Combined central serous chorioretinopathy, hypermetropia, short axial length, chorioretinal folds, enlarged/thickened ocular coats, with varying association of scleral changes (CHAFES).

PURPOSE: To describe a condition with the following features: chronic central serous chorioretinopathy (CCSC), chorioretinal folds, scleral changes (including any of the following flattened or 'squared off' posterior pole, 'T sign', or thickened ocular coats), accompanied by a short axial length and hypermetropia in a series of 7 patients. METHODS: The case notes of 7 patients presenting with a combination of CSC, choroidal folds scleral changes and hypermetropia were reviewed as part of a retrospective case series. Corrected visual acuities, serial refraction, colour imaging, fluorescein and indocyanine green angiography findings, together with B-ultrasound scan features were recorded, with axial length measurements as available (< 23.3 mm was defined as short). RESULTS: The study included 14 eyes of 7 subjects (2 females and 5 males) with a primary presentation of central vision disturbance. All patients showed signs of previous or current episodes of the following features in at least one eye: CSC (5/7 bilateral); choroidal folds (6/7 bilateral), thickening of ocular coats in the 5 in whom this was measured, at least one scleral abnormality on ultrasound in at least one eye. A short axial length at final appointment was recorded in 13/14 eyes. CONCLUSIONS AND RELEVANCE: The combination of CCSC with choroidal folds, hypermetropia with apparent shortening of the eyeball associated with one or more scleral abnormalities such as a flattened or 'squared off 'appearance of the B ultrasound may be a specific ocular condition. The aetiology of this particular combination of posterior segment manifestations is unknown; the choroid could be the primary focus of disease with secondary involvement of the sclera. Alternatively, the features observed may result from a chronic inflammatory process affecting the sclera with secondary effects on the choroid, retinal pigment epithelium and retina. In our case series, the final vision was not significantly different from vision at presentation.

Quantitative Autofluorescence in Non-Neovascular Age Related Macular Degeneration.

Quantitative autofluorescence (qAF8) level is a presumed surrogate marker of lipofuscin content in the retina. We investigated the changes in the qAF8 levels in non-neovascular AMD. In this prospective cohort study, Caucasians aged ≥50 years with varying severity of non-neovascular AMD in at least one eye and Snellen visual acuity ≥6/18 were recruited. The qAF8 levels were analysed in the middle eight segments of the Delori pattern (HEYEX software, Heidelberg, Germany). The AMD categories were graded using both the Beckman classification and multimodal imaging (MMI) to include the presence of subretinal drusenoid deposits (SDD). A total of 353 eyes from 231 participants were analyzed. Compared with the age-matched controls, the qAF8 values decreased in the eyes with AMD (adjusted % difference = -19.7% [95% CI -28.8%, -10.4%]; p < 0.001) and across the AMD categories, (adjusted % differences; Early, -13.1% (-24.4%, -1%), p = 0.04; intermediate AMD (iAMD), -22.9% (-32.3%, -13.1%), p < 0.001; geographic atrophy -25.2% (-38.1%, -10.4%), p = 0.002). On MMI, the qAF8 was reduced in the AMD subgroups relative to the controls, (adjusted % differences; Early, -5.8% (-18.9%, 8.3%); p = 0.40; iAMD, -26.7% (-36.2%, -15.6%); p < 0.001; SDD, -23.7% (-33.6%, -12.2%); p < 0.001; atrophy, -26.7% (-39.3%, -11.3%), p = 0.001). The qAF8 levels declined early in AMD and were not significantly different between the severity levels of non-neovascular AMD, suggesting the early and sustained loss of function of the retinal pigment epithelium in AMD.

Macular Telangiectasia Type 2: A Classification System Using MultiModal Imaging MacTel Project Report Number 10.

Purpose: To develop a severity classification for macular telangiectasia type 2 (MacTel) disease using multimodal imaging. Design: An algorithm was used on data from a prospective natural history study of MacTel for classification development. Subjects: A total of 1733 participants enrolled in an international natural history study of MacTel. Methods: The Classification and Regression Trees (CART), a predictive nonparametric algorithm used in machine learning, analyzed the features of the multimodal imaging important for the development of a classification, including reading center gradings of the following digital images: stereoscopic color and red-free fundus photographs, fluorescein angiographic images, fundus autofluorescence images, and spectral-domain (SD)-OCT images. Regression models that used least square method created a decision tree using features of the ocular images into different categories of disease severity. Main Outcome Measures: The primary target of interest for the algorithm development by CART was the change in best-corrected visual acuity (BCVA) at baseline for the right and left eyes. These analyses using the algorithm were repeated for the BCVA obtained at the last study visit of the natural history study for the right and left eyes. Results: The CART analyses demonstrated 3 important features from the multimodal imaging for the classification: OCT hyper-reflectivity, pigment, and ellipsoid zone loss. By combining these 3 features (as absent, present, noncentral involvement, and central involvement of the macula), a 7-step scale was created, ranging from excellent to poor visual acuity. At grade 0, 3 features are not present. At the most severe grade, pigment and exudative neovascularization are present. To further validate the classification, using the Generalized Estimating Equation regression models, analyses for the annual relative risk of progression over a period of 5 years for vision loss and for progression along the scale were performed. Conclusions: This analysis using the data from current imaging modalities in participants followed in the MacTel natural history study informed a classification for MacTel disease severity featuring variables from SD-OCT. This classification is designed to provide better communications to other clinicians, researchers, and patients. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Functional clinical endpoints and their correlations in eyes with AMD with and without subretinal drusenoid deposits-a pilot study.

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 < 0.0001 respectively). Patients with SDD also had reduced scotopic function and delayed RIT compared to iAMD without SDD (p = 0.005 and p < 0.0001). Eyes with SDD and non-foveal atrophy did not differ functionally. Nor did healthy subjects compared with iAMD without SDD. Functional parameters were significantly associated with scotopic thresholds (r = 0.39-0.64). BCVA, LLVA and scotopic thresholds correlated well with ONL volume, ONL thickness and choroidal thickness (r = 0.34-0.61). CONCLUSION: Eyes with SDD are surrogate markers of photoreceptor abnormalities comparable with non-central atrophy and should be sub-analysed in clinical trials evaluating potential prophylactic agents to decrease the progression of AMD and may even require different therapeutic interventions.

Scotopic thresholds on dark-adapted chromatic perimetry in healthy aging and age-related macular degeneration.

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.

Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression.

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.

Incidence and phenotypical variation of outer retina-associated hyperreflectivity in macular telangiectasia type 2.

BACKGROUND: Macular 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. METHODS: Different 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). RESULTS: Of 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. CONCLUSIONS: The 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.

Role of retinal pigment epithelium in age-related macular disease: a systematic review.

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.

The X-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies.

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.

Exploratory Study on Visual Acuity and Patient-Perceived Visual Function in Patients with Subretinal Drusenoid Deposits.

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-function relations. Compared with healthy participants, BCVA and LLVA scores were significantly reduced in the atrophic AMD group (p < 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.

A Pilot Study Evaluating the Effects of 670 nm Photobiomodulation in Healthy Ageing and Age-Related Macular Degeneration.

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.

Reanalysis of Association of Pro50Leu Substitution in Guanylate Cyclase Activating Protein-1 With Dominant Retinal Dystrophy.

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 gene GUCA1A was 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 the RPGR gene. Results: A frame-shifting single-nucleotide deletion was found in the ORF15 exon of RPGR (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 in GUCA1A was 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 in RPGR. The findings suggest that the p.(Pro50Leu) variant in GUCA1A should 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.

Incomplete Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Classification of Atrophy Meeting Report 4.

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.

Progression characteristics of ellipsoid zone loss in macular telangiectasia type 2.

PURPOSE: To investigate the progression characteristics of ellipsoid zone (EZ) loss in eyes with macular telangiectasia type 2 (MacTel) as reflected by area and linear measurements, and their relevance for visual acuity. METHODS: Participants were selected from the MacTel Study cohort. Linear and area measurements of EZ loss were performed in Spectral-Domain Optical Coherence Tomograph (SD-OCT) volume scans. Progression characteristics and correlations between linear and area measurements were analysed using linear mixed effects models. RESULTS: A total of 134 eyes of 70 patients were included (85 eyes with follow-up, mean 4.7 years, range: 1.4-8 years). Ellipsoid zone (EZ) loss significantly progressed at a mean annual increment of 0.057 mm2 (p = 0.005). The progression rate was non-linear and interacted significantly with initial EZ lesion size indicating an exponential growth before reaching a plateau. There was a strong heterogeneity in area sizes between fellow eyes. EZ break length had a significant linear effect on EZ break area (b = 1.06, p < 0.001) and could predict it. The location of the EZ break had a significant impact on visual acuity. CONCLUSION: Ellipsoid zone (EZ) loss in MacTel has a non-linear progression characteristic, and its rate depends on area size at baseline, which must be taken into account at sample selection in clinical trials. Our results show a good correlation of linear and area measures of EZ loss and a segregation of best-corrected visual acuity by EZ location, which may help routine clinical practice.

Effect of Ciliary Neurotrophic Factor on Retinal Neurodegeneration in Patients with Macular Telangiectasia Type 2: A Randomized Clinical Trial.

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 < 0.0001). The mean retinal sensitivity loss of the sham group was 45% greater than that of the treated group (decrease, 15.81±8.93 dB; P = 0.07). Reading speed deteriorated in the sham group (-13.9 words per minute) with no loss in the treated group (P = 0.02). Serious adverse ocular effects were found in 2 of 51 persons (4%) in the sham group and 2 of 48 persons (4%) in the treated group. 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.

Peripheral Retinal Imaging Biomarkers for Alzheimer's Disease: A Pilot Study.

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.

Consensus Definition for Atrophy Associated with Age-Related Macular Degeneration on OCT: Classification of Atrophy Report 3.

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.

CHARACTERISTICS OF PIGMENTED LESIONS IN TYPE 2 IDIOPATHIC MACULAR TELANGIECTASIA.

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.