Relation of interdigitation zone changes and right-angle vessels in Macular Telangiectasia Type-2 (MacTel)

To study the relation between interdigitation zone (IDZ) and right-angle vessel (RAV) in Macular Telangiectasia Type-2 (MacTel). A total of 43 eyes of 38 patients with presence of definite RAV on colour fundus photograph (Gass and Blodi-only stage-3) were confirmed on multimodal imaging. The relation of IDZ changes and associated ellipsoid zone (EZ) alterations on spectral-domain optical coherence tomography (OCT) with RAV were studied at baseline and these OCT changes were followed up in 15 eyes over a mean of 3.86 years. A total of 58 RAVs were found in the 43 eyes and 53/58 (91.3%) RAVs were associated with IDZ alterations in 39 eyes. On follow-up, IDZ attenuation progressed to IDZ loss and subsequent EZ attenuation and loss. A pre-existing IDZ loss was associated with subsequent EZ defect (P = 0.002). In 36 eyes that had OCT angiography, eyes with RAV showed deep capillary plexus telangiectasia in all 36 (100%) eyes and 32/36 (89%) eyes showed IDZ changes with or without EZ loss. IDZ attenuation and/or loss are associated with RAV and may serve as predictor of EZ loss in MacTel.


INTRODUCTION
Macular Telangiectasia Type-2 (MacTel) is a bilateral slowly progressive macular condition.It has been staged according to Gass and Blodi system that mainly describes progression of the characteristic telangiectasia and macular changes on colour fundus photographs (CFP) and fundus fluorescein angiography [1].With the availability of multimodal imaging, it is now evident that telangiectasia of deep capillary plexus (DCP) visualized on optical coherence tomography angiography (OCT-A) is an early sign of MacTel [2,3].Indeed, we have shown that these DCP changes occur before any visible neuronal changes [3] which may include subclinical photoreceptor layer dysfunction that are not discernible on optical coherence tomography (OCT).However, clinico-pathological reports suggest that degeneration or loss of Müller and photoreceptor cells precede vascular changes in MacTel [4,5].
The loss of ellipsoid zone (EZ), a marker of loss of preservation of photoreceptors, has been validated as an endpoint in clinical trials in MacTel as it progresses over time and also correlates with visual function [6][7][8].Gaudric et al. showed that outer retina hyper-reflectivity that represent outer retina neovascularization correlate with the topography of EZ loss in MacTel but these vascular changes occurred after EZ loss [9].This may be a further stage of compensatory vascular response which occurs as the disease progresses.
There have been recent reports on the changes in interdigitation zone (IDZ) in MacTel [10].IDZ is the third hyper-reflective outer retinal band on SD-OCT that represents cone outer segment tips (COST) that is in contact with the underlying specialized apical processes of retinal pigment epithelium (RPE) [11,12].Histologic studies in cat eyes have demonstrated that following retinal detachment, outer segment degeneration of rods and cones precedes inner segment degeneration, suggesting that IDZ loss may precede EZ loss [13,14].Studies in some retinal conditions have suggested that IDZ disruption is associated with overlying EZ loss and visual acuity decline [15][16][17].Recently, Ong et al. showed that in 35 study eyes, all 35 eyes with IDZ attenuation and 33 eyes with IDZ loss in MacTel were associated with DCP telangiectasia and the overlap between DCP telangiectasia and IDZ attenuation decreased with increasing MacTel severity.In addition, IDZ loss do progress to EZ loss [10].In the present study, we evaluated the relation of right-angle vessel (RAV) in MacTel with DCP changes and both IDZ and EZ changes over time to further add knowledge to the relation between vascular and neuronal changes in MacTel.RAV, although typically described in stage-3 MacTel, have been observed in earlier stages of MacTel [18].
In this study, we investigated the relation of IDZ changes with RAV and the corresponding OCT-A DCP findings.We also substantiated whether IDZ layer changes serve as a precursor to EZ layer changes.Since the current study focussed only on the earliest changes on OCT and OCT-A associated with RAV, we excluded eyes with MacTel stages-4 and 5 which had advanced OCT changes in the form of RPE migration and subretinal hyper-reflective material.Eyes with coexistent macular conditions (5 eyes), eyes of diabetes patients (6 eyes of 4 patients) and those with incomplete imaging (2 eyes) and poor imaging quality (4 eyes) across any modality as well as image artifact from vessel shadowing on OCT and motion artifacts on OCT-A and where artefacts persisted despite using the projection artifact removal tool were also excluded.A total of 43 eyes of 38 patients were finally recruited for the study.Of the patients analysed, none had record of history of drug intake, solar exposure, radiotherapy to head and neck or total body irradiation, trauma or previous vitreoretinal surgery.Electronic medical records of complete ophthalmologic examination, bestcorrected visual acuity (BCVA), fundus examination, CFP and SD-OCT were performed in all cases.Other multimodal imaging such as confocal blue reflectance (CBR) [20] and OCT-A [21] were evaluated, if available.

Image acquisition and analysis
In all patients, CFP was taken using Carl Zeiss (FF 450 plus IR) fundus camera.CBR images were acquired using the Heidelberg confocal system, followed by SD-OCT [volume scans of 15 mm×10 mm (high-resolution detail-scan mode, 97 scans) Spectralis; Heidelberg Engineering, Heidelberg, Germany], and OCT-A [10°x 10°(3 mm × 3 mm) high resolution mode; lateral resolution of 5.7 µm/pixel (512 A-scans x 512 B-scans), Heidelberg].These images were captured by senior fellows of the retina department in our institute and centred on the posterior pole covering 30-degrees scanning field.
Image analysis.Outer retinal layer microstructural alterations on SD-OCT were defined as follows: Although not a defect, "at-risk" IDZ was defined as photoreceptor areas with a ragged (irregular) appearance that precede an IDZ and EZ defect (Figs.2a-C and 2b-C) [2].The SD-OCT B-scans were carefully analysed in all 97 detail scan sections.Corresponding SD-OCT radial distance measurement of IDZ attenuation, IDZ loss, EZ attenuation and EZ loss was traced manually using the built-in overlay "caliper measurement tool" of Heidelberg eye explorer of Heidelberg machine.The length of IDZ was defined as ends of the continuous and highly reflective line between EZ and retinal pigment epithelium-Bruch's membrane (RPE-BM) and the radial distance measure of IDZ defect was any discontinuity in IDZ band.The length of EZ was defined as ends of the continuous line between external limiting membrane (ELM) and IDZ and radial distance measure of the EZ defect was any discontinuity involving EZ band.The measurements were done independently by two authors (KC, AG) in a masked fashion.In the event of any discrepancy, the two graders evaluated the images together and reached a final consensus.
Our definition of RAV is in line with published data -on CFP as one or several visible, blunted, slightly dilated vessels, mainly located in the temporal parafovea, and that seem not to narrow towards the foveola, but suddenly dive at a right angle into deeper retinal layers [1,18,19].On CBR and OCT-A (especially whole retina slab), vessels demonstrating the same characteristics that course the superficial and deep retinal layers with an apparent discontinuation were similarly defined as RAV [18].
RAV was determined initially on CFP and further corroborated using CBR and OCT-A, if available [19].
OCT-A segmentation was done to study the changes in the macular capillary beds at the level of superficial vascular complex (SVC) and DCP.SVC was segmented from internal limiting membrane (ILM) to 55 µm above inner plexiform layer (IPL) while DCP was segmented from 6 µm above IPL to 50 µm below IPL.Telangiectatic vessels in DCP were defined as dilated capillaries with non-tapering ends [2].Artifacts from SVC were removed using the in-built projection removal tool of the Heidelberg OCT-A machine.The confirmation of DCP telangiectasia as opposed to superficial vessel artifact was done by 2 authors (KC and AG).
Follow-up was available in a subset of eyes (15 eyes) for which we determined whether IDZ defect was a precursor to EZ defect in eyes with early MacTel.We also calculated the predictive value which described the likelihood of a preceding IDZ defect to predict future EZ defect.
For statistical analyses, the annual progression in IDZ loss [(a) baseline to follow-up 1 and (b) follow-up 1 to final follow-up] and EZ attenuation (follow-up 1 to final follow-up) were determined (all patients with IDZ attenuation at presentation had IDZ loss at follow-up).This annual progression was defined as the values calculated by dividing the difference between baseline and follow-up 1 values and between follow-up 1 and final follow-up values by the number of years between the examinations.Comparison in changes of IDZ loss and EZ attenuation values was done during the observation period calculated from baseline.

Intergrader agreement
The intergrader agreement of 2 masked graders (KC and AG) was performed for qualitative and quantitative parameters in the study eyes at presentation (Supplementary Table 1).

Statistical analysis
Statistical analysis was performed using SPSS Statistics software version 26 (IBM Corp., Armonk, NY).Paired t-test and Wilcoxon signed rank test were used to determine the significance of changes in the IDZ (IDZ loss) and EZ (EZ attenuation) values, respectively, during the observation period.The association between baseline IDZ defect and follow-up EZ defect was determined using generalized estimating equations (GEE) regression analysis.Intergrader agreement for qualitative and quantitative data was determined using kappa statistic (k) and intraclass correlation (ICC) coefficient, respectively.A p-value ≤ 0.05 was accepted as statistically significant.

Relation of RAV with outer retinal alterations in each eye
There was a total of 58 RAVs in the 43 eyes.53/58 (91.3%)RAVs were associated with IDZ alterations in 39 eyes.All extrafoveal IDZ/EZ alterations were associated with RAV.Another interesting observation was that in eyes with RAV in proximity to each other, the IDZ defect coalesced between them and formed a common IDZ defect [an example is depicted in Fig. 2a showing a common IDZ defect for 2 RAVs (best appreciated on whole retina OCT-A)].

DCP telangiectasia and outer retinal alterations
Of the 43 RAV eyes, 36 eyes had OCT-A.Of these 36 eyes, DCP telangiectasia was present in 36/36 (100%) eyes, out of which 32 (89%) eyes had extrafoveal IDZ/EZ alterations.Table 1 demonstrates the details of demography and visual acuity as well as RAV, outer retinal alterations and DCP changes of study eyes at presentation.

Follow-up data
Longitudinal data was available in 15 (35%) eyes.A sequential pattern of outer retinal changes on OCT was seen in association with RAV.These were progression from "at-risk" IDZ to IDZ attenuation in 2 (13%) eyes, IDZ attenuation to IDZ loss in 1 (7%) eye, IDZ attenuation to IDZ loss + EZ attenuation in 3 (20%) eyes, IDZ loss to EZ attenuation in 2 (13%) eyes and to EZ loss in 3 (20%) eyes.The remaining 4 (27%) eyes already had baseline EZ alterations.IDZ loss showed progression at 142.24 ± 108.95 μm/ year (baseline to follow-up at 1 year) and 171.51 ± 79.39 μm/year (follow-up from year 1 to final follow-up), while EZ attenuation showed progression at rate of 83.33 ± 30.13 μm/year from year 1 to final follow-up.2 eyes with RAV and DCP telangiectasia but no IDZ defect at presentation ("at-risk" IDZ), progressed to IDZ attenuation and later to IDZ loss in 1 eye (patient 3, Fig. 2a) and to EZ attenuation in 1 eye (patient 4, Fig. 2b).Longitudinal imaging demonstrated that pre-existing IDZ defect associated with RAV was relatively predictive of subsequent EZ defect [regression coefficient = 0.463, confidence interval = 0.151-0.167;p-value = 0.002].New location of IDZ loss was noted in 2 eyes (1 eye had associated new EZ attenuation) and both eyes had an associated same RAV, albeit new onset of EZ change at the proximal portion of that RAV (Figs. 2b and 3b; marked in red).No new location of EZ loss was noted.Table 2a shows the follow-up data of IDZ and EZ parameters.Table 2b illustrates the comparison of RAV-associated IDZ loss and EZ attenuation over time.

Intergrader agreement
The intergrader reliability of changes related to RAV on OCT and OCT-A at presentation, using k and ICC statistics have been summarized in supplementary table 1.
The agreement on OCT for qualitative data ranged from moderate for IDZ attenuation to perfect for EZ loss, while that for quantitative data ranged from good for IDZ attenuation to excellent for EZ loss.There was substantial agreement between the two graders concerning telangiectasia on OCT-A DCP.
Based on the results presented, a sequence of SD-OCT changes has been demonstrated in association with RAV in early MacTel eyes.

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Stage 5-EZ loss (Fig. 3a, b).Summarizing, we observed a stagewise progression of changes associated with RAV in MacTel eyes.Initially, the changes commence as RAV draining an area of telangiectasia on DCP.This area of normal or at-risk IDZ then transitions to IDZ attenuation before progressing to IDZ loss, EZ attenuation and lastly EZ loss.RAV was noted to be already present in areas without IDZ defect on SD-OCT, but we are currently unable to ascertain whether there are neuronal changes that are not visible on available multimodal imaging that precede RAV and DCP telangiectasia.

DISCUSSION
The present study illustrates the relationship between photoreceptor changes identified as IDZ and EZ abnormalities, RAV, and DCP telangiectasia in MacTel.
We found that vascular changes in terms of DCP telangiectasia and RAV precede outer neuronal changes in MacTel.Also, the earliest neuronal changes associated with RAV is in the IDZ layer.Previous OCT-A studies in MacTel have revealed vascular alterations, to possibly originate in DCP [22,23].It is postulated that venules in RAV become dilated due to increased blood flow in the paracentral telangiectatic capillaries [19].RAVs have been studied to be associated with abnormally dilated vessels in OCT-A and hyper-reflective lesions in the outer retina and neovascular changes in MacTel [18].
Recently, it was demonstrated that in eyes with nonproliferative MacTel, areas of DCP telangiectasia corresponded to the borders of EZ loss. 10However, the temporal relation of neuronal changes relates to RAV, the pathognomonic finding of stage-3 MacTel as per Gass and Blodi staging [1].
We found that IDZ changes precede EZ loss and are located around RAV.The COST that makes up the IDZ band experience significant daily recycling and regeneration.Previous studies have suggested that degenerative changes in the inner segments occurs at a slower pace compared to those in the outer segments [10,13].This is because COST/IDZ undergoes high turnover making it more sensitive to early photoreceptor dysfunction than the EZ, which is comprised of inner segments primarily containing cellular organelles.Due to the extensive physiologic cycling of the outer segment membranes and the significance of Müller cells in cone outer segment turnover, IDZ tends to show earlier signs of    photoreceptor dysfunction in MacTel eyes.Previously, studies done in mouse models have shown that photoreceptor loss following selective Müller cell ablation triggers a pro-angiogenic state [24][25][26].In normal retina, photoreceptors synthesize and release an endogenous inhibitor of vascular endothelial growth factor A (VEGF-A) called as soluble VEGF receptor-1 which maintains the avascularity in normal outer retina and this molecule has been found to be reduced in eyes with age macular degeneration which also shows vascular invasion of outer retina, as seen in MacTel [27].
RAV associated vascular changes may represent a proangiogenic stimulus from Müller cells or primary photoreceptor dysfunction before structural photoreceptor changes become obvious.These vascular changes in the form of DCP telangiectasias may represent an earlier, "pre-IDZ" stage of photoreceptor dysfunction that cannot be visualized on SD-OCT but may be detected on imaging modalities such as adaptive optics scanning laser ophthalmoscopy (AOSLO) [2].These photoreceptors have been previously labelled as "photoreceptors at risk" [2,28].Telangiectasias were studied in OCT-A to be associated with and without RAV even in the absence of any visible neurodegenerative changes on SD-OCT in early MacTel patients [3].Thus, these findings strengthen the belief that RAV, and vascular alterations on OCT-A, may occur in MacTel earlier than previously thought.
Based on the results presented, we believe, initially, the "at-risk" photoreceptors seem to suppress normal anti-angiogenic signalling leading to abnormal DCP telangiectasia (stage 1) [2].It is believed that these "at-risk" photoreceptors in turn predict the location of future IDZ defects.Studies utilizing AOSLO previously demonstrated that cone mosaic lesions corresponded to IDZ disruption even in areas of intact EZ [2].The absence of IDZ in OCT images could be the earliest sign of a loss of the normal cone mosaics in adaptive optics [29].In addition, areas of photoreceptor abnormalities do not always correlate with areas of EZ loss on SD-OCT [30,31].It may be that there is a larger area of photoreceptors at risk than the area marked by IDZ and EZ loss.The "at-risk" IDZ gives way to an IDZ attenuation (stage 2) and IDZ loss (stage 3) with compensatory vascular changes.EZ band [EZ attenuation (stage 4) and EZ loss (stage 5)] gets affected eventually in the course of the disease process.Thus, RAV associated vascular changes in the form of DCP telangiectasia and earliest neuronal changes affecting the IDZ layer at extrafoveal location suggest that they could be early predictors of disease progression in MacTel.
The study is not without its limitations.We would like to acknowledge that while observations of IDZ defects were made by 2 experienced graders and based on a specific detail scan SD-OCT protocol, since the regions of low attenuation of IDZ were done subjectively, it may not be reproducible on different examinations in some cases.Also, the cause of telangiectasia is poorly understood as well as proliferative changes in intraretinal and subretinal layers in MacTel.Although our study does not focus on this issue, it correlates the presence of mild defects in the photoreceptor layer with telangiectasia and RAV.

CONCLUSION
Our findings suggest that the earliest changes associated with RAV begin at the level of IDZ in extrafoveal locations that progress to EZ loss with relatively intact ELM.Future longitudinal studies with larger sample size incorporating AOSLO to assess subtle photoreceptor changes corresponding to RAV would further improve our understanding of this intricate relationship in MacTel.

SUMMARY
What was known before • Early-stage Macular Telangiectasia type-2 (MacTel) vascular abnormalities are associated with interdigitation zone (IDZ) disruption which eventually progress to ellipsoid zone (EZ) loss.

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This study illustrates the earliest changes associated with right angle-vessel (RAV) in MacTel.

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The earliest RAV associated abnormality is seen on optical coherence tomography angiography (OCT-A) in the form of deep capillary plexus telangiectasia (which precede visible neuronal changes), while the earliest change on spectraldomain OCT (SD-OCT) corresponding to RAV is in the IDZ.

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The EZ gets involved later as the disease progresses and a preexisting IDZ defect predicts subsequent EZ changes.

(
protocol number 58/2021) and the study adhered to tenets of declaration of Helsinki.Informed consent was obtained from all patients.From a MacTel registry of 745 patients, we searched for patients with at least one eye with a clinical diagnosis of stage-3 MacTel based on Gass and Blodi classification for whom multimodal imaging was done.

Fig. 1
Fig. 1 Representative example showing only deep capillary plexus (DCP) changes (STAGE 1) (a) and interdigitation zone (IDZ) attenuation (STAGE 2) (b).a, b Multimodal imaging of patients 1 and 2 showing only DCP telangiectasia with normal spectral-domain optical coherence tomography (SD-OCT) (a) (STAGE 1).Multimodal imaging of left eye (OS) of patient 8 showing IDZ attenuation only (b) (STAGE 2). a Patient 1 (A) -OCTangiography (OCT-A) whole retina slab showing right-angle vessel (RAV) (yellow arrow; A-1) and flow signals on B-scan (blue arrow), and corresponding DCP slab showing telangiectasia (circled yellow; A-2).Multiple SD-OCT sections showing normal IDZ at RAV dipping (circled yellow; A-3).Fundus autofluorescence showing increased parafoveal autofluorescence and RAV (black open-arrow; A-4).Patient 2 (B) -Colour fundus photograph showing RAV temporally (black open-arrow; B-4), confirmed on whole retina OCT-A (B-1; bending and termination portions of RAV depicted by yellow and blue arrows, respectively) with corresponding DCP telangiectasia (circled yellow; B-2).The corresponding flow signals associated with RAV on B-scan are depicted by blue star.Multiple SD-OCT sections showing no visible IDZ alteration corresponding to RAV (circled yellow; B-3).b Colour fundus photograph showing loss of retinal transparency at macula with a superotemporal RAV (A).Confocal blue reflectance (CBR) demonstrating hyper-reflectance at macula with better depiction of RAV (black open arrow; B).SD-OCT demonstrating IDZ attenuation (yellow arrowhead) (367 µm) corresponding to RAV (yellow arrow; C).OCT-A showing RAV on whole retina slab [(1), yellow arrow] and telangiectasia [(2) red arrows] with vascular rarefaction ((2) delineated in blue) in DCP corresponding to RAV associated IDZ attenuation (D).OCT B-scan shows dense cluster of flow signals associated with RAV seen predominantly in the DCP [(3), circled yellow]; the red rectangle indicates the extent of RAV associated IDZ attenuation.

Fig. 2
Fig. 2 Representative example showing interdigitation zone (IDZ) loss (STAGE 3) (a) and ellipsoid zone (EZ) attenuation (STAGE 4) (b).a, b Multimodal imaging of right eye (OD) of patient 3 showing progression to IDZ loss (a) (STAGE 3).Multimodal imaging of right eye (OD) of patient 4 showing progression to EZ attenuation (b) (STAGE 4). a Colour fundus photograph showing loss of retinal transparency at macula and an inferotemporal right-angle vessel (RAV, black open arrow) (A).On confocal blue reflectance (CBR), a well delineated hyper-reflectance is seen at macula with better depiction of this RAV (black open-arrow; B).At presentation, spectral domain optical coherence tomography (SD-OCT) shows only ragged/irregular IDZ temporal to fovea, called photoreceptor "at-risk" (circled yellow; C), but no obvious IDZ defect is noted.Follow-up (5 years in total) SD-OCT four years later shows IDZ attenuation [301 µm], with progression to IDZ loss [518 µm] one year later corresponding to the visible ending portion of RAV with intact ellipsoid zone (EZ) at all visits (D, E).Optical coherence tomography angiography (OCT-A) at presentation (F) demonstrating an additional inferotemporal RAV [(a) on whole retina slab numbered 2; yellow openarrows)] and telangiectasia temporal to foveal avascular zone in the deep capillary plexus (DCP) [(b) yellow square]; OCT B-scan shows flow signals associated with RAV [(c) for RAV 1 and (d) for RAV 2] with the red rectangle depicting the extent of "at-risk" IDZ.Note the IDZ loss is confined to the space between these 2 RAV (E).b Multicolour fundus photo showing circumferential greying at macula with temporal rightangle vessel (RAV, black open arrow) (A).CBR demonstrating incomplete ring-shaped hyper-reflectance at macula with better depiction of RAV (black open arrow; B).At presentation, SD-OCT shows ragged/irregular IDZ and EZ temporal to fovea (photoreceptor "at-risk") corresponding to RAV and minimal downward projection of outer retinal layers (C).Follow-up (4 years in total) SD-OCT shows IDZ attenuation [256 µm] at one year (D), while at two years there is an IDZ loss [249 µm at ending portion (yellow arrow) and 204 µm anteriorly at the bending portion (red arrow) of RAV] with intact EZ (E).In the final follow-up at four years, a co-existing EZ attenuation [378 µm] can be seen along with progressing IDZ loss [501 µm] (F).OCT-A, at presentation (G) -(a) whole retina slab showing the RAV (yellow square); (b) DCP showing telangiectasia (circled yellow) corresponding to RAV associated at-risk IDZ and (c) OCT B-scan showing dense cluster of flow signals corresponding to RAV (blue arrow) associated at-risk IDZ (red box) seen predominantly in the DCP.

Fig. 3
Fig. 3 Representative example showing ellipsoid zone (EZ) loss (STAGE 5) (a, b).a, b Multimodal imaging of (a) left eye (OS) of patient 35 and (b) right eye (OD) of patient 15 showing progression to EZ loss (STAGE 5).(a)-Colour fundus photograph (CFP) showing loss of retinal transparency at macula (A).Confocal blue reflectance (CBR) demonstrating hyper-reflectance temporally with depiction of RAV (black openarrow) with 2 branches (black asterisks; B).At presentation, spectral domain optical coherence tomography (SD-OCT) shows interdigitation zone (IDZ) loss [871 µm] with EZ attenuation [636 µm] corresponding to medial RAV branch (C-1), while the lateral RAV branch shows a greater temporal IDZ loss [1175 µm] and EZ loss extending to fovea [536 µm] (C-2).Follow-up (2 years) SD-OCT of the medial RAV branch shows subtle downward dent of outer plexiform layer with EZ loss [145 µm] (D-1), while the lateral RAV branch is now associated with collapse of outer retinal layers and greater extent of loss of EZ [1231 µm] and IDZ [1337 µm] with external limiting membrane loss [838 µm] (D-2).Optical coherence tomography angiography (OCT-A) at presentation demonstrating flow signals on corresponding OCT B-scan and telangiectasia temporal to fovea in deep capillary plexus (DCP) (yellow box; E).Fundus fluorescein angiography showing late phase (9.02 min) leak from telangiectasia temporally in region drained by RAV (F).(b)-CFP shows loss of retinal transparency at macula and superotemporal quadrant RAV (A, black open-arrow).CBR demonstrating incomplete ring-shaped hyper-reflectance at macula with RAV being depicted against white background (black open-arrow; B).At presentation, SD-OCT shows IDZ loss [231 µm] temporal to fovea corresponding to RAV (C).Follow-up SD-OCT at 4 years shows subtle EZ loss [54 µm] with further progression of pre-existing IDZ loss (241 µm) (yellow) with an additional new IDZ loss (731 µm) proximally along RAV (red) (D).OCT-A at presentation (E) -(a) whole retina slab shows the prominence of RAV (yellow square) with corresponding OCT B-scan showing flow signals corresponding to RAV (blue arrow) and IDZ loss (green arrow) depicted in red box; (b) DCP shows few telangiectasia (circled green, yellow arrows) corresponding to location of RAV associated IDZ loss.
Spectral-domain optical coherence tomography, OCT-A Optical coherence tomography angiography, PT Patient, G Gender, VA Best corrected visual acuity (log MAR), RAV Right-angle vessel, IDZ Interdigitation zone, EZ Ellipsoid zone, ELM External limiting membrane, DCP Deep capillary plexus, TEL Telangiectasia, FU Follow-up, M Male, F Female, OD Right eye, OS Left eye, Quad

Follow-up data
of RAV with corresponding IDZ attenuation, IDZ loss, EZ attenuation and EZ loss; b: Comparison of RAV-associated IDZ loss and EZ attenuation over time.