Familial exudative vitreoretinopathy (FEVR) is a rare, inherited disorder of retinal vascular development leading to incomplete and anomalous vascularization of the peripheral retina.1,2 The disease is thought to be caused by genetic mutations in the Wnt-signaling pathway that is necessary for retinal angiogenesis.3 Genetic mutations in Wnt pathway genes NDP,4 FZD4,5,6LRP5,7TSPAN12,8ZNF408,9CTNNB1,10 and KIF1111 have been implicated in the pathogenesis of FEVR; however, these genes account for only a fraction of patients with clinically diagnosed disease.12 Thus, clinical examination remains the gold standard for diagnosis. Patients with FEVR present with varying severity, possibly due to variable gene expressivity,2,13,14 ranging from asymptomatic areas of nonperfusion in the retinal periphery to vitreoretinal adhesions, retinal folds, temporal macular dragging, neovascularization, subretinal exudation, and tractional retinal detachments that form secondary to the retinal ischemia.14–16
Prior imaging studies of the retinal vasculature in patients with FEVR using ultra-widefield imaging and fluorescein angiography (FA) have described a range of associated retinal features, such as aberrant peripheral vessels, arterial tortuosity, telangiectasias, and capillary agenesis, and have advanced the understanding of this disease.16,17 However, those modalities do not allow for depth-resolved assessment of the retinal microvasculature. Optical coherence tomography angiography (OCTA) is a noninvasive, high-resolution imaging modality that enables superior visualization of macular retinal microvasculature with differentiation of superficial, penetrating, and deep vascular complexes.18–20 Based on previously reported findings in mutant mice with deficient Wnt signaling,21,22 we hypothesized that patients with FEVR imaged using OCTA would not only exhibit the gross vascular abnormalities observed on FA, but would also show abnormalities in the vertical penetration of the deeper retinal layers due to incomplete angiogenesis. In this study, we describe the macular superficial and deep retinal microvasculature changes observed in 11 eyes of six patients with FEVR compared to 11 age-appropriate control eyes.
Patients and Methods
A total of 22 eyes were imaged, including 11 eyes of six patients with clinically diagnosed FEVR16 (mean age: 17.5 years ± 7.5 years; median age: 20 years; range: 2 years to 25 years). Four patients were female, two were male; two were black, two were white, and two were Hispanic. Five patients were born full-term, one was born at 31 weeks' gestation. Additionally, 11 control eyes of 11 patients without retinal disease per ophthalmic exam were included (age range: 1.25 years to 64 years; mean age: 18.3 years ± 15.8 years; median age: 15 years). Five of the control patients were female, six were male; three were black, six were white, two were Hispanic, and all were born full-term. Diagnosis of FEVR was determined by pediatric retinal specialists (LV, CAT) and based on clinical diagnostic criteria including fundus exam, history, and FA findings. Genetic testing was offered to all patients; however, due to insurance coverage, testing was only available to a few patients. The age-appropriate control patients were recruited from the existing patient population at the Duke University Eye Center who presented for routine dilated ophthalmic exams or refractive error (n = 2), strabismus surgery in the fellow eye (n = 1), or unilateral pathology in the fellow eye (n = 7). All patients were imaged using investigational Spectralis SD-OCT tabletop or Flex modules integrated with the OCTA software (version 6.9; Heidelberg Engineering, Heidelberg, Germany). The Duke University Institutional Review Board approved this study, and informed consent was prospectively obtained in all cases. The study followed the tenets of the Declaration of Helsinki.
Two infants were imaged supine in the operating room using the Flex module,23,24 and the remaining patients were imaged upright in clinic using the tabletop unit. One eye with FEVR was excluded due to significant media opacity that prevented acquisition of high-quality images.
For all eyes imaged, a 10° × 10° image comprising 512 A-scans per B-scan and 512 B-scans of the macula was captured. A trained grader (STH) reviewed the automated segmentation of the retinal layers and manually corrected the segmentation if needed. OCTA images were segmented and rendered by Spectralis software as follows: superficial vascular complex (SVC) from internal limiting membrane (ILM) to 17 μm above the lower boundary of the internal plexiform layer (IPL), and deep vascular complex (DVC) from 17 μm above the IPL to the bottom boundary of the outer plexiform layer (OPL). The DVC images had the projection artifact removal feature of the software enabled.
The OCTA images of the SVC and DVC of all 22 eyes were then randomly ordered for masked grading. Five experienced graders (APF, XC, RH, CAT, LV) with experience in reviewing OCTA images were masked to all clinical information including diagnosis, age, sex, and race/ethnicity. The graders were first trained on a set of OCTA images of the SVC and DVC of three control eyes. They then graded the 22 sets of OCTA images of the de-identified eyes and analyzed the images qualitatively for each of these features: abnormal foveal avascular zone (FAZ) shape, heterogeneous areas of increased or decreased vessel density, disorganized vessel pattern, vessel dilation, stub-like vessel terminations, vascular curls and loops, and straightened vessels. These parameters are defined in Table 1 and examples of these findings are demonstrated in Figure 1. Qualitative features were considered present on OCTA if the majority of readers (at least three of five) agreed.
Definitions of Qualitative OCTA Grading Characteristics in FEVR
Optical coherence tomography angiography showing the superficial vascular complex (SVC) (top row, A–E) and corresponding deep vascular complex (DVC) (bottom row, F–J) for a 16-year-old healthy control (A, F), a 22-year-old patient with familial exudative vitreoretinopathy (FEVR) stage 2a in the right eye (B, G), a 2-year-old with FEVR stage 2b in the left eye (C, H), a 16-year-old with FEVR stage 3b in the right eye (D, I), and a 21-year-old with FEVR stage 3b in the left eye (E, J). The SVC images show vessel dilation (C–E), disorganization (C–E), straightening (D, E), areas of increased and/or decreased density (C–E), and curls and loops (C, E). The DVC images show areas of decreased density (H–J), disorganization (H–J), and “end bulbs,” or stub-like vessel terminations (H–J).
Clinical and demographic information including gestational age at birth, age, sex, race/ethnicity, ophthalmic examination findings, and any genetic testing performed for known FEVR mutations were reviewed for all patients. Eyes were classified into FEVR stages at initial presentation using the clinical staging criteria previously published by Pendergast and Trese.25 An ophthalmologist (APF) also retrospectively analyzed FA images, all of which were obtained on a widefield imaging system (Optos 200Tx; Optos, Dunfermline, Scotland; or Retcam3; Natus Medical, Pleasanton, CA) corresponding to the time of OCTA imaging focusing on characterizing any macular abnormalities.
The OCTA and FA findings of this study are summarized in Table 2. FEVR staging15,25 based on examination at the time of presentation was as follows: stage 2a (n = 2 eyes), stage 2b (n = 5 eyes), stage 3b (n = 3 eyes), and stage 5a (n = 1 eye). Four of the 11 eyes (two of two eyes with FEVR stage 2a, two of five eyes with stage 2b) of two patients who were siblings showed no vascular abnormalities on OCTA in either the SVC or DVC. The remaining seven eyes (three of five eyes with FEVR stage 2b, three of three eyes with stage 3b, one of one eye with stage 5) imaged had abnormal FAZs, SVCs, and DVCs with specific features described below, based on the masked reviewer grading.
Retinal Vascular Features on OCTA and FA of FEVR
SVC abnormalities in eyes with FEVR were further characterized as having the following abnormal features: vessel dilation (seven of seven eyes; 100%), disorganized vessel pattern (six of seven eyes; 86%), straightened vessels (five of seven eyes; 71%), areas of decreased vessel density (five of seven eyes; 71%), areas of increased vessel density (one of seven eyes; 14%), and vascular curls and loops (three of seven eyes; 43%) (Figure 1, Table 2). Straightening of the vessels and vascular dilatation were abnormalities marked in only the SVC and not the DVC. In contrast to these prominent abnormalities noted in the eyes with FEVR, none of 11 control eyes displayed these features in the SVC and no specific vascular abnormalities were noted.
The same seven eyes with FEVR that had abnormal SVCs also displayed abnormal DVCs. DVC abnormalities in eyes with FEVR were further characterized as follows: areas of decreased density (seven of seven eyes; 100%), disorganized vessel pattern (seven of seven eyes; 100%), “end bulbs” or stub-like vessel terminations (seven of seven eyes; 100%), and vascular curls and loops (four of seven eyes; 57%) (Figure 1, Table 2). A prominent feature in the DVC of FEVR eyes were the end bulbs (Figure 2) (Figure A available at www.healio.com/OSLIRetina), which presumably represented premature capillary endings without further arborization around the INL. They were associated with decreased vascular density but not noted in the SVC of any eye. In contrast to the FEVR eyes, one of 11 control eyes had areas of increased vessel density and vascular curls and loops but no other specific vascular abnormalities were noted.
A 19-year-old, white, term-born male was diagnosed at 1.5 years old with familial exudative vitreoretinopathy (FEVR). Genetic testing showed a heterozygous mutation in the Wnt pathway LRP5 gene. The right eye (A, fundus photo; B, fluorescein angiography [FA]) underwent peripheral laser and cryotherapy. Optical coherence tomography angiography (OCTA) of the macula showed vessel dilation, areas of nonuniform vessel density, vascular loops, and straightened vessels in the superficial vascular complex (SVC) (C). The deep vascular complex (DVC) had a disorganized pattern, curls and loops, areas of decreased density, and characteristic end bulbs (D). (E) An OCT/OCTA B-scan of the location of the green line in (D) is shown, with the blue crosshair over one of the end bulbs. The dotted red lines indicate the segmentation of the retinal layers used to form the en face OCTA image of the DVC. The pattern seen in the patient resembles that of vasculature in mutant mice with defective Wnt signaling (F–H). (F, G) Image adapted from Ye et al.31 showing a wildtype (WT) mouse compared to a Frizzled4 knockout (FZ4−/−) mouse with white arrows pointing to clusters of endothelial cells only partially penetrating into the retina. (H) Image adapted from Xia et al.21 demonstrating incomplete vascularization with attenuated vessels in a homozygous r18 mutant mouse carrying a frameshift mutation in the LRP5 gene.
Cross-sectional optical coherence tomography (OCT)/OCT angiography (OCTA) scans corresponding to each of the eyes shown in Figure 1: control, familial exudative vitreoretinopathy (FEVR) stage 2a, FEVR stage 2b, FEVR stage 3b, and FEVR stage 3b. The dotted lines show the segmentation boundaries used to generate the en face OCTA images of the superficial vascular complex (internal limiting membrane to inner plexiform layer [IPL]) and deep vascular complex (IPL to outer plexiform layer).
There were minimal FA changes in the macula of the 11 eyes with FEVR. Macular dragging and straightening of the vessels in the macula were the only features noted and were present in six of 11 eyes. One eye showed telangiectatic vessels in the temporal macula. All 11 eyes showed peripheral findings on FA, including nonperfusion, leakage, and staining of prior laser treatment (five representative eyes are shown in Figure 1 and a sixth eye is shown in Figure 2).
Of the six patients with clinically diagnosed FEVR, two underwent genetic testing. One patient was negative for any mutations in the known genes FZD4, LRP5, TSPAN12, and NDP; the other patient (Figure 2) was confirmed as heterozygous for a mutation in LRP5.
This case series of depth-resolved macular imaging in FEVR revealed abnormalities of both the superficial and deep vascular plexuses. To our knowledge, this is the first report of such findings; although there has been one report of OCTA in a patient with FEVR,26 these microvascular abnormalities were not otherwise evident on FA and not previously described (PubMed search on October 4, 2018: “familial exudative vitreoretinopathy” and “fluorescein angiography;” “familial exudative vitreoretinopathy” and “optical coherence tomography angiography”). In the seven eyes with vascular abnormalities, imaging of the SVC revealed increased vessel dilation, presence of vascular curls and loops, and straightening of the macular vasculature, and imaging of the DVC revealed disorganized vascular pattern with stub-like vessel terminations. Notably, these findings were present in eyes of patients ranging in age from 2 years to 25 years. These unique macular microvascular changes provide new insights into the disease pathogenesis of FEVR.
The abnormally terminated vascular flow with end bulbs, or stub-like dilated vasculature, in the DVC appears to be unique in FEVR in this small sample. This was not visible in any of the control eyes and larger studies of healthy pediatric retinas,27 nor has this been reported in OCTA of other pediatric vascular diseases such as retinopathy of prematurity.24,28,29 Although OCTA images work by capturing motion (blood flow) rather than structure (blood vessels), thus making histology necessary to confirm vessel termination, we believe these end bulbs visualized on OCTA could correlate with structural vessel termination, with suspended red blood cells in motion captured on OCTA within these end bulbs.30 Upon close evaluation of the OCTA cross-sections of regions adjacent, lateral, and vertical to the end-bulbs, we did not find continuous flow suggestive of vertical vessels. And on OCT, although we did find previously reported structural changes31,32 such as diminished foveal contour, cystoid macular edema, retinal thickening, and ellipsoid zone disruption in our eyes with more severe FEVR, in this small sample of eyes, no unique associations were found between the eyes with end bulbs and these structural OCT changes.
The prevalence of macular microvasculature findings in seven of 11 eyes suggests that FEVR is more than a disease of peripheral nonperfusion as previously thought and suggests a more widespread and defective retinal angiogenesis particularly in the deeper retinal layers. This intriguing finding will need to be validated in larger studies, and we look forward to future findings from other researchers and our team in investigating these novel findings in additional patients with FEVR.
Interestingly, these DVC vascular end bulbs visible on OCTA in humans (including one with documented LRP5 mutation) parallel mouse models of FEVR with mutations in the Wnt-signaling pathway (Figure 2). Mice with defective Norrin/FZD4 signaling or LRP5 signaling demonstrate retinal hypovascularization with both delayed radial migration of endothelial cells as well as defective arborization of deeper capillaries following the vertical endothelial innervation from the vitreal surface.21,33 This similarity observed in patients with FEVR and mutant mice with defective Wnt signaling indicates a conservative retinal vascular growth pattern across species and suggests a potential role for OCTA in the diagnosis of FEVR, especially when a range of diagnoses are considered.
Limitations of this study include a small sample size; the cross-sectional nature of the study; and heterogeneity of FEVR disease stages, treatment history, and clinical findings. Although the data presented here include eyes at different stages of disease and those that have undergone various vitreoretinal treatments, observations of vascular defects, particularly in the DVC, appear consistent and were generally distinguishable from normal controls by masked graders. Two of the patients imaged (four eyes: two that were stage 2a and two that were stage 2b, without any macular abnormalities seen on OCTA) were siblings, and thus may have had related genotypes that led to a less severe FEVR phenotype. The cross-sectional nature of the study limits the longitudinal assessment of the FEVR disease course. Since FEVR can be a progressive disease with progressive ischemic changes, we cannot conclude from these data that the DVC failed to develop normally in these severe eyes, only that higher stages of FEVR were associated with multiple abnormalities in the vasculature. Future studies with larger sample size will allow for quantification and robust statistical analysis of these OCTA findings with potential correlation to OCT structural findings, FEVR disease stage, and clinical presentation along with comparison to control eyes of the same race/ethnicity, age, and sex. Additionally, this study aimed to investigate depth-resolved vascular abnormalities of the macular vasculature; future studies may explore imaging of the retinal periphery to investigate the changes in periphery retinal vasculature and their response to treatment.
OCTA allows for depth-resolved visualization of striking vascular abnormalities in the macula that have not been previously described or imaged in patients with FEVR. These findings suggest that FEVR, often defined as a disease of the retinal periphery, exhibits central microvascular changes and decreased vascularization of the deeper retina. Such findings may potentially assist in distinguishing FEVR from other diseases with similar clinical findings, such as retinopathy of prematurity.24,34 As FEVR is a progressive disease that requires life-long monitoring, being able to accurately diagnose and potentially predict prognosis would greatly benefit patients. As we investigate these findings further in a larger number of patients and correlate with disease severity, the extent of these vascular abnormalities may aid not only in diagnosis, staging and prognosis of this retinal vascular disease but also in monitoring response to future treatment.
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Definitions of Qualitative OCTA Grading Characteristics in FEVR
|OCTA Characteristic||Defining Characteristics When Compared to Normal Eyes|
|Abnormal FAZ shape||Elongated, abnormally stretched FAZ or overall irregularity in shape|
|Increased or decreased vessel density||Areas of subjectively increased or decreased concentration of vessels|
|Disorganized vessel pattern||Deviation from the expected patterns of larger caliber vessels branching intofiner vessels in the SVC and a regular and uniform lacy pattern in the DVC|
|Vessel dilation||Any vessels of larger than expected diameter|
|Stub-like terminations||Abnormally truncated vessels that exhibited bulbous ends|
|Vascular curls and loops||Evidence of vascular shunting, anastomoses, or curling patterns not seen in controls|
|Straightened vessels||Abnormally dragged or more linear appearing vessels than expected|
Retinal Vascular Features on OCTA and FA of FEVR
|Patient, Eye||FEVR Stage||Macular OCTA Findings||FA Findings|
|1, OD||2a||Normal||No abnormalities||No abnormalities||Mild vessel straightening||Temporal/inferotemporal nonperfusion, leakage at the border of perfused and nonperfused retina|
|1, OS||2b||Normal||No abnormalities||No abnormalities||No abnormalities||Temporal nonperfusion, two small peripheral vascular loops, staining of prior laser|
|2, OD||2b||Normal||No abnormalities||No abnormalities||No abnormalities||Staining of laser, leakage in inferotemporal periphery|
|2, OS||2a||Normal||No abnormalities||No abnormalities||No abnormalities||Temporal nonperfusion, no leakage|
|3, OD||2b||Abnormal||Decreased density, dilated vessels||Decreased density, disorganized, end bulbs, curls/loops||No abnormalities||Leakage in the temporal/superotemporal mid-periphery, mild peripheral nonperfusion, staining of prior laser|
|3, OS||2b||Abnormal||Decreased density, disorganized, dilated vessels, curls/loops||Decreased density, disorganized, end bulbs, curls/loops||Mild vessel straightening||Staining 360-degree laser treatment|
|4, OD||3b||Abnormal||Disorganized, dilated, straightened vessels||Decreased, density, disorganized, end bulbs||Macular dragging, vessel straightening, hyper-fluorescence of preretinal fibrosis||Nonperfusion in the temporal/nasal periphery, late leakage in inferotemporal periphery, hyperfluoresence of preretinal fibrosis|
|4, OS||2b||Abnormal||Disorganized, dilated, straightened vessels||Decreased density, disorganized, end bulbs, curls/loops||Significant macular dragging and straightening||Superotemporal/temporal/inferotemporal nonperfuson, temporal vascular shunting, leakage of vasculature in superotemporal/temporal periphery|
|5, OD||3b||Abnormal||Decreased density, disorganized, dilated, straightened vessels, curls/loops||Decreased density, disorganized, end bulbs, curls/loops||Mild staining of macular pigmentary changes||Leakage in temporal periphery, staining of prior laser|
|5, OS||5||Not imaged due to bullous keratopathy|
|6, OD||5||Abnormal||Decreased density, disorganized, dilated, straightened vessels||Decreased density, disorganized, end bulbs||Macular dragging, vessel straightening||Staining of peripheral chorioretinal scarring|
|6, OS||3b||Abnormal||Decreased density, disorganized, dilated, straightened vessels, curls/loops||Decreased density, disorganized, end bulbs||Macular dragging, vessel straightening, telangiectatic vessels in temporal macula, leakage in temporal macula||Staining of peripheral chorioretinal scarring, late temporal/nasal/inferior leakage|