Faculty Bibliography

Purpose:By optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Müller glia. Methods:In clinical OCT (61 eyes, 44 patients with AMD, 79.4 ± 7.7 years; 29 female; follow-up = 4.7 ± 0.9 years), one HRF type, RPE plume (n = 129 in 4 morphologies), was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy, 6; neovascular AMD, 3). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semiquantitatively by one observer (none, some cells, all cells). Results:Plume morphology evolved over time and many resolved (40%). Trajectories of RPE plume and cellular debris paralleled Müller glia, including near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Müller glia remained CRALBP positive. Plume cells approached and contacted retinal capillaries. Conclusions:HRF are indicators not predictors of overall disease activity. Gain and loss of function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PURPOSE/OBJECTIVE:To determine if the stress of normal eye movements results in gaze-induced globe deformations, vitreous chamber axial length and vitreous chamber axial volume (VCAV) change in highly myopic eyes. METHODS:A prospective imaging study was performed on 82 eyes of 43 patients with high myopia (>27 mm of axial length) with a clinical diagnosis of staphyloma. Three-dimensional MRI scans were acquired while subjects gazed in five directions (primary, nasal, temporal, superior and inferior). Surface renderings were generated, and a processing pipeline was created to automate alignment of the eye and to measure VCAV within 5.5 mm of the visual axis for each eye in every gaze. The degree of gaze-induced globe deformation was determined by calculating the Dice coefficient to assess the degree of overlap of the sclera at each eccentric gaze with that found in primary gaze. Each eccentric gaze VCAV was compared to VCAV in primary gaze using a fixed-effects regression allowing for subject-specific and eye-specific effects. RESULTS:(p=0.002, 95% CI 1.71 to 7.86). CONCLUSION/CONCLUSIONS:Significant gaze-induced globe deformation was noted in all gazes, but a reversible, instantaneous VCAV increase occurred only in downgaze, which is consistent with studies supporting the association of environmental factors such as near work with myopia development and progression.

PURPOSE/OBJECTIVE:To determine histologic correlates for defined stages of drusen-associated atrophy observed with multimodal imaging including fundus autofluorescence (FAF) and color fundus photography (CFP) of eyes with advanced age-related macular degeneration (AMD). DESIGN/METHODS:Case study and clinicopathologic correlation. SUBJECT/METHODS:A white woman in whom AMD findings of inactive subretinal fibrosis (right eye) and untreated non-exudative type 1 macular neovascularization (left eye) were followed for 9 years before death at age 90 years. METHODS:Eyes preserved 6.25 hours after death were post-fixed in osmium tannic acid paraphenylenediamine and prepared for sub-micrometer epoxy resin sections (n=115, 90 in right and left eyes, respectively), with 19 aligned to clinical OCT B-scans. Drusen visible by CFP at the last visit were assigned to 4 stages of in vivo FAF: Stage 1, isoFAF, no obvious FAF alteration; Stage 2, mildly uniform hyperFAF; Stage 3, a ring of hyperFAF around a center of hypoFAF; and Stage 4, uniform hypoFAF. MAIN OUTCOME MEASURES/METHODS:Light microscopic morphology at known FAF stages, including druse size, druse contents and changes in overlying retinal pigment epithelium (RPE), photoreceptors and external limiting membrane (ELM). RESULTS:Histology of 166 drusen demonstrated that stage 1 iso-FAF drusen were visible in CFP. HyperFAF in Stage 2 corresponded to short photoreceptors and complete coverage by RPE. HypoFAF in Stage 3 and 4 corresponded to different extents of RPE atrophy (RPE gap and no RPE, respectively). Of stage 4 drusen, 67% have no ONL and an undetectable ELM. Stage 4 includes a high proportion of refractile drusen (82%) with many calcific nodules, visible in CFP. CONCLUSION/CONCLUSIONS:This represents the first direct clinicopathologic correlation for FAF imaging of drusen-associated atrophy. Our data support 4 FAF stages of drusen-associated atrophy. Stage 2 is the earliest detected stage in which loss of screening by photoreceptor photopigment contributes to uniform hyperFAF. Stages 3 and 4 are consistent with incomplete RPE and outer retinal atrophy (iRORA) as defined by the Classification of Atrophy Meetings group. Loss of RPE, ONL and ELM in Stage 4 indicates that atrophy can begin over individual drusen. Our findings will help the identification of new therapeutic approaches and clinical study endpoints.

PURPOSE/OBJECTIVE:To analyze imaging characteristics and the clinical course of patients demonstrating coincident lesions of paracentral acute middle maculopathy (PAMM) and acute macular neuroretinopathy (AMN) in the same eye. DESIGN/METHODS:Retrospective, observational, case series. METHODS:Lesions from patients presenting with coincident PAMM and AMN in the same eye were evaluated with multimodal imaging including optical coherence tomography (OCT). The association with ocular and systemic findings was also investigated. RESULTS:Fifteen subjects (17 eyes) were included in the study. Mean age was 44.4±15.3 years old and follow-up period ranged from 1-32 weeks (mean 11.9±11.4 weeks). Mean visual acuity was 0.8±0.6 logMAR (Snellen equivalent 20/126) at baseline and 0.3±0.4 logMAR (Snellen equivalent 20/40) at the last follow-up. PAMM and AMN lesions occurred in the setting of Purtscher's retinopathy (4 eyes, 3 patients), retinal vein occlusion (7 eyes, 7 patients), central retinal artery occlusion (1 eye, 1 patient), and idiopathic retinal vasculitis (1 eye, 1 patient). In 4 eyes (3 patients) an association with other ocular disorders was not identified as evaluated with multimodal imaging. Of the total cohort,11 eyes (64.7%) showed extension of the AMN hyperreflective bands in the Henle's fiber layer (HFL) with a Z-shaped morphology on OCT B-scan. CONCLUSIONS:Presence of coincident PAMM and AMN suggest a common pathophysiologic etiology. This may be the result of retinal vein impairment and hypoperfusion at the level of the deep retinal capillary plexus possibly leading to injury to the Müller glia or photoreceptors in the HFL.

The choroid provides nutritional support for the retinal pigment epithelium and photoreceptors. Choroidal dysfunction plays a major role in several of the most important causes of vision loss including age-related macular degeneration, myopic degeneration, and pachychoroid diseases such as central serous chorioretinopathy and polypoidal choroidal vasculopathy. We describe an imaging technique using depth-resolved swept-source optical coherence tomography (SS-OCT) that provides full-thickness three-dimensional (3D) visualization of choroidal anatomy including topographical features of individual vessels. Enrolled subjects with different clinical manifestations within the pachychoroid disease spectrum underwent 15 mm × 9 mm volume scans centered on the fovea. A fully automated method segmented the choroidal vessels using their hyporeflective lumens. Binarized choroidal vessels were rendered in a 3D viewer as a vascular network within a choroidal slab. The network of choroidal vessels was color depth-encoded with a reference to the Bruch's membrane segmentation. Topographical features of the choroidal vasculature were characterized and compared with choroidal imaging obtained with indocyanine green angiography (ICGA) from the same subject. The en face SS-OCT projections of the larger choroid vessels closely resembled to that obtained with ICGA, with the automated SS-OCT approach proving additional depth-encoded 3D information. In 16 eyes with pachychoroid disease, the SS-OCT approach added clinically relevant structural details, including choroidal thickness and vessel depth, which the ICGA studies could not provide. Our technique appears to advance the in vivo visualization of the full-thickness choroid, successfully reveals the topographical features of choroidal vasculature, and shows potential for further quantitative analysis when compared with other choroidal imaging techniques. This improved visualization of choroidal vasculature and its 3D structure should provide an insight into choroid-related disease mechanisms as well as their responses to treatment.

PURPOSE/OBJECTIVE:To report a detachment that apparently separated photoreceptor inner segment myoids from inner segment ellipsoids as a manifestation of toxoplasmosis chorioretinitis in a patient with pachychoroid spectrum disease. METHODS:Multimodal imaging including fundus photography, spectral domain and enhanced-depth imaging optical coherence tomography (OCT), indocyanine green angiography, and OCT angiography. RESULTS:A 33-year-old man with a history of toxoplasmosis chorioretinitis reported 1 week of decreased vision to 20/200 in his right eye. Examination of the right eye demonstrated mild vitritis with recurrent chorioretinitis inferior to the fovea and adjacent to a chorioretinal scar. A dome-shaped, foveal photoreceptor layer-splitting detachment was noted on OCT. Because degenerating cone photoreceptors are capable of shedding their inner segments, we inferred the location of the detachment at the level of the inner segment myoid and provided a histological example of such from an unrelated donor case. In addition, multimodal imaging revealed dilated choroidal veins (pachyvessels) with attenuation of the inner choroid in both eyes and asymptomatic findings of central serous chorioretinopathy in the left eye. After 1 month of antibiotic and steroid therapy, the chorioretinitis resolved, as did the detachment. Hyperreflective foci on the vitreoretinal interface were appreciated with en face OCT that appeared to aggregate throughout the course of therapy, induce inner retinal striae, and resolve without inducing epiretinal membrane formation. CONCLUSION/CONCLUSIONS:Patients with preexisting pachychoroid spectrum disease may manifest a more significant retinal fluid accumulation in the setting of superimposed chorioretinal inflammation. In this case of macular toxoplasmosis chorioretinitis, inflammation manifested as a retinal detachment at the level of photoreceptor inner segment myoids that we named as a bacillary layer detachment. In this case, inflammatory sequelae of toxoplasmosis reactivation responded well to oral and intravitreal therapy.

A panel of imaging experts was assembled to review neovascular age-related macular degeneration optical coherence tomography angiography descriptors published to date, and test agreement on use of these terms, which was found to be low. Optical coherence tomography angiography (OCTA) has been used to identify and characterize macular neovascularization (MNV) secondary to age-related macular degeneration (AMD).^1-4 Many studies have explored OCTA morphological features of MNV that might serve as biomarkers to assess disease activity and response to treatment.^1-6 The proliferation of studies however has resulted in an OCTA terminology that has been variable and inconsistent. To address inconsistency of nomenclature and allow harmonization, a multidisciplinary panel of retinal imaging experts with a history of relevant research contributions to the field was assembled with the purpose of reviewing published terminology and to recommend a reduced list of key terms pertinent to OCTA. The group was called UNICORN, because of its ultimate goal of generating a UNIfied COmmentary of the committee of inteRnational experts on the nomenclature for Neovascular AMD in OCTA. In this report we describe the first steps, which included a review of OCTA descriptors of neovascular AMD (nAMD) published to date, and an exercise that tested agreement of these terms among retinal imaging experts. Prior to the first UNICORN meeting, a non-systematic review of the literature was performed, using the search terms "optical coherence tomography angiography" or "OCT angiography" or "OCT-A", AND "neovascular macular degeneration" or "neovascular age-related macular degeneration" or "neovascular AMD" or "nAMD" or "wet age-related macular degeneration" or "wet AMD" or "wet ARMD". A dictionary of OCTA descriptors relating to the features of MNV in AMD was generated and circulated to the panel.

A major cause of poor visual prognosis in Coats disease is the formation of fibrovascular changes following dense foveal lipid deposition. The authors document the multimodal imaging findings of a 38-year-old woman and a 23-year-old man with adult-onset Coats disease who presented with macular edema and foveal lipid accumulation. Thermal laser targeting individual capillary macroaneurysms combined with intravitreal anti-vascular endothelial growth factor (VEGF) therapy was performed. Although there was a subsequent increase in foveal lipid immediately following the resolution of macular edema, these lipids largely resolved, leaving behind no evidence macular neovascular fibrosis. This report highlights the potential protective effect of combination therapy with thermal laser and intravitreal anti-VEGF therapy for macular exudation associated with Coats disease. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:396-399.].

PURPOSE/OBJECTIVE:To study the effect of the suspended scattering particles in motion (SSPiM) on optical coherence tomography angiography (OCTA) vessel density metrics in eyes with diabetic macular edema (DME) METHODS:: Thirty-four eyes with DME from 27 patients (16 males and 11 females, 61.4 ± 9.6 years) with DME were included in this retrospective cohort study. Among these eyes, 19 (55.9%) showed the SSPiM artifact on OCTA. All participants received 3-mm and 6-mm optical coherence tomography angiography (OCTA) imaging. Perfusion density and skeletonized vessel density were calculated for the superficial capillary plexus (SCP) and the deep capillary plexus (DCP), and these were compared between eyes with and without SSPiM. Additionally, foveal vessel density in a 300-µm-wide region around the foveal avascular zone (FVD) was evaluated on 3-mm OCTA scans. The main outcome measures were vessel density in the SCP and the DCP. RESULTS:Among the 3-mm OCTA images, there was no statistically significant difference in SCP vessel density in eyes with and without SSPiM (p = 0.98). Vessel density in the DCP (p = 0.001 and p = 0.028 for perfusion and skeletonized vessel density, respectively) and FVD (p = 0.03) on 3-mm OCTA scans were significantly higher in DME eyes with SSPiM than in those without SSPiM. There were no statistically significant differences in vessel density in SCP and DCP between eyes with and without SSPiM based on 6-mm OCTA scans. CONCLUSION/CONCLUSIONS:The presence of SSPiM may lead to an overestimation of DCP vessel density in eyes with DME when 3-mm OCTA scans are used for analysis.