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    Research Update 568


    Impact Of Age-Related Macular Degeneration And Related Visual Disability on the Risk Of Depression: A Nationwide Cohort Study.

    Ophthalmology. 2023 Jan 27:

    Hwang S, Kang SW, Kim SJ, Han K, Kim BS, Jung W, Lim DH, Shin DW.

    Purpose: To evaluate the prospective association of age-related macular degeneration (AMD) and related visual disability (VD) with the risk of depression.

    Design: This nationwide population-based cohort study used authorized clinical data provided by the Korean National Health Insurance Service. PARTICIPANTS: A total of 3,599,589 individuals over 50 years of age participated in the Korean National Health Screening Program in 2009.

    Methods: AMD diagnosis and the presence of accompanying VD were verified using diagnostic codes and disability registration data. Data on covariates, including age, sex, income level, residential area, systemic comorbidities, and behavioral factors, were collected from health screening results and claims data. Patients were followed until December 2019, and incident cases of depression were identified using registered diagnostic codes. The prospective association of AMD and related VD with new-onset depression was investigated using the multivariable-adjusted Cox proportional hazard model.

    Main Outcome Measures: Hazard ratios and 95% confidence intervals for depression development according to the presence of AMD and VD.

    Results: During an average follow-up period of 8.52 years, 1,037,088 patients were newly diagnosed with depression. Patients previously diagnosed with AMD had a greater risk of new-onset depression, with a hazard ratio (95% confidence interval) of 1.15 (1.13-1.17), compared to the control group in the fully adjusted model. Patients with AMD and accompanying VD had a further increased risk of depression, with a hazard ratio (95% confidence interval) of 1.23 (1.16-1.30).

    Conclusions: Individuals diagnosed with AMD have a higher risk of developing depression in the future. The risk of depression is further increased in AMD patients with VD.

    DOI: 10.1016/j.ophtha.2023.01.014


    The Effects Of Treatment Regimen On The Initial Management Of Macular Neovascularization Subtypes In Age-Related Macular Degeneration.

    Ophthalmologica. 2023 Jan 31

    Kodaday K, Kodjikian L, Gadiollet E, Chirpaz N, Loria O, Feldman A, De Bats F, Burillon C, Denis P, Pradat P, Mathis T.

    Objective: To evaluate the effect of initial treatment regimen individualization, (Pro Re nata (PRN) or Treat-and-Extend (TAE)), according to macular neovascularization (MNV) subtype, on the functional and anatomical response in neovascular age-related macular degeneration (nAMD). The secondary objective is to compare the treatment burden between each MNV subtypes.

    Methods: Consecutive treatment-naïve nAMD patients were retrospectively included. MNV subtype was graded by 2 independent blinded investigators on multimodal imaging. Functional and anatomical outcomes were analysed according to treatment regimen and MNV subtypes.

    Results: A total of 281 eyes from 243 patients were included in the study. According to the treatment regimen, there was no significant difference in best-corrected visual acuity gain within the 2 first year of treatment for type 1 (p=0.106) and type 3 MNV (p=0.704). Conversely, there was a significant difference in favour of TAE regimen for type 2 (p=0.017) and type 4 MNV (p=0.047). Type 1 MNV had a higher proportion of visits with subretinal fluid (p=0.0007), but not with intraretinal fluid (p=0.22). The mean interval between the last 2 injections was significantly shorter for type 1 MNV (p=0.0045).

    Conclusions: The individualization of the initial treatment protocol according to MNV subtype can improve the functional outcome and may decrease the treatment burden.

    DOI: 10.1159/000529409

    Sustained Biweekly Aflibercept For Refractory Neovascular Age-Related Macular Degeneration: The Prospective TRISTAR Study.

    Retina (Philadelphia, Pa.) 2022 Dec 26.

    Schneider EW, Thomas MK, Recchia FM, Reichstein DA, Awh CC

    Purpose: To assess the safety and efficacy of biweekly (every 2 week) intravitreal aflibercept injections (IAI) 2 mg in eyes with refractory neovascular age-related macular degeneration (NVAMD).

    Methods: A prospective, single-arm, interventional study was conducted. Eyes with refractory NVAMD received six biweekly IAIs through week 12, followed by a 4-week treatment pause until week 16. Eyes with residual SRF at week 16 were randomized 1:1 to either four additional biweekly IAIs or to 4-week (q4W) IAI dosing through week 24. All eyes were subsequently treated q4W through week 52.

    Results: Enrolled eyes (n=22) had persistent SRF despite a mean of 11.8 injections over the prior 12 months. One patient developed endophthalmitis at week 12. There were no additional drug/procedure-related adverse events. BCVA improved significantly from baseline to week 14 (2.52 letters, p<0.001). Mean CST was also significantly improved at week 14 (-31.9µm, p<0.001) with 8 of 22 eyes achieving complete SRF resolution. Only 2 of 8 eyes remained free of SRF at week 16, with a corresponding increase in mean CST of 26.7µm compared with week 14. By week 52, improvements in BCVA and CST were lost.

    Conclusion: In patients with refractory NVAMD-related SRF, sustained biweekly IAIs resulted in significant functional and anatomic improvements during biweekly dosing. These gains, however, were lost upon return to monthly dosing. These findings suggest that efforts to reduce refractory SRF in NVAMD with biweekly dosing may provide added benefit compared with standard of care treatment if biweekly dosing is sustained.

    DOI: 10.1097/IAE.0000000000003729

    Defining “Strong” versus “Weak” Response to Anti-VEGF Treatment for Center-Involved Diabetic Macular Edema.

    Retina (Philadelphia, Pa.) 2022 Dec 29.

    Sun JK, Beaulieu WT, Melia M, Ferris FL , Maturi RK, Nielsen JS, Solomon SD, Jampol LM

    Purpose: To define “strong” versus “weak” anti-VEGF treatment response in eyes with center-involved diabetic macular edema (CI-DME).

    Methods: Exploratory analyses of three DRCR Retina Network randomized trials of eyes with CI-DME treated with aflibercept, bevacizumab, or ranibizumab. Thresholds of 5, 10, and 15-letter gain defined strong visual acuity (VA) response when baseline VA was 20/25-20/32, 20/40-20/63, or 20/80-20/320, respectively. Thresholds of 50, 100, or 200-μm reduction defined strong anatomic response when baseline central subfield thickness (CST) was <75, ≥75 to <175, or ≥175-μm above standard thresholds. Additional thresholds from regression equations were calculated.

    Results: At 24 weeks, outcomes for strong response were achieved by 476 of 958 eyes (50%) for VA and 505 eyes (53%) for CST. At 104 weeks among the 32% of eyes with strong VA and CST response at 24 weeks, 195 of 281 (69%) maintained strong VA and CST response, whereas 20 (7%) had neither strong VA nor strong CST response. Outcomes rates were similar across protocols and when defined using regression equations.

    Conclusions: These phenotypes are suitable for efforts to identify predictive biomarkers for response to anti-VEGF therapy for DME and might facilitate comparison of treatment response among diverse cohorts with DME.

    DOI: 10.1097/IAE.0000000000003730


    Time to fellow eye Involvement in Patients with Unilateral Diabetic Macular Oedema.

    Eye (London, England). 2023 Feb 3.

    Alsaloum P, Russell MW, Blaga V, Kuo BL, Wu AK, Liu BJ, Valentim CCS, Xu CM, Muste JC, Kumar M, Singh RP.

    Objective: To examine the time to onset of disease in the fellow eye of patients with unilateral DMO in routine clinical practice and to identify risk factors for development of bilateral DMO.

    Design: Retrospective cohort study.

    Participants: One hundred forty treatment-naive patients 18 years or older with unilateral DMO presenting to Cole Eye Institute between January 2012 and July 2021.

    Methods: Records of patients with unilateral DMO were reviewed for development of DMO in the fellow eye. Demographic, diabetic, ocular, and systemic characteristics were collected at initial DMO diagnosis date. Bivariate and multivariate analyses were performed and significant factors were modelled using Kaplan-Meier curves.

    Results: Fifty patients with conversion to bilateral DMO and 90 patients without conversion were identified. Average time to bilateral DMO was 15.0 ± 15.7 months. 64% of patients converted within 1 year and 90% converted within 3 years. HbA1c (p = 0.003), diabetic retinopathy duration (p = 0.029), and diabetic foot disease (DFD) (p = 0.002) were identified as significant risk factors for conversion. Patients with better visual acuity at time of initial diagnosis and history of panretinal photocoagulation (PRP) (p = 0.044) or focal laser (p = 0.035) in the primary eye were also more likely to convert.

    Conclusions: Participants were most likely to develop fellow eye DMO within the first year after initial DMO diagnosis. In routine clinical practice, poor glycaemic control and DFD were risk factors associated with bilateral eye involvement. Clinicians may consider screening the fellow eye of high-risk individuals at each appointment within the first year of diagnosis.

    DOI: 10.1038/s41433-023-02410-5

    Nascent geographic Atrophy as a Predictor of Type 3 mnv Development.

    Ophthalmology, Retina. 2023 Feb 1

    Sacconi R, Sarraf D, Sadda SR, Freund KB, Servillo A, Fogel Levin MM, Costanzo E, Corradetti G, Cabral D, Zur D, Trivizki O, Parravano M, Bandello F, Loewenstein A, Querques G.

    Purpose: To investigate the association of nascent geographic atrophy (GA) preceding the development of exudative type 3 macular neovascularization (MNV) in patients with age-related macular degeneration (AMD).

    Design: Retrospective longitudinal study. PARTICIPANTS: AMD patients diagnosed with treatment-naïve exudative type 3 MNV in one or both eyes were evaluated. Inclusion criteria included serial tracked structural optical coherence tomography (OCT) examinations for ≥ 2 years prior to the detection of exudative type 3 MNV.

    Methods: Clinical characteristics and retinal imaging including structural OCT at baseline and at each follow-up examination were analyzed. Eyes showing the presence of nascent GA during the follow-up were selected for analysis of prevalence, and clinical characteristics at the site of subsequent type 3 MNV development.

    Main Outcome Measures: Description of prevalence and clinical characteristics of nascent GA at the site of subsequent type 3 MNV development. RESULTS: Ninety-seven eyes affected by type 3 MNV meeting inclusion criteria were analyzed. Of 97 eyes (71 patients), 22 eyes of 21 patients (mean age 82±9 years) showed nascent GA preceding exudative type 3 MNV. The observed prevalence of nascent GA preceding exudative type 3 MNV was 22.7% (95% CI: 14.4-31.0%). Exudative Type 3 MNV developed a mean of 9±6 months following detection of nascent GA. The presence of reticular pseudodrusen in the study eye did not significantly influence the timing of exudative type 3 MNV development after the observation of nascent GA (p>0.1 in all analyses). Reduced BCVA was recorded at the exudative type 3 stage in comparison to the nascent GA stage (p=0.003).

    Conclusion: As nascent GA may precede the development of exudative type 3 MNV, the detection of nascent GA in eyes with AMD may warrant closer surveillance in order to identify early exudative type 3 MNV warranting treatment.

    DOI: 10.1016/j.oret.2023.01.019


    Two-Year Outcomes After Variable Duration of Drug Cessation in Patients With Maculopathy Associated With Pentosan Polysulfate Use.

    JAMA Ophthalmology. 2023 Feb 2.

    Jung EH, Lindeke-Myers A, Jain N.

    Importance: Prior retrospective studies have provided limited evidence on disease progression following drug cessation in patients with maculopathy associated with pentosan polysulfate (PPS).

    Objective: To evaluate the 2-year evolution of maculopathy associated with PPS use after drug cessation.

    Design, Setting and Participants: This cohort study prospectively evaluated the natural history of patients with maculopathy associated with PPS use. Participants seen at the Emory Eye Center were enrolled between December 1, 2018, and December 1, 2019, and data were collected through November 30, 2021.

    Main Outcome and Measures: The main outcomes were changes in visual function and structure. Visual function was assessed annually with refraction and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), mesopic microperimetry, and dark adaptometry. Structural outcomes included presence and extent of complete retinal pigment epithelium and outer retinal atrophy (cRORA), macular central subfield thickness (CST), and subfoveal choroidal thickness (SFCT). RESULTS: Of the 12 participants (23 eyes), 11 (91.7%) were female (1 [8.3%] male), 11 (91.7%) were White (1 [8.3%] Black), and median (IQR) age at enrollment was 58 (47-64) years. Median (IQR) time from PPS discontinuation to initial visit was 0.6 (0.4-1.9) years. Median baseline ETDRS BCVA letter score was 83 (Snellen equivalent, 20/20) (IQR, 80-86.5 [20/25-20/20]), with a median 2-year change of -3 (IQR, -6 to -0.5; P = .08). Four eyes (17.4%) had a letter score decline of 15 or more, all associated with progressive cRORA. Median change in microperimetry average threshold was -3.5 dB (IQR, -4.1 to -2.5 dB; P = .001), and percent reduced threshold was 32.5% (IQR, 20.3%-52.8%; P = .004). Nine eyes (39%) had macular cRORA at baseline, with a median linearized growth rate of 0.23 mm/y (IQR, 0.22-0.25 mm/y). Two eyes (8.7%) without atrophy at baseline developed new-onset cRORA. Median baseline CST was 284 μm (IQR, 253-291 μm), with a median 2-year change of -5 μm (IQR, -13 to 0.5 μm; P = .0497). Median 2-year change in SFCT was 1 μm (IQR, -18 to 16 μm; P = .91).

    Conclusions and Relevance: The findings of this cohort study suggest that functional and structural deficits continue to progress in PPS-associated maculopathy even after drug cessation. Additional study is needed to determine whether these findings can be generalized to other patients with PPS-associated maculopathy and whether longer follow-up could determine subsequent disease course.

    DOI: 10.1001/jamaophthalmol.2022.6093


    Advantages of Optical Coherence Tomography as a High Dynamic Range Imaging Modality in Subretinal Hyperreflective Material.

    Retina (Philadelphia, Pa.) 2022 Dec 14.

    Montolío-Marzo S, Pinazo RG, Palacios-Pozo E, Dolz-arco R.

    Purpose: We aim to describe the utility of high dynamic range optical coherence tomography (OCT) imaging to study subretinal hyperreflective material (SHRM) in patients with age-related macular degeneration (AMD).

    Methods: We retrospectively reviewed clinical information including visual acuity (VA) and OCT images (Heidelberg Engineering Inc., Germany) of patients undergoing antiangiogenic treatment for neovascular AMD and showing SHRM at baseline. We increased contrast between strong signal structures (high dynamic range image) re-classifying SHRM as hyperreflective, isoreflective and hyporeflective. We evaluated the patients at baseline, 3, 6 and 12-months follow-up.

    Results: Forty-four eyes were classified as 15 hyperreflective (34.1%); 21 as isoreflective (47.7%); and 8 as hyporeflective (18.2%). During follow-up, hyporeflective SHRM disappeared in all cases, isoreflective SHRM faded in 16 cases (76,2%); hyperreflective SHRM remained in all cases. Hyporreflective SHRM showed a greater VA improvement than hyperreflective SHRM group (p=0,033). After 12-month follow-up only the hyporeflective and isoreflective groups significantly reduced the presence of fluid in 37,5% (p=0,250) and 46,62% (p=0,006) of the patients respectively; and outer retinal layers were disrupted more frequently in the presence of hyperreflective SHRM (ellipsoid zone, p=0,16; external limiting membrane, p=0,007).

    Conclusion: Contrast-enhanced OCT images enabled us to classify SHRM according to its reflectivity showing groups with different disappearance rates, visual acuity improvement and outer retinal layer disruption. This easy to access tool may be helpful as a prognostic factor in neovascular AMD cases.

    DOI: 10.1097/IAE.0000000000003705


    Anatomical and Functional Outcomes of Bevacizumab Treatment In Pediatric Autosomal Recessive Bestrophinopathy.

    Retinal Cases Brief reports. 2022 Dec 8.

    Jacobs M, May ER, Nicholas F, Belinda S, John K, Ramiro S M.

    Purpose: To report functional and anatomical outcomes of anti-VEGF treatment in eyes with autosomal recessive Bestrophinopathy (ARB) presenting in the first decade of life.

    Methods: Case series of four eyes from two siblings with compound heterozygous mutations in the BEST1 gene who were treated with eight monthly intravitreal bevacizumab (IVB) injections. Response to treatment was analyzed using fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), OCT angiography (OCTA), and Microperimetry (MP).

    Results: Patient-1 (male, age 9 yrs.) with visual acuity of 20/20 OD and 20/50 OS. Patient-2 (female, age 10 yrs.), with visual acuity of 20/25 OD, 20/20 OS. All eyes had multifocal subretinal deposition of lipofuscin, subretinal fluid and three had choroidal neovascularization (CNV). Lipofuscin material reabsorbed in 2/4 eyes, the CNV regressed in 3/3, a bacillary detachment resolved (1/1) but the subretinal fluid did not change. Functional improvement in visual acuity was noted but MP showed scattered areas of reduced retinal sensitivity. No ocular or systemic side effects were detected.

    Conclusions: Anti-VEGF treatment of choroidal neovascularization in eyes with ARB resulted in anatomical changes that were only clinically significant in the eye with decreased visual acuity. The hyporeflective subretinal material remained unchanged suggesting a non-exudative cause. These findings provide new insights into the management of ARB, especially in pediatric subjects with CNV.

    DOI: 10.1097/ICB.0000000000001390