Abstract
Purpose
To investigate microvascular growth defects in the temporal midperipheral retina and their correlations with vitreoretinal microstructural abnormalities (VRMAs) in early-stage familial exudative vitreoretinopathy (FEVR).
Methods
We enrolled 127 patients (127 eyes) with early-stage FEVR and 31 healthy subjects (31 eyes). Widefield optical coherence tomography angiography was conducted for all enrolled eyes. Vessel density (VD), vessel diameter index (VDI), and vessel index (VI; VD/VDI) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) in temporal midperiphery were further evaluated. The distance from the vessel sprouting point of the optic disc to the avascular area margin (Optic-AVA) was measured to assess retinal vascular dysplasia.
Results
In early-stage FEVR, 61.42% of eyes showed retinal microvascular abnormalities (MVAs) in the temporal midperiphery, all combined with VRMAs. Common MVAs presented disordered vascular anastomoses in the SCP and capillary loss in the DCP, corresponding to deficient neuroretina. The preretinal vasculature (PRV) was detected in 36 eyes. VD and VI were lower in FEVR eyes compared to controls, whereas the VDI in the SCP was larger (all P < 0.001). Optic-AVA was positively correlated with VD and VI in both plexuses and negatively correlated with the VDI in the SCP. PRV existence was independently correlated with decreased VI in the DCP (odds ratio [OR] = 0.322; P < 0.001), and VRMA existence was independently correlated with decreased VI in SCP and DCP (SCP OR = 0.282, P = 0.010; DCP OR = 0.562, P = 0.002).
Conclusions
MVAs in the temporal midperipheral retina were revealed. Microvascular loss may be correlated with Optic-AVA reduction, PRV, and the presence of VRMAs.
Keywords: microvascular growth defects, vitreoretinal microstructural abnormalities, familial exudative vitreoretinopathy, widefield optical coherence tomography angiography
Familial exudative vitreoretinopathy (FEVR) is a rare, inherited disorder characterized by vitreoretinal vascular dysplasia, potentially resulting in severe vision impairment during childhood.1–3 Canny and Oliver4 first described fluorescein angiography (FA) findings of peripheral vascular abnormalities in 1976. The clinical manifestations are variable and present various symptoms, including peripheral avascular zone, supernumerary vascular branching, vitreoretinal adhesions, macular dragging, radial retinal folds, and retinal detachment with irreversible vision loss.5,6
Abnormal retinal vascularization is the primary pathology and the most prominent feature of FEVR. In recent years, the progress of angiography imaging techniques has improved our understanding of FEVR. Widefield FA has detected various vascular anomalies in the far periphery, such as bulbous vascular endings, peripheral telangiectasias, and aberrant venous–venous loops.5,7 Nevertheless, FA is invasive and unable to detect subtle microvascular features and disassemble the retinal capillary layers. Optical coherence tomography angiography (OCTA) is a noninvasive imaging technique that has proved to be reliable for the visualization of both microstructural and microvascular details within each retinal layer.8 We previously investigated macular capillary loss in FEVR and its correlation with visual loss and the severity of FEVR using OCTA,9 but the viewing field of the early device was limited only to the posterior region.
Recently, widefield OCTA has been improved to expand its viewing field to midperiphery or even periphery.10 Moreover, previous studies have validated its ability to distinctly and reliably detect abnormal microvasculature in the vitreous and vitreoretinal interface.11–13 A previous study demonstrated that ultra-widefield OCTA served as an effective and noninvasive method for screening and diagnosing FEVR, which focused on the morphological vascular abnormalities in the periphery and vitreoretinal microstructural anomalies in the temporal midperiphery.14 However, the subtle retinal microvascular defects in the temporal midperiphery secondary to FEVR, particularly in the deep capillary layer, have remained largely unexplored. Also, the relationships of microvascular defects in the temporal midperiphery with vitreoretinal microstructural abnormalities are also unknown.
In this study, we enrolled a large cohort of early-stage FEVR and employed widefield swept-source OCTA (WF SS-OCTA) to explore the subtle retinal microvasculature defects and associated vitreoretinal microstructural abnormalities in the temporal midperiphery simultaneously. We further performed quantitative assessments of microvascular parameters and evaluated their correlations with retinal vascular dysplasia and vitreoretinal microstructural abnormalities formation. We aimed to reveal the unrecognized patterns of retinal microvascular development defects in the temporal midperiphery and their possible pathophysiological significance.
Methods
Study Population
This cross-sectional, case–control study was conducted following the tenets of the Declaration of Helsinki. The study and control groups included 127 eyes (127 pediatric patients) with FEVR without nystagmus and 31 healthy eyes (31 age- and gender-matched patients) with normal vision, respectively. The enrollment and diagnosis of participants were conducted at the Shanghai Eye and ENT Hospital of Fudan University between December 12, 2018, and September 20, 2021, and ethical approval and informed consent was obtained from participants or their guardians.
Classification
All participants underwent widefield fundus photography and FA for diagnosis and staging. The clinical diagnostic criteria for FEVR were as follows: (1) classical retinal vascular development defects as previously described,7 (2) full-term birth to exclude retinopathy of prematurity (ROP), and (3) a positive family history or genetic evidence of FEVR. The exclusion criteria included eyes with retinal fold, retinal detachment, or vitreous hemorrhage; confounding diagnoses such as persistent fetal vasculature, ROP, or Norrie disease; systemic symptoms or other congenital disorders; or prior intraocular surgeries. FEVR was classified following the staging system proposed by Kashani et al.7 Only the eyes of patients with mild FEVR (stage 1, avascular periphery; stage 2, avascular retinal periphery with extraretinal vascularization) were enrolled in this study to evaluate the quality of the OCTA images and conduct statistical analyses. Further ensuring the diagnostic accuracy of the early-stage FEVR eyes, all enrolled eyes presented classical peripheral nonperfusion with vascular leakage findings on the widefield FA.7 Also, 57 eyes presented positive genetic information tested via the xGen Exome Research Panel 1.0 (Integrated DNA Technologies, Coralville, IA, USA), including 18 eyes with mutations in the frizzled 4 gene (FZD4), 13 eyes with mutations in the low-density lipoprotein receptor-related protein gene (LRP5), two eyes with mutations in the Norrie disease protein gene (NDP), and 24 eyes with mutations in the tetraspanin-12 gene (TSPAN12) (Table 1). The other eyes chosen to be enrolled with their fellow eyes presented classically clinical phenotypes, including retinal fold or retinal detachment in severe stages, as well as positive phenotypes in family members.
Table 1.
Demographic Characteristics of Study Population
| FEVR | Control | P | |
|---|---|---|---|
| Eyes/patients, n | 127/127 | 31/31 | — |
| Age (yr), mean ± SD | 13.03 ± 3.51 | 12.61 ± 3.21 | 0.546* |
| Male/female, n | 69/58 | 19/12 | 0.549† |
| BCVA (logMAR), mean ± SD | 0.16 ± 0.19 | 0.00 ± 0.00 | <0.001 * |
| AL (mm), mean ± SD | 24.22 ± 1.52 | 23.79 ± 1.74 | 0.173* |
| Stage, n (%) | |||
| 1 | 71 (55.91) | — | — |
| 2 | 56 (44.09) | — | — |
| Patients with genetic mutation, n (%) | 57 (44.88) | — | — |
| FZD4 | 18 (14.1) | — | — |
| LRP5 | 13 (10.24) | — | — |
| NDP | 2 (1.57) | — | — |
| TSPAN12 | 24 (18.90) | — | — |
Values in bold font are statistically significant at P < 0.05.
Unpaired t-test.
Fisher's exact test.
OCTA Imaging Protocol
Retinal microvascular features were detected using a WF SS-OCTA device (ZEISS PLEX Elite 9000; Carl Zeiss Meditec, Dublin, CA, USA) with a scan rate of 100,000 A-scans per second and a 1050-nm central wavelength laser. An 80° montage OCTA image, automatically synthesized from 12 × 12-mm scans from four predefined quadrants and the posterior pole, was processed after quality check and projection removal to reveal microvascular abnormalities (MVAs) and vitreoretinal microstructural abnormalities (VRMAs). Additionally, a detailed 6 × 6-mm scan was targeted on these abnormalities in the temporal midperiphery for precise analysis. For quantitative analysis, the standard 6 × 6 mm scans for each enrolled eye in both groups were located as follows (Fig. 1): Default scanning of a 12 × 12-mm box centered on the fovea was performed, and a line was drawn from the retinal vessel sprouting point of the optic disc to the center of the fovea. The intersection point of this line with the temporal edge of the box was the center of the standard 6 × 6-mm scanning. This location was accomplished by double-clicking this point to make the instrument automatically adjust the internal fixation position. The OCTA images were acquired separately at least twice for each eye. Unqualified OCTA images with a low signal strength index (<8), extensive segmentation errors, or motion artifacts were excluded, and the best quality image was analyzed. Other ocular examinations included best-correlated visual acuity (BCVA; logarithm of the minimum angle of resolution [logMAR]), axial length (AL) via A-mode ultrasound, and intraocular pressure.
Figure 1.
Standard OCTA imaging protocol. Ophthalmological images of a 12-year-old girl with mutation in TSPAN12. (A) On the montage OCTA en face image, the standard location of the 6 × 6-mm scan (purple box) was centered on the intersection of the red line (a line from the optic disc to the fovea) and the blue box (a 12 × 12-mm box centered on the fovea). A grayish-white spindle-shaped band was detected in the corresponding region on the en face images (B, F, G). The 6 × 6-mm OCTA scan detected disordered vascular anastomosis (termed TMPVAD) with AVAs in the SCP (C) and the DCP (D) in the center of the band (yellow arrows), alongside neuroretina structure deficiencies replaced by hyperreflective glial-like material (yellow arrows) in the B-scan angiography and structure images (E, H).
Analysis of OCTA Images
Retinal vascular beds were automatically segmented using the PLEX Elite 9000 device. Preretinal vasculature (PRV) detected via OCTA imaging was defined as the appearance of an extraretinal vessel in the vitreoretinal interface (VRI) Angio slab, which extended from 10 nm to 300 nm above the internal limiting membrane. The superficial capillary plexus (SCP) enface image was segmented from the internal limiting membrane to the inner plexiform layer, and the deep capillary plexus (DCP) enface image was segmented from the inner plexiform layer to the outer plexiform layer with projection removal.
As previously reported, quantitative analysis of the standard 6 × 6-mm OCTA images in the temporal midperiphery was conducted using ImageJ (National Institutes of Health, Bethesda, MD, USA).15,16 The OCTA images were binarized to assess vessel density (VD) and then skeletonized to measure the total vessel length. The vessel diameter index (VDI), the ratio of vessel area to total vessel length, represented the average vessel caliber. The vessel index (VI), the ratio of VD to VDI, was calculated to refine the accuracy of VD assessments by normalizing differences in vessel caliber.
Based on the pattern of retinal vascular development,17 the distance from the vessel sprouting point of the optic disc to the posterior margin of the retinal vascular–avascular area (AVA) boundary in FEVR was measured (the length of the red line in Supplementary Fig. S1). The ratio of the length of the red line to the diameter of the optic disc (referred to as the Optic-AVA) was evaluated to quantitatively assess the level of retinal vascular development in the coronal section. Two masked ophthalmologists (JZ, LR) independently reviewed all images for qualitative and quantitative analyses as well as statistical analyses of variables. The tiebreaker classification protocol included a masked senior reviewer (XH) and a voting system.
Statistical Analysis
All data analyses were performed using SPSS Statistics 20.0 (IBM Corp., Chicago, IL, USA). The sex difference was addressed using Fisher's exact test. Continuous data are presented as the median ± standard deviation (SD). After normal distribution testing using the Shapiro–Wilk test, continuous parameters were compared using the unpaired t-test. Correlation analyses between vascular parameters and the Optic-AVA were conducted using Pearson's correlation test. Binary logistic regression models were used to evaluate the independent factors associated with PRV and VRMAs; variables in the models included age, AL, and VD/VDI/VI in the SCP and DCP. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were determined, and differences were considered statistically significant at a two-sided P < 0.05.
Results
Overall, 127 eyes of 127 patients with mild FEVR and 31 healthy eyes of 31 participants in the control group were enrolled in the final analysis. Table 1 summarizes the demographic and clinical data. Age, sex, and AL were comparable between the two groups (P > 0.05). The BCVA eyes with FEVR and eyes in the control group were 0.16 ± 0.19 logMAR and 0.00 ± 0.00 logMAR, respectively (P < 0.001).
Morphological Microvascular Findings and Corresponding VRMAs in Temporal Midperiphery
In this study, retinal microvascular features were detected using the en face and B-scan imaging of WF SS-OCTA. Among the 127 FEVR eyes examined, 78 eyes (61.42%) presented with various morphological MVAs in the temporal midperiphery, all of which were combined with VRMAs. The detection rate via ultra-widefield (UWF) FA for these 78 eyes was 65.22%, presenting as mild hyperfluorescent leakage in the late angiographic phase.
The predominant MVA (61/78, 78.21%) was the disordered vascular anastomosis of superior and inferior vascular branches located at the temporal midperipheral region, manifesting as grayish-white V-shaped or spindle-shaped bands on widefield fundus photographs (Figs. 12–3), which we termed temporal midperipheral vascular anastomosis defects (TMPVADs). These disordered anastomotic vascular branches in SCP exhibited aberrant, tortuous, and dilated vessels at the demarcation of the aforementioned bands. Conversely, central areas exhibited sparse vessels or avascularity, and corresponding vascular defects in DCP exhibited large AVAs, occasionally interspersed but with dilated microvasculature. B-scan WF SS-OCTA images disclosed that the VRMAs in areas with AVAs exhibited neuroretina structure deficiencies, with hyperreflective glial-like substitutes (45/61, 73.77%), retinoschisis/retinal cystic changes (30/77, 49.18%), or sudden retinal thinning/atrophy (13/61, 21.31%), either alone or in combination.
Figure 2.
Multimodel imaging of TMPVADs. Ophthalmological images are of a 17-year-old girl with mutation in TSPAN12. The TMPVAD was located in the temporal midperiphery on montage OCTA (A, purple box), presenting as a grayish-white V-shaped band on fundus photography (B, yellow arrowhead), and mild hyperfluorescent leakage in the late phase on FA (C, yellow arrowhead), the peripheral nonperfusion area (C, yellow star) and leaking vascular endings (C, yellow arrow) on FA. The 6 × 6-mm OCTA scan of the purple box revealed AVAs in the SCP (D, yellow arrow) and compensatory capillaries in the DCP (E, green arrowhead), corresponding to retinoschisis (F, G, yellow arrows) and glial-like hyperreflectivity (G, yellow arrowhead). The AVAs in the DCP corresponded to the outer retinoschisis (E–G, green arrows).
Figure 3.
Different types of TMPVADs and corresponding VRMAs. The yellow star, arrowhead, and arrow represent the lesions in the en face and B-scan images. (A) AVAs with aberrant vessels at the demarcation in the SCP, compensatory capillaries in the DCP, and inner retinal thinning. (B) Aberrant capillaries in the SCP, large AVAs in the DCP, and retinal cystic changes. The orange curve represents the boundary of the changes. (C) AVAs in both the SCP and the DCP and the inner and outer retinoschisis (red line). The AVA solely in the DCP corresponded to outer retinoschisis (green line). Vitreoretinal adhesions exhibited flow signals (yellow arrowhead).
Moreover, 16 eyes (20.51%, 16/78) with FEVR presented dragging, aberrant, and expanded vascular branches in the SCP, with capillary agenesis in DCP manifesting as large avascular zones, sometimes with an immature vascular structure without a grid. The corresponding VRMAs exhibited hyperreflective glial-like filling and retinal thickening (Fig. 4).
Figure 4.
Representative OCTA imaging of aberrant and expanded capillaries in the SCP and large AVAs in the DCP. (A) Montage OCTA enface image. (B) The 6 × 6-mm enface angiography image of the purple box in the SCP. (C) Large AVAs with flow signals lacking a grid structure in the DCP. (D–F) B-scan images of the blue line (D), green line (E), and red line (F) showed retinal thickening without flow signal (yellow arrows) and hyperreflective spots in the outer retina (yellow arrowheads).
Furthermore, membranous vitreoretinal adhesions in the temporal midperipheral retina were detected by OCTA in 39 FEVR eyes (30.7%, 39/127), with 92.31% (36/39) showing flow signals in the OCTA B-scans and vascular structure in the OCTA en face VRI segmentation. These vascular structures in the VRI, originating from the aberrant SCP branches and protruding into the vitreous, were defined as PRV (Fig. 5), encompassing the neovascular (NV) network, as well (Fig. 5H). Among these eyes, some primary vascular branches protruded into the vitreous from the midperiphery as PRV and extended peripherally to form an intravitreal NV network (Supplementary Fig. S2). Sparse vessels or large AVAs in the DCP were detected in the corresponding region. Retinoschisis combined with vitreoretinal adhesion was found in 53.33% of eyes with retinoschisis (16/30), all exhibiting PRV on OCTA (Fig. 3C).
Figure 5.
Representative OCTA imaging of PRV. (A–E) PRV originated from the aberrant branches in the SCP (D) and protruded into the vitreous (A, B, yellow arrow), with sparse vessels in the DCP (E). Vascular branches were detected in the VRI (C, yellow arrow). (F–J) Moderately reflective signals were detected in front of the retina (F, yellow arrow), showing flow signals on B-scan angiography (G, yellow arrow). These flow signals presented a scalloped neovascular network structure in the VRI (H, yellow arrow), corresponding to abnormal vessel termination with capillary–capillary loops in the SCP (I, green arrow) and large AVAs in the DCP (J, green star).
Quantitative Microvascular Analysis in Temporal Midperiphery
Table 2 shows the differences in microvascular characteristics in the temporal midperipheral retina between the FEVR and control groups. All enrolled eyes were included in the quantitative analysis. The mean VD values in the SCP in FEVR eyes were significantly lower than those in healthy eyes (P < 0.001), whereas the mean SD VDI values in the SCP were significantly larger in FEVR eyes (P < 0.001). Adjusting for vascular diameter interference, the VI values, calculated as VD/VDI, remained significantly lower in FEVR eyes (P < 0.001). With regard to the DCP, eyes with FEVR presented lower VD (44% lower) and VI (47% lower) values than the healthy eyes (both P < 0.001), although the difference in the mean VDI in the DCP between the two groups was not statistically significant (P = 0.233).
Table 2.
Retinal Vessel Variables in Midperipheral Retina Between FEVR and Control Groups
| Control | FEVR | P | |
|---|---|---|---|
| Eyes/patients, n | 31/31 | 127/127 | — |
| Superficial vessel plexuses, mean ± SD | |||
| VD (%) | 52.80 ± 2.67 | 39.78 ± 6.95 | <0.001 |
| VDI | 7.09 ± 0.75 | 7.93 ± 1.36 | <0.001 |
| VI | 7.52 ± 0.89 | 5.12 ± 1.09 | <0.001 |
| Deep vessel plexuses, mean ± SD | |||
| VD (%) | 47.33 ± 3.07 | 26.76 ± 11.61 | <0.001 |
| VDI | 3.59 ± 0.37 | 3.49 ± 0.46 | 0.233 |
| VI | 13.30 ± 1.39 | 7.57 ± 2.99 | <0.001 |
Values in bold font are statistically significant at P < 0.05 (unpaired t-test).
Correlation Analysis of MVAs With Retinal Vasculature Development Defects
The VD values in the SCP and DCP both had significantly positive correlations with the Optic-AVA (r = 0.612, P < 0.001 vs. r = 0.764, P < 0.001, respectively). Conversely, the VDI in the SCP was negatively correlated with Optic-AVA (r = –0.306, P = 0.001), whereas the VDI in the DCP demonstrated no significant association (r = 0.096, P = 0.285). Subsequent analysis revealed that VI values in both layers were positively correlated with Optic-AVA (r = 0.740, P < 0.001 vs. r = 0.827, P < 0.001) (Fig. 6).
Figure 6.
The correlations of vascular parameters with the Optic-AVA. (A–F) The VD/VDI in the SCP and DCP were all positively correlated with the Optic-AVA (A, C, D, F). The VDI in the SCP had a significantly negative correlation with the Optic-AVA (B), but the VDI in the DCP was not significantly correlated with Optic-AVA (E).
As presented in Table 3, eyes with PRV in the midperiphery detected via OCTA imaging and eyes with neovascularization in the periphery, revealed exclusively via widefield FA imaging, were collectively categorized as the PRV and neovascularization groups, comprised of a total of 56 eyes. In contrast, the no PRV or no neovascularization groups encompassed 71 eyes without these characteristics. Compared with FEVR eyes without PRV or neovascularization, the FEVR eyes with PRV/neovascularization presented significantly lower VD and VI values in the SCP and DCP (all P < 0.001). The VDI values in the SCP were significantly higher in the eyes with FEVR with PRV (P < 0.001), but the VDI values in the DCP were not significantly different between subgroups (P = 0.133). The AL variables between the two subgroups were not statistically different (23.84 ± 1.33 vs. 24.21 ± 1.36, P = 0.134). Binary logistic regression further confirmed that decreased VI in the DCP was independently associated with the presence of PRV with FEVR, after adjusting for other factors (aOR = 0.322; P < 0.001).
Table 3.
Association Between Midperipheral Vascular Variables With PRV Among FEVR Patients
| Existence of PRV in FEVR | Analysis* | ||||
|---|---|---|---|---|---|
| FEVR Without PRV/NV | FEVR With PRV/NV | P † | OR (95% CI) | P | |
| Eyes/patients, n | 71/71 | 56/56 | — | — | — |
| Superficial vessel plexuses, mean ± SD | |||||
| VD (%) | 42.56 ± 5.52 | 36.25 ± 7.01 | <0.001 | 0.945 (0.410–2.177) | 0.454 |
| VDI | 7.50 ± 1.09 | 8.47 ± 1.48 | <0.001 | 1.728 (0.996–2.997) | 0.052 |
| VI | 5.75 ± 0.92 | 4.32 ± 0.71 | <0.001 | 0.883 (0.001–951.736) | 0.417 |
| Deep vessel plexuses, mean ± SD | |||||
| VD (%) | 33.93 ± 8.48 | 17.67 ± 8.18 | <0.001 | 3.213 (1.112–9.283) | 0.393 |
| VDI | 3.55 ± 0.38 | 3.42 ± 0.55 | 0.133 | 0.000 (0.000–0.301) | 0.809 |
| VI | 9.56 ± 2.13 | 5.04 ± 1.77 | <0.001 | 0.322 (0.209–0.496) | <0.001 |
Values in bold font are statistically significant at P < 0.05. NV, neovascular network in the periphery detected via widefield FA.
Binary logistic regression, adjusted by age, axial length, and variables presented above (VD, VDI and VI in superficial vessel plexuses and deep vessel plexuses).
FEVR without PRV/NV versus FEVR with PRV/NV (unpaired t-test).
Correlation Analysis of MVAs With VRMAs
As showed in Table 4, FEVR eyes with VRMAs (78 eyes) exhibited significantly lower VD and VI in the SCP and DCP compared to those without VRMAs (49 eyes) (all P < 0.001). VDI values in the SCP were significantly higher in FEVR with PRV (P < 0.001), whereas the VDI values in the DCP were not statistically different (P = 0.715). The AL variables between the two subgroups were not statistically different (23.98 ± 1.38 vs. 24.15 ± 1.32, P = 0.529). The decreased VI values in the SCP and DCP were further confirmed to be independently correlated with VRMAs presence using binary logistic analysis (SCP aOR = 0.282, P = 0.010; DC aOR = 0.562, P = 0.002).
Table 4.
Association Between Midperipheral Vascular Variables With Midperipheral VRMAs Among FEVR Patients
| Existence of Peripheral VRMAs of FEVR | Analysis* | ||||
|---|---|---|---|---|---|
| FEVR Without VRMAs | FEVR With VRMAs | P † | OR (95% CI) | P | |
| Eyes/patients, n | 49/49 | 78/78 | — | — | — |
| Superficial vessel plexuses, mean ± SD | |||||
| VD (%) | 44.12 ± 4.57 | 37.05 ± 6.82 | <0.001 | 0.794 (0.395–1.599) | 0.873 |
| VDI | 7.39 ± 0.96 | 8.27 ± 1.46 | <0.001 | 2.654 (0.072–97.503) | 0.948 |
| VI | 6.04 ± 0.78 | 4.54 ± 0.84 | <0.001 | 0.282(0.107–0.743) | 0.010 |
| Deep vessel plexuses, mean ± SD | |||||
| VD (%) | 35.78 ± 7.52 | 21.09 ± 10.04 | <0.001 | 1.960 (0.868–4.429) | 0.224 |
| VDI | 3.51 ± 0.33 | 3.48 ± 0.53 | 0.715 | 0.009 (0.000–6.426) | 0.378 |
| VI | 10.19 ± 1.82 | 5.91 ± 2.34 | <0.001 | 0.562 (0.392–0.805) | 0.002 |
Values in bold font are statistically significant at P < 0.05.
Binary logistic regression, adjusted by age, axial length, and variables presented above (VD, VDI and VI in superficial vessel plexuses and deep vessel plexuses).
FEVR without PRV/NV versus FEVR with PRV/NV (unpaired t-test).
Discussion
Retinal microvascular features in the temporal midperiphery in FEVR have seldom been the focus of previous studies. However, VRMAs in the temporal midperiphery were recently revealed in FEVR using UWF-OCT and UWF-OCTA,14,18 although detailed microvascular defects in the corresponding area remain largely under-investigated. Overall, this study was designed to disclose the subtle microvascular defects in the temporal midperipheral retina using WF SS-OCTA and to analyze their correlations with the development anomalies of retinal vasculature and vitreoretinal microstructure in the early stages. To the best of our knowledge, this study enrolled the largest population to date of patients with early-stage FEVR undergoing widefield OCTA examination.
This study systematically disclosed several under-identified microvascular defects in the temporal midperipheral retina of FEVR patients, particularly in the DCP. TMPVAD, a novel and highly prevalent MVA, characterized by disordered vascular anastomosis of the superior and inferior temporal vascular branches in the midperiphery, was revealed (Figs. 12–3). These disordered anastomotic vessels exhibited aberrant, tortuous, and thickened vessels at the band demarcation, with sparse vessels or even AVAs in the center of these bands in the SCP, and large AVAs in the DCP. The high prevalence of disordered anastomosis indicates that it could be a discernible defect in early-stage FEVR.
TMPVAD was predominantly located in the temporal aspect of the macula, exhibiting grayish-white V-shaped or spindle-shaped bands on en face images, similar to en face imaging findings in previous studies.14,18 These findings may possibly be explained by the pattern of retinal vascular development. At around 15 weeks of gestation, the primary vasculature expands centrifugally from the optic disc following the guidance of retinal ganglion cells and astrocytes.19 The vessel growth in the temporal retina follows a physiologically V-shaped pattern, presenting as a developmental delay of the anastomotic vascular network bridging the superior and inferior temporal vasculature before 30 weeks of gestation.19,20 Therefore, the temporal vascular anastomosis might be considered as the termination of vascular transit networks, which are pathologically hindered in FEVR.
Our findings indicate that midperipheral microvascular inhibition in the SCP in FEVR eyes results in a reduced and thickened appearance, as quantitatively proven by reduced VD (25% lower) and VI (32% lower) in the SCP, despite increased VDI. Conversely, immature clusters of vessels without a grid structure and even large AVAs were apparent in the DCP, and both VD and VI showed more obvious reductions (45% and 47% lower), suggesting possibly more severe developmental failure. Previous studies have found similar differences in vascular growth defects in the SCP and DCP in mice with deleted FEVR genes.17,21 The DCP, emerging from veins in the SCP, is known to represent the cross-sectional endings of the retinal vasculature.17 Together, the aforementioned findings suggest that the developmental disorder of temporal midperipheral vascular endings in the cross-section may be more severe than their superior vessels. However, the underlying molecular mechanisms remain unclear.
Further correlation analysis between vascular variables and the Optic-AVA, which evaluates the developing level of retinal vascular networks on the coronal section, were conducted. We found positive correlations of VD and VI in the DCP with the Optic-AVA, suggesting that vertical and horizontal growth failures of retinal vascular may be congruent. Moreover, in the SCP, reduced VD and VI values and a greater VDI were significantly correlated with Optic-AVA reduction, suggesting that sparser and thicker superficial vessels may indicate more severe developmental impairments.
Another novel finding was that a high presence of PRV (92%) was detected in membrane vitreoretinal adhesions, which were reported as classical vitreoretinal microstructure changes on OCT imaging and could be located in the posterior, midperipheral, or far peripheral regions6,14,18,22; however, the components of these membrane-like structures have been unknown. Our findings indicate that vitreoretinal adhesions in the temporal midperiphery may be abnormal vascular structures emerging from aberrant superficial vessels that protrude into the vitreous. Interestingly, VD and VI in the SCP and DCP were decreased in eyes with FEVR with PRV, whereas the VDI in the SCP was greater. Furthermore, after adjustment, a decreased VI in the DCP was independently associated with the presence of PRV. Therefore, these findings indicate that PRV formation in the temporal midperiphery may be associated with insufficient blood supply to the neuroretina, particularly in the deep plexus. Overall, our findings may help to update previous understandings regarding the possible formation of vitreoretinal adhesions.
VRMAs in the temporal midperiphery have been reported in a previous study14,18; however, the pathology of these microstructural abnormalities has yet to be determined. In this study, despite vitreoretinal adhesions, we also revealed various VRMAs, mostly presenting as neuroretina deficiencies, all of which were combined with MVAs. In addition, quantitative analysis revealed that FEVR eyes with VRMAs presented reduced VD and VI in both vascular layers but a greater VDI in the SCP. Furthermore, decreased VI values in the SCP and DCP were factors independently associated with the existence of VRMAs. These findings indicate that VRMA formation in the temporal midperiphery may be closely correlated with retinal microvascular growth failure. Also worthy of discussion is whether retinoschisis in the temporal midperiphery in FEVR is associated with vitreoretinal traction, as 53% of eyes with retinoschisis or cystic retinal changes also had vitreoretinal adhesions; however, most of these adhesions presented as preretinal vessels. Therefore, the traction theory may be debatable and require more studies.
We hypothesized that the pattern of retinal microvascular growth inhibition in the temporal midperiphery may be as follows (Fig. 7): The reduced retinal vascular growth might mainly affect the terminal microvascular networks, including the DCP and center of the anastomotic capillaries of the superior and inferior temporal vascular branches, which could exhibit large AVAs. In contrast, the primary or secondary vascular branches of the SCP could be partially restrained and exhibit vessel thickening and reduction. These vascular defects may also be exacerbated with increased severity of retinal vascular dysplasia. Along with the failure of retinal vascular growth, particularly in the DCP, we observed that abnormal preretinal vessels formed and vitreoretinal microstructures were disrupted.
Figure 7.
The patterns of retinal microvascular growth defects in temporal midperiphery in FEVR. (A) Organized and complete vasculature in the SCP and DCP in healthy eyes. (B) Retarded growth of the DCPs and the center of anastomotic capillaries in FEVR eyes, with PRV protruding into the vitreous.
This study had some limitations. First, the widefield OCTA was automatically montaged using the built-in software, and image artifacts may have been generated due to poor eye fixation. However, unqualified cases were manually excluded, and the values of OCTA we obtained exhibited good intradevice comparability. Second, to minimize bias due to midperipheral retinal detachment and to ensure accurate ocular fixation for widefield OCTA, the stages of FEVR in this study included only stages 1 and 2; thus, the findings in this study may be more representative of early-stage FEVR. In spite of these limitations, we believe that this study, which enrolled the largest cohort of FEVR patients undergoing widefield OCTA, still provides a comprehensive investigation into retinal midperipheral MVAs and their relationships with VRMAs in FEVR.
In conclusion, our research reveals that microvascular growth stunts exist in the temporal midperipheral retina, presenting as reduced and thickened vasculature in the SCP alongside severe capillary loss in the DCP. Moreover, the microvascular loss was closely correlated with the Optic-disc reduction and the presence of PRV and VRMAs. Our findings may provide novel insights into the patterns of midperipheral microvascular growth defects and the interactions between retinal microvasculature and microstructure formation in FEVR, especially in early stages.
Supplementary Material
Acknowledgments
Supported by research grants from the National Natural Science Foundation of China (82070975 and 82201208) and Shanghai Science and Technology Commission Sailing Plan (21YF1405200).
Disclosure: J. Zhang, None; L. Ruan, None; C. Jiang, None; Q. Yang, None; Q. Chang, None; X. Huang, None
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