Faculty Bibliography

PURPOSE/UNASSIGNED:The purpose of this study was to develop ground-truth histology about contributors to variable fundus autofluorescence (FAF) signal and thus inform patient selection for treating geographic atrophy (GA) in age-related macular degeneration (AMD). METHODS/UNASSIGNED:One woman with bilateral multifocal GA, foveal sparing, and thick choroids underwent 535 to 580 nm excitation FAF in 6 clinic visits (11 to 6 years before death). The left eye was preserved 5 hours after death. Eye-tracked ex vivo imaging aligned sub-micrometer epoxy resin sections (n = 140, 60 µm apart) with clinic data. Light microscopic morphology corresponding to FAF features assessed included drusen-driven atrophy, persistent hyperautofluorescence (hyperFAF) islands and peninsulas within atrophy, and hyperFAF and hypoautofluorescence (hypoFAF) inner junctional zone (IJZ) and outer junctional zone (OJZ) relative to descent of external limiting membrane (ELM). Atrophy growth rate was calculated. RESULTS/UNASSIGNED:HypoFAF atrophic spots appeared in association with drusen, and then expanded and coalesced. Over drusen (n = 45, all calcified), RPE was continuous and thin, photoreceptors were short or absent, and initially intact ELM descended where RPE was absent. In persistent hyperFAF within atrophy and in the OJZ, the RPE was continuous and dysmorphic, photoreceptors were present and short, and BLamD was thick. In the IJZ, mottled FAF corresponded to dissociated RPE atop persistent BLamD. Overall linear growth rate (0.198 mm/ year) typified multifocal GA. CONCLUSIONS/UNASSIGNED:FAF in GA is locally multifactorial, with photoreceptor shortening potentially promoting hyperFAF by increasing incoming excitation light available to RPE fluorophores. RPE dysmorphia may lead to either longer or shorter pathlength for excitation light. At both atrophy initiation and expansion Müller glia are major participants.

PURPOSE/OBJECTIVE:To report the multimodal imaging features of hyperpigmented chorioretinal lesions originating from the retinal pigment epithelium (RPE) within punched-out lesions of punctate inner choroidopathy (PIC). METHODS:Retrospective case report. Multimodal imaging findings including fundus photography, optical coherence tomography (OCT), and OCT-angiography (OCTA) were analyzed. RESULTS:A 49-year-old female with myopic degeneration developed progressive lesions of PIC requiring immunosuppressive therapy with adalimumab. Within areas of punched-out chorioretinal atrophic lesions, the occurrence of hyperpigmented lesions were observed which enlarged and extended into the choroid over a multiyear follow-up. CONCLUSION/CONCLUSIONS:This case illustrates the development of pigmented choroidal lesions appearing to originate from the RPE through transdifferentiation following previous chorioretinal inflammatory lesions. The introduction of adalimumab treatment may have activated the cellular migration of the RPE. To the best of our knowledge, this is the first report of intrachoroidal RPE migration in PIC.

PURPOSE/UNASSIGNED:To investigate whether consensus can be reached on the acceptability of end-stage atrophy onset as a clinical end point in early intervention trials of age-related macular degeneration (AMD), and the criteria for defining such an end point. DESIGN/UNASSIGNED:A modified Delphi study. PARTICIPANTS/UNASSIGNED:International panel of experts in AMD, retinal imaging, and histopathology that are part of the Classification of Atrophy Meetings group. METHODS/UNASSIGNED:A modified Delphi study was undertaken to determine if there is consensus on the acceptability of the onset of end-stage atrophic AMD as a clinical end point to evaluate early interventions and the criteria for defining such an end point. Two initial rounds of online surveys were conducted. Aggregate results and anonymized comments were provided after each round, followed by a face-to-face meeting before a final survey round was completed. MAIN OUTCOME MEASURES/UNASSIGNED:Statements where consensus was reached, defined as ≥80% of responses within the 3-point bracket for agreement or disagreement based on a 9-point Likert rating scale, from a total of 33 statements included in the final round of the survey. RESULTS/UNASSIGNED:Consensus was reached for the statement that the onset of end-stage atrophic AMD was an appropriate clinical end point to evaluate early interventions (82% responses in agreement). Consensus was also reached for the statement that such an end point should be defined based on anatomical changes that have been previously shown in clinical studies to be associated with marked, but not necessarily complete, functional loss (95% responses in agreement). Consensus was nearly reached for the specific criterion that ≥90% of such atrophic AMD lesions should have ≥1 test location that was ≤10 decibels on 2 microperimetry tests (77% responses in agreement). CONCLUSIONS/UNASSIGNED:There was expert group consensus that the onset of end-stage atrophy is an appropriate clinical end point to evaluate early interventions in AMD, and that such an end point should show evidence of marked functional loss in prior clinical studies. We believe these findings will help to define incident clinical end points that are acceptable to regulatory authorities. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE/UNASSIGNED:Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas. METHODS/UNASSIGNED:We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD). RESULTS/UNASSIGNED:Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments. CONCLUSION/UNASSIGNED:We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition.

PURPOSE/OBJECTIVE: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/METHODS:Retrospective, consecutive case series. SUBJECTS/METHODS: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/METHODS: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)/BACKGROUND:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE/OBJECTIVE:To describe a new retinal phenotype characterized by bilateral, multifocal, subretinal vitelliform lesions along the vascular arcades that we refer to as multifocal vitelliform paravascular retinopathy (MVPR). DESIGN/METHODS:Observational case series. METHODS:Multimodal retinal imaging including color fundus photography, fundus autofluorescence and cross sectional and en-face optical coherence tomography was performed to evaluate and characterize the lesions of MVPR. RESULTS:Thirteen asymptomatic patients aged 10 to 78 [mean 49±24, 49% under 50] were evaluated for bilateral retinal lesions. Initial visual acuity was 20/30 or better in 22 (85%) eyes. Of the 20 eyes with follow-up, 14 (70%) exhibited visual acuity 20/30 or better at final follow-up. Multifocal small round yellow lesions with distinct borders were identified along the vascular arcades in all patients. The vitelliform lesions were brightly hyperautofluorescent and consisted of focal areas of subretinal hyperreflective material on optical coherence tomography (OCT) that in some cases evolved to hyporeflective spaces (or retinal pigment epithelium atrophy) with associated hypoautofluorescence. When performed, electroretinography (ERG) and electrooculography (EOG) testing were normal and genetic testing was negative for variants in BEST1 and other genes associated with vitelliform retinopathies. CONCLUSIONS:MVPR may represent a novel entity of vitelliform disorders with a distinct clinical presentation and phenotype and generally favorable prognosis.

PURPOSE/OBJECTIVE:To describe remarkable choroidal thickness fluctuations corresponding to episodes of recurrent anterior uveitis with subretinal fluid development when exceeding a choroidal thickness threshold. METHODS:A patient with pachychoroid pigment epitheliopathy and unilateral acute anterior uveitis of the left eye was evaluated over a period of 3 years with multimodal retinal imaging including optical coherence tomography (OCT). Longitudinal changes in subfoveal choroidal thickness (CT) were measured and correlated with episodes of recurrent inflammation. RESULTS:Over the course of 5 recurrent episodes of inflammation in the left eye treated with oral antiviral and topical steroid therapy, subfoveal CT increased as much as 200 um or more. Subfoveal CT in the fellow quiescent right eye by contrast, was within normal limits and minimally changed throughout the follow up. Increased CT occurred with each episode of anterior uveitis and decreased by 200 µm or more during periods of quiescence in the affected left eye. Subretinal fluid and macular edema developed with a maximum CT of 468 um and spontaneously resolved when CT decreased after treatment. CONCLUSION/CONCLUSIONS:In eyes with pachychoroid disease, anterior segment inflammation may lead to marked increases in subfoveal CT and the development of subretinal fluid at a threshold thickness value.

PURPOSE/OBJECTIVE:The purpose of this study was to report the multimodal imaging features of a cavitary choroidal nevus showing thickness fluctuations that mirrored the response of diabetic macular edema (DME) to intravitreal antivascular endothelial growth factor (VEGF) therapy. METHODS:This is a retrospective case report. Multimodal imaging findings including fundus photography, optical coherence tomography (OCT), fluorescein and indocyanine green angiography, OCT-angiography (OCTA), and B-scan ultrasonography were analyzed. RESULTS:A woman in her 80s with a cavitary choroidal nevus and DME was treated with intravitreal anti-VEGF therapy using a pro re nata regimen over 5 years. The choroidal nevus showed thickness fluctuations paralleling the response of DME to anti-VEGF therapy. Worsening of the DME was associated with marked increased choroidal lesion thickness on OCT. Conversely, resolution of DME after intravitreal anti-VEGF injections was followed by choroidal lesion flattening on OCT. Variations of the choroidal lesion thickness were mainly dependent on changes of intralesional hyporeflective caverns on OCT. CONCLUSION/CONCLUSIONS:Our report shows thickness variations of a cavitary choroidal nevus that paralleled the clinical course of DME treated with intravitreal anti-VEGF therapy. To the best of our knowledge, this is the first report on volume variations of a cavitary choroidal nevus after anti-VEGF therapy.

PURPOSE/OBJECTIVE:This study aims to define the characteristics of acquired vitelliform lesions (AVLs) in patients with intermediate age-related macular degeneration (iAMD). DESIGN/METHODS:Retrospective, observational, cross sectional study. SUBJECTS/METHODS: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/METHODS: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)/BACKGROUND:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.