Retinopathy of prematurity (ROP) is a disease of abnormal retinal vascular development in premature infants that can progress to retinal detachment and blindness. Peripheral retinal ablation using cryotherapy was the first effective treatment for ROP.1 Later, laser photocoagulation of avascular retina was also found to improve visual, structural, and refractive outcomes in ROP, comparable to cryotherapy.2,3 Nevertheless, complications and unfavorable outcomes can still occur from these ROP treatments. Complications associated with laser treatment for ROP include anterior segment issues such as cataract and hyphema,4 posterior segment conditions such as rhegmatogenous retinal detachment,5 and other outcomes such as pachyphakia, microcornea, and angle closure.6 Although some complications are transient with minimal long-term visual consequences, others may have long-term effects on vision. Exudative retinal detachment (ERD) is another rare outcome following cryotherapy7 and laser in ROP cases.8–13 In this article, we report short and long-term macular changes among 11 eyes of seven patients with ERD following laser photocoagulation, associated with visual acuity (VA) for 10 eyes of six patients.
Patients and Methods
Institutional review board approval was obtained from the University of Chicago. ROP cases that had undergone laser therapy from 2005 to 2015 were retrospectively identified from one tertiary referral retina practice. Seven patients were identified to have developed ERD following laser treatment. All patients fulfilled Type 1 ETROP criteria for laser treatment. ERD was defined as a retinal detachment unexplained by tractional elements, with a bullous, convex appearance rather than a concave appearance with tractional apex. One eye that required vitrectomy was excluded, as this procedure may have affected macular findings. The charts for each patient were reviewed and clinical course, interventions, imaging, and visual acuity outcomes were noted. Normal vision was defined as 20/40 or better, according to the ETROP study.14
Eleven eyes of seven patients with ERD following laser photocoagulation were identified. Table 1 provides birth parameters, clinical course, treatment of ERD, and visual outcomes. The median age at laser treatment was 35 weeks postmenstrual age (PMA) (interquartile range [IQR]: 33–39 weeks). The median length of time from laser to ERD diagnosis was 7 days (IQR: 5–7 days). Excluding one patient who expired at 3 months, median length of follow-up was 10 years (IQR: 9–13.5 years). The time to resolution of the ERD ranged from 1 to 5 weeks.
Since several infants underwent laser at other hospitals and were then transferred for care due to ERD complications, initial clock hours of ROP at the time of primary treatment and laser parameter data for several patients were not able to be obtained. Although usually bilateral, unilateral ERD was observed in Cases 3 and 5; thus, the eye without detachment was not included in the table. Case 6 developed ERD bilaterally following laser, but the left eye was excluded from the study because it underwent vitrectomy. Management of the ERD predominantly included topical, systemic, and/or intravitreal steroid treatment. Bevacizumab (Avastin; Genentech, South San Francisco, CA) was also used for Cases 4 and 6 due to persistent ERD with poor response to initial steroid therapy. The right eye of Case 3 received a scleral buckle but was not excluded from the study because the buckle was placed subsequent to resolution of the ERD to support residual peripheral traction which remained after ERD resolution and was unlikely to have contributed to macular findings.
Following resolution of ERD, macular changes were seen in all patients. Figure 1 shows initial and short-term sequelae of ERD. Short-term evolution of the exudative detachment revealed prominent macular fold in four eyes. Figure 2 shows the spectrum of long-term macular changes observed following ERD resolution among all patients from whom fundus photography was available, demonstrating pigment mottling and RPE loss as evidenced by window defect on FA. Figure 3 shows corresponding changes on optical coherence tomography, which reveal the extent of photoreceptor loss following resolution of ERD and macular excavation.
Exudative retinal detachment findings and early sequelae observed in this case series. (a, b) Case 1 at 34 weeks postmenstrual age (PMA), 7 days status post laser photocoagulation with large bullous detachment in the right (a) and macular fold in the left (b). (c,d) Right eye (OD) of Case 3 showing posterior exudative retinal detachment (c) with folds extending inferiorly (d), vascular tortuosity, and loss of choroidal markings. (e, f) Case 4 at 40 weeks PMA, 5 days after peripheral laser, showing bullous serous detachment OD (e) and small macular fold in the left eye (OS) (f) and residual vascular tortuosity in both eyes. (g, h) Case 4, 1 week later at 41 weeks PMA showing improvement of serous detachment following sub-Tenon's injection of triamcinolone and topical prednisolone, but persistent fluid OD (g) and macular fold OS (h). (i, j) Fluorescein angiography of Case 4 at 41 weeks PMA showing vascular dilation and tortuosity, leakage at temporal vascular-avascular junction, and mild pooling posteriorly. (k, l) Case 4, 1 week later at 42 weeks PMA demonstrate resolution of detachment. Hard exudate is seen OD (k) and lower macular fold OS (l). (m, n) OD of Case 5 at 39 weeks PMA showing macular fold (m, 80 degree) and trace temporal subretinal exudate (n, 130 degree) 3 weeks after laser and 2 weeks after oral prednisone treatment. (o, p) Fundus photo and fluorescein angiogram of Case 6 OD at 36 weeks PMA after treatment with bevacizumab and intravitreal methylprednisolone showing nonperfusion in both the central zone and far periphery, with loss of capillaries posteriorly.
Late macular findings following exudative retinal detachment (ERD) resolution. (a, b) Right (OD) and left eye (OS) of Case 1 at 43 weeks postmenstrual age (PMA) showing prominent retinal pigment epithelium (RPE) dropout OD and more subtle pigment changes OS. (c, d) Fluorescein angiography of Case 1 at 43 weeks PMA showing mottled appearance and window defect centrally indicating RPE injury OD and smaller window defect OS. (e) OD of Case 2 at age 11 years showing RPE loss and pigment deposition. (f, g) Fundus photo and fluorescein angiogram of Case 2 at age 4 years showing RPE atrophy, pigment changes, and window defect in central macula with linear pattern consistent with prior macular fold. (h, i) OD of Case 3 at 69 weeks PMA showing attached retina and RPE atrophy in central macula. Fluorescein angiography (FA) shows hyperfluorescence in area of atrophy and window defect. (j) FA of Case 3 OD at age 13 years showing loss of fluorescence in macular area and fluorescence of area inferior to disc. (k, l) OD and OS of Case 7 at age 20 months showing mild pigmentary changes. He developed ERD, although less extensive than his twin brother (Case 1/Figure 1), despite intentionally treating more lightly with laser.
Available optical coherence tomography images of later macular findings. (a) Case 1 right eye (OD) at age 11 years showing foveal thinning and diffuse photoreceptor loss. (b) Case 2 OD at age 11 years showing retinal pigment epithelium and photoreceptor loss in the central macula. (c) Case 3 OD at age 7 years showing photoreceptor loss and shallow excavation in the central macula. (d) Case 3 OD 6 years later at age 13 years showing deep excavation and profound choroidal atrophy resembling ectasia.
In Case 1, the most recent visit at age 9 years showed persistent prominent macular pigment changes (Figures 2a and 2b) in the right eye with a smaller area of pigment changes in the left. OCT of the right eye (Figure 3a) showed thin fovea and profound photoreceptor loss. Interestingly, his twin brother (Case 7) was diagnosed with Type 1 ROP 1 week later and, given his twin's ERD, was treated more lightly with laser. He did develop ERD and subsequently very mild macular pigmentary changes (Figures 2k and 2l), and was the single patient with normal vision in this case series.
Similarly, Case 2 (Figures 2f and 2g) showed RPE atrophy; corresponding optical coherence tomography (OCT) showed retinal pigmented epithelium (RPE) and photoreceptor loss in the central macula (Figure 3b). Case 3 also showed a circular lesion in the right eye (Figure 2f) corresponding to profound choroidal atrophy in the central macula with progressive excavation on OCT (Figures 3c and 3d).
Although VA data were limited by developmental delays, most patients appeared to have decreased VA associated with macular sequelae of ERD. Of the nine eyes of five patients with at least 5 years' follow-up, three eyes of two patients were legally blind with 20/400 vision, four eyes of two patients had nystagmus suggestive of subnormal vision; only two eyes of one patient had normal vision. One eye of one patient with 16 months' follow-up was also presumed to have subnormal vision with nystagmus. Of note, the patient with normal vision (Case 7) had a more mild ERD than the other cases.
In this study, we report the largest series to date of ERD after laser photocoagulation for ROP and include late structural findings and VA. Although ERD is not an “adverse outcome” as defined by the CRYO-ROP study,1 most patients in this case series had chronic macular changes and poor visual outcomes. It is possible that these exudative changes may occur with some frequency, but sub-clinically, after laser for ROP. ETROP 6-year results showed unfavorable retinal structural outcomes to be 8.9%, whereas poor visual outcomes were much higher at 24.7%, and only 34.6% had normal VA, defined as 20/40 or better.14 Explanations for this discrepancy may be amblyopia, optic neuropathy, or cortical-visual impairment. However, the trial did not make a distinction between tractional retinal detachments, which is a progression of acute ROP, and exudative retinal detachments, which is a treatment complication. We hypothesize that an additional reason for the disconnect between favorable structural outcomes and poor visual outcomes may be due to macular changes after ERD, such as those observed in our study: pigment changes, RPE mottling, and macular atrophy, which were not included in CRYO-ROP or ETROP unfavorable structural outcomes. It is possible that the topography of retinal layers with the RPE and choroid is disrupted due to exudative fluid. The subsequent atrophy observed may be similar to the retinal pigmentary changes observed after spontaneous reattachment of a retinal detachment.15
ERD following treatment of ROP is an uncommon phenomenon and has been reported after cryotherapy,7 laser,8–13 and bevacizumab monotherapy.16 Outside of ROP, ERD has also been commonly reported following laser for diabetic retinopathy17,18 and across the spectrum of vascular disease.19,20
ERD may be caused by 1) pre-existing vascular disease and 2) RPE insult, even in absence of vascular disease. It has been suggested that the primary pathology of most exudative cases is due to a diffuse vascular abnormality,21 which certainly applies to ROP. In the latter category, ERD has been reported following scleral buckling and cryotherapy,22 indicating that functional alteration of the RPE and choriocapillaris can lead to subretinal fluid exudation.
When laser photocoagulation is performed, direct damage to the RPE and sensory retina and subsequent inflammation may induce damage to the blood-retinal barrier and lead to ERD.10,12 Clinically, attempts to avoid failure from undertreatment (eg, skip lesions) during laser therapy may lead to a bias toward heavy treatment or overtreatment, which may also play a role in ERD onset. Similarly, treatment of proliferative diabetic retinopathy in a single session of laser has been associated with greater occurrence of exudative detachment compared to treatment over multiple sessions.23 This is not practical in premature infants since sedation or general anesthesia is required. Interestingly, in our series, Case 7 was treated with laser more lightly than his twin, Case 1, with less extensive ERD and better vision. Moreover, 2,000 laser spots would certainly not be excessive for treatment of type 1 ROP. This suggests that RPE and retina injury from laser treatment plays a role in ERD. In addition, two patients in this series had thrombocytopenia, which may predispose patients to diffuse vascular leakage and subsequent ERD following laser. Due to this risk factor, it may be worthwhile to check platelets prior to laser and consider platelet transfusion.
In previous reports, ERD treatment included simple observation,8,9 topical steroid therapy,13 topical and systemic steroids,12 intravitreal bevacizumab,10 and intravitreal bevacizumab with scleral buckling and drainage.11 We report usage of steroids and bevacizumab for certain cases. Our rationale was to decrease the inflammatory component from the laser injury and thus aid in resolution of detachment to decrease the long-term damage from ERD. It should be noted that postnatal systemic steroid use has been associated with significant increases in neurodevelopmental issues in preterm infants,24 and the long-term effects of bevacizumab use for ROP are still being studied.25,26 Whether the exudative detachment would have resolved in a similar time frame without treatment is unknown. In addition, care must be taken when performing intravitreal injection on an infant with a bullous retinal detachment, as the 30-gauge half-inch needles that are commonly used can cause retinal perforation if inserted too deeply. In the current study, scleral buckle was used in one eye to address concomitant traction from ROP which became apparent after improvement of ERD. From this small series, the impact of treatment choice on vision could not be discerned, but short-term topical steroid and cycloplegic drops should be considered. For cases that progress after a brief trial of topical therapy, systemic steroids and/or intravitreal bevacizumab might be considered, with particular care taken to avoid injecting the needle more than 2 mm to 3 mm.
In several patients with long-term follow-up, imaging showed round atrophic lesions, macular atrophy, and other pigmentary disruption following ERD resolution. Most of these patients had poor visual acuity. Although RPE pigmentary disruption after ERD is a known occurrence,9,12 the presence of round atrophic lesions observed in two of our cases is a finding of particular note. Similar abnormalities have also been reported following cryotherapy and have previously been mistaken as coloboma-like lesions.27 Because of its similarity with the pigmented retinochoroidal scar observed in toxoplasmosis and other maculopathies, we believe that history of ERD should be added to the differential diagnosis of round macular lesions alongside North Carolina dystrophy, cone-rod dystrophy, achromatopsia, macular staphyloma, and torpedo maculopathy, among others. This macular disease could lead to visual loss, even after resolution of the active ROP and ERD, and we hypothesize that this shape reflects the symmetric, macula-centered, bullous ERD seen in some cases.
Limitations of this study include relatively small size, retrospective design, loss of follow-up, and missing laser parameters or neonatal data for several patients. In addition, because most cases in this series received primary treatment at other institutions, referral bias limits our ability to determine of the true frequency of ERD following laser. Given the infrequent, and unexpected, nature of exudative detachment after laser, large prospective data are unlikely to be available. Perhaps by using OCT images obtained routinely a few days to one week after laser, more subtle edema or fluid could be found more frequently, and if subclinical macular edema is noted, perhaps topical treatment should be initiated to reduce the potential for long-term vision loss from structural changes to the macula.
In conclusion, this study presents the largest case series of ERD following laser for ROP. Upon resolution, late sequelae such as macular pigmentary changes and atrophy may be an underrecognized factor in poor visual outcomes, which was noted for nearly all patients in this series. Although not all occurrences of this complication result in round atrophic lesions, the presence of these findings upon presentation years after ROP regression may suggest history of ERD and should be considered if the patient has a history of prematurity and laser treatment. Further study is needed to ascertain the best treatments that allow for the best visual outcomes in premature children.
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|Case||Eye||GA (Weeks)||Sex||BW (Grams)||PMA at Laser||Total Laser Spot Number||Days to ERD Diagnosis||ERD Treatment||Days to ERD Resolution||Age at Last Exam||Final VA||Systemic Conditions||Short-Term Macular Anatomy||Long-Term Macular Sequelae|
|1||OD||33||2,326||7||SS, Tri||28||C US M||IVH, BPD, anemia, autism||Bullous macular detachment||Foveal thinning, diffuse pigment changesand photoreceptor loss|
|OS||25||M||850||33||2,110||7||SS||28||9 years||C US M||Macular fold||Pigment changes|
|2||OD||35||1,646||7||TS, Tri||34||20/400||RDS, thrombocytopenia, osteopenia||Bullous macular detachment||RPE loss and pigment deposition|
|OS||25||M||538||35||1,804||7||TS||21||11 years, 3 months||20/400||Bullous macular detachment||RPE and photoreceptor loss; mild excavation|
|3||OD||27||F||662||39||1764||7||TS, SB*||-||13 yr 6 mo||20/400||IVH, BPD, hypernatremia||Macular fluid with fold extending inferiorly||RPE loss and progressive excavation|
|4||OD||39||—||5||TS, SS, IVB, Tri||7||UC US UM||CLD, HTN, ostopenia||Exudate, bullous macular detachment||Macular heterotopia, RPE lossand pigment deposition|
|OS||25||F||530||39||—||5||TS, SS, IVB, Tri||7||4 years. 11 months||C US M||Exudate, macular fold||Macular heterotopia, RPE lossand pigment deposition|
|5||OD||25||M||645||36||—||7||SS, Atr||21||3 mo 9 days||Pt Passed||RDS, schizencephaly||Bullous detachment left macular fold||Pt Passed|
|6||OD||24||F||1000||33||—||14||SS, IVB, LPC||28||1 yr 4 mo||C US M||Emphysema, thrombocytopenia||Fluid and exudate||Not available|
|7||OD||35||—||2||TS||14||20/30–2||BPD, developmental delays, IVH||Low macular fluid||Mild pigmentary change|
|OS||25||M||840||35||—||2||TS||14||9 years||20/40–2||Low macular fluid||Mild pigmentary change|