Faculty Bibliography

PURPOSE/OBJECTIVE:To present a clinicopathologic correlation of indolent, non-progressive multifocal choroidal lesions, clinically presumed to be lymphoid in nature, using multimodal imaging and histopathological analysis of a donor eye. DESIGN/METHODS:Case study and clinicopathologic correlation. PARTICIPANT/METHODS:A 77-year-old man of Caucasian ancestry was followed for nineteen years with indolent non-progressive multifocal choroidal infiltration of his right eye, presumed to be lymphocytic in nature based on the appearance of the lesions. METHODS:Multimodal imaging including fundus photography, B-scan ultrasonography, optical coherence tomography, fluorescein angiography, and indocyanine green angiography were performed throughout 19 years of follow up prior to the patient's death. The involved eye was preserved 21 hours postmortem and analyzed using standard histopathological and immunohistochemical techniques. MAIN OUTCOME MEASURES/METHODS:Correlation of findings on multimodal imaging with histopathological and immunohistochemical findings in the involved eye. RESULTS:Clinical examination over the course of 19 years showed no deterioration in visual acuity of the involved eye. Multimodal imaging revealed yellow-orange choroidal lesions that showed no appreciable progression during the 19 year follow up. These areas stained minimally on fluorescein angiography. Indocyanine green angiography revealed tortuous choroidal vessels and fluorescence blockage. Enhanced-depth imaging optical coherence tomography revealed hyporeflective homogenous choroidal thickening. Light microscopy, histopathology, and immunohistochemistry showed that the lesions were composed of small, mature-appearing B-cells that spared the choriocapillaris. The findings were most consistent with an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). CONCLUSIONS:Indolent non-progressive multifocal choroidal lymphoid lesions in this patient remained confined to the choroid on clinical examination and imaging for almost two decades, with no clinical evidence of extension into the retina. Light microscopy, histopathology, and immunohistochemistry postmortem showed that the lesions were composed of small, mature-appearing B-cells that spared the choriocapillaris. The findings were consistent with an extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). This entity is distinct from more aggressive uveal and choroidal lymphoma and is expected to remain relatively stationary on long-term clinical follow-up, with a good visual prognosis.

PURPOSE/OBJECTIVE:To analyze the spectrum of the perivenular fern-like leakage on ultra-widefield fluorescein angiography (UWFA) and to discuss its potential implications in the current understanding of the retinal venous outflow. DESIGN/METHODS:Retrospective observational case series. PARTICIPANTS/METHODS:Eyes presenting with a fern-like pattern of dye leakage on UWFA were included in this study. METHODS:Analysis of the clinical characteristics and multimodal imaging findings using UWFA and wide-angle swept-source optical coherence tomography angiography (SS-OCTA). MAIN OUTCOME MEASURES/METHODS:To elucidate the disease spectrum, anatomic origin and clinical implications of this fern-like leakage. RESULTS:Multimodal retinal imaging from 40 eyes of 29 patients with fern-like leakage on UWFA was studied. Underlying etiologies included a wide range of inflammatory disorders including pars planitis (18 eyes), and central retinal vein occlusion (2 eyes). On UWFA, the fern-like leakage originated from the retinal capillaries and venules directly adjacent to the veins and spared the peri-arterial zone. This perivenular fern-like leakage involved the far periphery in all cases and progressed more diffusely and centripetally in cases with more severe intra-ocular inflammation. On wide-angle SS-OCTA, deep capillary plexus (DCP) flow signal impairment precisely co-localized with the perivenular fern-like leakage identified on UWFA. CONCLUSIONS:The fern-like leakage on UWFA refers to the distinctive perivenular dye leakage originating from the retinal capillaries and venules. Multimodal imaging correlation suggests predominant impairment at the level of the DCP. Axial symmetry of the fern-like leakage with the veins and sparing of the peri-arterial zone may support the dominant venous role of the DCP.

INTRODUCTION/UNASSIGNED:White dot syndromes are a heterogeneous group of diseases that affect different layers in the retina and choroid. Multimodal imaging is fundamental in the diagnosis, but also can be crucial in unveiling the pathogenesis of these entities. MATERIAL AND METHODS/UNASSIGNED:Literature review. RESULTS/UNASSIGNED:Optical coherence tomography (OCT) provides depth-resolved, histological grade images of the vitreous, retina, and choroid. This technology is very useful to localize the primary nature and level of pathology of the various white dot syndromes. En face OCT can provide additional information regarding the interrelationship of lesion types. Vascular involvement at the level of the retina, choriocapillaris or choroid can be assessed by en face OCT angiography (OCT-A) and is not limited by masking, leakage or staining as can occur with conventional angiography (fluorescein or indocyanine green angiography) which requires dye injection. CONCLUSION/UNASSIGNED:OCT and OCTA are fundamental in the diagnosis and follow-up of white dots syndromes.

Importance/UNASSIGNED:By validating optical coherence tomography angiography (OCTA) in the analysis of type 3 macular neovascularization secondary to age-related macular degeneration, the overall value of clinical OCTA for disease observation, diagnosis, and staging is increased. Objective/UNASSIGNED:To assess the association of in vivo OCTA of type 3 macular neovascularization secondary to age-related macular degeneration with corresponding ex vivo histology. Design, Setting, and Participants/UNASSIGNED:This study included clinical imaging, laboratory microscopy, and eye-tracked clinicopathologic correlation of a single case from a community-based practice evaluated at a university-based research laboratory from 2014 to 2019. Exposures/UNASSIGNED:Infrared reflectance and eye-tracked spectral-domain OCTA clinical imaging was correlated with ex vivo high-resolution histologic images of the preserved donor eye. Eye tracking, applied to the donor eye, enabled identification of histologic features corresponding with clinical OCTA signatures. Projection artifact removal based on 2-dimensional vessel-shape estimation and a Gaussian blur filter demonstrated a robust preservation of neovascular flow signal. Main Outcomes and Measures/UNASSIGNED:Histology findings associated with clinical OCTA signatures. Three-dimensional view of neovascularization via video. Results/UNASSIGNED:A White woman in her 90s with type 3 neovascularization secondary to age-related macular degeneration was treated with 37 intravitreal injections of ranibizumab and aflibercept in the right eye. The index lesion displayed a drusenoid pigment epithelium detachment, characteristic of type 3 neovascularization. OCTA decorrelation signal in the index lesion corresponded in histology to a collagen-ensheathed vascular complex contacting basal laminar deposit that outlasted the retinal pigment epithelium. The subretinal pigment epithelium-basal laminar space contained calcified material and glial processes. No connection between the choriocapillaris and this space was observed. Video showed a columnar tangle of flow signal in the outer nuclear layer, with inflow and outflow vessels connecting to the superficial artery and vein. Conclusions and Relevance/UNASSIGNED:While this study presents only 1 case in which a vascular connection between subretinal pigment epithelium-basal laminar space and choriocapillaris was undetected, these results support the potential value of OCTA for diagnosis. OCTA decorrelation signal of type 3 neovascularization corresponded with intraretinal neovessels on histology. Projection artifact removal based on 2-dimensional vessel-shape estimation and Gaussian blur filter demonstrated their potential value for further use in OCTA decorrelation signal processing.

INTRODUCTION/BACKGROUND:Since July 2021, a worldwide shortage of verteporfin (Visudyne®) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first-choice treatment or regarded as a major treatment option. MATERIALS AND METHODS/METHODS:A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage. RESULTS:Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries. CONCLUSION/CONCLUSIONS:The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public-private partnerships.

PURPOSE/OBJECTIVE:Soft drusen and subretinal drusenoid deposits (SDDs) characterize two pathways to advanced age-related macular degeneration (AMD), with distinct genetic risks, serum risks and associated systemic diseases. METHODS:126 Subjects with AMD were classified as SDD (with or without soft drusen), or non-SDD (drusen only) by retinal imaging, with serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke. RESULTS:There were 62 SDD subjects and 64 non-SDD subjects, 51 total had CVD or stroke.SDD correlated significantly with: lower mean serum HDL (61±18 vs. 69±22 mg/dl, p= 0.038, t test); CVD and stroke (34/51 SDD, p= 0.001, chi square); ARMS2 risk allele (p= 0.019, chi square), but not with CFH risk allele (p = 0.66). Non-SDD (drusen only) correlated/trended with: APOE2 (p= 0.032) and CETP (p= 0.072) risk alleles (chi square). Multivariate independent risks for SDD were: CVD and stroke (p= 0.008), and ARMS2 homozygous risk (p= 0.038). CONCLUSION/CONCLUSIONS:SDD and non-SDD subjects have distinct systemic associations, serum and genetic risks. SDD are associated with CVD and stroke, ARMS2 risk, and lower HDL; non-SDD with higher HDL, CFH risk and two lipid risk genes. These and other distinct associations suggest these lesions are markers for distinct diseases.

PURPOSE/OBJECTIVE:To characterize relationships between Consensus on Neovascular Age-Related Macular Degeneration Nomenclature (CONAN) Study Group classifications of macular neovascularization (MNV) and visual responses to ranibizumab in patients with neovascular age-related macular degeneration (nAMD). METHODS:This was a post hoc analysis of the phase 3 HARBOR trial of ranibizumab in nAMD. Analyses included ranibizumab-treated eyes with baseline multimodal imaging data; baseline MNV; subretinal and/or intraretinal fluid at screening, baseline, or week 1; and spectral-domain optical coherence tomography images through month 24 (n = 700). Mean best-corrected visual acuity (BCVA) over time and mean BCVA change at months 12 and 24 were compared between eyes with type 1, type 2/mixed type 1 and 2 (type 2/M), and any type 3 MNV at baseline. RESULTS:At baseline, 263 (37.6%), 287 (41.0%), and 150 (21.4%) eyes had type 1, type 2/M, and any type 3 lesions, respectively. Type 1 eyes had the best mean BCVA at baseline (59.0 [95% CI: 57.7-60.3] letters) and month 24 (67.7 [65.8-69.6] letters), whereas type 2/M eyes had the worst (50.0 [48.6-51.4] letters and 60.8 [58.7-62.9] letters, respectively). Mean BCVA gains at month 24 were most pronounced for type 2/M eyes (10.8 [8.9-12.7] letters) and similar for type 1 (8.7 [6.9-10.5] letters) and any type 3 eyes (8.3 [6.3-10.3] letters). CONCLUSION/CONCLUSIONS:Differences in BCVA outcomes between CONAN lesion type subgroups support the use of an anatomic classification system to characterize MNV and prognosticate visual responses to anti-vascular endothelial growth factor therapy for nAMD. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov identifier: NCT00891735. Date of registration: April 29, 2009.

PURPOSE:To analyze the nature of multiple evanescent white dot syndrome (MEWDS) and differentiate an idiopathic or primary form of MEWDS from a secondary form that is seen in association with other clinical conditions affecting the posterior segment of the eye. METHODS:Clinical and multimodal imaging findings including color fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral-domain optical coherence tomography, and optical coherence tomography angiography of patients with secondary MEWDS are presented. RESULTS:Twenty consecutive patients with secondary MEWDS were evaluated. Fifteen patients were female. Most were young adults aged between 20 to 40 years with myopia (less than -6 diopters). Pathologic conditions associated with the secondary MEWDS reaction were high myopia (greater than -6 diopters) in two eyes, previous vitreoretinal surgery for rhegmatogenous retinal detachment in 2 eyes, and manifestations of multifocal choroiditis in 18 eyes. In all eyes, the MEWDS lesions followed a course of progression and resolution independent from the underlying condition. CONCLUSION:Secondary MEWDS seems to be an epiphenomenon ("EpiMEWDS") that may be seen in association with clinical manifestations disruptive to the choriocapillaris-Bruch membrane-retinal pigment epithelium complex.