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    Research Update 563


    Hyperreflective foci in age-related macular degeneration are associated with disease severity and functional impairment.

    Ophthalmology, Retina. 2022 Nov 17

    Duic C, Pfau K, Keenan TDL, Wiley H, Thavikulwat A, Chew EY, Cukras C.

    Purpose: To analyze presence of hyperreflective foci (HRF) across different age-related macular degeneration (AMD) severities, and examine its correlation with other structural and functional AMD features, including subretinal drusenoid deposits (SDD), hyperpigmentation, and rod intercept time (RIT).

    Design: Longitudinal, single-center, case-control study

    Participants: 158 participants older than 50 years old with varying AMD severities (including no AMD).

    Methods: Color fundus imaging was used to assess AMD severity and presence of hyperpigmentation. SDD and HRF were detected on optical coherence tomography (OCT) volumes. The correlations of HRF with additional AMD features were evaluated using linear and logistic mixed-effects models. One study eye per participant underwent dark adaptation (DA) testing to measure rod intercept time (RIT) for structure function associations. Eyes were followed longitudinally and changes in AMD severity and RIT were measured relative to HRF presence.

    Main outcome measures: The primary outcome was presence of HRF which was compared to presence of other AMD features and impairment on DA.

    Results: 158 participants (median baseline age of 73.1 [IQR = 66-79] years) contributing 1277 eye visits were included. HRF were detected more frequently in higher AMD severities. HRF presence was significantly associated with hyperpigmentation presence (odds ratio 832.9, p<0.001) and SDD presence (odds ratio 9.42, p=0.017). Eyes with HRF demonstrated significantly longer DA (median 27.1 [IQR=16-40] mins), compared to eyes without HRF (13.5 [10-22] mins), but less than eyes with SDD only (40 [28-40] mins). Highest RIT values were found in eyes with both HRF and SDD (40.0 [40-40] mins). Age and HRF explained a similar proportion of RIT variability as age and SDD. Eyes that developed HRF demonstrated baseline RITs closer to eyes with HRF at baseline, compared to eyes that never developed HRF (29.1 [16-40], 38.5 [22-40] vs 13.1 [10-22] mins; Kruskal-Wallis p < 0.001).

    Conclusions: The progressively increased presence of HRF in higher AMD severity levels, in addition to its correlation with previously associated AMD biomarkers, suggests that HRF is an important OCT feature adding to the understanding of disease progression. HRF presence was associated with delays in DA, indicating that HRF is a marker for visual cycle impairment.

    DOI: 10.1016/j.oret.2022.11.006


    Atrophy of retinal vessels in neovascular age-related macular degeneration following long-term treatment with 20 intravitreal anti-VEGF injections.

    BMC Ophthalmology. 2022 Dec 5

    Resch MD, Balogh A, Kurth T, Nagy ZZ, DeBuc DC, Papp A.

    Background: The study aimed to evaluate the changes in retinal vascular density in exudative age-related macular degeneration (AMD) after long-term anti-VEGF treatment using optical coherence tomography angiography (OCT-A), and to compare these changes with the vascular density in AMD treated for one year and healthy eyes.

    Methods: In our cross-sectional study OCT-A was performed on 60 eyes of 60 patients. Group AMD 20 × consisted of patients receiving long-term (minimum 20 injections) aflibercept therapy (n = 17), and Group AMD one year consisted of patients treated for one year with a treat & extend protocol (n = 25). The vascular density values obtained with OCT-A were compared with an age-matched control group of 18 healthy eyes. We examined the central retinal thickness (CRT), the vascular density of the fovea and parafovea in the superficial and deep retinal plexus, and evaluated the extent of the non-flow area and the foveal avascular zone (FAZ) on a 3 × 3 mm macular region. Kruskal-Wallis test was performed for statistical analysis.

    Results: In Group AMD 20x, the vascular density of superficial retinal plexus in the fovea (p = 0.0022) and parafovea (p < 0.0001) was significantly lower compared to Group one year and control group. In the deep retinal plexus, vascular density in the fovea (p = 0.0033) was significantly lower in both AMD groups compared to the control group, with no difference in the parafoveal region (p = 0.0774). The extent of non-flow area (p = 0.0003) and FAZ (p = 0.0008) were significantly larger in both AMD groups compared to the control group. There was a significant difference in CRT between those treated for one year and control eyes (p = 0.0036).

    Conclusions: In our study, we demonstrated that macular vessel density was lower in the foveal area in the superficial retinal plexus in AMD patients after one year and long-term anti-VEGF treatment. These vascular density changes were absent in the parafoveal and whole areas of the deep retinal plexus. Our results indicate that long-term anti-VEGF treatment reduces the vascular density of the superficial retinal plexus to a greater extent compared to the deep retinal plexus.

    DOI: 10.1186/s12886-022-02700-8

    Suppression of Pathological Ocular Neovascularization by a Small Molecular Multi-Targeting Kinase Inhibitor, DCZ19903.

    Translational Vision Science & Technology. 2022 Dec 1

    Ding J, Li B, Zhang H, Xu Z, Zhang Q, Ye R, Feng S, Jiang Q, Zhu W, Yan B.

    Purpose: The administration of anti-vascular endothelial growth factor agents is the standard firs-line therapy for ocular vascular diseases, but some patients still have poor outcomes and drug resistance. This study investigated the role of DCZ19903, a small molecule multitarget kinase inhibitor, in ocular angiogenesis.

    Methods: The toxicity of DCZ19903 was evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays, flow cytometry, Calcein-AM/PI staining, and terminal uridine nick-end labeling staining. Oxygen-induced retinopathy and laser-induced choroidal neovascularization models were adopted to assess the antiangiogenic effects of DCZ19903 by Isolectin B4 (GS-IB4) and hematoxylin-eosin staining. EdU assays, transwell migration assays, tube formation, and choroid sprouting assays were performed to determine the antiangiogenic effects of DCZ19903. The antiangiogenic mechanism of DCZ19903 was determined using network pharmacology approach and western blots.

    Results: There was no obvious cytotoxicity or tissue toxicity after DCZ19903 treatment. DCZ19903 exerted the antiangiogenic effects in OIR model and choroidal neovascularization model. DCZ19903 inhibited the proliferation, tube formation, migration ability of endothelial cells, and choroidal explant sprouting. DCZ19903 plus ranibizumab achieved greater antiangiogenetic effects than DCZ19903 or ranibizumab alone. DCZ19903 exerted its antiangiogenic effects via affecting the activation of ERK1/2 and p38 signaling. CONCLUSIONS: DCZ19903 is a promising drug for antiangiogenic treatment in ocular vascular diseases.

    Translational relevance: These findings suggest that DCZ19903 possesses great antiangiogenic potential for treating ocular vascular diseases.

    DOI: 10.1167/tvst.11.12.8


    In vivo longitudinal measurement of cone photoreceptor density in intermediate age-related macular degeneration.

    American Journal of Ophthalmology. 2022 Nov 24

    Wang X, Sadda SR, Ip M, Sarraf D, Zhang Y.

    Purpose: To evaluate cone photoreceptor density in clinically unremarkable retinal regions in patients with age-related macular degeneration (AMD) using adaptive optics scanning laser ophthalmoscopy (AOSLO). DESIGN: Prospective case series with normal comparison group.

    Methods: Ten eyes of seven patients with intermediate AMD were studied, including four with predominantly subretinal drusenoid deposits (SDD) and three without SDD. Macular regions with a clinical absence of AMD-associated lesions were identified by cone packing structure on AOSLO and optical coherence tomography. Cone density was measured in 1174 clinically unremarkable regions within the central subfield (CSF), the inner (IR), and outer rings (OR) of the Early Treatment Diabetic Retinopathy Study grid over 39.6 ± 3.3 months and compared with age-matched normal values obtained in 17 subjects.

    Results: Cone density decreased at 98.3% of the examined locations over time in the eyes with AMD. In the CSF, IR, and OR, cones declined by -255 ± 135, -133 ± 45, and -59 ± 24 cones/degree2/year, respectively, in eyes with SDD, and by -212 ± 89, -83 ± 37, and -27 ± 18 cones/degree2/year, respectively, in eyes without SDD. The percentage of retinal loci with cone density lower than normal (Z-score < -2) increased over the follow-up: from 42% at the baseline to 80% at the last visit in eyes with SDD and from 31% to 70% in eyes without SDD.

    Conclusions: AOSLO revealed cone photoreceptor loss in regions that appear otherwise unremarkable clinically. These findings may help explain the loss of mesopic sensitivity reported in these areas in eyes with intermediate AMD.

    DOI: 10.1016/j.ajo.2022.11.020

    RP2-associated X-linked Retinopathy: Clinical Findings, Molecular Genetics, and Natural History.

    Ophthalmology. 2022 Nov 21

    Georgiou M, Robson AG, Jovanovic K, Cabral De Guimarães TA, Ali N, Pontikos N, Uwaydat SH, Mahroo OA, Cheetham ME, Webster A, Hardcastle AJ, Michaelides M.

    Purpose: To review and describe in detail the clinical course, functional and anatomical characteristics of RP2-associated retinal degeneration.

    Design: Retrospective case series.

    Participants: Males with disease-causing variants in the RP2 gene.

    Methods: Review of all case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT)) and electrophysiology assessment.

    Main outcome measures: Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis, and electrophysiology parameters. RESULTS: Fifty-four molecularly confirmed patients were identified, from 38 pedigrees. Twenty-eight disease-causing variants were identified; with 20 not previously clinically characterized. Fifty-three patients (98.1%) presented with retinitis pigmentosa. The mean age of onset (range, ±SD) was 9.6 years of age (1-57 years, ± 9.2 years). Forty-four patients (91.7%) had childhood-onset disease, with mean age of onset of 7.6 years. The commonest first symptom was night blindness (68.8%). Mean BCVA (range, ±SD) was 0.91 LogMAR (0-2.7, ±0.80) and 0.94 LogMAR (0-2.7, ±0.78) for right and left eyes respectively. Based on the WHO visual impairment criteria, 18 patients (34%) had low vision. The majority (17/22) showed ERG evidence of a rod-cone dystrophy. Pattern ERG P50 was undetectable in all but 2 patients. A range of FAF findings was observed, from normal to advanced atrophy. There were no statistically significant differences between right and left eyes for ellipsoid zone (EZ) width and outer nuclear layer (ONL) thickness. The mean annual rate of EZ width loss was 219 μm/year and the mean annual decrease in ONL thickness was 4.93 μm/year. No patient with childhood-onset disease had identifiable EZ after the age of 26 years at baseline or follow-up. Four patients had adulthood-onset disease and a less severe phenotype.

    Conclusions: This study details the clinical phenotype of RP2 retinopathy in a large cohort. The majority presented with early-onset severe retinal degeneration, with early macular involvement and complete loss of the foveal photoreceptor layer by the third decade of life. Full-field ERGs revealed rod-cone dystrophy in the vast majority, but with generalised (peripheral) cone system involvement of widely varying severity in the first two decades of life.

    DOI: 10.1016/j.ophtha.2022.11.015


    Visual outcomes of macula-involving rhegmatogenous retinal detachment in patients with and without age-related macular degeneration.

    BMC Ophthalmology. 2022 Dec 6

    Paulk PB, Eloubeidi D, Johnson M, Swain T, Mason JO 3rd, Curcio CA, Crosson JN.

    Background: The prognosis for patients with macula-off rhegmatogenous retinal detachment (RRD) and concomitant age-related macular degeneration (AMD) is not well known. The purpose of this study is to compare visual outcomes in macula-off RRD in eyes with AMD versus a group of comparison eyes without AMD.

    Methods: This was a retrospective chart review of 1149 patients. A total of 191 eyes met study criteria, 162 non-AMD eyes (controls), and 29 AMD eyes. The main outcome measure was postoperative visual acuity following pars plana vitrectomy (PPV), scleral buckle (SB), or combined PPV/SB in control eyes versus AMD eyes. This was compared using Fisher’s exact test.

    Results: There was a statistically significant difference in postoperative visual acuity by AMD status, with those without AMD having a worse visual outcome overall (p = 0.0048). A similar percentage of AMD versus non-AMD eyes achieved vision better than 20/40. More patients in the non-AMD group achieved a final visual acuity between 20/40 and 20/200. Of patients with AMD, more had vision worse than 20/200 though 58% maintained functional vision (better than 20/200). Those without AMD had a higher frequency of Count Fingers (CF), Hand Motion (HM), Light Perception (LP), or No Light Perception (NLP) vision (p = 0.023).

    Conclusions: Though postoperative visual acuity was worse overall in the non-AMD group with a higher frequency of patients having final vision of CF, HM, LP, or NLP, this is likely a function of the difference in sample size and composition between the two groups. Importantly, this study suggests AMD patients can expect similar outcomes to non-AMD patients after RRD repair. We conclude that AMD patients can achieve functional vision after RRD surgery, similar to those without AMD.

    DOI: 10.1186/s12886-022-02718-y


    Perspectives of diabetic retinopathy-challenges and opportunities.

    Eye (London, England). 2022 Dec 9

    Sivaprasad S, Sen S, Cunha-Vaz J.

    Diabetic retinopathy (DR) may lead to vision-threatening complications in people living with diabetes mellitus. Decades of research have contributed to our understanding of the pathogenesis of diabetic retinopathy from non-proliferative to proliferative (PDR) stages, the occurrence of diabetic macular oedema (DMO) and response to various treatment options. Multimodal imaging has paved the way to predict the impact of peripheral lesions and optical coherence tomography-angiography is starting to provide new knowledge on diabetic macular ischaemia. Moreover, the availability of intravitreal anti-vascular endothelial growth factors has changed the treatment paradigm of DMO and PDR. Areas of research have explored mechanisms of breakdown of the blood-retinal barrier, damage to pericytes, the extent of capillary non-perfusion, leakage and progression to neovascularisation. However, knowledge gaps remain. From this perspective, we highlight the challenges and future directions of research in this field.

    DOI: 10.1038/s41433-022-02335-5


    Case of Repeated Full-Thickness Macular Hole Formations and Spontaneous Closure following Intravitreal Bevacizumab Treatment for Central Retinal Vein Occlusion.

    Case Reports in Ophthalmology. 2022 Nov 18

    Furukawa R, Matsubara H, Uchiyama E, Sugimoto M, Kondo M.

    The development of a full-thickness macular hole (FTMH) is a rare complication of intravitreal injections, and only a small subset of eyes with an FTMH has a spontaneous closure. We report a case of repeated FTMH formations and a spontaneous closure following an intravitreal injection of bevacizumab (IVB) for a central retinal vein occlusion (CRVO). A 39-year-old male patient presented with reduced vision in his right eye and was diagnosed with a CRVO. Two months later, neovascular glaucoma and macular edema (ME) developed and IVB was performed. After 2 weeks, optical coherence tomography revealed an improvement of the ME and the formation of an FTMH with a hyperreflective material in the FTMH. Two months later, there was a recurrence of the ME and a closure of the FTMH, but the hyperreflective material was still present in the retina. Then, another IVB and panretinal photocoagulation were performed. One month later, the ME had improved and the FTMH was closed, but the hyperreflective material was still present in the retina. After another 2 months, the ME recurred and a third IVB was performed. The ME improved without a recurrence of an FTMH. After that, there were no recurrences of the ME, but the FTMH recurred with the progression of a posterior vitreous detachment and development of an epiretinal membrane 1 year after the third IVB. We suggest that an FTMH be included as a complication of intravitreal injections, and it may close spontaneously during the course of the primary disease.

    DOI: 10.1159/000527211

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