Optical coherence tomography (OCT) imaging reveals cystoid macular edema (CME) in about half of preterm infants screened for retinopathy of prematurity (ROP); however, the finding is often undetected on standard clinical exam, and its pathogenesis remains poorly understood.1–5 Cystoid spaces are typically bilateral, confined to the inner nuclear layer, and separated by hyperreflective septae representing stretched Müller cells, which regulate fluid homeostasis.2,4,6,7 Mechanisms remain speculative and controversial, but proposed hypotheses include increased vascular permeability, neurodegeneration, mechanical traction, and systemic disease.3–5,8–11 Given the high prevalence among infants screened for ROP, CME may also be simply a transient part of physiological development.3 Whereas CME in adulthood is believed to reflect fluid accumulation influenced by vascular endothelial growth factor (VEGF), among infants this has not yet been demonstrated.7,11
A male infant born prematurely at 25 weeks gestational age and 680 grams birthweight was treated with bilateral laser for zone 2, stage 2–3 ROP with pre-plus disease at 43 weeks postmenstrual age (PMA). The infant was imaged with an arm-mounted spectral-domain OCT (Spectralis FLEX; Heidelberg Engineering, Heidelberg, Germany) with institutional board review approval and informed parental consent at 43 and 46 weeks PMA. Images with an image quality index of 22 (pre-laser) and 17 (post-laser) decibels were captured without sedation.
Prior to laser treatment, OCT imaging revealed severe CME featuring large foveal and parafoveal cysts with a disrupted foveal contour and photo-receptor layer (Figures 1A and 1B). There was no evidence of fluid overload based on physical exam, medical history, or weight changes. Three weeks after laser treatment, repeat OCT imaging showed significantly smaller parafoveal cystoid spaces (Figures 1C and 1D). A foveal contour with clear foveal pit was observed. A comparison of infrared OCT images from the first imaging date with color fundus photos from the second imaging date demonstrated plus disease regression (Figure 2).
Comparison of cystoid macular edema (CME) in the eye of a preterm infant before and after laser treatment for retinopathy of prematurity. (A) Optical coherence tomography (OCT) image of the fovea of an eye at 43 weeks postmenstrual age (PMA) prior to laser treatment showing severe CME with both foveal and parafoveal cysts, bulging foveal contour, and disrupted photoreceptor layer, and (B) a magnified image of the foveal center. (C) OCT image of the fovea of the same eye at 46 weeks PMA following laser treatment revealing significantly regressed CME with much smaller parafoveal cysts and a nearly normal foveal contour and (D) magnified image of the foveal center. In A and C, white arrows indicate central foveal thickness (CFT), and white lines indicate parafoveal thickness 1,000 µm to either side of the foveal center. In B and D, white arrows indicate inner retinal layer (IRL) thickness at the fovea. CFT, foveal-parafoveal thickness ratio, and IRL thickness measurements all reduced.
Regression of plus disease following laser treatment for retinopathy of prematurity. Infrared optical coherence tomography images of the (A) right eye and (B) left eye at 43 weeks postmenstrual age (PMA), before laser, showing pre-plus disease status. Color fundus photos of the (C) right eye and (B) left eye at 46 weeks PMA, 3 weeks after laser, showing regressed plus.
For quantitative assessment of CME severity, we measured central foveal thickness (CFT), from Bruch's membrane to the inner limiting membrane (ILM), and inner retinal layer (IRL) thickness at the foveal center, from the inner nuclear layer to the ILM. The foveal-parafoveal (FP) thickness ratio was calculated as a ratio of CFT to the average retinal thickness 1,000 µm to either side of the fovea. Comparing pre- to post-treatment, CFT reduced from 543 µm to 178 µm, IRL thickness from 474 µm to 99 µm, and FP thickness ratio from 1.28 to 0.53.
To our knowledge, this is the first report of CME regression following laser treatment for ROP. As laser treatment arrests VEGF-mediated angiogenesis, this case supports the hypothesis of VEGF-mediated CME in eyes with treatment-warranting ROP, similar to peripheral ischemia and diabetic macular edema in adults.12 Whereas infants typically need laser for Type 1 ROP around 37 weeks GA, delayed treatment has been reported for infants with persistent ROP after 40 weeks PMA.13,14 This infant was offered laser for Type 2, borderline Type 1 ROP, before discharge to another distant hospital where reliable follow-up was uncertain.
Although reports of neonatal CME on OCT imaging are few, most studies have shown CME to persist or increase after ROP treatment.10,11,15 Rothman et al. describe an infant treated with laser prior to OCT imaging, with CME observed upon subsequent OCT imaging.15 Two other infants in this paper were imaged both before and after laser with persistent bilateral CME. Dubis et al. reported that CME remained unresolved or developed in infants 1 to 2 weeks following laser or anti-VEGF injection for ROP.11 Among five infants with CME treated with anti-VEGF, Erol et al. noted worsened CME in three of them.10 Dubis et al. hypothesized that ROP treatment may not effectively treat CME because VEGF has already set off an irreversible cascade.11 Our case is unique in that CME regressed 3 weeks after ROP laser.
Neonatal CME without ROP treatment is often self-limiting, with reports of resolution between 35 and 65 weeks PMA, although the exact timeline remains to be elucidated.1,3,4,11 In the present case, it is possible that CME may have been in the process of resolving with or without laser treatment.16 Fluorescein angiography could be considered in future cases to look for macular leakage, which could help further distinguish different etiologies of neonatal CME.
Although CME in preterm infants is often self-limited, associated structural and functional abnormalities have been noted in both the eye and brain. Infants born prematurely, particularly those with CME, have been found to have delayed foveal photoreceptor development.17 Two groups have reported lower visual acuity in infants and young children at 3 months, 9 to 14 months, and 4 to 5 years corrected age with a history of neonatal CME.15,18 With the retina as an extension of the central nervous system, neonatal CME has further been correlated with anomalies on brain magnetic resonance imaging and poorer language and motor development Bayley Scale subscores at 18 to 24 months corrected age.5,15 More severe CME, quantified by higher FP thickness ratios on OCT imaging, was linked to lower cognitive and motor subscores.5
In conclusion, the expanded use of portable OCT imaging devices has made visualizing the pre-term macula and investigating CME mechanisms increasingly feasible. We demonstrate the utility of OCT imaging as an adjunct to standard clinical exam for monitoring the preterm retina, as well as consider the roles of VEGF and laser treatment in CME. Taken together with previous studies, this report highlights the multi-factorial etiology of macular edema in infants with ROP and the possible role of anti-VEGF should be confirmed with more patients. Larger, more comprehensive, and longitudinal studies are needed to better understand the pathogenesis and significance of macular edema in the preterm retina, and how patterns can be used to predict later visual acuity and neurodevelopmental outcomes.
- Maldonado RS, O'Connell RV, Sarin N, et al. Dynamics of human foveal development after premature birth. Ophthalmology. 2011;118(12):2315–2325. doi:10.1016/j.ophtha.2011.05.028 [CrossRef] PMID:21940051
- Lee AC, Maldonado RS, Sarin N, et al. Macular features from spectral-domain optical coherence tomography as an adjunct to indirect ophthalmoscopy in retinopathy of prematurity. Retina. 2011;31(8):1470–1482. doi:10.1097/IAE.0b013e31821dfa6d [CrossRef] PMID:21792089
- Maldonado RS, O'Connell R, Ascher SB, et al. Spectral-domain optical coherence tomographic assessment of severity of cystoid macular edema in retinopathy of prematurity. Arch Ophthalmol. 2012;130(5):569–578. doi:10.1001/archopthalmol.2011.1846 [CrossRef] PMID:22232366
- Vinekar A, Avadhani K, Sivakumar M, et al. Understanding clinically undetected macular changes in early retinopathy of prematurity on spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52(8):5183–5188. doi:10.1167/iovs.10-7155 [CrossRef] PMID:21551410
- Rothman AL, Tran-Viet D, Gustafson KE, et al. Poorer neurodevelopmental outcomes associated with cystoid macular edema identified in preterm infants in the intensive care nursery. Ophthalmology. 2015;122(3):610–619. doi:10.1016/j.ophtha.2014.09.022 [CrossRef] PMID:25439600
- Vajzovic L, Hendrickson AE, O'Connell RV, et al. Maturation of the human fovea: correlation of spectral-domain optical coherence tomography findings with histology. Am J Ophthalmol. 2012;154(5):779–789.e2. doi:10.1016/j.ajo.2012.05.004 [CrossRef] PMID:22898189
- Bringmann A, Reichenbach A, Wiedemann P. Pathomechanisms of cystoid macular edema. Ophthalmic Res. 2004;36(5):241–249. doi:10.1159/000081203 [CrossRef] PMID:15583429
- Chen X, Mangalesh S, Tran-Viet D, Freedman SF, Vajzovic L, Toth CA. Fluorescein Angiographic Characteristics of Macular Edema During Infancy. JAMA Ophthalmol. 2018;136(5):538–542. doi:10.1001/jamaophthalmol.2018.0467 [CrossRef] PMID:29621379
- Maldonado RS, Freedman SF, Cotten CM, Ferranti JM, Toth CA. Reversible retinal edema in an infant with neonatal hemochromatosis and liver failure. J AAPOS. 2011;15(1):91–93. doi:10.1016/j.jaapos.2010.11.016 [CrossRef] PMID:21397814
- Erol MK, Ozdemir O, Turgut Coban D, et al. Macular findings obtained by spectral domain optical coherence tomography in retinopathy of prematurity. J Ophthalmol. 2014;2014:468653. doi:10.1155/2014/468653 [CrossRef] PMID:25544895
- Dubis AM, Subramaniam CD, Godara P, Carroll J, Costakos DM. Subclinical macular findings in infants screened for retinopathy of prematurity with spectral-domain optical coherence tomography. Ophthalmology. 2013;120(8):1665–1671. doi:10.1016/j.ophtha.2013.01.028 [CrossRef] PMID:23672969
- Young TL, Anthony DC, Pierce E, Foley E, Smith LE. Histopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity. J AAPOS. 1997;1(2):105–110. doi:10.1016/S1091-8531(97)90008-2 [CrossRef] PMID:10875087
- Al-Taie R, Simkin SK, Douçet E, Dai S. Persistent Avascular Retina in Infants With a History of Type 2 Retinopathy of Prematurity: To Treat or Not to Treat?J Pediatr Ophthalmol Strabismus. 2019;56(4):222–228. doi:10.3928/01913913-20190501-01 [CrossRef] PMID:31322711
- Ni YQ, Huang X, Xue K, et al. Natural involution of acute retinopathy of prematurity not requiring treatment: factors associated with the time course of involution. Invest Ophthalmol Vis Sci. 2014;55(5):3165–3170. doi:10.1167/iovs.13-13744 [CrossRef] PMID:24764065
- Rothman AL, Tran-Viet D, Vajzovic L, et al. Functional Outcomes Of Young Infants With And Without Macular Edema. Retina. 2015;35(10):2018–2027. doi:10.1097/IAE.0000000000000579 [CrossRef] PMID:25932550
- Gursoy H, Bilgec MD, Erol N, Basmak H, Colak E. The macular findings on spectral-domain optical coherence tomography in premature infants with or without retinopathy of prematurity. Int Ophthalmol. 2016;36(4):591–600. doi:10.1007/s10792-016-0176-9 [CrossRef] PMID:26750097
- Vajzovic L, Rothman AL, Tran-Viet D, Cabrera MT, Freedman SF, Toth CA. Delay in retinal photoreceptor development in very preterm compared to term infants. Invest Ophthalmol Vis Sci. 2015;56(2):908–913. doi:10.1167/iovs.14-16021 [CrossRef] PMID:25587063
- Vinekar A, Mangalesh S, Jayadev C, et al. Macular edema in Asian Indian premature infants with retinopathy of prematurity: impact on visual acuity and refractive status after 1-year. Indian J Ophthalmol. 2015;63(5):432–437. doi:10.4103/0301-4738.159879 [CrossRef] PMID:26139806