Is It Possible to Preserve Vision without Compromising Metastases-Free Survival by Use of Fully Fractionated Stereotactic Radiotherapy for Posterior Choroidal Melanoma?

Introduction: Stereotactic radiotherapy (SRT) is used for choroidal melanoma (CM) abutting the optic nerve. Visual acuity (VA) deterioration to ≤6/60 is common. We report a pilot study of reduced-dose SRT using 2 Gy/day, aiming to preserve vision without compromising survival. Method: 60 Gy SRT was delivered in 30 fractions over 6 weeks. Liver metastasis surveillance was annual ultrasound. The primary endpoint was 5-year metastasis-free survival (5yMFS). Secondary endpoints were 2-year freedom from local progression (2yFFLP), VA, enucleation rate, and radiation toxicity. Results: Twenty adults aged ≤70 years with T1-T2M0 CM without diabetes mellitus were enrolled. Median follow-up was 5.1 years. About 85% and 90% of tumours were ≤3 mm of the macula and optic disc, respectively. Median tumour height was 2.2 mm (range 1.0-4.4 mm), and median basal diameter was 8.2 mm (range: 4.3-15.0 mm). 5yMFS was 88% (95% CI: 61-97), and the 2yFFLP rate was 90% (95%: CI 66-97). There were three enucleations for disease progression. Final VA in retained eyes was ≥6/7.5 in 6 (30%), 6/9 to 6/12 in 5 (25%), 6/15 to 6/48 in 2 (10%), and ≤6/60 in 4 (20%) eyes. Retinopathy was the main cause of vision loss besides tumour progression. Conclusion: Meaningful vision was preserved 5 years after SRT, despite high-risk tumour locations for vision loss. 2yFFLP and 5yMFS were acceptable. This dose fractionation warrants further investigation.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Foveal hypoplasia in a Chinese adolescent with 48, XXYY syndrome.

BACKGROUND: 48, XXYY syndrome is a rare sex chromosome aneuploidy with severe systemic features. Ophthalmic manifestation of 48, XXYY syndrome include hypertelorism, epicanthic folds, hooded eye lids, strabismus, retinitis pigmentosa and Duane's syndrome. CASE: We present mild foveal hypoplasia in a 12-year-old boy with 48, XXYY syndrome using swept-source optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). The boy was referred for assessment of strabismus and poor visual acuity. OCT revealed persistence of inner retinal layers, and thinning of the outer nuclear layer in the perifoveal region with thickening of the outer plexiform layer. OCTA revealed increased vessel density with reduced foveal avascular zone. CONCLUSION: We described novel OCT and OCTA features of bilateral foveal hypoplasia and reduction of FAZ in a case of 48, XXYY syndrome based on detailed clinical observation and thorough genetic testing. This case expanded the current literature of this rare sex chromosome abnormality and suggest the importance of retinal examinations in 48, XXYY syndrome.

Macular Thickness Profile and Its Association With Best-Corrected Visual Acuity in Healthy Young Adults.

Purpose: To describe the thickness profiles of the full retinal and outer retinal layers (ORL) at the macula in healthy young adults, and associations with best-corrected visual acuity (BCVA). Methods: In total, 1604 participants (19-30 years) underwent an eye examination that included measurements of their BCVA, axial length, and autorefraction. The retinal thickness at the foveal pit and at the nine Early Treatment of Diabetic Retinopathy Study macular regions (0.5-mm radius around the fovea, and superior, inferior, temporal, and nasal quadrants of the inner and outer rings of the macula) were obtained using spectral-domain optical coherence tomography imaging. A custom program was used to correct for transverse magnification effects because of different axial lengths. Results: The median full retinal and ORL thicknesses at the central macula were 285 µm and 92 µm. The full retina was thinnest centrally and thickest at the inner macula ring, whereas the ORL was thickest centrally and gradually decreased in thickness with increasing eccentricity. There was no association between axial length and the full retinal or ORL thickness. Increased thicknesses of the full retina at the central macula was associated with better BCVA; however, the effect size was small and not clinically significant. Conclusions: This article mapped the full retinal and ORL thickness profile in a population-based sample of young healthy adults. Translational Relevance: Thickness values presented in this article could be used as a normative reference for future studies on young adults and in clinical practice.

ENDOGENOUS ENDOPHTHALMITIS IN WESTERN AUSTRALIA: A Sixteen-Year Retrospective Study.

PURPOSE: To review the clinical features, microbiology spectrum, management, and outcomes of patients with endogenous endophthalmitis in Western Australia over a 16-year period. METHODS: This is a retrospective chart review of all patients with endogenous endophthalmitis who presented to all tertiary ophthalmology departments between 2000 and 2015 in Western Australia. RESULTS: Sixty-six eyes of 57 patients with endogenous endophthalmitis were identified, and follow-up data were available for a mean of 554 days. The average frequency was 1.6 per 1,000,000 population per year. Diabetes mellitus (33%) and intravenous drug use (30%) were the most common risk factors. Concurrent systemic infections included urinary tract infection (28%), pneumonia (23%), and endocarditis (21%). Among culture-positive cases (93%), 57% were bacterial and 43% were fungal. Visual acuity improved in 33 (50%) and declined in 15 eyes (22.7%). Baseline visual acuity and the presence of Gram-negative or filamentous fungi were the only predictors of final visual acuity (P = 0.023 and P = 0.001). CONCLUSION: The population frequency of endogenous endophthalmitis has not changed over 16 years despite the changing profile of pathogen and risk factors. Similar to previous studies in Asian and Western countries, visual and anatomical prognosis depends on initial visual acuity and isolated pathogen. Gram-negative and filamentous fungi culture predicted a worse visual outcome.

Neuronal degeneration and associated alterations in cytokine and protein in an experimental branch retinal venous occlusion model.

The mechanisms of neuronal degeneration and associated acute alterations in intraretinal cytokine and protein levels remain poorly understood in variable ischaemic retinopathies such as in branch retinal vein occlusion (BRVO). Herein we investigate neuronal damage and alterations in retinal cytokines and proteins in a pig model of acute BRVO. Twelve pigs had a BRVO induced photothrombotically in both eyes. Three pigs (6 eyes) each at 2, 6, 10 and 20 days were sacrificed together with an additional 3 control (6 eyes), enucleated, retinas dissected and processed. Apoptosis in the inner retina was determined by terminal deoxyynuclotidyl transferase mediated dUTP nick end labelling (TUNEL) and histology. Expression of glial acidic fibrillary protein (GFAP), aquaporin-4 (AQP4), inward rectifier potassium channel 10 protein (Kir 4.1) encoded by KCNJ10 gene, vascular endothelial growth factor (VEGF), stromal derived growth factor-1α (SDF-1) encoded by CXCL12 gene and interleukin (IL) -6 and 8 were analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry. TUNEL labelling showed positive nuclei in the ganglion cell layer (GCL) and the inner nuclear layer (INL) which was significantly higher at 2 days after BRVO compared to other time points (p < 0.05). Analysis by RT-qPCR revealed that compared with controls, BRVO significantly increased mRNA expression of GFAP at 6, 10 and 20, AQP4 at 20, VEGF at 6, SDF-1 at 20 and IL-8 at 2 and 10 days respectively (p < 0.05): Kir 4.1 at 6, VEGF at 2 and 10, and IL-6 at 2 days were significantly decreased (p < 0.05). This study indicates that neural cell death occurs early in this acute model and the responses include inflammation and breakdown of osmohomeostasis as evidenced by the upregulation of GFAP and IL-8 and down regulation of Kir 4.1 associated with glyotic changes. Early short term VEGF upregulation seen may be related to involvement of Muller glial cells. These findings support the development of acute therapeutic strategies aimed at preservation of retinal neural cells as part of an overall management plan for BRVO.

Intersession test-retest variability of conventional and novel parameters using the MP-1 microperimeter.

PURPOSE: To investigate the intersession test-retest variability (TRV) of topography- and threshold-based parameters derived from the Nidek MP-1. DESIGN: Prospective observational study. METHODS: Sixteen participants with and without central scotoma underwent microperimetry in one eye over three sessions at 1-month intervals in a single institution. We calculated 95% coefficient of repeatability (CR) for the number of normal-suspect (NS) loci, relative scotoma (RS) and dense scotoma (DS), median macular sensitivity (MS), mean sensitivity of responding loci (RLS), perilesional loci (PLS), and extralesional loci (ELS). Topographical agreement score of mapping NS and DS loci (TASNS and TASDS) were also calculated for each patient. RESULTS: Mean (range) age was 50 (21-86) years. The CR (95% confidence intervals) for NS, RS, and DS were 9.9 (6.5-13.3), 9.5 (6.2-12.7), and 3.0 (1.1-4.1) respectively. CR (95% CIs) for median MS, mean RLS, PLS, and ELS were 3.4 (2.3-4.5), 1.6 (1.1-2.2), 1.8 (0.9-2.6), and 2.8 (1.5-4.0) dB. We found significant change in thresholds between Test 1, and Tests 2 and 3 (both P=0.03), but not between Tests 2 and 3 (P=0.8). Medians (range) TASNS and TASDS were 74% (39%-100%) and 77% (0%-97%), respectively, between Tests 2 and 3. CONCLUSION: We recommend the use of four DS loci (upper limit of CR) as the limit of TRV for assessing change. There was large interindividual variability in NS or DS mapping agreement. We recommend discarding the first microperimetry test and caution the use of a change in spatial distribution to determine disease progression.

Near-Infrared Autofluorescence Imaging in Geographic Atrophy Using Spectralis Single and Combined Wavelength Modes.

PURPOSE: The Spectralis Heidelberg retina angiography + optical coherence tomography (OCT) device often fails to acquire near-infrared autofluorescence (NI-AF) due to poor signal because of interference by the beam splitter used for aligning the laser source with the OCT diode light source. We report the rates of successful NI-AF image acquisition using indocyanine green angiography (ICGA) mode (without dye) compared with combined fluorescein angiography (FA) + ICGA mode (without dye) in patients with geographic atrophy (GA). DESIGN: This was a retrospective review. METHODS: Two hundred images from 50 eyes of 25 patients with GA were included. All patients underwent NI-AF imaging using ICGA (787 nm) and combined FA + ICGA (488 + 787 nm) modes in both eyes. Each eye had macula- and disc-centered imaging. The rates of successful image acquisition were compared using McNemar test. RESULTS: Successful NI-AF acquisition using ICGA was 48% to 52% in macula-centered views and 36% to 56% in disc-centered views. Only 36% of patients had successful bilateral NI-AF imaging. This improved to 100% in all views in both eyes after switching to combined FA + ICGA mode (P < 0.001). Logistic regression showed no patient or ocular factors were predictive of NI-AF acquisition failure in ICGA mode. CONCLUSIONS: Acquisition of NI-AF images in GA using ICGA mode has a high failure rate, which can be eliminated by using combined FA + ICGA mode. This finding has implications on the design of imaging protocols for routine assessment and clinical trials of geographic atrophy.

Angiography reveals novel features of the retinal vasculature in healthy and diabetic mice.

The mouse retina is a commonly used animal model for the study of pathogenesis and treatment of blinding retinal vascular diseases such as diabetic retinopathy. In this study, we aimed to characterize normal and pathological variations in vascular anatomy in the mouse retina using fluorescein angiography visualized with scanning laser ophthalmoscopy and optical coherence tomography (SLO-OCT). We examined eyes from C57BL/6J wild type mice as well as the Ins2(Akita) and Akimba mouse models of diabetic retinopathy using the Heidelberg Retinal Angiography (HRA) and OCT system. Angiography was performed on three focal planes to examine distinct vascular layers. For comparison with angiographic data, ex vivo analyses, including Indian ink angiography, histology and 3D confocal scanning laser microscopy were performed in parallel. All layers of the mouse retinal vasculature could be readily visualized during fluorescein angiography by SLO-OCT. Blood vessel density was increased in the deep vascular plexus (DVP) compared with the superficial vascular plexus (SVP). Arteriolar and venular typologies were established and structural differences were observed between venular types. Unexpectedly, the hyaloid artery was found to persist in 15% of C57BL/6 mice, forming anastomoses with peripheral retinal capillaries. Fluorescein leakage was easily detected in Akimba retinae by angiography, but was not observed in Ins2(Akita) mice. Blood vessel density was increased in the DVP of 6 month old Ins2(Akita) mice, while the SVP displayed reduced branching in precapillary arterioles. In summary, we present the first comprehensive characterization of the mouse retinal vasculature by SLO-OCT fluorescein angiography. Using this clinical imaging technique, we report previously unrecognized variations in C57BL/6J vascular anatomy and novel features of vascular retinopathy in the Ins2(Akita) mouse model of diabetes.

Cone photoreceptor definition on adaptive optics retinal imaging.

AIMS: To quantitatively analyse cone photoreceptor matrices on images captured on an adaptive optics (AO) camera and assess their correlation to well-established parameters in the retinal histology literature. METHODS: High resolution retinal images were acquired from 10 healthy subjects, aged 20-35 years old, using an AO camera (rtx1, Imagine Eyes, France). Left eye images were captured at 5° of retinal eccentricity, temporal to the fovea for consistency. In three subjects, images were also acquired at 0, 2, 3, 5 and 7° retinal eccentricities. Cone photoreceptor density was calculated following manual and automated counting. Inter-photoreceptor distance was also calculated. Voronoi domain and power spectrum analyses were performed for all images. RESULTS: At 5° eccentricity, the cone density (cones/mm(2) mean±SD) was 15.3±1.4×10(3) (automated) and 13.9±1.0×10(3) (manual) and the mean inter-photoreceptor distance was 8.6±0.4 µm. Cone density decreased and inter-photoreceptor distance increased with increasing retinal eccentricity from 2 to 7°. A regular hexagonal cone photoreceptor mosaic pattern was seen at 2, 3 and 5° of retinal eccentricity. CONCLUSIONS: Imaging data acquired from the AO camera match cone density, intercone distance and show the known features of cone photoreceptor distribution in the pericentral retina as reported by histology, namely, decreasing density values from 2 to 7° of eccentricity and the hexagonal packing arrangement. This confirms that AO flood imaging provides reliable estimates of pericentral cone photoreceptor distribution in normal subjects.

The Power and the Promise of Cell Reprogramming: Personalized Autologous Body Organ and Cell Transplantation.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) or direct reprogramming to desired cell types are powerful and new in vitro methods for the study of human disease, cell replacement therapy, and drug development. Both methods to reprogram cells are unconstrained by the ethical and social questions raised by embryonic stem cells. iPSC technology promises to enable personalized autologous cell therapy and has the potential to revolutionize cell replacement therapy and regenerative medicine. Potential applications of iPSC technology are rapidly increasing in ambition from discrete cell replacement applications to the iPSC assisted bioengineering of body organs for personalized autologous body organ transplant. Recent work has demonstrated that the generation of organs from iPSCs is a future possibility. The development of embryonic-like organ structures bioengineered from iPSCs has been achieved, such as an early brain structure (cerebral organoids), bone, optic vesicle-like structures (eye), cardiac muscle tissue (heart), primitive pancreas islet cells, a tooth-like structure (teeth), and functional liver buds (liver). Thus, iPSC technology offers, in the future, the powerful and unique possibility to make body organs for transplantation removing the need for organ donation and immune suppressing drugs. Whilst it is clear that iPSCs are rapidly becoming the lead cell type for research into cell replacement therapy and body organ transplantation strategies in humans, it is not known whether (1) such transplants will stimulate host immune responses; and (2) whether this technology will be capable of the bioengineering of a complete and fully functional human organ. This review will not focus on reprogramming to iPSCs, of which a plethora of reviews can be found, but instead focus on the latest developments in direct reprogramming of cells, the bioengineering of body organs from iPSCs, and an analysis of the immune response induced by iPSC-derived cells and tissues.

Enhanced depth imaging of the choroid in patients with neovascular age-related macular degeneration treated with anti-VEGF therapy versus untreated patients.

PURPOSE: To compare the subfoveal choroidal thickness (SFCT) between patients with neovascular age-related macular degeneration (nAMD) who had multiple intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents and those with treatment-naïve nAMD. METHODS: This retrospective case-control study included 15 patients in group 1 (nAMD in one eye which had received at least three anti-VEGF injections and early AMD in the fellow eye) and 15 patients in group 2 (newly diagnosed nAMD in one eye which had not received any treatment and early AMD in the fellow eye). They underwent enhanced depth imaging optical coherence tomography (OCT), and two OCT readers manually measured the SFCT. Inter-ocular difference in SFCT (nAMD eye minus fellow eye) was calculated for each patient. RESULTS: The nAMD eyes in group 1 had received a median (range) of four (3-8) intravitreal injections of anti-VEGF agents, and the OCT scans were performed at a median (range) of 9 (4-17) months after the first injection. The median inter-ocular difference in SFCT in groups 1 and 2 were not significantly different (13.5 and 3.0 µm in groups 1 and 2 respectively, p=0.60). There was also no statistically significant difference in SFCT between nAMD and fellow eyes (p=0.16), although there was a trend for greater median SFCT in the nAMD eyes. CONCLUSION: The data from this small cohort suggests that no gross reduction in SFCT appears in nAMD patients after a time interval of at least 4 months between initiating repeated treatment with anti-VEGF therapy and OCT imaging. However, a study with a much larger sample size or longitudinal design is required to detect possible small fluctuations in SFCT in nAMD eyes receiving anti-VEGF therapy.

Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography.

PURPOSE: The aim of this study was to investigate the repeatability of manual measurements of choroidal thickness in healthy subjects imaged on spectral domain optical coherence tomography (OCT) using the enhanced depth imaging (EDI) technique. METHODS: Fifty consecutive, healthy, young, adult volunteers with no known eye disease were enrolled prospectively. Two good-quality horizontal and vertical line scans through the fovea were obtained for each eye. Using the manual calipers provided by the software of the proprietary device, two experienced OCT readers measured the subfoveal choroidal thickness (SFCT) of the horizontal and vertical line scans for all eyes. The readers were masked to each other's readings. Intraobserver, interobserver, and intrasession coefficients of repeatability (CRs) were calculated. RESULTS: Mean (standard deviation [SD]) age of the study subjects was 38 (5) years (range, 30-49 years). Mean (SD) subfoveal choroidal thickness was 332 (90) µm (right eyes) and 332 (91) µm (left eyes). Intraobserver CR was approximately 23 (95% confidence interval [CI], 19-26) µm, whereas interobserver and intrasession CRs were greater at 32 (95% CI, 30-34) and 34 (95% CI, 32-36) µm, respectively. There was no significant difference in SFCT between all pairs of SFCT measurements except for the two intrasession vertical line scans. CONCLUSION: A change of >32 µm was likely to exceed interobserver variability in SFCT. Future studies are required to estimate the repeatability of SFCT measurements in patients with chorioretinal pathology.

Indocyanine green-assisted phacoemulsification in cases of complicated or simple advanced cataracts.

BACKGROUND/PURPOSE: During phacoemulsification for advanced cataracts, particularly when complicated by anterior segment abnormalities, capsulorhexis is very difficult and carries a high risk of complications. This study investigated the efficacy and safety of indocyanine green (ICG)-assisted phacoemulsification in complicated or simple advanced cataracts. METHODS: Thirty-two patients (35 eyes) underwent phacoemulsification for complicated advanced cataracts (group 1) or simple advanced (mature/hypermature) cataracts (group 2). Anterior segment abnormalities (corneal opacity, small pupil, or glaucoma) in group 1 complicated phacoemulsification. In both groups, 0.5% ICG was used for capsulorhexis, and subsequent procedures were performed in the same routine manner. RESULTS: Group 1 included 15 patients (17 eyes) with a mean age of 60.0 years. Group 2 included 17 patients (18 eyes) with a mean age of 69.4 years (p<0.05). Continuous curvilinear capsulorhexis was completed in all eyes in group 2, but radial tears occurred in four (23.5%) eyes in group 1 (p<0.05). Phacoemulsification was performed uneventfully in all eyes in both groups. Postoperative complications (corneal edema, vitreous prolapse, posterior capsule opacity, elevated intraocular pressure) were seen in five (27.8%) eyes in group 1 and four (23.5%) eyes in group 2 (p>0.05). None of these were attributed to the use of ICG. Visual acuity improved in all eyes in group 2, but in only 11 (64.7%) in group 1 (p<0.01). CONCLUSION: ICG-assisted phacoemulsification is safe and helpful for complicated or simple advanced cataracts. Differences between the two groups in patient age, intraoperative complications, and visual outcome could be explained by differences in the cause(s) of advanced cataracts.

Effect of artificial tears on corneal surface regularity, contrast sensitivity, and glare disability in dry eyes.

OBJECTIVE: To investigate the effects of artificial tears on corneal surface regularity and visual function in dry eyes. DESIGN: Nonrandomized, comparative trial. PARTICIPANTS: Forty patients (40 eyes) with dry eyes with (group 1, n = 15 eyes) or without (group 2, n = 25 eyes) punctate epithelial keratopathy and a normal control group of 20 individuals (20 eyes) with no ocular abnormalities (group 3). METHODS: In both dry and normal eyes, the surface regularity index (SRI), surface asymmetry index (SAI), and potential visual acuity (PVA) were measured by computer-assisted videokeratography (TMS-1; Computed Anatomy, New York, NY). Spatial-contrast sensitivity and glare disability were also measured before and 1 minute after instillation of artificial tears. MAIN OUTCOME MEASURES: Differences in SRI, SAI, PVA, spatial-contrast sensitivity, and glare disability between groups, before instillation of tears, and within groups, after instillation of tears. RESULTS: Compared with group 3, eyes in group 1 had significantly worse SRI, SAI, PVA, and contrast sensitivity (incomplete glare disability data precluded analysis) before instillation of artificial tears. Differences in corneal surface regularity and visual function between groups 2 and 3 were not significant except for a significantly increased glare disability at low spatial frequency (1.5 cycles per degree [cpd]) in group 2. Significant improvement in SRI, SAI, PVA, and contrast sensitivity were observed after instillation of artificial tears in group 1. In groups 2 and 3, the only significant changes were improvement in glare disability at 1.5 cpd and worsening of the SRI, respectively. CONCLUSIONS: Tear film changes in dry eye patients may lead to irregularities on the corneal surfaces, causing glare disability. However, these changes may be too subtle in the early stages of dry eyes to be detected by corneal topography or contrast sensitivity measurements. Significant improvement in SRI, SAI, PVA, and contrast sensitivity were found after instillation of artificial tears in dry eyes with punctate epithelial keratopathy.