Faculty Bibliography

Purpose:By optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Müller glia. Methods:In clinical OCT (61 eyes, 44 patients with AMD, 79.4 ± 7.7 years; 29 female; follow-up = 4.7 ± 0.9 years), one HRF type, RPE plume (n = 129 in 4 morphologies), was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy, 6; neovascular AMD, 3). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semiquantitatively by one observer (none, some cells, all cells). Results:Plume morphology evolved over time and many resolved (40%). Trajectories of RPE plume and cellular debris paralleled Müller glia, including near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Müller glia remained CRALBP positive. Plume cells approached and contacted retinal capillaries. Conclusions:HRF are indicators not predictors of overall disease activity. Gain and loss of function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PURPOSE/OBJECTIVE:To determine if the stress of normal eye movements results in gaze-induced globe deformations, vitreous chamber axial length and vitreous chamber axial volume (VCAV) change in highly myopic eyes. METHODS:A prospective imaging study was performed on 82 eyes of 43 patients with high myopia (>27 mm of axial length) with a clinical diagnosis of staphyloma. Three-dimensional MRI scans were acquired while subjects gazed in five directions (primary, nasal, temporal, superior and inferior). Surface renderings were generated, and a processing pipeline was created to automate alignment of the eye and to measure VCAV within 5.5 mm of the visual axis for each eye in every gaze. The degree of gaze-induced globe deformation was determined by calculating the Dice coefficient to assess the degree of overlap of the sclera at each eccentric gaze with that found in primary gaze. Each eccentric gaze VCAV was compared to VCAV in primary gaze using a fixed-effects regression allowing for subject-specific and eye-specific effects. RESULTS:(p=0.002, 95% CI 1.71 to 7.86). CONCLUSION/CONCLUSIONS:Significant gaze-induced globe deformation was noted in all gazes, but a reversible, instantaneous VCAV increase occurred only in downgaze, which is consistent with studies supporting the association of environmental factors such as near work with myopia development and progression.

PURPOSE/OBJECTIVE:To describe the differential response of two distinct inflammatory signs occurring in eyes with punctate inner choroidopathy (PIC). METHODS:Retrospective, observational case series utilizing multimodal imaging (MMI). RESULTS:Four eyes of 4 myopic female patients (mean age 35 years, range 31-42) presenting with retinal manifestations of PIC. All study eyes had 2 distinct signs of active disease: 1) acute focal hyperreflective lesions splitting the retinal pigment epithelium/Bruch's membrane (RPE/BrM) complex on optical coherence tomography (OCT) which appeared hypoautofluorescent on fundus autofluorescence (FAF), and 2) more diffuse areas of outer retinal disruption (ORD) limited to the ellipsoid zone and interdigitation zone on OCT and corresponding to hyperautofluorescence on FAF. All patients were treated with oral prednisone and demonstrated prompt regression of the RPE/BrM complex lesions with a concurrent, paradoxical centrifugal expansion of ORD. The ORD eventually resolved in all eyes (mean time 6 weeks, range 4-10 weeks). CONCLUSIONS:In patients with PIC, two distinct inflammatory signs observed with MMI display a differential response to systemic corticosteroids. Whereas focal inflammatory lesions splitting the RPE/BrM complex appear to respond rapidly, the more diffuse, transient ORD shows little response. This difference in treatment response may reflect different immunological phenomena with independent natural history.

PURPOSE/OBJECTIVE:To longitudinally characterize structural/angiographic findings of retinal-choroidal anastomosis (RCA) in macular telangiectasia type 2 (MacTel2). METHODS:Combined retrospective/prospective review of MacTel2 patients with >2 visits and >2 months follow-up, including examination, fundus photography, fluorescein angiography, spectral-domain optical coherence tomography (SD-OCT), and projection-resolved OCT angiography. RESULTS:There were 24 eyes of 12 patients with mean age 61.1 (±7.3 [SD]) years and median follow-up 447 (range 81-1511) days. There were 5 eyes diagnosed with new RCA after not having any previously. RCA was diagnosed in 8 (33%) eyes initially and eventually 13 (54%). In the 8 eyes initially diagnosed with RCA, the number of RCAs and outer retinal hyperrflective lesions increased over the follow-up. The RCAs were found in clusters, generally temporal to the fovea. RCA was uniformly associated with complete retinal subsidence, defined as the loss of outer nuclear layer substance such that the middle retinal layers sank down toward retinal pigment epithelium (RPE), was also present in each case. Each RCA colocalized with a region of hyperreflectivity, previously termed outer retinal hyperreflective lesion (ORHL). There was a lack of fluorescein leakage, lipid, hemorrhage, or any structural correlates to fluid exudation, and no signs of subretinal/sub-RPE neovascularization. CONCLUSION/CONCLUSIONS:De novo RCA development appears to be associated with retinal subsidence, and after RCAs form, they increase in number and topographic distribution over time. Initially after formation, there was no sign of exudation. These data suggest descent of the deep capillary plexus occurs with RCA, devoid subretinal/sub-RPE neovascularization in MacTel2.

PURPOSE/OBJECTIVE:To describe the retinal findings in a 25-year-old white woman in whom a diagnosis of Boucher-Neuhäuser Syndrome (BNS) was supported by genetic testing, which identified a missense and novel nonsense mutation in the PNPLA6 gene. METHODS:Observational case report of a 25-year-old woman who presented with primary amenorrhea, cerebellar ataxia, and mild retinal pigmentary abnormalities. Neurologic, endocrine, and genetic evaluations established a diagnosis of BNS. RESULTS:Clinical examination and multimodal imaging documented focal outer retinal and retinal pigment epithelium changes including bilateral foveal stippling and a circular area of hypopigmentation in the superior macula of the left eye. Optical coherence tomography showed a linear area of outer retinal attenuation superonasal to the fovea and multiple foci of pinpoint outer retinal defects in the temporal macula of the left eye. Humphrey visual field 24-2 testing showed nonspecific defects in both eyes. Full-field electroretinography showed no evidence of a generalized retinal dysfunction. CONCLUSION/CONCLUSIONS:Recognition that the chorioretinal abnormalities occurring in BNS can be rather subtle is essential because the diagnosis of BNS may depend on their detection. To the best of our knowledge, this is the first report in the ophthalmic literature of mild chorioretinal changes in a patient with BNS testing positive for a mutation in the PNPLA6 gene.

Misusing the selective laser trabeculoplasty (SLT) mode of capsulotomy-SLT systems to attempt capsulotomy causes severe, permanent macular injuries. We present a multimodal imaging injury analysis and detail engineering and administrative controls to prevent further injuries.

PURPOSE/OBJECTIVE:To describe the presence of subretinal lipid globules (SLG), analyze the multimodal imaging features inherent in their optical properties and provide a means to distinguish them from other retinal structures and clinical signs. DESIGN/METHODS:Retrospective cohort study. METHODS:The clinical data and multimodal imaging features of 39 patients (49 eyes) showing SLG were evaluated. Patients underwent color fundus photography, near-infrared reflectance (NIR), spectral-domain (SD) and swept-source (SS) optical coherence tomography (OCT) and OCT angiography. In vitro phantom models were used to model OCT optical properties of water, mineral oil, and intralipid droplets and to investigate the optical mechanisms producing hypertransmission tails beneath SLG. RESULTS:The SLG were not visible in color fundus photographs or NIR images. With both SD- and SS-OCT B-scans, SLG appeared as 31-157 micron round hyporeflective structures demonstrating a characteristic hypertransmission tail previously described with lipid globules found in the choroid and in neovascular membranes. Similarly, with en face OCT, SLG appeared as small round hyporeflective structures. SLG were encountered most often in eyes with neovascular age-related macular degeneration (AMD) that had type 1 macular neovascularization (MNV) (91.8%). Of these eyes, 93.3% were receiving intravitreal anti-vascular endothelial growth factor (VEGF) therapy (median of 15 injections) with a mean follow-up of 52.6 months. The number of prior injections positively correlated with the number of SLG. The detection of MNV preceded the presence of SLG in 66.7% of cases. En face OCT showed that in many eyes (49%) SLG appeared in clusters of >10. In 38.8% of eyes, SLG were found overlying type 1 MNV and in 44.9% of eyes, often those with more numerous SLG, the SLG were located near the lesion border. In 2 eyes with AMD followed for nonexudative type 1 MNV, SLG were detected prior to the detection of other imaging signs of exudation. SLG were observed in several other exudative macular diseases. Phantom models demonstrated that the hypertransmission tail beneath SLG is related to a lensing effect produced by these hyporeflective spherical structures. CONCLUSIONS:SLG are a newly recognized OCT feature frequently seen in eyes receiving intravitreal anti-VEGF therapy for type 1 MNV due to AMD. OCT B-scans show SLG as small, round, hyporeflective structures with a characteristic hypertransmission tail. This OCT signature is influenced by the OCT focal plane and it relates to reduced signal attenuation through oil and a lensing effect created by a higher refractive index compared to surrounding tissue.

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare and unusual paraneoplastic ocular syndrome with generally poor prognosis. The authors present a case of BDUMP in a patient with bladder cancer, examined with current multimodal imaging. In the clinical setting with drusen and exudative macular detachments, the fundus simulated neovascular age-related macular degeneration, warranting standard-of-care therapy. The imaging actually showed the typical manifestations of BDUMP, but also newly recognized, associated manifestations, including the bacillary layer detachment, a gravitating retinal detachment, and multifocal choroidal hyperpermeability, but no evidence of neovascularization. Recognition of these associated manifestations is of value in appreciating the pathophysiology of this paraneoplastic disorder. Based on the imaging, the correct diagnosis was possible along with a better understanding of the nature of the clinical features in the posterior fundus. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:413-417.].

PURPOSE/OBJECTIVE:Type 1 macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) may sustain hypoxic and micronutrient-insufficient outer retinal cells compensatorily. We explored this hypothesis via histologic analysis of an eye with a shallow irregular retinal pigment epithelial elevation (SIRE) on OCT and good vision. DESIGN/METHODS:Case study and clinicopathologic correlation. PARTICIPANT/METHODS:A white woman with untreated nonexudative neovascular AMD and 20/30 visual acuity (left eye) and neovascular AMD (right eye), with 9 years' multimodal imaging before dying at 90 years of age. METHODS:The left eye was preserved 6.25 hours after death and prepared for submicrometer epoxy resin sections and transmission electron microscopy aligned to clinical OCT B-scans. Inside and outside the MNV area, layer thicknesses, phenotypes, and vascular density of native choriocapillaris and neovessels were measured. Lengths of choriocapillaries and intervening gaps in the index eye and in early AMD eyes and healthy eyes with similar age (n = 19 each) from the Project MACULA (Maculopathy Unveiled by Laminar Analysis) online histopathologic resource (http://projectmacula.cis.uab.edu/) were measured with custom software (Caps and Gaps). MAIN OUTCOME MEASURES/METHODS:Descriptive features, vascular density, histologic and OCT layer thicknesses, and distribution of choriocapillaries and intervening gaps. RESULTS:The SIRE correlated to a type 1 MNV that expanded slowly without evidence of exudation and with numerous choroidal vessels traversing Bruch's membrane defects, some visible on OCT. Tissue layers in and adjacent to the MNV area showed continuous RPE and characteristic AMD deposits. Capillary-like neovessels with fenestrations and caveolae resembling native choriocapillaris lined the retinal pigment epithelium (RPE) with a vascular density comparable with surrounding non-MNV areas. Relative to early AMD and healthy aged eyes, the index eye showed similar capillary lengths but larger gaps between vessels, indicating dropout. Outer nuclear layer thickness was preserved and showed less photoreceptor degeneration over areas of relative choriocapillaris health, including the type 1 MNV. CONCLUSIONS:Eyes with nonexudative type 1 MNV in AMD may progress to exudation, yet this stable MNV complex supported outer retinal structure for 9 years. Distinguishing features were numerous connecting vessels, high density of neovessels, continuous RPE, and slow growth. Maintaining beneficial type 1 MNV may be a therapeutic strategy.