VITELLIFORM LESIONS ASSOCIATED WITH LEPTOCHOROID AND PSEUDODRUSEN.

OBJECTIVE: To characterize clinical and prognostic implications of leptovitelliform maculopathy (LVM), a distinctive phenotype of vitelliform lesion characterized by the coexistence of subretinal drusenoid deposits (SDD) and leptochoroid. DESIGN: Retrospective, cohort study. SUBJECTS: The study compares patients affected by leptovitelliform maculopathy with cohorts displaying a similar phenotypic spectrum. This includes patients with acquired vitelliform lesions (AVL) and those with SDD alone. METHODS: A total of 60 eyes of 60 patients were included, of whom 20 eyes had LVM, 20 eyes had AVL, and the remaining had SDD. Patients older than 50 years with complete medical records and multimodal imaging for at least 6 months of follow-up, including color fundus photograph (CFP) or MultiColor, optical coherence tomography (OCT), fundus autofluorescence (FAF), and OCT angiography (OCTA) were included. MAIN OUTCOME MEASURES: Choroidal vascularity index (CVI); proportion of late-stage complications (macular neovascularization, atrophy). RESULTS: The AVL subgroup exhibited a significantly higher CVI compared to both LVM (p<0.001) and SDD subgroups (p<0.001). The proportion of late-stage complications significantly differed among subgroups (χ2=7.5, p=0.02). Eyes with LVM presented the greatest proportion of complications (55%) after a mean of 29.3 months, while the remaining eyes presented a similar proportion of complications, including 20% in AVL after 27.6 months and 20% in SDD after 36.9 months. Kaplan-Meier estimates of survival demonstrated a significant difference in atrophy development between groups (p<0.001), with a median survival of 3.9 years for LVM and 7.1 years for controls. The presence of LVM correlated with a fourfold increase in the likelihood of developing complications. CONCLUSIONS: Leptovitelliform maculopathy, characterized by the association of vitelliform lesions with SDD and leptochoroid, represents a distinct clinical phenotype in the broader spectrum of vitelliform lesions. The importance of a clinical distinction for these lesions is crucial due to a higher propensity for faster progression and an elevated rate of complications, particularly toward atrophic conversion.

International Classification System for Ocular Complications of Anti-Vascular Endothelial Growth Factor Agents in Clinical Trials.

OBJECTIVE: Complications associated with intravitreal anti-vascular endothelial growth factor (VEGF) therapies are inconsistently reported in the literature, thus limiting an accurate evaluation and comparison of safety between studies. This study aimed to develop a standardized classification system for anti-VEGF ocular complications using the Delphi consensus process. DESIGN: Systematic review and Delphi consensus process. PARTICIPANTS: 25 international retinal specialists participated in the Delphi consensus survey. METHODS: A systematic literature search was conducted to identify complications of intravitreal anti-VEGF agent administration based on randomized controlled trials (RCTs) of anti-VEGF therapy. A comprehensive list of complications was derived from these studies, and this list was subjected to iterative Delphi consensus surveys involving international retinal specialists that voted on inclusion, exclusion, rephrasing, and addition of complications. As well, surveys determined specifiers for the selected complications. This iterative process helped refine the final classification system. MAIN OUTCOME MEASURES: The proportion of retinal specialists who choose to include or exclude complications associated with anti-VEGF administration. RESULTS: After screening 18,229 articles, 130 complications were initially categorized from 145 included RCTs. Participant consensus via the Delphi method resulted in the inclusion of 91 (70%) complications after three rounds. After incorporating further modifications made based on participant suggestions, such as rewording certain phrases and combining similar terms, 24 redundant complications were removed, leaving a total of 67 (52%) complications in the final list. A total of 14 (11%) complications met exclusion thresholds and were eliminated by participants across both rounds. All other remaining complications not meeting inclusion or exclusion thresholds were also excluded from the final classification system after the Delphi process terminated. In addition, 47 out of 75 (63%) proposed complication specifiers were included based on participant agreement. CONCLUSION: Using the Delphi consensus process, a comprehensive, standardized classification system consisting of 67 ocular complications and 47 unique specifiers was established for intravitreal anti-VEGF agents in clinical trials. The adoption of this system in future trials could improve consistency and quality of adverse event reporting, potentially facilitating more accurate risk-benefit analyses.

Evaluating fingerprint-like patterns in the healthy Henle fiber layer using enface OCT imaging.

PURPOSE: Enface OCT may disclose a distinct "fingerprint-like' pattern within the HFL in various macular disorders. This study aims to investigate the frequency and characteristics of this pattern in healthy eyes and identify potential factors influencing its visibility. METHODS: Two, independent masked reading center graders evaluated for the presence and prominence of a fingerprint pattern in the Henle fiber layer (HFL) on enface OCT images from 33 healthy subjects (66 eyes). The prominence of the pattern was rated qualitatively using a 0-3 scale, with 3 indicating the strongest prominence. Tilt angles (relative to the normal/perpendicular at the center) of the retina were measured on horizontal and vertical B-scans, and the retinal curvature was assessed using ImageJ, in order to determine the impact of the incident light angle on the visibility and prominence of the fingerprint pattern. Inter-grader agreement using Cohen's kappa and the frequency and percentage of patterns in the entire enface image and in each quadrant were calculated and compared using the Friedman test with Dunn's post-test. A generalized estimating equation (GEE) was used to analyze the association between these metrics and fingerprint prominence. RESULTS: Substantial inter-grader agreement was observed (Cohen's kappa = 0.71) for assessing the prominence of the fingerprint pattern. Over 70% of eyes exhibited some evidence of the pattern (score ≥1). Significant difference in pattern prominence across quadrants was detected (p < 0.05), with lowest prominence in the temporal quadrant (p < 0.001 for pairwise comparisons against all other quadrants). The GEE analysis to account for the extent of the effect of scan tilt angle and RPE curvature was not able to predict the prominence of the fingerprint pattern, highlighting that angle of incidence (of the scanning laser light) alone could not explain the pattern. CONCLUSIONS: This study confirms that a fingerprint-like pattern within the HFL can also be observed in healthy eyes, challenging the notion that this finding is only manifest in the setting of disease. In addition, the lack of correlation with angle of incident light suggests that the pattern may be related to other intrinsic characteristics of the HFL.

Autoimmune retinopathy associated with systemic autoimmune disease: a case series.

OBJECTIVE: To describe various presentations of autoimmune retinopathy (AIR) associated with systemic autoimmune diseases. DESIGN: Case series. PATIENTS AND METHODS: Four patients with systemic autoimmune disorders and AIR are described in this report. The clinical and multimodal imaging characteristics, systemic work-up, genetic testing results, management, and course of disease are detailed. RESULTS: The multimodal retinal features of 4 cases of AIR including the findings of fundus autofluorescence, optical coherence tomography, and electrophysiology necessary to document progressive photoreceptor loss are described. Each case of AIR was associated with a complicated autoimmune disorder. Case 1 was associated with chronic inflammatory demyelinating polyneuropathy and showed marked improvement with systemic steroid and intravenous immunoglobulin therapy. Case 2 was associated with rheumatoid arthritis, and the AIR condition progressed despite systemic immune therapy. Case 3 was associated with Lambert-Eaton myasthenic syndrome, and AIR developed 6 years later and stabilized with systemic immune therapy. Case 4 was associated with necrobiotic xanthogranuloma followed by AIR and was managed by systemic immune therapy. CONCLUSIONS: AIR in association with these systemic conditions is rarely reported. Our cases highlight the gaps in our current understanding of the definition, systemic associations, pathogenesis, and management of AIR and the importance of multimodal imaging and a multidisciplinary approach in managing patients with suspected AIR.

Clinical Implications of Alternating Hypointense Bands on OCT Angiography in Retinal Vascular Occlusive Disease.

PURPOSE: To demonstrate the relationship between alternating hypointense signal bands on OCT angiography (OCTA), real-time fluorescein angiography (FA), and structural OCT findings in patients with retinal vascular occlusive disease (RVOD). DESIGN: Retrospective, consecutive case series. SUBJECTS: Consecutive patients with a clinical diagnosis of acute RVOD and alternating bands of hypointense OCTA flow signal on en face projections. METHODS: Complete ophthalmic examination and multimodal imaging, including color fundus photography, real-time FA, spectral-domain OCT, and OCTA performed with different instruments having different scan speeds and acquisition protocols. MAIN OUTCOME MEASURES: The primary outcomes were: hypointense OCTA band characteristics (number, width, orientation, and location), OCTA acquisition characteristics (speed and scan direction), and FA findings including delayed arteriovenous (AV) transit and pulsatile flow. Secondary outcomes were: structural OCT changes including retinal fluid, paracentral acute middle maculopathy (PAMM) lesion, and a prominent middle limiting membrane (p-MLM) sign. RESULTS: OCT angiography hypointense bands were detected in the superficial and deep vascular plexuses in 9 eyes of 9 patients with either partial central retinal vein occlusion (RVO) or nonischemic RVO. When obtained on the same device, hypointense bands were thinner and more numerous at lower (100 kHz) scan speeds compared with higher (200 kHz) scan speeds. Band orientation was parallel to the OCTA scan direction, and their extent correlated with the area of delayed AV transit on FA. Structural OCT showed multiple PAMM lesions in 78% of cases and a p-MLM sign centered in the fovea in 44% of cases. CONCLUSIONS: OCT hypointense bands are a novel biomarker in RVOD indicating delayed AV transit and pulsatile filling without the need for dye angiography. Structural OCT often shows PAMM in these eyes and, less commonly, a p-MLM sign. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Mitochondrial retinopathies and optic neuropathies: The impact of retinal imaging on modern understanding of pathogenesis, diagnosis, and management.

Advancements in ocular imaging have significantly broadened our comprehension of mitochondrial retinopathies and optic neuropathies by examining the structural and pathological aspects of the retina and optic nerve in these conditions. This article aims to review the prominent imaging characteristics associated with mitochondrial retinopathies and optic neuropathies, aiming to deepen our insight into their pathogenesis and clinical features. Preceding this exploration, the article provides a detailed overview of the crucial genetic and clinical features, which is essential for the proper interpretation of in vivo imaging. More importantly, we will provide a critical analysis on how these imaging modalities could serve as biomarkers for characterization and monitoring, as well as in guiding treatment decisions. However, these imaging methods have limitations, which will be discussed along with potential strategies to mitigate them. Lastly, the article will emphasize the potential advantages and future integration of imaging techniques in evaluating patients with mitochondrial eye disorders, considering the prospects of emerging gene therapies.

Pathogenesis of Central Serous Chorioretinopathy and the Link Between Choroidal Hyperpermeability and Retinal Pigment Epithelium Pump Reversal.

PURPOSE: To describe 6 cases of acute central serous chorioretinopathy (CSCR) and the response to laser treatment, focusing on the underlying pathogenic mechanism. METHODS: Multimodal imaging from 6 eyes of 6 patients with acute and recurrent CSCR were reviewed, including fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT) at baseline and after laser therapy. RESULTS: In 3 of the 6 cases with acute CSCR, the hyporeflective lucency sign was identified with cross-sectional and en face OCT and co-localized with an intense active inkblot retinal pigment epithelium (RPE) leak on FA. The development of this sign was suggestive of active leakage into the subretinal space displacing overlying subretinal hyperreflective material (SHRM) and suggestive of a reversal of RPE pump function. All 6 cases were treated with focal laser to directly target the intense leakage points with remarkable resolution of the fluid due to destruction of the RPE cells mediating reversal of pump function. CONCLUSIONS: Unlike chronic CSCR in which degenerative changes of the RPE lead to oozing of fluid into the subretinal space, in acute forms of CSCR including bullous CSCR, there are focal leaks of the RPE that actively drive fluid into the subretinal space suggestive of RPE pump reversal. We propose that pachychoroid disease causes increased hydrostatic pressure and increased resistance to the RPE pump, thereby triggering a reversal in pump function. Understanding this concept can have therapeutic implications.

Predictive Factors Influencing the Evolution of Acquired Vitelliform Lesions in Intermediate Age-Related Macular Degeneration Eyes.

PURPOSE: In this study, we identify risk factors that predict the progression of acquired vitelliform lesions (AVLs) over time. DESIGN: Retrospective cohort study. SUBJECTS: One hundred sixty-three eyes of 132 patients with a diagnosis of intermediate age-related macular degeneration (iAMD) with AVL. METHODS: This retrospective study evaluated consecutive eyes with AMD from a retina clinic population and included 1181 patients and 2362 eyes. After excluding cases with associated geographic atrophy, macular neovascularization (MNV), vitreomacular traction, and those with <2 years of follow-up data, the final analysis cohort consisted of 163 eyes (132 patients) with ≥1 AVL. The first available visit in which an AVL was evident was considered the baseline visit, and follow-up data were collected from a visit 2 years (± 3 months) later. Progression outcomes at the follow-up visit were classified into 6 categories: resorbed, collapsed, MNV, stable, increasing, and decreasing. Subsequently, we analyzed the baseline characteristics for each category and calculated odds ratios (ORs) to predict these various outcomes. MAIN OUTCOME MEASURES: The study focused on identifying predictive factors influencing the evolution of AVL in iAMD eyes. RESULTS: In total, 163 eyes with AVL had follow-up data at 2 years. The collapsed group demonstrated a significantly greater baseline AVL height and width compared with other groups (P < 0.001). With regard to qualitative parameters, subretinal drusenoid deposits (SDDs) and intraretinal hyperreflective foci (IHRF) at the eye level, AVL located over drusen, and IHRF and external limiting membrane disruption over AVL were significantly more prevalent in the collapsed group compared with other groups (P < 0.05 for all comparisons). Odds ratios for progressing to atrophy after 2 years of follow-up, compared with the resorbed group, were significant for SDD (OR, 2.82; P = 0.048) and AVL height (OR, 1.016; P = 0.006). CONCLUSIONS: The presence of SDDs and greater AVL height significantly increases the risk of developing atrophy at the location of AVL after 2 years of follow-up. These findings may be of value in risk prognostication and defining patient populations for inclusion in future early intervention trials aimed at preventing progression to atrophy. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Acquired Vitelliform Lesions in Intermediate Age-Related Macular Degeneration: A Cross Sectional Study.

PURPOSE: This study aims to define the characteristics of acquired vitelliform lesions (AVLs) in patients with intermediate age-related macular degeneration (iAMD). DESIGN: Retrospective, observational, cross sectional study. SUBJECTS: This study included 217 eyes with AVLs associated with iAMD, and an equivalent number of control patients. METHODS: OCT scans were evaluated for qualitative and quantitative parameters at both the eye and lesion level. Eye-level parameters included the presence of: hyporeflective core drusen, intraretinal hyperreflective foci (IHRF), subretinal drusenoid deposits, macular pachyvessels, central retinal thickness, and central choroidal thickness. Lesion-level qualitative parameters included the presence of ellipsoid zone (EZ) and external limiting membrane disruption overlying the AVL, IHRF overlying the AVL, AVL overlying drusen, pachyvessels under the AVL, a solid core within AVL, and AVL location. Lesion-level quantitative characteristics included AVL height and width, AVL distance from the fovea, and sub-AVL choroidal thickness. MAIN OUTCOME MEASURES: The primary outcomes assessed included the frequency of IHRF, the presence of macular pachyvessels, central choroidal thickness, and the dimensions (both height and width) of AVLs. RESULTS: Comparing the AVL and control groups, the frequency of IHRF (AVL: 49.3% vs. control: 26.3%) and macular pachyvessels (37.3% vs. 6.9%) was significantly higher in the AVL case group, and the central choroidal thickness (256.8 ± 88 µm vs. 207.1± 45 µm) was thicker in the AVL group. Acquired vitelliform lesions located over drusen, with overlying IHRF, or situated subfoveally, and AVL lesions with EZ disruption were found to have a greater lesion height and width compared with AVL lesions lacking these characteristics (P value < 0.001 for all). Additionally, a significant negative correlation was observed between the distance from the fovea and AVL height (Spearman rho: -0.19, P = 0.002) and width (Spearman rho: -0.30, P = 0.001). CONCLUSIONS: This study represents the largest reported cohort of AVL lesions associated with iAMD. Novel findings include the higher frequency of pachyvessels in addition to the presence of a thicker choroid in these eyes, as well as the greater height and width of AVL closer to the foveal center. These findings may offer insights into pathophysiologic mechanisms underlying the development of AVL. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinal Ischemic Perivascular Lesions Are Associated With Myocardial Infarction in Patients With Coronary Artery Disease.

PURPOSE: To evaluate the association of retinal ischemic perivascular lesions (RIPLs) with myocardial infarction (MI) among patients diagnosed with coronary artery diseases (CAD). DESIGN: Retrospective cross-sectional study. METHODS: Consecutive patients (317 patients) with CAD who underwent macular spectral domain optical coherence tomography (SD-OCT) were captured. Patients with CAD who developed MI were compared to those without MI. SD-OCT were reviewed by 2 independent and masked graders for the presence of RIPLs. Medical records were reviewed. Multivariate logistic regression analysis was used to evaluate the relationship between RIPLs and MI including the following covariates age, gender, smoking status, hypertension, diabetes, dyslipidemia and body mass index. RESULTS: Of 317 patients with CAD for whom OCT scans were available to study, there were 54 (17%) with a history of MI. A higher prevalence of RIPLs was observed in the MI group compared to the non-MI group (59.3% vs 35.7%; P < .001). The presence of RIPLs was significantly associated with MI with an odds ratio of 3 (1.91-4.74; P < .001), after adjusting for age, gender, smoking status, hypertension, diabetes, dyslipidemia, and body mass index. CONCLUSIONS: The presence of RIPLs, detected with SD-OCT, is significantly associated with MI in patients with CAD. These findings underscore the potential clinical utility of incorporating RIPL evaluation in the medical management of CAD.

Risk factors for development of hyper-reflective foci overlying drusen in eyes with intermediate age-related macular degeneration.

AIMS: The aim of this study is to assess baseline characteristics of drusen preceding the development of intraretinal hyper-reflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD). METHODS: In this retrospective case-control study, longitudinal optical coherence tomography (OCT) volume data from eyes with intermediate AMD in a retina clinic population were screened. All drusen that developed overlying IHRF were marked. A random number generator was used to select for further grading three drusen that did not develop IHRF. RESULTS: Ninety eyes (from 72 patients), including 140 drusen with overlying IHRF and 270 IHRF- drusen, were analysed. Greater drusen height, basal drusen width and overlying ellipsoid zone (EZ) and external limiting membrane disruption were associated with a significantly greater risk for IHRF development (p≤0.001). Regression analysis revealed EZ disruption increased these odds by 4.1 (p≤0.001). Each 10-µm increase in drusen height and width increased the odds by 34% (p≤0.001) and 3% (p: 0.005), respectively. Each 100-µm increase in distance from the fovea decreased the odds by 10% (p: 0.013). CONCLUSIONS: The presence of overlying EZ disruption and a greater drusen height substantially increased the risk for IHRF development, whereas drusen further from the fovea indicated reduced risk. Given the importance of IHRF as a biomarker for AMD progression, these findings may be of value in defining patient populations for future early intervention trials.

Cystoid macular edema as a complication of central retinal artery occlusion.

Purpose: To describe the development of cystoid macular edema (CME) as a complication of central retinal artery occlusion (CRAO) in 2 cases. Observations: The first patient was a 51-year-old female who presented with acute loss of vision in the left eye. Multimodal retinal imaging revealed a CRAO with a perfused cilioretinal artery. CME acutely developed one week after presentation. Cystoid spaces predominantly involved the outer nuclear layer (ONL) on optical coherence tomography (OCT) and completely resolved in two weeks. The second case was a 50-year-old man who presented with acute vision loss in the right eye for 3 weeks. Multimodal retinal imaging illustrated an acute CRAO of the right eye. Four weeks later, visual acuity spontaneously improved to 20/20 and was maintained at 20/20 for more than 2 years. After 28 months, the patient returned with a recurrent drop of vision in the right eye. Cross sectional and en face OCT revealed CME in the right eye without leakage on FA. Cystoid spaces predominantly involved the inner nuclear layer (INL) and resolved with intravitreal anti-VEGF injection combined with carbonic anhydrase inhibitor (CAI) and steroid topical drop therapy. Conclusions and Importance: CME can rarely complicate both the acute and chronic phase of CRAO. In the acute phase, cystoid spaces were transient and confined to the ONL on OCT. While in the chronic phase, cystoid spaces were confined to the INL on OCT and angiographically silent on FA. Further studies are needed to identify the incidence, underlying pathophysiology and visual prognosis of CME in cases of CRAO.

En Face Optical Coherence Tomography Illustrates the Trizonal Distribution of Drusen and Subretinal Drusenoid Deposits in the Macula.

PURPOSE: To analyze the topographic distribution of macular drusen and subretinal drusenoid deposits (SDDs) using single-capture en face spectral domain optical coherence tomography (SD-OCT) imaging. DESIGN: Retrospective case series. METHODS: Analysis of 33 eyes of 20 patients with evidence of SDDs. Structural en face OCT images were reconstructed using a 40-µm-thick slab positioned from 48 to 88 µm above the Bruch membrane. The Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and a rod/cone density map were overlaid on the en face OCT images, and the distribution of different subtypes of SDDs and macular drusen were assessed. RESULTS: A total of 31 eyes (94%) showed a trizonal distribution pattern of drusen and SDDs. Whereas small to large drusen tended to aggregate in the central circle, dot SDDs predominated in the inner ring and the inner portion of the outer ring of the ETDRS grid and ribbon SDDs localized to the outer ring and outside the ETDRS grid. Of note, drusen colocalized to the region of greatest cone density, whereas ribbon SDDs colocalized to the area of greatest rod density. The dot SDDs mapped to the intermediate region with mixed rod and cone representation. CONCLUSION: Dot and ribbon subtypes of SDDs and macular drusen show a characteristic trizonal distribution. The locations of these lesions colocalize according to the different densities of the cones and rods in the retina and may reflect varying pathophysiological activities of these photoreceptor subtypes.

En face OCT analysis of Bietti's crystalline dystrophy.

Objective: To describe the multimodal imaging features, including en face optical coherence tomography (OCT), of Bietti's crystalline dystrophy (BCD). Methods: Wide field fundus photography, autofluorescence (FAF) imaging, and cross sectional and en face OCT were performed in a case of BCD. The level of the crystals in the retina were analyzed. Results: A 42-year-old patient was referred for retinal evaluation with nyctalopia, photophobia and metamorphopsia. Retinal examination and wide field color fundus photography were remarkable for bilateral crystalline deposits in the posterior pole and midperipheral retina. Wide field FAF showed extensive nummular atrophy of the retinal pigment epithelium (RPE) in the macula and periphery. Spectral-domain (SD) OCT illustrated bilateral chorioretinal atrophy in the macula. En face SD OCT captured the hyperreflective crystals in various retinal layers, depending on the selected segmentation. The patient was diagnosed with BCD and genetic testing confirmed the diagnosis (CYP4V positive for two variants). Conclusion: In this case report, we describe the multimodal imaging features of Bietti's Crystalline Dystrophy. Wide field FAF illustrated diffuse nummular RPE atrophy in the posterior pole and periphery and en face OCT captured the hyperreflective crystals in different layers of the retina.

FROM DRUSEN TO TYPE 3 MACULAR NEOVASCULARIZATION.

PURPOSE: To investigate the imaging features preceding the occurrence of type 3 (T3) macular neovascularization (MNV) using tracked spectral-domain optical coherence tomography. METHOD: From a cohort of eyes with T3 MNV and ≥ 12 months of previously tracked spectral-domain optical coherence tomography, T3 lesions that developed above soft drusen were selected for optical coherence tomography analysis. Retinal imaging findings at the location where type T3 MNV occurred were analyzed at each follow-up until the onset of T3 MNV. The following optical coherence tomography parameters were assessed: drusen size (height and width), outer nuclear layer/Henle fiber layer thickness at the drusen apex, and the presence of intraretinal hyperreflective foci, retinal pigment epithelium disruption, incomplete retinal pigment epithelium and outer retina atrophy, and complete retinal pigment epithelium and outer retina atrophy. RESULTS: From a cohort of 31 eyes with T3 MNV, T3 lesions developed above soft drusen in 20 eyes (64.5%). Drusen showed progressive growth ( P < 0.001) associated with outer nuclear layer/Henle fiber ( P < 0.001) thinning before T3 MNV. The following optical coherence tomography features were identified preceding the occurrence of T3 MNV, typically at the apex of the drusenoid lesion: disruption of the external limiting membrane/ellipsoid zone and/or the retinal pigment epithelium, hyperreflective foci, and incomplete retinal pigment epithelium and outer retina atrophy/complete retinal pigment epithelium and outer retina atrophy. CONCLUSION: The results demonstrate specific anatomic alterations preceding the occurrence of T3 MNV that most commonly originates above soft drusen. Drusen growth, reduced outer nuclear layer/Henle fiber thickness, and retinal pigment epithelium atrophy at the drusen apex precede the development of T3 MNV. Identifying these optical coherence tomography features should warrant close monitoring for identification of T3 MNV, which can benefit from prompt intravitreal anti-vascular endothelial growth factor therapy.