Faculty Bibliography

Nonneovascular (dry) AMD is a retinal disease with potential for significant central visual impairment. The hallmarks of this disease are macular drusen, RPE alterations, and geographic atrophy (GA). Classification schemes for nonneovascular AMD have evolved over the years as major advances in retinal imaging have enabled a greater understanding of disease pathophysiology. The original classifications of nonneovascular AMD were based on color fundus photography (CFP), while more modern schemes rely on a multimodal imaging approach. Effective diagnosis and management of nonneovascular AMD requires a thorough understanding of its multimodal imaging features as detailed in this review. Future imaging modalities and imaging biomarkers that may aid in diagnosis and management are also discussed.

PURPOSE/OBJECTIVE:Widespread adoption of optical coherence tomography has revolutionized the diagnosis and management of retinal disease. If the cellular and subcellular sources of reflectivity in optical coherence tomography can be identified, the value of this technology will be advanced even further toward precision medicine, mechanistic thinking, and molecular discovery. Four hyperreflective outer retinal bands are created by the exquisite arrangement of photoreceptors, Müller cells, retinal pigment epithelium, and Bruch membrane. Because of massed effects of these axially compartmentalized and transversely aligned cells, reflectivity can be localized to the subcellular level. This review focuses on the second of the four bands, called ellipsoid zone in a consensus clinical lexicon, with the central thesis that mitochondria in photoreceptor inner segments are a major independent reflectivity source in this band, because of Mie scattering and waveguiding. METHODS:We review the evolution of Band 2 nomenclature in published literature and discuss the origins of imaging signals from photoreceptor mitochondria that could make these organelles visible in vivo. RESULTS:Our recent data pertain to outer retinal tubulation, a unique neurodegenerative and gliotic structure with a highly reflective border, prominent in late age-related macular degeneration. High-resolution histology and multimodal imaging of outer retinal tubulation together provide evidence that inner segment mitochondria undergoing fission and translocation toward the nucleus provide the reflectivity signal. CONCLUSION/CONCLUSIONS:Our data support adoption of the ellipsoid zone nomenclature. Identifying subcellular signal sources will newly inform clinical.

The term aneurysmal type 1 neovascularization is derived from terminology, which is established in the literature but has fallen out of use. We believe that aneurysmal type 1 neovascularization accurately describes the lesions which define the entity known as polypoidal choroidal vasculopathy (PCV). Over the last three decades, the clinical spectrum of PCV has expanded to recognize the occurrence of the aneurysmal (polypoidal) lesions in different contexts, resulting in a complex and unwieldy taxonomy based sometimes on circumstantial findings rather than mechanistic considerations. Advances in multimodal imaging provides increasingly convincing evidence that the lesions which define various forms of PCV are indeed vascular and arise from type 1 neovascular networks. The understanding of PCV as type 1 neovascularization with aneurysms renews focus on the question as to why some patients with type 1 neovascularization develop aneurysms while others do not. Conceptual themes and potential for further study are discussed.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) that leads to progressive and irreversible loss of visual function. Geographic atrophy is defined by the presence of sharply demarcated atrophic lesions of the outer retina, resulting from loss of photoreceptors, retinal pigment epithelium (RPE), and underlying choriocapillaris. These lesions typically appear first in the perifoveal macula, initially sparing the foveal center, and over time often expand and coalesce to include the fovea. Although the kinetics of GA progression are highly variable among individual patients, a growing body of evidence suggests that specific characteristics may be important in predicting disease progression and outcomes. This review synthesizes current understanding of GA progression in AMD and the factors known or postulated to be relevant to GA lesion enlargement, including both affected and fellow eye characteristics. In addition, the roles of genetic, environmental, and demographic factors in GA lesion enlargement are discussed. Overall, GA progression rates reported in the literature for total study populations range from 0.53 to 2.6 mm2/year (median, approximately 1.78 mm2/year), assessed primarily by color fundus photography or fundus autofluorescence (FAF) imaging. Several factors that could inform an individual's disease prognosis have been replicated in multiple cohorts: baseline lesion size, lesion location, multifocality, FAF patterns, and fellow eye status. Because best-corrected visual acuity does not correspond directly to GA lesion enlargement due to possible foveal sparing, alternative assessments are being explored to capture the relationship between anatomic progression and visual function decline, including microperimetry, low-luminance visual acuity, reading speed assessments, and patient-reported outcomes. Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis.

PURPOSE/OBJECTIVE:The mitochondrial DNA point mutation A3243G leads to a spectrum of syndromes ranging from MIDD to MELAS. Ocular manifestations include pattern macular dystrophy and concentric perifoveal atrophy. Given the high metabolic demand of corneal endothelial cells, we performed specular biomicroscopy analysis in patients harboring the mitochondrial DNA point mutation A3243G to assess for the associated presence of corneal endothelial abnormalities. METHODS:We present a case series with participants from two institutions. Patients diagnosed with macular dystrophy associated with MIDD or MELAS, and the mitochondrial DNA point mutation A3243G were recruited. Exclusion criteria included a prior diagnosis, or a positive family history, of endothelial corneal dystrophy. Slit-lamp corneal examination and specular biomicroscopy were performed. Corneal endothelial cell count, cell size and polymegathism, and central corneal thickness were assessed. Patients diagnosed with MIDD or MELAS based on clinical history and examination were genetically tested for the mitochondrial DNA point mutation A3243G using pyrosequencing. RESULTS:and the average central corneal thickness (CCT) was 551 ± 33 μm. These values were similar to that of the average population. The average coefficient of variation (COV), an index of heterogeneity in cell size, was 42.0 ± 4.1%. When compared to the average population, the average COV was significantly higher than predicted for the patients' age. None of the patients had signs of corneal edema. One patient had a pre-Descemet's opacity. CONCLUSIONS:In patients with the mitochondrial DNA point mutation A3243G, corneal endothelial polymegathism is present. This is mainly associated with mild guttata. The findings of corneal endothelial cell polymegathism may be a biomarker of mitochondrial disease, specifically in patients with the mitochondrial DNA A3243G mutation.

PURPOSE: To correlate histologic results with previously recorded multimodal imaging results from a patient with type 3 neovascularization secondary to age-related macular degeneration (AMD). DESIGN: Case study, clinical imaging, laboratory imaging, and eye-tracked clinicopathologic correlation. PARTICIPANT: An 86-year-old white woman with type 3 neovascularization secondary to AMD treated with 6 intravitreal injections of bevacizumab. METHODS: Multimodal retinal imaging at each clinic visit was correlated with ex vivo and high-resolution histologic images of the preserved donor eye. Clinical imaging included serial near-infrared reflectance and eye-tracked spectral-domain optical coherence tomography (OCT). Eye tracking, applied to the donor eye, enabled identification of histologic features corresponding to clinical OCT signatures. MAIN OUTCOME MEASURES: Histologic correlates for clinical OCT signatures were sought, including reflectivity of the vascular complex, intraretinal hyperreflective foci and intraretinal cellularity, analysis of the topography of pathologic features, and evaluation of the sub-retinal pigment epithelium (RPE) plus basal lamina (BL) space. RESULTS: Clinical imaging showed a deep neovascular lesion in close relationship with a mixed serous and drusenoid pigment epithelium detachment (PED), characteristic of type 3 neovascularization. Antiangiogenic therapy achieved a complete resolution of exudation. The PED progressively flattened with each treatment, leaving a persistent triangular hyperreflectivity in the outer retina. This persistent deep lesion histologically correlated with a vascular complex implanted into sub-RPE basal laminar deposit. No connection between the choriocapillaris and the sub-RPE plus BL space was observed. Both RPE-derived and lipid-filled cells were correlated with clinical intraretinal hyperreflective foci. The sub-RPE plus BL space contained macrophages, lymphocytes, Muller cell processes, and subducted RPE. CONCLUSIONS: Clinicopathologic correlation of type 3 neovascularization showed vascular elements of retinal origin accompanied by collagenous material and Muller cell processes implanting into thick sub-RPE basal laminar deposit, which may simulate the appearance of chorioretinal anastomosis. Surrounding RPE-derived and lipid-filled cells thought to be microglia correlated with clinical intraretinal hyperreflective foci.

PURPOSE: To define the range and life cycles of cuticular drusen phenotypes using multimodal imaging and to review the histologic characteristics of cuticular drusen. DESIGN: Retrospective, observational cohort study and experimental laboratory study. PARTICIPANTS: Two hundred forty eyes of 120 clinic patients with a cuticular drusen phenotype and 4 human donor eyes with cuticular drusen (n = 2), soft drusen (n = 1), and hard drusen (n = 1). METHODS: We performed a retrospective review of clinical and multimodal imaging data of patients with a cuticular drusen phenotype. Patients had undergone imaging with various combinations of color photography, fluorescein angiography, indocyanine green angiography, near-infrared reflectance, fundus autofluorescence, high-resolution OCT, and ultrawide-field imaging. Human donor eyes underwent processing for high-resolution light and electron microscopy. MAIN OUTCOME MEASURES: Appearance of cuticular drusen in multimodal imaging and the topography of a cuticular drusen distribution; age-dependent variations in cuticular drusen phenotypes, including the occurrence of retinal pigment epithelium (RPE) abnormalities, choroidal neovascularization, acquired vitelliform lesions (AVLs), and geographic atrophy (GA); and ultrastructural and staining characteristics of druse subtypes. RESULTS: The mean age of patients at the first visit was 57.9+/-13.4 years. Drusen and RPE changes were seen in the peripheral retina, anterior to the vortex veins, in 21.8% of eyes. Of eyes with more than 5 years of follow-up, cuticular drusen disappeared from view in 58.3% of eyes, drusen coalescence was seen in 70.8% of eyes, and new RPE pigmentary changes developed in 56.2% of eyes. Retinal pigment epithelium abnormalities, AVLs, neovascularization, and GA occurred at a frequency of 47.5%, 24.2%, 12.5%, and 25%, respectively, and were significantly more common in patients older than 60 years of age (all P < 0.015). Occurrence of GA and neovascularization were important determinants of final visual acuity in eyes with the cuticular drusen phenotype (both P < 0.015). Small cuticular drusen typically demonstrated a homogenous ultrastructural appearance similar to hard drusen, whereas fragmentation of the central and basal contents was seen frequently in larger cuticular drusen. CONCLUSIONS: Although the ultrastructural characteristics of cuticular drusen appear more similar to those of hard drusen, their lifecycle and macular complications are more comparable with those of soft drusen. Cuticular drusen phenotype may confer a unique risk for the development of GA and neovascularization.

Background/UNASSIGNED:Aneurysmal type 1 neovascularization (AT1) is a term recently introduced to better describe the aneurysmal dilatation that may arise from neovascular lesions, more commonly known as polypoidal choroidal vasculopathy. The proposed term, AT1, includes an expanded clinical spectrum of aneurysmal (polypoidal) lesions observed in both different ethnicities and associated with varied clinical phenotypes. Case presentation/UNASSIGNED:A 61-year-old woman of European descent was referred for a new, asymptomatic retinal hemorrhage found on routine examination. Ophthalmoscopy revealed cuticular drusen in both eyes best appreciated on fundus autofluorescence, and a hemorrhagic retinal pigment epithelium detachment above the superior arcade in the right eye. In the fellow eye, a reddish appearing pigment epithelial detachment was noted nasal to the optic nerve. Indocyanine green angiography showed findings of AT1 in both eyes. Optical coherence tomography angiography showed intrinsic flow signal within the aneurysmal lesions. Conclusions/UNASSIGNED:Eyes with cuticular drusen may develop AT1 which, to our knowledge, has not been described. This is an important observation because the documented coexistence of AT1 in the setting of a variant of age-related macular degeneration lends supports to this new understanding of AT1 as a growth pattern of neovascular tissue proliferating between the RPE and Bruch membrane, rather than as a distinct disease entity.