Faculty Bibliography

PURPOSE: Drusenoid pigment epithelium detachment (DPED) is a known precursor to geographic atrophy in age-related macular degeneration (AMD). We sought histologic correlates for spectral-domain (SD) optical coherence tomography (OCT) signatures in DPED and determined the frequency and origin of these OCT signatures in a clinical cohort of DPED eyes. DESIGN: Laboratory imaging and histologic comparison, and retrospective, observational cohort study. PARTICIPANTS: Four donor eyes with histopathologic diagnosis of AMD (2 with nonneovascular DPED and 2 with neovascular pigment epithelium detachment [PED]) and 49 eyes of 33 clinic patients with nonneovascular DPED more than 2 mm in diameter. METHODS: Donor eyes underwent multimodal ex vivo imaging, including SD OCT, then processing for high-resolution histologic analysis. All clinic patients underwent SD OCT, near-infrared reflectance, and color photography. MAIN OUTCOME MEASURES: Histologic correlates for SD OCT signatures in DPED, estimate of coverage by different retinal pigment epithelium (RPE) phenotypes in the DPED surface; frequency and origin of histologically verified SD OCT signatures in a clinical cohort of DPED eyes, and comparisons of histologic features between neovascular PED and DPED resulting from AMD. RESULTS: Intraretinal and subretinal hyperreflective foci as seen on SD OCT correlated to RPE cells on histologic examination. Hypertransmission of light below the RPE-basal lamina band correlated with dissociated RPE. Subretinal hyperreflective material resulting from acquired vitelliform lesions corresponded to regions of apically expelled RPE organelles. In the clinical cohort, all histologically verified reflectivity signatures were visible and quantifiable. The appearance of intraretinal hyperreflective foci was preceded by thickening of the RPE-basal lamina band. Compared with PEDs associated with neovascular AMD, DPEDs had different crystallization patterns, no lipid-filled cells, and thinner basal laminar deposits. CONCLUSIONS: Multiple RPE fates in AMD, including intraretinal cells that are highly prognostic for progression, can be followed and quantified reliably using eye-tracked serial SD OCT. This information may be particularly useful for obtaining an accurate timeline of incipient geographic atrophy in clinic populations and for quantifying anatomic end points and response to therapy in AMD clinical trials.

PURPOSE: To assess the spectrum of perivenular ischemia in eyes with retinal vascular obstruction (typically central or hemicentral retinal vein obstruction) using en face optical coherence tomography (OCT). DESIGN: Retrospective observational case series. METHODS: Eyes with recent retinal vascular occlusion illustrating paracentral acute middle maculopathy (PAMM) in a perivenular fern-like pattern with en face OCT were evaluated in this study. Multimodal retinal imaging including en face OCT segmentation of the inner nuclear layer was performed in all patients. Color fundus photography and fluorescein angiography (FA) images were used to create a vascular overlay of the retinal veins versus the retinal arteries to map the distribution of PAMM with en face OCT analysis. RESULTS: Multimodal retinal imaging was performed in 11 eyes with acute retinal vascular obstruction. While 7 eyes demonstrated obvious findings of retinal vein obstruction (5 with central and 2 with hemicentral retinal vein occlusion), 4 eyes were unremarkable at presentation. En face OCT analysis demonstrated a spectrum of perivenular PAMM illustrating a fern-like pattern with sparing of the periarteriolar area in all cases. CONCLUSION: En face OCT may illustrate a remarkable perivenular pattern of PAMM in eyes with retinal vascular obstruction even in the absence of significant funduscopic findings. Perivenular PAMM with en face OCT demonstrates a wide spectrum of variation with narrow fern-like perivenular lesions at the mildest end and more diffuse lesions with only periarterial sparing at the most severe end of the spectrum. Arterial hypoperfusion secondary to outflow obstruction from a central retinal vein obstruction appears to be the most common cause of this presentation although primary arterial hypoperfusion may also be an etiology.

BACKGROUND/AIMS: To assess the microvascular response of type 3 neovascularisation secondary to age-related macular degeneration (AMD) after antivascular endothelial growth factor (anti-VEGF) therapy using optical coherence tomography angiography (OCTA). METHODS: Consecutive patients diagnosed with AMD and type 3 neovascularisation based on clinical examination, structural optical coherence tomography and fluorescein angiography when available were retrospectively evaluated. En face OCTA imaging (3x3 mm scans) with quantitative microvascular analysis was performed at baseline and after a single anti-VEGF intravitreal injection. RESULTS: 17 eyes of 14 patients underwent OCTA before and after anti-VEGF treatment. OCTA demonstrated significant regression of small calibre type 3 neovascular tufts in all eyes. Median lesion area was 0.061 mm2 (range 0.003-0.198 mm2) at baseline and 0.009 mm2 (range 0-0.085 mm2, p=0.0003) at follow-up. Cystoid macular oedema and/or subretinal fluid resolved in all cases after treatment. The type 3 lesions became undetectable with OCTA post-treatment in 5 of the 17 eyes. However, in 11 eyes, large feeder vessels were identified and remained unchanged after treatment. CONCLUSIONS: The microvascular morphology of type 3 neovascularisation secondary to AMD was assessed at baseline and follow-up and showed significant regression in response to anti-VEGF therapy by OCTA. Quantitative OCTA analysis was also performed and confirmed remarkable regression in response to a single intravitreal anti-VEGF injection.

Purpose: Histologic details of progression routes to geographic atrophy (GA) in AMD are becoming available through optical coherence tomography (OCT). We studied the origins and evolution of an OCT signature called plateau in eyes with GA and suggested a histologic correlate. Methods: Serial eye-tracked OCT scans and multimodal imaging were acquired from eight eyes of seven patients with GA and plateau signatures over a mean follow-up of 7.7 years (range, 3.7-11.6). The histology of unrelated donor eyes with AMD was reviewed. Results: Drusenoid pigment epithelial detachment (PED) on OCT imaging progressed into wide-based mound-like signatures with flattened apices characterized by a hyporeflective yet heterogeneous interior and an overlying hyperreflective exterior, similar to outer retinal corrugations previously ascribed to persistent basal laminar deposit (BLamD) but larger. These new signatures are described as "plateaus." An initial increase of the PED volume and hyporeflectivity of its contents was followed by a decrease in PED volume and thinning of an overlying hyperreflective band attributable to the loss of the overlying RPE leaving persistent BLamD. Both imaging and histology revealed persistent BLamD with defects through which gliotic Muller cell processes pass. Conclusions: Plateaus can be traced back to drusenoid PEDs on OCT imaging. We hypothesize that during progressive RPE atrophy, Muller cell extension through focal defects in the residual persistent BLamD may contribute to the heterogeneous internal reflectivity of these entities. The role of Muller cell activation and extension in the pathogenesis of AMD should be explored in future studies.

Purpose: To study the retinal capillary microvasculature and the choriocapillaris (CC) in myopic eyes using quantitative optical coherence tomography angiography (OCTA) analysis. Methods: Macular OCTA images of 3 x 3 mm were obtained using the RTVue-XR Avanti with AngioVue. Quantitative measurements of the retinal capillary microvascular layers and the CC were analyzed using en face projection images. Vessel density and fractal dimension of the superficial and deep retinal capillary plexus, and area and density of flow reduction in the CC were analyzed, quantified, and compared with an age-matched control group. Results: Fifty eyes with myopia and 34 age-matched healthy eyes were included in this study. The vessel density and the vessel branching complexity using fractal dimension of the retinal capillary microvasculature were significantly lower in myopic eyes (P < 0.001 and P = 0.001). The total number of flow voids in the CC was lower (108.93 vs. 138.63, P = 0.001) but the total and average flow void area was significantly higher (total area 3.715 +/- 0.257 vs. 3.596 +/- 0.194 mm2, P = 0.026; average area 0.044 +/- 0.029 vs. 0.028 +/- 0.010 mm2, P = 0.002) compared with the healthy control group. Average choroidal thickness was lower in the myopic group versus the normal control cohort (123.538 +/- 73.477 vs. 246.97 +/- 41.745 mum, P < 0.05) and significantly reduced in eyes with lacquer cracks (LC) compared with myopic eyes without LC formation (P = 0.003). There was no correlation between choroidal thickness and quantitative parameters of the CC in the myopic eyes. Conclusions: The density of the retinal capillary microvasculature is reduced and the area of flow deficit in the CC is increased in eyes with greater myopia. The relevance of microvascular alterations in the setting of myopia warrants further study.

PURPOSE: To report intraocular manifestations of Erdheim-Chester Disease (ECD) with multimodal imaging. DESIGN: A retrospective observational case series. METHODS: This was a multicenter case series of 3 patients with confirmed tissue diagnosis of ECD that showed intraocular manifestations and were imaged at baseline and follow-up visits. RESULTS: Intraocular manifestations are rarely observed in association with ECD. Intraocular manifestations of ECD seen on multimodal imaging include histiocytic choroidal infiltration causing choroidal lesions, complicated by recurrent serous retinal detachment (SRD). Short-term resolution of SRD was observed with ocular therapies including intravitreal injections of anti-vascular endothelial growth factor or verteporfin photodynamic therapy in combination with systemic chemotherapy therapies and oral corticosteroids; however, recurrences were common. Chorioretinal biopsy confirmed the diagnosis of ECD in 1 case, with the presence of histiocytic infiltration, fibrosis, and characteristic immunohistologic staining. In another case, with a novel ARAF positive mutation, treatment with sorafenib showed regression of the choroidal lesions and resolution of the SRD on multimodal imaging. These lesions were previously resistant to other forms of therapy. CONCLUSIONS: Rare intraocular manifestations of ECD confirmed on histopathology can be imaged with multimodal imaging. We report 3 cases, including 1 case diagnosed through histology from chorioretinal biopsy and another case associated with a novel ARAF mutation responsive to targeted therapy with sorafenib. The identification of novel somatic mutation associated with ECD enabled treatment with a new-targeted systemic agent. Multimodal imaging in these cases can also be used to monitor response to therapy.

PURPOSE/OBJECTIVE:To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN/METHODS:Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS/METHODS:A panel of retina specialists. METHODS:During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES/METHODS:Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS:Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. CONCLUSIONS:A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.