Aberrant lipid accumulation and retinal pigment epithelium dysfunction in PRCD-deficient mice.

Progressive Rod-Cone Degeneration (PRCD) is an integral membrane protein found in photoreceptor outer segment (OS) disc membranes and its function remains unknown. Mutations in Prcd are implicated in Retinitis pigmentosa (RP) in humans and multiple dog breeds. PRCD-deficient models exhibit decreased levels of cholesterol in the plasma. However, potential changes in the retinal cholesterol remain unexplored. In addition, impaired phagocytosis observed in these animal models points to potential deficits in the retinal pigment epithelium (RPE). Here, using a Prcd-/- murine model we investigated the alterations in the retinal cholesterol levels and impairments in the structural and functional integrity of the RPE. Lipidomic and immunohistochemical analyses show a 5-fold increase in the levels of cholesteryl esters (C.Es) and lipid deposits in the PRCD-deficient retina, respectively, indicating alterations in total retinal cholesterol. Furthermore, the RPE of Prcd-/- mice exhibit a 1.7-fold increase in the expression of lipid transporter gene ATP-binding cassette transporter A1 (Abca1). Longitudinal fundus and spectral domain optical coherence tomography (SD-OCT) examinations showed focal lesions and RPE hyperreflectivity. Strikingly, the RPE of Prcd-/- mice exhibited age-related pathological features such as lipofuscin accumulation, Bruch's membrane (BrM) deposits and drusenoid focal deposits, mirroring an Age-related Macular Degeneration (AMD)-like phenotype. We propose that the extensive lipofuscin accumulation likely impairs lysosomal function, leading to the defective phagocytosis observed in Prcd-/- mice. Our findings support the dysregulation of retinal cholesterol homeostasis in the absence of PRCD. Further, we demonstrate that progressive photoreceptor degeneration in Prcd-/- mice is accompanied by progressive structural and functional deficits in the RPE, which likely exacerbates vision loss over time.

How is eyeball growth associated with optic nerve head shape and glaucoma? The Lamina cribrosa/Bruch's membrane opening offset theory.

The optic nerve head (ONH) is a complex structure wherein the axons of the retinal ganglion cells extrude from the eyeball through three openings: 1) the Bruch's membrane opening (BMO) in the retinal layer, 2) the anterior scleral canal opening in the anterior scleral layer, and 3) the lamina cribrosa (LC). Eyeball expansion during growth induces an offset among openings, since the expansion affects the inner retinal and outer scleral layers differently: the posterior polar retinal structure is preserved by the preferential growth in the equatorial region, whereas no such regional difference is observed in the scleral layer. The various modes and extents of eyeball expansion result in diverse directionality and amount of offset among openings, which causes diverse ONH morphology in adults, especially in myopia. In this review, we summarize the ONH changes that occur during myopic axial elongation. These changes were observed prospectively in our previous studies, wherein LC shift and subsequent offset from the BMO center could be predicted by tracing the central retinal vascular trunk position. This offset induces the formation of γ-zone parapapillary atrophy or externally oblique border tissue. As a presumptive site of glaucomatous damage, the LC/BMO offset may render the LC pores in the opposite direction more vulnerable. To support such speculation, we also summarize the relationship between LC/BMO offset and glaucomatous damage. Indeed, LC/BMO offset is not only the cause of diverse ONH morphology in adults, but is also, potentially, an important clinical marker for assessment of glaucoma.

Accuracy of Bruch's membrane opening minimum rim width and retinal nerve fiber layer thickness in glaucoma diagnosis depending on optic disc size.

BACKGROUND/AIM: The aim of this paper is to compare retinal nerve fiber layer thickness (RNFL) and Bruch's membrane opening-based minimum rim width (BMO-MRW) in terms of their performance in detecting early and moderate/advanced glaucoma using receiver operating characteristics (ROC) analysis and the classification using the 5th percentile as a cut-off. METHODS: One hundred eyes from 100 patients with early glaucoma (mean deviation (MD): < -5.0 dB) and 100 eyes from 100 patients with moderate/advanced glaucoma (MD: > -5.0 dB) were carefully matched to healthy controls based on optic disc size. Then, the dataset was divided, based on the 50th percentile of the measured Bruch's membrane opening area (BMO-A), into small (BMO-A < 1.95 mm2) and large optic discs (BMO-A > 1.95 mm2). Finally, the discriminative performance of BMO-MRW and RNFL between glaucoma and controls using ROC analysis and the manufacturer's classification based on the 5th percentile was analyzed. RESULTS: In discriminating between glaucoma and matched healthy controls, global BMO-MRW and global RNFL thickness had comparable areas under the ROC curve for eyes with early glaucoma and both small BMO-As (ROC ± confidence interval [CI] 0.91 [0.87 to 0.95] and 0.88 [0.83 to 0.93]) and large BMO-As (0.86 [0.82 to 0.92] and 0.84 [0.79 to 0.90]), as well as in moderate/advanced glaucoma with small BMO-As (0.99 [0.98 to 1.00] and 0.97 [0.95 to 1.00]) and large BMO-As (0.94 [0.91 to 0.98] and 0.97 [0.94 to 1.00]). Using the calculated 5th percentile as a threshold value, the sensitivities for the detection of early and moderate/advanced glaucoma were comparable for BMO-MRW and RNFL in eyes with small optic discs (early glaucoma: fifty-two percent and 61%; moderate/advanced glaucoma: ninety-one percent and 92%). In eyes with large optic discs, the sensitivity of BMO-MRW was inferior to that of RNFL for both early (38% versus 51%) and moderate/advanced (80% versus 91%) glaucoma. CONCLUSION: Based on an ROC analysis, the discriminative performance of BMO-MRW and RNFL between patients with early and moderate/advanced glaucoma and a healthy control group matched based on optic disc size is comparable in eyes with BMO-As smaller and larger 1.95 mm2. Using a classification based on the 5th percentile, as used in clinical practice, RNFL is shown to be superior to BMO-MRW regarding sensitivity in glaucoma detection with large optic discs. This study underscores the importance of RNFL imaging and measurement in the diagnostic evaluation of glaucoma, especially in cases of large optic discs.

Drusen in the macula and parapapillary region.

PURPOSE: To examine histological characteristics and differences between drusen beneath the retinal pigment epithelium (small hard drusen) located in the macula and located in the parapapillary region. METHODS: We histomorphometrically examined human eyes enucleated due to uveal melanomas or secondary angle-closure glaucoma. RESULTS: The study included 106 eyes (age, 62.6 ± 15.2 years) with macular drusen (n = 7 globes) or parapapillary drusen (n = 29 eyes) and 70 eyes without drusen. In all drusen, periodic-acid-Schiff-positive material was located between the RPE basal membrane and the inner collagenous layer of Bruch's membrane (BM). Macular drusen as compared with parapapillary drusen had lower height (15.2 ± 10.1 µm versus 34.3 ± 19.8 µm; P = 0.003), while both groups did not differ significantly in basal drusen width (74.0 ± 36.3 µm versus 108.7 ± 101.0 µm; P = 0.95). Eyes with macular drusen and eyes without drusen did not differ significantly in BM thickness (2.74 ± 0.44 µm versus 2.55 ± 0.88 µm; P = 0.57) or in RPE cell density (35.4 ± 10.4 cells/480 µm versus 32.8 ± 7.5 cells/480 µm; P = 0.53), neither in the drusen region nor in the drusen vicinity, while BM thickness (4.60 ± 1.490 µm; P < 0.001) and RPE cell density (56.9 ± 26.8 cells/480 µm; P = 0.005) were higher at the parapapillary drusen. Eyes with macular drusen, eyes with parapapillary drusen, and eyes without drusen did not differ significantly in choriocapillaris density (all P > 0.10) and thickness (all P > 0.35). Limitations of the study, among others, were a small number and size of drusen examined, diseases leading to enucleation, lack of serial sections, limited resolution of light microscopy, and enucleation-related and histological preparation-associated artefacts. CONCLUSIONS: The findings of this study, also taking into account its methodological limitations, suggest that macular drusen and parapapillary drusen shared the morphological feature of periodic-acid-Schiff-positive material between the RPE basal membrane and BM and that they did not vary significantly in choriocapillaris thickness and density. RPE cell density and BM thickness were higher in parapapillary drusen than in macular drusen.

PHENOTYPIC CHARACTERIZATION OF PREDICTORS FOR DEVELOPMENT AND PROGRESSION OF GEOGRAPHIC ATROPHY USING OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the impact of optical coherence tomography phenotypes preceding atrophy related to age-related macular degeneration on the progression of atrophic lesions. METHODS: In this observational retrospective cohort study, a total of 70 eyes of 60 consecutive patients with intermediate age-related macular degeneration with a minimum follow-up of 24 months were included. The atrophy was quantified using fundus autofluorescence, also considering the directionality of atrophy as centrifugal and centripetal progression rates. The main outcome measures were geographic atrophy (GA) progression rate (mm 2 /year) and square root transformation of GA (mm 2 /year). RESULTS: The best-fit model for GA (odds ratio: 1.81, P < 0.001) and square root transformation of GA (odds ratio: 1.36, P < 0.001) areas revealed that the main baseline predictor was the presence of a retinal pigment epithelium-basal lamina-Bruch membrane splitting. Large drusen at baseline appeared protective for the GA area lesion expansion over time (odds ratio: 0.52, P < 0.001) when considered with other confounders. CONCLUSION: A thin retinal pigment epithelium-basal lamina-Bruch membrane splitting without evidence of neovascularization on optical coherence tomography angiography likely represents an optical coherence tomography signature for late basal laminar deposits. Identifying this phenotype can help identify individuals with a higher risk of rapid progression and atrophy expansion.

Porcine models of choroidal neovascularization: A systematic review.

Animal models of choroidal neovascularization (CNV) are extensively used in translational studies of CNV formation and to evaluate angiostatic treatment strategies. However, the current paucity of large animal models compared with rodent models constitutes a knowledge gap regarding the clinical translation of findings. Ocular anatomical and physiological similarities to humans suggest the pig as a relevant model animal. Thus, a systematic survey of porcine CNV models was performed to identify pertinent model parameters and suggest avenues for model standardization and optimization. A systematic search was performed in PubMed and EMBASE on November 28, 2022 for porcine models of CNV. Following inclusion by two investigators, data from the articles were extracted according to a predefined protocol. A total of 14 articles, representing 19 independent porcine CNV models were included. The included models were almost equally divided between laser-induced (53%) and surgically-induced (47%) models. Different specified breeds of domestic pigs (71%) were most commonly used in the studies. All studies used normal animals. Female pigs were reported used in 43% of the studies, while 43% did not report on sex of the animals. Younger pigs were typically used. The surgical models reported consistent CNV induction following mechanical Bruch's membrane rupture. The laser models used variants of the infrared diode laser (40%) or the frequency-doubled Nd:YAG laser (50%). Both lasers enabled successful CNV induction with reported induction rates ranging from 60 to 100%. Collateral damage to the neuroretina was reported for the infrared diode laser. CNV evaluation varied across studies with fluorescein angiography (50%) as the most used in vivo method and retinal sections (71%) as the most used ex vivo method. In interventional studies, quantification of lesions was in general performed between 7 and 14 days. The field of porcine CNV models is relatively small and heterogeneous and almost equally divided between surgically-induced and laser-induced models. Both methods have allowed successful modeling of CNV formation with induction rates comparable to those of non-human primates. However, the field would benefit from standardization of model parameters and reporting. This includes laser parameters and validation of CNV formation as well as methods of CNV evaluation and statistical analysis.

ARTIFICIAL INTELLIGENCE'S ROLE IN DIFFERENTIATING THE ORIGIN FOR SUBRETINAL BLEEDING IN PATHOLOGIC MYOPIA.

PURPOSE: To identify salient imaging features to support human-based differential diagnosis between subretinal hemorrhage (SH) due to choroidal neovascularization (CNV) onset and SH without CNV (simple bleeding [SB]) in pathologic myopia eyes using a machine learning (ML)-based step-wise approach. METHODS: Four different methods for feature extraction were applied: GradCAM visualization, reverse engineering, image processing, and human graders' measurements. GradCAM was performed on a deep learning model derived from Inception-ResNet-v2 trained with OCT B-scan images. Reverse engineering consisted of merging U-Net architecture with a deconvolutional network. Image processing consisted of the application of a local adaptive threshold. Available OCT B-scan images were divided in two groups: the first group was classified by graders before knowing the results of feature extraction and the second (different images) was classified after familiarization with the results of feature extraction. RESULTS: Forty-seven and 37 eyes were included in the CNV group and the simple bleeding group, respectively. Choroidal neovascularization eyes showed higher baseline central macular thickness ( P = 0.036). Image processing evidenced in CNV eyes an inhomogeneity of the subretinal material and an interruption of the Bruch membrane at the margins of the SH area. Graders' classification performance improved from an accuracy of 76.9% without guidance to 83.3% with the guidance of the three methods ( P  = 0.02). Deep learning accuracy in the task was 86.0%. CONCLUSION: Artificial intelligence helps identifying imaging biomarkers suggestive of CNV in the context of SH in myopia, improving human ability to perform differential diagnosis on unprocessed baseline OCT B-scan images. Deep learning can accurately distinguish between the two causes of SH.

HISTOLOGY, DIMENSIONS, AND FLUORESCEIN STAINING CHARACTERISTICS OF NODULAR AND CUTICULAR DRUSEN IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To enable in vivo analysis of drusen composition and lifecycle, the macular nodular and cuticular drusen were assessed using histology. METHODS: Median and interquartile range of base widths of single (nonconfluent) nodular drusen in three sources were determined histologically: 43 eyes of 43 clinically undocumented donors, in an online resource; one eye with punctate hyperfluorescence in fluorescein angiography; and two eyes of one patient with bilateral "starry sky" cuticular drusen. All tissues were processed for high-resolution epoxy-resin histology and for cuticular drusen, transmission electron microscopy. RESULTS: All drusen localized between the retinal pigment epithelium basal lamina and inner collagenous layer of the Bruch membrane. They were solid, globular, homogeneously stained with toluidine blue, and uncovered by basal laminar deposit and basal mounds. Median base widths were 13.0 µ m (Source 1, N = 128 drusen, interquartile range 7.7, 20.0 µ m), 15.3 µ m (Source 2, N = 87, interquartile range 10.6, 20.5 µ m), and 7.3 µ m (Source 3, N = 78, interquartile range 3.9, 14.1 µ m). CONCLUSION: In three samples, >90% of solitary nodular drusen were <30 µ m, the visibility threshold in color fundus photography; these drusen are hyperfluorescent in fluorescein angiography. Whether these progress to soft drusen, known as high-risk from epidemiology studies and hypofluorescent, may be determinable from multimodal imaging datasets that include fluorescein angiography.

Elastin Layer in Bruch's Membrane as a Target for Immunization or Tolerization to Modulate Pathology in the Mouse Model of Smoke-Induced Ocular Injury.

Age-related macular degeneration (AMD) is associated with an overactive complement system and an increase in circulating antibodies. Our search for potential neoantigens that can trigger complement activation in disease has led us to investigate elastin. A loss of the elastin layer (EL) of Bruch's membrane (BrM) has been reported in aging and AMD together with an increase of serum elastin-derived peptides and α-elastin antibodies. In the mouse model of cigarette smoke exposure (CSE), damage in BrM, loss of the EL, and vision loss are dependent on complement activation. We have examined the hypothesis that CSE generates immunogenic elastin neoepitopes that trigger an increase in α-elastin IgG and IgM antibodies, which can then bind to the neoepitopes in the target cells or membranes, triggering complement activation. Specifically, we showed that immunization with elastin peptide oxidatively modified by cigarette smoke (ox-elastin) exacerbated ocular pathology and vision loss in CSE mice. In contrast, mice receiving peptide immunotherapy (PIT) with ox-elastin did not lose vision over the smoking period and exhibited a more preserved BrM. Immunization and PIT correlated with humoral immunity and complement activation and IgG/IgM deposition in the RPE/BrM/choroid. Finally, PIT modulated immune markers IFNγ and IL-4. The data further support the hypothesis that complement activation, triggered by immune complex formation in target tissues, plays a role in ocular damage in the CSE model. As PIT with ox-elastin peptides reduces damage, we discuss the possibility that AMD progression might be preventable.

Cuticular Drusen in Age-Related Macular Degeneration: Association with Progression and Impact on Visual Sensitivity.

PURPOSE: To determine the prognostic significance and impact on visual function of the cuticular drusen phenotype in a cohort with intermediate age-related macular degeneration (AMD). DESIGN: Longitudinal, observational study. PARTICIPANTS: Participants aged 50 years or older, with bilateral large conventional drusen, without late AMD. METHODS: Multimodal imaging (MMI) and microperimetry were performed at baseline and then every 6 months for up to 3 years. Eyes were graded for the MMI-based presence of cuticular drusen at baseline. Color fundus photographs were used to grade for the presence of pigmentary abnormalities. OCT scans were used to calculate drusen volume. The associations between cuticular drusen and progression to MMI-defined late AMD (including OCT signs of atrophy) and the impact on visual sensitivity were examined with and without adjustment for the confounders of baseline age, pigmentary abnormalities, and drusen volume. MAIN OUTCOME MEASURES: Time to develop MMI-defined late AMD and change in mean visual sensitivity. RESULTS: A total of 280 eyes from 140 participants were included, with 70 eyes from 35 individuals (25%) having cuticular drusen at baseline. Cuticular drusen were not significantly associated with an increased rate of progression to late AMD with and without adjustment for confounders (P ≥ 0.784 for both). In an adjusted model, cuticular drusen were not associated with lower baseline visual sensitivity (P = 0.758) or a faster rate of visual sensitivity decline (P = 0.196). CONCLUSIONS: In a cohort with bilateral large conventional drusen, individuals with the cuticular drusen phenotype had neither a higher nor lower risk of developing late AMD over 3 years and were not associated with a difference in rate of visual sensitivity decline compared with those without this phenotype. As such, individuals with this phenotype currently warrant similar monitoring strategies as those with conventional drusen.

Elastin turnover in ocular diseases: A special focus on age-related macular degeneration.

The extracellular matrix (ECM) and its turnover play a crucial role in the pathogenesis of several inflammatory diseases, including age-related macular degeneration (AMD). Elastin, a critical protein component of the ECM, not only provides structural and mechanical support to tissues, but also mediates several intracellular and extracellular molecular signaling pathways. Abnormal turnover of elastin has pathological implications. In the eye elastin is a major structural component of Bruch's membrane (BrM), a critical ECM structure separating the retinal pigment epithelium (RPE) from the choriocapillaris. Reduced integrity of macular BrM elastin, increased serum levels of elastin-derived peptides (EDPs), and elevated elastin antibodies have been reported in AMD. Existing reports suggest that elastases, the elastin-degrading enzymes secreted by RPE, infiltrating macrophages or neutrophils could be involved in BrM elastin degradation, thus contributing to AMD pathogenesis. EDPs derived from elastin degradation can increase inflammatory and angiogenic responses in tissues, and the elastin antibodies are shown to play roles in immune cell activity and complement activation. This review summarizes our current understanding on the elastases/elastin fragments-mediated mechanisms of AMD pathogenesis.

Clinicopathological study of the polypoidal lesions of polypoidal choroidal vasculopathy.

PURPOSE: To investigate the pathogenic features of the polypoidal lesions from the specimens of polypoidal choroidal vasculopathy extracted from human subjects. METHODS: Seven specimens of polypoidal lesions extracted from five eyes of six patients (mean age, 60.16 ± 10.41 years) of polypoidal choroidal vasculopathy were examined. The polypoidal lesions were obtained by surgical excision. Thereafter, a histopathological analysis of the specimens was performed. RESULTS: The polypoidal lesions were oval nodules located underneath the retinal pigment epithelium. A pathological study of the lesions revealed that Bruch's membrane schisis was observed in all specimens and they were all located in the Bruch's membrane. The Bruch's membrane schisis and serosanguineous materials constituted the main structure of the lesions in five of the seven specimens, with small vessels being observed in two specimens. One specimen was composed of two polypoidal lesions of different characteristics, and one specimen had a neovessel membrane complex with several polypoidal lesions. Inflammatory cells and blood vessels were observed in the polypoidal lesion of the specimen with neovessel membrane complex. CONCLUSION: Polypoidal lesions of polypoidal choroidal vasculopathy are abnormalities of the Bruch's membrane. The lesions are characterized by the Bruch's membrane schisis, which is filled with serosanguineous materials. The lesions are progressive and may contain inflammatory cells and blood vessels.

Localised relative scotoma in cuticular drusen.

PURPOSE: To investigate retinal sensitivity changes in eyes with pure cuticular drusen. METHODS: Multimodal imaging and microperimetry (37-loci grid) data were examined retrospectively to evaluate functional changes in eyes with pure cuticular drusen. Mean sensitivity in the cuticular drusen cohort was compared to age-matched normals. An age- and loci-specific normative reference was created to analyse localised sensitivity deviation. RESULTS: The mean number loci with relative scotoma in the cuticular drusen cohort (n = 27, mean [SD] age: 48.5 [12.4] years) referenced to normal eyes (n = 80, 53.5 [14.6] years) was 5.5 (95% confidence interval 3.0 to 8.1). However, mean sensitivity was not statistically different to the age-matched normal cohort (95% CI, - 2.3 to + 3.4 dB). The 37-loci grid was stratified into three rings of the approximately same number of loci, and the percentage of cuticular drusen eyes with pointwise deviation was significantly lower in the inner compared to the middle ring (12.3 [5.3]% vs. 17.3 [5.1]%, p < 0.05). CONCLUSIONS: Eyes with cuticular drusen demonstrated relative scotoma, but mean sensitivity was not affected. Pointwise sensitivity provides a more robust measure of retinal sensitivity than mean sensitivity in cuticular drusen and should be assessed both in the clinic and in future clinical trials.

A COMMON FINDING IN FOVEAL-SPARING EXTENSIVE MACULAR ATROPHY WITH PSEUDODRUSEN IMPLICATES BASAL LAMINAR DEPOSITS.

PURPOSE: To characterize structural and clinical alterations preceding the diffuse macular atrophy in extensive macular atrophy with pseudodrusen (EMAP) and their evolution toward atrophic changes. METHODS: A retrospective chart review was performed of patients with early-onset reticular pseudodrusen (i.e., pre-EMAP) younger than 55 years and EMAP with foveal sparing. Patients were included if they had complete medical records and multimodal imaging. RESULTS: A total of 12 patients were reviewed, of whom 4 of 12 patients (7 eyes) presented a pre-EMAP stage, characterized by the presence of pseudodrusen-like deposits without atrophic changes, while the remaining 8 of 12 patients (10 eyes) exhibited EMAP with foveal sparing (60.1 ± 6.4 years). Subretinal deposits of various stages tended to fade, leaving subretinal pigment epithelium accumulation of hyperreflective material with a physical separation between the retinal pigment epithelium-basal lamina and the Bruch membrane, along with the persistence of hyperreflective material after retinal pigment epithelium loss. These findings preceded atrophy development in a pre-EMAP stage and the EMAP stage with foveal sparing. CONCLUSION: Our findings presented distinct multimodal imaging features in eyes with reticular pseudodrusen depicting a peculiar phenotype of rapidly progressing atrophy in midlife. The disease spectrum may include other forms of geographic atrophy allied by thickened basal laminar deposits.

MORPHOLOGIC AND ANATOMICAL FEATURES OF TYPE 1 MACULAR NEOVASCULARIZATION TRUNKS IN AGE-RELATED MACULAR DEGENERATION USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To evaluate the morphologic features of macular neovascularization (MNV) trunks at different layers using optical coherence tomography angiography. METHODS: Type 1 MNV trunks in age-related macular degeneration were retrospectively evaluated at the subretinal pigment epithelium and sub-Bruch membrane (subBM) layers. The detectability and location of the trunks were compared. MNV trunks at the subBM layer on optical coherence tomography angiography B-scans were evaluated using a flow overlay. The correlations of the MNV trunk with optical coherence tomography angiography and optical coherence tomography parameters were evaluated. RESULTS: Among the 63 included eyes, 27 showed core vessels at the subretinal pigment epithelium layer and 52 showed MNV trunks at the subBM layer, which were connected with the MNV at the subretinal pigment epithelium layer. The locations of the MNV trunks in each layer were different. MNV trunk types at the subBM layer were related to disease duration, distance from the large choroidal vessels, and MNV vessel density. The large choroidal vessel diameter was correlated with the MNV trunk diameter at the subBM layer. CONCLUSION: Macular neovascularization trunks at the subBM layer were detected more frequently than distal MNV trunks at the subretinal pigment epithelium layer. Macular neovascularization trunk features at the subBM layer may be related to disease duration and a large choroidal vessel.

ARE THERE TWO FORMS OF MULTIPLE EVANESCENT WHITE DOT SYNDROME?

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.

Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina.

The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.

Relationship between Three-Dimensional Magnetic Resonance Imaging Eyeball Shape and Optic Nerve Head Morphology.

PURPOSE: To determine if the 3-dimensional (3D) eyeball shape is associated with the positions of the central retinal vascular trunk (CRVT) and the externally oblique border (EOB) in the optic nerve head (ONH). DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Fifty-six subjects (112 eyes) with a diagnosis of glaucoma or glaucoma suspect. METHODS: The eyeball shape on 3D magnetic resonance imaging (MRI) scans was classified according to the dimension of the longest diameter: axial dimension (prolate sphere), group 1; horizontal dimension (horizontally oblate sphere), group 2; and vertical dimension (vertically oblate sphere), group 3. The deviation of the CRVT, as a surrogate of lamina cribrosa (LC) shift, was measured from the center of the Bruch's membrane opening (BMO) demarcated by OCT imaging, with the horizontal midline as 0° and the superior location as a positive value. The angular location of the longest EOB was also measured. MAIN OUTCOME MEASURE: Positions of CRVT and EOB according to the 3D eyeball shape. RESULTS: Among 112 eyes, 54 (48%) had a prolate shape (group 1), 23 (21%) had a horizontally oblate shape (group 2), and 35 (31%) had a vertically oblate shape (group 3). The angular deviation of the CRVT differed among the groups: to the nasal side in group 1, to the temporal side in group 2, and along the vertical meridian in group 3. In cases of asymmetric eyeball shape, the CRVT was deviated toward the undergrown side from the overgrown side, regardless of grouping. The angular location of the longest EOB was in the direction opposite to the CRVT position (P < 0.001). A generalized estimating equation analysis revealed that the temporal location of the CRVT was associated with older age (P = 0.001), nasal location of the longest EOB (P < 0.001), and oblate shape of the eyeball (P < 0.001, group 2; P = 0.007, group 3). CONCLUSIONS: The position of the CRVT and EOB were associated with the 3D eyeball shape. Considering that infant ONH morphology is highly uniform, various modes of eyeball expansion during growth can result in diverse directionalities of offset between the LC and the BMO in adults.

Recent developments in the use of optical coherence tomography for glaucoma.

PURPOSE OF REVIEW: The aim of this article is to summarize findings of recent reports highlighting the utility of novel optical coherence tomography (OCT) parameters in the diagnosis and monitoring of glaucomatous optic neuropathy. RECENT FINDINGS: Optic nerve head (ONH), retinal nerve fiber layer (RNFL), and macular parameters show high levels of diagnostic capability. The Bruch's membrane opening-minimum rim width (BMO-MRW) measurement is a novel ONH parameter obtained using the Spectralis SD-OCT device (Heidelberg Engineering, Inc., Heidelberg, Germany). The inferotemporal BMO-MRW sector shows the highest diagnostic performance for this parameter. Minimum ganglion cell and inner plexiform layer thickness shows the highest diagnostic performance among macular parameters obtained with the Cirrus HD-OCT (Carl Zeiss, Inc., Dublin, CA, USA). Optic nerve head, macular, and retinal nerve fiber layer parameters are not interchangeable across protocols generated by varying OCT manufacturers. Novel machine-learning algorithms show promise with regards to achieving higher levels of diagnostic accuracy using OCT imaging platforms. SUMMARY: Digital imaging in glaucoma continues to evolve with novel parameters of the optic nerve head, retinal nerve fiber layer, and macula. Diagnostic abilities of these parameters are high and complementary to each other.

DIFFERENTIAL RESPONSE TO GLUCOCORTICOID IMMUNOSUPPRESSION OF TWO DISTINCT INFLAMMATORY SIGNS ASSOCIATED WITH PUNCTATE INNER CHOROIDOPATHY.

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