Alterations of the foveal central bouquet associated with cystoid macular edema.

OBJECTIVE: The central bouquet (CB) of the fovea comprises a dense array of cone photoreceptors intertwined with Müller cells. The aim of this investigation was to study visual outcomes and structural alterations in the foveal CB associated with cystoid macular edema (CME) of different etiologies. DESIGN: Retrospective case series. PARTICIPANTS AND METHODS: This study analyzed eyes with various etiologies of CME, including diabetic macular edema, central retinal vein occlusion (CRVO), pseudophakic or Irvine-Gass (IG) syndrome, uveitis, and retinitis pigmentosa using spectral-domain optical coherence tomography (SD-OCT). SD-OCT was used to classify the CB alterations as either (1) thickened hyper-reflectivity associated with indistinct ellipsoid zone (EZ), or (2) subretinal fluid with intact EZ. Comparisons were made using the Students t test and Fisher's exact test. RESULTS: The total cohort consisted of 61 eyes from 61 patients with various etiologies of CME. CB alterations were observed in 91% of uveitis eyes, 82% of CRVO eyes and 50% of IG eyes. Presence of CB alteration correlated with greater central macular thickness (p = 0.0020), horizontal extent of edema (p = 0.0042), and worse baseline visual acuity (p = 0.0195). Type 2 CB alterations were associated with worse logMAR vision compared with type 1 at baseline and final examinations (p = 0.0002, p = 0.0470). CONCLUSIONS: CB alterations were noted in the majority of eyes with CME from CRVO, uveitis, and IG. The association observed between CB alterations and central macular thickness suggests that these alterations may develop as a result of mechanical stress of Müller cells on the CB.

Expression of ABCA4 in the retinal pigment epithelium and its implications for Stargardt macular degeneration.

Recessive Stargardt disease (STGD1) is an inherited blinding disorder caused by mutations in the Abca4 gene. ABCA4 is a flippase in photoreceptor outer segments (OS) that translocates retinaldehyde conjugated to phosphatidylethanolamine across OS disc membranes. Loss of ABCA4 in Abca4-/- mice and STGD1 patients causes buildup of lipofuscin in the retinal pigment epithelium (RPE) and degeneration of photoreceptors, leading to blindness. No effective treatment currently exists for STGD1. Here we show by several approaches that ABCA4 is additionally expressed in RPE cells. (i) By in situ hybridization analysis and by RNA-sequencing analysis, we show the Abca4 mRNA is expressed in human and mouse RPE cells. (ii) By quantitative immunoblotting, we show that the level of ABCA4 protein in homogenates of wild-type mouse RPE is about 1% of the level in neural retina homogenates. (iii) ABCA4 immunofluorescence is present in RPE cells of wild-type and Mertk-/- but not Abca4-/- mouse retina sections, where it colocalizes with endolysosomal proteins. To elucidate the role of ABCA4 in RPE cells, we generated a line of genetically modified mice that express ABCA4 in RPE cells but not in photoreceptors. Mice from this line on the Abca4-/- background showed partial rescue of photoreceptor degeneration and decreased lipofuscin accumulation compared with nontransgenic Abca4-/- mice. We propose that ABCA4 functions to recycle retinaldehyde released during proteolysis of rhodopsin in RPE endolysosomes following daily phagocytosis of distal photoreceptor OS. ABCA4 deficiency in the RPE may play a role in the pathogenesis of STGD1.

Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease.

Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4-/- (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4-/- mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRY-treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY-treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.

Safety of Concurrent Boston Type I Keratoprosthesis and Glaucoma Drainage Device Implantation.

PURPOSE: To evaluate the safety of concurrent Boston type I keratoprosthesis (KPro) and glaucoma drainage device (GDD) implantation. DESIGN: Retrospective comparative study of a consecutive cohort of patients. SUBJECTS: Patients who underwent KPro implantation by a single surgeon (A.J.A.) with or without 1 concurrent Ahmed GDD (New World Medical, Inc., Rancho Cucamonga, CA) implantation between January 1, 2005, and January 31, 2015, were included. Patients with fewer than 3 months of follow-up or a history of previous KPro implantation were excluded. METHODS: Preoperative, operative, and postoperative data were collected for each procedure. All comparisons were made between KPro procedures performed with or without concurrent GDD implantation. The Fisher exact test (2-tailed) was used to compare proportions, Student t test and Wilcoxon rank-sum test were used to compare means, and the log-rank test was used to compare time-to-outcome events. MAIN OUTCOME MEASURES: The primary outcome was frequency of the composite variable, that is, any serious vision-threatening postoperative complication, which included sterile vitreitis, endophthalmitis, hypotony maculopathy, suprachoroidal hemorrhage, retinal detachment, stromal necrosis, and infectious keratitis. Secondary outcomes included intraocular pressure control, worsening of visual acuity, cystoid macular edema, retroprosthetic membrane formation, persistent epithelial defect formation, GDD exposure, and KPro removal. RESULTS: One hundred thirty-seven KPro procedures were performed in 129 patients: 91 (66.4%) KPro alone and 46 (33.6%) KPro plus GDD. There were no statistically significant differences between the 2 groups in terms of the incidence of vision-threatening postoperative complications. None of the 46 GDDs placed at the same time as the KPro became exposed during an average follow-up of 44 months. CONCLUSIONS: Compared with KPro alone, GDD placement combined with KPro was not associated with increased postoperative complications.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF TYPE 3 NEOVASCULARIZATION SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To characterize the vascular structure of Type 3 neovascularization secondary to age-related macular degeneration using optical coherence tomography angiography. METHODS: Optical coherence tomography angiography cube scans (3 mm × 3 mm) were acquired in 29 eyes of 24 patients with Type 3 lesions secondary to age-related macular degeneration using the RTVue XR Avanti with AngioVue, Split-spectrum amplitude-decorrelation, and motion correction technology. Automated layer segmentation boundaries were adjusted to best visualize the neovascular complex on en face projection images. RESULTS: A distinct neovascular complex could be identified in 10 (34%) eyes, all of which were active on optical coherence tomography imaging. In all 10 eyes, the neovascular complex appeared as a small tuft of bright, high-flow tiny vessels with curvilinear morphology located in the outer retinal layers with a feeder vessel communicating with the inner retinal circulation (i.e., deep retinal capillary plexus). The mean (SD) size of the neovascular complex measured 0.07 (± 0.07) mm. CONCLUSION: With optical coherence tomography angiography, it is possible to identify small intraretinal neovascular complexes communicating with the deep retinal capillary plexus in eyes with Type 3 neovascularization secondary to age-related macular degeneration. Qualitative and quantitative analyses of Type 3 neovascular complexes can be performed using optical coherence tomography angiography.

Optical Coherence Tomography Angiography of Type 1 Neovascularization in Age-Related Macular Degeneration.

PURPOSE: To analyze type 1 neovascular membranes in age-related macular degeneration (AMD) using optical coherence tomography (OCT) angiography, to correlate morphologic characteristics with imaging and clinical criteria, and to analyze structural features of type 1 neovascularization sequentially after anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Prospective interventional case series. METHODS: Macular OCT angiography images were acquired using the RTVue XR Avanti with AngioVue. Distinct morphologic patterns and quantifiable features of the neovascular membranes were studied on en face projection images at baseline and follow-up. RESULTS: Thirty-three eyes of 25 patients were included. In 75% of the eyes, a highly organized vascular complex could be identified. A large main central vessel trunk/feeder vessel could be seen in 72% of these eyes, with vessels radiating in a branching pattern either in all directions from the center of the lesion ("medusa" pattern), or from one side of the lesion ("seafan" pattern). Of the 18 eyes with follow-up OCT angiography, the lesion area and vessel density remained unchanged, even after anti-vascular endothelial growth factor (VEGF) therapy, indicating a more mature longstanding neovascular complex resistant to anti-VEGF therapy. CONCLUSIONS: OCT angiography provides a unique opportunity to study the morphology of occult type 1 neovascular membranes in AMD and allows precise structural and vascular assessment noninvasively. We identified a large mature neovascular complex in approximately 75% of eyes, typically consisting of a feeder vessel and large branching vessels resistant to anti-VEGF therapy. OCT angiography may better guide evaluation and treatment of neovascular AMD, and may contribute to the development of improved therapies.