Faculty Bibliography

PURPOSE/OBJECTIVE:To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors. PARTICIPANTS/METHODS:A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT). DESIGN/METHODS:Single-center, retrospective cohort study. METHODS:Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point. MAIN OUTCOME MEASURES/METHODS:Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation. RESULTS:The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001). CONCLUSION/CONCLUSIONS:The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage.

Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10^-8) were identified at three independent loci (rs73171800 at 5q14.3, P = 7.74 × 10^-17; rs715 at 2q34, P = 9.97 × 10^-14; rs477992 at 1p12, P = 2.60 × 10^-12) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1,134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences in blood serum levels of glycine (P = 4.04 × 10^-6) and serine (P = 2.48 × 10^-4) between MacTel cases and controls.

PURPOSE/OBJECTIVE:To expand our understanding of the uncommon entity, referred to as perifoveal exudative vascular anomalous complex (PEVAC) by describing multimodal imaging findings, including optical coherence tomography angiography (OCT-A). DESIGN/METHODS:Retrospective cohort study. METHODS:Patients diagnosed with PEVAC were identified at 4 retina referral centers worldwide and underwent complete ophthalmologic examination including structural OCT, OCT-A, fluorescein angiography (FA), and indocyanine green angiography (ICGA). Demographics and clinical findings were analyzed at baseline and at available follow-ups. RESULTS:Fifteen eyes (15 patients, mean age 73 ± 13 years) were included. Six of 15 eyes were diagnosed with coincident age-related macular degeneration (AMD) and 2 with myopic macular degeneration. On fundus examination PEVAC presented as a large perifoveal isolated aneurysm, unifocal in 12 of 15 eyes, associated with small retinal hemorrhages and intraretinal exudation. On structural OCT, PEVAC appeared as a round hyperreflective lesion with hyporeflective lumen, typically surrounded by intraretinal cystic spaces. Dye angiography demonstrated a well-defined hyperfluorescent lesion with variable leakage on FA and without leakage on ICGA. OCT-A showed flow signal correlating with the aneurysmal lesion connecting to retinal capillary plexuses. Seven patients were followed for 13.0 ± 10.5 months with no evidence of functional/anatomic changes. Three patients underwent anti-vascular endothelial growth factor (VEGF) intravitreal injections without improvement. Two eyes were associated with a type 3 neovascularization eccentric to PEVAC. CONCLUSIONS:PEVAC is an isolated, perifoveal, aneurysmal abnormality, occurring in otherwise healthy patients who may manifest other macular disease including AMD and myopic macular degeneration. PEVAC did not typically respond to anti-VEGF therapy, and may be associated with type 3 neovascularization.

Importance:Acute zonal occult outer retinopathy (AZOOR) remains a challenging diagnosis. Early recognition of the disease depends on advances in imaging modalities that can improve phenotyping and contribute to the understanding of the underlying pathogenesis. Objectives:To expand the range of approaches available to assist in the identification of AZOOR by multimodal imaging and to analyze the fundus lesions by quantifying short-wavelength fundus autofluorescence (quantitative fundus autofluorescence [qAF]) and spectral-domain optical coherence tomography. Design, Setting, and Participants:In this observational study, patients underwent imaging at Columbia University Medical Center between November 2010 and March 2016 and were analyzed between September 2015 and August 2016. Six patients diagnosed as having AZOOR were studied by qAF and spectral-domain optical coherence tomography and were compared with 30 age and race/ethnicity–matched controls from a database of 277 healthy control eyes. Main Outcomes and Measures:In unaffected regions of the macula, qAF was calculated within predetermined circularly arranged segments (qAF8). In addition, qAF was measured within specified regions of interest positioned at the autofluorescent lesion border (AZOOR line). Electroretinograms and electro-oculograms were recorded in 5 of 6 patients. Results:Among 6 patients (age range, 26-61 years; 4 female; 4 of white race/ethnicity, 1 Asian, and 1 Hispanic), 5 exhibited an autofluorescent AZOOR line in short-wavelength fundus autofluorescence images, delineating the peripapillary lesion. The mean (SD) region-of-interest qAF measured on the AZOOR line was 60 (26) times higher than in healthy control eyes (P = .03) at equivalent fundus locations. The qAF8 within nondiseased macular regions were within the normal range. At the lesion border, spectral-domain optical coherence tomography revealed a loss of outer retinal integrity in all patients. Single-flash cone b-wave latency and 30-Hz flicker latency responses were significantly delayed bilaterally. Lesions with smooth, homogeneous borders exhibited only minimal expansion in size over time, while the lesion in a patient with a heterogeneous border progressed more rapidly. Conclusions and Relevance:The finding that qAF is elevated at the border between diseased and nondiseased retina in patients with AZOOR contributes to the understanding of the natural history of the disease.

Purpose: Perifoveal Exudative Vascular Anomalous Complex (PEVAC) is an uncommon disease recently described by our group as a unilateral, isolated, single, perifoveal, large aneurismal change. It generally affects otherwise healthy patients that do not show evidence of arterial hypertension, diabetes or any other vasculopathy. We reviewed the charts of patients with diagnosis of PEVAC to report their imaging features on optical coherence tomography angiography (OCT-A). Methods: All patients affected by PEVAC were identified from a pool of patients at 4 retina referral centers. The main exclusion criteria were the presence of retinal vascular diseases (e.g. diabetic retinopathy, hypertension retinopathy, retinal vein occlusion and retinal inflammatory diseases). All patients underwent a complete ophthalmologic examination including structural optical coherence tomography (OCT) and OCT-A (3x3 area). All OCT-A imagines were analyzed by two trained examiners (GQ and RS) to investigate the qualitative features of PEVAC. Results: A total of 12 eyes of 12 patients were included in the analysis. In 11 out of 12 cases, PEVAC was located inside 500 mum from the center of the fovea. In all cases, OCT-A showed an isolated large dilation in the retinal capillary plexuses, with a detectable flow inside the complex. Typically, PEVAC was characterized by a rarefaction of retinal capillaries surrounding the lesion. Three out of 12 cases were detected only in superficial retinal plexus, 2 out of 12 only in deep retinal plexus and 7 out of 12 in both superficial and deep retinal plexuses. In all cases there was no sign of flow in the avascular plexus and no sign of anastomosis between the retinal capillary plexuses and the choriocapillaris; a shadow effect was constantly present in the choriocapillaris segmentation. No other macular abnormalities were present on OCTA outside the area of the lesion. Conclusions: Optical coherence tomography angiography of PEVAC showed almost constantly a high-flow, isolated large dilation in the retinal vascularization associated with a surrounding rarefaction of normal retinal capillaries

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: 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.