Faculty Bibliography

PURPOSE/OBJECTIVE:To use swept-source optical coherence tomography and swept-source optical coherence tomography angiography to investigate potential relationships between choroidal vascular hyperpermeability (CVH) seen with indocyanine green angiography (ICGA), choriocapillaris flow density, and choroidal thickness in eyes with pachychoroid pigment epitheliopathy. METHODS:Patients with pachychoroid pigment epitheliopathy were prospectively imaged with 12-mm × 12-mm swept-source optical coherence tomography, 12-mm × 12-mm swept-source optical coherence tomography angiographyA, and ICGA. Binarized choriocapillaris OCTA images were superimposed with ICGA images in which CVH area had been isolated. Choriocapillaris flow density within or outside the quadrants of CVH was calculated and the ratio of these two values was determined. The presence of CVH and choroidal thickness was evaluated at 9 locations within a central 3-mm × 3-mm area to explore the relationship between these 2 factors. RESULTS:Ten eyes from 10 patients were enrolled in the present study. Choriocapillaris flow density within quadrants of CVH area was significantly lower compared with quadrants without CVH (P < 0.001). The mean choriocapillaris flow density ratio was 0.86 ± 0.10 (range: 0.65-0.99). From among the 90 locations in 10 study eyes, 48 were within areas of CVH. Choroidal thickness was greater in quadrants of CVH compared with areas without CVH (P < 0.001, 455 ± 122 µm vs. 297 ± 93 µm). CONCLUSION/CONCLUSIONS:Reduced choriocapillaris flow density, increased choroidal thickness, and CVH appear to co-localize in eyes with pachychoroid pigment epitheliopathy.

PURPOSE/OBJECTIVE:Immunotherapy with atezolizumab, a checkpoint inhibitor targeting the programmed cell death 1 (PD-1) axis, has shown promising results for the treatment of certain metastatic cancers. Atezolizumab-associated acute macular neuroretinopathy (AMN) with retinal venulitis is a newly reported immune-related adverse event (irAE) that further expands the range of adverse effects associated with checkpoint inhibitor therapy. We describe the clinical course and imaging findings of a similar AMN-like retinopathy after treatment with atezolizumab. DESIGN/METHODS:Retrospective case series. PARTICIPANTS/METHODS:Three patients treated with atezolizumab for metastatic breast cancer (n = 1) and non-small-cell lung cancer (n = 2). METHODS:Inclusion criterion was a clinical diagnosis of AMN-like retinopathy with or without retinal vasculitis after atezolizumab administration. MAIN OUTCOME MEASURES/METHODS:Clinical course and multimodal retinal imaging including color photographs, spectral-domain OCT, near-infrared reflectance, and fluorescein angiography were investigated. RESULTS:Three patients (1 woman and 2 men; mean age, 51 years) experienced the acute onset of reduced visual acuity and paracentral scotomas 2 weeks after their first infusion of atezolizumab. Visual symptoms corresponded to focal areas of pericentral photoreceptor disruption in all cases. In 1 patient imaged with fluorescein angiography, focal segments of retinal venulitis were detected. After treatment cessation, incomplete visual recovery was related to persistent photoreceptor damage. All patients died of their cancer within 6 months after the onset of retinopathy. CONCLUSIONS:To our knowledge, there are 3 previously published cases of atezolizumab-associated AMN with retinal vasculitis. This series of 3 similar cases strengthens the association of programmed death ligand 1 (PD-L1) inhibition with this rare form of retinopathy that was termed "anti-PD-L1-associated retinopathy." This irAE seems to be a consistent occurrence in the second week postadministration with lasting structural and functional deficits seen after treatment cessation. Pathophysiologic mechanisms may include loss of tolerance in an immune-privileged organ and subsequent development of T-cell-driven inflammation. In this emerging field, expanding the spectrum and pathogenesis of irAEs is essential to define strategies for prevention, early detection, and appropriate management.

PURPOSE/OBJECTIVE:To clarify the role of subretinal drusenoid deposits (SDD; pseudodrusen) in the progression of age-related macular degeneration through high-resolution histology. METHODS:In 33 eyes of 32 donors (early age-related macular degeneration, n = 15; geographic atrophy, n = 9; neovascular age-related macular degeneration, n = 7; unremarkable, n = 2), and 2 eyes of 2 donors with in vivo multimodal imaging including optical coherence tomography, examples of SDD contacting photoreceptors were assessed. RESULTS:Subretinal drusenoid deposits were granular extracellular deposits at the apical retinal pigment epithelium (RPE); the smallest were 4-µm wide. Outer segment (OS) fragments and RPE organelles appeared in some larger deposits. A continuum of photoreceptor degeneration included OS disruption, intrusion into inner segments, and disturbance of neurosensory retina. In a transition to outer retinal atrophy, SDD appeared to shrink, OS disappeared, inner segment shortened, and the outer nuclear layer thinned and became gliotic. Stage 1 SDD on optical coherence tomography correlated with displaced OS. Confluent and disintegrating Stage 2 to 3 SDD on optical coherence tomography and dot pseudodrusen by color fundus photography correlated with confluent deposits and ectopic RPE. CONCLUSION/CONCLUSIONS:Subretinal drusenoid deposits may start at the RPE as granular, extracellular deposits. Photoreceptor OS, RPE organelles, and cell bodies may appear in some advanced deposits. A progression to atrophy associated with deposit diminution was confirmed. Findings support a biogenesis hypothesis of outer retinal lipid cycling.

PURPOSE/OBJECTIVE:To evaluate the subfoveal choroidal thickness (SFCT) and vascular architecture in the fellow eyes of patients with circumscribed choroidal hemangioma (CCH). METHODS:In this retrospective observational study, patients were selected from outpatient ophthalmology clinics at the Memorial Sloan Kettering Cancer Center and Vitreous Retina Macula Consultants of New York. Subfoveal choroidal thickness was measured using enhanced depth imaging spectral domain optical coherence tomography from the outer portion of Bruch membrane to the choroidal-scleral interface. Choroidal vascular architecture was qualitatively examined. The main outcome measure was SFCT in fellow eyes of patients with CCH, which was compared with an age- and gender-matched control group. RESULTS:Thirty-one fellow eyes (15 right eyes and 16 left eyes) of patients with CCH (23 males and 8 females) were examined. The fellow eye had a mean SFCT of 361.2 ± 99.9 μm compared with 252.0 ± 77.6 μm in the control group (P < 0.0001). Vascular architecture was disorganized in 13 (42%) fellow eyes and 1 (3%) control eye (P < 0.0001), with no apparent gradient of vessel sizes or discrete choroidal layers. The normal association between older age and a thinner choroid existed in control eyes but not in fellow eyes. Hemangioma thickness measured by ultrasound and the presence of subfoveal fluid in the CCH eye did not correlate with the fellow-eye SFCT. CONCLUSION/CONCLUSIONS:In patients with CCH, fellow eyes had thicker SFCT when compared with age- and gender-matched control eyes. Choroidal architecture was often irregular, without segmented vascular layers. These findings suggest that inherent choroidal changes may exist in patients with CCH.

PURPOSE/OBJECTIVE:To describe novel spectral-domain (SD) and swept-source (SS) optical coherence tomography (OCT) linear and planar reflection artifacts produced by hyperreflective crystalline deposits (HCD). METHODS:Imaging from 10 eyes with HCD producing linear and planar artifacts on OCT was retrospectively analyzed. All eyes had SD-OCT (Spectralis HRA + OCT, Heidelberg Engineering, Germany) and SS-OCT angiography (PLEX Elite 9000, Carl Zeiss Meditec, Inc., Dublin, CA) acquired on the same day. The horizontal extent of planar artifacts and the corresponding HCD on B-scans was measured using a digital caliper. Artifact features from HCD in eyes with non-neovascular age-related macular degeneration (AMD) were analyzed and compared to those seen in two eyes with the "onion sign," an OCT signature previously shown to represent cholesterol crystals (CC) in the sub-retinal pigment epithelium-basal laminar space of eyes with neovascular AMD. A third eye with the "onion sign" was imaged with dense B-scan (DB)-OCTA. RESULTS:Ten eyes of ten patients (77.4 ± 8.7 years) with HCD were analyzed. On SS-OCTA, HCD produced linear artifacts of high signal intensity passing through the HCD and spanning the entire scan depth. On SD-OCT, HCD produced planar artifacts located anterior to both the retina and a hyporeflective space representing normal vitreous signal. The horizontal extent of the artifact did not differ significantly from the corresponding HCD on OCT B-scans (P = 0.62). The OCT artifacts produced by the "onion sign" appeared similar to those of HCD. The additional eye with neovascular AMD imaged with DB-OCTA was characterized by a single, vertical, linear false-flow signal crossing retinal layers. CONCLUSIONS:To the authors' knowledge, this is the first description of SD- and SS-OCT/OCTA artifacts corresponding to both HCD and the "onion sign." These artifacts are likely due to highly reflective CC previously shown on histology to correspond to both of these OCT signatures.

PURPOSE/OBJECTIVE:To describe disorders that can masquerade as multiple evanescent white dot syndrome (MEWDS). DESIGN/METHODS:Retrospective, multicenter case series. PARTICIPANTS/METHODS:Patients who presented with clinical findings compatible with a diagnosis of MEWDS but were ultimately diagnosed with an alternative inflammatory, infectious, or neoplastic disorder. METHODS:Clinical records and multimodal imaging findings including fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography (OCT), and OCT angiography (OCTA) were analyzed. MAIN OUTCOME MEASURES/METHODS:Inclusion criteria to be defined as a masquerade syndrome for MEWDS included the presence of disseminated grayish-white outer retinal spots that were hyperautofluorescent on FAF and associated with ellipsoid zone (EZ) disruption on OCT. RESULTS:Twenty-two eyes of 13 patients were identified. All patients presented with the classic findings of MEWDS listed above. A MEWDS-like presentation was bilateral in nine of 13 patients (69%). Final diagnosis was determined on the basis of additional investigations including serologies and biopsy. These diagnoses included syphilis (three patients), lymphoma (three patients), idiopathic multifocal choroiditis (two patients), idiopathic retinal phlebitis (one patient), idiopathic acute zonal occult outer retinopathy (one patient), sarcoidosis (one patient), tuberculosis (one patient), and cancer-associated retinopathy (one patient). The outer retinal lesions and imaging findings resolved with treatment for the associated systemic disorders. CONCLUSIONS:Widespread grayish-white outer retinal spots associated with hyperautofluorescence on FAF and disruption of the EZ on OCT are not pathognomonic for MEWDS. A high index of suspicion must be maintained for masqueraders of MEWDS, which can include serious inflammatory, infectious, and neoplastic disorders.

PURPOSE/OBJECTIVE:To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. DESIGN/METHODS:Consensus meeting. PARTICIPANTS/METHODS:Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. METHODS:As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. MAIN OUTCOME MEASURES/METHODS:Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. RESULTS:OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. CONCLUSIONS:An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.

PURPOSE/OBJECTIVE:Cuticular drusen (CD) have been associated with manifestations of age-related macular degeneration such as atrophy and neovascularization in the macula. In this study, eyes with CD were followed and investigated for the estimated 5-year risk of progression to sequelae of age-related macular degeneration such as geographic atrophy (GA) and macular neovascularization (MNV). METHODS:A consecutive series of patients with CD were followed for the development of GA and MNV. Whenever possible, they were also studied retrospectively. The patients with CD were categorized into three phenotypic groups. Phenotype 1: eyes had concentrated, densely populated CD in the macular and paramacular area, Phenotype 2: eyes showed scattered CD in the posterior fundus, and Phenotype 3: involved eyes with CD mixed with large drusen (>200 µm). The 5-year incidence of progression was then estimated using a Kaplan-Meier estimator. RESULTS:A total of 63 eyes from 38 patients (35 women with a mean age at presentation of 58.9 ± 14.2 years) were studied and followed for a mean of 40 ± 18 months. Thirteen patients had single eyes with GA (84.5%; 11/13) or MNV (15.5%; 2/13) in one eye at presentation and were subsequently excluded. Geographic atrophy developed in 19.0% (12/63) of eyes and MNV in 4.8% (3/63) of eyes. The cumulative estimated 5-year risk of GA and MNV was 28.4% and 8.7%, respectively. The estimated 5-year incidence of MNV or GA was 12.6%, 50.0%, and 51.6% in Phenotype 1, Phenotype 2, and Phenotype 3, respectively (P = 0.0015, log-rank test). No difference in risk was found in the development of GA or MNV (P = 0.11) between the subgroup of patients presenting with GA or MNV in their fellow eye and those with both eyes included. CONCLUSION/CONCLUSIONS:When patients with CD are followed longitudinally, there was a significant risk of progression to GA or MNV for Phenotype 2 and Phenotype 3. Patients with CD are commonly first diagnosed in the fifth decade of life, and there is a female predominance. Clinicians should use multimodal imaging to detect and be aware of the risk of progression to manifestations of GA and MNV. These risks of GA and MNV suggest that patients with CD may be part of the overall spectrum of age-related macular degeneration.

PURPOSE/OBJECTIVE:To characterize the topographic relationships among vitreous structures, including the premacular bursa, prevascular vitreous fissures, cisterns, and lacunae, in healthy participants using en face and cross-sectional swept-source (SS) OCT. DESIGN/METHODS:Prospective, comparative study. PARTICIPANTS/METHODS:Sixty eyes of 60 healthy participants (age range, 4-35 years). Eyes of individuals younger than 20 years (n = 29) were compared with eyes of individuals 20 years of age or older (n = 31). METHODS:From each study eye, 12 × 12-mm SS OCT volume scans comprising 1024 × 1024 A-scans centered at the fovea were acquired. MAIN OUTCOME MEASURES/METHODS:En face and cross-sectional data were analyzed to characterize topographic relationships between hyperreflective spaces anterior to the vitreoretinal interface. RESULTS:Prevascular vitreous fissures are an almost universal feature of human eyes. Cisterns became more prevalent over the course of the first 20 years (r = 0.49; P = 0.002). In 97% of eyes in individuals older than 20 years, en face and cross-sectional SS OCT showed the premacular bursa and prepapillary gap merge at a distance superior to the optic nerve and then follow a superonasal course anteriorly. However, only 69% of individuals younger than 20 years demonstrated such a connection (P = 0.01). A close topographic relationship of vitreous fissures and cisterns to the underlying vasculature of the posterior pole was visible on en face projections. En face imaging readily distinguished these spaces. Degenerative, eyewall-parallel fissure planes and their course were described for the first time in a 3-dimensional manner. The fissure planes were rare in younger eyes (12%) and significantly more common in older eyes (42%; P < 0.001). CONCLUSIONS:En face SS OCT demonstrated that (1) premacular bursa and Cloquet's canal are not connected in younger patients, but are connected in older patients; (2) prevascular vitreous fissures overly the retinal vessels; and (3) cisterns are continuous with prevascular fissures.