Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease.

Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the E3 ubiquitin ligase complex comprising pVHL, elongin C, elongin B, cullin 2 and ring box 1 (VCB-CR complex), which plays a key role in oxygen sensing and degradation of hypoxia-inducible factors. To date, only variants in VHL have been shown to cause VHL disease. We undertook trio analysis by whole-exome sequencing in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma (RCC) dataset was undertaken. A de novo pathogenic variant in ELOC NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent RCC and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of an RCC from the proband showed similar findings to that in somatically ELOC-mutated RCC (expression of hypoxia-responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.

Developing a Continuous Severity Scale for Macular Telangiectasia Type 2 Using Deep Learning and Implications for Disease Grading.

PURPOSE: Deep learning (DL) models have achieved state-of-the-art medical diagnosis classification accuracy. Current models are limited by discrete diagnosis labels, but could yield more information with diagnosis in a continuous scale. We developed a novel continuous severity scaling system for macular telangiectasia (MacTel) type 2 by combining a DL classification model with uniform manifold approximation and projection (UMAP). DESIGN: We used a DL network to learn a feature representation of MacTel severity from discrete severity labels and applied UMAP to embed this feature representation into 2 dimensions, thereby creating a continuous MacTel severity scale. PARTICIPANTS: A total of 2003 OCT volumes were analyzed from 1089 MacTel Project participants. METHODS: We trained a multiview DL classifier using multiple B-scans from OCT volumes to learn a previously published discrete 7-step MacTel severity scale. The classifiers' last feature layer was extracted as input for UMAP, which embedded these features into a continuous 2-dimensional manifold. The DL classifier was assessed in terms of test accuracy. Rank correlation for the continuous UMAP scale against the previously published scale was calculated. Additionally, the UMAP scale was assessed in the κ agreement against 5 clinical experts on 100 pairs of patient volumes. For each pair of patient volumes, clinical experts were asked to select the volume with more severe MacTel disease and to compare them against the UMAP scale. MAIN OUTCOME MEASURES: Classification accuracy for the DL classifier and κ agreement versus clinical experts for UMAP. RESULTS: The multiview DL classifier achieved top 1 accuracy of 63.3% (186/294) on held-out test OCT volumes. The UMAP metric showed a clear continuous gradation of MacTel severity with a Spearman rank correlation of 0.84 with the previously published scale. Furthermore, the continuous UMAP metric achieved κ agreements of 0.56 to 0.63 with 5 clinical experts, which was comparable with interobserver κ values. CONCLUSIONS: Our UMAP embedding generated a continuous MacTel severity scale, without requiring continuous training labels. This technique can be applied to other diseases and may lead to more accurate diagnosis, improved understanding of disease progression, and key imaging features for pathologic characteristics. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

OUTER RETINAL COLUMNAR ABNORMALITIES: A Novel Optical Coherence Tomography Sign of CRB1 Maculopathy?

PURPOSE: To report a novel optical coherence tomography sign in the context of CRB1 -related maculopathy termed outer retinal columnar abnormalities (ORCA). METHODS: Retrospective, multicenter, observational case series of 14 eyes of eight patients with molecularly confirmed CRB1 -related maculopathy and ORCA. Multimodal imaging scans and medical records of patients with CRB1 -related maculopathy were reviewed. Outcome measures included best-corrected visual acuity, central subfield thickness on spectral-domain optical coherence tomography, presence of ORCAs, and analysis of their change in appearance over time. RESULTS: At baseline, mean age was 18±10 years (range 9-36 years). All patients had an isolated macular dystrophy except for 1 case harboring a triallelic pathogenic variant. Variant c.498_506del was found in 9 cases (88%). At presentation, ORCA were visible on macular spectral-domain optical coherence tomography in all cases as multiform, vertical, hyperreflective, columnar alterations extending from the ellipsoid to the outer plexiform layer, with a variable degree of hyporeflective cystic spaces in the outer and inner nuclear layers. Over 6±4.7 follow-up years, the presence of ORCA varied greatly with a decrease in ORCA associated with sequential development of retinal atrophy. CONCLUSION: A high suspicion for CRB1 -associated retinal dystrophy should arise in the presence of ORCA on spectral-domain optical coherence tomography, prompting genetic testing.

Training Deep Learning Models to Work on Multiple Devices by Cross-Domain Learning with No Additional Annotations.

PURPOSE: To create an unsupervised cross-domain segmentation algorithm for segmenting intraretinal fluid and retinal layers on normal and pathologic macular OCT images from different manufacturers and camera devices. DESIGN: We sought to use generative adversarial networks (GANs) to generalize a segmentation model trained on one OCT device to segment B-scans obtained from a different OCT device manufacturer in a fully unsupervised approach without labeled data from the latter manufacturer. PARTICIPANTS: A total of 732 OCT B-scans from 4 different OCT devices (Heidelberg Spectralis, Topcon 1000, Maestro2, and Zeiss Plex Elite 9000). METHODS: We developed an unsupervised GAN model, GANSeg, to segment 7 retinal layers and intraretinal fluid in Topcon 1000 OCT images (domain B) that had access only to labeled data on Heidelberg Spectralis images (domain A). GANSeg was unsupervised because it had access only to 110 Heidelberg labeled OCTs and 556 raw and unlabeled Topcon 1000 OCTs. To validate GANSeg segmentations, 3 masked graders manually segmented 60 OCTs from an external Topcon 1000 test dataset independently. To test the limits of GANSeg, graders also manually segmented 3 OCTs from Zeiss Plex Elite 9000 and Topcon Maestro2. A U-Net was trained on the same labeled Heidelberg images as baseline. The GANSeg repository with labeled annotations is at https://github.com/uw-biomedical-ml/ganseg. MAIN OUTCOME MEASURES: Dice scores comparing segmentation results from GANSeg and the U-Net model with the manual segmented images. RESULTS: Although GANSeg and U-Net achieved comparable Dice scores performance as human experts on the labeled Heidelberg test dataset, only GANSeg achieved comparable Dice scores with the best performance for the ganglion cell layer plus inner plexiform layer (90%; 95% confidence interval [CI], 68%-96%) and the worst performance for intraretinal fluid (58%; 95% CI, 18%-89%), which was statistically similar to human graders (79%; 95% CI, 43%-94%). GANSeg significantly outperformed the U-Net model. Moreover, GANSeg generalized to both Zeiss and Topcon Maestro2 swept-source OCT domains, which it had never encountered before. CONCLUSIONS: GANSeg enables the transfer of supervised deep learning algorithms across OCT devices without labeled data, thereby greatly expanding the applicability of deep learning algorithms.

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).

Description of a patient cohort with Hereditary Sensory Neuropathy type 1 without retinal disease Macular Telangiectasia type 2 - implications for retinal screening in HSN1.

Pathogenic variants in the genes encoding serine palmitoyl transferase (SPTLC1 or SPTLC2) are the most common causes of the rare peripheral nerve disorder Hereditary Sensory Neuropathy Type 1 (HSN1). Macular telangiectasia type 2 (MacTel), a retinal disorder associated with disordered serine-glycine metabolism, has been described in some patients with HSN1. This study aims to further investigate this association in a cohort of people with HSN1. Fourteen patients with a clinically and genetically confirmed diagnosis of HSN1 from the National Hospital for Neurology and Neurosurgery (NHNN, University College London Hospitals NHS Foundation Trust, London, United Kingdom) were recruited to the MacTel Registry, between July 2018 and April 2019. Two additional patients were identified from the dataset of the international clinical registry study (www.lmri.net). Ocular examination included fundus autofluorescence, blue light and infrared reflectance, macular pigment optical density mapping and optical coherence tomography. Twelve patients had a pathogenic variant in the SPTLC1 gene, with p.Cys133Trp in 11 cases (92%) and p.Cys133Tyr in one case (8%). Four patients had a variant in the SPTLC2 gene. None of the patients showed clinical evidence of MacTel. The link between HSN1 and MacTel seems more complex than can solely be explained by the genetic variants. An extension of the spectrum of SPTLC1/2-related disease with phenotypic pleiotropy is proposed. HSN1 patients should be screened for visual symptoms and referred for specialist retinal screening, but the association of the two diseases is likely to be variable and remains unexplained.

Long-term vision outcomes for patients with albinism and diabetic retinopathy.

PURPOSE: Albinism defines a group of genetic diseases which result from disordered melanin biosynthesis. Proliferative diabetic retinopathy (PDR) results from poorly controlled type 1 or 2 diabetes mellitus (DM) and can lead to blindness due to progressive neovascularisation. However, the treatment of PDR in patients with ocular/oculocutaneous albinism may be more challenging. In this study, we compared a group of patients with albinism and PDR, to a group with albinism and diabetes mellitus but no PDR, to examine the long-term implications. METHODS: Retrospective observational study included all patients with ocular albinism (OA) or oculocutaneous albinism (OCA) and DM who presented at a single specialist centre. Participants were allocated into either group 1 (eyes with PDR) or group 2 (all eyes without PDR). Statistical analysis was performed using SPSS V26.0. Between-group differences were investigated. RESULTS: Outcome data was available for 5 eyes from 3 participants in group 1 and 26 eyes from 13 participants in group 2. Despite interventions, a large and significant difference in vision at follow-up was observed between group 1 and group 2 (mean change in visual acuity: 1.11 (± 1.00) versus - 0.15 (± 0.46), respectively; p = < 0.0001). CONCLUSION: PDR is associated with poor long-term prognosis despite interventions for patients with albinism. Those without PDR appear to maintain stable vision. Alternative treatments for PDR and its complications may be required in this population. Measures to prevent the development of diabetic eye disease and progression towards PDR should be employed at an early stage.

Feasibility and Safety of a Coaxial Dual-Wavelength Optical Coherence Tomography Apparatus.

PURPOSE: To evaluate the feasibility and safety of a coaxial dual-wavelength optical coherence tomography (OCT) device (marked as Hydra-OCT). METHODS: Healthy participants without ocular pathology underwent retinal imaging using the Hydra-OCT allowing for simultaneous measurement of retinal scanning of 840 and 1,072 nm wavelength. Before and after measurement, best-corrected visual acuity and patients' comfort were assessed. Representative OCT images from both wavelengths were compared by 5 independent graders using a subjective grading scheme. RESULTS: A total of 30 eyes of 30 participants (8 females and 22 males) with a mean age of 26.5 years (range from 19 to 55 years) were included. Dual-wavelength image acquisition was made possible in each subject. The participant's effort and comfort assessment using the Hydra-OCT imaging revealed an equivalent value as compared to the commercially available OCT machine. No adverse events were reported, and visual acuity was not altered by the Hydra-OCT. Imaging between the systems was comparable. CONCLUSIONS: This study provides evidence for the feasibility and safety of a coaxial dual-wavelength OCT imaging method under real-life conditions. The novel Hydra-OCT imaging device may offer additional insights into the pathology of retinal and choroidal diseases.

Macular Telangiectasia Type 2: Visual Acuity, Disease End Stage, and the MacTel Area: MacTel Project Report Number 8.

PURPOSE: To report the visual acuity measures from the macular telangiectasia type 2 (MacTel) registry and to investigate and describe phenotypic findings in eyes with substantial vision loss resulting from MacTel. DESIGN: Cross-sectional multicenter study. PARTICIPANTS: Participants in the MacTel Natural History Observation Registration Study. METHODS: Best-corrected visual acuity (BCVA) data, retinal imaging data, and clinical data were accessed from the MacTel Study databases in May 2019. MAIN OUTCOME MEASURES: Frequency distribution of BCVA and its relationship to age; morphologic changes in eyes with very late disease stages, defined by a BCVA of 20/200 or worse; average retinal thickness of macular subfields on OCT; and dimensions of the area affected by MacTel (i.e., the MacTel area). RESULTS: Best-corrected visual acuity was 20/50 or worse in 37.3% and 20/200 or worse in 3.8% of 4449 eyes of 2248 patients; 18.4% and 0.7% of all patients showed bilateral BCVA of 20/50 or worse and 20/200 or worse, respectively. Asymmetry between right and left eyes was present (median BCVA, 71 letters vs. 74 letters), a finding supported by more advanced morphologic changes in right eyes. Participant age correlated with BCVA, but the effect size was small. If a neovascularization or macular hole were present, bilateral occurrence was frequent (33% or 17%, respectively), and BCVA was better than 20/200 (79% or 78%, respectively) or 20/50 or better (26% or 13%, respectively). Eyes with advanced disease (BCVA, ≤20/200) showed the following characteristics: (1) atrophy of the foveal photoreceptor layer with or without associated subretinal fibrosis; (2) an affected area, termed MacTel area, limited to a horizontal diameter not exceeding the distance between the temporal optic disc margin and foveal center, and the vertical diameter not exceeding approximately 0.8 times this distance (exceptions were eyes with large active or inactive neovascular membranes); (3) reduced retinal thickness measures within the MacTel area; and (4) less frequent retinal greying and more frequent hyperpigmentations compared with eyes that have better BCVA. CONCLUSIONS: Severe vision loss is rare in MacTel and is related to photoreceptor atrophy in most people. Results indicate disease asymmetry with slightly worse vision and more advanced disease manifestation in right eyes. MacTel-related neurodegeneration does not spread beyond the limits of the MacTel area.

Novel biomarker of sphericity and cylindricity indices in volume-rendering optical coherence tomography angiography in normal and diabetic eyes: a preliminary study.

PURPOSE: Preliminary to evaluate geometric indices (vessel sphericity and cylindricity) for volume-rendered optical coherence tomography angiography (OCTA) in healthy and diabetic eyes. METHODS: Twenty-six eyes of 13 healthy subjects and 12 eyes of patients with central ischemic, non-proliferative diabetic retinopathy were included. OCTA volume and surface area of the foveal vessels were measured and compared to determine OCTA sphericity and cylindricity indices and surface efficiency (SE). RESULTS: The overall average OCTA volume in healthy was 0.49 ± 0.09 mm3 (standard deviation [SD]), compared to 0.44 ± 0.07 mm3 (SD) in the diabetic eyes (difference in means 0.06 mm3, p = 0.054). The overall average OCTA surface area in the healthy eyes was 87.731 ± 9.51 mm2 (SD), compared to 76.65 ± 13.67 mm2 (SD) in the diabetic eyes (difference in means 11.08 mm2, p = 0.021). In relation to total foveolar tissue volume, the proportion of blood vessels was 22% in healthy individuals and only 20% in diabetics. The difference between the groups was more pronounced with respect to the total OCTA surface area, with a decrease of 13% in diabetics. A diabetic eye was most likely using geometric vessel indices analysis if the sphericity value was ≥ 0.190, with a cylindricity factor of ≥ 0.001. Reproducibility of the method was good. CONCLUSIONS: A method for OCTA surface area and volume measurements was developed. The application of the novel OCTA sphericity and cylindricity indices could be suitable as temporal biomarker to characterize stable disease or disease progression and may contribute to a better understanding in the evolution of diabetic retinopathy.

COMPARING FUNDUS FLUORESCEIN ANGIOGRAPHY AND SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN THE EVALUATION OF DIABETIC MACULAR PERFUSION.

PURPOSE: To compare fundus fluorescein angiography (FFA) and swept-source optical coherence tomography angiography (SS-OCTA) in the evaluation of macular perfusion in diabetic patients. METHODS: Forty-one eyes (21 diabetic patients) seen at Moorfields Eye Hospital (London) over a 1-month interval underwent color fundus photography, FFA, and SS-OCTA imaging of the capillary superficial plexus using 2 different protocols: 3 × 3 mm and 4.5 × 4.5 mm. Quantitative assessment (foveal avascular zone diameters and area), qualitative analysis (macroscopic and microscopic levels) and Early Treatment Diabetic Retinopathy Study diabetic macular ischemia grading were performed. Artifacts were recorded. Intraclass correlation coefficients and weighted kappa values were calculated. RESULTS: Mean (SD) foveal avascular zone area was 0.695 (0.52) mm on FFA, 0.627 (0.54) mm on SS-OCTA 3 × 3 and 0.701 (0.54) mm on SS-OCTA 4.5 × 4.5 protocol. Intraclass correlation coefficients showed good agreement between FFA and SS-OCTA for both vertical diameter and foveal avascular zone area measurements. The agreement between SS-OCTA 3 × 3 and 4.5 × 4.5 was good for all quantitative measurements. Weighted kappa for diabetic macular ischemia grading showed low to fair agreement between FFA and SS-OCTA, whereas the agreement was good between two different SS-OCTA protocols. CONCLUSION: Swept-source OCTA is a reproducible technique in the assessment of macular perfusion in diabetic patients with special regards to foveal avascular zone analysis. The agreement with FFA is limited especially for diabetic macular ischemia grading. Fundus fluorescein angiography is more sensitive in identifying microaneurysms.

MACULAR TELANGIECTASIA TYPE 2: Quantitative Analysis of a Novel Phenotype and Implications for the Pathobiology of the Disease.

PURPOSE: To investigate retinal microcystoid spaces in macular telangiectasia type 2 with spectral domain optical coherence tomography. METHODS: Retrospective review of 135 patients enrolled in the MacTel Natural History Observation and Registry Study at Moorfields Eye Hospital, United Kingdom. One hundred seventy-two eyes from 86 patients who had a comparable scan protocol of at least 30 µm interval were included for analysis. Retinal microcystoid spaces were identified and segmented and metrics analyzed. RESULTS: From 172 eyes of 86 patients, microcystoid spaces were found in 11 eyes (6.4%) from 8 patients (9.3%). The mean number of microcystoid spaces per eye was 12.9 ± 18.2. Most were located in the inner nuclear layer. The inferonasal quadrant of the macula was the least commonly affected region. Microcystoid spaces were distributed entirely within the assumed macular telangiectasia area on blue light reflectance in all but 2 eyes (4 of 142 microcysts). The median diameter of the microcystoid spaces was 31 µm (range 15 µm-80 µm). CONCLUSION: Microcystoid spaces as a phenotype of macular telangiectasia should be considered in the differentials for microcystic edema. Understanding the pathogenesis of these lesions may provide further insight into the role of Müller cell dysfunction in this disorder.

EFFECT OF DARK ADAPTATION AND BLEACHING ON BLUE LIGHT REFLECTANCE IMAGING IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: In patients with macular telangiectasia Type 2, blue light reflectance imaging reveals an oval, parafoveal area in the macula that has increased reflectance compared with its surrounding. Here, we examine how dark adaptation and photobleaching can affect the blue light reflectance imaging pattern. METHODS: Prospective study of patients with macular telangiectasia enrolled in the MacTel Natural History Observation Study. After dark adaptation, a sequence of images was obtained with a confocal scanning laser ophthalmoscope at 488 nm. Change of reflectance patterns was analyzed over time. RESULTS: Eighteen eyes from 16 patients were analyzed. Initially, increased reflectivity in the parafoveal area resulted in higher gray values compared with the paramacular surrounding on blue light reflectance imaging. The difference between parafoveal and paramacular reflectance intensity decreased steadily during imaging, from 17.7 gray-value units (95% confidence interval: 12.1-23.2) down to 2.8 (95% confidence interval: -0.8 to 6.5) after around 30 seconds, and recovered after 5 minutes of dark adaptation. CONCLUSION: A bleaching effect was evident in our study. Understanding these changes is important for both diagnosis and assessment of blue light reflectance phenotype in patients with macular telangiectasia and could also provide further insights into the pathophysiology of this disease.

FUNDUS-WIDE SUBRETINAL AND PIGMENT EPITHELIAL ABNORMALITIES IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: Macular telangiectasia Type 2 (MacTel) causes glial and photoreceptor cell death in a small, oval patch in the central retina. Beyond this oval area, no disease manifestations have been described so far. Here, we describe a novel pathological aspect of MacTel in the retinal pigment epithelium (RPE) that is not restricted to the clinically affected area but covers the entire retina. METHODS: We have studied postmortem eyes from four patients with MacTel by immunohistochemistry and electron microscopy. RESULTS: We found cellular debris in the subretinal space (between photoreceptor outer segments and RPE), consisting mainly of outer segments and RPE components. In healthy eyes, the RPE normally phagocytoses the tips of the continuously growing outer segments, a process considered to be essential for photoreceptor survival. However, in the patients with MacTel, we found no evidence of ongoing outer segment phagocytosis, and the apical surface of the RPE appeared abnormal throughout most of the retina. CONCLUSION: Reduced outer segment phagocytosis may explain the accumulating debris in the subretinal space but is a surprising finding because visual function in the peripheral retina is normal in patients with MacTel. Nevertheless, the subclinical pathology might induce a specific stress to which the central area is uniquely susceptible.

ELECTROPHYSIOLOGICAL CHARACTERIZATION OF MACULAR TELANGIECTASIA TYPE 2 AND STRUCTURE-FUNCTION CORRELATION.

PURPOSE: To investigate the electrophysiological features of macular telangiectasia Type 2 and their relationship to structure as determined by optical coherence tomography imaging. METHODS: Forty-two eyes from 21 patients enrolled in the Macular Telangiectasia Natural History Observation Study were reviewed. All patients had full-field and pattern electroretinography (ERG; PERG) with some patients additionally having multifocal electroretinography (mfERG; N = 15) or electrooculography (N = 12). Multiple linear regression modeling assessed the relationship between the ellipsoid zone break size on optical coherence tomography and the central mfERG response. RESULTS: Full-field ERG and electrooculography were normal in all eyes. Six eyes (14%) from five patients had subnormal PERG P50 amplitudes. Twenty-two of 30 eyes (73%) had reduced central or paracentral stimulus on mfERG. There was a significant correlation between ellipsoid zone break size and both the P1 amplitude (R = 0.37, P = 0.002) and P1:N1 ratio (R = 0.32, P = 0.002) of the central response on mfERG. CONCLUSION: The electrophysiological findings in macular telangiectasia Type 2 are those of localized central dysfunction and are consistent with the structural data available from imaging and histologic studies. The ellipsoid zone break size correlates with mfERG reduction. The reduced mfERG P1:N1 ratio is consistent with inner retinal dysfunction.

ABNORMAL RETINAL REFLECTIVITY TO SHORT-WAVELENGTH LIGHT IN TYPE 2 IDIOPATHIC MACULAR TELANGIECTASIA.

PURPOSE: Macular telangiectasia Type 2 (MacTel) is a bilateral, progressive, potentially blinding retinal disease characterized by vascular and neurodegenerative signs, including an increased parafoveal reflectivity to blue light. Our aim was to investigate the relationship of this sign with other signs of macular telangiectasia Type 2 in multiple imaging modalities. METHODS: Participants were selected from the MacTel Type 2 study, based on a confirmed diagnosis and the availability of images. The extent of signs in blue-light reflectance, fluorescein angiographic, optical coherence tomographic, and single- and dual-wavelength autofluorescence images were analyzed. RESULTS: A well-defined abnormality of the perifovea is demonstrated by dual-wavelength autofluorescence and blue-light reflectance in early disease. The agreement in area size of the abnormalities in dual-wavelength autofluorescence and in blue-light reflectance images was excellent: for right eyes: ρ = 0.917 (P < 0.0001, 95% confidence interval 0.855-0.954, n = 46) and for left eyes: ρ = 0.952 (P < 0.0001, 95% confidence interval 0.916-0.973, n = 49). Other changes are less extensive initially and expand later to occupy that area and do not extend beyond it. CONCLUSION: Our findings indicate that abnormal metabolic handling of luteal pigment and physical changes giving rise to increased reflectance are widespread in the macula throughout the natural history of the disease, precede other changes, and are relevant to early diagnosis.

VISUAL ACUITY IMPROVEMENT WHEN SWITCHING FROM RANIBIZUMAB TO AFLIBERCEPT IS NOT SUSTAINED.

PURPOSE: To assess whether visual benefits exist in switching to aflibercept in patients who have been chronically treated with ranibizumab for neovascular age-related macular degeneration. METHODS: A multicenter, national, electronic medical record database study was performed. Patients undergoing six continuous monthly ranibizumab injections and then switched to continuous aflibercept were matched to those on continuous ranibizumab therapy. Matching was performed in a 2:1 ratio and based on visual acuity 6 months before and at the time of the switch, and the number of previous ranibizumab injections. RESULTS: Patients who were switched to aflibercept demonstrated transiently significant improvement in visual acuity that peaked at an increase of 0.9 Early Treatment Diabetic Retinopathy Study letters 3 months after the switch, whereas control patients continued on ranibizumab treatment showed a steady decline in visual acuity. Visual acuity differences between the groups were significant (P < 0.05) at 2, 3, and 5 months after the switch. Beginning at 4 months after the switch, the switch group showed a visual acuity decline similar to the control group. CONCLUSION: Transient, nonsustained improvement in visual acuity occurs when switching between anti-vascular endothelial growth factor agents, which may have implications in treating patients on chronic maintenance therapy on one anti-vascular endothelial growth factor medication.

PERIPAPILLARY PACHYCHOROID SYNDROME.

PURPOSE: To describe the features of peripapillary pachychoroid syndrome (PPS), a novel pachychoroid disease spectrum (PDS) entity. METHODS: Medical records of 31 eyes (16 patients) with choroidal thickening associated with intraretinal and/or subretinal fluid in the nasal macula extending from the disk were reviewed (patients with PPS). Choroidal thickness was compared with 2 age-matched cohorts: typical PDS (17 eyes with central serous chorioretinopathy or pachychoroid neovasculopathy) and 19 normal eyes. RESULTS: The patients with PPS were 81% men aged 71 ± 7 years. Peripapillary pachychoroid syndrome eyes displayed thicker nasal versus temporal macular choroids, unlike PDS eyes with thicker temporal macular choroids (P < 0.0001). Peripapillary intraretinal and/or subretinal fluid was often overlying dilated Haller layer vessels (pachyvessels). Fundus autofluorescence and fluorescein angiography illustrated peripapillary pigmentary mottling without focal leakage. Most PPS eyes (70%) exhibited other PDS findings including serous pigment epithelial detachment or gravitational tracks. Indocyanine green angiography illustrated dilated peripapillary pachyvessels and choroidal hyperpermeability. The disk was usually crowded, with edema noted in 4/31 (13%) eyes and mild late fluorescein disk leakage identified in half of the cases. Choroidal folds (77%), short axial lengths (39% less than 23 mm), and hyperopia (86%) were common. CONCLUSION: Peripapillary pachychoroid syndrome is a distinct PDS variant, in which peripapillary choroidal thickening is associated with nasal macular intraretinal and/or subretinal fluid and occasional disk edema. Recognition of PPS is important to distinguish it from disorders with overlapping features such as posterior uveitis and neuro-ophthalmologic conditions.

Automated Diabetic Retinopathy Image Assessment Software: Diagnostic Accuracy and Cost-Effectiveness Compared with Human Graders.

OBJECTIVE: With the increasing prevalence of diabetes, annual screening for diabetic retinopathy (DR) by expert human grading of retinal images is challenging. Automated DR image assessment systems (ARIAS) may provide clinically effective and cost-effective detection of retinopathy. We aimed to determine whether ARIAS can be safely introduced into DR screening pathways to replace human graders. DESIGN: Observational measurement comparison study of human graders following a national screening program for DR versus ARIAS. PARTICIPANTS: Retinal images from 20 258 consecutive patients attending routine annual diabetic eye screening between June 1, 2012, and November 4, 2013. METHODS: Retinal images were manually graded following a standard national protocol for DR screening and were processed by 3 ARIAS: iGradingM, Retmarker, and EyeArt. Discrepancies between manual grades and ARIAS results were sent to a reading center for arbitration. MAIN OUTCOME MEASURES: Screening performance (sensitivity, false-positive rate) and diagnostic accuracy (95% confidence intervals of screening-performance measures) were determined. Economic analysis estimated the cost per appropriate screening outcome. RESULTS: Sensitivity point estimates (95% confidence intervals) of the ARIAS were as follows: EyeArt 94.7% (94.2%-95.2%) for any retinopathy, 93.8% (92.9%-94.6%) for referable retinopathy (human graded as either ungradable, maculopathy, preproliferative, or proliferative), 99.6% (97.0%-99.9%) for proliferative retinopathy; Retmarker 73.0% (72.0 %-74.0%) for any retinopathy, 85.0% (83.6%-86.2%) for referable retinopathy, 97.9% (94.9%-99.1%) for proliferative retinopathy. iGradingM classified all images as either having disease or being ungradable. EyeArt and Retmarker saved costs compared with manual grading both as a replacement for initial human grading and as a filter prior to primary human grading, although the latter approach was less cost-effective. CONCLUSIONS: Retmarker and EyeArt systems achieved acceptable sensitivity for referable retinopathy when compared with that of human graders and had sufficient specificity to make them cost-effective alternatives to manual grading alone. ARIAS have the potential to reduce costs in developed-world health care economies and to aid delivery of DR screening in developing or remote health care settings.

Previous Intravitreal Therapy Is Associated with Increased Risk of Posterior Capsule Rupture during Cataract Surgery.

PURPOSE: To investigate if previous intravitreal therapy is a predictor of posterior capsule rupture (PCR) during cataract surgery. DESIGN: Multicenter, national electronic medical record (EMR) database study with univariate and multivariate regression modeling. PARTICIPANTS: A total of 65 836 eyes of 44 635 patients undergoing cataract surgery. METHODS: Anonymized data were extracted for eyes undergoing cataract surgery from 20 hospitals using the same EMR for cases performed between 2004 and 2014. Variables included as possible risk indicators for PCR were age, sex, number of previous intravitreal injections, indication for intravitreal therapy, grade of healthcare professional administering intravitreal therapy, advanced cataract, and cataract surgeon grade. MAIN OUTCOME MEASURES: Presence or absence of posterior capsular rupture during cataract surgery. RESULTS: Data were available on 65 836 cataract operations, of which 1935 had undergone previous intravitreal therapy (2.9%). In univariate regression analyses, patient age, advanced cataract, junior cataract surgeon grade, and number of previous intravitreal injections were significant predictors of PCR. By considering the number of previous intravitreal injections as a continuous variable, the odds ratio for PCR per intravitreal injection was 1.04 (P = 0.016) after adjusting for age, advanced cataract, and cataract surgeon grade. Repeat analysis considering intravitreal injections as a categoric variable showed 10 or more previous injections were associated with a 2.59 times higher likelihood of PCR (P = 0.003) after again adjusting for other significant independent predictors. CONCLUSIONS: Previous intravitreal therapy is associated with a higher likelihood of PCR during cataract surgery. This study provides data to help inform surgeons and patients about the risk of complications when undergoing cataract surgery after multiple prior intravitreal injections. Further investigation is required to determine the cause behind the increased PCR risk.