity. Am J Ophthalmol. 2012;154(5):767–778. doi:10.1016/j.ajo.2012.05.007 [CrossRef]
- Sjöstrand J, Popovic Z. A time-line model of developmental events within the human fovea based on imaging and histology data. Acta Ophthalmol. 2013;91(s252). doi:10.1111/j.1755-3768.2013.S100.x [CrossRef]
- Hammer DX, Iftimia NV, Ferguson RD, et al. Foveal fine structure in retinopathy of prematurity: An adaptive optics Fourier domain optical coherence tomography study. Invest Ophthalmol Vis Sci. 2008;49(5):2061–2070. doi:10.1167/iovs.07-1228 [CrossRef]
- Mintz-Hittner HA, Knight-Nanan DM, Satriano DR, Kretzer FL. A small foveal avascular zone may be an historic mark of prematurity. Ophthalmology. 1999;106(7):1409–1413. doi:10.1016/S0161-6420(99)00732-0 [CrossRef]
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- Vogel RN, Strampe M, Fagbemi OE, et al. Foveal development in infants treated with bevacizumab or laser photocoagulation for retinopathy of prematurity. Ophthalmology. 2018;125(3):444–452. doi:10.1016/j.ophtha.2017.09.020 [CrossRef]
- Clark A, Wright T, Isaac M, Westall C, Mireskandari K, Tehrani NN. Macular morphology following unilateral bevacizumab injection for retinopathy of prematurity: An OCT study. J AAPOS. 2017;21(6):499–501. doi:10.1016/j.jaapos.2017.06.024 [CrossRef]
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