Early Diagnosis and Management of Aggressive Posterior Vitreoretinopathy Presenting in Premature Neonates

Introduction

Familial exudative vitreoretinopathy (FEVR) is an ischemic vitreoretinopathy characterized by retinal ischemia, neovascularization, and tractional retinal folds and detachments. An ischemic vitreoretinopathy in the FEVR spectrum may present in the neonatal or early infancy period and shares some features, when diagnosed in premature infants, with retinopathy of prematurity (ROP). Although, historically, clinical history was critical in distinguishing FEVR from ROP (with presence of family history and / or lack of the prematurity or low birth weight suggestive of FEVR),^1,2 it is becoming clear that there exists a vitreoretinopathy more consistent with FEVR than with ROP in premature infants.^3–5 In this report, we refer to this entity as “aggressive posterior vitreoretinopathy” (APVR). Consideration of this entity in neonates undergoing ROP screening is necessary, given the aggressive nature of this condition and the potential for early intervention to control this aggressive disease. We report here a series of three cases of APVR diagnosed in three moderately premature neonates being screened for ROP in whom early intervention was undertaken.

Patients and Methods

This is a multicenter, retrospective, consecutive case series of neonates diagnosed and treated (with laser retinal photocoagulation, intravitreal anti-vascular growth factor [VEGF] injection, and / or surgery) before 3 months of age for a non-ROP clinical entity in the FEVR spectrum, characterized by severe retinal avascularity involving the posterior pole, retinal neovascularization, and tractional retinal detachment in either eye. Features that distinguish this entity from ROP include retinal findings more severe than expected for gestational age and birth weight, highly asymmetric retinal vasculopathy, absence of plus disease, and / or other characteristic features on examination and fluorescein angiogram (FA).³ The clinical history and findings of these patients were reviewed retrospectively. This retrospective case series was approved by the institutional review boards at Weill Cornell Medical College and University of Illinois at Chicago and prepared in accordance with the Health Insurance Portability and Accountability Act.

Results

Three neonates were identified who met inclusion criteria. All three cases were premature infants diagnosed during ROP screening exams. The mean age at birth was 29.6 weeks (range: 27 weeks to 31 weeks) gestational age and mean birth weight was 1,436 grams (range: 1,360 grams to 1,560 grams). Mean age at the time of the first therapeutic intervention (laser photocoagulation and / or pars plana vitrectomy surgery) in these premature neonates was 39 weeks (range: 35 weeks to 46 weeks) postmenstrual age (PMA). No cases were identified that underwent early treatment with anti-VEGF therapy. Below are the detailed clinical courses for each case.

Case 1

A female born at 27 weeks gestational age weighing 1,389 grams who had undergone ROP screening at a referring hospital was transferred to our institution for a second opinion at 46 weeks PMA. Exam under anesthesia (EUA) revealed trace vitreous hemorrhage, a broad area of retinal avascularity in both eyes (OU), and preretinal membranes, resulting in a tractional retinal detachment involving the macula OU (Figures 1A and 1B). FA showed extensive retinal nonperfusion with neovascularization OU with bulbous vascular terminals, along with abnormal course of the retinal vessels with areas of arteriovenous anastomosis and irregular sprouts of vasculature beyond the vascular-avascular transition zone (Figures 1C and 1D). There was no plus disease. Laser photocoagulation (810 nm) was applied to the peripheral avascular retina OU. Two months later, the patient underwent 25-gauge vitrectomy OU for progression of retinal traction, during which traction was released from a dense fibrotic tractional membrane overlying the posterior pole OU. EUA at last follow-up 1 month postoperatively (age 6 months) revealed improvement in the retinal detachment OD (Figure 1E) and resolution of the macular detachment in the left eye (OS) (Figure 1F). Vision was noted to be at least light perception OU. Genetic testing, including sequence analysis of Norrie disease gene (NDP), Frizzled-4 (FZD4), and tetraspanin12 (TSPAN12), and deletion / duplication testing of NDP, was negative.

Figure 1. Fundus photographs and fluorescein angiogram of Case 1. Fundus photograph of Case 1 at presentation revealed a thick membrane overlying the disc in both eyes (OU) resulting in macular detachment and retinal avascularity OU (A: right eye [OD], B: left eye [OS]). There was marked avascularity, with irregular sprouts of neovascularization and bulbous vascular terminals along the vascular-avascular border, arteriovenous anastomoses, irregular sprouting of vasculature beyond the transition zone, and areas of pinpoint hyperfluorescence beyond the transition zone OU (C: OD, 12 seconds; D: OS, 1 minute, 22 seconds). After laser photocoagulation to avascular retina and pars plana vitrectomy, fundus photographs at last follow-up at 6 months of age revealed improvement OD (E) and resolution OS (F) of the macular detachment.

Case 2

A female born at 30 and five-sevenths weeks gestational age weighing 1,560 grams who had underwent ROP screening at a referring hospital was transferred to our institution for a second opinion at 35 weeks PMA. EUA revealed peripheral retinal avascularity and tractional retinal detachment nasally OU (Figures 2A–2C). There was no plus disease. FA confirmed severe retinal avascularity and neovascularization OU. The retinal vessels exhibited dense networks of arteriovenous anastomosis and areas of irregular sprouting beyond the vascular-avascular transition zone (Figures 2D and 2E). Laser photocoagulation (810 nm) was applied to the avascular retina OU. Three days later, progression of the nasal traction was noted. The patient underwent vitrectomy OU with dissection of a dense fibrotic preretinal membrane overlying the tractional detachment. At 38 weeks PMA, further anterior-posterior traction was noted OU, with involvement to the retrolenticular space in the right eye (OD). Additional vitrectomy and preretinal membrane peeling were performed OU. The traction gradually settled OS, but there was progression of the retinal detachment OD to a retrolenticular plaque. A third vitrectomy with lensectomy and capsulectomy was performed OD at 45 weeks PMA. The stalk tissue and plaque were delaminated from the retinal surface without incident. However, the underlying macula was noted to have lipid accumulation and a central stretch break. Extensive efforts to dissect the fibrous membranes that were incorporated into the retina were unsuccessful. In OS, the fibrovascular proliferation subsequently contracted into a posterior volcano-shaped funnel detachment. Lens-sparing vitrectomy with delamination of preretinal fibrovascular membranes was performed, with gradual settling of the retina and maintenance of at least light perception vision OS at last follow-up at 12 months of age. Sequence analysis of NDP, FZD4, low-density lipoprotein receptor-related protein 5 (LRP5), and TSPAN12, as well as deletion / duplication testing of LRP5 and NDP, was negative.

Figure 2. Fundus photographs and fluorescein angiogram of Case 2. Fundus photograph of Case 2 at presentation reveals anomalous retinal vasculature and avascularity, as well as a membrane overlying the disc and arcades causing nasal retinal detachment in both eyes (OU) (A, B: right eye [OD], C: left eye [OS]). Fluorescein angiography reveals severe retinal avascularity, dense networks of arteriovenous anastomosis, irregular sprouts of vascularization beyond the vascular-avascular transition zone, and leakage consistent with neovascularization along the disc and arcades OU (D: OD, 9 seconds; E: OS, 42 seconds).

Case 3

A male born at 31 weeks gestational age weighing 1,360 grams undergoing ROP screening examinations at a referring hospital was transferred to our institution for a second opinion at 38 weeks PMA. EUA revealed a morning glory optic nerve and a persistent fetal vasculature (PFV) stalk extending from the posterior lens to the posterior pole and optic nerve OD. There was no plus disease. At 43 weeks PMA age, EUA revealed progression to a temporal tractional retinal detachment OD (Figure 3A) and normal retinal features OS (Figure 3B). FA revealed severe retinal avascularity with bulbous vascular terminals and retinal neovascularization OD (Figures 3C and 3D) and mild peripheral nonperfusion OS (Figure 3E). B-scan confirmed a stalk extending from the posterior lens capsule to the posterior tractional retinal detachment. Laser photocoagulation (810 nm) was applied to the peripheral avascular retina OD, followed by lensectomy and pars plana vitrectomy to relieve vitreoretinal traction extending from the stalk to the temporal retinal detachment. At 6 months follow-up (age 9 months), repeat EUA revealed improvement of the retina traction and laser scars OD. OS was unremarkable (Figure 3F). FA revealed areas of unlasered areas of retinal ischemia OD and peripheral retinal avascularity OS. Additional laser photocoagulation (810 nm) was applied OU. Vision was noted to be light perception OD and at least fix-and-follow OS. Next-generation sequencing of the NDP, FZD4, LRP5, and TSPAN12 genes was unable to be performed due to pending issues with insurance authorization.

Figure 3. Fundus photographs and fluorescein angiogram of Case 3. Fundus photograph of Case 3 at presentation reveals hazy media due to cataract, a fibrovascular stalk noted clinically to extend from the nerve to the posterior lens, and morning glory disc abnormality. There was a macular tractional retinal detachment (A). The left eye (OS) was unremarkable clinically (B). Fluorescein angiography revealed severe retinal avascularity with bulbous vascular terminals, pinpoint areas of hyperfluorescence noted beyond the transition zone (inferiorly), and neovascularization extending from the disc to the temporal avascular-vascular junction in the right eye (OD) (C: 1 min 26 seconds; D: 35 seconds) and peripheral avascularity without neovascularization OS (E: 5 min 56 seconds). At 6 months follow-up (age 9 months), repeat exam under anesthesia revealed interval reduction in retinal detachment with attached posterior pole OD (F) and stable clinical findings OS.

Discussion

The key findings of this case series are: (1) A diagnosis of APVR, a non-ROP clinical entity in the FEVR spectrum, should be considered in premature neonates undergoing ROP screening; (2) features in premature infants that may suggest APVR rather than ROP include unilateral or bilateral large areas of retinal avascularity with neovascularization and / or tractional retinal detachment in the absence of plus disease that are more severe than that expected based on demographics and clinical history; that exhibit atypical clinical or angiographic features; and, possibly, that may be associated with PFV and / or optic nerve anomalies; (3) EUA with FA should be considered early; (4) genetic testing for FEVR-associated genes should be considered; and (5) since APVR, which is in the spectrum of FEVR, may progress rapidly, these patients may require close monitoring and early intervention such as laser to areas of ischemia, intravitreal anti-VEGF therapy, and / or early vitrectomy. In addition, dilated funduscopic examination of the family members of the patients should be considered to identify any potential retinal abnormalities that may be consistent with the diagnosis of FEVR.

All infants included in this study were identified during routine ROP screening exams. Indeed, it has recently become clear that a non-ROP ischemic vitreoretinopathy in the FEVR spectrum may present in premature infants.³ Although ROP typically follows a predictable stage-wise course with a relatively finite period of activity, FEVR can often progress faster and more unpredictably and can reactivate years later.^1,2 Distinguishing ROP from other ischemic vitreoretinopathies that may present during the neonatal period thus has important management implications. In the reported cases, APVR rather than ROP was diagnosed based on severe retinal pathology despite relatively older gestational age at birth and larger birth weights, highly asymmetric retinal vascular abnormalities in association with features of PFV and / or morning glory optic disc (Case 3), absence of plus disease, and / or characteristic features on examination and FA.³ Also, distinct from the previously described entity of “ROPER” (ROP vs. FEVR), which was meant to indicate cases that are actually FEVR and occur in cases of children who meet ROP screening criteria,³ APVR has a more aggressive appearance and may be mistaken for aggressive posterior-ROP (AP-ROP) in some cases. APVR rather than AP-ROP is suggested in the reported cases by the lack of plus disease and by the patients' relatively older birth age and larger birth weights, as well as by their relatively benign neonatal course in intensive care units in the United States with stringent oxygen management protocols.⁸

Other non-ROP conditions that can manifest with retinal avascularity in the early neonatal setting include incontinentia pigmenti (IP), Norrie disease, and rarer diseases such as microvillus inclusion disease and Potter's syndrome. IP is an X-linked disorder due to a mutation in the NFκB essential modulator (NEMO) gene. IP is usually lethal in male embryos and is characterized by a tri-phasic dermopathy, along with abnormalities involving the and central nervous system, teeth, and hair. Retinal manifestations include peripheral avascularity, irregular vessels with arborizing arteriovenous anastomoses, and aneurysmal and neovascular changes that can result in exudation, vitreous hemorrhage, and / or retinal detachment.^9,10 None of the cases reported herein exhibited cutaneous or other systemic manifestations consistent with IP. Norrie's disease is an X-linked recessive disorder of males due to a mutation in the NDP gene. Norrie's disease manifests at birth or shortly thereafter as retinal dysplasia, often with a grayish-yellow pseudoglioma appearance. Retinal avascularity, neovascularization, and detachment may be noted. Other ocular dysplastic features such as microophthalmia, cataract, iris atrophy, synechiae, and / or glaucoma may also be noted. Systemic features of Norrie's disease include sensorineural hearing loss and central nervous system manifestations, such as developmental delay and / or seizures.^11–14NDP mutation testing was negative in Cases 1 and 2. Though not performed in Case 3, the clinical ophthalmologic and systemic features were not characteristic of Norrie's disease in this patient. Microvillus inclusion disease is a condition of life-threatening watery diarrhea at birth due to a defect in the intestinal villi related to mutations in myosin VB (MYO5B) and other genes.¹⁵ Paulus et al. previously reported a case of peripheral retinal avascularity treated with laser in a 1-month-old patient with microvillus inclusion disease. In addition to its known role in vitreoretinopathy, the Wnt signaling pathway has also been implicated in intestinal development.¹⁶ None of the cases reported herein exhibited gastrointestinal abnormalities consistent with microvillus inclusion disease. Potter's syndrome includes a constellation of developmental abnormalities including bilateral renal agenesis, compressed facies, foot and leg deformities, and pulmonary hypoplasia. Retinal abnormalities including persistent fetal vasculature and peripheral retinal avascularity with or without secondary retinal neovascularization have been described in Potter's syndrome.^17,18 However, none of the cases reported herein exhibited systemic findings consistent with Potter's syndrome.

Case 3 exhibited PFV in the eye with more severe ischemic vitreoretinopathy. Several reports have, for example, noted a combination PFV plus FEVR phenotype in patients with a family history of FEVR and documented Wnt pathway mutations.^19,20 Wnt pathway mutations have been noted in animal models to cause delay in regression of the hyaloid vascular system,^21,22 and thus the PFV stalk may be one manifestation of FEVR. As was noted in Case 3, prior reports have also identified an association of PFV and morning glory,²³ and with morning glory disc with ischemic vitreoretinopathy.²⁴ One study of patients with both optic nerve anomalies and peripheral retinal avascularity noted a high rate of retinal neovascularization (75%) and tractional retinal detachment (63%),²⁵ suggesting that the co-localization of these entities may herald a more aggressive retinal course. Thus, cases of PFV and / or morning glory variant associated with retinal vascular abnormalities should be considered for early EUA with FA to evaluate for APVR.

As noted above, APVR is likely a part of the FEVR spectrum. Wnt pathway mutations (NDP, FZD4, LRP5, and TSPAN12) are implicated in only up to 50% of cases of FEVR; thus absence of such a mutation does not rule out the condition.⁴ In this study, no Wnt pathway mutations were identified in either of the two infants (Cases 1 and 2) tested.

In this series, early diagnosis of APVR during the neonatal period allowed for early intervention — first with laser and then, in some cases, with prompt surgery. Two of the reported cases were treated while still preterm, due to identification of disease during ROP screening exams. This approach resulted in stabilization or improvement in the retinal detachment and maintenance of at least light perception vision in all but one eye that presented with retinal detachment (Case 1 OU, Case 2 OS, and Case 3 OD) and stabilization of anatomy with no progression to retinal detachment in one eye that did not present with detachment (Case 3 OS). Several prior reports have suggested that early intervention may improve visual outcomes in advanced and aggressive pediatric vitreoretinopathies, which are frequently associated with progression to no light perception vision and phthisis bulbi.^26,27 Shapiro et al. reported previously on a patient with a family history of Norrie disease, in whom prenatal amniocentesis identified a Norrie disease gene mutation and who was thus delivered at 37 weeks by elective induction of labor. Laser photocoagulation was applied to areas of retinal avascularity at 1 day of life, and the patient maintained retinal attachment and visual acuity of 20/125 in both eyes through 2 years of follow-up.²⁷ In addition to early laser intervention, although not employed in any of the reported cases, intravitreal anti-VEGF may also be considered as a potential treatment for these patients.

All three reported cases were diagnosed with APVR early, as pre-term infants, because their demographics had prompted ROP screening. This underscores not only the importance of vigilance for findings more suggestive of FEVR than ROP while performing ROP screening, given the potential for rapid and unpredictable progression of the former, but also raises the question about a potential role for universal neonatal screening eye exams. In fact, two of the three patients in this series (Cases 2 and 3) just barely met birth age and weight criteria for ROP screening. Had they been born a few days later or slightly heavier, their retinopathy likely would not have been diagnosed until end-stage findings resulted in abnormal visual behavior, leukocoria, and / or strabismus. A universal screening program of 3,574 health neonates in China found a 24.4% incidence of abnormal eye pathology, including 6% with potentially sight-threatening or amblyogenic hemorrhage. Only 0.05% of these infants, however, exhibited vitreoretinopathy or persistent fetal vasculature.²⁸ Further studies regarding the utility and cost-effectiveness of universal screening are necessary.

There are a number of potential limitations of this case series that may affect our ability to make definitive conclusions regarding the diagnosis and management of this clinical entity. (1) This is a retrospective study that discusses the characteristics and management of neonates with a posterior vitreoretinopathy. However, the purpose of this study is to present a case series and not to draw any definitive conclusions regarding management. We do feel that a larger series is required and longer follow-up of these children is needed. (2) All of the cases presented had laser as the initial treatment either alone or in combination with vitrectomy. It is possible that laser therapy could promote progression of disease and retinal detachment. We do not have a comparative group that uses anti-VEGF as first-line treatment, and we do not have a control group where no treatment was performed. It would be difficult to perform a study with such a control, given that historical data suggests that children with significant retinal ischemia in this age group are at risk of progressing to retinal detachment without any intervention.^2–6,26 (3) We did not perform electroretinograms (ERG) on these patients prior to treatment. ERGs may provide useful information for these patients, but due to the significant amount of retinal ischemia noted on examinations, we believe that treatment was warranted and ERG testing would not have altered our management plan.

In summary, we report a series of three cases of APVR, likely in the FEVR spectrum, diagnosed in the neonatal period and in whom such early intervention was effective at improving or stabilizing the retinal pathology and maintaining light perception or better vision in all eyes. Moreover, this series further supports the existence of a clinical entity more consistent with FEVR than ROP in premature infants and highlights the importance of considering other diagnoses when screening for ROP, since FEVR spectrum conditions can progress more rapidly and unpredictably than ROP. Early intervention may mitigate the typical aggressive course and poor prognosis of this condition. Further, larger studies of this entity are necessary.