Faculty Bibliography

PURPOSE/OBJECTIVE:To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural optical coherence tomography. DESIGN/METHODS:Consensus meeting METHODS: As part of the Classification of Atrophy Meeting program, an international group of experts analyzed and discussed retinal multimodal imaging features in eyes with AMD associated with GA and/or risk of progression to GA. Attendees undertook pre-meeting grading exercises that were reviewed during the meeting sessions. Meeting presentations illustrated established and investigational multimodal imaging features and associated histology. These different features were then each discussed openly by the entire group to arrive at consensus definitions. These definitions were applied to 40 additional images that were graded independently by attendees, to further refine the consensus definitions and descriptions. RESULTS:Consensus was reached on images with descriptors for 12 features. These features included components of outer retinal atrophy (e.g., ellipsoid zone disruption), components of complete retinal pigment epithelium (RPE) and outer retinal atrophy (e.g., RPE perturbation with associated hypo- or hyper-transmission), features frequently seen in eyes with atrophy (e.g., refractile drusen) and features conferring risk for atrophy development (e.g., hyperreflective foci, drusen, and subretinal drusenoid deposits). CONCLUSIONS:An International consensus on terms and descriptions was reached on multimodal imaging features associated GA and with risk for GA progression in eyes with AMD. We believe this information will be useful to clinicians who manage patients with AMD, researchers who study AMD disease interventions and pathogenesis, and those who design clinical trials for therapies targeting earlier AMD stages than GA expansion.

PURPOSE/OBJECTIVE:To study microvascular characteristics of small resolved paracentral acute middle maculopathy (PAMM) lesions in fellow eyes of patients with unilateral retinal vein occlusion (RVO). DESIGN/METHODS:Prospective cross-sectional study. PARTICIPANTS/METHODS:Patients with prior unilateral branch or central RVO and optical coherence tomography (OCT) evidence of resolved PAMM in their fellow, otherwise normal, eyes were prospectively recruited and imaged with OCT angiography (OCTA). METHODS:The resolved PAMM lesions were identified as focal areas of inner nuclear layer thinning over an anteriorly displaced outer plexiform layer (OPL). En face OCTA projections showing the location and size of the resolved PAMM lesions were created using 2 OPL segmentation lines with -9 μm and 0 μm offsets, and the cumulative distribution was evaluated. Anterior to the resolved PAMM lesions, vessels in the superficial vascular plexus were traced to identify small arterioles supplying the affected areas. MAIN OUTCOME MEASURES/METHODS:Cumulative spatial distribution on small resolved PAMM lesions. RESULTS:From 24 fellow eyes of 24 patients with unilateral RVO (15 males and 9 females, mean age 62.0 ± 15.1 years) 152 resolved PAMM lesions were identified. Of these lesions, 130 (85.5%) were found within the perifoveal region, and only 12 (7.9%) were found within the temporal quadrant. Of 28 lesions analyzed, the arteriole supplying the affected area was a single side branch of a larger vessel, with only 3 supplied by a terminal branch. CONCLUSION/CONCLUSIONS:Small resolved PAMM lesions in fellow eyes of patients with unilateral RVO are most prevalent in perifovea regions supplied by side branches of low order retinal arteries.

Purpose:To analyze the morphology of foveal hyperreflective dots (HRD) identified with en face optical coherence tomography (OCT) and evaluate the effects of internal limiting membrane (ILM) peeling and posterior vitreous detachment (PVD) on the number of these lesions. Methods:Retrospective cross-sectional study of patients with OCT angiography and en face OCT. Using en face OCT, superficial HRD lying on the foveal floor were measured and quantitated in eyes with ILM peel and in the fellow nonsurgical eyes. Eyes with foveal PVD were also compared to fellow eyes without foveal PVD. High-magnification en face OCT was also performed to better understand the morphology of HRD in the fovea. Results:Eyes that underwent ILM peel (n = 10) displayed fewer HRD (P = 0.012) compared to control fellow nonoperated eyes. In eyes with foveal PVD, the mean number of HRD was numerically greater, but without statistical significance, compared to the contralateral eye without foveal PVD. High-magnification en face OCT illustrated HRD with irregular shapes and fine cilia-like or dendriform extensions. Average length of HRD was between 15 to 21 µm in all four groups. Conclusions:HRD decreased in eyes with ILM peeling by en face OCT compared with fellow nonoperated eyes and exhibited a glial cell-like morphology and size closely resembling the white dot fovea described previously using scanning electron microscopy. HRD may represent processes of activated retinal glia, possibly Muller cells, that traverse defects in the ILM.

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 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 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 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.