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PurposeTo report the retinal phenotype in two patients simulating type 2 macular telangiectasis with new variants inCYP2U1implicated in Hereditary Spastic Paraplegia type 56 (HSP 56).MethodsFive members of a non-consanguineous family (parents and three male children) were investigated. All family members underwent a full ophthalmological evaluation and multimodal retinal imaging. Two family members demonstrating retinal anomalies underwent additional OCT angiography, dual wavelength autofluorescence and fluorescence lifetime imaging ophthalmoscopy, kinetic perimetry, fundus-correlated microperimetry, electroretinography and electro-oculography. Whole exome sequencing was performed in all five family members.ResultsThe two siblings with compound heterozygous novel variants c.452C>T; p.(Pro151Leu), c.943C>T; p.(Gln315Ter) inCYP2U1demonstrated parafoveal loss of retinal transparency and hyperreflectivity to blue light, redistribution of luteal pigment to the parafoveal edge, photoreceptor loss, FLIO anomalies: a pattern compatible with that seen in macular telangiectasia type 2 (MacTel). One had manifest neurological abnormalities since early childhood, the second had no neurological abnormalities. Each parent and the third sibling were heterozygous for one variant and were neurologically and ophthalmologically normal.ConclusionTheseCYP2U1variants are associated with a retinal phenotype very similar to that otherwise specific for MacTel, suggestive of possible links in the aetiology/pathogenesis of these diseases.

To evaluate the effect of aging, intra- and intersession repeatability and regional scotopic sensitivities in healthy and age-related macular degeneration (AMD) eyes. Intra- and intersession agreement and effect of age was measured in healthy individuals. The mean sensitivity (MS) and pointwise retinal sensitivities (PWS) within the central 24° with 505 nm (cyan) and 625 nm (red) stimuli were evaluated in 50 individuals (11 healthy and 39 AMD eyes). The overall intra- and intersession had excellent reliability (intraclass correlation coefficient, ICC > 0.90) and tests were highly correlated (Spearman rs = 0.75–0.86). Eyes with subretinal drusenoid deposit (SDD) had reduced PWS centrally, particularly at inferior and nasal retinal locations compared with controls and intermediate AMD (iAMD) without SDD. There was no difference in MS or PWS at any retinal location between iAMD without SDD and healthy individuals nor between iAMD with SDD and non-foveal atrophic AMD groups. Eyes with SDD have reduced rod function compared to iAMD without SDD and healthy eyes, but similar to eyes with non-foveal atrophy. Our results highlight rod dysfunction is not directly correlated with drusen load and SDD location.

Purpose To describe the defining features of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA), a consensus term referring to the OCT-based anatomic changes often identified before the development of complete RPE and outer retinal atrophy (cRORA) in age-related macular degeneration (AMD). We provide descriptive OCT and histologic examples of disease progression. Design Consensus meeting. Participants Panel of retina specialists, including retinal imaging experts, reading center leaders, and retinal histologists. Methods As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analyzed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred before the development of atrophy secondary to AMD. New terms of iRORA and cRORA were defined. This report describes in detail the CAM consensus on iRORA. Main Outcome Measures Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. Results OCT was used in cases of early and intermediate AMD as the base imaging method to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid, (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. Conclusions An international consensus classification for OCT-defined anatomic features of iRORA are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly is essential to understand better the natural history of the disease, to identify high-risk signs of progression, and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavors, acknowledging that the classification will be refined as new data are generated.

Purpose To test the effects of an encapsulated cell-based delivery of a neuroprotective agent, ciliary neurotrophic factor (CNTF), on progression of macular telangiectasia type 2, a neurodegenerative disease with no proven effective therapy. Design Randomized sham-controlled clinical trial. Participants Ninety-nine study eyes of 67 eligible participants were enrolled. Methods Single-masked randomized clinical trial of 24 months’ duration conducted from May 2014 through April 2017 in 11 clinical centers of retinal specialists in the United States and Australia. Participants were randomized 1:1 to surgical implantation of intravitreal sustained delivery of human CNTF versus a sham procedure. Main Outcome Measures The primary outcome was the difference in the area of neurodegeneration as measured in the area of the ellipsoid zone disruption (or photoreceptor loss) measured on spectral-domain (SD) OCT images at 24 months from baseline between the treated and untreated groups. Secondary outcomes included comparison of visual function changes between treatment groups. Results Among the 67 participants who were randomized (mean age, 62±8.9 years; 41 women [61%]; 58 white persons [86%]), 65 (97%) completed the study. Two participants (3 study eyes) died and 3 participants (4 eyes) were found ineligible. The eyes receiving sham treatment had 31% greater progression of neurodegeneration than the CNTF-treated eyes. The difference in mean area of photoreceptor loss was 0.05±0.03 mm2 (P = 0.04) at 24 months. Retinal sensitivity changes, measured using microperimetry, were correlated highly with the changes in the area of photoreceptor loss (r = 0.86; P Conclusions In participants with macular telangiectasia type 2, a surgical implant that released CNTF into the vitreous cavity, compared with a sham procedure, slowed the progression of retinal degeneration. Further research is needed to assess longer-term clinical outcomes and safety.

Background Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. Methods We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. Results Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. Conclusions Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.

BackgroundMacular telangiectasia type 2 (MacTel) is a neurodegenerative disease resulting in photoreceptor loss. Optical coherence tomography (OCT) reveals outer retina-associated hyperreflectivity (ORaH) as part of this process. The purpose of this study was to describe the incidence and phenotypical variation of ORaH.MethodsDifferent parameters of ORaH were analysed: OCT characteristics (Spectralis SD-OCT), correlation with vascular changes (OCT angiography; OCTA 3×3 mm Optovue) and correlation with hyperpigmentation (autofluorescence/fundus images). ORaH was also evaluated regarding the grade of severity of photoreceptor loss (Disease Severity Scale).ResultsOf 220 eyes with MacTel type 2, 106 demonstrated ORaH. On OCT, the size, the extension into the inner retina and the contact with retinal pigment epithelium (RPE) of the ORaH were variable. On OCTA neovascularisation (NV) in the outer retina (OR) was present at the location of the ORaH in 97.6%. Increasing size of NV correlated with progressive photoreceptor loss. In 86.6% with NV, the flow signals were visible between the OR and the choriocapillaris. In 85.7%, the ORaH was associated with hyperpigmentation on autofluorescence and fundus colour images.ConclusionsThe presence of ORaH is associated with increasing photoreceptor loss and disease severity. In these more advanced cases of the present study, a variable presentation of ORaH in respect to size and form was seen, but in most cases, ORaH was in contact to the RPE. Additionally, ORaH was associated with hyperpigmentation and OR NV on OCTA. These results are consistent with the concept of ORaH representing fibrovascular OR-NV with RPE proliferation after contact with the RPE.

PURPOSE: To evaluate functional clinical endpoints and their structural correlations in AMD, with a focus on subretinal drusenoid deposits (SDD). METHODS: This prospective study enroled 50 participants (11 controls, 17 intermediate AMD (iAMD) with no SDD, 11 iAMD with SDD and 11 non-foveal atrophic AMD). Participants underwent best-corrected visual acuity (BCVA), low luminance visual acuity (LLVA), low luminance questionnaire (LLQ), scotopic thresholds, rod-intercept time (RIT), photopic flicker electroretinograms and multimodal imaging. Functional and structural relationships were assessed. RESULTS: Compared with healthy participants, BCVA, LLVA, scotopic thresholds were depressed, and RIT prolonged in iAMD patients with SDD (p = 0.028, p = 0.045, p = 0.014 and p

Purpose: To investigate the value of visual acuity and patient-perceived visual function test when subretinal drusenoid deposits (SDD) are incorporated into the classification of age-related macular degeneration (AMD). A total of 50 participants were recruited into the study in these groups: healthy ageing (n = 11), intermediate AMD (iAMD) with no SDD (n = 17), iAMD with SDD (n = 11) and non-foveal atrophic AMD (n = 11) confirmed by two retinal imaging modalities. Best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) were measured and low luminance deficit (LLD) was calculated. Participants were also interviewed with the low luminance questionnaire (LLQ). Linear regression was used to assess function&ndash, function relations. Compared with healthy participants, BCVA and LLVA scores were significantly reduced in the atrophic AMD group (p &lt, 0.0001 and p = 0.00016, respectively) and in patients with SDD (p = 0.028 and p = 0.045, respectively). Participants with atrophy also had reduced BCVA (p = 0.001) and LLVA (p = 0.009) compared with the iAMD no SDD group. However, there were no differences in visual function tests between healthy aging and iAMD without SDD and between iAMD with SDD and atrophic AMD groups. The LLD score did not differ between groups. BCVA and LLVA correlated well. The LLQ did not correlate with visual function tests. This study shows that LLD is not a marker of disease severity as assessed clinically. Although LLQ is a good marker for disease severity using the current AMD classification, it does not differentiate between eyes with and without SDD. Eyes with non-macular geographic atrophy and SDD had lower function than eyes with no SDD and healthy controls.

Age-related macular disease (AMD) is a major cause of blindness and there is little treatment currently available by which the progress of the basic disorder can be modulated. Histological and clinical studies show that the major tissues involved are the outer retina, retinal pigment epithelium, Bruch’s membrane and choroid. Because of a wide variation of phenotype from one case to another, it has been suggested that accurate phenotyping would be necessary for assessment of the effectiveness of treatment that is tissue-directed. However, based on findings from the study of human donor material and animal models of disease and of cell culture, it is concluded that retinal pigment epithelial dysfunction plays a central role in the disease process in most, if not all, cases of early AMD. The metabolism of phagosomal material, particularly lipids, and energy generation are interdependent, and dysfunction of both appears to be important in the genesis of disease. Evidence exists to suggest that both can be modulated therapeutically. These metabolic functions are amenable to further investigation in both the normal state and in disease. Once fully characterised, it is likely that treatment could be directed towards a limited number of functions in single tissue, thus simplifying treatment strategies.

Limited evidence suggests that the application of 670 nm of red light alters the course of aged decline. A previous report on 18 patients showed regression of drusen and improvement in visual functions in patients with intermediate age-related macular degeneration (AMD) by 12 months. We evaluated the functional and structural effects of applying 670 nm light to 31 patients with intermediate AMD and 11 people aged 55 years or above with normal retina. The study eyes were treated daily in the morning with a 670 nm hand-held light source housed in a torch-like tube that emitted energy equivalent to 40 mW/cm2 or 4.8J/ cm2 for 2 min at the viewing aperture. Visual function in terms of best-corrected visual acuity, low luminance visual acuity, scotopic thresholds and rod-intercept time were compared between baseline and 1, 3, 6 and 12 months. Structural changes on optical coherence tomography OCT and colour photographs were also assessed. Five withdrew consent voluntarily due to the intensity of the study visit assessments and two developed neovascular AMD and were excluded from further treatment and the analysis. In normal ageing, there was an improvement in scotopic thresholds in the group with no AMD by 1.77dB (p = 0.03) and no other parameters showed any clinically significant change. In eyes with intermediate AMD, there was no significant improvement in any functional or structural changes at any time point up to 12 months although the compliance was good. This pilot study shows that photobiomodulation with 670 nm has no effect in patients who have already progressed to intermediate AMD.

X-linked retinopathies represent a significant proportion of monogenic retinal disease. They include progressive and stationary conditions, with and without syndromic features. Many are X-linked recessive, but several exhibit a phenotype in female carriers, which can help establish diagnosis and yield insights into disease mechanisms. The presence of affected carriers can misleadingly suggest autosomal dominant inheritance. Some disorders (such as RPGR-associated retinopathy) show diverse phenotypes from variants in the same gene and also highlight limitations of current genetic sequencing methods. X-linked disease frequently arises from loss of function, implying potential for benefit from gene replacement strategies. We review X-inactivation and X-linked inheritance, and explore burden of disease attributable to X-linked genes in our clinically and genetically characterised retinal disease cohort, finding correlation between gene transcript length and numbers of families. We list relevant genes and discuss key clinical features, disease mechanisms, carrier phenotypes and novel experimental therapies. We consider in detail the following: RPGR (associated with retinitis pigmentosa, cone and cone-rod dystrophy), RP2 (retinitis pigmentosa), CHM (choroideremia), RS1 (X-linked retinoschisis), NYX (complete congenital stationary night blindness (CSNB)), CACNA1F (incomplete CSNB), OPN1LW/OPN1MW (blue cone monochromacy, Bornholm eye disease, cone dystrophy), GPR143 (ocular albinism), COL4A5 (Alport syndrome), and NDP (Norrie disease and X-linked familial exudative vitreoretinopathy (FEVR)). We use a recently published transcriptome analysis to explore expression by cell-type and discuss insights from electrophysiology. In the final section, we present an algorithm for genes to consider in diagnosing males with non-syndromic X-linked retinopathy, summarise current experimental therapeutic approaches, and consider questions for future research.

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Purpose To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD). Design Consensus meeting. Participants Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers. Methods As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy. Main Outcome Measures A consensus classification system for atrophy and OCT-based criteria to identify atrophy. Results OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear. Conclusions A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.

PURPOSE To characterize scotomas in macular telangiectasia Type 2 (MacTel). METHODS Five of the 27 centers performed microperimetry as part of the MacTel Natural History Observation Study. Data were analyzed in the Moorfields Eye Hospital Reading Centre. The number of stimuli under a threshold of 12, 10, 8, and

The regional susceptibility of the retina to diseases has been well known by clinicians for many years. It is surprising that the implications of these observations have not spawned major research efforts to characterise the structural and functional attributes of the outer retina in different regions of a foveate retina. Without such an effort, the understanding of the disease mechanisms in retinal dystrophies will remain limited and may hamper therapeutic efforts. That outer retinal disease is responsible for over 50% of blind registration in the western world underlines the importance of these considerations.

PURPOSE: To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials. DESIGN: Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings. PARTICIPANTS: A panel of retina specialists. METHODS: During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held. MAIN OUTCOME MEASURES: Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials. RESULTS: Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions. CONCLUSIONS: A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.

PURPOSE: To describe the defining features of “incomplete retinal pigment epithelial (RPE) and outer retinal atrophy” (iRORA), a consensus term referring to the optical coherence tomography (OCT) based anatomical changes often identified prior to the development of “complete RPE and outer retinal atrophy (cRORA)” in age-related macular degeneration (AMD). We provide descriptive OCT and histological examples of disease progression. DESIGN: Consensus meeting PARTICIPANTS: Panel of retina specialists, including retinal imaging experts, reading center leaders and retinal histologists. METHODS: As part of the Classification of Atrophy Meeting (CAM) program, an international group of experts analysed and discussed longitudinal multimodal imaging of eyes with AMD. Consensus was reached on a classification system for OCT-based structural alterations that occurred prior to the development of atrophy secondary to AMD. New terms of complete and incomplete RPE and outer retinal atrophy (iRORA and cRORA) were defined. This report describes in detail the CAM consensus on iRORA. MAIN OUTCOME MEASURES: Defining the term iRORA through OCT imaging and longitudinal cases showing progression of atrophy, with histologic correlates. RESULTS: OCT was used in cases of early and intermediate AMD as the base imaging modality to identify cases of iRORA. In the context of drusen, iRORA is defined on OCT as (1) a region of signal hypertransmission into the choroid and (2) a corresponding zone of attenuation or disruption of the RPE, and (3) evidence of overlying photoreceptor degeneration. The term iRORA should not be used when there is an RPE tear. Longitudinal studies confirmed the concept of progression from iRORA to cRORA. CONCLUSIONS: An international consensus classification for OCT-defined anatomical features of iRORA, are described and examples of longitudinal progression to cRORA are provided. The ability to identify these OCT changes reproducibly, is essential to better understand the natural history of disease, to identify high risk signs of progression and to study early interventions. Longitudinal data are required to quantify the implied risk of vision loss associated with these terms. The CAM classification provides initial definitions to enable these future endeavours, acknowledging that the classification will be refined as new data are generated.

Importance As genetic and genomic screening is becoming more widely accessed, correctly distinguishing pathogenic from nonpathogenic variants is of increasing relevance. Objective To reevaluate a previously reported family in whom the p.(Pro50Leu) variant in the geneGUCA1Awas associated with a dominant retinal dystrophy, in light of new examination findings in the proband’s daughter. Design, Setting, and Participants A genetic study relating to a family with an inherited retinal dystrophy was performed at the retinal genetics service of Moorfields Eye Hospital from October 27, 2009, to May 23, 2019, after the proband’s daughter underwent fundus examination. Main Outcomes and Measures Results of sequencing of X chromosome–linked retinitis pigmentosa genes in the proband and specific analysis of the repetitive ORF15 region of theRPGRgene. Results A frame-shifting single-nucleotide deletion was found in the ORF15 exon ofRPGR(GRCh37 [hg19] x:38145160delT;NM_001034853.1: c.3092delA p.[Glu1031Glyfs*58]), which may be associated with the loss of 121 amino acid residues at the carboxyl terminus of the protein. The p.(Pro50Leu) variant inGUCA1Awas also found to be too common in a publicly available genome database to be a fully penetrant cause of a dominant retinal dystrophy. Conclusions and Relevance The phenotype in the family is now associated with the variant inRPGR. The findings suggest that the p.(Pro50Leu) variant inGUCA1Ashould not be regarded as pathogenic. This report also highlights the relevance of examining relatives, of reevaluating diagnoses in light of new data, and of considering X chromosome–linked inheritance in apparently autosomal dominant pedigrees unless there is clear male-to-male transmission.

Purpose: To examine whether ultra-widefield (UWF) retinal imaging can identify biomarkers for Alzheimer’s disease (AD) and its progression. Methods: Images were taken using a UWF scanning laser ophthalmoscope (Optos P200C AF) to determine phenotypic variations in 59 patients with AD and 48 healthy controls at baseline (BL). All living participants were invited for a follow-up (FU) after 2 years and imaged again (if still able to participate). All participants had blood taken for genotyping at BL. Images were graded for the prevalence of age-related macular degeneration-like pathologies and retinal vascular parameters. Comparison between AD patients and controls was made using the Student t test and the χ2 test. Results: Analysis at BL revealed a significantly higher prevalence of a hard drusen phenotype in the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%) [χ2 = 9.9, df = 4, p = 0.04]. A markedly increased drusen number was observed at the 2-year FU in patients with AD compared to controls. There was a significant increase in venular width gradient at BL (zone C: 8.425 × 10–3 ± 2.865 × 10–3 vs. 6.375 × 10–3 ± 1.532 × 10–3, p = 0.008; entire image: 8.235 × 10–3 ± 2.839 × 10–3 vs. 6.050 × 10–3 ± 1.414 × 10–3, p = 0.004) and a significant decrease in arterial fractal dimension in AD at BL (entire image: 1.250 ± 0.086 vs. 1.304 ± 0.089, p = 0.049) with a trend for both at FU. Conclusions: UWF retinal imaging revealed a significant association between AD and peripheral hard drusen formation and changes to the vasculature beyond the posterior pole, at BL and after clinical progression over 2 years, suggesting that monitoring pathological changes in the peripheral retina might become a valuable tool in AD monitoring.

PURPOSE: To evaluate progression of macular telangiectasia Type 2 lesions and their correlation with visual acuity. METHODS: An international multicenter prospective study with annual examinations including best-corrected visual acuity (BCVA), fundus photography, fluorescein angiography, and optical coherence tomography images graded centrally. Mixed models were used to estimate progression rates, and a generalized linear model to compute the relative risk of BCVA loss, loss of ellipsoid zone (EZ) reflectivity, development of pigment plaques, or neovascularization. RESULTS: One thousand and fourteen eyes of 507 participants were followed for 4.2 ± 1.6 years. Best-corrected visual acuity decreased 1.07 ± 0.05 letters (mean ± SE) per year. Of all eyes, 15% lost ≥15 letters after 5 years. Of the eyes without EZ loss, 76% developed a noncentral loss. Of the eyes with noncentral loss, 45% progressed to central EZ loss. The rate of BCVA loss in eyes with noncentral EZ loss at baseline was similar to eyes without EZ loss. The rate of BCVA loss was significantly higher in eyes with central EZ loss at baseline (-1.40 ± 0.14 letters, P < 0.001). CONCLUSION: Ellipsoid zone loss is frequently found in macular telangiectasia Type 2 and is an important structural component reflecting visual function. Its presence in the fovea significantly correlates with worse visual prognosis.

Purpose: To investigate the influence of hormone therapy with tamoxifen or estrogens on morphological changes in macular telangiectasia (MacTel) type 2 patients as revealed clinically in multiple imaging modalities. Methods: Patients with a history of tamoxifen or estrogen use were selected from the cohort of the MacTel Study. A race-, age- and best-corrected visual acuity-matched group of MacTel participants not under hormone therapy served as the comparison group. The frequencies of typical features of the MacTel phenotype apparent in color fundus, red-free, fluorescein angiographic and optical coherence tomographic images were graded and analyzed statistically. Results: Thirty-nine MacTel patients were included in the analyses, of whom 13 were receiving tamoxifen, 13 estrogens and 13 patients no hormone treatment. Patients treated with estrogens showed significantly fewer breaks in the ellipsoid zone on optical coherence tomography (7 eyes, 29.1%, vs. tamoxifen: 14 eyes, 53.8%, and vs. controls: 14 eyes, 53.8%, p = 0.04 in both analyses, Fisher exact test). Retinal crystalline deposits were significantly more frequent in patients receiving estrogens (12 eyes, 16.2%, vs. 2 eyes, 2.7%, p = 0.003, Fisher exact test). No significant between-group differences were apparent with regard to other features of the phenotype (extent of retinal low reflective spaces, late hyperfluorescence on fluorescein angiography or retinal thickness). Conclusions: Tamoxifen treatment does not seem to accentuate structural changes in patients with MacTel type 2. Treatment with estrogens may exhibit a neuroprotective effect as suggested by the decreased frequency of ellipsoid zone breaks in corresponding patients, although corroborative studies are warranted to confirm these exploratory data.

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.

Macular telangiectasia Type 2 is a bilateral, progressive potentially blinding retinal disease characterized by both vascular and neurodegenerative signs that have been documented using different imaging techniques. The correlation between macular telangiectasia Type 2 signs from various imaging modalities is unknown. Our aim was to investigate the relationship of various macular telangiectasia Type 2 signs using fundus fluorescein angiography, optical coherence tomography and dual-wavelength autofluorescence images.Participants were selected from the macular telangiectasia Type 2 Natural History Observation Study, based on a confirmed diagnosis and the availability of images. Signs in fundus fluorescein angiography, dual-wavelength autofluorescence, and optical coherence tomography images were graded according to standardized categories, and agreement among the multimodel imaging was assessed statistically.One hundred and ninety-one eyes of 96 patients were examined. Significant correlations were found between early and late fundus fluorescein angiography (ρ = 0.82, P0.0001), luteal pigment loss and early/late fundus fluorescein angiography signs (ρ = 0.52, P0.0001 and ρ = 0.62, P0.0001, respectively), inner and outer segment break length and pigment loss (Class 1 vs. 2/3, P0.0001; Class 2 vs. 3, P = 0.04). Correlation between pigment loss and retinal spaces/atrophic retinal restructuring was fair (κ = 0.25-0.33). Bilateral symmetry was slight to substantial (κ = 0.18-0.62).Our data demonstrate the relative extent of neurodegenerative and vascular signs; it may be useful for designing systems for staging disease severity using multimodal imaging and may also provide clues to the pathogenesis of the disease.

PURPOSE: Pigment in the midretina is a characteristic sign in Type 2 idiopathic macular telangiectasia (MacTel) and is considered to characterize the late stage of the disease. Our aim was to investigate its incidence, and relationship with risk factors for MacTel, including outer retinal vascularization and subretinal neovascular proliferation (SRNV). METHODS: Pigment extent was measured in fundus autofluorescence images of 150 eyes of 75 MacTel probands, using the Region Finder tool of Heidelberg Eye Explorer. A linear mixed model was used to analyze the dynamics of pigment and its associations with other features of the phenotype. The relative incidence of pigment and of outer retinal outer retinal vascularization and SRNV was analyzed within the full MacTel Study cohort (1,244 probands). RESULTS: Mean pigment area at baseline was 0.157 mm (range = 0-1.295 mm, SD = 0.228 mm, n = 101). Progression demonstrated a nonlinear pattern (P < 0.001) at an overall rate of 0.0177 mm/year and was associated with the initial plaque size and with SRNV. There was a strong correlation between fellow eyes (P ≤ 0.0001). In approximately 25% of all SRNV cases, SRNV may coincide with or precede pigment. CONCLUSION: Our data may be useful for refining the current system for staging disease severity in MacTel.

PURPOSE: To compare ellipsoid zone (EZ) loss and functional loss in macular telangiectasia (MacTel) type 2 longitudinally. METHODS: Prospective natural history study. Ellipsoid zone loss was measured in en-face images created from spectral domain optical coherence tomography. Functional loss was assessed by best-corrected visual acuity and microperimetry, counting the number of test points with impaired function. RESULTS: A total of 56 eyes of 31 participants were followed for 4.5 ± 1.2 years. Ellipsoid zone loss was 18,600 ± 3,917.3 pixel at baseline (≈0.59 mm(2)) and increased 2,627.8 ± 427.9 pixel (≈0.08 mm(2)) per year. Best-corrected visual acuity decreased 2.2 ± 0.9 letters per year. Change in EZ loss correlated significantly with change in relative and absolute scotomas (r = 0.62; P-value < 0.0001 and r = 0.72; P-value < 0.0001), but not with loss of best-corrected visual acuity. Functional loss showed a similar frequency of progression as EZ loss, but a higher rate of “regression,” likely due to higher variability of the measurement, assuming a progressive neurodegenerative disease. CONCLUSION: The results of the authors support EZ loss as surrogate measure for visual function in MacTel type 2. Being objective, EZ loss might be considered more suitable than microperimetry as primary end point in future interventional trials.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P

Purpose: To determine whether the prevalences of various systemic conditions in participants of the MacTel Project Natural History Observation (NHO) Study differ from the corresponding prevalences in the general population. Methods: This report compares the prevalence of systemic disease in participants of the NHO Study with age- and sex-matched controls from three population-based studies from the US, the Netherlands and Australia. Bootstrap simulations were used to evaluate the impact and reliability of the computed statistics. Results: We identified a number of systemic conditions that appear to be more prevalent in cases with macular telangiectasia (MacTel) Type 2 than in the general population that were matched for age and sex with the MacTel cases. Patients with MacTel Type 2 had significantly increased prevalence of diabetes mellitus, higher prevalence of obesity, hypertension and history of cardiovascular disease, compared to their same-aged peers in generally older communities. Conclusion: Systemic disease associated with MacTel Type 2 may help to improve understanding of possible causes of MacTel Type 2. It is hoped that future studies will help to improve our understanding of the pathogenesis of the condition and lead to potential treatments for this ocular disease.

Purpose: To estimate the conversion factors to transpose macular thickness measurements on time-domain (TD) to various spectral-domain (SD) optical coherence tomography (OCT) machines in patients with macular telangiectasia type 2a (MacTel). Procedures: Macular scans on TD- and SD-OCT were performed on patients at the same visit. The retinal thickness values in various ETDRS subfields and macular volume were compared between different OCT machines. Results: The macular thickness and volume were significantly greater (p < 0.0001, r = 0.678-0.822) on SD-OCT. The mean differences in macular thickness between TD Stratus and SD-OCT by Spectralis, Cirrus and Topcon were 62, 41 and 20 μm, respectively. The conversion factor of macular thickness from TD-OCT to Spectralis, Cirrus and Topcon were +65, +39 and +25 μm, respectively. Conclusion and Message: The estimates of conversion of macular thickness from TD- to SD-OCT using simple mean differences between machines and those by linear regression were similar suggesting that the former may be used for the longitudinal follow-up of MacTel patients.

PURPOSE: To provide long-term (> or =5 years) follow-up data on patients who had previously undergone macular retinal pigment epithelium (RPE) translocation surgery for choroidal new vessels (CNVs) associated with age-related macular degeneration. DESIGN: Retrospective interventional case series. PARTICIPANTS: Four of 9 patients who originally underwent surgery and whose results were reported after 2 years of follow-up were reviewed again 5 to 6 years after surgery. METHODS: All surviving patients from the original trial were contacted, and those who consented to full ocular examination were called in for review. Examination included best-corrected visual acuity (VA), optical coherence tomography (OCT), fundus autofluorescence, fluorescein angiography (FA), and indocyanine green angiography. MAIN OUTCOME MEASURES: Long-term success of RPE translocation was assessed by VA, imaging, angiography, and maintenance of overlying foveal fixation. Comparisons were made to the original 2-year follow-up data previously published. RESULTS: Over the long term, VA had declined further in 3 patients and improved slightly in 1 patient. Significantly, all 4 patients had lost foveal fixation and autofluorescence of translocated RPE, which had been present at the original 2-year follow-up assessment. The RPE graft, however, seemed viable when assessed by OCT, FA, and indocyanine green angiography, and no patient had suffered a recurrence of CNVs. CONCLUSIONS: In these 4 patients, RPE choroidal grafts had survived in the subfoveal space for at least 5 to 6 years, but rescue of visual function had been transient. The long-term loss of foveal fixation and graft autofluorescence might be explained by chronic photoreceptor apoptosis, initiated by either surgery or the disease process itself. Caution should be applied when drawing firm conclusions from similar studies that provide data after only 2 years' follow-up.

PURPOSE: The complement factor H (CFH) gene polymorphism Y402H (1277T-->C) has been associated with susceptibility to age-related macular degeneration (AMD). The purpose of this study was to confirm this association in a U.K. population, to determine whether the association holds for both geographic atrophy (GA) and choroidal neovascularization (CNV), and to investigate interactions with smoking. METHODS: A case-control study was undertaken in 443 cases of AMD, with 262 spouses as control subjects. All subjects completed a health and lifestyle questionnaire, had an ophthalmic assessment with fundus photography, and were genotyped. RESULTS: The frequencies of the C allele and CC genotype were significantly higher in cases than in controls. In comparison to the TT genotype, the odds ratios for AMD associated with the CT and CC genotypes were 3.1 (CI 2.0-4.6) and 6.3 (CI 3.8-10.4), respectively. The results were similar in subgroup analyses confined to cases with GA or CNV. The findings were also similar for subgroup analyses restricted to subjects who had never smoked, moderate smokers, or heavier smokers (>20 pack years of smoking). Heavier smokers with the CC genotype may be particularly at risk. The frequency of the CC genotype did not differ significantly between cases with and without a family history of AMD. There was no evidence that genotype had any influence on age at onset of disease. CONCLUSIONS: The CFH Y402H variant is strongly associated with both GA and CNV in the U.K. population. This association is similar in smokers and nonsmokers. Heavier smokers with the CC genotype may be at particular risk.

PURPOSE: Fundus autofluorescence (FAF), as an index of lipofuscin accumulation in the retinal pigment epithelium (RPE), provides indirect information on the level of metabolic activity of the RPE and thus the integrity of the RPE/photoreceptor complex. To investigate whether the photoreceptor/RPE complex is still viable in patients with Leber congenital amaurosis (LCA), FAF imaging was performed. METHODS: Three patients with LCA (patients A, B, and C; ages, 24, 15, and 37 years, respectively) were enrolled and one patient with RP with preserved visual acuity (age, 28 years) was included as a control. The diagnosis was based on history, visual function, and Ganzfeld electroretinography (International Society for Clinical Electrophysiology of Vision [ISCEV] standard). FAF was recorded with a confocal scanning laser ophthalmoscope (cSLO; Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany). RESULTS: All patients with LCA had vision reduced to perception of light and had undetectable ERGs. FAF was normal in patient A. In patient B, there was a parafoveal ring of mildly increased FAF. The midperiphery showed mildly decreased FAF. Patient C showed a parafoveal ring of moderately increased FAF. FAF was moderately decreased along the arcades and the midperiphery. The patient with RP showed a parafoveal ring of moderately increased FAF and severely decreased FAF eccentric to the macula including the periphery. CONCLUSIONS: The FAF findings in these patients with LCA suggest that there is continuous metabolic demand from the photoreceptors and that the RPE/photoreceptor complex is, at least in part, anatomically intact, but the photoreceptors have lost function. These findings may have implications for future treatment. It is notable that more than 20 years of severe visual impairment associated with LCA can be associated with normal FAF, indicating that photoreceptor function may be rescuable.

The condition now known as AZOOR was probably reported initially by neuro-ophthalmologists when patients were recognized as having a big blind spot without disc swelling or any other visible retinal abnormalities. The field loss was reported to be persistent over many months. It was then recognized that in some patients, the visual field loss was progressive extending temporally around the macula. Electrophysiological testing showed that the functional loss was due to retinal dysfunction.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrial counties. Recent findings indicate that the autoimmunity is involved in the pathogenesis of the disease. However, there is no autoantibody biomarker applied in a clinical setting for diagnosis and prognosis of AMD. In order to reveal retinal antigens targeted by serum IgG from AMD patients, mouse retinal tissue proteins were separated by 2-dimensional electrophoresis and the proteins in the immunoblots that were specific for dry and wet AMD patients IgG were identified by LC–MS/MS. Retinol-binding protein 3 and aldolase C (ALDOC) were mainly recognized by IgG form wet AMD patients. Pyruvate kinase M2 (PKM2) was targeted by both dry and wet AMD and level of anti-PKM2 IgG antibody was correlated best with the stage of AMD. Expression of ALDOC and PKM2 was decreased in mouse retina from aging whereas PKM2 deposit on RPE was increased in aged mice. Our data demonstrate that sera of AMD patients contain autoantibodies against retinal proteins and anti-PKM2 IgG serves as a biomarker for diagnosis and prognosis of AMD. Further investigation of the association of anti-retinal antibody level with expression level of antigens in retina will be needed to reveal the disease pathogenesis.

Age-related macular degeneration (AMD) is a leading cause of visual loss in Western populations. Susceptibility is influenced by age, environmental and genetic factors. Known genetic risk loci do not account for all the heritability. We therefore carried out a genome-wide association study of AMD in the UK population with 893 cases of advanced AMD and 2199 controls. This showed an association with the well-established AMD risk loci ARMS2 (age-related maculopathy susceptibility 2)-HTRA1 (HtrA serine peptidase 1) (P =2.7 × 10(-72)), CFH (complement factor H) (P =2.3 × 10(-47)), C2 (complement component 2)-CFB (complement factor B) (P =5.2 × 10(-9)), C3 (complement component 3) (P =2.2 × 10(-3)) and CFI (P =3.6 × 10(-3)) and with more recently reported risk loci at VEGFA (P =1.2 × 10(-3)) and LIPC (hepatic lipase) (P =0.04). Using a replication sample of 1411 advanced AMD cases and 1431 examined controls, we confirmed a novel association between AMD and single-nucleotide polymorphisms on chromosome 6p21.3 at TNXB (tenascin XB)-FKBPL (FK506 binding protein like) [rs12153855/rs9391734; discovery P =4.3 × 10(-7), replication P =3.0 × 10(-4), combined P =1.3 × 10(-9), odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.3-1.6] and the neighbouring gene NOTCH4 (Notch 4) (rs2071277; discovery P =3.2 × 10(-8), replication P =3.8 × 10(-5), combined P =2.0 × 10(-11), OR = 1.3, 95% CI = 1.2-1.4). These associations remained significant in conditional analyses which included the adjacent C2-CFB locus. TNXB, FKBPL and NOTCH4 are all plausible AMD susceptibility genes, but further research will be needed to identify the causal variants and determine whether any of these genes are involved in the pathogenesis of AMD.

PURPOSE: Type 2 idiopathic macular telangiectasia (MacTel) is a progressive retinal disease associated with a slow deterioration of visual acuity, starting in the fifth to seventh decades of life. The etiology and pathogenesis of the disease are little known, and no effective therapy is available. We aimed to estimate the prevalence and describe the phenotype of type 2 MacTel in two African populations. METHODS: From two population-based cross-sectional surveys conducted nationally in Nigeria and in the Nakuru district of Kenya, patients with fundus features of type 2 MacTel were selected. Diagnosis was based on color fundus images, grading performed according to the MacTel Study protocol and staged using the Gass and Blodi system. Disease phenotype and clinical characteristics of affected participants were assessed. RESULTS: Of 8599 total participants, five showed a phenotype compatible with type 2 MacTel. Prevalence was estimated as 0.06% (95% confidence interval [CI] 0.02-0.21%) in Kenya, 0.06% (95% CI 0.01-0.17%) in Nigeria, and overall at 0.06% (95% CI 0.02-0.14%). Mean age was 62 years (SD 5 years), four of five affected participants were female, and none had a history of diabetes. Median corrected visual acuity was 6/12 in the better eye and 6/69 in the worse eye. CONCLUSIONS: The estimated prevalence and phenotype of type 2 MacTel in the African populations examined were similar to those in predominantly white populations. All data published so far are based on the analysis of color fundus images only and are thus likely to underestimate the true prevalence of this disease.

Drusen have been considered the clinical hallmark of age-related macular degeneration (AMD). Reticular pseudodrusen (RPD), although first described about 25 years ago, have only been recently recognized as an additional clinical phenotype of AMD with distinct characteristics on multimodal imaging and significant impact on visual function. Eyes with RPD are at greater risk of progression to advanced AMD when compared with eyes with drusen only. RPD can also occur in the absence of drusen. Unlike features external to the retinal pigment epithelium that have received most attention in AMD, evidence suggests that RPD are associated with changes internal to the RPE. Therefore, new avenues regarding the pathogenesis of AMD are highlighted by these recent observations. We summarize the current knowledge regarding the histology, imaging, and functional changes in eyes with RPD in AMD and offer concepts of future research for the AMD community to discuss.

Drusen are discussed frequently in the context of their association with age-related macular degeneration (AMD). Some types may, however, be regarded as a normal consequence of ageing; others may be observed in young age groups. They also occur in a number of inherited disorders and some systemic conditions. Whilst drusen are classically located external (sclerad) to the retinal pigment epithelium, accumulations of material internal (vitread to) this layer can display a drusen-like appearance, having been variously termed pseudodrusen or subretinal drusenoid deposits. This review first briefly presents an overview of drusen biogenesis and subclinical deposit. The (frequently overlapping) subtypes of clinically detectable deposit, seen usually in the context of ageing or AMD, are then described in more detail, together with appearance on imaging modalities: these include hard and soft drusen, cuticular drusen, reticular pseudodrusen and “ghost drusen”. Eye disorders other than AMD which may exhibit drusen or drusen-like features are subsequently discussed: these include monogenic conditions as well as conditions with undefined inheritance, the latter including some types of early onset drusen such as large colloid drusen. A number of systemic conditions in which drusen-like deposits may be seen are also considered. Throughout this review, high resolution images are presented for most of the conditions discussed, particularly the rarer ones, providing a useful reference library for images of the range of conditions associated with drusen-like appearances. In the final section, some common themes are highlighted, as well as a brief discussion of some future avenues for research.

Purpose: To document the evolution and functional and structural significance of parafoveal rings of high-density fundus autofluorescence (AF) in patients with retinitis pigmentosa and preserved visual acuity.Methods: Fifty-two patients with nonsyndromic retinitis pigmentosa or Usher syndrome, who had a parafoveal ring of high-density AF and a visual acuity of 20/30 or better, were ascertained. All had international standard full-field electroretinography and pattern electroretinography. Autofluorescence imaging was repeated in 30 patients after periods of up to 9.3 years. Of the 52 patients, 35 underwent optical coherence tomography.Results: Progressive constriction of the ring was detected in 17 patients. Ring radius reduced by up to 40% at a mean rate of between 0.8% and 15.8% per year. In 1 patient, a small ring was replaced by irregular AF; visual acuity deteriorated over the same period. There was a high correspondence between the lateral extent of the preserved optical coherence tomography inner segment/outer segment band and the diameter of the ring along the same optical coherence tomographic scan plane (slope, 0.9; r = 0.97; P < 0.005; n = 35) and between preserved inner segment/outer segment lamina and the pattern electroretinography P50 measure of macular function (R = 0.72; P < 0.005; n = 34).Conclusion: Rings of increased AF surround areas of preserved outer retina and preserved photopic function. Serial fundus AF may provide prognostic indicators for preservation of central acuity and potentially assist in the identification and evaluation of patients suitable for treatment aimed at preservation of remaining function. RETINA 31: 1670-1679, 2011

Age-related macular disease (AMD) accounts for more than 50% of blind registration in Western society. Patients with AMD are classified as having early disease, in which visual function is well preserved, or late disease, in which central vision is lost. Until recently, there was no therapy available by which the course of the disorder could be modified. Now, the most common form of late-stage AMD — choroidal neovascularization — responds to treatment with anti-VEGF therapies; although visual loss is modified in a portion of these cases, no therapeutic approach exists that alters the evolution from early to late disease. However, as discussed in this Review, research over the last few years has demonstrated several features of AMD that are likely to be amenable to treatment. Potential targets for treatment are described, and possible therapeutic approaches are discussed.

Macular degeneration is known to be a bilateral disease. This study set out to determine the symmetry of phenotype between eyes of patients with bilateral early AMD (or drusen) or late-stage AMD. This may be important information when considering the likelihood of anti-VEGF treatment. This prospective, observational, cross-sectional study graded the color fundus photographs of both eyes of 1,114 Caucasian patients with either early or late-stage AMD. Patients were recruited from a tertiary referral UK population. The main outcomes were phenotype, comparison of number, type and overall area of drusen in early AMD and symmetry of late AMD. The overall agreement of phenotype in the entire cohort of patients was 53%, kappa statistic (κ)=0.31, (95% CI = 0.27–0.36). Within this group, a total of 271 patients were identified with bilateral soft and hard drusen (early AMD). Symmetry of phenotype within this group was high in terms of total of area of drusen (agreement = 79%, weighted κ = 0.75) and number of drusen. In those with bilateral geographic atrophy (GA), symmetry between area of GA was moderate (agreement 72%, weighted κ = 0.54), and in those with bilateral neovascular disease (choroidal neovascularization or pigment epithelial detachment), symmetry was poor (agreement 45%, weighted κ = 0.16). Out of the entire cohort, 62% (n = 688) had neovascular disease in at least one eye and 37.5% of these had bilateral disease. The observed symmetry of phenotype between eyes with drusen appears to reduce in GA and neovascular forms of AMD. Overall, 53% of the cohort had symmetrical disease in terms of phenotype, 23% had neovascular disease in both eyes, 9.3% had GA in both eyes, and 39% of patients had neovascular disease in one eye and non-neovascular disease in the other. This may have implications for the potential need for anti-VEGF treatment of AMD in second eye involvement.

In several disease states, abnormal growth of blood vessels is associated with local neuronal degeneration. This is particularly true in ocular diseases such as retinal angiomatous proliferation (RAP) and macular telangiectasia (MacTel), in which, despite the absence of large-scale leakage or hemorrhage, abnormal neovascularization (NV) is associated with local neuronal dysfunction. We describe here a retinal phenotype in mice with dysfunctional receptors for VLDL (Vldlr–/– mice) that closely resembles human retinal diseases in which abnormal intra- and subretinal NV is associated with photoreceptor cell death. Such cell death was evidenced by decreased cone and, to a lesser extent, rod opsin expression and abnormal electroretinograms. Cell death in the region of intraretinal vascular abnormalities was associated with an increased presence of markers associated with oxidative stress. Oral antioxidant supplementation protected against photoreceptor degeneration and preserved retinal function, despite the continued presence of abnormal intra- and subretinal vessels. What we believe to be novel, Müller cell–based, virally mediated delivery of neurotrophic compounds specifically to sites of NV was also neuroprotective. These observations demonstrate that neuronal loss secondary to NV can be prevented by the use of simple antioxidant dietary measures or cell-based delivery of neurotrophic factors, even when the underlying vascular phenotype is not altered.

Autofluorescence (AF) of the retinal pigment epithelium (RPE) are thought to reflect metabolic activity of the RPE cells, which in turn is largely driven by photoreceptor outer segment renewal. In exudative AMD, choroidal new vessels (CNV) may be confined to Bruch's membrane, or transgress the RPE, with consequence loss of photoreceptor cells. It has been suggested that they may be distinguished with autofluorescence imaging. The aim of our study was to analyze the prognostic value of RPE autofluorescence in relationship to the therapeutic outcome of anti-VEGF (vascular endothelial growth factor) therapy in exudative AMD.AF images (Heidelberg Retina Angiograph) were obtained from 95 eyes (95 patients, mean age 77.64 years, 39 male and 56 female) with exudative macular lesions and associated drusen before therapy with intravitreal Bevacizumab (Avastin). Increased, normal, or decreased AF of a central area with diameters of 500 and 1,000 microm around the foveola were distinguished, and compared with the outcome of central vision. As a measure of data reproducibility (inter- and intraobserver variability), the kappa statistics (K0.6 "good", K0.8 "excellent") and exact agreement in % were calculated.Analysis of AF showed a significant difference in outcome of visual acuity in eyes with changes in AF of the central 500 and 1000 microm (Mann-Whitney test, p500 mum0.001, p1,000 microm = 0.02). Comparison of eyes with increased AF to the other eyes also resulted a significant difference in visual acuity at follow-up (p (incr)0.001); those with decreased AF had no significant difference to the eyes with normal or increased AF (p (decr) = 0.1733).The RPE-AF of exudative AMD lesions varies greatly. The AF differences probably represent different kinds of metabolism disorders in the RPE. Furthermore, they apparently have a great influence on the chances of anti- vascular endothelial growth factor (VEGF) therapy success; in particular the development of visual acuity is less favorable in eyes with initially increased central AF.

Fundus autofluorescence (FAF) imaging is a novel imaging method that allows topographic mapping of lipofuscin distribution in the retinal pigment epithelium cell monolayer as well as of other fluorophores that may occur with disease in the outer retina and the subneurosensory space. Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases, including age-related macular degeneration. FAF imaging has been shown to be useful with regard to understanding of pathophysiologic mechanisms, diagnostics, phenotype-genotype correlation, identification of predictive markers for disease progression, and monitoring of novel therapies. FAF imaging gives information above and beyond that obtained by conventional imaging methods, such as fundus photography, fluorescein angiography, and optical coherence tomography. Its clinical value coupled with its simple, efficient, and noninvasive nature is increasingly appreciated. This review summarizes basic principles and FAF findings in various retinal diseases.