Abstract
Purpose
To investigate retinal microvascular and choriocapillaris changes across the newly proposed seven-step classification for macular telangiectasia type 2 (MacTel) using swept-source optical coherence tomography angiography (SS-OCTA).
Methods
Cross-sectional, observational study including 111 eyes with MacTel (56 patients) and 120 matched control eyes (60 subjects). Participants underwent comprehensive ophthalmic examinations, including macular 6 × 6-mm SS-OCTA. MacTel eyes were categorized into one of seven grades (0–6) using multimodal imaging. SS-OCTA scans were processed to measure vessel density (VD), vessel skeletonized density (VSD), foveal avascular zone (FAZ) metrics, and choriocapillaris flow deficit percentage (CCFD%). Differences between groups were assessed using Mann–Whitney U, Kruskal–Wallis tests, and generalized mixed-effects models. Cluster analysis assessed the agreement between clinical grades and OCTA-based clusters.
Results
Of the MacTel eyes, 32% were grade 0, 9% grade 1, 18% grade 2, 5% grade 3, 15% grade 4, 13% grade 5, and 8% grade 6. MacTel eyes exhibited significant alterations in VD and VSD, particularly in the central 1-mm circle and temporal/inferior sectors, alongside consistently higher CCFD% across all macular regions. Advanced grades (5–6) showed pronounced differences in VD, VSD, and CCFD% compared to early grades (0–2). Agreement between MacTel grading and OCTA-based clusters was fair to moderate (Adjusted Rand Index = 0.233), with higher concordance for grades 0 and 4 to 6.
Conclusions
SS-OCTA reveals significant retinal vascular and choriocapillaris impairment in MacTel, with pronounced alterations in advanced disease grades. The observed vascular damage, extending beyond the MacTel area, underscores the value of OCTA in identifying disease severity and aiding in its classification.
Keywords: OCTA, MacTel, macular telangiectasia type 2, MacTel Project Classification, vascular metrics
Macular telangiectasia type 2 (MacTel) is a bilateral neurodegenerative condition characterized by secondary vascular changes.1 It typically manifests between the fifth and seventh decades of life, with an estimated prevalence of 0.1% in the United States.1,2 Visual acuity (VA) declines gradually,3,4 with severe bilateral vision loss (<20/200) reported in only 0.7% to 4% of affected individuals.3 Early signs are often localized to the temporal paracentral macula but may extend nasally to form an oval-shaped “MacTel area.”2 Key features include parafoveal graying, superficial crystalline deposits, and, with disease progression, pigment plaques, right-angled venules, and occasionally subretinal neovascularization. Historically, fluorescein angiography has been the diagnostic gold standard, with temporal late-phase hyperfluorescence often preceding the appearance of telangiectasia.2,3
The initial clinical classification system for MacTel, proposed by Gass and Blodi5 in 1993, relied on biomicroscopic and fluorescein angiographic findings. The introduction of spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) has since enhanced our understanding of MacTel's pathogenesis and natural history.2 Building on these advances, the MacTel Project—a global collaboration of scientists and clinicians—recently introduced a revised seven-step classification system (grades 0–6).6 This system, guided by a machine learning–derived algorithm, incorporates imaging features such as hyperreflectivity on SD-OCT, ellipsoid zone defect, pigment, and macular neovascularization (MNV).6
However, this classification does not integrate data from OCT angiography (OCTA), a noninvasive modality capable of providing rapid, depth-resolved assessments of retinal and choroidal circulation.7,8 Prior OCTA studies have identified distinct vascular changes in MacTel, including rarefaction of the superficial capillary plexus (SCP) and deep capillary plexus (DCP), early-stage vessel dilation in the DCP, and vascular invasion into the outer retinal and subretinal spaces in advanced stages.9,10
Despite these findings, quantitative studies remain limited and controversial, often hampered by small sample sizes and inconsistent disease classification across studies.11,12 Additionally, investigations into choriocapillaris impairment in MacTel are particularly scarce, leaving a gap in understanding its role in disease progression.13 This study aims to explore retinal vascular and choriocapillaris alterations in a large cohort of MacTel eyes and matched controls. Additionally, it seeks to validate the recently proposed seven-step classification system through a cluster analysis based on selected swept-source (SS)–OCTA metrics.
Methods
Study Design and Population
This cross-sectional, observational study was conducted at the Retina Service of Massachusetts Eye and Ear (Boston, MA, USA) between January 2019 and September 2023. The research adhered to the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Massachusetts General Brigham (protocol no: 2019P001863). Written informed consent was obtained from all participants before SS-OCTA acquisition.
Participants met the following criteria: (1) clinical diagnosis of MacTel by an experienced retinal specialist, (2) age over 18 years, (3) VA better than 20/200 Snellen, and (4) acquisition of a high-quality 6 × 6-mm macular SS-OCTA scan (signal strength index >7, free of motion or blink artifacts). Exclusion criteria included (1) additional ocular or uncontrolled systemic conditions that could affect the analysis (e.g., diabetic retinopathy, glaucoma, or hypertension), (2) refractive errors exceeding ±6 diopters (spherical equivalent), (3) significant media opacities, (4) prior intraocular inflammation, (5) history of ocular surgery other than cataract extraction or intravitreal anti-VEGF injections, (6) use of retinotoxic medications, and (7) OCTA images with incorrect foveal centration. Controls were obtained from a large, previously published database comprising healthy adults with no known retinal disease, all imaged using the 100-kHz Zeiss PLEX Elite 9000 (Dublin, CA, USA) between December 2018 and January 2022.14 Eyes from this database were selected using propensity score matching for age, gender, and race to closely align with the demographic characteristics of the MacTel group.
Data Collection and Study Protocol
Participants underwent a comprehensive ophthalmic evaluation, including VA measurement, slit-lamp biomicroscopy, ultra-widefield (Optos California; Optos plc., Dunfermline, UK) or posterior pole (TRC-50DX; Topcon Corp., Tokyo, Japan) fundus photography, macular SD-OCT scan, and FAF (λ = 488 nm; Spectralis HRA+OCT2; Heidelberg Engineering GmbH, Heidelberg, Germany), as well as a 6 × 6-mm SS-OCTA scan of the macula (PLEX Elite 9000; Carl Zeiss Meditec, Dublin, CA). Electronic medical records were reviewed for relevant data, including age, sex, race, ethnicity, lens status, systemic comorbidities, previous ophthalmic procedures, and MNV presence.
Imaging Analysis
Imaging data were analyzed by two independent graders (IS and FR), with discrepancies resolved by a senior ophthalmologist (JBM). Each MacTel eye was classified into one of the seven grades of the MacTel Project's system based on multimodal imaging.6 This grading system ranges from grade 0 (no distinguishing OCT features) to 6 (MNV), with intermediate grades defined by specific OCT and color fundus photograph features. In brief, following the MacTel Project's proposed classification, SD-OCT and color fundus photo (CFP) studies were evaluated for the presence of ellipsoid zone breaks, pigment, subretinal hyperreflectivity, and neovascularization. The presence and location of these features correspond to increased disease severity, on a scale ranging from 0 to 6.6 For each eye, color fundus photography was reviewed to confirm the OCT features. The staging criteria are detailed in Table 1.
Table 1.
Newly Proposed Classification of MacTel by the MacTel Project and Related OCTA Findings
| Grade | Description | OCTA Findings |
|---|---|---|
| 0 | No EZ break/pigmentation/HR on OCT | Retinal vascular plexuses; FAZ and choriocapillaris similar to controls and grades 0–2 |
| 1 | Noncentral EZ break; no pigment or HR on OCT | Retinal vascular plexuses; FAZ and choriocapillaris similar to controls and grades 0–2 |
| 2 | Central EZ break; no pigment or HR on OCT | Retinal vascular plexuses; FAZ and choriocapillaris similar to controls and grades 0–2 |
| 3 | Noncentral pigment, any EZ break; no HR on OCT | Altered retinal, FAZ, and choriocapillaris compared to controls and grades 0–2 without reaching significance |
| 4 | HR on OCT, any EZ break; no pigment | Higher VD and VSD at the DCP in the central 1-mm circle compared to grade 0 |
| Altered retinal, FAZ, and choriocapillaris compared to controls and grades 0–2 without reaching significance | ||
| 5 | Central pigment; no exudative neovascularization | Lower VD in the inner ring and temporal sector compared to controls and most lower grades |
| Lower VSD at the SCP in the inner ring and temporal sector compared to controls and most lower grades | ||
| Higher VD and VSD at the DCP in the central 1-mm circle compared to grade 0 | ||
| Lower VSD at the DCP in multiple sectors compared to controls and most lower grades | ||
| Lower FAZ circularity compared to controls | ||
| Higher CCFD% compared to controls and most lower grades | ||
| 6 | Exudative neovascularization, ± central pigment | Lower VD and VSD at the SCP in the inner ring and temporal sector compared to control and most lower grades |
| Higher VD and VSD at the DCP in the central 1-mm circle compared to controls and some lower grades | ||
| Lower VD and VSD at the DCP in multiple sectors compared to controls and some lower grades | ||
| Lower FAZ circularity, length, and area compared to controls and most lower grades | ||
| Higher CCFD% compared to controls and most lower grades |
EZ, ellipsoid zone; HR, hyperreflectivity.
SS-OCTA volume scans (6 × 6 mm) were acquired using the PLEX Elite 9000 (Carl Zeiss Meditec) at a scanning rate of 100,000 A-scans per second with a 1050-nm central wavelength. Images were reviewed using the device software (version 2.1.0.55513) to ensure correct foveal centration, defined as the intersection of the horizontal and vertical navigation lines falling within the foveal avascular zone (FAZ) boundaries, as well as accurate layer segmentation and the absence of artifacts. Manual segmentation was applied when errors occurred in the built-in multiretinal layer segmentation algorithm. For B-scans where the inner plexiform layer (IPL) and outer plexiform layer (OPL) were not clearly visualized, adjacent B-scans were consulted to guide the expected segmentation. Eligible SS-OCTA scans were uploaded to the Advanced Research and Innovation Network (Zeiss portal v5.4–1206) and processed using the macular density algorithm (v.0.7.3.3). This algorithm generates standard vascular metrics, including FAZ (area, circularity, and perimeter), vessel density (VD; ratio of the binarized vessel area divided to the total analyzed area), and vessel skeletonized density (VSD; ratio of skeletonized vessel length to total analyzed area). Metrics were calculated for three slabs: the whole retina (WR; internal limiting membrane to 41 µm above Bruch's membrane), SCP (internal limiting membrane to the bottom of the IPL), and DCP (top of the IPL to the bottom of the OPL).15 Measurements were recorded from multiple regions of interest (ROIs), including the 6-mm circle, outer and inner Early Treatment for Diabetic Retinopathy Study (ETDRS) rings, the 1-mm circle, and four ETDRS quadrants (superior, nasal, inferior, and temporal) (Fig. 1).
Figure 1.
ROIs and OCTA metrics analyzed for the various retinal vascular plexuses and choriocapillaris. The analyzed ROIs included the 6-mm circle (red area), the outer (orange) and inner (yellow) ETDRS rings, the central 1-mm circle (green), and the four ETDRS sectors (blue; superior, nasal, inferior, and temporal). The slabs from the whole retina, superficial capillary plexus, and deep capillary plexus were binarized and skeletonized prior to the measurement of the VD and VSD, respectively. Angiographic 16-µm-thick choriocapillaris slabs were compensated by multiplication with the respective inverted structural en face slabs and subsequently binarized using a local thresholding technique (Phansalkar) with a window radius of 4 pixels.
Choriocapillaris analysis followed the guidelines recommended by Chu et al.16 A customized 16-µm-thick slab, starting 4 µm beneath Bruch's membrane, was used for evaluation. Resulting angiograms and structure en face images were exported as .tiff files and processed in FIJI (ImageJ2 version 2.9.0; National Institutes of Health, Bethesda, MD, USA). To compensate for signal attenuation caused by hyperreflective retinal pigment epithelium (RPE) alterations,17 angiograms were multiplied by the corresponding inverted structural en face images prior to binarization. This correction enhances the accuracy of flow deficit detection by mitigating shadowing artifacts. The resulting images were then binarized using Phansalkar's method (r = 4 pixels).16,18,19 Choriocapillaris flow deficit percentage (CCFD%) was quantified for the same ROIs used for retinal vascular metrics via the “Analyze Particles” tool, after importing the corresponding ROIs from the Advanced Research and Innovation Network portal. Before choriocapillaris (CC) quantification, eyes with pigment underwent additional processing to correct for masking artifacts caused by overlying hyperreflective material. An en face RPE–RPE slab with an offset of 64 to 400 µm was generated to highlight pigment as hyporeflective regions.20 These areas were manually delineated and excluded from the binarized CC slab prior to flow deficit analysis. For MNV cases, an additional angiographic slab (OPL to Bruch's membrane) was imported to delineate the subretinal neovascular complex and exclude it from CCFD% quantification. Figure 2 illustrates the postprocessing workflow for measuring CCFD%, including steps for excluding pigment and MNV.
Figure 2.
Quantification of the CCFD% in eyes affected by MacTel complicated by MNV (A) and pigment material (B). (A) Upper left: The structural OCT scan with superimposed flow signal shows the segmentation of the slab to visualize the macular neovascularization (orange dotted line) and the choriocapillaris slab (yellow dotted lines; 4–20 µm underneath the Bruch's membrane, BrM). Bottom, left to right: The customized 6 × 6-mm choriocapillaris angiographic slab and the associated structural en face slab were compensated by multiplication prior to binarization using Phansalkar's method (window radius = 4). Due to the presence of MNV, an additional angiographic slab between the external border of the outer plexiform layer and the BrM was imported into FIJI, and the neovascular complex was delineated (green line) and excluded from the calculation. Right: The final binarized choriocapillaris slab, excluding the MNV, is obtained for CCFD% calculation. (B) Upper left: The structural OCT with superimposed flow shows the loss of the foveal ellipsoid zone, the segmentation of the choriocapillaris (yellow dotted lines; 4–20 µm underneath BrM), and the segmentation lines of the en face slab (orange dotted lines) for the delineation of parafoveal hyperreflective material compatible with pigment (green line). Bottom, left to right: Angiographic and structural 6 × 6-mm choriocapillaris en face slabs are shown in yellow boxes prior to compensation and binarization. A previously validated RPE–RPE structural slab lying between 64 and 400 µm underneath the BrM was used to exclude pigment accumulation, appearing as dark areas (orange dotted box). Right: The final binarized choriocapillaris slab, excluding pigment, is obtained for CCFD% measurement.
Statistical Analysis
Statistical analyses were performed using RStudio Version 2023.12.0+369. Statistical significance was set at P < 0.05, and all tests were two-sided. Variable distributions were tested using the Shapiro–Wilk test, and descriptive data are presented as mean ± standard deviation (range), median (interquartile range), or frequency (%), accordingly. Intergrader agreement was evaluated using Cohen's κ (95% confidence interval [CI]).
Differences in SS-OCTA metrics between MacTel and control groups, as well as across the seven MacTel grades, were assessed using Mann–Whitney U tests for pairwise comparisons and Kruskal–Wallis tests with Dunn's post hoc correction for unadjusted group comparisons. Generalized linear mixed-effects models, fit by restricted maximum likelihood, were employed to confirm these findings while accounting for clustering of both eyes from the same patient and adjusting for age. Bonferroni correction was applied within the regression models to control for type I errors arising from multiple comparisons.
Cluster analysis was performed to compare the seven-step classification with vascular alterations, using selected SS-OCTA metrics. Given the high collinearity among these metrics, least absolute shrinkage and selection operator (LASSO) regression for logistic models was employed to identify the most significant variables associated with MacTel. LASSO's regularization penalty shrinks less important coefficients toward zero, effectively selecting a statistically meaningful subset of independent variables for robust cluster formation. The selected metrics were standardized to reduce dimensionality, and Ward's method was applied to subdivide eyes into seven clusters. This approach minimizes variance by optimizing the sum of squared differences within clusters, making it particularly suitable for nonnormal data and potential outliers, such as OCTA metrics. Agreement between clinical grades and OCTA-based clusters was assessed using the Adjusted Rand Index (ARI) and visualized via a heatmap of a confusion matrix.
Results
A total of 111 MacTel eyes from 56 patients (64% female) and 120 control eyes from 60 subjects (62% female) were included. Four MacTel eyes were excluded due to incorrect foveal centration and three due to significant motion artifacts. The median age was 61 (56–70) and 57 (43–63) years for the MacTel and control groups, respectively. Control eyes demonstrated better best-corrected visual acuity than MacTel eyes (84 [82–85] vs. 74 [66–83] ETDRS letters). Complete demographic and clinical characteristics are reported in Table 2.
Table 2.
Demographic and Clinical Features of MacTel and Control Groups
| MacTel Grades | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Controls | MacTel (All) | 0 | 1 | 2 | 3 | 4 | 5 | 6 | |
| Subjects (eyes), n | 60 (120) | 56 (111) | 24 (36) | 9 (10) | 19 (20) | 5 (5) | 16 (17) | 10 (14) | 7 (9) |
| Age, y | 57 (43–63) | 61 (56–70) | 61 (55–66) | 60 (58–72) | 58 (55–68) | 77 (56–78) | 63 (56–71) | 68 (56–75) | 60 (58–70) |
| Sex | |||||||||
| Males | 23 (38) | 20 (36) | 13 (36) | 3 (30) | 8 (40) | 1 (20) | 5 (29) | 3 (21) | 7 (78) |
| Females | 37 (62) | 36 (64) | 23 (64) | 7 (70) | 12 (60) | 4 (80) | 12 (71) | 11 (79) | 2 (22) |
| Race/ethnicity | |||||||||
| White non-Hispanic | 42 (70) | 46 (82) | 25 (69) | 9 (90) | 17 (85) | 5 (100) | 12 (71) | 14 (100) | 9 (100) |
| Other | 18 (30) | 10 (18) | 11 (31) | 1 (10) | 3 (15) | 0 (0) | 5 (29) | 0 (0) | 0 (0) |
| VA, ETDRS letters | 84 (82–85) | 74 (66–83) | 83 (75–84) | 76 (70–83) | 76 (68–83) | 81 (75–82) | 69 (59–73) | 68 (60–69) | 63 (55–69) |
| (Snellen equivalent) | (20/20) | (20/32) | (20/20–) | (20/32+) | (20/30+) | (20/25+) | (20/40–) | (20/40–) | (20/50–) |
Values are presented as median (interquartile range) or number (%) unless otherwise indicated.
+/− Indicate letters gained (+) or letters missed(−) relative to the Snellen line.
Based on multimodal imaging, 36 MacTel eyes (32.3%) were classified as grade 0, 10 (9.0%) as grade 1, 20 (18.0%) as grade 2, 5 (4.5%) as grade 3, 17 (15.3%) as grade 4, 14 (12.6%) as grade 5, and 9 (8.1%) as grade 6 (Fig. 3). Intergrader agreement for the novel MacTel Project classification was substantial, with a Cohen's κ of 0.74 (95% CI, 0.66–0.83). Manual segmentation of retinal capillary plexuses was required for two grade 0 eyes (5.6%), one grade 1 eye (10.0%), three grade 2 eyes (15.0%), two grade 3 eyes (40.0%), three grade 4 eyes (17.6%), five grade 5 eyes (37.6%), and four grade 6 eyes (44.4%). Supplementary Figure S1 illustrates the segmentation across MacTel grades.
Figure 3.
Multimodal retinal imaging and OCTA findings in the different grades of MacTel. Multimodal imaging findings and OCTA vascular plexuses across the various MacTel grades are outlined by continuous and dotted white lines, respectively. No or minimal structural OCT and OCTA alterations can be observed in grade 0. With the appearance of ellipsoid zone discontinuity (grades 1–2), mild vascular alterations appear, especially in the parafovea and DCP. In more advanced disease (grades 3–5), vascular alterations become more pronounced, with FAZ distortion and telangiectasias becoming prominent. Lastly, signs of subretinal neovascularization can be seen in grade 6.
OCTA Differences Between MacTel and Control Eyes
Significant differences were observed in several macular OCTA metrics between the MacTel and control groups. In the SCP, MacTel eyes had lower VD and VSD in the inferior sector (P < 0.05) but higher VD in the central 1-mm circle (P = 0.03). In the DCP, MacTel eyes exhibited reduced VD and VSD in the inferior and temporal ETDRS sectors (all P < 0.05) but increased VD and VSD in the central 1 mm compared to controls (both P < 0.001). FAZ analysis revealed reduced circularity and area in MacTel eyes compared to controls (P = 0.01 and P = 0.04, respectively). Additionally, CCFD% was significantly higher in MacTel eyes across all analyzed regions (all P < 0.05), except for the inferior sector (P = 0.08). Multivariable linear regression models confirmed most of these findings (Table 3).
Table 3.
Comparison of OCTA Metrics in MacTel and Control Groups
| Whole Retina | SCP | DCP | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VD | MacTel | Controls | U (P Value) | β* (P Value) | MacTel | Controls | U (P Value) | β* (P Value) | MacTel | Controls | U (P Value) | β (P Value) |
| 6 mm, % | 44.7 (41.5–47.9) | 45.3 (42.7–47.9) | −2.08 (0.02) | −1.88 (0.06) | 42.3 (39.8–44.1) | 42.4 (40.8–44.5) | −1.13 (0.13) | −1.29 (0.20) | 23.3 (15.6–28.4) | 24.4 (17.4–29.5) | −0.93 (0.17) | −0.63 (0.53) |
| Outer ring, % | 45.1 (41.4–48.8) | 46.2 (43.7–48.7) | −3.11 (0.0009) | −2.71 (0.007) | 42.6 (40.5–44.6) | 43.6 (41.3–45.3) | −1.96 (0.02) | −2.07 (0.04) | 24.3 (15.6–28.9) | 25.0 (17.3–30.3) | −1.14 (0.13) | −1.07 (0.29) |
| Inner ring, % | 45.6 (41.4–49.8) | 45.4 (42.1–48.7) | −0.33 (0.37) | −0.78 (0.44) | 42.0 (36.0–44.4) | 42.1 (39.3–44.3) | −1.24 (0.11) | −1.53 (0.13) | 22.6 (17.8–30.6) | 25.5 (18.9–30.9) | −1.09 (0.14) | −0.63 (0.53) |
| 1 mm, % | 27.3 (17.9–36.7) | 24.4 (17.6–31.2) | 3.05 (0.001) | 2.08 (0.04) | 25.7 (19.5–32.1) | 23.4 (20.1–27.8) | 1.86 (0.03) | 1.39 (0.16) | 4.9 (1.0–10.0) | 1.1 (0.1–3.9) | 5.04 (<0.001) | 4.23 (<0.001) |
| Superior sector, % | 45.4 (41.5–49.3) | 46.1 (42.1–50.1) | −0.70 (0.24) | −0.39 (0.69) | 43.4 (40.5–44.6) | 43.0 (40.4–45.3) | 0.16 (0.44) | −0.16 (0.88) | 24.3 (16.5–30.3) | 24.4 (17.1–30.8) | −0.17 (0.43) | −0.23 (0.82) |
| Inferior sector, % | 45.2 (41.1–49.3) | 46.5 (43.6–49.4) | −3.40 (0.0003) | −2.92 (0.004) | 42.6 (40.4–44.8) | 43.4 (40.4–45.3) | −1.89 (0.03) | −2.12 (0.04) | 23.1 (16.2–30.5) | 27.8 (19.5–32.6) | −1.95 (0.03) | –1.65 (0.10) |
| Temporal sector, % | 45.2 (40.1–50.3) | 44.5 (40.4–48.6) | 0.02 (0.49) | −0.63 (0.53) | 40.2 (35.4–42.9) | 40.2 (37.1–42.7) | −0.21 (0.41) | −0.47 (0.64) | 22.3 (17.6–28.9) | 23.5 (19.6–29.4) | −1.95 (0.03) | −2.21 (0.03) |
| Nasal sector, % | 46.4 (43.0–49.8) | 47.2 (44.4–50.0) | −1.53 (0.06) | −1.45 (0.15) | 44.6 (35.4–42.9) | 44.8 (42.8–46.7) | –0.56 (0.29) | −0.72 (0.47) | 25.2 (19.1–32.4) | 26.9 (19.7–32.1) | −0.62 (0.27) | −0.77 (0.44) |
| Whole Retina | SCP | DCP | ||||||||||
| VSD | MacTel | Controls | U (P Value) | β* (P Value) | MacTel | Controls | U (P Value) | β* (P Value) | MacTel | Controls | U (P Value) | β (P Value) |
| 6 mm, mm | 20.1 (18.6–21.6) | 20.6 (19.4–21.8) | −3.30 (0.0005) | −2.87 (0.004) | 18.9 (17.9–19.9) | 19.2 (18.6–20.1) | −2.47 (0.01) | −2.29 (0.02) | 11.6 (8.0–13.8) | 12.2 (8.9–14.6) | −1.21 (0.11) | −0.86 (0.39) |
| Outer ring, mm | 20.3 (18.6–22.0) | 20.8 (19.7–21.9) | −3.64 (0.0001) | −3.22 (0.001) | 19.1 (18.1–20.0) | 19.5 (18.8–20.4) | −2.51 (0.01) | −2.27 (0.02) | 12.2 (8.6–15.2) | 12.4 (8.8–14.9) | −0.95 (0.17) | −0.87 (0.39) |
| Inner ring, mm | 20.6 (18.7–22.5) | 21.1 (19.6–22.6) | −2.92 (0.002) | −2.52 (0.01) | 19.1 (17.4–20.5) | 19.6 (18.6–20.7) | −2.15 (0.02) | −2.10 (0.04) | 12.0 (8.6–15.2) | 12.6 (9.5–15.3) | −0.65 (0.26) | −0.59 (0.56) |
| 1 mm | 12.8 (8.7−16.9) | 12.0 (8.7−15.3) | 1.93 (0.03) | 1.11 (0.27) | 11.8 (9.5−15.3) | 11.6 (9.9−13.8) | 0.93 (0.18) | 0.64 (0.52) | 2.2 (0.4−4.7) | 0.7 (0−2.1) | 5.06 (<0.001) | 4.09 (<0.001) |
| Superior sector, mm | 20.5 (18.8−22.2) | 20.9 (1.0−22.8) | −2.12 (0.02) | −1.26 (0.21) | 19.5 (17.7–20.4) | 19.7 (18.5–20.5) | −1.16 (0.12) | −0.87 (0.38) | 12.2 (10.1–13.2) | 12.0 (8.6–15.2) | 0.79 (0.21) | 1.93 (0.05) |
| Inferior sector, mm | 20.4 (18.5–22.3) | 21.1 (19.8–22.4) | −3.86 (0.0001) | −3.54 (0.02) | 19.5 (17.8–20.4) | 19.9 (18.9–20.7) | −2.49 (0.01) | −2.59 (0.01) | 11.8 (10.0–13.2) | 13.8 (9.5–16.1) | −3.67 (<0.001) | −10.61 (<0.001) |
| Temporal sector, mm | 20.3 (18.1–22.5) | 20.6 (18.9–22.3) | −2.23 (0.01) | −2.36 (0.02) | 18.8 (16.4–19.9) | 18.7 (17.3–19.8) | −0.84 (0.20) | −1.28 (0.20) | 9.86 (7.5–11.7) | 11.8 (8.7–14.4) | −4.28 (<0.001) | −11.68 (<0.001) |
| Nasal sector, mm | 21.2 (19.7–22.7) | 21.8 (20.5–23.1) | −3.25 (0.0006) | −2.76 (0.006) | 20.2 (19.0–21.3) | 20.8 (19.9–21.5) | −2.34 (0.01) | −2.06 (0.04) | 12.9 (10.7–14.2) | 13.3 (9.9–15.6) | −1.42 (0.07) | −12.84 (<0.001) |
| Whole Retina | ||||||||||||
| FAZ | MacTel | Controls | U (P Value) | β (P Value) | ||||||||
| Length | 1.86 (1.48–2.33) | 2.05 (1.71–2.38) | −1.64 (0.05) | −1.04 (0.30) | ||||||||
| Circularity | 0.71 (0.60–0.77) | 0.73 (0.68–0.79) | −2.25 (0.01) | −2.79 (0.01) | ||||||||
| Area | 0.20 (0.14–0.32) | 0.25 (0.17–0.33) | −1.75 (0.04) | −0.73 (0.47) | ||||||||
| Choriocapillaris | ||||||||||||
| CCFD% | MacTel | Controls | U (P Value) | β (P Value) | ||||||||
| 6 mm, % | 16.9 (14.8–19.3) | 15.5 (14.5–17.2) | 3.59 (<0.001) | 3.04 (<0.01) | ||||||||
| Outer ring, % | 16.7 (14.3–19.0) | 15.6 (14.5–17.1) | 3.04 (0.001) | 2.71 (0.01) | ||||||||
| Inner ring, % | 17.3 (15.1–19.8) | 15.3 (14.0–17.1) | 4.54 (<0.001) | 2.59 (0.01) | ||||||||
| 1 mm, % | 17.7 (15.2–20.0) | 17.0 (14.5–18.2) | 2.74 (<0.01) | 2.63 (0.01) | ||||||||
| Superior sector, % | 15.8 (13.5–18.4) | 15.1 (13.9–16.6) | 2.18 (0.01) | 2.02 (0.04) | ||||||||
| Inferior sector, % | 15.9 (13.1–18.5) | 15.2 (14.2–16.9) | 1.40 (0.08) | 1.48 (0.14) | ||||||||
| Temporal sector, % | 15.9 (13.2–18.8) | 15.7 (13.9–17.1) | 1.72 (0.03) | 1.97 (0.04) | ||||||||
| Nasal sector, % | 17.2 (14.3–19.5) | 16.1 (14.6–17.7) | 2.00 (0.02) | 1.90 (0.06) | ||||||||
β* represents adjusted beta values.
U indicates Mann–Whitney's U test, and β represents the beta-coefficient.
The bold and italic values represent statistically significant results.
OCTA Features Within MacTel Grades
Significant differences in OCTA metrics were observed between control eyes and various MacTel grades, particularly 5 and 6. In the SCP, VD and VSD were significantly reduced in the inner ring of grades 5 and 6 compared to controls and MacTel eyes classified as grade 0 through 4 (all P < 0.05). Conversely, VD and VSD in the central 1 mm were increased in grade 5 to 6 eyes relative to controls and grade 0 MacTel eyes (all P < 0.05).
In the DCP, grade 5 eyes demonstrated reduced VD in the inner ring compared to controls and lower disease grades (0–2; all P < 0.05). Similarly, VD and VSD were reduced in multiple ETDRS sectors in grade 5 and 6 eyes compared to controls and lower grades (all P < 0.05). FAZ length and area were significantly reduced in grade 6 eyes relative to controls and grade 0 eyes (all P < 0.01), whereas FAZ circularity was also reduced compared to grades 1 through 4 (all P < 0.05).
CCFD% progressively increased across the MacTel grades, with grades 4 to 6 showing significantly greater CCFD% compared to controls and grade 0 eyes in all analyzed sectors (all P < 0.05). Notably, grade 5 eyes exhibited higher CCFD% compared to grades 1 and 2 in the temporal sector (P < 0.05).
Multivariable linear regression models with contrast assessments confirmed the majority of these associations. Detailed differences among grades, including WR analysis and full ETDRS sector data, are reported in Supplementary Tables S1 to S8.
Cluster Definition and Analysis
OCTA metrics were analyzed using LASSO logistic regression with MacTel diagnosis as the outcome variable. The following metrics were selected: VD of SCP in the inner ring, VSD of SCP in 6 mm, VD of DCP in the inner ring, VSD of DCP in the inner ring and temporal sector, FAZ circularity, and CCFD% in the inner ring.
After dimensionality reduction, seven clusters were generated based on these selected metrics and compared to the MacTel grading system. The ARI for the two cluster assignments was 0.233, indicating a fair to moderate agreement. Notably, higher agreement was observed for grade 0 and advanced grades (4–6), as shown in Figure 4.
Figure 4.
Confusion matrix showing the level of agreement between the seven grades of the recent MacTel Project classification and the seven clusters generated based on selected OCTA metrics. An overall fair to moderate agreement can be observed (ARI = 0.233), especially for correlations between grade cluster 0 and grade clusters 4 to 6.
Discussion
In this study, we evaluated retinal vascular and choriocapillaris alterations in MacTel using SS-OCTA, comparing affected eyes to matched controls. Significant vascular changes were observed across all layers, with pronounced alterations in the inner ring and temporal ETDRS sectors. Analysis of OCTA vascular metrics across the seven grades defined by the MacTel Project Classification revealed substantial differences in advanced grades (5–6) compared to controls and grade 0 eyes, which lacked structural OCT alterations.
Although MacTel is primarily considered a neurodegenerative condition, distinctive juxtafoveal microvascular alterations—particularly in the DCP—may precede visible photoreceptor loss and contribute to disease progression.2,12 OCTA provides unique depth-resolved insights into these vascular changes, surpassing fluorescein angiography in elucidating MacTel pathophysiology and identifying potential new biomarkers.7,8 Earlier studies by Spaide et al.9,21 and Zeimer et al.10 described qualitative vascular changes, including dilations and telangiectasias in the DCP, as well as rarefaction of the inner retinal vascular plexuses.
Quantitative OCTA studies on MacTel remain limited and have yielded controversial results.11,22–25 For instance, Toto et al.11 reported significant reductions in foveal VD at the SCP and DCP, as well as in parafoveal VD at the SCP, compared to controls. However, subsequent research has not consistently confirmed these results, likely due to heterogeneity within the MacTel spectrum and differences in disease staging across cohorts.13,23 To address this gap, our study utilized the largest known cohort of MacTel eyes examined with SS-OCTA, comparing them with propensity score–matched controls from a normative database.14
Our findings show that MacTel eyes exhibit higher VD and VSD within the central 1 mm of the whole retina, SCP, and DCP compared to controls, diverging from earlier studies.11,22,23 This discrepancy may be attributed to the presence of juxtafoveal telangiectasias and a smaller FAZ in our cohort. Outside the central 1 mm, however, our results indicate widespread vessel rarefaction in the parafovea, reflected by significantly decreased VSD in all other macular ROIs.13,24 Individual analysis of the SCP and DCP further revealed decreased vascularization in multiple sectors beyond the central fovea, including the inner ETDRS ring and the temporal and inferior sectors. Regarding the FAZ, our regression analysis found a significant reduction in circularity relative to controls, likely representing early-stage juxtafoveal alterations. Collectively, these findings demonstrate that vascular damage in MacTel extends beyond the classic “MacTel area,” involving peripheral macular areas that could potentially affect the disease course.
The advent of swept-source technology has significantly enhanced the assessment of choriocapillaris, particularly through measurements like CCFD%,16 offering valuable insights into its role in MacTel pathogenesis. Tzaridis et al.13 reported a marked increase in choriocapillaris flow voids from the earliest disease stages, particularly in the central parafovea and around MNV. This aligns with our findings of increased CCFD% across most analyzed ETDRS regions. However, the significance of choriocapillaris changes across different MacTel stages was not demonstrated in previous studies, possibly due to smaller sample sizes and methodological constraints, such as the use of thicker slabs (30 µm) and larger binarization radii (50 pixels).13
By performing a subanalysis across the seven grades of the MacTel Project, our study provides new insights into OCTA patterns within this classification system (summarized in Table 1).6 We found that advanced disease grades (4–6) were associated with increased foveal VD and VSD in the DCP, corresponding to the presence of outer retinal hyperreflectivity on OCT, central pigment, and MNV. Conversely, significant vascular rarefaction was observed in the inner ETDRS ring and temporal sector in grades 5 to 6, with less pronounced changes in the DCP, potentially due to concomitant vessel telangiectasias. Interestingly, early stages of MacTel did not show significant retinal vascular differences compared to controls, suggesting that vascular changes occur later in the disease course. Advanced grades demonstrated increased vascular metrics in the central 1-mm circle but decreased metrics in the outer ETDRS regions when assessing the WR. Notably, no differences were observed among MacTel grades when analyzing the whole retinal vasculature in the four ETDRS sectors, indicating that individual capillary plexus analysis may be more sensitive for detecting vascular changes. Yet, we cannot exclude that a more complex interplay governs the relationships between MacTel grades and whole-retinal alterations, underscoring the need for improved three-dimensional OCTA metrics.
The detection of more evident choriocapillaris perfusion deficits in later grades (4–6), compared to controls and early grades, supports the progressive nature of these alterations. This corroborates previous findings, suggesting that choroidal hypoperfusion may drive subretinal neovascularization and retinal-choroidal anastomosis in MacTel.13,26
In an effort to validate the new classification system from a vascular standpoint, we performed a cluster analysis using selected OCTA metrics. Our approach revealed fair to moderate agreement between the seven MacTel grades and clusters generated using Ward's method, with higher concordance for grades and clusters 0, 4, 5, and 6. These findings highlight the absence of vascular changes in eyes without structural changes (grade 0) and suggest a strong link between vascular changes and clinical biomarkers, such as outer retinal hyperreflectivity on OCT, central pigment, and MNV. The lower agreement observed among intermediate grades (1–3) may be partially attributed to the smaller sample sizes. This limitation warrants further investigation, as longitudinal studies could better elucidate how vascular changes relate to disease progression. Additionally, it is plausible that other OCTA biomarkers may correlate more strongly with the early MacTel stages, as suggested by Micevych et al.27
This study has certain limitations. Although our cohort is the largest to date utilizing SS-OCTA in MacTel, the sample size was skewed, with limited representation for some grades. This imbalance may have influenced the results and reduced the power to detect small differences among intermediate grades. Moreover, our findings lack correlation with fluorescein angiography and external validation, limiting their generalizability. Segmentation and quantification of the retinal vascular plexuses and choriocapillaris may have been affected by factors such as vascular invasion in the outer retinal space and masking from overlying hyperreflective material (e.g., pigment). To mitigate these issues, we manually corrected segmentation errors and used optimized vascular density algorithms alongside swept-source technology tailored for choriocapillaris imaging, reducing the likelihood of artifacts.28 The Macular Density algorithm (v0.7.3.3), although a beta version, has demonstrated moderate to good repeatability since its early iterations29 and excellent sensitivity in distinguishing eyes with retinal vascular disorders from healthy controls.30 Lastly, reliance on the WR slab to address segmentation challenges may have contributed to the loss of statistical significance in some regions, such as the temporal quadrant and inner ETDRS ring, likely due to the two-dimensional compression of multiple retinal plexuses. These results highlight the need for reliable and validated OCTA metrics in MacTel, with particular attention to the three-dimensional architecture of retinal vascular plexuses.
Conclusions
This study highlights the intricate interplay between neurodegeneration and vascular alterations in MacTel, as assessed by SS-OCTA. Compared to matched controls, MacTel eyes demonstrate increased vascularization around the FAZ, pronounced vessel rarefaction in the inner ring and temporal sector, and significant impairment of the macular choriocapillaris. Substantial OCTA metric changes are evident in advanced disease grades, while grade 0 eyes show no significant differences from controls, underscoring the progressive nature of vascular alterations in MacTel. These findings enhance our understanding of MacTel pathogenesis and support the clinical utility of OCTA across various disease stages, especially given the current lack of established functional and structural endpoints. This study lays the groundwork for future longitudinal research to explore the prognostic value of OCTA in predicting complications, such as subretinal neovascularization.
Supplementary Material
Acknowledgments
Disclosure: I. Stettler, None; F. Romano, None; X. Ding, None; I. Garg, None; S. Hoyek, None; K.M. Overbey, None; C. Bennett, None; F. Vingopoulos, None; M. Finn, None; M. Garcia, None; J. Rodriguez, None; G. Baldwin, None; I. Ploumi, None; I. Laìns, None; N.A. Patel, Regeneron (C), Dutch Ophthalmic (C), Genentech (C), EyePoint Pharmaceuticals (C), Alcon Vision (C); D.M. Wu, Massachusetts Eye and Ear (P); L.A. Kim, Ingenia Therapeutics (C), CureVac AG (C), Pykus Therapeutics (C), National Eye Institute (F), Department of Defense (F); D. Husain, Allergan (C), Genentech (C), Omeicos Therapeutics (C), National Eye Institute (F), Lions VisionGift (F), Commonwealth Grant (F), Lions International (F), Macula Society (F); D.G. Vavvas, Drusolv (C), Massachusetts Eye and Ear (P), Sumitomo Pharma (C), Inhibikase (C), Twenty Twenty (C), Olix Phrma (C), Valitor (C); J.W. Miller, Genentech/Roche (C), Sunovion (C), KalVista Pharmaceuticals (C), ONL Therapeutics (C), Heidelberg Engineering (F), Lowy Medical Research Institute (F), Massachusetts Eye and Ear (P); J.B. Miller, Alcon (C), Allergan (C), Carl Zeiss (C), Sunovion (C), Topcon (C), Genentech (C)
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