FEATURED ARTICLE
Macular Telangiectasia Type 2: A Classification System Using MultiModal Imaging MacTel Project Report Number 10.
Ophthalmology science. 2022 Dec 8;
Chew EY, Peto T, Clemons TE, Sallo FB, Pauleikhoff D, Leung I, Jaffe GJ, Heeren TFC, Egan CA, Charbel Issa P, Balaskas K, Holz FG, Gaudric A, Bird AC, Friedlander M.
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.
DOI: 10.1016/j.xops.2022.100261
DRUG TREATMENT
Treat-and-extend dosing of intravitreal anti-VEGF agents in neovascular age-related macular degeneration: a meta-analysis.
Eye (London, England). 2023 Mar 1.
Nichani PAH, Popovic MM, Dhoot AS, Pathak A, Muni RH, Kertes PJ.
Intravitreal injections of antiangiogenic agents are pivotal in treating neovascular age-related macular degeneration (nAMD). The comparative efficacy and safety of treat-and-extend (T&E) versus bimonthly, monthly, and pro re nata (PRN) dosing remains unclear. A systematic review and meta-analysis of English-language RCTs reporting on efficacy and/or safety outcomes of dosing regimens of anti-VEGF agents in nAMD was performed. Best-corrected visual acuity (BCVA, ETDRS letters) at last follow-up represented the primary endpoint, while central subfield thickness (CSFT, μm), injection burden, and ocular adverse events were secondary endpoints. A random effects meta-analysis was performed, and 95% confidence intervals were calculated. Across six RCTs, 781 T&E-, 663 monthly-, 130 PRN-, and 123 bimonthly treated eyes were included. Mean changes in BCVA and CSFT at last follow-up were similar between T&E versus monthly (WMD, -0.62 letters; 95% CI, -2.12 to 0.87; P = 0.41; WMD, 5.30 microns; 95% CI, -10.67 to 21.26; P = 0.52, respectively), bimonthly (WMD, 1.68 letters; 95% CI, -3.55 to 6.91; P = 0.53; WMD, -18.91 microns; 95% CI, -46.41 to 8.60; P = 0.18, respectively), and PRN (BCVA WMD, 1.08 letters; 95% CI, -2.95 to 5.11; P = 0.60) regimens. T&E was associated with a reduced injection burden versus monthly (WMD, -4.52 injections; 95% CI, -6.66 to 2.39; P < 0.001) but higher injection burden versus PRN (WMD, 1.81 injections; 95% CI, 1.12 to 2.51; P < 0.001) dosing. There was no significant difference in safety outcomes amongst comparators. There was no significant difference in efficacy and safety between T&E, bimonthly, monthly, and PRN dosing. T&E resulted in fewer injections versus monthly and fewer clinic visits versus PRN.
DOI: 10.1038/s41433-023-02439-6
GENETICS
Stargardt-like Clinical Characteristics and Disease Course Associated with Variants in the WDR19 Gene.
Genes. 2023 Jan 22;
Sajovic J, Meglič A, Volk M, Maver A, Jarc-Vidmar M, Hawlina M, Fakin A.
Variants in WDR19 (IFT144) have been implicated as another possible cause of Stargardt disease. The purpose of this study was to compare longitudinal multimodal imaging of a WDR19-Stargardt patient, harboring p.(Ser485Ile) and a novel c.(3183+1_3184-1)_(3261+1_3262-1)del variant, with 43 ABCA4-Stargardt patients. Age at onset, visual acuity, Ishihara color vision, color fundus, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (OCT) images, microperimetry and electroretinography (ERG) were evaluated. First symptom of WDR19 patient was nyctalopia at the age of 5 years. After the age of 18 years, OCT showed hyper-reflectivity at the level of the external limiting membrane/outer nuclear layer. There was abnormal cone and rod photoreceptor function on ERG. Widespread fundus flecks appeared, followed by perifoveal photoreceptor atrophy. Fovea and peripapillary retina remained preserved until the latest exam at 25 years of age. ABCA4 patients had median age of onset at 16 (range 5-60) years and mostly displayed typical Stargardt triad. A total of 19% had foveal sparing. In comparison to ABCA4 patients, the WDR19 patient had a relatively large foveal preservation and severe rod photoreceptor impairment; however, it was still within the ABCA4 disease spectrum. Addition of WDR19 in the group of genes producing phenocopies of Stargardt disease underlines the importance of genetic testing and may help to understand its pathogenesis.
DOI: 10.3390/genes14020291
Development of a CRISPRi Human Retinal Pigmented Epithelium Model for Functional Study of Age-Related Macular Degeneration Genes.
International journal of molecular sciences 2023 Feb 8;
Wang JH, Urrutia-Cabrera D, Lees JG, Mesa Mora S, Nguyen T, Hung SSC, Hewitt AW, Lim SY, Edwards TL, Wong RCB.
Age-related macular degeneration (AMD) is a blinding disease characterised by dysfunction of the retinal pigmented epithelium (RPE) which culminates in disruption or loss of the neurosensory retina. Genome-wide association studies have identified >60 genetic risk factors for AMD; however, the expression profile and functional role of many of these genes remain elusive in human RPE. To facilitate functional studies of AMD-associated genes, we developed a human RPE model with integrated CRISPR interference (CRISPRi) for gene repression by generating a stable ARPE19 cell line expressing dCas9-KRAB. We performed transcriptomic analysis of the human retina to prioritise AMD-associated genes and selected TMEM97 as a candidate gene for knockdown study. Using specific sgRNAs, we showed that knockdown of TMEM97 in ARPE19 reduced reactive oxygen species (ROS) levels and exerted a protective effect against oxidative stress-induced cell death. This work provides the first functional study of TMEM97 in RPE and supports a potential role of TMEM97 in AMD pathobiology. Our study highlights the potential for using CRISPRi to study AMD genetics, and the CRISPRi RPE platform generated here provided a useful in vitro tool for functional studies of AMD-associated genes.
DOI: 10.3390/ijms24043417
DIAGNOSIS AND IMAGING
Macular Telangiectasia Type 2: A Classification System Using MultiModal Imaging MacTel Project Report Number 10.
Ophthalmology science. 2022 Dec 8;
Chew EY, Peto T, Clemons TE, Sallo FB, Pauleikhoff D, Leung I, Jaffe GJ, Heeren TFC, Egan CA, Charbel Issa P, Balaskas K, Holz FG, Gaudric A, Bird AC, Friedlander M.
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.
DOI: 10.1016/j.xops.2022.100261
Predictive value of pigment epithelial detachment markers for visual acuity outcomes in neovascular age-related macular degeneration.
BMC ophthalmology. 2023 Mar 3
Shu Y, Ye F, Liu H, Wei J, Sun X.
Background: To determine the predictive value of quantitative morphological parameters for pigment epithelial detachment (PED) of neovascular age-related macular degeneration (nAMD) patients.
Methods: One eye from each of 159 patients with nAMD were studied. Polypoidal choroidal vasculopathy (PCV) group included 77 eyes, and non-PCV group 82. Patients received conbercept 0.05 ml (0.5 mg) in a 3 + ProReNata (PRN) treatment regimen. Correlations between retinal morphologic parameters at baseline and best-corrected visual acuity (BCVA) gain at 3 or 12 months after treatment (structure-function correlations) were assessed. Optical coherence tomography (OCT) scans were used to assess retinal morphologic features including intraretinal cystoid fluid (IRC), subretinal fluid (SRF), PED or PED type (PEDT), and vitreomacular adhesion (VMA). Greatest height (PEDH) and width of PED (PEDW), and volume of PED (PEDV) at baseline were also measured.
Results: For non-PCV group, BCVA gain from 3 or 12 months after treatment was negatively correlated with PEDV at baseline (r = -0.329, -0.312, P = 0.027, 0.037). BCVA gain at 12 months after treatment was negatively correlated with PEDW at baseline (r = -0.305, P = 0.044). For PCV group, there were no correlations with PEDV, PEDH, PEDW, and PEDT in BCVA gain between baseline and 3 or 12 months after treatment (P > 0.05). SRF, IRC, VMA at baseline did not correlate with short-term and long-term BCVA gain in patients with nAMD (P > 0.05).
Conclusion: For patients with non-PCV, PEDV at baseline was negatively correlated with short-term and long-term BCVA gain, and PEDW was negatively correlated with long-term BCVA gain. On the contrary, quantitative morphological parameters for PED at baseline had no correlation with BCVA gain in patients with PCV.
DOI: 10.1186/s12886-023-02797-5
PATHOPHSIOLOGY
Retinal Pigment Epithelial Abnormality and Choroidal Large Vascular Flow Imbalance Are Associated with Choriocapillaris Flow Deficits in Age-Related Macular Degeneration in Fellow Eyes.
Journal of clinical medicine. 2023 Feb 8;
Nagai N, Mushiga Y, Ozawa Y.
Choriocapillaris flow deficits detected on optical coherence tomography angiographs were retrospectively analyzed. In 38 age-related macular degeneration (AMD) fellow eyes, without fundus findings (26 men, 71.7 ± 1.9 years old), and 22 control eyes (11 men, 69.4 ± 1.8), the choriocapillaris flow area (CCFA) ratio and coefficient of variation (CV) of the CCFA ratio (which represented the heterogeneity of the ratio), negatively and positively correlated with age (all p < 0.01), respectively. Moreover, the respective mean values were lower (p = 0.0031) and greater (p = 0.002) in AMD fellow eyes than in the control eyes. The high-risk condition of AMD fellow eyes was defined by a CCFA ratio <58.5%, and the CV of the CCFA ratio ≥0.165 (odds ratio (OR), 5.408; 95% confidence interval (CI): 1.117-21.118, p = 0.035, after adjusting for age and sex) was related to the presence of fundus autofluorescence abnormality (OR, 16.440; 95% CI, 1.262-214.240; p = 0.033) and asymmetrically dilated choroidal large vasculature (OR, 4.176; 95% CI, 1.057-16.503; p = 0.042), after adjusting for age and sex. The presence of fundus autofluorescence abnormality indicated a retinal pigment epithelium (RPE) abnormality. The RPE volume was reduced in the latter eye group, particularly in the thinner choroidal vasculature. In addition to aging, RPE abnormality and choroidal large vascular flow imbalances were associated with exacerbated heterogeneous choriocapillaris flow deficits in AMD fellow eyes without macular neovascularization.
DOI: 10.3390/jcm12041360
NUTRITION AND LIFESTYLE
Macular and Plasma Xanthophylls Are Higher in Age-related Macular Degeneration than in Normal Aging: Alabama Study on Early Age-related Macular Degeneration 2 Baseline.
Ophthalmology science. 2022 Dec 22;
McGwin G Jr, Kar D, Berlin A, Clark ME, Swain TA, Crosson JN, Sloan KR, Owsley C, Curcio CA.
Purpose: Quantification of retinal xanthophyll carotenoids in eyes with and without age-related macular degeneration (AMD) via macular pigment optical volume (MPOV), a metric for xanthophyll abundance from dual wavelength autofluorescence, plus correlations to plasma levels, could clarify the role of lutein (L) and zeaxanthin (Z) in health, AMD progression, and supplementation strategies.
Design: Cross-sectional observational study (NCT04112667).
Participants: Adults ≥ 60 years from a comprehensive ophthalmology clinic, with healthy maculas or maculas meeting fundus criteria for early or intermediate AMD.
Methods: Macular health and supplement use was assessed by the Age-related Eye Disease Study (AREDS) 9-step scale and self-report, respectively. Macular pigment optical volume was measured from dual wavelength autofluorescence emissions (Spectralis, Heidelberg Engineering). Non-fasting blood draws were assayed for L and Z using high-performance liquid chromatography. Associations among plasma xanthophylls and MPOV were assessed adjusting for age.
Main Outcome Measures: Age-related macular degeneration presence and severity, MPOV in fovea-centered regions of radius 2.0° and 9.0°; plasma L and Z (μM/ml).
Results: Of 809 eyes from 434 persons (89% aged 60-79, 61% female), 53.3% eyes were normal, 28.2% early AMD, and 18.5% intermediate AMD. Macular pigment optical volume 2° and 9° were similar in phakic and pseudophakic eyes, which were combined for analysis. Macular pigment optical volume 2° and 9° and plasma L and Z were higher in early AMD than normal and higher still in intermediate AMD (P < 0.0001). For all participants, higher plasma L was correlated with higher MPOV 2° (Spearman correlation coefficient [Rs] = 0.49; P < 0.0001). These correlations were significant (P < 0.0001) but lower in normal (Rs = 0.37) than early and intermediate AMD (Rs = 0.52 and 0.51, respectively). Results were similar for MPOV 9°. Plasma Z, MPOV 2°, and MPOV 9° followed this same pattern of associations. Associations were not affected by supplement use or smoking status.
Conclusions: A moderate positive correlation of MPOV with plasma L and Z comports with regulated xanthophyll bioavailability and a hypothesized role for xanthophyll transfer in soft drusen biology. An assumption that xanthophylls are low in AMD retina underlies supplementation strategies to reduce progression risk, which our data do not support. Whether higher xanthophyll levels in AMD are due to supplement use cannot be determined in this study.
DOI: 10.1016/j.xops.2022.100263
RISK OF DISEASE
Air Pollution and Chronic Eye Disease in Adults: A Scoping Review.
Ophthalmic epidemiology. 2023 Mar 2:
Millen AE, Dighe S, Kordas K, Aminigo BZ, Zafron ML, Mu L.
Purpose: We conducted a scoping review of studies examining ambient air pollution as a risk factor for chronic eye disease influencing the lens, retina, and intraocular pressure in adults.
Methods: Terms related to air pollution and eye disease outcomes were used to search for publications on Embase, Web of Science Core Collection, Global Health, PubMed, and the Cochrane Central Register of Controlled Trials from January 1, 2010, through April 11, 2022.
Results: We identified 27 articles, focusing on the following non-mutually exclusive outcomes: cataract (n = 9), presbyopia (n = 1), retinal vein occlusion or central retinal arteriolar and venular equivalents (n = 5), intraocular pressure (IOP) (n = 3), glaucoma (n = 5), age-related macular degeneration (AMD) (n = 5), diabetic retinopathy (n = 2), and measures of retinal morphology (n = 3). Study designs included cross-sectional (n = 16), case-control (n = 4), and longitudinal (n = 7). Air pollutants were measured in 50% and 95% of the studies on lens and retina or IOP, respectively, and these exposures were assigned to geographic locations. Most research was conducted in global regions with high exposure to air pollution. Consistent associations suggested a possibly increased risk of cataract and retina-associated chronic eye disease with increasing exposure to particulate matter (PM2.5-PM10), NO2, NOx, and SO2. Associations with O3 were less consistent.
Conclusions: Accumulating research suggests air pollution may be a modifiable risk factor for chronic eye diseases of the lens and retina. The number of studies on each specific lens- or retina-related outcome is limited. Guidelines regarding the role of air pollution in chronic eye disease do not exist.
DOI: 10.1080/09286586.2023.2183513
IMPACT OF VISION LOSS
The associations and mediators between visual disabilities and anxiety disorders in middle-aged and older adults: A population-based study.
The American Psychologist. 2023 Feb 27.
Zhang X, Wang S, Du Z, Seth I, Wang Y, Liang Y, Wu G, Huang Y, Liu S, Hu Y, Shang X, Hu Y, Zhu Z, Yu H.
Visual disabilities significantly impact an individual’s mental health. Little is known about the prospective relationship between visual disabilities and anxiety disorders and the underlying effects of modifiable risk factors. Our analysis was based on 117,252 participants from the U.K. Biobank, with baseline data collected between 2006 and 2010. Habitual visual acuity was measured by a standardized logarithmic chart, and ocular disorders reported using questionnaires were collected at baseline. Incident hospitalized anxiety recorded using longitudinal linkage with hospital inpatient data, lifetime anxiety disorder, and current anxiety symptoms assessed by a comprehensive online mental health questionnaire were identified over a 10-year follow-up. After adjustments for confounding factors, one-line worse visual acuity (0.1 logarithm of the minimum angle of resolution [logMAR]) was associated with an increased risk of incident hospitalized anxiety (HR = 1.05, 95% CI = 1.01-1.08), lifetime anxiety disorder (OR = 1.07, 95% CI [1.01-1.12]), and current anxiety scores (β = 0.028, 95% CI [0.002-0.054]). Besides poorer visual acuity, the longitudinal analysis also supported that each ocular disorder (including cataracts, glaucoma, macular degeneration, and diabetes-related eye disease) was significantly associated with at least two anxiety outcomes. Mediation analyses highlighted that subsequent onset of eye diseases, especially cataracts, and lower socioeconomic status (SES) partly mediated the association between poorer visual acuity and anxiety disorders. This study demonstrates an overall association between visual disabilities and anxiety disorders in middle-aged and older adults. In particular, early interventions involving treatments for visual disabilities and effective psychological counseling services sensitive to socioeconomic status may help prevent anxiety in those living with poor vision. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
DOI: 10.1037/amp0001143
REVIEWS
Advances in Ophthalmic Epigenetics and Implications for Epigenetic Therapies: A Review.
Genes. 2023 Feb 5;
Moore SM, Christoforidis JB.
The epigenome represents a vast molecular apparatus that writes, reads, and erases chemical modifications to the DNA and histone code without changing the DNA base-pair sequence itself. Recent advances in molecular sequencing technology have revealed that epigenetic chromatin marks directly mediate critical events in retinal development, aging, and degeneration. Epigenetic signaling regulates retinal progenitor (RPC) cell cycle exit during retinal laminar development, giving rise to retinal ganglion cells (RGCs), amacrine cells, horizontal cells, bipolar cells, photoreceptors, and Müller glia. Age-related epigenetic changes such as DNA methylation in the retina and optic nerve are accelerated in pathogenic conditions such as glaucoma and macular degeneration, but reversing these epigenetic marks may represent a novel therapeutic target. Epigenetic writers also integrate environmental signals such as hypoxia, inflammation, and hyperglycemia in complex retinal conditions such as diabetic retinopathy (DR) and choroidal neovascularization (CNV). Histone deacetylase (HDAC) inhibitors protect against apoptosis and photoreceptor degeneration in animal models of retinitis pigmentosa (RP). The epigenome represents an intriguing therapeutic target for age-, genetic-, and neovascular-related retinal diseases, though more work is needed before advancement to clinical trials.
DOI: 10.3390/genes14020417
