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    Research Update 577


    Ten-Year Incidence of Fibrosis and risk factors for its development in Neovascular Age-related Macular Degeneration.

    American journal of ophthalmology. 2023 Apr 6:

    Romano F, Cozzi E, Airaldi M, Nassisi M, Viola F, Aretti A, Milella P, Giuffrida FP, Teo KC, Cheung CMG, Staurenghi G, Invernizzi A.

    Purpose: To report incidence and risk factors for fibrosis at 10 years in a large cohort of neovascular age-related macular degeneration (nAMD).

    Design: Retrospective, multicenter, cohort study.

    Methods: We included 225 naïve nAMD eyes who underwent intravitreal anti-vascular endothelial growth factor treatment over 10 years of follow-up at two Italian referral centers. Demographic and clinical data were reviewed at baseline and on an annual basis. Onset of fibrosis was defined clinically assessing photographs, fundus descriptions or fluorescein angiograms. Optical coherence tomography (OCT) scans of fibrosis were inspected by an external reading center and graded as sub-retinal pigment epithelium (RPE), mixed, sub-retinal.

    Results: Mean age at baseline was of 72.1±6.9 years. Incidence rate of fibrosis was estimated to be 8.9 per 100 person-years with a cumulative incidence of 62.7% at 10 years. Fibrotic lesions were sub-RPE in 46.1%, mixed in 29.8% and subretinal in 22.7%. Independent factors associated with fibrosis included: larger central subfield thickness variation (p<0.001), submacular hemorrhages (p=0.008), higher number of injections (p=0.01) and worse baseline visual acuity (VA) (p=0.03). Type 2 macular neovascularization was significantly associated with mixed and sub-retinal fibrosis. VA significantly declined over 10 years (-16.4 ETDRS letters), particularly in eyes with mixed and sub-retinal fibrosis (p<0.001).

    Conclusions: We identified a 62.7% cumulative incidence of fibrosis in a large nAMD cohort at 10 years. Fibrosis was more common with frequent reactivations and lower baseline VA; its onset significantly impacted on final VA. This supports the hypothesis that nAMD patients should be promptly treated with pro-active regimens.

    DOI: 10.1016/j.ajo.2023.03.033


    Prevalence and clinical implications of subretinal fluid in retinal diseases: a real-world cohort study.

    BMJ open Ophthalmology. 2023 Feb;8

    Park J, Felfeli T, Kherani IZ, Altomare F, Chow DR, Wong DT.

    Background/Aims: To characterise the baseline prevalence of subretinal fluid (SRF) and its effects on anatomical and visual acuity (VA) outcomes in diabetic macular oedema (DME) and retinal vein occlusion (RVO) following anti-vascular endothelial growth factor (VEGF).

    Methods: This is a retrospective cohort study of 122 DME and 54 RVO patients who were initiated on anti-VEGF therapy with real-world variable dosing. The DME and RVO cohorts were subclassified based on the presence of SRF at presentation. Snellen VA was measured and converted to logarithm of the minimum angle of resolution (LogMAR). Changes in VA and central subfield thickness (CST) were assessed up to 24 months.

    Results: SRF was present in 22% and 41% in DME and RVO patients, respectively. In the DME subcohort, eyes with SRF showed an improvement of 0.166 logMAR (1.7 Snellen chart lines) at 12 months and 0.251 logMAR (2.6 Snellen chart lines) at 24 months, which were significantly greater compared with those of the non-SRF group. A significantly greater reduction in CST was noted in the SRF eyes compared with the non-SRF eyes at 3 months and 1 month in the DME and RVO subcohorts, respectively.

    Conclusion: Baseline SRF is a good marker for a greater reduction in CST in both DME and RVO, but an improvement in VA associated with SRF may be only noted in DME.

    DOI: 10.1136/bmjophth-2022-001214


    Correlation between hyperreflective foci and visual function testing in eyes with intermediate age-related macular degeneration.

    International journal of retina and Vitreous. 2023 Apr 7;

    Liu TYA, Wang J, Csaky KG.

    Background: To investigate the relationship between intraretinal hyperreflective foci (HRF) and visual function in intermediate age-related macular degeneration (iAMD).

    Methods: Retrospective, cross-sectional study. iAMD patients underwent spectral domain optical coherence tomography (SD-OCT) imaging and vision function testing: normal luminance best corrected visual acuity (VA), low luminance VA (LLVA), quantitative contrast sensitivity function (qCSF), low luminance qCSF (LLqCSF), and mesopic microperimetry. Each OCT volume was graded for the presence and number of HRF. Each HRF was graded for: separation from the retinal pigment epithelium (RPE), above drusen, and shadowing. Central drusen volume was calculated by the built-in functionality of the commercial OCT software after manual segmentation of the RPE and Bruch’s membrane.

    Results: HRF group: 11 eyes; 9 patients; mean age 75.7 years. No-HRF group: 11 eyes; 10 patients; mean age 74.8 years. In linear mixed effect model adjusting for cube-root transformed drusen volume, HRF group showed statistically significant worse VA, LLVA, LLqCSF, and microperimetry. HRF group showed worse cone function, as measured by our pre-defined multicomponent endpoint, incorporating LLVA, LLqCSF and microperimetry (p = 0.018). For eyes with HRF, # of HRF did not correlate with any functional measures; however, % of HRF separated from RPE and # of HRF that created shadowing were statistically associated with low luminance deficit (LLD).

    Conclusions: The association between the presence of HRF and worse cone visual function supports the hypothesis that eyes with HRF have more advanced disease.

    DOI: 10.1186/s40942-023-00461-0


    Deep Learning for Diagnosing and Segmenting Choroidal Neovascularization in OCT Angiography in a Large Real-World Data Set.

    Translational vision science & technology 2023 Apr 3;

    Wang J, Hormel TT, Tsuboi K, Wang X, Ding X, Peng X, Huang D, Bailey ST, Jia Y.

    Purpose: To diagnose and segment choroidal neovascularization (CNV) in a real-world multicenter clinical OCT angiography (OCTA) data set using deep learning.

    Methods: A total of 10,566 OCTA scans from 3135 eyes, including 4701 with CNV and 5865 without, were collected in five eye clinics. Both 3 × 3-mm and 6 × 6-mm scans of the central and temporal macula were included. Scans with CNV were collected from multiple diseases, and scans without CNV were collected from both healthy controls and those with multiple diseases. No scans were removed during training or testing due to poor quality. The trained hybrid multitask convolutional neural network outputs a CNV diagnosis and membrane segmentation, respectively.

    Results: The model demonstrated a highly accurate CNV diagnosis (area under receiver operating characteristic curve = 0.97), achieving a sensitivity of 95% at 95% specificity. The model also correctly segmented CNV lesions (F1 score = 0.78 ± 0.19). Additionally, model performance was comparable on both high-definition 3 × 3-mm scans and low-definition 6 × 6-mm scans. The model did not suffer large performance variations under different diseases. We also show that a subclinical lesion in a patient with neovascular age-related macular degeneration can be monitored over a multiyear time frame using our approach.

    Conclusions: The proposed method can accurately diagnose and segment CNV in a large real-world clinical data set.

    Translational Relevance: The algorithm could enable automated CNV screening and quantification in the clinic, which will help improve CNV diagnosis and treatment evaluation.

    DOI: 10.1167/tvst.12.4.15

    Imaging Biomarkers of Mesopic and Dark-adapted Macular Functions in Eyes with Treatment-Naïve Mild Diabetic Retinopathy.

    American Journal of Ophthalmology. 2023 Apr 12:

    Bandello F, Borrelli E, Trevisi M, Lattanzio R, Sacconi R, Querques G.

    Purpose: To investigate the relationship between imaging biomarkers and mesopic and dark-adapted (i.e. scotopic) functions in patients with firstly detected treatment-naïve mild diabetic retinopathy (DR) and normal visual acuity.

    Design: Prospective cross-sectional study.

    Methods: In this study, 60 patients with treatment-naïve mild DR (ETDRS 20-35) and 30 healthy controls underwent microperimetry, structural optical coherence tomography (OCT) and OCT angiography (OCTA).

    Results: The foveal mesopic (22.4±4.5 dB and 25.8±2.0 dB, p=0.005), parafoveal mesopic (23.2±3.8 and 25.8±1.9, p<0.0001), and parafoveal dark-adapted (21.1±2.8 dB and 23.2±1.9 dB, p=0.003) sensitivities were reduced in DR eyes. For the foveal mesopic sensitivity, the regression analysis showed a significant topographical association with choriocapillaris flow deficits percentage (CC FD%; β: -0.234, p=0.046) and ellipsoid zone (EZ) “normalized” reflectivity (β: 0.282, p=0.048). The parafoveal mesopic sensitivity was significantly topographically associated with inner retinal thickness (β: 0.253, p=0.035), deep capillary plexus (DCP) vessel length density (VLD; β: 0.542, p=0.016), CC FD% (β: -0.312, p=0.032), and EZ “normalized” reflectivity (β: 0.328, p=0.031). Similarly, the parafoveal dark-adapted sensitivity was topographically associated with inner retinal thickness (β: 0.453, p=0.021), DCP VLD (β: 0.370, p=0.030), CC FD% (β: -0.282, p=0.048), and EZ “normalized” reflectivity (β: 0.295, p=0.042).

    Conclusions: In treatment-naïve mild DR eyes, both rod and cone functions are affected and they are associated with both DCP and CC flow impairment, which suggests that a macular hypoperfusion at these levels might implicate a reduction in photoreceptor function. The “normalized” EZ reflectivity may be a valuable structural biomarker for assessing the photoreceptor function in DR.

    DOI: 10.1016/j.ajo.2023.04.005


    Incidence and Timing of Pigment Epithelial Detachment and Subretinal Fluid Development in Type 3 Macular Neovascularization associated with Age-related Macular Degeneration.

    Retina (Philadelphia, Pa.) 2023 Mar 27

    Kim JH, Kim JW, Kim CG.

    Purpose: To evaluate the incidence and timing of pigment epithelial detachment (PED) and subretinal fluid(SRF) development in type 3 macular neovascularization (MNV).

    Methods: This retrospective study included 84 patients who were diagnosed with treatment-naïve type 3 MNV who did not show SRF at diagnosis. All patients were initially treated with three loading injections of ranibizumab or aflibercept. Following the initial loading injections, as-needed regimen was performed for retreatment. The development of either PED or SRF was identified. The incidence and timing of PED development in patients without PED at diagnosis and that of SRF development in patients with PED at diagnosis were evaluated.

    Results: The mean follow-up period was 41.3±20.7 months after diagnosis. Among the 32 patients without serous PED at diagnosis, PED developed in 20 (62.5%) at a mean of 10.9±5.1 months after diagnosis. PED development was noted within 12 months in 15 patients (46.8%; 75.0% among the PED development cases). In 52 patients with serous PED and without SRF at diagnosis, 15 developed SRF (28.8%) at a mean of 11.2±6.4 months after diagnosis. SRF development was noted within 12 months in 9 patients (17.3%; 66.6% among the SRF development cases).

    Conclusions: PED and SRF developed in a substantial proportion of patients with type 3 MNV. The average period of development of these pathologic findings was within 12 months of diagnosis, suggesting the need for active treatment during the early treatment period to improve treatment outcomes.

    DOI: 10.1097/IAE.0000000000003797


    Vision-related quality of life is selectively affected by comorbidities in patients with geographic atrophy.

    BMC ophthalmology. 2023 Apr 12;

    Holm DL, Nielsen MK, Højsted BB, Sørensen TL.

    Background: The atrophic late stage of age-related macular degeneration (AMD) is termed geographic atrophy (GA), and affects visual acuity (VA) as well as quality of life (QoL). Previous studies have found that best-corrected VA (BCVA), the standard vision assessment often underrepresents functional deficits. Therefore, the purpose of this study was to evaluate the correlation between atrophic lesion size, VA and QoL measured with the National Eye Institute Visual Function Questionnaire (VFQ-39) in a Danish population. Moreover, we wanted to evaluate the correlation between comorbidities, behavioural factors, and QoL.

    Methods: This was prospective clinical study of 51 patients with GA in one or both eyes, of these 45 patients had bilateral GA. Patients were consecutively included between April 2021 and February 2022. All patients filled in the VFQ-39 questionnaire except the subscales “ocular pain” and “peripheral vision.” Lesion size was measured from fundus autoflourescense images, and BCVA was assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol.

    Results: We found an overall low score in each VFQ-39 subscale scores reflected by GA. Lesion size and VA were both significantly associated with all VFQ-39 subscale scores except for “general health.” VA showed a larger effect on QoL than lesion size. Chronic obstructive pulmonary disease (COPD) was associated with a lower score in the subscale score “general health” but none of the other subscale scores were affected. Cardiovascular disease (CVD) was associated with a lower BCVA as well as in QoL reflected in the subscale scores “poor general vision,” “near activities,” and “dependency” of VFQ-39.

    Conclusion: Both atrophic lesion size and visual acuity affects QoL in Danish patients with GA, who reports an overall poor QoL. CVD seems to have a negative effect on disease, as well as in VFQ-39 in several subscales, whereas COPD did not affect disease severity or vision-related subscales in VFQ-39.

    DOI: 10.1186/s12886-023-02901-9


    Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: A meta-analysis of randomised trials.

    Acta Ophthalmologica. 2023 Apr 12.

    Nanji K, Sarohia GS, Xie J, Patil NS, Phillips M, Zeraatkar D, Thabane L, Guymer RH, Kaiser PK, Sivaprasad S, Sadda SR, Wykoff CC, Chaudhary V.

    Purpose: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months.

    Methods: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments.

    Results: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I2  = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I2  = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision.

    Conclusion: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events. PROSPERO REGISTRATION: CRD42022314418.

    DOI: 10.1111/aos.15673