Reactivation of Retinopathy of Prematurity (ROP) in Adults and Adolescents

Abstract

Purpose

To review the clinical features, treatment outcomes, and prevalence within our clinic population, of adolescent and adults with previously regressed ROP who develop late onset exudation and vasoproliferative changes.

Design

Retrospective review of consecutive patients at a single center.

Participants

Five patients (5 eyes) with a history of ROP who had new exudates or worsening fibrovascular proliferation diagnosed after age 10 years.

Methods

Patients were identified by a computerized search of the Emory Eye Center billing records. Data extracted from charts included baseline ROP information, visual acuity and other exam findings, imaging, and treatments.

Main Outcome Measures

Status of exudation and vasoproliferation.

Results

Among 138 patients older than 10 years with ROP seen at our tertiary referral center from 2000 to 2018, 5 (3.6%) developed late-onset exudation or vasoproliferation. Three patients were female and three had ROP treatment as a neonate. Mean age at onset of late reactivation was 25.6 years (range 13 – 43 years). Previous treatments for neonatal ROP included peripheral laser ablation (3), scleral buckle (2), pars plicata vitrectomy (2) and no treatment (2). Management strategies for late reactivation included observation (1), intravitreal anti-VEGF (4), vitrectomy (2), and cryotherapy (1). With mean follow-up of 4.8 years (range of 1–7 years), outcomes were: resolution of exudation/proliferation with return to baseline vision (2), stable mild exudation (1), and progressive vasoproliferation with traction leading to phthisis (2).

Conclusions

Late onset exudation and fibrovascular proliferation in adolescents and adults with ROP can rarely occur with previously regressed ROP. Two of 5 cases were refractory to all treatments and developed phthisis bulbi. One case had reactivation in the form of a reactive retinal astrocytic tumor. Our findings highlight the importance continued monitoring with regular fundus examination in adolescents and adults with regressed ROP.

Precis

Late onset exudation and fibrovascular proliferation can rarely occur in adults and adolescents with previously stable and regressed ROP. As infants, affected patients were either untreated or had suboptimal results of laser ablation.

Introduction

Retinopathy of prematurity (ROP) is generally considered to be a disease with self-limited fibrovascular proliferation and exudation. Most cases of ROP never require treatment and, after regression, never develop new exudation or vasoproliferative changes.^1,2 For severe cases that require treatment, the majority respond well to treatment with peripheral ablation and become permanently inactive.^3,4 Even in cases that do not respond favorably to peripheral ablation, the pathologic changes generally manifest as continued proliferation, exudation, traction, with retinal detachment (RD) that progress over weeks to months.⁵ Long-term ROP-related complications are generally thought to result from evolving cicatricial changes rather than recurrent fibrovascular proliferation or exudation. In long-term follow-up of patients enrolled in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP), a gradual increase in unfavorable structural outcomes between the 1-year and 15-year assessments was noted.³ The rate of increase in unfavorable status was 0.35% to 0.51% per year for treated and untreated patients respectively. However, the unfavorable outcomes with long-term follow-up in CRYO-ROP were not reported as resulting from recurrent exudation or fibrovascular proliferation. Unfavorable outcomes were categorized as retinal detachment, retinal folds, retinoschisis, retrolental membrane, cataract, or corneal opacity. There were no categories for active fibrovascular proliferation or exudation.³

Since the widespread adoption of anti-VEGF for ROP, there has been greater attention given to the possibility of late recurrence of ROP. There are multiple case reports of late reactivation of ROP after anti-VEGF treatment with often devastating consequences.^6–10 These cases of reactivation are thought to be driven by large areas of persistent avascular peripheral retina that continue to be a source of VEGF production long after the initial anti-VEGF treatment has worn off. Heightened awareness of the potential negative implications of persistent peripheral avascular retina has prompted concern that some untreated patients, who previously had spontaneous resolution of ROP but with incomplete vascularization of the peripheral retina, may be at risk for problems later in life.¹¹

Much has been written about the late sequelae of ROP in adolescence and adulthood, and patients with ROP are well known to be at risk for rhegmatogenous RD¹², glaucoma¹³, cataract¹⁴, and vitreous hemorrhage¹⁵ long after resolution of the acute phase of ROP. However, late reactivation of fibrovascular proliferation and exudation after having stable, regressed, ROP for many years has only rarely been reported. Herein we report the prevalence and clinical features of a group of such patients seen at our institution over a period of 18 years.

Methods

This study was approved by the Emory University Institutional Review Board and adhered to the Declarations of Helsinki. This was a retrospective case series of patients 10-years of age or older with a diagnosis of ROP evaluated at the Emory Eye Center from January 1, 2000 to December 31, 2018. To identify cases, two separate electronic health records utilized over this 18 year span were queried for patients 10-years of age or older and with a diagnosis of ROP based on ICD 9 and ICD 10 diagnostic codes. The query was performed in a manner to identify any patient meeting the age and diagnosis criteria whether they were seen in the retina clinic, the pediatric ophthalmology clinic, or any other clinic within the Emory Eye Center.

Patients were included for analysis if they had either of the following clinical features: 1) signs of active proliferation of fibrovascular membranes; or 2) signs of active exudation. Membranes were considered to be actively proliferating if they showed signs of growth over time by serial examinations or serial fundus photographs. Exudation was considered active when there was new accumulation of bright yellow material under the retina. Data extracted from the records included age, gender, neonatal history, zone and stage of ROP, type and timing of neonatal treatment of ROP, clinical features of the late reactivation, treatment for the late reactivation, ocular complications, and visual and anatomic outcomes. Fundus photographs and fluorescein angiography data were analyzed when available. Patients who had severe systemic arterial hypertension, diabetes mellitus, choroidal neovascularization, known genetic disorders such as familial exudative vitreoretinopathy (FEVR), or other diseases of the eye that can result in an exudation or vasoproliferation, were excluded.

Results

Our initial search identified 138 patients age 10-years or older who were evaluated for ROP at the Emory Eye Center during the study period. Of these, 128 were excluded because they had no exudation or fibrovascular proliferation. Three were excluded because of the presence of exudative diabetic retinopathy, and 2 because of FEVR. Five patients (3.6%), comprised of two females and three males, met the inclusion criteria. Gestational age at birth ranged from 23 weeks to 28 weeks (mean 25.8 weeks), and birth weight ranged from 624 g to 1106 g (mean 816.8 g) Other baseline clinical features are summarized in Table 1. Late ROP reactivation presented unilaterally in all patients. However, severe chronic manifestations of ROP were present in both eyes at presentation. Fellow eyes had chronic pigmentary changes, severe dragging, retinal folds, or retinal detachment in each patient. The age at onset of exudation or fibrovascular proliferation ranged from 13 to 43 years (mean 25.6 years, median 18 years). Each patient had at least 2 clinic visits before the detection of membrane proliferation or active exudation. Follow-up ranged from 1 year to 7 years, (mean 4.8, median 5 years). Table 2 summarizes treatments and outcomes.

Table 1.

Baseline clinical information.

Patient	Gender	GA at Birth (weeks)	BW (g)	Previous treatment for ROP in the affected eye	Age at presentation (years)	Visual acuity at presentation		Clinical features at time of onset
						Affected eye	Fellow eye
1	Male	23	624	Laser, vitrectomy, scleral buckle, lensectomy	17	20/200	NLP	Vitreous hemorrhage, subretinal yellow exudation, pigmentary disturbance in posterior pole OD
2	Male	25	680	Laser, scleral buckle	19	20/250	NLP	Superior dry fold, subretinal yellow exudation, pigmentary disturbance in posterior pole OD
3	Female	26	Unknown	None	43	20/200	20/250	Subhyaloid hemorrhage, subretinal yellow exudation, pigmentary disturbance in posterior pole OS
4	Female	28	1106	Laser, vitrectomy, scleral buckle, lensectomy	13	20/200	20/200	Subretinal yellow exudation, fibrovascular proliferation with optic disc dragging, pigmentary disturbance in posterior pole OD
5	Female	27	853	None	41	20/40	NLP	Subretinal yellow exudation, reactive retinal astrocytic tumor, pigmentary disturbance in posterior pole OS

GA- Gestational Age, BW - Birthweight, NLP - No light perception, PMA - Post-menstrual age.

Table 2.

Treatment and final outcomes of eyes with exudation and/or fibrovascular proliferation.

Patient	Treatment	Duration of follow-up (years)	Final Visual Acuity		Exudative and Anatomical Status
			Affected eye	Fellow eye	Affected eye	Fellow eye
1	IVB x4, PPV	6.7	20/250	NLP	Stable, no exudation	Phthisis
2	IVB x5,	4.7	NLP	NLP	Phthisis	Phthisis
3	IVB x3, PPV	5.3	NLP	HM	Phthisis	Retinal folds
4	None	1.0	20/200	20/200	Stable with yellow exudates	Retinal dragging
5	Cryotherapy, IVB x3	6.7	20/50	Enucleated	Stable with no exudation	Enucleated

IVB – Intravitreal bevacizumab, NLP - No light perception

Patient 1 was born in 1994 at 23 weeks gestation with a weight of 624 grams. He had laser, scleral buckle (SB), pars plicata vitrectomy (PPV), and pars plicata lensectomy (PPL) OD for ROP as a neonate. His right eye was stable with visual acuity (VA) of 20/200 for many years. The left eye had no light perception (NLP) since infancy. In 2011, at the age of 17, he presented with worsening vision. His VA was decreased from 20/200 to light perception OD. His exam revealed dense vitreous hemorrhage and he underwent PPV with injection of intravitreal bevacizumab OD. Intra-operatively he was found to have subretinal yellow exudates OD (Figure 1, arrow). In addition, severe tractional changes were visible in the peripheral retina. Post-operatively he stabilized for 3 years. He then had recurrent vitreous hemorrhage, for which he received a series of 3 bevacizumab injections and repeat PPV. He has been stable with no exudation or fibrovascular proliferation for the past 5 years, with 3+ vitreous flare and a visual acuity of 20/250 OD.

Figure 1.

Patient #1, OD. Contour of a scleral buckle is visible with subretinal yellow exudates at the 5 o’clock position (arrow). White fibrous membranes seen on the crest of the buckle nasally are evidence of chronic traction. Disruption of the retinal pigment epithelium (RPE) from severe ROP can be visualized as scattered hyperpigmented spots throughout the fundus. Sclerotic vessels and a pale optic disc are also evident.

Patient 2 was born in 1994 at 25 weeks gestation with a weight of 680 grams. He had laser OU at post-menstrual age (PMA) 43 weeks and SB OD at PMA 46 weeks for ROP. He was stable for many years with visual acuity of 20/250 OD. His left eye was blind from infancy. In 2008, at the age of 14 years, he presented with complaints about his vision OD, which included blurriness, difficulty reading, and floaters. His exam revealed a superior dry fold OD, which was observed. He was stable until 2013 when, at the age of 18, new subretinal yellow exudates appeared OD. The superior fold also developed vascular engorgement. He was treated with a series of 5 intravitreous bevacizumab injections OD. The vascular engorgement improved but he developed progressive membrane proliferation eventually filling the entire posterior segment. Visual acuity declined to no light perception.

Patient 3 was born in 1969 at 26 weeks gestation with an unknown birth weight. She did not have treatment for ROP as an infant. She worked as a secretary and used low vision aids for her left eye. Her baseline VA was hand motions (HM) OD and counting fingers (CF) at 10 inches OS. Examination at baseline revealed extensive pigmentary abnormalities with tractional retinal folding in both eyes (Figures 2A and 2B). In 2009, at age 40 years, she reported worsening vision in her left eye, though her visual acuity remained at baseline and no anatomic changes could be detected on exam or on color photographs of the posterior segment. She continued to report subjective gradual worsening of vision OS with no objective change in visual acuity or fundus appearance from 2009 to 2012. In 2012, at age 43 years, new with subretinal yellow exudates (Figure 2C) and new membrane growth (Figure 2D) appeared OS along with new preretinal blood. Her visual acuity remained stable. In 2013, more significant vitreous hemorrhage occurred OS with more extensive growth of fibrovascular membranes. VA dropped to bare CF at face. PPV was performed OS. Sheets and strands of organized vitreous membranes were segmented and removed. The media cleared, yet the vision did not improve. In 2014, recurrent vitreous hemorrhage was treated with a series of 3 intravitreous bevacizumab injections. Vascular engorgement of membranes improved somewhat with the injections but tractional folding and distortion of the retina worsened and VA gradually declined to no light perception.

Figure 2A-D.

Patient #3, OS. Baseline fundus photos in 2009 show chronic pigmentary changes (2A) and extensive retinal folding (2B). Figure 2C and 2D show the left eye in 2012. Subretinal yellow exudates (2C, arrow), new onset white fibrovascular proliferation (2D, arrow), and preretinal blood are evident.

Patient 4 was born in 2004 at 28 weeks gestation with a birth weight of 1106 grams. She underwent laser followed by SB, PPV, and PPL OU in infancy. Her visual acuity at baseline was 20/200 OU, which had been stable for many years. At age 13 years she presented for a routine examination and was noted to have new yellow subretinal exudates in addition to her baseline extensive temporal dragging OD (Figures 3A and 3B). She had no new symptoms. The posterior segment in her left eye looked similar but had no exudates. She was observed closely. With one year of follow-up, the exudates in the right eye were stable and her visual acuity was unchanged (Figure 3C).

Figure 3A-C.

Patient #4, OD. Severe temporal dragging and subretinal yellow exudates (3A, arrow) are visible in 2018. Indentation from a scleral buckle is evident circumferentially. The fluorescein angiogram highlights vessel dragging (3B). Figure 3C shows the appearance in 2019 after one-year of follow-up. Subretinal yellow exudates are stable (3C, arrow).

Patient 5 was born in 1971 at 27 weeks gestation with a birth weight of 853 grams. She had no treatment for ROP as an infant. At baseline, she was blind OD from a previous retinal detachment and had been stable OS for many years with retinal dragging and 20/40 vision. In 2008, at the age of 37 years, she presented with complaints of blurred vision OS. Her visual acuity was reduced to 20/80 and her posterior exam showed a reactive retinal astrocytic tumor (RRAT) (Figure 4A), also known as a vasoproliferative tumor, with yellow exudates. Fluorescein angiography showed avascular retina peripheral to the mass lesion and staining of the mass itself (Figures 4B and 4C). She was observed closely and was stable until 2015, when she presented with worsening subretinal yellow exudates (Figure 4D). There was no change in visual acuity. The RRAT was treated with cryotherapy, followed by a series of 3 intravitreous bevacizumab injections. At her last follow-up in 2018, the exudates had resolved and her visual acuity had improved to 20/50 OS.

Figure 4A-D.

Patient #5, OS. Figure 4A from 2012 shows a reactive retinal astrocytic tumor (RRAT) (arrow), also known as vasoproliferative tumor, along with distorted and dragged vessels. The fluorescein angiogram of the RRAT shows avascular retina peripheral to the mass lesion (4B, arrows), with staining of the lesion in the late frame (4C). Figure 4D shows worsening exudates the left eye in 2015, prompting treatment.

Three patients were treated for ocular hypertension after onset of exudation or fibrovascular proliferation. Patient 3 had angle closure glaucoma and was treated with surgical iridotomy. Patients 1 and 4 had elevated IOP managed with topical timolol 0.5%. Each patient had normal intraocular pressure in the affected eye at most recent follow-up.

Discussion

This study found that 3.6% of patients age 10 years and older evaluated at our tertiary referral practice had signs of recurrent exudation or proliferation after having previously regressed and stable ROP. All patients showed yellow exudates, 2 had progressive growth and proliferation of membranes, and 2 had vitreous hemorrhage. One presented with a reactive retinal astrocytic or vasoproliferative tumor. Treatment included serial intravitreal bevacizumab in 4, cryotherapy in 1, vitrectomy in 2, and no treatment in 1. With treatment, two patients had resolution of exudation/proliferation with recovery to baseline visual acuity (patients 1 and 5), and 2 had progressive tractional changes with complete loss of vision (patients 2 and 3). One had stable peripheral exudates with no treatment (patient 4). In addition to the posterior segment changes, three cases had ocular hypertension. All three were treated topically and one underwent surgical iridotomy.

Persistent peripheral avascular retina in patients with ROP has been a topic of debate since the introduction of anti-VEGF agents.¹⁶ Recurrent ROP after anti-VEGF treatment is known to occur in some cases and is thought to result from persistent peripheral avascular retina after treatment.^6–10 Persistent peripheral avascular retina may also be present in some patients after spontaneous regression.¹⁶ This is particularly true in cases that develop ROP of moderate severity that nearly meets criteria for treatment but never does. Whether persistent peripheral avascular retina predisposes to late recurrence in this setting is unknown. We undertook this study to determine the prevalence and clinical features of late exudation and progressive fibrosis in older previously stable patients with ROP in our clinic population. We found such cases to be present in a small but not insignificant proportion of our adult and adolescent ROP population.

We are not the first to recognize exudative retinopathy or fibrovascular proliferation as late sequelae of ROP but, to our knowledge, no other case series have been published on this topic in the last 25 years.¹⁷ In 1994 Brown et al reported a series of 11 eyes in 11 patients who all had yellow exudates many years after acute ROP (age range 22–39 years). All had dragging of retinal vessels and 91% had abnormal telangiectatic vessels in close proximity to the yellow exudates. A mass lesion was present in the periphery of 2 eyes. One progressed to NLP and the others stabilized with various treatments. None of the patients in this series had been treated for ROP as infants.¹⁷ Another more recent case report described a 19-year-old ROP patient with a history of peripheral ablation in one eye who developed a late recurrence of ROP in the untreated eye. The authors concluded that the reactivation was likely due to persistent peripheral avascular retina.¹¹

The pathogenesis of these late onset manifestations is uncertain. Two of the five patients in our series were untreated in infancy. These two patients were born, in 1969 and 1971, before ROP treatment was widely available. They both had evidence of severe disease in the form of tractional dragging or folding of the retina. Persistent peripheral avascular retina was confirmed by FA in one of these untreated patients and was almost certainly present in both. In addition, among the 3 patients who were treated for ROP, the outcomes of laser treatment were suboptimal. All of the laser-treated patients also underwent scleral buckling in infancy and all had severe dragging or folding of the retina after the acute neonatal disease stabilized. We did not personally perform the laser treatments in this series and available records do not allow us to comment on the completeness of treatment. It is possible that the laser was not thorough and that incomplete treatment contributed to the subsequent development of traction. Patient 2 was treated too late by current standards, as he had laser at 43 weeks post-menstrual age. So, in considering all five patients, they each had substantial tractional changes that had been present for many years. Two had untreated peripheral avascular retina and the other 3 had laser but did not have an optimal response to laser treatment. This combination of either absent treatment of peripheral avascular retina, or suboptimal response to laser treatment, along with chronic tractional changes, may predispose to late recurrence of exudation and/or proliferation of membranes.

One of our patients presented with a mass lesion at the border of vascular and avascular retina with associated yellow exudates. The patient was diagnosed with a vasoproliferative tumor (VPT) in association with regressed ROP. VPTs have been described previously in association with ROP.^18,19 In these reports, authors speculate that the pathogenesis of VPT may be related to persistent ischemia creating a microenvironment conducive to vasoproliferation. In addition to presumed ischemia, it is interesting to note that previous reports of VPT in association with ROP also describe the presence of chronic retinal traction.^{18, 19} Thus, previous reports are consistent with our proposed explanation of the pathogenesis of late ROP reactivation as being related to a combination of ischemia and chronic traction. The nomenclature for VPT has recently been a point of controversy and we have elected to also use the more recent term, reactive retinal astrocytic tumor, to describe the lesion. In their histopathological and immunohistochemical study proposing “reactive retinal astrocytic tumor”, or RRAT, as a better name for this entity, Perry and associates point out that the lesions display a paucity of microvessels. Instead, their study showed that proliferating fibrous astrocytes were predominant.²⁰

The limitations of our study include its retrospective nature, small sample size, and potential for referral bias to a tertiary care center that may have increased the percentage of patients seen with severe ROP. Our patient population is undoubtedly enriched with severe disease because of the nature of our tertiary referral practice. Thus, the prevalence of late reactivation in the general population of former ROP patients may be much lower than our 3.6% and this figure may be useful only for clinic populations similar to ours. In addition, none of our patients underwent genetic testing for FEVR mutations. FEVR is a condition that is phenotypically similar to ROP and is known to have recurrences of exudation and proliferation later in life.²¹ However, all of our patients were premature infants and 3 out of 5 were treated for ROP as infants and all were diagnosed with ROP during infancy. Nevertheless, the possibility of FEVR mutations in these former premature patients cannot be excluded. Finally, we do not have complete records from the neonatal period for our patients so we cannot comment on some of the details of disease severity during that period. The strengths of our study include the duration of follow-up, the fundus imaging, and fact that that all patients were examined by a single retina specialist during the period of late recurrence. As the first study examining late recurrence of ROP since 1994, it adds to our understanding of the importance of persistent peripheral avascular retina in patients with regressed ROP.

In summary, recurrence of exudation and fibrovascular proliferation in adults and adolescents with previously regressed and stable ROP can occur. All patients in this series had severe disease and, were either untreated as infants, or had suboptimal results of peripheral laser ablation in infancy. All had retinal traction manifest as dragging or folding of the retina before onset of recurrent exudation or fibrovascular proliferation. Two of 5 recurrences in our series were severe and refractory to all forms of treatment including serial anti-VEGF. Our findings highlight the importance of lifelong monitoring for patients with regressed ROP. Patients with regressed ROP who also have chronic tractional changes in the setting of either untreated peripheral avascular retina, or a sub-optimal response to previous laser treatment, may warrant particularly close follow-up.